Incidence of chronic atrial fibrillation in general practice and its treatment pattern.
The object of this article was to estimate the incidence rate of chronic atrial fibrillation (AF) in a general practice setting, to identify factors predisposing to its occurrence, and to describe treatment patterns in the year following the diagnosis. The method used was a population-based cohort study using the General Practice Research Database (GPRD) in the UK. We identified patients aged 40-89 years with a first ever recorded diagnosis of AF. The diagnosis was validated through a questionnaire sent to the general practitioners. A nested case-control analysis was performed to assess risk factors for AF using 1,035 confirmed incident cases of chronic AF and a random sample of 5,000 controls from the original source population. The incidence rate of chronic AF was 1.7 per 1,000 person-years, and increased markedly with age. The age adjusted rate ratio among males was 1.4 (95% CI 1.2-1.6). The major risk factors were age, high BMI, excessive alcohol consumption, and prior cardiovascular comorbidity, in particular, valvular heart disease and heart failure. Digoxin was used in close to 70% of the patients, and close to 15% did not receive any antiarrhythmic treatment. Close to 40% did not receive either warfarin or aspirin in the 3 months period after the diagnosis. Among the potential candidates for anticoagulation only 22% of those aged 70 years or older were prescribed warfarin in comparison to 49% among patients aged 40-69 years. Chronic AF is a disease of the elderly, with women presenting a lower incidence rate than men specially in young age. Age, weight, excessive alcohol consumption, and cardiovascular morbidity were the main independent risk factors for AF. Less than half of patients with chronic AF and no contraindications for anticoagulation received warfarin within the first trimester after the diagnosis.


Neuroligins determine synapse maturation and function.
Synaptogenesis, the generation and maturation of functional synapses between nerve cells, is an essential step in the development of neuronal networks in the brain. It is thought to be triggered by members of the neuroligin family of postsynaptic cell adhesion proteins, which may form transsynaptic contacts with presynaptic alpha- and beta-neurexins and have been implicated in the etiology of autism. We show that deletion mutant mice lacking neuroligin expression die shortly after birth due to respiratory failure. This respiratory failure is a consequence of reduced GABAergic/glycinergic and glutamatergic synaptic transmission and network activity in brainstem centers that control respiration. However, the density of synaptic contacts is not altered in neuroligin-deficient brains and cultured neurons. Our data show that neuroligins are required for proper synapse maturation and brain function, but not for the initial formation of synaptic contacts.


An overview of structure, function, and regulation of pyruvate kinases.
In the last step of glycolysis Pyruvate kinase catalyzes the irreversible conversion of ADP and phosphoenolpyruvate to ATP and pyruvic acid, both crucial for cellular metabolism. Thus pyruvate kinase plays a key role in controlling the metabolic flux and ATP production. The hallmark of the activity of different pyruvate kinases is their tight modulation by a variety of mechanisms including the use of a large number of physiological allosteric effectors in addition to their homotropic regulation by phosphoenolpyruvate. Binding of effectors signals precise and orchestrated movements in selected areas of the protein structure that alter the catalytic action of these evolutionarily conserved enzymes with remarkably conserved architecture and sequences. While the diverse nature of the allosteric effectors has been discussed in the literature, the structural basis of their regulatory effects is still not well understood because of the lack of data representing conformations in various activation states. Results of recent studies on pyruvate kinases of different families suggest that members of evolutionarily related families follow somewhat conserved allosteric strategies but evolutionarily distant members adopt different strategies. Here we review the structure and allosteric properties of pyruvate kinases of different families for which structural data are available.


HIV-related discrimination among grade six students in nine Southern African countries.
HIV-related stigmatisation and discrimination by young children towards their peers have important consequences at the individual level and for our response to the epidemic, yet research on this area is limited. We used nationally representative data to examine discrimination of HIV-positive children by grade six students (n = 39,664) across nine countries in Southern Africa: Botswana, Lesotho, Malawi, Mozambique, Namibia, South Africa, Swaziland, Zambia and Zimbabwe. Descriptive statistics are used to compare discrimination by country, gender, geographic location and socioeconomic status. Multivariate logistic regression is employed to assess potential determinants of discrimination. The levels and determinants of discrimination varied significantly between the nine countries. While one in ten students in Botswana, Malawi, South Africa and Swaziland would "avoid or shun" an HIV positive friend, the proportions in Lesotho, Mozambique, Zambia and Zimbabwe were twice as high (approximately 20%). A large proportion of students believed that HIV positive children should not be allowed to continue to attend school, particularly in Zambia (33%), Lesotho (37%) and Zimbabwe (42%). The corresponding figures for Malawi and Swaziland were significantly lower at 13% and 12% respectively. Small differences were found by gender. Children from rural areas and poorer schools were much more likely to discriminate than those from urban areas and wealthier schools. Importantly, we identified factors consistently associated with discrimination across the region: students with greater exposure to HIV information, better general HIV knowledge and fewer misconceptions about transmission of HIV via casual contact were less likely to report discrimination. Our study points toward the need for early interventions (grade six or before) to reduce stigma and discrimination among children, especially in schools situated in rural areas and poorer communities. In particular, interventions should focus on correcting misconceptions that HIV can be transmitted via casual contact.


High level of Bcl-2 counteracts apoptosis mediated by a live rabies virus vaccine strain and induces long-term infection.
We report here that rabies virus strains, currently used to immunize wildlife against rabies, induce not only caspase-dependent apoptosis in the human lymphoblastoid Jurkat T cell line (Jurkat-vect), but also a caspase-independent pathway involving the apoptosis-inducing factor (AIF). In contrast, a strain of neurotropic RV that does not induce apoptosis did not activate caspases or induce AIF translocation. Bcl-2 overproduction in Jurkat T cells (Jurkat-Bcl-2) abolished both pathways. ERA infection and production were similar in Jurkat-vect and Jurkat-Bcl-2 cells, indicating Bcl-2 has no direct antiviral effects. Bcl-2 production is naturally upregulated by day 3 in ERA-infected Jurkat-vect cultures. The increase in Bcl-2 levels seems to be controlled by the virus infection itself and results in the establishment of long-term, persistently infected cultures that continue to produce virus. Thus, in infections with live RV vaccine strains, infected cells may be productive reservoirs of virus in the long term. This may account for the high efficacy of live rabies vaccines.


Risk of ovarian cancer and inherited variants in relapse-associated genes.
We previously identified a panel of genes associated with outcome of ovarian cancer. The purpose of the current study was to assess whether variants in these genes correlated with ovarian cancer risk. Women with and without invasive ovarian cancer (749 cases, 1,041 controls) were genotyped at 136 single nucleotide polymorphisms (SNPs) within 13 candidate genes. Risk was estimated for each SNP and for overall variation within each gene. At the gene-level, variation within MSL1 (male-specific lethal-1 homolog) was associated with risk of serous cancer (p = 0.03); haplotypes within PRPF31 (PRP31 pre-mRNA processing factor 31 homolog) were associated with risk of invasive disease (p = 0.03). MSL1 rs7211770 was associated with decreased risk of serous disease (OR 0.81, 95% CI 0.66-0.98; p = 0.03). SNPs in MFSD7, BTN3A3, ZNF200, PTPRS, and CCND1A were inversely associated with risk (p<0.05), and there was increased risk at HEXIM1 rs1053578 (p = 0.04, OR 1.40, 95% CI 1.02-1.91). Tumor studies can reveal novel genes worthy of follow-up for cancer susceptibility. Here, we found that inherited markers in the gene encoding MSL1, part of a complex that modifies the histone H4, may decrease risk of invasive serous ovarian cancer.


Perceptions of ductal carcinoma in situ (DCIS) among UK health professionals.
Ductal carcinoma in situ (DCIS) is a complex medical entity which presents challenges for the health professionals who manage the treatment and support of the increasing numbers of women diagnosed with the condition. Health professionals' perceptions and experiences of working with DCIS have rarely been explored, which this study sought to address. Two hundred and ninety-six UK health professionals involved with the treatment of DCIS patients were surveyed. Respondents had diverse perceptions of the condition. Explaining DCIS to patients was challenging for many respondents, and the terminology used varied considerably. This exploratory study highlights the substantial diversity in the perceptions and communication of DCIS among UK health professionals. The nature and implication of these variations and the professional challenges presented by DCIS warrant further exploration and debate in order to inform the provision of appropriate care, support and information to patients.


Apple juice improved behavioral but not cognitive symptoms in moderate-to-late stage Alzheimer's disease in an open-label pilot study.
Preclinical studies demonstrate that apple juice exerts multiple beneficial effects including reduction of central nervous system oxidative damage, suppression of Alzheimer's disease (AD) hallmarks, improved cognitive performance, and organized synaptic signaling. Herein, we initiated an open-label clinical trial in which 21 institutionalized individuals with moderate-to-severe AD consumed 2 4-oz glasses of apple juice daily for 1 month. Participants demonstrated no change in the Dementia Rating Scale, and institutional caregivers reported no change in Alzheimer's Disease Cooperative Study (ADCS)-Activities of Daily Living (ADL) in this brief study. However, caregivers reported an approximate 27% (P < .01) improvement in behavioral and psychotic symptoms associated with dementia as quantified by the Neuropsychiatric Inventory, with the largest changes in anxiety, agitation, and delusion. This pilot study suggests that apple juice may be a useful supplement, perhaps to augment pharmacological approaches, for attenuating the decline in mood that accompanies progression of AD, which may also reduce caregiver burden.


Inherited predisposition to cancer: a historical overview.
The hereditary predisposition to cancer dates historically to interest piqued by physicians as well as family members wherein striking phenotypic features were shown to cluster in families, inclusive of the rather grotesque cutaneous findings in von Recklinghausen's neurofibromatosis, which date back to the sixteenth century. The search for the role of primary genetic factors was heralded by studies at the infrahuman level, particularly on laboratory mouse strains with strong susceptibility to carcinogen-induced cancer, and conversely, with resistance to the same carcinogens. These studies, developed in the 19th and 20th centuries, continue today. This article traces the historical aspects of hereditary cancer dealing with identification and ultimate molecular genetic confirmation of commonly occurring cancers, particularly of the colon in the case of familial adenomatous polyposis and its attenuated form, both due to the APC germline mutation; the Lynch syndrome due to mutations in mismatch repair genes, the most common of which were found to be MSH2, MLH1, and MSH6 germline mutations; the hereditary breast-ovarian cancer syndrome with BRCA1 and BRCA2 germline mutations; the Li-Fraumeni (SBLA) syndrome due to the p53 mutation; and the familial atypical multiple mole melanoma in association with pancreatic cancer due to the CDKN2A (p16) germline mutation. These and other hereditary cancer syndromes have been discussed in some detail relevant to their characterization, which, for many conditions, took place in the late 18th century and, in the more modern molecular genetic era, during the past two decades. Emphasis has been placed upon the manner in which improved cancer control will emanate from these discoveries.


Factors that Affect Patients' Decision-Making about Mastectomy or Breast Conserving Surgery, and the Psychological Effect of this Choice on Breast Cancer Patients.
BACKGROUND: Breast cancer is the most common cancer in women. Primary treatment is surgery, with breast conserving surgery (BCS) being widely used for early-stage disease. Due to changes in body image, depressive symptoms can occur after surgery. Here, we evaluate factors that affect patients' decision on surgery, and investigate differences in the level of depression after mastectomy or BCS in a population of Turkish patients. PATIENTS AND METHODS: One hundred breast cancer patients who had undergone mastectomy or BCS and were followed up at our institution between 2007 and 2008 were included. Patients were questioned about their involvement in surgical decision-making. Depression was diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-III) criteria via a Structural Clinical Interview for DSM (SCID). Severity of depression was evaluated by using the Beck Depression Inventory (BDI). RESULTS: Patients who were older than 50 years, had more than 1 child, a history of lactation, and a positive family history of breast cancer mostly preferred mastectomy. However, patients who sought a second opinion and further information on BCS preferred BCS (p < 0.005). There was no statistical correlation between marital status, first childbearing age, and educational status and the decision on surgery type (p > 0.005). Mastectomy patients were prone to depression, but this was not statistically significant (p = 0.099). CONCLUSION: Age, parenthood, lactation, and positive familial history, as well as thorough information about the type of surgery were important factors for the patients' decision. After breast cancer surgery, patients might experience depression affecting treatment and quality of life. Therefore, adequate information and communication are essential.


Oocyst wall formation and composition in coccidian parasites.
The oocyst wall of coccidian parasites is a robust structure that is resistant to a variety of environmental and chemical insults. This resilience allows oocysts to survive for long periods, facilitating transmission from host to host. The wall is bilayered and is formed by the sequential release of the contents of two specialized organelles - wall forming body 1 and wall forming body 2 - found in the macrogametocyte stage of Coccidia. The oocyst wall is over 90% protein but few of these proteins have been studied. One group is cysteine-rich and may be presumed to crosslink via disulphide bridges, though this is yet to be investigated. Another group of wall proteins is rich in tyrosine. These proteins, which range in size from 8-31 kDa, are derived from larger precursors of 56 and 82 kDa found in the wall forming bodies. Proteases may catalyze processing of the precursors into tyrosine-rich peptides, which are then oxidatively crosslinked in a reaction catalyzed by peroxidases. In support of this hypothesis, the oocyst wall has high levels of dityrosine bonds. These dityrosine crosslinked proteins may provide a structural matrix for assembly of the oocyst wall and contribute to its resilience.


Historical changes (1905-present) in catch size and composition reflect altering fisheries practices on a small Caribbean island.
Effective assessments of the status of Caribbean fish communities require historical baselines to adequately understand how much fish communities have changed through time. To identify such changes and their causes, we compiled a historical overview using data collected at the beginning (1905-1908), middle (1958-1965) and end (1984-2016) of the 20th century, of the artisanal fishing practices and their effects on fish populations around Curaçao, a small island in the southern Caribbean. We documented historical trends in total catch, species composition, and catch sizes per fisher per month for different types of fisheries and related these to technological and environmental changes affecting the island's fisheries and fish communities. We found that since 1905, fishers targeted species increasingly farther from shore after species occurring closer to shore had become rare. This resulted in surprisingly similar catches in terms of weight, but not composition. Large predatory reef fishes living close to shore (e.g., large Epinephelid species) had virtually disappeared from catches around the mid-20th century, questioning the use of data from this period as baseline data for modern day fish assessments. Secondly, we compared fish landings to in-situ counts from 1969 to estimate the relative contributions of habitat destruction and overfishing to the changes in fish abundance around Curaçao. The decline in coral dominated reef communities corresponded to a concurrent decrease in the abundance and diversity of smaller reef fish species not targeted by fishers, suggesting habitat loss, in addition to fishing, caused the observed declines in reef fish abundance around Curaçao.


Perceptions of women medical students and their influence on career choice.
Although women make up nearly half of medical school classes in the United States, just over 20% of residents in surgery are women (excluding obstetrics/gynecology). The objective of this study was to identify whether the proportion of women surgeons on the faculty who have frequent encounters with medical students during their surgery rotation influences the student's perceptions about women surgeons or their career choice. Seven US medical schools with proportions of women surgeons on the fulltime faculty varying from 10% to 40% were selected to participate in this survey. Women medical students graduating in the spring of 2000 were asked to complete an anonymous 29 question survey designed to assess their perceptions of women surgeons' career satisfaction. Demographic information about the students such as career choice, age, and marital status was also collected. The differences in responses between those schools with 40% women faculty and those with less than 15% were analyzed. The overall response rate was 74% (305 of 413). Forty-five percent of students had daily or weekly contact with a woman surgery attending. There were no differences in perceptions of women surgeons' career satisfaction for those students at schools with 40% women surgeons versus those with less than 15%. However, 21 of 24 (88%) students choosing surgery as a career were from the three schools with a greater number of women surgical role models (P <0.0001). Students who chose a career in surgery perceived the women faculty's career satisfaction to be higher than did those students not choosing a surgical career (P <0.01). Women medical students perception of women surgeons' career satisfaction did not appear to be affected by the proportion of women surgeons on the faculty at their medical school. However, their choice of surgery as a career was strongly associated with a higher proportion of women on the surgical faculty.


Low plasma levels of L-arginine, impaired intraplatelet nitric oxide and platelet hyperaggregability: implications for cardiovascular disease in depressive patients.
Major depression (MD) is an independent cardiovascular risk factor, but the exact mechanisms are not clear. In this study we have investigated the intraplatelet L-arginine-nitric oxide (NO) pathway and platelet function in depressive patients. Nineteen unmedicated patients with MD (34±4years) and 19 control subjects (CS, 34±3years) were included. L-[(3)H]-arginine influx, NO synthase (NOS) activity and intracellular cGMP levels were evaluated in platelets, as well as the expression of eNOS, iNOS, arginase and soluble guanylate cyclase (sGC), platelet aggregation and the systemic amino acid profile in MD patients and CS. L-arginine influx (pmol/10(9)cells/min) in platelets was reduced from 46.2±9.5 to 20.02±2.12 in depression. NOS activity (pmol/10(8) cells) was diminished in MD patients (0.09±0.01) compared to CS (0.17±0.01). Intracellular cGMP levels were also impaired in MD patients associated with hyperaggregability. Moreover, the concentration of plasma L-arginine was reduced by 20% in MD patients. The expression of eNOS, iNOS, arginase II and sGC in platelet lysates was not affected by MD. Small number of patients in the study. This study has demonstrated an impairment of L-arginine-NO signaling in platelets from MD patients, suggesting a role in platelet activation and cardiovascular events.


The shifting burden of neurosurgical disease: Vietnam and the middle-income nations.
The Global Burden of Disease (GBD) is an international collaboration and the largest comprehensive investigation of global health disease burden ever conducted. It has been particularly insightful for understanding disease demographics in middle-income nations undergoing rapid development, such as Vietnam, where 6 of the top 10 causes of death are relevant to the neurosurgeon. The burden of stroke-the number one cause of death in Vietnam-is particularly impressive. Likewise, road injuries, with a disproportionate rate of traumatic brain injury, continue to increase in Vietnam following economic development. Low-back and neck pain is the number one cause of disability. Simultaneously, more patients have access to care, and healthcare spending is increased. It is imperative that neurosurgical capital and infrastructure keep pace with Vietnam's growth. The authors searched the existing literature for assessments of neurosurgical infrastructure or initiatives to address neurosurgical disease burden. Using GBD data, the authors also abstracted data for death by cause and prevalence of years of life lost due to disability (YLD) for common neurosurgical pathologies for Vietnam and comparison nations. Interventions aimed at primary prevention of risk factors for neurosurgical disease and focused on the transference of self-sustainable technical skills were found to be analogous to those that have been successful in other regions. Efforts toward stroke prevention have been focused on causal risk factors. Multiple investigators have found that interventions aimed at increasing helmet use were successful in preventing traumatic brain injury. Government-led reforms and equipment donation programs have improved technical capacity. Nevertheless, Vietnam lags behind other nations in neurosurgeons per capita; cause-attributable death and YLD attributable to neurosurgical disease are considerably higher in Vietnam and middle-income nations compared to both lower-income nations and upper-income nations. More than two-thirds of deaths attributable to neurosurgical pathologies in Vietnam and other middle-income nations were due to stroke, and one-fifth of both cause-attributable death and YLD was associated with neurosurgical pathologies. Vietnam and other middle-income nations continue to assume a global burden of disease profile that ever more closely resembles that of developed nations, with particular cerebrovascular, neurotrauma, and spinal disease burdens, leading to exponentially increased demand for neurosurgeons that threatens to outpace the training of neurosurgeons.


Increased risk of preterm births among women with uterine leiomyoma: a nationwide population-based study.
Using a 3-year nationwide population-based database, this study examines the risk of adverse pregnancy outcomes [lower birthweight, preterm gestation and babies small for gestational age (SGA)] in pregnant women with uterine leiomyoma. This study linked two data sets: Taiwan's birth certificate registry and its National Health Insurance Research Data set. A total of 5627 mothers with uterine leiomyoma and 28 135 unaffected mothers were included for analysis. After adjusting for mother and infant characteristics and monthly family income, log-binominal regression and multivariate regression analyses were conducted to examine the risks of preterm birth, SGA and lower birthweight among mothers with uterine leiomyoma and unaffected mothers. Women with uterine leiomyoma had a significantly higher percentage of preterm births (10.98 versus 7.78%, P < 0.001) and SGA infants (19.00 versus 17.28%, P = 0.002) than unaffected mothers. The mean birthweights for mothers with and without uterine leiomyoma were 3083 and 3172 g, respectively (P < 0.001). Log-binominal regression models show that the adjusted risk ratios of preterm births and SGA infants for mothers with uterine leiomyoma were 1.32 (95% CI 1.19-1.46) and 1.16 (95% CI 1.08-1.26), respectively, compared with unaffected mothers. After finally adjusting for gestational age and other covariates, a multivariate regression analysis revealed that women with uterine leiomyoma had, on average, a 14.7 g lower birthweight than unaffected mothers (P = 0.022). We concluded that after adjusting for potential confounders, women with uterine leiomyoma experience a small yet significant increased risk of preterm and SGA infants. We suggest that clinicians intensively monitor women with uterine leiomyoma during pregnancy.


Hospital admissions in relation to body mass index in UK women: a prospective cohort study.
Adiposity is associated with many adverse health outcomes but little direct evidence exists about its impact on the use of health care services. We aim to describe the relationship between body mass index (BMI) and rates of hospital admission in middle-aged UK women. Among 1,251,619 Million Women Study participants, 50- to 64-years old at entry into the study, routine data on hospital admissions were used to estimate hospitalization rates according to BMI after standardization for age, region of recruitment, socioeconomic status, reproductive history, smoking status, hormonal therapy use and alcohol intake. Proportional hazards models were used to estimate adjusted relative risks of hospitalization separately for 25 common types of admission. During an average of 9.2 years follow-up, there were 2,834,016 incident hospital admissions. In women with BMIs (in kg/m2) of <22.5, 22.5 to <25, 25 to <30, 30 to <35 and 35+ standardized admission rates (and 95% confidence intervals (CIs)) per woman over a 10-year period were 2.4 (2.4 to 2.4), 2.4 (2.3 to 2.4), 2.6 (2.6 to 2.6), 3.0 (3.0 to 3.0) and 3.5 (3.4 to 3.5), respectively (P-value for heterogeneity <0.001). The relative increase in admission rates per 5 kg/m2 increase in BMI was 1.12 (1.12 to 1.13). This relationship did not vary materially by age. Corresponding average durations of stay (in days) per hospital visit within the same categories of BMI were: 3.1 (3.1 to 3.2), 2.8 (2.7 to 2.8), 2.9 (2.9 to 2.9), 3.2 (3.1 to 3.2) and 3.8 (3.7 to 3.8), respectively (P <0.001).Significant increases in the risk of admission with increasing BMI were observed for 19 of the 25 types of hospital admission considered. BMI was most strongly associated with admissions with diabetes, knee-replacement, gallbladder disease and venous thromboembolism, but marked associations were found with many other common categories of admission including cataracts, carpal tunnel syndrome and diverticulitis. Among women 50- to 84-years old in England, around one in eight hospital admissions are likely to be attributable to overweight or obesity, translating to around 420,000 extra hospital admissions and two million extra days spent in hospital, annually.


Recruitment and activation of caspase-8 by the Huntingtin-interacting protein Hip-1 and a novel partner Hippi.
In Huntington disease, polyglutamine expansion of the protein huntingtin (Htt) leads to selective neurodegenerative loss of medium spiny neurons throughout the striatum by an unknown apoptotic mechanism. Binding of Hip-1, a protein normally associated with Htt, is reduced by polyglutamine expansion. Free Hip-1 binds to a hitherto unknown polypeptide, Hippi (Hip-1 protein interactor), which has partial sequence homology to Hip-1 and similar tissue and subcellular distribution. The availability of free Hip-1 is modulated by polyglutamine length within Htt, with disease-associated polyglutamine expansion favouring the formation of pro-apoptotic Hippi-Hip-1 heterodimers. This heterodimer can recruit procaspase-8 into a complex of Hippi, Hip-1 and procaspase-8, and launch apoptosis through components of the 'extrinsic' cell-death pathway. We propose that Htt polyglutamine expansion liberates Hip-1 so that it can form a caspase-8 recruitment complex with Hippi. This novel non-receptor-mediated pathway for activating caspase-8 might contribute to neuronal death in Huntington disease.


The evaluation of monoclonal gammopathy of renal significance: a consensus report of the International Kidney and Monoclonal Gammopathy Research Group.
The term monoclonal gammopathy of renal significance (MGRS) was introduced by the International Kidney and Monoclonal Gammopathy Research Group (IKMG) in 2012. The IKMG met in April 2017 to refine the definition of MGRS and to update the diagnostic criteria for MGRS-related diseases. Accordingly, in this Expert Consensus Document, the IKMG redefines MGRS as a clonal proliferative disorder that produces a nephrotoxic monoclonal immunoglobulin and does not meet previously defined haematological criteria for treatment of a specific malignancy. The diagnosis of MGRS-related disease is established by kidney biopsy and immunofluorescence studies to identify the monotypic immunoglobulin deposits (although these deposits are minimal in patients with either C3 glomerulopathy or thrombotic microangiopathy). Accordingly, the IKMG recommends a kidney biopsy in patients suspected of having MGRS to maximize the chance of correct diagnosis. Serum and urine protein electrophoresis and immunofixation, as well as analyses of serum free light chains, should also be performed to identify the monoclonal immunoglobulin, which helps to establish the diagnosis of MGRS and might also be useful for assessing responses to treatment. Finally, bone marrow aspiration and biopsy should be conducted to identify the lymphoproliferative clone. Flow cytometry can be helpful in identifying small clones. Additional genetic tests and fluorescent in situ hybridization studies are helpful for clonal identification and for generating treatment recommendations. Treatment of MGRS was not addressed at the 2017 IKMG meeting; consequently, this Expert Consensus Document does not include any recommendations for the treatment of patients with MGRS.


The Argyre Region as a Prime Target for in situ Astrobiological Exploration of Mars.
At the time before ∼3.5 Ga that life originated and began to spread on Earth, Mars was a wetter and more geologically dynamic planet than it is today. The Argyre basin, in the southern cratered highlands of Mars, formed from a giant impact at ∼3.93 Ga, which generated an enormous basin approximately 1800 km in diameter. The early post-impact environment of the Argyre basin possibly contained many of the ingredients that are thought to be necessary for life: abundant and long-lived liquid water, biogenic elements, and energy sources, all of which would have supported a regional environment favorable for the origin and the persistence of life. We discuss the astrobiological significance of some landscape features and terrain types in the Argyre region that are promising and accessible sites for astrobiological exploration. These include (i) deposits related to the hydrothermal activity associated with the Argyre impact event, subsequent impacts, and those associated with the migration of heated water along Argyre-induced basement structures; (ii) constructs along the floor of the basin that could mark venting of volatiles, possibly related to the development of mud volcanoes; (iii) features interpreted as ice-cored mounds (open-system pingos), whose origin and development could be the result of deeply seated groundwater upwelling to the surface; (iv) sedimentary deposits related to the formation of glaciers along the basin's margins, such as evidenced by the ridges interpreted to be eskers on the basin floor; (v) sedimentary deposits related to the formation of lakes in both the primary Argyre basin and other smaller impact-derived basins along the margin, including those in the highly degraded rim materials; and (vi) crater-wall gullies, whose morphology points to a structural origin and discharge of (wet) flows.


Fundamentals of Light Chain Cardiac Amyloidosis: A Focused Review.
The estimated prevalence of AL CA in the US is approximately 8-12 cases per million. Almost 30-50% diagnosed cases of AL amyloid in the US have multisystem involvement, including cardiac involvement. Even with the availability of advanced diagnostic testing and novel therapies, prognosis remains poor. It is overlooked as a cause of heart failure with preserved ejection fraction leading to a delay in diagnosis when management options are limited and associated with poor survival outcomes. Therefore, the education of physicians is needed to ensure that it would be highly considered as a differential diagnosis. The purpose of this manuscript is to review the advances in the diagnosis and management of cardiac amyloidosis with the aim of educating colleagues who provide care in the primary care setting. We have summarized the pathogenesis of amyloidosis, its association with plasma cell dyscrasias, novel diagnostic and surveillance approaches including echocardiography, cardiovascular magnetic resonance imaging, histopathologic techniques, systemic biomarkers, and advanced treatment approaches including supportive symptomatic management and standard of care chemotherapy targeting the amyloid deposits. Given the overall poor prognosis of amyloidosis, we have also discussed the role of palliative and hospice care.


Drinking water microbiome assembly induced by water stagnation.
What happens to tap water when you are away from home? Day-to-day water stagnation in building plumbing can potentially result in water quality deterioration (e.g., lead release or pathogen proliferation), which is a major public health concern. However, little is known about the microbial ecosystem processes in plumbing systems, hindering the development of biological monitoring strategies. Here, we track tap water microbiome assembly in situ, showing that bacterial community composition changes rapidly from the city supply following ~6-day stagnation, along with an increase in cell count from 103 cells/mL to upwards of 7.8 × 105 cells/mL. Remarkably, bacterial community assembly was highly reproducible in this built environment system (median Spearman correlation between temporal replicates = 0.78). Using an island biogeography model, we show that neutral processes arising from the microbial communities in the city water supply (i.e., migration and demographic stochasticity) explained the island community composition in proximal pipes (Goodness-of-fit = 0.48), yet declined as water approached the faucet (Goodness-of-fit = 0.21). We developed a size-effect model to simulate this process, which indicated that pipe diameter drove these changes by mediating the kinetics of hypochlorite decay and cell detachment, affecting selection, migration, and demographic stochasticity. Our study challenges current water quality monitoring practice worldwide which ignore biological growth in plumbing, and suggests the island biogeography model as a useful framework to evaluate building water system quality.


Graphene Oxide and Lipid Membranes: Size-Dependent Interactions.
We have investigated the interaction of graphene oxide (GO) sheets with supported lipid membranes with focus on how the interaction depends on GO sheet size (three samples in the range of 90-5000 nm) and how it differs between small and large liposomes. The layer-by-layer assembly of these materials into multilamellar structures, as discovered in our previous research, is now further explored. The interaction processes were monitored by two complementary, real time, surface-sensitive analytical techniques: quartz crystal microbalance with dissipation monitoring (QCM-D, electroacoustic sensing) and indirect nanoplasmonic sensing (INPS, optical sensing). The results show that the sizes of each of the two components, graphene oxide and liposomes, are important parameters affecting the resulting multilayer structures. Spontaneous liposome rupture onto graphene oxide is obtained for large lateral dimensions of the graphene oxide sheets.


Lipid rafts as a membrane-organizing principle.
Cell membranes display a tremendous complexity of lipids and proteins designed to perform the functions cells require. To coordinate these functions, the membrane is able to laterally segregate its constituents. This capability is based on dynamic liquid-liquid immiscibility and underlies the raft concept of membrane subcompartmentalization. Lipid rafts are fluctuating nanoscale assemblies of sphingolipid, cholesterol, and proteins that can be stabilized to coalesce, forming platforms that function in membrane signaling and trafficking. Here we review the evidence for how this principle combines the potential for sphingolipid-cholesterol self-assembly with protein specificity to selectively focus membrane bioactivity.


Monoclonal antibody definition of T cell acute leukemia: a Pediatric Oncology Group study.
Leukemic blasts from 774 children with newly diagnosed acute lymphocytic leukemia (ALL) have been phenotyped by microcytotoxicity testing with a panel of monoclonal antibodies and heteroantisera as part of a Pediatric Oncology Group classification study of acute leukemia. One hundred twenty-two cases, or 16% were designated as T cell leukemia based on the reactivity of blast cells with previously well-characterized antisera (PT) against a T lymphocyte-associated antigen. Using this antisera-based definition as a standard, we looked for a monoclonal antibody combination that would be a suitable substitute. An algorithm calling for reactivity with either monoclonal antibody 3A1 or Leu-1 was a 92% sensitive and 97% specific predictor of PT reactivity. Only 27 of 755 cases of leukemia were incorrectly classified using this algorithm. Subsequently, Ficoll-Hypaque-separated bone marrow cells from 118 additional patients with ALL (21 of whom had T cell ALL) were stained by immunofluorescence using a combination of directly fluoresceinated 3A1 and Leu-1. Reactivity of 20% or more of the cells with this antibody combination was a 100% sensitive and 94% specific indicator of T cell ALL defined by PT positivity; with a higher cutoff value for positive values, or the use of supplemental tests, even this small number of false-positives could be eliminated. We conclude that this monoclonal antibody combination is a satisfactory replacement for our heteroantisera definition of T cell ALL.


Seahorse (Hippocampinae) population fluctuations in the Ria Formosa Lagoon, south Portugal.
Comparisons of three sets of surveys in the Ria Formosa Lagoon, Portugal, over a 13 year period (2001-2002, 2008-2009 and 2010-2013) revealed significant population fluctuations in at least one of the two seahorse (Hippocampinae) species living there, and that those fluctuations were potentially associated with habitat changes in the lagoon. After a significant decline between the first two survey periods (2001-2002 v. 2008-2009), long-snouted seahorse Hippocampus guttulatus populations increased significantly between 2008-2009 surveys and new 2010-2013 surveys. There were no significant differences in H. guttulatus populations between the 2001-2002 and 2010-2013 surveys. In contrast, there were no significant differences in short-snouted seahorse Hippocampus hippocampus densities among the 16 sites surveyed throughout the three sampling periods, although the ability to detect any change was hampered by the low densities of this species in all time periods. Fluctuations in H. guttulatus densities were positively correlated with the percentage of holdfast coverage, but with none of the other environmental variables tested. These results highlight the importance of holdfast availability in maintaining stable seahorse populations. While population fluctuations are certainly more promising than a consistent downward decline, such extreme fluctuations observed for seahorses in the Ria Formosa Lagoon could still leave these two species vulnerable to any additional stressors, particularly during low density periods.


Low vitamin D level is an independent predictor of poor outcomes in Clostridium difficile-associated diarrhea.
The incidence, recurrence, and all-cause mortality rate for Clostridium difficile-associated diarrhea (CDAD) has increased markedly over the past 10 years despite treatment. Low vitamin D levels are known to impair immune responses to infection and are associated with increased mortality. We compared the role of patient comorbidity measured by the Charlson Comorbidity Index (CCI) with vitamin D levels to ascertain whether vitamin D levels were an independent variable affecting the outcome of CDAD or a marker of overall comorbidity. A prospective cohort study studied 62 patients hospitalized between 2008 and 2009 with manifestations of CDAD and a positive C. difficile toxin assay. All patients received standard antibiotics (metronidazole and/or vancomycin). Their status at 30-day follow up was classified as resolved or recurred/expired. Patients' CCI was calculated using their medical history. Logistic regression analysis of variables including 25-hydroxyvitamin D, CCI, age, gender, white blood cell count (WBC), albumin and residence type were performed. There were 62 patients (43.6% men, 56.4% women) with CDAD; mean age was 75 ± 17 years. At 30-day follow up, 28 (45.2%) expired, 10 (16.1%) had persistent or recurrent diarrhea and 24 (38.7%) resolved. Nonresolution was seen in 38 (61.3%). There was no significant association between 30-day resolution status and CCI, gender, WBC, albumin level or residence type. Two variables were found to be independent predictors of resolution of CDAD: normal vitamin D levels (p = 0.028) and age <70 years (p = 0.024). Subjects with low vitamin D were 4.75 times more likely to fail to resolve CDAD than subjects with normal Vitamin D. In this study, vitamin D level and age are independent predictors of CDAD resolution in hospitalized patients. Low vitamin D levels and age >70 years old are associated with increased likelihood of recurrence. Low vitamin D levels are not a marker of comorbidity or advanced age.


HCC surveillance results in earlier HCC detection: results from an Indian cohort.
Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death worldwide, with an increased incidence in South Asia. In order to describe the effect of surveillance for HCC with biannual ultrasound and alpha-fetoprotein (AFP) on diagnosis and survival in an Indian population a retrospective cohort-control study was performed at two liver clinics in India. The medical records of 3,258 patients with cirrhosis who received surveillance for HCC were reviewed, and 100 patients who developed HCC identified. Sixty-four cirrhotic patients diagnosed with HCC during the same time period without a history of surveillance were included and survival, BCLC stage at diagnosis, and treatment were compared. Patients who underwent surveillance were more likely to be diagnosed with potentially curable or treatable BCLC Stage 0/A disease and Stage B/C disease respectively, than late Stage D disease (χ2 = 0.0007). Patients diagnosed at an earlier stage of HCC lived significantly longer after diagnosis than patients diagnosed at a later stage (Stage 0/A: 15.6 ± 14.2 months vs. Stage B/C: 9.43 ± 19.7 months vs. Stage D: 5.59 ± 11.9 months; p = 0.0006). While treatment for HCC improved overall survival, only 28% of eligible patients received treatment, explaining the lack of survival benefit noted in the surveillance group. Surveillance for HCC led to detection of HCC at earlier stages. The impact of surveillance on improved mortality could not be evaluated given the limited number of patients who received treatment. HCC surveillance has the potential to improve survival in South Asian patients with cirrhosis only if improvements in access to appropriate treatment are made.


Evolutionary coupling analysis identifies the impact of disease-associated variants at less-conserved sites.
Genome-wide association studies have discovered a large number of genetic variants in human patients with the disease. Thus, predicting the impact of these variants is important for sorting disease-associated variants (DVs) from neutral variants. Current methods to predict the mutational impacts depend on evolutionary conservation at the mutation site, which is determined using homologous sequences and based on the assumption that variants at well-conserved sites have high impacts. However, many DVs at less-conserved but functionally important sites cannot be predicted by the current methods. Here, we present a method to find DVs at less-conserved sites by predicting the mutational impacts using evolutionary coupling analysis. Functionally important and evolutionarily coupled sites often have compensatory variants on cooperative sites to avoid loss of function. We found that our method identified known intolerant variants in a diverse group of proteins. Furthermore, at less-conserved sites, we identified DVs that were not identified using conservation-based methods. These newly identified DVs were frequently found at protein interaction interfaces, where species-specific mutations often alter interaction specificity. This work presents a means to identify less-conserved DVs and provides insight into the relationship between evolutionarily coupled sites and human DVs.


Clustering of Lynch syndrome malignancies with no evidence for a role of DNA mismatch repair.
We ascertained a large kindred with an excess of Lynch syndrome-associated cancers. Our objective was to determine if a defect in one of the DNA mismatch repair (DMMR) genes was the probable cause of cancer susceptibility as microsatellite instability (MSI) and immunohistochemical (IHC) analysis of the probands' tumors did not provide a clear indication. A detailed history and review of medical records was undertaken to construct a four-generation pedigree. Blood samples were obtained for analysis of germline DNA. Polymorphic repeats from the MLH1, MSH2, MSH6, and PMS2 loci were genotyped and the co-segregation of markers and disease was assessed. DMMR gene expression for all available tumors was evaluated by IHC. Combined bisulfite restriction analysis (COBRA) of MLH1 was utilized to test for germline epimutation. Four gynecologic carcinomas, 3 colon carcinomas, and 13 cases of adenomatous polyps were identified. The family met Amsterdam II criteria. The mean age of cancer diagnosis in the kindred was 63 years (range 44-82 years). DNA marker analyses excluded linkage to MLH1, MSH2, MSH6, and PMS2. Furthermore, MSI and IHC analysis of tumors did not suggest a role for DMMR. Methylation of the MLH1 promoter was identified in the peripheral blood leukocytes (PBLs) of a family member with an early onset colon cancer. We identified a large family with multiple Lynch malignancies and no evidence for an inherited defect in DMMR. This family represents an important but poorly understood form of autosomal dominant inherited cancer susceptibility. Aberrant MLH1 promoter methylation in normal tissues may be a marker for cancer susceptibility in families such as this.


Default network connectivity during a working memory task.
The default network exhibits correlated activity at rest and has shown decreased activation during performance of cognitive tasks. There has been little investigation of changes in connectivity of this network during task performance. In this study, we examined task-related modulation of connectivity between two seed regions from the default network posterior cingulated cortex (PCC) and medial prefrontal cortex (mPFC) and the rest of the brain in 12 healthy adults. The purpose was to determine (1) whether connectivity within the default network differs between a resting state and performance of a cognitive (working memory) task and (2) whether connectivity differs between these nodes of the default network and other brain regions, particularly those implicated in cognitive tasks. There was little change in connectivity with the other main areas of the default network for either seed region, but moderate task-related changes in connectivity occurred between seed regions and regions outside the default network. For example, connectivity of the mPFC with the right insula and the right superior frontal gyrus decreased during task performance. Increased connectivity during the working memory task occurred between the PCC and bilateral inferior frontal gyri, and between the mPFC and the left inferior frontal gyrus, cuneus, superior parietal lobule, middle temporal gyrus and cerebellum. Overall, the areas showing greater correlation with the default network seed regions during task than at rest have been previously implicated in working memory tasks. These changes may reflect a decrease in the negative correlations occurring between the default and task-positive networks at rest.


Invasive Staphylococcus aureus infections associated with pain injections and reuse of single-dose vials--Arizona and Delaware, 2012.
Transmission of life-threatening bacterial infections can occur when health-care personnel do not adhere to Standard Precautions and instead use medication in containers labeled as single-dose or single-use for more than one patient. This report summarizes the investigation of two outbreaks of invasive Staphylococcus aureus infection confirmed in 10 patients being treated for pain in outpatient clinics. In each outbreak, the use of single-dose or single-use vials (SDVs) for more than one patient was associated with infection transmission. In both investigations, clinicians reported difficulty obtaining the medication type or vial size that best fit their procedural needs. These outbreaks are a reminder of the serious consequences that can result when SDVs are used for more than one patient. Clinician adherence to safe injection practices, particularly when appropriately sized SDVs are unavailable, is important to prevent infection transmission. If SDVs must be used for more than one patient, full adherence to U.S. Pharmacopeia standards is critical to minimize the risks of multipatient use.


Determinants of consumer intention to purchase animal-friendly milk.
Concern about the welfare of production animals is growing among various stakeholders, including the general public. Citizens can influence the market for premium welfare products by expressing public concerns, and consumers-the actors who actually purchase products-can do so through their purchasing behavior. However, current market shares for premium welfare products are small in Europe. To better align purchase behavior with public and individuals' concerns, insight is needed into determinants that influence the intention to purchase premium welfare products. A cross-sectional online survey of 787 Flemish milk consumers was conducted to investigate attitudes toward and intention to purchase animal-friendly milk. More than half of the sample (52.5%) expressed the intention to purchase animal-friendly milk. Linear regression modeling indicated that intention was positively influenced by (1) higher perceived product benefits from animal-friendly milk (milk with more health benefits and higher quality); (2) higher personal importance of extrinsic product attributes such as local production and country of origin; (3) higher personal importance of animal welfare; (4) a more natural living oriented attitude toward cows; and (5) a more positive general attitude toward milk. Intention was negatively influenced by (1) a stronger business-oriented attitude toward cows; and (2) by a higher personal importance attached to price. These insights in key components of purchase intention can assist producers, the dairy industry, and retailers to position and market animal-friendly milk.


Pathogenic Variation of Phakopsora pachyrhizi Isolates on Soybean in the United States from 2006 to 2009.
The introduction of Phakopsora pachyrhizi, the cause of soybean rust, into the United States is a classic case of a pathogen introduction that became established in a new geographical region overwintering on a perennial host (kudzu, Pueraria lobata). The objective of our study was to classify the pathogenic variation of P. pachyrhizi isolates collected in the United States, and to determine the spatial and temporal associations. In total, 72 isolates of P. pachyrhizi collected from infected kudzu and soybean leaves in the United States were purified, then established and increased on detached soybean leaves. These isolates were tested for virulence and aggressiveness on a differential set of soybean genotypes that included six genotypes with known resistance genes (Rpp), one resistant genotype without any known characterized resistance gene, and a susceptible genotype. Three pathotypes were identified among the 72 U.S. P. pachyrhizi isolates based on the virulence of these isolates on the genotypes in the differential set. Six aggressiveness groups were established based on sporulating-uredinia production recorded for each isolate on each soybean genotype. All three pathotypes and all six aggressiveness groups were found in isolates collected from the southern region and from both hosts (kudzu or soybean) in 2008. Shannon's index based on the number of pathotypes indicated that isolates from the South region were more diverse (H = 0.83) compared with the isolates collected in other regions. This study establishes a baseline of pathogenic variation of P. pachyrhizi in the United States that can be further compared with variation reported in other regions of the world and in future studies that monitor P. pachyrhizi virulence in association to deployment of rust resistance genes.


Incidence and risk factors for pacemaker implantation following aortic valve replacement.
Our aim was to identify the predictive factors for permanent pacemaker (PM) implantation in patients undergoing isolated aortic valve replacement (AVR). A total of 3534 patients received an AVR between January 1990 and December 2003 in our institution. Permanent PM implantation was performed in 234 (6.6%) patients, over median time of three days (range one to 24 days). This patient population was compared to a random sample of 191 patients undergoing AVR without permanent PM implantation. The overall mean age was 63.5 years (±14.2) and 261 patients (62%) were male. Univariate and multivariate logistic regression analysis of pre- and perioperative data were performed. Overall the 30 days mortality was 4.2% (10/234) in patients with PM and 1% (2/191) in the control group (P=0.046). Patients with PMs were older (P<0.001), had more additional coronary artery bypass grafting (CABG) surgery or mitral valve replacement (MVR) (P<0.001), complete right bundle branch block (RBBB) prior to surgery, and more frequently underwent re-operations compared to patients without PMs (P<0.001). The multivariate logistic regression model with PM implantation as the dependent variable demonstrated that older age was not independently associated with PM implantation. As independent predictors concomitant severe mitral valve insufficiency, CABG, subaortic stenosis (SAS) or re-do operations were identified.


[Morphological parameters of breast cancers detected by mammography with and without organized screening; a comparative study].
Some pathological findings and prognostic indices recorded in breast cancer cases, detected, on one hand, by a provider-initiated mammography screening program (Group 1), and, opportunistically, in self-referred symptomatic women (Group 2) on the other, are compared. In 8877 symptom-free women, aged 50-65 years, individually invited to attend the screening offered for the residents of the III., XII. and XIII. districts of Budapest, 67 cancer cases were detected (7.5 in 1000 screenees), in accordance with the cancer detection rate of the first, "prevalence" round of organised screening programmes. In the other group of 1593 symptomatic, self-referred women of the same age, 113 cancer cases were diagnosed by mammography. As far as the pathological parameters are concerned, the number of cases with invasive cancer less than 15 mm in diameter, and those with axillary nodes present was found to be significantly higher in the screened group as compared to the self-referred one (p < 0.01). In "small" cancers (i.e. less than 15 mm in diameter), no significant difference was found in the proportion of histologic grade III tumours among the two groups. In screen-detected cancers both the morphometric prognostic index (as calculated by Baak et al.) and the Nottingham Prognostic Index (NPI) proved to be more favourable, as compared to those in the self-referred group. The p-value as determined by Mann-Whithey test was 0.000003 in the screened group, and 0.000015 in the other one. These findings provide convincing evidence in support of the public health importance of provider-initiated, organised mammography screening for breast cancer, therefore, the introduction on service basis of organised breast screening into the health care system in Hungary is strongly recommended by the authors.


Right-angled vessels in macular telangiectasia type 2.
To evaluate the role of right-angled vessels (RAVs) during disease progression in macular telangiectasia type 2 (MacTel). In this study, 100 eyes of 52 patients and 52 eyes of 26 age-related controls were examined using fundus photography, spectral-domain optical coherence tomography (SD-OCT), OCT angiography (OCT-A) and fundus fluorescein angiography (FFA). Two masked readers graded fundus photographs of patients' eyes into five disease stages according to Gass and Blodi, and evaluated all eyes for the presence of RAVs. If RAVs were present, their course and origin (arterial vs venous) was evaluated with OCT-A and FFA, respectively. Additionally, we looked for morphological correlates of these vessels on SD-OCT scans. Neovascular eyes were analysed for the presence of RAVs and for morphological changes on formation of neovascularisations (NVs). In OCT-A, RAVs were already detectable in eyes with early stages (1 to 2), could be tracked from superficial to outer retinal layers and were shown to form anastomoses in the outer retina with disease progression. These vessels were of both arterial and venous origin as shown by early phase FFA. Dilated capillaries and RAVs in OCT-A corresponded to hyper-reflective alterations of the outer retina on SD-OCT scans. In 19/19 eyes, NVs were associated with the presence of RAVs, and RAVs were shown to directly connect to neovascular complexes and to undergo morphological changes upon NV formation. The results emphasise the role of RAVs during disease progression from an early stage on and demonstrate their involvement in the development of secondary NVs in MacTel.


Quality of life after rectal resection for cancer, with or without permanent colostomy.
For almost one hundred years abdominoperineal excision has been the standard treatment of choice for rectal cancer. With advances in the techniques for rectal resection and anastomosis, anterior resection with preservation of the sphincter function has become the preferred treatment for rectal cancers, except for those cancers very close to the anal sphincter. The main reason for this has been the conviction that the quality of life for patients with a colostomy after abdominoperineal excision was poorer than for patients undergoing an operation with a sphincter-preserving technique. However, patients having sphincter-preserving operations may experience symptoms affecting their quality of life that are different from stoma-patients. To compare the quality of life in rectal cancer patients with or without permanent colostomy. We searched PUBMED, EMBASE, LILACS, the Cochrane Central Register of Controlled Trials (CENTRAL), the Cochrane Colorectal Cancer Group's specialised register. Abstract books from major gastroenterological and colorectal congresses were searched. Reference lists of the selected articles were scrutinized. All controlled clinical trials and observational studies in which quality of life was measured in patients with rectal cancer having either abdominoperineal excision/Hartmann's operation or low anterior resection, using a validated quality of life instrument, were considered. One reviewer (JP) checked the titles and abstracts identified from the databases and hand search. Full text copies of all studies of possible relevance were obtained. The reviewer decided which studies met the inclusion criteria. Both reviewers independently extracted data. If information was insufficient the original author was contacted to obtain missing data. Extracted data were cross-checked and discrepancies resolved by consensus. Sixty-nine potential studies were identified. Thirty-five of these, all non-randomised and representing 5127 participants met the inclusion criteria. Fourteen trials found that people undergoing abdominoperineal excision/Hartmann's operation did not have poorer quality of life measures than patients undergoing anterior resection. The rest of the studies found some difference, but not always in favour of non-stoma patients. Due to clinical heterogeneity and the fact that all studies were observational trials, meta-analysis of the included studies was not possible. The studies included in this review do not allow firm conclusions as to the question of whether the quality of life of people after anterior resection is superior to that of people after abdominoperineal excision/Hartmann's operation. The included studies challenges the assumption that anterior resection patients fare better. Larger, better designed and executed prospective studies are needed to answer this question.


Expression of thrombomodulin on monocytes is associated with early outcomes in patients with coronary artery bypass graft surgery.
Thrombomodulin (TM) mediates blood coagulation and inflammation and is expressed constitutively on resting monocytes. This expression might be a key regulator of monocyte-related inflammation. Conventional cardiopulmonary bypass (CPB), beating-heart CPB, and off-pump techniques have been used widely in cardiac surgery. Although beating-heart CPB and off-pump techniques have reduced postoperative inflammation significantly, the underlying mechanisms remain unclear. Whether CPB affects the expression of TM and changes the actual immune capacity of monocytes is also unknown. In this study, we analyzed TM expression on monocytes and in plasma among patients undergoing elective coronary artery bypass graft surgery. The days spent in an intensive care unit (ICU) and incidence of fever in the ICU were significantly lower in the beating-heart CPB and off-pump groups than in the conventional CPB group. Enzyme-linked immunosorbent assay showed a significant increase in TM at 30 min after the commencement of CPB and at the end of surgery in the conventional CPB group, whereas the level increased less markedly in the beating-heart CPB group. Flow cytometry showed that conventional CPB markedly reduced the expression of TM on monocytes. Based on monocyte chemotaxis analysis and an actin polymerization assay, we propose that TM expression on monocytes is associated with systemic inflammation. We conclude that the beating-heart CPB and off-pump techniques have a lower impact on patients than conventional CPB. The reduced incidence of fever and shorter ICU stay seem to be associated predominantly with the lower concentration of TM in plasma and with a higher expression of TM on monocytes.


Tree Lab: Portable genomics for Early Detection of Plant Viruses and Pests in Sub-Saharan Africa.
In this case study we successfully teamed the PDQeX DNA purification technology developed by MicroGEM, New Zealand, with the MinION and MinIT mobile sequencing devices developed by Oxford Nanopore Technologies to produce an effective point-of-need field diagnostic system. The PDQeX extracts DNA using a cocktail of thermophilic proteinases and cell wall-degrading enzymes, thermo-responsive extractor cartridges and a temperature control unit. This closed system delivers purified DNA with no cross-contamination. The MinIT is a newly released data processing unit that converts MinION raw signal output into nucleotide base called data locally in real-time, removing the need for high-specification computers and large file transfers from the field. All three devices are battery powered with an exceptionally small footprint that facilitates transport and setup. To evaluate and validate capability of the system for unbiased pathogen identification by real-time sequencing in a farmer's field setting, we analysed samples collected from cassava plants grown by subsistence farmers in three sub-Sahara African countries (Tanzania, Uganda and Kenya). A range of viral pathogens, all with similar symptoms, greatly reduce yield or destroy cassava crops. Eight hundred (800) million people worldwide depend on cassava for food and yearly income, and viral diseases are a significant constraint to its production. Early pathogen detection at a molecular level has great potential to rescue crops within a single growing season by providing results that inform decisions on disease management, use of appropriate virus-resistant or replacement planting. This case study presented conditions of working in-field with limited or no access to mains power, laboratory infrastructure, Internet connectivity and highly variable ambient temperature. An additional challenge is that, generally, plant material contains inhibitors of downstream molecular processes making effective DNA purification critical. We successfully undertook real-time on-farm genome sequencing of samples collected from cassava plants on three farms, one in each country. Cassava mosaic begomoviruses were detected by sequencing leaf, stem, tuber and insect samples. The entire process, from arrival on farm to diagnosis, including sample collection, processing and provisional sequencing results was complete in under 3 h. The need for accurate, rapid and on-site diagnosis grows as globalized human activity accelerates. This technical breakthrough has applications that are relevant to human and animal health, environmental management and conservation.


CHILDHOOD RESPIRATORY MORBIDITY AND COOKING PRACTICES AMONG HOUSEHOLDS IN A PREDOMINANTLY RURAL AREA OF GHANA.
Household air pollution is a leading risk factor for respiratory morbidity and mortality in developing countries where biomass fuel is mainly used for cooking. A household cross-sectional survey was conducted in a predominantly rural area of Ghana in 2007 to determine the prevalence of respiratory symptoms and their associated risk factors. Household cooking practices were also assessed as part of the survey. Household heads of twelve thousand, three hundred and thirty-three households were interviewed. Fifty-seven percent (7006/12333) of these households had at least one child less than five years of age. The prevalence of symptoms of acute lower respiratory infections (ALRI) was 13.7% (n= 957, 95% CI 12.8 - 15.5%). A majority (77.8%, 95% CI, 77.7 - 78.5%) of households used wood as their primary fuel. Majority of respondents who used wood as their primary fuel obtained them by gathering wood from their neighborhood (95.6%, 9177/9595) and used a 3-stone local stove for cooking (94.9%, 9101/9595). In a randomly selected subset of respondents, females were the persons who mostly gathered firewood from the fields (90.8%, 296/326) and did the cooking (94.8%, 384/406) for the household. Symptoms of ALRI reported by caregivers is high in the Kintampo area of Ghana where biomass fuel use is also high. There is the need to initiate interventions that use improved cook stoves and to test the health benefits of such interventions.


Trends in added sugar intake and food sources in a cohort of older Australians: 15 years of follow-up from the Blue Mountains Eye Study.
The trend of added sugar (AS) intake has not been investigated in the Australian population, including in older adults. The present study aimed to assess trends and food sources of AS intake among a cohort of older Australians during 15 years of follow-up. Dietary data from participants of the Blue Mountains Eye Study (1264 men and 1614 women), aged ≥49 years at baseline, were collected. Dietary intakes were assessed at 5-yearly intervals (1992-94 to 2007-09) using a 145-item food frequency questionnaire (FFQ). AS content of FFQ food items was estimated using a stepwise systematic method. Trends for AS intake between baseline and the three follow-up periods were assessed using linear mixed modelling. In men, the mean (SEM) percentage of energy provided by AS intake (EAS%) declined from 10.4% (0.1%) at baseline to 9.4% (0.2%) at 15-year follow-up (Ptrend = 0.028). Women's mean (SEM) EAS% intake at baseline and 15-year follow-up was 9.2% (0.1%) and 8.8% (0.2%), respectively (Ptrend = 0.550). EAS% intake of men was significantly higher than that of women for 10 years (P < 0.05). Sugar products (table sugar, syrup, jam and honey) were the major sources of AS at all-time points and contributed to more than 40% and 35% of AS intake in men and women, respectively. Intake of sugar products decreased in men during follow-up (Ptrend < 0.001). An overall downward trend was observed in AS intake in both genders, however, was only significant for men during 15 years of follow-up. Table sugar and sugar-containing spreads represent the major source of AS in this cohort of older Australians.


The pertussis enigma: reconciling epidemiology, immunology and evolution.
Pertussis, a highly contagious respiratory infection, remains a public health priority despite the availability of vaccines for 70 years. Still a leading cause of mortality in developing countries, pertussis has re-emerged in several developed countries with high vaccination coverage. Resurgence of pertussis in these countries has routinely been attributed to increased awareness of the disease, imperfect vaccinal protection or high infection rates in adults. In this review, we first present 1980-2012 incidence data from 63 countries and show that pertussis resurgence is not universal. We further argue that the large geographical variation in trends probably precludes a simple explanation, such as the transition from whole-cell to acellular pertussis vaccines. Reviewing available evidence, we then propose that prevailing views on pertussis epidemiology are inconsistent with both historical and contemporary data. Indeed, we summarize epidemiological evidence showing that natural infection and vaccination both appear to provide long-term protection against transmission and disease, so that previously infected or vaccinated adults contribute little to overall transmission at a population level. Finally, we identify several promising avenues that may lead to a consistent explanation of global pertussis epidemiology and to more effective control strategies.


Endovascular treatment of proximal and distal posterior inferior cerebellar artery aneurysms.
Surgical clipping of posterior inferior cerebellar artery (PICA) aneurysms can be challenging and carries a potentially significant risk of morbidity and mortality. Experience with endovascular therapy has been limited to a few studies. The authors assess the feasibility, safety, and efficacy of endovascular therapy in the largest series of proximal and distal PICA aneurysms to date. A total of 76 patients, 54 with proximal and 22 with distal PICA aneurysms, underwent endovascular treatment at Jefferson Hospital for Neuroscience between 2001 and 2011. Endovascular treatment was successful in 52 patients (96.3%) with proximal aneurysms and 19 patients (86.4%) with distal aneurysms. Treatment consisted of selective aneurysm coiling in 60 patients (84.5%) (including 4 with stent assistance and 4 with balloon assistance) and parent vessel trapping in 11 patients (15.5%). Specifically, a deconstructive procedure was necessary in 9.6% of proximal aneurysms (5 of 52) and 31.6% of distal aneurysms (6 of 19). There were 9 overall procedural complications (12.7%), 6 infarcts (8.5%; 4 occurring after deliberate occlusion of the PICA), and 3 intraprocedural ruptures (4.2%). The rate of procedure-related permanent morbidity was 2.8%. Complete aneurysm occlusion was achieved in 63.4% of patients (45 of 71). One patient (1.4%) treated with selective aneurysm coiling suffered a rehemorrhage on postoperative Day 15. The mean angiographic follow-up time was 17.2 months. Recurrence and re-treatment rates were, respectively, 20% and 17.1% for proximal aneurysms compared with 30.8% and 23.1% for distal aneurysms. Favorable outcomes (moderate, mild, or no disability) at follow-up were seen in 93% of patients with unruptured aneurysms and in 78.7% of those with ruptured aneurysms. Endovascular therapy is a feasible, safe, and effective treatment in patients with proximal and distal PICA aneurysms, providing excellent patient outcomes and adequate protection against rehemorrhage. The long-term incidence of aneurysm recanalization appears to be high, especially in distal aneurysms, and requires careful angiographic follow-up.


Model of end stage liver disease (MELD) score greater than 23 predicts length of stay in the ICU but not mortality in liver transplant recipients.
The impact of model of end stage liver disease (MELD) score on postoperative morbidity and mortality is still elusive, especially for high MELD. There are reports of poorer patient outcome in transplant candidates with high MELD score, others though report no influence of MELD score on outcome and survival. We retrospectively analyzed data of 144 consecutive liver transplant recipients over a 72-month period in our transplant unit, from January 2003 until December 2008 and performed uni- and multivariate analysis for morbidity and mortality, in particular to define the influence of MELD to these parameters. This study identified MELD score greater than 23 as an independent risk factor of morbidity represented by intensive care unit (ICU) stay longer than 10 days (odds ratio 7.0) but in contrast had no negative impact on mortality. Furthermore, we identified transfusion of more than 7 units of red blood cells as independent risk factor for mortality (hazard ratio 7.6) and for prolonged ICU stay (odds ratio [OR] 7.8) together with transfusion of more than 10 units of fresh frozen plasma (OR 11.6). Postoperative renal failure is a strong predictor of morbidity (OR 7.9) and postoperative renal replacement therapy was highly associated with increased mortality (hazard ratio 6.8), as was hepato renal syndrome prior to transplantation (hazard ratio 13.2). This study identified MELD score greater than 23 as an independent risk factor of morbidity represented by ICU stay longer than 10 days but in contrast had no negative impact on mortality. This finding supports the transplantation of patients with high MELD score but only with knowledge of increased morbidity.


Pre-B cell receptor binding to galectin-1 modifies galectin-1/carbohydrate affinity to modulate specific galectin-1/glycan lattice interactions.
Galectins are glycan-binding proteins involved in various biological processes including cell/cell interactions. During B-cell development, bone marrow stromal cells secreting galectin-1 (GAL1) constitute a specific niche for pre-BII cells. Besides binding glycans, GAL1 is also a pre-B cell receptor (pre-BCR) ligand that induces receptor clustering, the first checkpoint of B-cell differentiation. The GAL1/pre-BCR interaction is the first example of a GAL1/unglycosylated protein interaction in the extracellular compartment. Here we show that GAL1/pre-BCR interaction modifies GAL1/glycan affinity and particularly inhibits binding to LacNAc containing epitopes. GAL1/pre-BCR interaction induces local conformational changes in the GAL1 carbohydrate-binding site generating a reduction in GAL1/glycan affinity. This fine tuning of GAL1/glycan interactions may be a strategic mechanism for allowing pre-BCR clustering and pre-BII cells departure from their niche. Altogether, our data suggest a novel mechanism for a cell to modify the equilibrium of the GAL1/glycan lattice involving GAL1/unglycosylated protein interactions.


Underestimating protection and overestimating risk: examining descriptive normative perceptions and their association with drinking and sexual behaviors.
Individuals who engage in risky sexual behavior face the possibility of experiencing negative consequences. One tenet of social learning theory is that individuals engage in behaviors partly based on observations or perceptions of others' engagement in those behaviors. The present study aimed to document these norms-behavior relationships for both risky and protective sexual behaviors, including alcohol-related sexual behavior. Gender was also examined as a possible moderator of the norms-behavior relationship. Undergraduate students (n = 759; 58.0% female) completed a Web-based survey, including various measures of drinking and sexual behavior. Results indicated that students underestimate sexual health-protective behaviors (e.g., condom use and birth control use) and overestimate the risky behaviors (e.g., frequency of drinking prior to sex, typical number of drinks prior to sex, and frequency of casual sex) of their same-sex peers. All norms were positively associated with behavior, with the exception of condom use. Furthermore, no gender differences were found when examining the relationship between normative perceptions and behavior. The present study adds to the existing literature on normative misperceptions as it indicates that college students overestimate risky sexual behavior while underestimating sexual health-protective behaviors. Implications for interventions using the social norm approach and future directions are discussed.


The Probability of A1C Goal Attainment in Patients With Uncontrolled Type 2 Diabetes in a Large Integrated Delivery System: A Prediction Model.
To assess patient characteristics and treatment factors associated with uncontrolled type 2 diabetes (T2D) and the probability of hemoglobin A1c (A1C) goal attainment. This was a retrospective cohort study using the electronic health record at Cleveland Clinic. Patients with uncontrolled T2D (A1C >9%) were identified on the index date of 31 December 2016 (n = 6,973) and grouped by attainment (n = 1,653 [23.7%]) or nonattainment (n = 5,320 [76.3%]) of A1C <8% by 31 December 2017, and subgroups were compared on a number of demographic and clinical variables. On the basis of these variables, a nomogram was created for predicting probability of A1C goal attainment. For the entire population, median age at index date was 57.7 years (53.3% male), and the majority were white (67.2%). Median A1C was 10.2%. Obesity (50.6%), cardiovascular disease (46.9%), and psychiatric disease (61.1%) were the most common comorbidities. Metformin (62.7%) and sulfonylureas (38.7%) were the most common antidiabetes medications. Only 1,653 (23.7%) patients achieved an A1C <8%. Predictors of increased probability of A1C goal attainment were older age, white/non-Hispanic race/ethnicity, Medicare health insurance, lower baseline A1C, higher frequency of endocrinology/primary care visits, dipeptidyl peptidase 4 inhibitor use, thiazolidinedione use, metformin use, glucagon-like peptide 1 receptor agonist use, and fewer classes of antidiabetes drugs. Factors associated with lower probability included insulin use and longer time in the T2D database (both presumed as likely surrogates for duration of T2D). A minority of patients with an A1C >9% achieved an A1C <8% at 1 year. While most identified predictive factors are nonmodifiable by the clinician, pursuit of frequent patient engagement and tailored drug regimens may help to improve A1C goal attainment.


Graph theory meets ab initio molecular dynamics: atomic structures and transformations at the nanoscale.
Social permutation invariant coordinates are introduced describing the bond network around a given atom. They originate from the largest eigenvalue and the corresponding eigenvector of the contact matrix, are invariant under permutation of identical atoms, and bear a clear signature of an order-disorder transition. Once combined with ab initio metadynamics, these coordinates are shown to be a powerful tool for the discovery of low-energy isomers of molecules and nanoclusters as well as for a blind exploration of isomerization, association, and dissociation reactions.


Polyglutamine disruption of the huntingtin exon 1 N terminus triggers a complex aggregation mechanism.
Simple polyglutamine (polyQ) peptides aggregate in vitro via a nucleated growth pathway directly yielding amyloid-like aggregates. We show here that the 17-amino-acid flanking sequence (HTT(NT)) N-terminal to the polyQ in the toxic huntingtin exon 1 fragment imparts onto this peptide a complex alternative aggregation mechanism. In isolation, the HTT(NT) peptide is a compact coil that resists aggregation. When polyQ is fused to this sequence, it induces in HTT(NT), in a repeat-length dependent fashion, a more extended conformation that greatly enhances its aggregation into globular oligomers with HTT(NT) cores and exposed polyQ. In a second step, a new, amyloid-like aggregate is formed with a core composed of both HTT(NT) and polyQ. The results indicate unprecedented complexity in how primary sequence controls aggregation within a substantially disordered peptide and have implications for the molecular mechanism of Huntington's disease.


Regulatory mechanisms of monofunctional and bifunctional anticarcinogenic enzyme inducers in murine liver.
Anticarcinogenic enzyme inducers are of two types: (a) bifunctional inducers [2,3,7,8-tetrachlorodibenzo-p-dioxin, polycyclic aromatics, azo dyes, beta-naphthoflavone] that elevate both Phase II enzymes [e.g., glutathione S-transferases, UDP-glucuronosyltransferases, and NAD(P)H:(quinone-acceptor) oxidoreductase] and certain Phase I enzymes [e.g., aryl hydrocarbon hydroxylase (AHH)]; and (b) monofunctional inducers [e.g., diphenols, thiocarbamates, 1,2-dithiol-3-thiones, isothiocyanates] that elevate primarily Phase II enzymes without significantly affecting AHH. Since Phase I enzymes such as AHH may activate precarcinogens to ultimate carcinogens whereas Phase II enzyme induction suffices to achieve chemoprotection, an understanding of the molecular mechanisms that regulate these enzymes is critical for devising methods for chemoprotection. We report a systematic analysis of the inductions of aryl hydrocarbon hydroxylase (AHH) and NAD(P)H:quinone reductase (QR) by seven monofunctional and eight bifunctional inducers, singly or in combination, in a murine hepatoma cell line (Hepa 1c1c7) and two mutants defective in either Ah (Aryl hydrocarbon) receptor function (BPrc1) or in AHH expression (c1). We have also examined such inductions in genetically defined mouse strains with high affinity (C57BL/6J) and low affinity (DBA/2J) Ah receptors. The combination of our earlier model for the induction of Phase I and Phase II enzymes (H. J. Prochaska, M. J. De Long, and P. Talalay, Proc. Natl. Acad. Sci. USA, 82: 8232, 1985) with mechanism(s) for autoregulation of AHH (O. Hankinson, R. D. Anderson, B. W. Birren, F. Sander, M. Negishi, and D. W. Nebert, J. Biol. Chem., 260: 1790, 1985) is compatible with our results. Thus, induction of QR by monofunctional inducers does not depend on a competent Ah receptor or AHH activity and appears to involve an electrophilic chemical signal. In contrast, bifunctional inducers require competent Ah receptors to induce both AHH and QR, although the latter process appears to be regulated by more than one mechanism. It is our view that bifunctional inducers bind to the Ah receptor thereby enhancing transcription of genes encoding both AHH and QR. Metabolizable bifunctional inducers are then converted by the induced AHH to products that resemble monofunctional inducers and are capable of generating the aforementioned chemical signal. The existence of mechanism(s) for AHH autoregulation that also affect Phase II enzyme expression would account for the high basal activities of QR in the AHH-defective mutant (c1).


Connection: an exploration of spirituality in nursing care.
This paper aims to explore the meaning of spirituality in relation to nursing care using concept synthesis. Walker and Avant give three ways in which concept synthesis can occur: discovering new dimensions to old concepts, searching for similarities and discrepancies among sets of related concepts, and observing previously undescribed phenomena. It is the first two of these methods which have been used here. The phenomena that emerged from a reading of the literature around spirituality were meaning, presencing, empathy/compassion, giving hope, love, religion/transcendence, touch and healing. These phenomena were studied in order to sort them into fewer categories. They all appeared to be products of a relationship, some physical (presencing, touch and healing), and others emotional (meaning, empathy/compassion, hope, love, and religion/transcendence). Some of the phenomena appeared to fit in both categories, especially healing, which could be of a physical or emotional/spiritual nature. Once the two main categories had been arranged, it was obvious that a split between psyche and soma was not appropriate for labelling the spiritual dimensions of nursing care, as the original definition of spirit was something which motivated the body. Spiritual care is inseparable from physical, social and psychological care because together they form the whole (Bradshaw 1994 p. 282). The two categories were then collapsed into one and given the label 'connection'.


Contribution of sams-1 and pmt-1 to lipid homoeostasis in adult Caenorhabditis elegans.
Accumulation of lipids inside the cell is primarily caused by disorders of lipid metabolism. S-adenosylmethionine synthetase (SAMS) produces SAM, an important methyl donor in various phospholipid methyltransferase reactions catalysed by phosphoethanolamine N-methyltransferase (PMT-1). A gel-based, quantitative proteomic analysis of the RNA interference (RNAi)-mediated inactivation of the pod-2 gene, which encodes acetyl-CoA carboxylase, showed a substantial down-regulation of SAMS-1. Consequently, RNAi of either sams-1 or pmt-1 caused a significant increase in lipid droplet size in the intestine of Caenorhabditis elegans. Lipid droplets exhibited increased triacylglycerol (TG) and decreased phosphatidylcholine (PC) levels, suggesting a reciprocal relationship between TG and PC regulation. These lipid-associated phenotypes were rescued by choline feeding. Among the five fat metabolism-related genes examined, two genes were highly induced by inactivation of sams-1 or pmt-1: pod-2 and stearoyl-CoA desaturase (fat-7). Thus, both SAMS-1 and PMT-1 were shown to contribute to the homoeostasis of TG and PC levels in C. elegans, which would provide an important survival strategy under harsh environmental conditions.


[Preparatory guidelines for local health services on how to respond to new cases of severe acute respiratory syndrome (SARS)].
The Centers for Disease Control and Prevention (CDC) of the United States of America recently issued a set of guidelines on how different community health services should prepare for and respond to the reemergence of severe acute respiratory syndrome (SARS). This document summarizes the recommendations of the CDC for basic health services. Disease surveillance in communities and hospitals should be performed in light of existing information on risk factors, particularly those related to geographic dissemination patterns and to documented transmission of SARS-CoV, the coronavirus that causes SARS. As long as no cases of person-to-person disease transmission are reported anywhere in the world, efforts should be aimed at early detection and notification of cases and of groups of people who are in contact with one another and who have severe respiratory infections of undetermined cause, such as pneumonia, which could signal the reemergence of SARS. If cases of transmission of SARS-CoV have been reported, the aim should be to immediately identify and notify any cases detected in order to take appropriate diagnostic and therapeutic measures and to facilitate outbreak control. The reach of surveillance and reporting activities in specific communities should depend on how widely the disease has spread, both in the community and in local health services. Physicians and public health workers should be familiar with ways to detect SARS cases early, as well as with existing norms for reporting any cases detected.


Novelty-Driven Cooperative Coevolution.
Cooperative coevolutionary algorithms (CCEAs) rely on multiple coevolving populations for the evolution of solutions composed of coadapted components. CCEAs enable, for instance, the evolution of cooperative multiagent systems composed of heterogeneous agents, where each agent is modelled as a component of the solution. Previous works have, however, shown that CCEAs are biased toward stability: the evolutionary process tends to converge prematurely to stable states instead of (near-)optimal solutions. In this study, we show how novelty search can be used to avoid the counterproductive attraction to stable states in coevolution. Novelty search is an evolutionary technique that drives evolution toward behavioural novelty and diversity rather than exclusively pursuing a static objective. We evaluate three novelty-based approaches that rely on, respectively (1) the novelty of the team as a whole, (2) the novelty of the agents' individual behaviour, and (3) the combination of the two. We compare the proposed approaches with traditional fitness-driven cooperative coevolution in three simulated multirobot tasks. Our results show that team-level novelty scoring is the most effective approach, significantly outperforming fitness-driven coevolution at multiple levels. Novelty-driven cooperative coevolution can substantially increase the potential of CCEAs while maintaining a computational complexity that scales well with the number of populations.


Repeated intermittent stress exacerbates myocardial ischemia-reperfusion injury.
Chronic stress in humans has been correlated with increased risk for ischemic heart disease. Thus experiments were conducted to determine if repeated intermittent restraint stress increased infarct size in a rat model of myocardial ischemia-reperfusion injury. Male Sprague-Dawley rats were subjected to no stress (control) or to daily restraint stress for 1-1.5 h for 8-14 days (stress protocol A) or for 2 h daily for 11 or 12 days (stress protocol B). Myocardial ischemia-reperfusion (30-min ischemia, 3-h reperfusion) was performed in anesthetized rats. Average baseline arterial pressures were 111 +/- 4, 120 +/- 10, and 125 +/- 7 mmHg in the control, stress protocol A, and stress protocol B groups, respectively. Infarct size (%area at risk) was significantly larger in both groups of stressed rats compared with control rats (58 +/- 5, 78 +/- 2, and 79 +/- 3% in the control, stress protocol A, and stress protocol B groups, respectively). During ischemia or early reperfusion, zero of eight control, two of six protocol A stress, and two of five protocol B stress rats had at least one period of severe arrhythmia. Therefore, these results provide experimental evidence corroborating correlative studies in humans that link chronic stress with increased morbidity and mortality from ischemic heart disease.


Moral self-concept and moral sensitivity in Iranian nurses.
Nurses are often faced with serious situations that require high levels of legal and ethical knowledge, and should therefore be sensitive to the moral issues in their profession in the decision making process. Some studies have investigated nurses' moral self-concept as an effective factor in moral sensitivity, but there is not sufficient evidence to support this. The purpose of this study was to determine the correlation between moral sensitivity and moral self-concept in nurses employed in the teaching hospitals in Zahedan, Iran. This cross-sectional descriptive study aimed to study the relationship between moral self-concept and moral sensitivity in nurses employed in the teaching hospitals affiliated with Zahedan University of Medical Sciences. Chang's Moral Self-Concept Questionnaire and Lutzen's Moral Sensitivity Questionnaire were used for data collection. Data analysis was performed using SPSS software version 17. A total of 188 nurses participated in this study. The results showed that there was a positive and significant relationship between moral self-concept and moral sensitivity (P < 0.05). Based on our findings, an individual's attention to moral issues can lead to greater sensitivity and result in morally responsible behavior at the time of decision making. Consequently, promotion of moral self-concept through personal effort or education can increase moral sensitivity, which in turn leads to behavioral manifestations of ethical knowledge.


Heart rate and premature atrial contractions at 24hECG independently predict atrial fibrillation in a population-based study.
Low resting heart rate and premature atrial contractions (PACs) predict incident atrial fibrillation (AF) and could be interdependent, since PACs occur in the gaps between normal beats. To study the association between low heart rate at 24hECG, PACs and incident AF in a prospective population-based cohort. In the Malmö Diet and Cancer study, 24hECGs were performed in 377 AF-free subjects. The endpoint was clinical AF retrieved from national hospital (mean follow-up 17 years). The interaction between increased supraventricular activity (SVA) top quartile of either PACs/hour or supraventricular tachycardias/hour) and mean heart rate (mHR) as regards AF risk was assessed in multivariable Cox regression analyses adjusted for age, sex, height, BMI, systolic blood pressure, antihypertensive medication, smoking and homeostasis model assessment of insulin resistance. There were 80 (21%) incident cases of AF. Below median mHR (80 bpm/75 bpm for women/men) was associated with increased AF incidence (HR: 1.89, 95% CI 1.18 to 3.02, p=0.008). There was no correlation between mHR and SVA (p=0.6) or evidence of a multiplicative interaction between these factors for AF risk (p for interaction=0.6) In the group with both increased SVA and below median mHR (17% of the population) the relative risk of AF was very high (HR 4.5, 95% CI 2.2 to 9.1, p=0.001). Low mHR at 24hECG independently predicts AF, but there is no association between mHR and SVA, and these factors are independent as regards AF risk. Subjects with both low mHR and increased SVA have high AF risk.


Real-Life Language Use Across Different Interlocutors: A Naturalistic Observation Study of Adults Varying in Age.
Amid the growing interest in studying language use in real life, this study, for the first time, examined age effects on real-life language use, as well as within-person variations across different interlocutors. We examined speech samples collected via the Electronically Activated Recorder (i.e., portable audio recorder that periodically records ambient sounds) for a larger project. This existing dataset included more than 18,000 sound snippets (50-s long) from 53 American couples (breast cancer patients and their spouses; aged 24 to 94 years) in their natural environments. Sound snippets that included participant speech were coded for different interlocutors and given scores on three linguistic measures that are associated with age-related cognitive changes: usage of unique words, usage of uncommon words, and grammatical complexity. Multilevel models showed that there were no age effects on the three linguistic measures when interlocutors were not taken into account. We found that interlocutors influenced usage of unique words and grammatical complexity. More specifically, compared to talking with their spouse, participants used fewer unique words with children and friends; and used simpler grammatical structures with children, strangers, and in multiparty conversations. Next, we found that interlocutors influenced the associations between age and language use. More specifically, young adults used more unique words and more uncommon words with children than older adults. They used more uncommon words with friends and uttered more complex grammatical structures with strangers than older adults. Our results offer preliminary evidence for a new perspective to understand real-life language use: focusing not only on individual characteristics (i.e., age), but also context (i.e., interlocutors). This perspective should be useful to researchers who are interested in collecting "big data" and understanding cognitive activities in real life.