Effect of hyperbaric oxygenation on intervertebral disc degeneration: an in vivo study with sprague-dawley rats.
An in vivo study was conducted to test the effect of hyperbaric oxygenation (HBO) on intervertebral disc degeneration in Sprague-Dawley rats. To observe the changes in intervertebral disc height and levels of glycosaminoglycan, collagen, interleukin-1β (IL-1β), prostaglandin E2 (PGE2), and inducible nitric oxide synthase (iNOS) in degenerated intervertebral discs after HBO therapy. Although the involvement of IL-1β, PGE-2, NO, and low O2 concentration has been demonstrated in intervertebral disc degeneration, the actual mechanism is not clear. It has been reported that HBO influences changes in IL-1β, PGE-2, NO, and O2 concentration. Previously, a study demonstrated an in vitro positive effect of HBO on the human nucleus pulposus. Thus, an in vivo study in animals was necessary. Twelve Sprague-Dawley rats were each injected with chondroitinase ABC in 2 proximal intervertebral discs of the tail. After treating with 100% oxygen at 2.5 atmospheres 2 hours per days for 10 days, the change in disc height was determined by radiography. The amounts of PGE-2, iNOS, glycosaminoglycan, and total collagen in the intervertebral disc were quantified by enzyme-linked immunosorbent assay. Tissue morphology and the distribution of glycosaminoglycan, IL-1β, and iNOS in the intervertebral disc were assessed by histology and immunohistochemistry. The area of IL-1β in the intervertebral discs was quantified using image analysis software. HBO therapy stopped the decrease in intervertebral disc height, caused an increase in the amount of glycosaminoglycan, and inhibited IL-1β, PGE-2, and iNOS production. HBO provides a potential treatment modality for intervertebral disc degeneration.


Mothers' Adverse Childhood Experiences and Their Young Children's Development.
This study examined how mothers' Adverse Childhood Experiences (ACEs) relate to their children's developmental risk and assessed how the association is mediated through mothers' depressive symptoms and fair/poor health. Mothers of children aged between 4 months and 4 years were recruited from the emergency department of a children's hospital between March 2012 and June 2015 and interviewed about ACEs, mothers' depressive symptoms and health status, and children's developmental risk (screened via Parents' Evaluations of Developmental Status [PEDS]). Between August and November 2016 a Cochran-Armitage test assessed trend of PEDS by ACEs. Multinomial regression models examined differences in PEDS by ACEs severity. Mediation by mothers' depressive symptoms and self-rated health was also assessed. Of 1,293 mothers, 56.7% reported one or more ACEs. Mothers also reported developmental risk (20.4% overall): 120 (9.2%) reported one concern and 144 (11.2%) reported two or more concerns on the PEDS. Mothers who reported household substance use, mental illness, or an incarcerated household member during childhood were more likely to report at least one child developmental concern on the PEDS. After controlling for covariates, odds of one PEDS concern were 1.86 (95% CI=1.16, 3.00) for ACEs, one to three versus none, and 2.21 (95% CI=1.26, 3.87) for ACEs four or more versus none. Adjusted odds of two or more concerns were 1.70 (95% CI=1.07, 2.72) for ACEs, one to three versus none, and 1.76 (95% CI=1.02, 3.05) for ACEs, four or more versus none. Mothers' depressive symptoms and self-rated health were potential mediators. Mothers' ACEs are significantly associated with their children's developmental risk. If replicated, findings suggest that addressing intergenerational trauma through focus on childhood adversity among young children's caregivers may promote child development.


In vitro effect of unacylated ghrelin and obestatin on human luteal cell function.
To evaluate whether unacylated ghrelin and obestatin were able to influence human luteal cell function. The effect of these two ghrelin-related peptides on progesterone (P4), prostaglandin (PG) F(2α), PGE(2), and vascular endothelial growth factor (VEGF) release and on VEGF expression in isolated human steroidogenic cells has been investigated. Prospective laboratory study. University hospital. Corpora lutea were obtained from 23 normally menstruating patients in the midluteal phase of the menstrual cycle. Human luteal cells were isolated from corpora lutea, and primary cultures were established. P4 and PGs release was assayed by enzyme immunoassay, VEGF secretion by ELISA, and VEGF mRNA expression by real-time polymerase chain reaction. P4 and VEGF release were significantly reduced by both unacylated ghrelin and obestatin. Moreover, the highest concentration of obestatin was able to reduce the release of PGE(2) and PGF(2α). VEGF mRNA expression was not affected by the incubation with any of these ghrelin-related peptides. As expected, CoCl(2) was able to induce VEGF release and mRNA expression in luteal cells. Our results suggest that, similar to ghrelin, both unacylated ghrelin and obestatin might play a role in regulating the luteal cell function that affects both luteal steroidogenesis and luteotrophic/luteolytic imbalance. These results further underline the pivotal correlation between the ghrelin system and reproduction.


Is lower and lower better and better? A re-evaluation of the evidence from the Cholesterol Treatment Trialists' Collaboration meta-analysis for low-density lipoprotein lowering.
Researchers from the Cholesterol Treatment Trialists' (CTT) Collaboration have argued for maximal lowering of low-density lipoprotein cholesterol (LDL-C) by the use of pharmacologic agents, with the strongest evidence coming from the five comparison statin studies in their second meta-analysis. The CTT meta-analysis has many strengths but also a number of limitations, which have not been discussed and which, given the clinical implications, require consideration. Among these are: (1) the impact and validity of including revascularizations within a composite primary end point; (2) the inclusion of the A-Z study, whose design does not allow for valid comparisons of two statin regimens; (3) the fact that baseline LDL-C levels in the comparison studies were not low enough to test whether statin therapy reduces risk significantly in groups with an initial low LDL-C; and, most important, (4) authors of the five studies compared doses at the extremes of statin regimens. However, the clinical choice is not between the lowest and the greatest dose of a statin statin regimens, for example, between 10 and 80 mg atorvastatin, but, more realistically, between intermediate and high dose, that is, between 40 and 80 mg atorvastatin. On the basis of the CTT meta-analysis, we calculate that any potential gain from increasing the dose from 40 to 80 mg atorvastatin would be very small, at best a further 2% further reduction in clinical events. The increase in dose, unfortunately, would likely be associated with increased side effects and decreased compliance. Accordingly, whether net benefit would be demonstrable cannot be assumed. It follows that definitive evidence supporting maximal lowering of LDL-C or maximal dose of statins is still lacking and guidelines, if they are to be evidence-based, should acknowledge this uncertainty.


Identifying factors associated with the discharge of male State patients from Weskoppies Hospital.
Designated psychiatric facilities are responsible for the care, treatment and reintegration of State patients. The necessary long-term care places a considerable strain on health-care resources. Resource use should be optimised while managing the risks that patients pose to themselves and the community. Identifying unique factors associated with earlier discharge may decrease the length of stay. Factors associated with protracted inpatient care without discharge could identify patients who require early and urgent intervention. We identify socio-economic, demographic, psychiatric and charge-related factors associated with the discharge of male State patients. We reviewed the files of discharged and admitted forensic State patients at Weskoppies Psychiatric Hospital. Data were captured in an electronic recording sheet. The association between factors and the outcome measure (discharged vs. admitted) was determined using chi-squared tests and Fischer's exact tests. Discharged State patients were associated with being a primary caregiver (p = 0.031) having good insight into illness (p = 0.025) or offence (p = 0.005) and having had multiple successful leaves of absences. A lack of substance abuse during admission (p = 0.027), an absence of a diagnosis of substance use disorder (p = 0.013) and the absence of verbal and physical aggression (p = 0.002 and p = 0.016) were associated with being discharged. Prolonged total length of stay (9-12 years, p = 0.031) and prolonged length of stay in open wards (6-9 years, p = 0.000) were associated with being discharged. A history of previous offences (p = 0.022), a diagnosis of substance use disorder (p = 0.023), recent substance abuse (p = 0.018) and a history of physical aggression since admission (p = 0.017) were associated with continued admission. Discharge of State patients is associated with an absence of substance abuse, lack of aggression, multiple successful leave of absences and length of stay in hospital.


Reaching minimal clinically important difference in adult spinal deformity surgery: a comparison of patients from North America and Japan.
The Scoliosis Research Society-22r questionnaire (SRS-22r) has been shown to be reliable, valid, and responsive to change in patients with adult spinal deformity (ASD) undergoing surgery. The minimal clinically important difference (MCID) is the smallest difference in a health-related quality of life score that is considered to be worthwhile or clinically important to the individual. The authors hypothesized that the proportion of patients with ASD achieving an MCID in the SRS-22r score would be different between two culturally different cohorts. The purpose of this study was to compare the proportion of patients with ASD achieving MCID for the SRS-22r domains in North American (NA) and Japanese cohorts. A total of 137 patients from North America (123 women, mean age 60.0 years) and 60 patients from Japan (56 women, mean age 65.5 years) with at least 2 years of follow-up after corrective spine surgery for ASD were included. Except for self-image, published Japanese MCID values of SRS-22r for ASD were higher (function = 0.90, pain = 0.85, self-image = 1.05, subtotal = 1.05) than the published NA MCID values (function = 0.60, pain = 0.40, self-image = 1.23, subtotal = 0.43). There was a statistically significant improvement in all SRS-22r domain scores at 2 years compared to baseline in both cohorts. Except for mental health (NA = 0.32, Japanese = 0.72, p = 0.005), the mean improvement from baseline to 2 years was similar between the NA and Japanese cohorts. The proportion of patients achieving MCID was higher in North America for function (NA = 51%, Japanese = 30%, p = 0.006), pain (NA = 80%, Japanese = 47%, p < 0.001), and subtotal (NA = 72%, Japanese = 35%, p < 0.001), while there was no significant difference for self-image (NA = 53%, Japanese = 58%, p = 0.454). Despite similar improvements in SRS-22r domain scores from baseline to 2 years postoperatively, the proportion of patients reaching SRS-22r MCID for function, pain, and subtotal after ASD surgery was higher in the NA cohort than in the Japanese cohort. This may imply that patients in North America and Japan may value observed changes in clinical status differently.


Economic Burden of HR+/HER2- Metastatic Breast Cancer Among Adult Premenopausal Women.
Premenopausal women with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (mBC) have complex treatment needs and may receive sequential combinations of endocrine therapy (ET) or chemotherapy. This study describes healthcare utilization (HRU) and costs among premenopausal women with HR+/HER2- mBC in real-world settings from a payer's perspective. In this retrospective cohort study, premenopausal women with HR+/HER2- mBC who received ET or chemotherapy were identified from the Truven Health Analytics MarketScan database (1 January 2006-31 December 2015). The main HRU outcomes per patient per 6 months (PPP6 M) were measured during each line of therapy and included number of days in inpatient (IP) and outpatient (OP) services. Healthcare costs per patient per month (PPPM) included medical and pharmacy costs. A total of 3203 patients received first-line, 2194 received second-line, and 1242 received third-line therapy for mBC. Mean number of IP days PPP6 M were 1.6, 1.3, and 1.5 days in the first, second, and third lines, respectively. Mean number of days with OP services PPP6 M was 31.4, 30.9, and 23.3 in the first, second, and third lines, respectively. Among patients receiving ET, mean total healthcare costs were $6521, $4440, and $4555 PPPM in the first, second, and third line, respectively. Among patients receiving chemotherapy, mean total healthcare costs were $16,842, $12,868, and $16,129 PPPM in the first, second, and third line, respectively. These costs were mainly driven by treatment and OP costs. Real-world HRU and costs among premenopausal women with HR+/HER2- mBC are extensive. Patients who received chemotherapy incurred approximately twice the costs of patients treated with ET. Novartis Pharmaceutical Corp.


A follow-up study of first episode major depressive disorder. Impairment in inhibition and semantic fluency-potential predictors for relapse?
The present study investigated the Executive Functions (EF) of inhibition, mental flexibility and phonemic and semantic fluency in a 1-year follow-up assessment of patients diagnosed with first episode Major Depressive Disorder (MDD). In the acute phase, the patient group performed significantly poorer compared to the control group (CG) in inhibition and semantic fluency. The present study pursued these findings from the acute phase to see if the impairment seen in inhibition and semantic fluency in the acute phase normalized or persisted in the follow-up assessment. In addition, the present study investigated the association between poor inhibition and semantic fluency performance and the experience of relapse during the 1-year period. Twenty eight patients and 28 individually matched control subjects were included. EF was reassessed using three tests from the Delis Kaplan Executive Function System (D-KEFS). There was a significant decrease in depression severity score from the acute phase, showing that most of the patients were in remission in the follow-up assessment. RESULTS showed a sustained impairment in inhibition and semantic fluency in the patient group. However, the performance in inhibition was more severe when an additional requirement of mental flexibility was included. There were no group differences in the other EF functions measured. Further, patients with a relapse in the course of 1 year performed significantly poorer in inhibition/switching at inclusion compared to patients that did not relapse and the CG. This relationship was not found for semantic fluency. Poor performance in inhibition and semantic fluency are prolonged despite symptom reduction in patients with a first episode of MDD. Moreover, although based on a small sample of patients, the present study showed that there may be a relationship between impaired ability in the EF of inhibition/switching and vulnerability for the experience of relapse.


Plasma lipids, lipoproteins, and mammographic densities.
There is strong evidence that the risk of breast cancer in populations is influenced by environmental factors. Plasma lipids and lipoproteins are known to be under environmental control and to have epidemiological and/or biological characteristics that suggest they may be relevant to breast cancer risk. The purpose of the study described here was to determine whether plasma lipids, lipoproteins, and the urinary excretion of the mutagen malondialdehyde (MDA) are associated with differences in breast cancer risk. We measured plasma lipids, lipoproteins, and urinary MDA in women without breast cancer but with different degrees of density of the breast parenchyma on mammography, a strong risk factor for breast cancer. Mammograms from 273 premenopausal women were digitized to high spatial resolution by a scanning densitometer, and images were analyzed to quantify the extent of density. The percentage of the breast occupied by mammographic densities was found, after controlling for the effects of age and the Quetelet index of obesity, to be significantly associated with plasma levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglyceride, apoprotein B, and urinary excretion of MDA. A multivariate model comprised of the Quetelet index of obesity, alcohol consumption, apoprotein B, parity, daily MDA excretion, and the skinfold thickness sum accounted for 36% of the variation in breast density. These results suggest that differences in lipid metabolism are associated with differences in breast cancer risk as defined by mammographic densities. These findings are consistent with several other observations that show a relationship between plasma lipids, lipoproteins, and risk factors for breast cancer.


Evaluation of a commercial ELISA for serodiagnosis of Helicobacter pylori infection.
A commercial ELISA for the detection of Helicobacter pylori IgG antibodies was evaluated using serum from 242 patients attending an endoscopy clinic. The efficacy of the ELISA was assessed in relation to the histological detection of H pylori on antral mucosal biopsy specimens. In patients under 61 years of age (n = 138) the ELISA was 97.5% sensitive and 85.5% specific for H pylori infection, with a positive predictive value of 91% and a negative predictive value of 96%. Over the whole group the sensitivity of the ELISA was 93.8% and the specificity 79.3%. The positive predictive value and negative predictive values were, respectively, 90% and 87%. These results suggest that the Bio-Rad GAP IgG H pylori ELISA is suitable for serodiagnosis of H pylori infections for most clinical purposes and thus makes H pylori serology available to routine diagnostic laboratories.


Phase 1 trial of the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin in patients with advanced hematologic malignancies.
Proteasome inhibitors, a novel class of chemotherapeutic agents, enhance the antitumor efficacy of anthracyclines in vitro and in vivo. We therefore sought to determine the maximum tolerated dose (MTD) and dose-limiting toxicities of bortezomib and pegylated liposomal doxorubicin (PegLD). Bortezomib was given on days 1, 4, 8, and 11 from 0.90 to 1.50 mg/m2 and PegLD on day 4 at 30 mg/m2 to 42 patients with advanced hematologic malignancies. Grade 3 or 4 toxicities in at least 10% of patients included thrombocytopenia, lymphopenia, neutropenia, fatigue, pneumonia, peripheral neuropathy, febrile neutropenia, and diarrhea. The MTD based on cycle 1 was 1.50 and 30 mg/m2 of bortezomib and PegLD, respectively. However, due to frequent dose reductions and delays at this level, 1.30 and 30 mg/m2 are recommended for further study. Pharmacokinetic and pharmacodynamic studies did not find significant drug interactions between these agents. Antitumor activity was seen against multiple myeloma, with 8 of 22 evaluable patients having a complete response (CR) or near-CR, including several with anthracycline-refractory disease, and another 8 having partial responses (PRs). One patient with relapsed/refractory T-cell non-Hodgkin lymphoma (NHL) achieved a CR, whereas 2 patients each with acute myeloid leukemia and B-cell NHL had PRs. Bortezomib/PegLD was safely administered in this study with promising antitumor activity, supporting further testing of this regimen.


[Circulating cancer cells in the peripheral blood].
Occasional observations on this subject were seen until 1995 when Engell reported the large study on circulating cancer cells in the peripheral blood. Engell's report generated great enthusiasm in our country also. But, these cytologic method have a low sensitivity. Consequently, studies on the circulating tumor cells have been abandoned. However, since 1987, RT-PCR and other molecular biologic method were introduced for the identification of circulating cancer cells and micrometastases in bone marrow as well as in lymphnode. Serial analysis of a large number of patients by well-qualified laboratories have been performed. Several authors have shown a significant correlation between detection of cancer cells and relapse in some forms of malignancies. These research may be beneficial in the staging of cancer, in monitoring the effectiveness of cancer treatment, etc. Detection of cancer cells in the peripheral blood likely to have a profound impact on the practice of clinical oncology.


Multiple-Pulse Sounds and Seals: Results of a Harbor Seal (Phoca vitulina) Telemetry Study During Wind Farm Construction.
Offshore construction and survey techniques can produce pulsed sounds with a high sound pressure level. In coastal waters, the areas in which they are produced are often also used by seals, potentially resulting in auditory damage or behavioral avoidance. Here, we describe a study on harbor seals during a wind farm installation off southeast England. The study used GPS/global system for mobile communication tags on 23 harbor seals that provided distribution and activity data; the closest range of individual seals to piling varied from 6.65 to 46.1 km. Furthermore, the maximum predicted received levels (RLs) at individual seals varied between 146.9 and 169.4 dB re 1 μPa peak to peak.


"I don't mind being ugly but I don't wanna have skin cancer": A qualitative study of attitudes to UV exposure and a facial morphing intervention in men 35 years and older.
Objectives: Skin cancer is a growing problem globally. Older men have been largely ignored in previous research, even though men may generally be prone to riskier exposure to the sun than women. Past research suggests that appearance-focused techniques such as facial morphing can increase motivations to use sun protection among women of all ages, and younger men.Design: was qualitative, consisting of individual interviews.Methods: were semi-structured interviews with 25 older men, to examine attitudes to UV exposure and reactions to a facial morphing intervention. Interviews were subjected to thematic analysis.Results: Three themes were constructed: masculine UV exposure; appearance that's accepted; personal responsibility. The men did not identify gaps in their sun protection behaviour and demonstrated a lack of concern about ageing and appearance. These attitudes translated into a lack of motivation for behaviour change due to ageing acceptance. However, motivation to change behaviour came from health concerns resulting from the intervention.Conclusions: The men experienced different motivations and barriers for sun protection use than women of similar ages. Facial morphing can be effective with older men but may need to be reframed to focus on health implications and personal choice.


Mutations in PIGY: expanding the phenotype of inherited glycosylphosphatidylinositol deficiencies.
Glycosylphosphatidylinositol (GPI)-anchored proteins are ubiquitously expressed in the human body and are important for various functions at the cell surface. Mutations in many GPI biosynthesis genes have been described to date in patients with multi-system disease and together these constitute a subtype of congenital disorders of glycosylation. We used whole exome sequencing in two families to investigate the genetic basis of disease and used RNA and cellular studies to investigate the functional consequences of sequence variants in the PIGY gene. Two families with different phenotypes had homozygous recessive sequence variants in the GPI biosynthesis gene PIGY. Two sisters with c.137T>C (p.Leu46Pro) PIGY variants had multi-system disease including dysmorphism, seizures, severe developmental delay, cataracts and early death. There were significantly reduced levels of GPI-anchored proteins (CD55 and CD59) on the surface of patient-derived skin fibroblasts (∼20-50% compared with controls). In a second, consanguineous family, two siblings had moderate development delay and microcephaly. A homozygous PIGY promoter variant (c.-540G>A) was detected within a 7.7 Mb region of autozygosity. This variant was predicted to disrupt a SP1 consensus binding site and was shown to be associated with reduced gene expression. Mutations in PIGY can occur in coding and non-coding regions of the gene and cause variable phenotypes. This article contributes to understanding of the range of disease phenotypes and disease genes associated with deficiencies of the GPI-anchor biosynthesis pathway and also serves to highlight the potential importance of analysing variants detected in 5'-UTR regions despite their typically low coverage in exome data.


Molecular markers for bladder cancer screening, early diagnosis, and surveillance: the WHO/ICUD consensus.
Due to the lack of disease-specific symptoms, diagnosis and follow-up of bladder cancer has remained a challenge to the urologic community. Cystoscopy, commonly accepted as a gold standard for the detection of bladder cancer, is invasive and relatively expensive, while urine cytology is of limited value specifically in low-grade disease. Over the last decades, numerous molecular assays for the diagnosis of urothelial cancer have been developed and investigated with regard to their clinical use. However, although all of these assays have been shown to have superior sensitivity as compared to urine cytology, none of them has been included in clinical guidelines. The key reason for this situation is that none of the assays has been included into clinical decision-making so far. We reviewed the current status and performance of modern molecular urine tests following systematic analysis of the value and limitations of commercially available assays. Despite considerable advances in recent years, the authors feel that at this stage the added value of molecular markers for the diagnosis of urothelial tumors has not yet been identified. Current data suggest that some of these markers may have the potential to play a role in screening and surveillance of bladder cancer. Well-designed protocols and prospective, controlled trials will be needed to provide the basis to determine whether integration of molecular markers into clinical decision-making will be of value in the future.


Effect of Financial Incentives to Physicians, Patients, or Both on Lipid Levels: A Randomized Clinical Trial.
Financial incentives to physicians or patients are increasingly used, but their effectiveness is not well established. To determine whether physician financial incentives, patient incentives, or shared physician and patient incentives are more effective than control in reducing levels of low-density lipoprotein cholesterol (LDL-C) among patients with high cardiovascular risk. Four-group, multicenter, cluster randomized clinical trial with a 12-month intervention conducted from 2011 to 2014 in 3 primary care practices in the northeastern United States. Three hundred forty eligible primary care physicians (PCPs) were enrolled from a pool of 421. Of 25,627 potentially eligible patients of those PCPs, 1503 enrolled. Patients aged 18 to 80 years were eligible if they had a 10-year Framingham Risk Score (FRS) of 20% or greater, had coronary artery disease equivalents with LDL-C levels of 120 mg/dL or greater, or had an FRS of 10% to 20% with LDL-C levels of 140 mg/dL or greater. Investigators were blinded to study group, but participants were not. Primary care physicians were randomly assigned to control, physician incentives, patient incentives, or shared physician-patient incentives. Physicians in the physician incentives group were eligible to receive up to $1024 per enrolled patient meeting LDL-C goals. Patients in the patient incentives group were eligible for the same amount, distributed through daily lotteries tied to medication adherence. Physicians and patients in the shared incentives group shared these incentives. Physicians and patients in the control group received no incentives tied to outcomes, but all patient participants received up to $355 each for trial participation. Change in LDL-C level at 12 months. Patients in the shared physician-patient incentives group achieved a mean reduction in LDL-C of 33.6 mg/dL (95% CI, 30.1-37.1; baseline, 160.1 mg/dL; 12 months, 126.4 mg/dL); those in physician incentives achieved a mean reduction of 27.9 mg/dL (95% CI, 24.9-31.0; baseline, 159.9 mg/dL; 12 months, 132.0 mg/dL); those in patient incentives achieved a mean reduction of 25.1 mg/dL (95% CI, 21.6-28.5; baseline, 160.6 mg/dL; 12 months, 135.5 mg/dL); and those in the control group achieved a mean reduction of 25.1 mg/dL (95% CI, 21.7-28.5; baseline, 161.5 mg/dL; 12 months, 136.4 mg/dL; P < .001 for comparison of all 4 groups). Only patients in the shared physician-patient incentives group achieved reductions in LDL-C levels statistically different from those in the control group (8.5 mg/dL; 95% CI, 3.8-13.3; P = .002). In primary care practices, shared financial incentives for physicians and patients, but not incentives to physicians or patients alone, resulted in a statistically significant difference in reduction of LDL-C levels at 12 months. This reduction was modest, however, and further information is needed to understand whether this approach represents good value. clinicaltrials.gov Identifier: NCT01346189.


Factors affecting a recently purchased handgun's risk for use in crime under circumstances that suggest gun trafficking.
While many handguns are used in crime each year in the USA, most are not. We conducted this study to identify factors present at the time of a handgun's most recent retail sale that were associated with its subsequent use in crime under circumstances suggesting that the handgun had been trafficked--purchased with the intent of diverting it to criminal use. Handguns acquired in multiple-gun purchases were of particular interest. Using data for 180,321 handguns purchased from federally licensed retailers in California in 1996, we studied attributes of the handguns, the retailers selling them, the purchasers, and the sales transactions. Our outcome measure was a handgun's recovery by a police agency, followed by a gun ownership trace, conducted by the Bureau of Alcohol, Tobacco, Firearms and Explosives, that determined (a) that the recovery had occurred within 3 years of the handgun's most recent purchase from a licensed retailer and (b) that the person who possessed the gun when it was recovered by police was not its most recent purchaser. Altogether, 722 handguns were recovered and had trace results that met the additional criteria. Handguns acquired in multiple-gun, same-day transactions were more likely to be traced than were single-purchase handguns (odds ratio [OR] 1.33, 95% confidence intervals [CI] 1.08 to 1.63). This was not the case for multiple-purchase handguns defined more broadly as multiple handguns purchased by one individual over any 30-day period as used in "one-gun-a-month" laws. Bivariate regressions indicated increased risk of a handgun being traced when it sold new for $150 or less (OR 4.28, 95% CI 3.59 to 5.11) or had been purchased by a woman (OR 2.02, 95% CI 1.62 to 2.52). Handguns sold by retailers who also had a relatively high proportion (>or=2%) of purchases denied because the prospective purchasers were prohibited from owning firearms were more likely to be traced than were those sold by other retailers (OR 4.09, 95% CI 3.39 to 4.94). These findings persisted in multivariate analyses. Our findings suggest specific strategies for intervention to prevent gun violence.


[Intracerebral aneurysm--treatment options, informed consent, and legal aspects].
All medical subspecialties and, in particular, high-tech field neurosurgery are subject to continuous change in therapeutic concepts due to novel treatment options emerging through research and evolution in the field. Hence, the question arises if the patient's informed consent needs to be adjusted in the face of multiple therapeutic options with different configurations of risk/benefit relationships. In this paper we discuss different therapeutic scenarios with regard to ruptured intracerebral aneurysms (RIA) and unruptured intracerebral aneurysms (UIA), and we advise the medical doctor involved in the process. Indeed, experienced neurosurgeons and endovascular interventionalists are very familiar with the management of these scenarios; likewise, interns, residents, and otherwise affiliated physicians may be faced with these situations. In general, asymptomatic and mentally capacitated patients as well as legal guardians of minor patients and of mentally incapacitated patients with incidental aneurysms and more than one therapeutic option need to be accurately informed about the advantages and disadvantages of the treatment options available to them. In case of emergency or when treating a mentally disabled patient who is incapable of making a sound judgment and has no legal guardian, the attending doctor will have to choose the best possible treatment option.


Virus disinfection mechanisms: the role of virus composition, structure, and function.
Drinking waters are treated for enteric virus via a number of disinfection techniques including chemical oxidants, irradiation, and heat, however the inactivation mechanisms during disinfection remain elusive. Owing to the fact that a number of significant waterborne virus strains are not readily culturable in vitro at this time (e.g. norovirus, hepatitis A), the susceptibility of these viruses to disinfection is largely unknown. An in-depth understanding of the mechanisms involved in virus inactivation would aid in predicting the susceptibility of non-culturable virus strains to disinfection and would foster the development of improved disinfection methods. Recent technological advances in virology research have provided a wealth of information on enteric virus compositions, structures, and biological functions. This knowledge will allow for physical/chemical descriptions of virus inactivation and thus further our understanding of virus disinfection to the most basic mechanistic level.


Lipid Droplets Protect Human β-Cells From Lipotoxicity-Induced Stress and Cell Identity Changes.
Free fatty acids (FFAs) are often stored in lipid droplet (LD) depots for eventual metabolic and/or synthetic use in many cell types, such a muscle, liver, and fat. In pancreatic islets, overt LD accumulation was detected in humans but not mice. LD buildup in islets was principally observed after roughly 11 years of age, increasing throughout adulthood under physiologic conditions, and also enriched in type 2 diabetes. To obtain insight into the role of LDs in human islet β-cell function, the levels of a key LD scaffold protein, perilipin 2 (PLIN2), were manipulated by lentiviral-mediated knockdown (KD) or overexpression (OE) in EndoCβH2-Cre cells, a human cell line with adult islet β-like properties. Glucose-stimulated insulin secretion was blunted in PLIN2KD cells and improved in PLIN2OE cells. An unbiased transcriptomic analysis revealed that limiting LD formation induced effectors of endoplasmic reticulum (ER) stress that compromised the expression of critical β-cell function and identity genes. These changes were essentially reversed by PLIN2OE or using the ER stress inhibitor, tauroursodeoxycholic acid. These results strongly suggest that LDs are essential for adult human islet β-cell activity by preserving FFA homeostasis.


Determination of the structures of symmetric protein oligomers from NMR chemical shifts and residual dipolar couplings.
Symmetric protein dimers, trimers, and higher-order cyclic oligomers play key roles in many biological processes. However, structural studies of oligomeric systems by solution NMR can be difficult due to slow tumbling of the system and the difficulty in identifying NOE interactions across protein interfaces. Here, we present an automated method (RosettaOligomers) for determining the solution structures of oligomeric systems using only chemical shifts, sparse NOEs, and domain orientation restraints from residual dipolar couplings (RDCs) without a need for a previously determined structure of the monomeric subunit. The method integrates previously developed Rosetta protocols for solving the structures of monomeric proteins using sparse NMR data and for predicting the structures of both nonintertwined and intertwined symmetric oligomers. We illustrated the performance of the method using a benchmark set of nine protein dimers, one trimer, and one tetramer with available experimental data and various interface topologies. The final converged structures are found to be in good agreement with both experimental data and previously published high-resolution structures. The new approach is more readily applicable to large oligomeric systems than conventional structure-determination protocols, which often require a large number of NOEs, and will likely become increasingly relevant as more high-molecular weight systems are studied by NMR.


Host factors, occupation, and testicular cancer in Saskatchewan, Canada: 1979-2002.
The incidence rates of testicular cancer are increasing in several countries, especially among younger adults. The role of agricultural exposure in the etiology of testicular cancer is contentious. We extracted information related to the host, lifestyle, and tumor characteristics from the files of the Saskatchewan Cancer Agency for all cases (n = 517) of testicular cancer diagnosed in Saskatchewan between 1979 and 2000. The following questions were the subject of this initial inquiry: (1) Are tumor characteristics similar or different among occupational groups dichotomized into farmer/nonfarmer? (2) Are host characteristics similar or different among occupational groups? (3) Is farming as an occupation one of the independent predictors of tumor stage at diagnosis? Statistical analyses were restricted on 486 cases. The nonfarmers (n = 349) had smaller tumors in length on average, and more of them were diagnosed at stage I compared to farmers (n = 72). Occupation was not recorded for 65 cases. Farmers were older than nonfarmers. In logistic regression analyses with adjustment for relevant variables as cited in the literature, individuals with nonseminomas [OR (95% CI) 1.99 (1.30-3.31)] and < or = 26 years old at diagnosis [2.12 (1.15-3.93)] were significantly more likely to be diagnosed with a stage 2 or higher tumor. Farmers were significantly more likely than nonfarmers to be diagnosed at stage 2 or higher [1.76 (1.00-3.10)]. Based on our data, the significant predictors of being diagnosed with stage 2 and higher are: presence of nonseminoma, < or = 26 years old, and farming as an occupation.


An observation of venous gas emboli in divers and susceptibility to decompression sickness.
Decompression sickness (DCS) results from the formation of bubbles within the tissues and blood in response to a reduction in environmental pressure. Venous gas emboli (VGE) are common after diving and are usually only present in small numbers. Greater VGE numbers are an indication of decompression stress, and can be reliably detected using ultrasound imaging. To examine the relationship between production of VGE following a routine dive and the risk of DCS. A matched population of divers with and without a history of DCS were monitored for the production of VGE at 15-minute intervals using ultrasound, following a 405 kPa air dive in a hyperbaric chamber using the DCIEM air decompression table. VGE production was graded using a validated grading system and the data analysed to compare maximum VGE grade and duration of VGE formation. Eleven divers with a history of DCS were compared with 13 divers with no history of DCS. Divers with a history of DCS demonstrated both a higher maximum grade (P=0.04) and longer duration (P=0.002) of VGE production compared to divers without a history of DCS. Higher maximum VGE grades and longer durations of VGE following decompression were associated with a history of DCS and, in particular, musculoskeletal DCS. Although the exact mechanism of DCS remains poorly understood, our data suggest some individuals are inherently more prone to develop VGE, increasing the probability of DCS. Modification of diving practices in those with high VGE grades could potentially decrease DCS risk in these individuals.


Suicide risk and choice of antidepressant.
There is presently concern that patients treated for depression with venlafaxine have a higher suicide rate than those treated with other antidepressants, based on results from observational studies. The aim of this study was to determine whether higher suicide risk, defined as previous suicide attempt or suicidal ideation, influenced the choice of antidepressant prescribed in an outpatient mental health unit, the Bedford East Community Mental Health Team. A database held by a the Community Mental Health Team was used to identify patients with Depression who have been treated with Venlafaxine, Citalopram, and patients diagnosed with bipolar II affective disorder. The data was analysed in terms of presence of suicide risk, gender, and whether bipolar II patients on venlafaxine were treated with mood stabilisers. The results showed that a risk of suicide did not prevent the prescription of venlafaxine, that less venlafaxine was prescribed to male patients than females, and that bipolar II patients were indeed treated with mood stabilisers. It appears that in this Community Mental Health Team, the possibility of suicide risk with venlafaxine therapy is considered and appropriately managed. Early diagnosis and appropriate treatment of bipolar disorder is likely to be the most effective step that we can take to reduce the risk of suicide in patients with bipolar disorder .Appropriate care regarding the judicious use of Venlafaxine as a first line treatment in Unipolar Depression is secondary to this.


Diagnostic criteria for cryopyrin-associated periodic syndrome (CAPS).
Cryopyrin-associated periodic syndrome (CAPS) is a rare, heterogeneous disease entity associated with NLRP3 gene mutations and increased interleukin-1 (IL-1) secretion. Early diagnosis and rapid initiation of IL-1 inhibition prevent organ damage. The aim of the study was to develop and validate diagnostic criteria for CAPS. An innovative process was followed including interdisciplinary team building, item generation: review of CAPS registries, systematic literature review, expert surveys, consensus conferences for item refinement, item reduction and weighting using 1000Minds decision software. Resulting CAPS criteria were tested in large cohorts of CAPS cases and controls using correspondence analysis. Diagnostic models were explored using sensitivity analyses. The international team included 16 experts. Systematic literature and registry review identified 33 CAPS-typical items; the consensus conferences reduced these to 14. 1000Minds exercises ranked variables based on importance for the diagnosis. Correspondence analysis determined variables consistently associated with the diagnosis of CAPS using 284 cases and 837 controls. Seven variables were significantly associated with CAPS (p<0.001). The best diagnosis model included: Raised inflammatory markers (C-reactive protein/serum amyloid A) plus ≥two of six CAPS-typical symptoms: urticaria-like rash, cold-triggered episodes, sensorineural hearing loss, musculoskeletal symptoms, chronic aseptic meningitis and skeletal abnormalities. Sensitivity was 81%, specificity 94%. It performed well for all CAPS subtypes and regardless of NLRP3 mutation. The novel approach integrated traditional methods of evidence synthesis with expert consensus, web-based decision tools and innovative statistical methods and may serve as model for other rare diseases. These criteria will enable a rapid diagnosis for children and adults with CAPS.


Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis.
Homozygous alpha1-antitrypsin (AAT) deficiency increases the risk for developing cirrhosis, whereas the relevance of heterozygous carriage remains unclear. Hence, we evaluated the impact of the two most relevant AAT variants ('Pi*Z' and 'Pi*S'), present in up to 10% of Caucasians, on subjects with non-alcoholic fatty liver disease (NAFLD) or alcohol misuse. We analysed multicentric case-control cohorts consisting of 1184 people with biopsy-proven NAFLD and of 2462 people with chronic alcohol misuse, both cohorts comprising cases with cirrhosis and controls without cirrhosis. Genotyping for the Pi*Z and Pi*S variants was performed. The Pi*Z variant presented in 13.8% of patients with cirrhotic NAFLD but only in 2.4% of counterparts without liver fibrosis (p<0.0001). Accordingly, the Pi*Z variant increased the risk of NAFLD subjects to develop cirrhosis (adjusted OR=7.3 (95% CI 2.2 to 24.8)). Likewise, the Pi*Z variant presented in 6.2% of alcohol misusers with cirrhosis but only in 2.2% of alcohol misusers without significant liver injury (p<0.0001). Correspondingly, alcohol misusers carrying the Pi*Z variant were prone to develop cirrhosis (adjusted OR=5.8 (95% CI 2.9 to 11.7)). In contrast, the Pi*S variant was not associated with NAFLD-related cirrhosis and only borderline with alcohol-related cirrhosis (adjusted OR=1.47 (95% CI 0.99 to 2.19)). The Pi*Z variant is the hitherto strongest single nucleotide polymorphism-based risk factor for cirrhosis in NAFLD and alcohol misuse, whereas the Pi*S variant confers only a weak risk in alcohol misusers. As 2%-4% of Caucasians are Pi*Z carriers, this finding should be considered in genetic counselling of affected individuals.


The effects of lutein on cardiometabolic health across the life course: a systematic review and meta-analysis.
The antioxidant lutein is suggested as being beneficial to cardiometabolic health because of its protective effect against oxidative stress, but evidence has not systematically been evaluated. We aimed to evaluate systematically the effects of lutein (intake or concentrations) on cardiometabolic outcomes in different life stages. This is a systematic review with meta-analysis of literature published in MEDLINE, Embase, Cochrane Central, Web of Science, PubMed, and Google Scholar up to August 2014. Included were trials and cohort, case-control, and cross-sectional studies in which the association between lutein concentrations, dietary intake, or supplements and cardiometabolic outcomes was reported. Two independent investigators reviewed the articles. Seventy-one relevant articles were identified that included a total of 387,569 participants. Only 1 article investigated the effects of lutein during pregnancy, and 3 studied lutein in children. Furthermore, 31 longitudinal, 33 cross-sectional, and 3 intervention studies were conducted in adults. Meta-analysis showed a lower risk of coronary heart disease (pooled RR: 0.88; 95% CI: 0.80, 0.98) and stroke (pooled RR: 0.82; 95% CI: 0.72, 0.93) for the highest compared with the lowest tertile of lutein blood concentration or intake. There was no significant association with type 2 diabetes mellitus (pooled RR: 0.97; 95% CI: 0.77, 1.22), but higher lutein was associated with a lower risk of metabolic syndrome (pooled RR: 0.75; 95% CI: 0.60, 0.92) for the highest compared with the lowest tertile. The literature on risk factors for cardiometabolic diseases showed that lutein might be beneficial for atherosclerosis and inflammatory markers, but there were inconsistent associations with blood pressure, adiposity, insulin resistance, and blood lipids. Our findings suggest that higher dietary intake and higher blood concentrations of lutein are generally associated with better cardiometabolic health. However, evidence mainly comes from observational studies in adults, whereas large-scale intervention studies and studies of lutein during pregnancy and childhood are scarce.


Changes in Drinking Patterns, and Attitudes Toward and Knowledge About Alcohol Consumption During Pregnancy in a Population of Pregnant Danish Women.
In 1997, The Danish Health Authority recommended that "it is safest not to drink alcohol when you are pregnant," and in 1999 expanded recommendations. There are only a few studies evaluating the possible change of average alcohol consumption following changes in national recommendations, and no studies have been found comparing the changes in pregnant women's attitudes toward alcohol consumption during pregnancy. We aimed to evaluate the changes in drinking pattern, and knowledge about and attitudes toward alcohol consumption during pregnancy before and after the change of national recommendations. This is a cross-sectional interview study with a representative sample of 1,418 woman attending antenatal care at the beginning of their second trimester in Aarhus, Denmark, in the year 2000, and a comparable sample of 439 pregnant women from 1998 in Aarhus. Participants were interviewed about their average alcohol consumption, binge drinking, and attitudes toward and knowledge about alcohol consumption during pregnancy. Data collection procedures and questions were identical for both samples. There were no differences between the 2 samples in terms of average alcohol consumption before (p = 0.19) and during (p = 0.45) pregnancy, and binge drinking in early pregnancy (p = 0.47). Attitudes toward and knowledge about alcohol in pregnancy did not change either (p > 0.5). Women's knowledge about guidelines was less precise in 2000 (p < 0.001). Worse knowledge was associated with younger age considering both samples (OR = 2.63, 95% CI: 1.63 to 4.26). Most pregnant women reported that they had not been informed or advised about alcohol consumption during pregnancy, but they would like to be advised by their healthcare professionals. After the changes in the national guidelines about alcohol consumption during pregnancy, there were no changes in behavior, attitudes, and knowledge of pregnant women. This would indicate that healthcare specialists should be encouraged to initiate a conversation about alcohol consumption during the first antenatal visit.


Activated mutants of the alpha subunit of G(o) promote an increased number of neurites per cell.
The high concentration of the GTP-binding protein G(o) in the neuronal growth cone suggests that G(o) activation state may after neurite outgrowth. We find that activation of pertussis toxin-sensitive G-proteins by mastoparan increases neurite outgrowth from neuroblastoma cells. To examine G(o) activation specifically, point mutations homologous to activating, oncogenic mutations in alpha i2 and alpha s were introduced into the alpha subunit of G(o). The stability of the alpha o mutants to tryptic digestion confirms that they are activated. When expressed in PC12 or N1E-115 cells, activated alpha o doubles total neurites length per cell, primarily by increasing the number of neurites per cell. The growth cones of cells expressing activated alpha o are narrower than control growth cones. Expression of wildtype alpha o or the activated alpha subunits of other G-proteins did not affect total neurite length per cell. Thus, factors that lead to activation of G(o) can modulate neurite number per cell.


Blood pressure recordings during hemodialysis access interventions: implications for acute management.
A retrospective study evaluating the pattern of blood pressure and its related complications before, during, and after percutaneous hemodialysis interventions was performed in patients presenting with asymptomatic hypertension. Hemodialysis patients undergoing percutaneous interventions including tunneled hemodialysis catheter insertion, percutaneous balloon angioplasty and thrombectomy procedure, and stage II hypertension (systolic blood pressure ≥160 mmHg) were included in this analysis. Blood pressure medications were not used while midazolam and fentanyl were routinely administered. Patients were followed for up to 4 weeks to monitor any complications. The mean blood pressure before, during, and after the procedures were 185 ± 18/96 ± 14, 172 ± 22/92 ± 15, and 153 ± 25/87 ± 14, respectively. There was a statistically significant difference between the blood pressure readings before and after the procedure (before = 185 ± 18/96 ± 14, after = 153 ± 25/87 ± 14; p = 0.001). None of the patients had a stroke, myocardial infarction, or acute pulmonary edema before, during, or after the procedure or during the 4-week follow-up period. A significant reduction in blood pressure was observed after the procedure without the administration of any antihypertensive medication. These results suggest that the reduction in blood pressure observed after percutaneous dialysis access interventions (particularly in the presence of midazolam and fentanyl) may make it unnecessary to treat asymptomatic hypertension prior to these procedures.


Determinants of sugar-sweetened beverage consumption in young children: a systematic review.
Sugar-sweetened beverage (SSB) consumption is associated with adverse health outcomes. Improved understanding of the determinants will inform effective interventions to reduce SSB consumption. A total of 46,876 papers were identified through searching eight electronic databases. Evidence from intervention (n = 13), prospective (n = 6) and cross-sectional (n = 25) studies on correlates/determinants of SSB consumption was quality assessed and synthesized. Twelve correlates/determinants were associated with higher SSB consumption (child's preference for SSBs, TV viewing/screen time and snack consumption; parents' lower socioeconomic status, lower age, SSB consumption, formula milk feeding, early introduction of solids, using food as rewards, parental-perceived barriers, attending out-of-home care and living near a fast food/convenience store). Five correlates/determinants were associated with lower SSB consumption (parental positive modelling, parents' married/co-habiting, school nutrition policy, staff skills and supermarket nearby). There was equivocal evidence for child's age and knowledge, parental knowledge, skills, rules/restrictions and home SSB availability. Eight intervention studies targeted multi-level (child, parents, childcare/preschool setting) determinants; four were effective. Four intervention studies targeted parental determinants; two were effective. One (effective) intervention targeted the preschool environment. There is consistent evidence to support potentially modifiable correlates/determinants of SSB consumption in young children acting at parental (modelling), child (TV viewing) and environmental (school policy) levels.


Increased methylation of the MOR gene proximal promoter in primary sensory neurons plays a crucial role in the decreased analgesic effect of opioids in neuropathic pain.
The analgesic potency of opioids is reduced in neuropathic pain. However, the molecular mechanism is not well understood. The present study demonstrated that increased methylation of the Mu opioid receptor (MOR) gene proximal promoter (PP) in dorsal root ganglion (DRG) plays a crucial role in the decreased morphine analgesia. Subcutaneous (s.c.), intrathecal (i.t.) and intraplantar (i.pl.), not intracerebroventricular (i.c.v.) injection of morphine, the potency of morphine analgesia was significantly reduced in nerve-injured mice compared with control sham-operated mice. After peripheral nerve injury, we observed a decreased expression of MOR protein and mRNA, accompanied by an increased methylation status of MOR gene PP, in DRG. However, peripheral nerve injury could not induce a decreased expression of MOR mRNA in the spinal cord. Treatment with 5-aza-2'-deoxycytidine (5-aza-dC), inhibited the increased methylation of MOR gene PP and prevented the decreased expression of MOR in DRG, thereby improved systemic, spinal and periphery morphine analgesia. Altogether, our results demonstrate that increased methylation of the MOR gene PP in DRG is required for the decreased morphine analgesia in neuropathic pain.


Collagen-hydroxyapatite composites for hard tissue repair.
Bone is the most implanted tissue after blood. The major solid components of human bone are collagen (a natural polymer, also found in skin and tendons) and a substituted hydroxyapatite (a natural ceramic, also found in teeth). Although these two components when used separately provide a relatively successful mean of augmenting bone growth, the composite of the two natural materials exceeds this success. This paper provides a review of the most common routes to the fabrication of collagen (Col) and hydroxyapatite (HA) composites for bone analogues. The regeneration of diseased or fractured bones is the challenge faced by current technologies in tissue engineering. Hydroxyapatite and collagen composites (Col-HA) have the potential in mimicking and replacing skeletal bones. Both in vivo and in vitro studies show the importance of collagen type, mineralisation conditions, porosity, manufacturing conditions and crosslinking. The results outlined on mechanical properties, cell culturing and de-novo bone growth of these devices relate to the efficiency of these to be used as future bone implants. Solid free form fabrication where a mould can be built up layer by layer, providing shape and internal vascularisation may provide an improved method of creating composite structures.


Face recognition and description abilities in people with mild intellectual disabilities.
People with intellectual disabilities (ID) are as likely as the general population to find themselves in the situation of having to identify and/or describe a perpetrator's face to the police. However, limited verbal and memory abilities in people with ID might prevent them to engage in standard police procedures. Two experiments examined face recognition and description abilities in people with mild intellectual disabilities (mID) and compared their performance with that of people without ID. Experiment 1 used three old/new face recognition tasks. Experiment 2 consisted of two face description tasks, during which participants had to verbally describe faces from memory and with the target in view. Participants with mID performed significantly poorer on both recognition and recall tasks than control participants. However, their group performance was better than chance and they showed variability in performance depending on the measures introduced. The practical implications of these findings in forensic settings are discussed.


Pharmacokinetic Parameters of Quinine in Healthy Subjects and in Patients with Uncomplicated Malaria in Nigeria: Analysis of Data using a Population Approach.
The varied disposition of the antimalarial quinine partly explains its poor tolerance and toxicity in humans. Using a population approach, the disposition of quinine in healthy subjects and patients with acute uncomplicated symptomatic malaria from Nigeria was re-examined with a view to providing population-specific attributes. Concentration versus time profiles of quinine over 48 hours in healthy individuals, and over 7 days in malaria-infected patients, were stratified to reflect: concentration versus time data during the first 48 hours of quinine administration for healthy subjects and infected patients, concentration versus time data after 48 hours in infected patients, and all concentration versus time data available for healthy subjects and infected patients. Pharmacokinetic parameters were then estimated with a stochastic approximation expectation maximization algorithm. All datasets were fitted by a 1-compartment model with covariate contributions from body weight and infection status. The absorption rate constant, and volume of distribution and clearance were 1.72 h-1, 86.8 to 157.4 L, and 6.6 to 9.6 L/h, respectively. Infected patients experienced a 38% decrease in volume of distribution and a 31% decrease in clearance in the first 48 hours relative to healthy individuals. The contraction in volume of distribution and clearance diminished significantly after 48 hours of chronic quinine dosing in infected patients. The study findings suggest that clinical interventions aimed at enhancing the safety and tolerance of quinine might be achieved by a rational decrease in dose size and/or dosing interval, post-48 hours of chronic quinine administration, in malaria-infected patients.


Genotyping-by-sequencing based intra-specific genetic map refines a ''QTL-hotspot" region for drought tolerance in chickpea.
To enhance the marker density in the "QTL-hotspot" region, harboring several QTLs for drought tolerance-related traits identified on linkage group 04 (CaLG04) in chickpea recombinant inbred line (RIL) mapping population ICC 4958 × ICC 1882, a genotyping-by-sequencing approach was adopted. In total, 6.24 Gb data from ICC 4958, 5.65 Gb data from ICC 1882 and 59.03 Gb data from RILs were generated, which identified 828 novel single-nucleotide polymorphisms (SNPs) for genetic mapping. Together with these new markers, a high-density intra-specific genetic map was developed that comprised 1,007 marker loci spanning a distance of 727.29 cM. QTL analysis using the extended genetic map along with precise phenotyping data for 20 traits collected over one to seven seasons identified 49 SNP markers in the "QTL-hotspot" region. These efforts have refined the "QTL-hotspot" region to 14 cM. In total, 164 main-effect QTLs including 24 novel QTLs were identified. In addition, 49 SNPs integrated in the "QTL-hotspot" region were converted into cleaved amplified polymorphic sequence (CAPS) and derived CAPS (dCAPS) markers which can be used in marker-assisted breeding.


Polar groups in membrane channels: consequences of replacing alanines with serines in membrane-spanning gramicidin channels.
To explore the consequences of burying polar, hydrogen-bonding hydroxyl groups within the hydrocarbon core of lipid bilayer membranes, we examined the structural and functional effects of alanine-to-serine substitutions in bilayer-spanning gramicidin channels. A native Ala was replaced by Ser at position 3 or 5 in the gramicidin A (gA) sequence: formyl-VG(2)A(3)LA(5)VVVWLWLWLW-ethanolamide (d-residues underlined). In the head-to-head dimers that form the conducting, membrane-spanning gA channels, these sequence positions are located near the lipid bilayer center (and subunit interface). The sequence substitutions at positions 3 and 5 were tested within the context of having either Gly or d-Ala at position 2, because d-Ala(2) causes the channel lifetimes to increase 3-fold relative to Gly(2) [Mattice et al. (1995) Biochemistry 34, 6827]. Size-exclusion chromatograms and circular dichroism spectra show that the Ala --> Ser replacements are well tolerated and have little effect on channel structure. In planar bilayers, the Ser-substituted gramicidins form well-defined channels, with cation conductances that are approximately 60% of those of the reference channels. The Ser-substituted channels are structurally equivalent to native gramicidin channels, as demonstrated by the formation of heterodimeric channels between a Ser-containing subunit and a native gramicidin subunit. These hybrid channels exhibit rectification, attributable to asymmetric placement of the single Ser hydroxyl group with respect to the bilayer center. Compared to the corresponding Ala-containing reference channels, the polar Ser residues decrease the analogues' channel-forming potency by 3 orders of magnitude, indicating a substantial energetic penalty ( approximately 15 kJ/mol) for burying the polar Ser side chain in the bilayer hydrophobic core.


A Phase II Randomized Study of Neoadjuvant Letrozole Plus Alpelisib for Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer (NEO-ORB).
Addition of alpelisib to fulvestrant significantly extended progression-free survival in PIK3CA-mutant, hormone receptor-positive (HR+) advanced/metastatic breast cancer in the phase III SOLAR-1 study. The combination of alpelisib and letrozole also had promising activity in phase I studies of HR+ advanced/metastatic breast cancer. NEO-ORB aimed to determine whether addition of alpelisib to letrozole could increase response rates in the neoadjuvant setting.Patients and Methods: Postmenopausal women with HR+, human epidermal growth factor receptor 2-negative, T1c-T3 breast cancer were assigned to the PIK3CA-wild-type or PIK3CA-mutant cohort according to their tumor PIK3CA status, and randomized (1:1) to 2.5 mg/day letrozole with 300 mg/day alpelisib or placebo for 24 weeks. Primary endpoints were objective response rate (ORR) and pathologic complete response (pCR) rate for both PIK3CA cohorts. In total, 257 patients were assigned to letrozole plus alpelisib (131 patients) or placebo (126 patients). Grade ≥3 adverse events (≥5% of patients) in the alpelisib arm were hyperglycemia (27%), rash (12%), and maculo-papular rash (8%). The primary objective was not met; ORR in the alpelisib versus placebo arm was 43% versus 45% and 63% versus 61% in the PIK3CA-mutant and wild-type cohorts, respectively. pCR rates were low in all groups. Decreases in Ki-67 were similar across treatment arms and cohorts. In PIK3CA-mutant tumors, alpelisib plus letrozole treatment induced a greater decrease in phosphorylated AKT versus placebo plus letrozole. In contrast to initial results in advanced/metastatic disease, addition of alpelisib to 24-week neoadjuvant letrozole treatment did not improve response in patients with HR+ early breast cancer.


Rapid SNP discovery and genetic mapping using sequenced RAD markers.
Single nucleotide polymorphism (SNP) discovery and genotyping are essential to genetic mapping. There remains a need for a simple, inexpensive platform that allows high-density SNP discovery and genotyping in large populations. Here we describe the sequencing of restriction-site associated DNA (RAD) tags, which identified more than 13,000 SNPs, and mapped three traits in two model organisms, using less than half the capacity of one Illumina sequencing run. We demonstrated that different marker densities can be attained by choice of restriction enzyme. Furthermore, we developed a barcoding system for sample multiplexing and fine mapped the genetic basis of lateral plate armor loss in threespine stickleback by identifying recombinant breakpoints in F(2) individuals. Barcoding also facilitated mapping of a second trait, a reduction of pelvic structure, by in silico re-sorting of individuals. To further demonstrate the ease of the RAD sequencing approach we identified polymorphic markers and mapped an induced mutation in Neurospora crassa. Sequencing of RAD markers is an integrated platform for SNP discovery and genotyping. This approach should be widely applicable to genetic mapping in a variety of organisms.


Associations of neighborhood-level workplace violence with workers' mental distress problems: a multilevel analysis of Taiwanese employees.
Workplace violence is known to pose mental health risks. However, whether or not workplace violence in a surrounding area might further increase the risk of mental distress in workers has rarely been examined. The study subjects were 9,393 male and 7,716 female employees who participated in a nationwide survey in 2010. Their personal experiences of workplace violence over the past 1 year were ascertained by a standardized questionnaire. Also assessed were their psychosocial work characteristics and mental distress problems. Neighborhood-level workplace violence was computed based on aggregated data at the county level and was categorized into low-, medium-, and high-level categories. Multilevel logistic regression models were constructed to examine the associations between neighborhood-level workplace violence and individual-level mental distress problems, with adjustment of individual-level experience of workplace violence. The neighborhood-level prevalence of workplace violence ranged from 4.7 to 14.7% in men and from 6.4 to 14.8% in women across 22 counties. As compared with those who live in counties of the lowest tertile of workplace violence, female workers who lived in counties of the highest tertile of workplace violence had a 1.72-fold increased risk for mental distress problems after controlling for individual experience of workplace violence and other psychosocial work characteristics. Neighborhood-level workplace violence was associated with poor mental health in female workers. Preventative strategies targeting workplace violence should pay attention to neighborhood factors and gender-specific effects that might influence societal tolerance of abusive work practices and workers' vulnerability to mental health impacts of workplace violence.


Variations in the service quality of medical practices.
To examine regional variation in the service quality of physician practices and to assess the association of this variation with the supply and organization of physicians. Secondary analyses of the Community Tracking Study (CTS) household and physician surveys. A total of 40,339 individuals who had seen a primary care physician because of an illness or injury and 17,345 generalist physicians across 4 survey time periods in 60 CTS sites were included. Service quality measures used were lag between making an appointment and seeing a physician, and wait time at the physician's office. Our supply measure was the physician-to-population ratio. Our organizational measure was the percentage of physicians in group practices. Multivariate regressions were performed to examine the relationship between service quality and the supply and organization of physicians. There was substantial variation in the service quality of physician visits across the country. For example, in 2003, the average wait time to see a doctor was 16 minutes in Milwaukee but more than 41 minutes in Miami; the average appointment lag for a sick visit in 2003 was 1.2 days in west-central Alabama but almost 6 days in Northwestern Washington. Service quality was not associated with the primary care physician-to-population ratio and had varying associations with the organization of practices. Cross-site variation in service quality of care in primary care has been large, persistent, and associated with the organization of practices. Areas with higher primary care physician-to-population ratios had longer, not shorter, appointment lags.


Role of the autonomic nervous system and neuropeptides in the development of obesity in humans: targets for therapy?
Obesity and type 2 diabetes have reached epidemic proportions worldwide. These metabolic disorders, particularly obesity, are characterised by increased basal sympathetic nervous system (SNS) activity but an impaired sympathetic response to certain stimuli, such as insulin. Although targeting the SNS may seem an attractive avenue for the pharmacological prevention and treatment of obesity and related metabolic disorders, it remains unknown whether changes in SNS tone are primary and contribute to the development of these metabolic conditions or whether they develop secondary to the obese state. This question can be answered by the study of insulin-resistant individuals prior to the development of obesity and type 2 diabetes. Using this model, it has been shown that early insulin resistance is associated with increased SNS activity in genetically-predisposed humans. It has been suggested that in insulin-resistant states, hyperinsulinaemia is the initiating factor that increases sympathetic neural activity. Over time, adrenoreceptor down-regulation and/or reduced sensitivity are likely to develop, resulting in reduced sympathetic responsiveness. In the postprandial state, this will lead to impaired diet-induced thermogenesis and post-prandial fat oxidation, promoting the accumulation of body fat. More recent evidence demonstrates that stress-induced SNS overactivity up-regulates Neuropeptide Y, an orexigenic hormone, and its Y2 receptor, in visceral adipose tissue, the fat depot most strongly linked to insulin resistance and type 2 diabetes. There is evidence that SNS overactivity specifically contributes to the development of abdominal obesity via this pathway, which could represent a novel target for the prevention and treatment of abdominal obesity and related metabolic consequences.


Development of a novel mass spectrometric technique for studying DNA damage.
An experimental system, based upon UV and IR laser desorption, has been constructed to enable the production and characterization of neutral biomolecular targets. These targets are to be used for interaction experiments investigating radiation-induced damage to DNA. The viability of the laser-desorption techniques of MALDI (matrix-assisted laser-desorption ionization), SALDI (surface-assisted laser-desorption ionization) and DIOS (desorption/ionization on silicon), for production of these gas targets is discussed in the present paper. Fluorescent dye tagging and LIF (laser-induced fluorescence) imaging has been used to characterize the biomolecular plumes, revealing their spatial density profiles and temporal evolution.


Effect of recombinant human bone morphogenetic protein-2 in an absorbable collagen sponge with space-providing biomaterials on the augmentation of chronic alveolar ridge defects.
Recombinant human bone morphogenetic protein-2 (rhBMP-2) in an absorbable collagen sponge (ACS) carrier has been shown to support significant bone formation in the craniofacial skeleton. When used as an onlay, however, rhBMP-2/ACS may become compressed with limited resulting bone formation. The objective of this study was to evaluate the effect of two space-providing biomaterials, bioactive glass (BG) and demineralized/mineralized bone matrix (DMB), on rhBMP-2/ACS induced alveolar ridge augmentation. Bilateral alveolar ridge defects were produced in the mandible in six mongrel dogs. rhBMP-2/ACS with biomaterials was surgically implanted into contralateral defects in four animals. Treatments were alternated between jaw quadrants in consecutive animals. Two animals received rhBMP-2/ACS or sham-surgery in contralateral defects. The animals were injected with fluorescent bone labels to monitor bone formation. Clinical evaluations were made at ridge augmentation and 12 weeks post-implantation when the animals were euthanized and block biopsies collected for histopathologic evaluation. Sham-surgery produced limited horizontal alveolar augmentation (0.1 +/- 0.6 mm). Implantation of rhBMP-2/ACS resulted in alveolar augmentation amounting to 2.2 +/- 1.8 mm. Alveolar augmentation in sites receiving rhBMP-2/ACS with DMB or BG was 2-fold greater compared to rhBMP-2/ACS alone averaging 4.4 +/- 1.3 and 4.6 +/- 1.5 mm, respectively. The DMB biomaterial appeared substituted by newly formed bone. The BG particles were observed imbedded in bone or encapsulated in dense connective tissue without associated bone metabolic activity. Fluorescent light microscopy suggested that the new bone was formed within 4 weeks. The bioglass and demineralized/mineralized bone matrix biomaterials utilized in this study in combination with rhBMP-2/ACS supported clinical and histological ridge augmentation.


Identification of low-molecular weight inhibitors of HIV-1 reverse transcriptase using a cell-based high-throughput screening system.
A cell-based drug screening system that utilizes a green fluorescent protein (GFP)-tagged recombinant lentiviral vector has been used to screen a chemical library of 34,000 small molecules for antiretroviral compounds. Thirty-three initial hits were analyzed and four compounds were selected based on their anti-human immunodeficiency virus type 1 (HIV-1) activity (EC(50) values ranging from 0.17 to 1.9 μM) and low cellular toxicity (CC(50) values >50 μM). The four compounds blocked reverse transcription and were able to inhibit the replication of a panel of different HIV-1 strains, including non-B subtype and viruses resistant to different drug classes. Serial in vitro passages of HIV-1(B-HXB2) in the presence of increasing drug concentrations selected for viruses with reduced susceptibility. Mutations previously associated with resistance to non-nucleoside reverse transcriptase (RT) inhibitors (L100I and Y181C for CBL-17 and CBL-21, respectively) or linked to nucleoside analogue resistance (A62V for CBL-4.0 and CBL-4.1) were identified. Viruses with reduced susceptibility to CBL-17 and CBL-21 but not the ones resistant to CBL-4.0 or CBL-4.1 showed a decrease in replicative fitness. Interestingly, two of the small molecules (CBL-4.0 and CBL-4.1) are indolopyridinones that were previously described as nucleotide-competing RT inhibitors.


Wideband silicon-photonic thermo-optic switch in a wavelength-division multiplexed ring network.
Using a compact (0.03 mm(2)) silicon-photonic bias-free thermo-optic cross-bar switch, we demonstrate microsecond-scale switching of twenty wavelength channels of a C-band wavelength-division multiplexed optical ring network, each carrying 10 Gbit/second data concurrently, with 15 mW electrical power consumption (no temperature control required). A convenient pulsed driving scheme is demonstrated and eye patterns and bit-error rate measurements are shown. An algorithm is developed to measure the power-division ratio between the two output ports, the insertion and switching losses, and non-ideal phase deviations.


Changes in and Impact of the Death Review Process in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial.
Death review was conducted for the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial to avoid the biases associated with causes of death entered on death certificates. An algorithm selected deaths for review. Records on diagnosis and terminal illness were perused in the coordinating center and by the chair of the death review committee (DRC). Identifying information and randomization arm was removed. Three reviewers independently determined the cause of death. Disagreement was resolved at a meeting of the DRC. This process was subsequently simplified. The cause of death was determined by one DRC member and compared to the death certificate. With agreement the case was finalized. When discordant, the records were sent to a second DRC member. If the reviewers agreed, the case was finalized. If not, a third member reviewed. If two of the three reviewers agreed, the case was sent back to the discordant reviewer. If the reviewer remained discordant the case was resolved by a conference call. Of the 4728 death reviews that were completed, the DRC confirmed the death certificate underlying cause for over 90%. Between 5% and 13% of the certified deaths were regarded as indirect causes of death, associated with the treatment of the ascertained cancer; differential for prostate cancer, 11% in the intervention arm and 6% in the control. Without review, between 1% and 6% of the deaths that occurred would not have been assigned to the relevant PLCO cancer. The DRC completed 76% of those requiring review before the process ceased.


Hypnotic suggestion reduces conflict in the human brain.
Many studies have suggested that conflict monitoring involves the anterior cingulate cortex (ACC). We previously showed that a specific hypnotic suggestion reduces involuntary conflict and alters information processing in highly hypnotizable individuals. Hypothesizing that such conflict reduction would be associated with decreased ACC activation, we combined neuroimaging methods to provide high temporal and spatial resolution and studied highly and less-hypnotizable participants both with and without a suggestion to interpret visual words as nonsense strings. Functional MRI data revealed that under posthypnotic suggestion, both ACC and visual areas presented reduced activity in highly hypnotizable persons compared with either no-suggestion or less-hypnotizable controls. Scalp electrode recordings in highly hypnotizable subjects also showed reductions in posterior activation under suggestion, indicating visual system alterations. Our findings illuminate how suggestion affects cognitive control by modulating activity in specific brain areas, including early visual modules, and provide a more scientific account relating the neural effects of suggestion to placebo.


Clinical and radiographic evaluation of nanocrystalline hydroxyapatite with or without platelet-rich fibrin membrane in the treatment of periodontal intrabony defects.
Nano-sized ceramics may represent a promising class of bone graft substitutes due to their improved osseointegrative properties. Nanocrystalline hydroxyapatite (NcHA) binds to bone and stimulate bone healing by stimulation of osteoblast activity. Platelet-rich fibrin (PRF), an intimate assembly of cytokines, glycan chains, and structural glycoproteins enmeshed within a slowly polymerized fibrin network, has the potential to accelerate soft and hard tissue healing. The present study aims to explore the clinical and radiographical outcome of NcHA bone graft with or without PRF, in the treatment of intrabony periodontal defects. In a split-mouth study design, 20 patients having two almost identical intrabony defects with clinical probing depth of at least 6 mm were selected for the study. Selected sites were randomly divided into two groups. In Group I, mucoperiosteal flap elevation followed by the placement of NcHA was done. In Group II, mucoperiosteal flap elevation, followed by the placement of NcHA with PRF was done. Clinical and radiographic parameters were recorded at baseline and at 6-month postoperatively. Both treatment groups showed a significant probing pocket depth (PPD) reduction, clinical attachment gain, increase bone density 6-month after surgery compared with baseline. However, there was a significantly greater PPD reduction and clinical attachment gain when PRF was added to NcHA. The NcHA bone graft in combination with PRF demonstrated clinical advantages beyond that achieved by the NcHA alone.


The accuracy of titanium contrast-enhanced mammography: a retrospective multicentric study.
Recently, a new mammography system to perform contrast-enhanced mammography has become available in the market. For the high-energy acquisition, it uses a titanium filter instead of a copper one, reducing the tube load while maintaining image quality. To retrospectively evaluate the accuracy of contrast-enhanced mammography with a titanium filter (TiCEM) in three readers with different grades of experience. IRB-approved retrospective multicentric lesion by lesion study with 200 lesions, all of them initially classified as BI-RADS categories 0/3/4/5 on mammography and/or ultrasound and with pathological confirmation, in 135 patients. Three readers with different levels of experience (expert, resident, intermediate) blinded to the final diagnosis, retrospectively evaluated the low-energy (LE) images and the combination of LE and recombined (subtracted) images and classified the lesions according to the BI-RADS categories. Reader 1 also categorized the breast density. ROC curves were performed for each reader. Out of the 200 lesions, 82 were benign and 118 malignant (20 DCIS, 10 ILC, 88 IDC). The AUCs of LE versus TiCEM for were: Reader 1: 0.7 vs. 0.88, P < 0.001; Reader 2: 0.63 vs. 0.83, P < 0.001; and Reader 3: 0.63 vs. 0.84, P < 0.001. For the three readers, the AUCs of LE versus TiCEM were significantly superior in both dense and non-dense breasts (P < 0.001). Comparing the AUC of LE for Reader 1 (expert) versus the AUC of TiCEM for Reader 2 (resident) there were significant differences (0.7 vs. 0.83, P < 0.001). The accuracy of TiCEM was significantly better for all the readers, in both dense and non-dense breasts. The accuracy of a resident reading a TiCEM study was better than the accuracy of an expert radiologist reading LE images.


Improving influenza vaccine virus selection: report of a WHO informal consultation held at WHO headquarters, Geneva, Switzerland, 14-16 June 2010.
• For almost 60 years, the WHO Global Influenza Surveillance and Response System (GISRS) has been the key player in monitoring the evolution and spread of influenza viruses and recommending the strains to be used in human influenza vaccines. The GISRS has also worked to continually monitor and assess the risk posed by potential pandemic viruses and to guide appropriate public health responses. • The expanded and enhanced role of the GISRS following the adoption of the International Health Regulations (2005), recognition of the continuing threat posed by avian H5N1 and the aftermath of the 2009 H1N1 pandemic provide an opportune time to critically review the process by which influenza vaccine viruses are selected. In addition to identifying potential areas for improvement, such a review will also help to promote greater appreciation by the wider influenza and policy-making community of the complexity of influenza vaccine virus selection. • The selection process is highly coordinated and involves continual year-round integration of virological data and epidemiological information by National Influenza Centres (NICs), thorough antigenic and genetic characterization of viruses by WHO Collaborating Centres (WHOCCs) as part of selecting suitable candidate vaccine viruses, and the preparation of suitable reassortants and corresponding reagents for vaccine standardization by WHO Essential Regulatory Laboratories (ERLs). • Ensuring the optimal effectiveness of vaccines has been assisted in recent years by advances in molecular diagnosis and the availability of more extensive genetic sequence data. However, there remain a number of challenging constraints including variations in the assays used, the possibility of complications resulting from non-antigenic changes, the limited availability of suitable vaccine viruses and the requirement for recommendations to be made up to a year in advance of the peak of influenza season because of production constraints. • Effective collaboration and coordination between human and animal influenza networks is increasingly recognized as an essential requirement for the improved integration of data on animal and human viruses, the identification of unusual influenza A viruses infecting human, the evaluation of pandemic risk and the selection of candidate viruses for pandemic vaccines. • Training workshops, assessments and donations have led to significant increases in trained laboratory personnel and equipment with resulting expansion in both geographical surveillance coverage and in the capacities of NICs and other laboratories. This has resulted in a significant increase in the volume of information reported to WHO on the spread, intensity and impact of influenza. In addition, initiatives such as the WHO Shipment Fund Project have facilitated the timely sharing of clinical specimens and virus isolates and contributed to a more comprehensive understanding of the global distribution and temporal circulation of different viruses. It will be important to sustain and build upon the gains made in these and other areas. • Although the haemagglutination inhibition (HAI) assay is likely to remain the assay of choice for the antigenic characterization of viruses in the foreseeable future, alternative assays - for example based upon advanced recombinant DNA and protein technologies - may be more adaptable to automation. Other technologies such as microtitre neuraminidase inhibition assays may also have significant implications for both vaccine virus selection and vaccine development. • Microneutralization assays provide an important adjunct to the HAI assay in virus antigenic characterization. Improvements in the use and potential automation of such assays should facilitate large-scale serological studies, while other advanced techniques such as epitope mapping should allow for a more accurate assessment of the quality of a protective immune response and aid the development of additional criteria for measuring immunity. • Standardized seroepidemiological surveys to assess the impact of influenza in a population could help to establish well-characterized banks of age-stratified representative sera as a national, regional and global resource, while providing direct evidence of the specific benefits of vaccination. • Advances in high-throughput genetic sequencing coupled with advanced bioinformatics tools, together with more X-ray crystallographic data, should accelerate understanding of the genetic and phenotypic changes that underlie virus evolution and more specifically help to predict the influence of amino acid changes on virus antigenicity. • Complex mathematical modelling techniques are increasingly being used to gain insights into the evolution and epidemiology of influenza viruses. However, their value in predicting the timing and nature of future antigenic and genetic changes is likely to be limited at present. The application of simpler non-mechanistic statistical algorithms, such as those already used as the basis of antigenic cartography, and phylogenetic modelling are more likely to be useful in facilitating vaccine virus selection and in aiding assessment of the pandemic potential of avian and other animal influenza viruses. • The adoption of alternative vaccine technologies - such as live-attenuated, quadrivalent or non-HA-based vaccines - has significant implications for vaccine virus selection, as well as for vaccine regulatory and manufacturing processes. Recent collaboration between the GISRS and vaccine manufacturers has resulted in the increased availability of egg isolates and high-growth reassortants for vaccine production, the development of qualified cell cultures and the investigation of alternative methods of vaccine potency testing. WHO will continue to support these and other efforts to increase the reliability and timeliness of the global influenza vaccine supply. • The WHO GISRS and its partners are continually working to identify improvements, harness new technologies and strengthen and sustain collaboration. WHO will continue in its central role of coordinating worldwide expertise to meet the increasing public health need for influenza vaccines and will support efforts to improve the vaccine virus selection process, including through the convening of periodic international consultations.


Preserving Minority Structures in Graph Sampling.
Sampling is a widely used graph reduction technique to accelerate graph computations and simplify graph visualizations. By comprehensively analyzing the literature on graph sampling, we assume that existing algorithms cannot effectively preserve minority structures that are rare and small in a graph but are very important in graph analysis. In this work, we initially conduct a pilot user study to investigate representative minority structures that are most appealing to human viewers. We then perform an experimental study to evaluate the performance of existing graph sampling algorithms regarding minority structure preservation. Results confirm our assumption and suggest key points for designing a new graph sampling approach named mino-centric graph sampling (MCGS). In this approach, a triangle-based algorithm and a cut-point-based algorithm are proposed to efficiently identify minority structures. A set of importance assessment criteria are designed to guide the preservation of important minority structures. Three optimization objectives are introduced into a greedy strategy to balance the preservation between minority and majority structures and suppress the generation of new minority structures. A series of experiments and case studies are conducted to evaluate the effectiveness of the proposed MCGS.


Quantitative trait loci in the Ogle/TAM O-301 oat mapping population controlling resistance to Puccinia coronata in the field.
Crown rust is the most damaging disease of cultivated oat (Avena sativa) and genetic resistance is the primary means of controlling the disease. Quantitative trait loci (QTL) with major and minor effects have been identified in Ogle1040 and TAM O-301 (most notably, Pc58 and PcNQMG/LGCG from TAM O-301 and OT-27 from Ogle1040) through single-isolate greenhouse and field tests. To map loci and determine the effectiveness of previously identified QTL against naturally occurring pathogen populations in highly disease-conducive environments, the Ogle/TAM O-301 (OT) recombinant inbred line (RIL) population was grown in Texas and Louisiana over 2 years and in Manitoba, Canada. The genetic region characterized by the Pc58 resistance gene complex, particularly Pc58a, accounted for most of the diseased leaf area (DLA) and infection type (IT) variance in all five experiments. Additionally, the genetic region characterized by PcNQMG/LGCG accounted for a portion of the IT variance in three experiments. Although no QTL was detected on OT-27 in this study, all the markers on this linkage group were associated (P < 0.0001) with reducing both IT and DLA using single-marker analysis. Screening with 25 Puccinia coronata isolates from six different states indicated that Pc58abc and Pc58a were highly effective, while characterization using F(2) populations derived from OT RILs containing the two main genetic regions responsible for crown rust resistance in TAM O-301 (Pc58 and PcNQMG/LGCG) and a minor QTL in Ogle (OT-27) indicated that Pc58a, in combination with a locus in Ogle1040, provided high levels of resistance to natural races in Texas. This study provides new information and key loci in OT mapping population and may be useful for effective control of crown rust in North America.


Eradicating chancroid.
Genital ulcers are important cofactors of HIV transmission in the countries most severely affected by HIV/AIDS. Chancroid is a common cause of genital ulcer in all 18 countries where adult HIV prevalence surpasses 8% and is rare in countries with low-level HIV epidemics. Haemophilus ducreyi, the causative organism of chancroid, is biologically vulnerable and occupies a precarious epidemiological niche. Both simple, topical hygiene and male circumcision greatly reduce risk of infection and several classes of antibiotics--some of which can be administered in single-dose treatment regimens--provide rapid cure. H. ducreyi depends on sexual networks with high rates of partner change for its survival, thriving in environments characterized by male mobility and intensive commercial sex activity. Elimination of H. ducreyi infection from vulnerable groups results in disappearance of chancroid from the larger community. Once endemic in Europe and North America, chancroid began a steady decline early in the twentieth century, well before the discovery of antibiotics. Social changes--resulting in changing patterns of commercial sex--probably disrupted the conditions needed to sustain chancroid as an endemic disease. Sporadic outbreaks are now easily controlled when effective curative and preventive services are made available to sex workers and their clients. More recently, chancroid prevalence has declined markedly in countries such as the Philippines. Senegal, and Thailand, a development that may contribute to stabilization of the HIV epidemics in these countries. Eradication of chancroid is a feasible public health objective. Protecting sex workers and their clients from exposure to sexually transmitted diseases (STDs) and improving curative services for STDs are among the proven strategies that could be employed.


Implications of non-native species for mutualistic network resistance and resilience.
Resilience theory aims to understand and predict ecosystem state changes resulting from disturbances. Non-native species are ubiquitous in ecological communities and integrated into many described ecological interaction networks, including mutualisms. By altering the fitness landscape and rewiring species interactions, such network invasion may carry important implications for ecosystem resistance and resilience under continued environmental change. Here, I hypothesize that the tendency of established non-native species to be generalists may make them more likely than natives to occupy central network roles and may link them to the resistance and resilience of the overall network. I use a quantitative research synthesis of 58 empirical pollination and seed dispersal networks, along with extinction simulations, to examine the roles of known non-natives in networks. I show that non-native species in networks enhance network redundancy and may thereby bolster the ecological resistance or functional persistence of ecosystems in the face of disturbance. At the same time, non-natives are unlikely to partner with specialist natives, thus failing to support the resilience of native species assemblages. Non-natives significantly exceed natives in network centrality, normalized degree, and Pollination Service Index. Networks containing non-natives exhibit lower connectance, more links on average, and higher generality and vulnerability than networks lacking non-natives. As environmental change progresses, specialists are particularly likely to be impacted, reducing species diversity in many communities and network types. This work implies that functional diversity may be retained but taxonomic diversity decline as non-native species become established in networks worldwide.


Stochasticity in the miR-9/Hes1 oscillatory network can account for clonal heterogeneity in the timing of differentiation.
Recent studies suggest that cells make stochastic choices with respect to differentiation or division. However, the molecular mechanism underlying such stochasticity is unknown. We previously proposed that the timing of vertebrate neuronal differentiation is regulated by molecular oscillations of a transcriptional repressor, HES1, tuned by a post-transcriptional repressor, miR-9. Here, we computationally model the effects of intrinsic noise on the Hes1/miR-9 oscillator as a consequence of low molecular numbers of interacting species, determined experimentally. We report that increased stochasticity spreads the timing of differentiation in a population, such that initially equivalent cells differentiate over a period of time. Surprisingly, inherent stochasticity also increases the robustness of the progenitor state and lessens the impact of unequal, random distribution of molecules at cell division on the temporal spread of differentiation at the population level. This advantageous use of biological noise contrasts with the view that noise needs to be counteracted.