Salinity Influences Plant-Pest-Predator Tritrophic Interactions.
Climate change-induced salinity intrusion into agricultural soils is known to negatively impact crop production and food security. However, the effects of salinity increase on plant-herbivore-natural enemy systems and repercussions for pest suppression services are largely unknown. Here, we examine the effects of increased salinity on communities of rice (Oryza sativa), brown planthopper (BPH), Nilaparvata lugens, and green mirid bug (GMB), Cyrtorhinus lividipennis, under greenhouse conditions. We found that elevated salinity significantly suppressed the growth of two rice cultivars. Meanwhile, BPH population size also generally decreased due to poor host plant quality induced by elevated salinity. The highest BPH density occurred at 2.0 dS/m salinity and declined thereafter with increasing salinity, irrespective of rice cultivar. The highest population density of GMB also occurred under control conditions and decreased significantly with increasing salinity. Higher salinity directly affected the rice crop by reducing plant quality measured with reference to biomass production and plant height, whereas inducing population developmental asynchrony between BPH and GMB observed at 2 dS/m salinity and potentially uncoupling prey-predator dynamics. Our results suggest that increased salinity has harmful effects on plants, herbivores, natural enemies, as well as plant-pest-predator interactions. The effects measured here suggest that the bottom-up effects of predatory insects on rice pests will likely decline in rice produced in coastal areas where salinity intrusion is common. Our findings indicate that elevated salinity influences tritrophic interactions in rice production landscapes, and further research should address resilient rice insect pest management combining multipests and predators in a changing environment.


Probing Site-Selective Conjugation Chemistries for the Construction of Homogeneous Synthetic Glycodendriproteins.
Methods that site-selectively attach multivalent carbohydrate moieties to proteins can be used to generate homogeneous glycodendriproteins as synthetic functional mimics of glycoproteins. Here, we study aspects of the scope and limitations of some common bioconjugation techniques that can give access to well-defined glycodendriproteins. A diverse reactive platform was designed via use of thiol-Michael-type additions, thiol-ene reactions, and Cu(I)-mediated azide-alkyne cycloadditions from recombinant proteins containing the non-canonical amino acids dehydroalanine, homoallylglycine, homopropargylglycine, and azidohomoalanine.


Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial.
Patients with squamous non-small-cell lung cancer that is refractory to multiple treatments have poor outcomes. We assessed the activity of nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, for patients with advanced, refractory, squamous non-small-cell lung cancer. We did this phase 2, single-arm trial at 27 sites (academic, hospital, and private cancer centres) in France, Germany, Italy, and USA. Patients who had received two or more previous treatments received intravenous nivolumab (3 mg/kg) every 2 weeks until progression or unacceptable toxic effects. The primary endpoint was the proportion of patients with a confirmed objective response as assessed by an independent radiology review committee. We included all treated patients in the analyses. This study is registered with ClinicalTrials.gov, number NCT01721759. Between Nov 16, 2012, and July 22, 2013, we enrolled and treated 117 patients. 17 (14·5%, 95% CI 8·7-22·2) of 117 patients had an objective response as assessed by an independent radiology review committee. Median time to response was 3·3 months (IQR 2·2-4·8), and median duration of response was not reached (95% CI 8·31-not applicable); 13 (77%) of 17 of responses were ongoing at the time of analysis. 30 (26%) of 117 patients had stable disease (median duration 6·0 months, 95% CI 4·7-10·9). 20 (17%) of 117 patients reported grade 3-4 treatment-related adverse events, including: fatigue (five [4%] of 117 patients), pneumonitis (four [3%]), and diarrhoea (three [3%]). There were two treatment-associated deaths caused by pneumonia and ischaemic stroke that occurred in patients with multiple comorbidities in the setting of progressive disease. Nivolumab has clinically meaningful activity and a manageable safety profile in previously treated patients with advanced, refractory, squamous non-small cell lung cancer. These data support the assessment of nivolumab in randomised, controlled, phase 3 studies of first-line and second-line treatment. Bristol-Myers Squibb.


Financial burdens and barriers to care among nonelderly adults: The role of functional limitations and chronic conditions.
People with functional limitations and chronic conditions account for the greatest resource use within the health care system. To examine financial burdens and barriers to care among nonelderly adults, focusing on the role of functional limitations and chronic conditions. High financial burden is defined as medical spending exceeding 20 percent of family income. Financial barriers are defined as delaying care/being unable to get care for financial reasons, and reporting that delaying care/going without was a big problem. Data are from the Medical Expenditure Panel Survey (2008-2012). Functional limitations are associated with increased prevalence of financial burdens. Among single adults, the frequency of high burdens is 20.3% for those with functional limitations, versus 7.8% for those without. Among those with functional limitations, those with 3 or more chronic conditions are twice as likely to have high burdens compared to those without chronic conditions (22.2% versus 11.1%, respectively). Similar patterns occur among persons in multi-person families whose members have functional limitations and chronic conditions. Having functional limitations and chronic conditions is also strongly associated with financial barriers to care: 40.2% among the uninsured, 21.9% among those with public coverage, and 13.6% among those with private group insurance were unable to get care. Functional limitations and chronic conditions are associated with increased prevalence of burdens and financial barriers in all insurance categories, with the exception that an association between functional limitations and the prevalence of burdens was not observed for public coverage.


Distant from input: Evidence of regions within the default mode network supporting perceptually-decoupled and conceptually-guided cognition.
The default mode network supports a variety of mental operations such as semantic processing, episodic memory retrieval, mental time travel and mind-wandering, yet the commonalities between these functions remains unclear. One possibility is that this system supports cognition that is independent of the immediate environment; alternatively or additionally, it might support higher-order conceptual representations that draw together multiple features. We tested these accounts using a novel paradigm that separately manipulated the availability of perceptual information to guide decision-making and the representational complexity of this information. Using task based imaging we established regions that respond when cognition combines both stimulus independence with multi-modal information. These included left and right angular gyri and the left middle temporal gyrus. Although these sites were within the default mode network, they showed a stronger response to demanding memory judgements than to an easier perceptual task, contrary to the view that they support automatic aspects of cognition. In a subsequent analysis, we showed that these regions were located at the extreme end of a macroscale gradient, which describes gradual transitions from sensorimotor to transmodal cortex. This shift in the focus of neural activity towards transmodal, default mode, regions might reflect a process of where the functional distance from specific sensory enables conceptually rich and detailed cognitive states to be generated in the absence of input.


The involvement of suppressor T cells in Ir gene regulation of secondary antibody responses of primed (responder X nonresponder)F1 mice to macrophage-bound L-glutamic acid60-L-alanine30-L-tyrosine.
(Responder [R] X nonresponder [NR])F1 mice give indistinguishable primary in vitro plaque-forming cell (PFC) responses to either R or NR parental macrophages (Mphi) pulsed with the Ir-gene controlled antigen L-glutamic acid60-L-alanine30-L-tyrosine10 (GAT). However, such (R X NR)F1 mice, if primed to GAT, retained in vitro responsiveness to GAT-R-Mphi, but no longer responded to GAT-NR-Mphi. This suggested (a) a possible Mphi-related locus for Ir gene activity in this model, and (b) the occurrence of active suppression after priming with GAT leading to a selective loss of the usual primary responsiveness of (R X NR)F1 mice to GAT-NR-Mphi. This latter interpretation was tested in the current study. [Responder C57BL/6 (H-2b) X nonresponder DBA/1 (H-2q)]F1 mice were primed with 100 microgram GAT in pertussis adjuvant. 4-8 wk later, spleen cells from such mice were tested alone or mixed with normal unprimed F1 spleen cells for PFC responses to GAT-R-Mphi and GAT-NR-Mphi. The primed cells failed to respond to GAT-NR-Mphi, and moreover, actively suppressed the normal response of unprimed F1 cells to GAT-NR-Mphi. If the primed spleen cell donor had been treated with 5 mg/kg cyclophosphamide 3 days before priming or with 5-10 microliter/day of an antiserum to the I-Jb subregion [B10.A(5R) anti B10.A(3R)] during the first 4 days postpriming (both procedures known to inhibit suppressor T-cell activity), cells from such mice responded in secondary culture to both GAT-R-Mphi and also GAT-NR-MPhi. In addition, such spleen cells no longer were capable of suppressing normal F1 cells in response to GAT-NR-Mphi. Similar data were obtained using [CBA (H-2k) X DBA/1 (H-2q)]F1. Further, it was shown that (a) primary responsiveness to GAT-NR-Mphi was not an artifact of in vitro Mphi pulsing, because in vivo GAT-pulsed Mphi showed the same activity and (b) the secondary restriction for Mphi-antigen presentation was controlled by H-2 linked genes. These data suggest an important role for suppressor T cells in H-2 restricted secondary PFC responses, and also provide additional support for the hypothesis that Ir-gene controlled differences in Mphi antigen presentation are related to both suppressor cell generation and overall responsiveness in the GAT model.


Adaptation of Hansenula polymorpha to methanol: a transcriptome analysis.
Methylotrophic yeast species (e.g. Hansenula polymorpha, Pichia pastoris) can grow on methanol as sole source of carbon and energy. These organisms are important cell factories for the production of recombinant proteins, but are also used in fundamental research as model organisms to study peroxisome biology. During exponential growth on glucose, cells of H. polymorpha typically contain a single, small peroxisome that is redundant for growth while on methanol multiple, enlarged peroxisomes are present. These organelles are crucial to support growth on methanol, as they contain key enzymes of methanol metabolism.In this study, changes in the transcriptional profiles during adaptation of H. polymorpha cells from glucose- to methanol-containing media were investigated using DNA-microarray analyses. Two hours after the shift of cells from glucose to methanol nearly 20% (1184 genes) of the approximately 6000 annotated H. polymorpha genes were significantly upregulated with at least a two-fold differential expression. Highest upregulation (> 300-fold) was observed for the genes encoding the transcription factor Mpp1 and formate dehydrogenase, an enzyme of the methanol dissimilation pathway. Upregulated genes also included genes encoding other enzymes of methanol metabolism as well as of peroxisomal beta-oxidation.A moderate increase in transcriptional levels (up to 4-fold) was observed for several PEX genes, which are involved in peroxisome biogenesis. Only PEX11 and PEX32 were higher upregulated. In addition, an increase was observed in expression of the several ATG genes, which encode proteins involved in autophagy and autophagy processes. The strongest upregulation was observed for ATG8 and ATG11.Approximately 20% (1246 genes) of the genes were downregulated. These included glycolytic genes as well as genes involved in transcription and translation. Transcriptional profiling of H. polymorpha cells shifted from glucose to methanol showed the expected downregulation of glycolytic genes together with upregulation of the methanol utilisation pathway. This serves as a confirmation and validation of the array data obtained. Consistent with this, also various PEX genes were upregulated. The strong upregulation of ATG genes is possibly due to induction of autophagy processes related to remodeling of the cell architecture required to support growth on methanol. These processes may also be responsible for the enhanced peroxisomal beta-oxidation, as autophagy leads to recycling of membrane lipids. The prominent downregulation of transcription and translation may be explained by the reduced growth rate on methanol (td glucose 1 h vs td methanol 4.5 h).


Clinical and cost-effectiveness of computerised cognitive behavioural therapy for depression in primary care: design of a randomised trial.
Major depression is a common mental health problem in the general population, associated with a substantial impact on quality of life and societal costs. However, many depressed patients in primary care do not receive the care they need. Reason for this is that pharmacotherapy is only effective in severely depressed patients and psychological treatments in primary care are scarce and costly. A more feasible treatment in primary care might be computerised cognitive behavioural therapy. This can be a self-help computer program based on the principles of cognitive behavioural therapy. Although previous studies suggest that computerised cognitive behavioural therapy is effective, more research is necessary. Therefore, the objective of the current study is to evaluate the (cost-) effectiveness of online computerised cognitive behavioural therapy for depression in primary care. In a randomised trial we will compare (a) computerised cognitive behavioural therapy with (b) treatment as usual by a GP, and (c) computerised cognitive behavioural therapy in combination with usual GP care. Three hundred mild to moderately depressed patients (aged 18-65) will be recruited in the general population by means of a large-scale Internet-based screening (N = 200,000). Patients will be randomly allocated to one of the three treatment groups. Primary outcome measure of the clinical evaluation is the severity of depression. Other outcomes include psychological distress, social functioning, and dysfunctional beliefs. The economic evaluation will be performed from a societal perspective, in which all costs will be related to clinical effectiveness and health-related quality of life. All outcome assessments will take place on the Internet at baseline, two, three, six, nine, and twelve months. Costs are measured on a monthly basis. A time horizon of one year will be used without long-term extrapolation of either costs or quality of life. Although computerised cognitive behavioural therapy is a promising treatment for depression in primary care, more research is needed. The effectiveness of online computerised cognitive behavioural therapy without support remains to be evaluated as well as the effects of computerised cognitive behavioural therapy in combination with usual GP care. Economic evaluation is also needed. Methodological strengths and weaknesses are discussed. The study has been registered at the Netherlands Trial Register, part of the Dutch Cochrane Centre (ISRCTN47481236).


A cross-sectional study of Jamaican adolescents' risk for type 2 diabetes and cardiovascular diseases.
To compare obese versus non-obese Jamaican adolescents' risk for type 2 diabetes (T2D) and cardiovascular diseases (CVDs); and to explore a suitable and economical method of screening for these risk factors in the school settings. A descriptive cross-sectional study of adolescents' risk for T2D and CVD. All the participants were examined at their respective schools. Jamaica, West Indies. 276 Jamaican adolescents aged 14-19 years, randomly selected from grades 9 to 12 from 10 high schools on the island and included both boys and girls. All ethnicities on the island were represented. High fasting blood glucose, total cholesterol, glycated haemoglobin (HbA1c), blood pressure, body mass index (BMI), waist circumference, waist-to-hip ratio, family history of obesity, T2D and CVDs, low physical activity, and presence of Acanthosis Nigricans. All blood measures were analysed using the finger prick procedure. Waist circumference, waist-to-hip ratio, Acanthosis Nigricans, total cholesterol, family history of T2D and blood pressure were the strongest predictors of BMI (p=0.001). Over one-third of the participants were overweight. Jamaican adolescent females had a significantly higher number of risk factors and were less physically active than males (p<0.05). Over 80% of participants reported ≥3 risk factors for T2D and CVD. Participants with BMI ≥25 reported five or more risk factors. One-third of the overweight participants were classified with metabolic syndrome. Jamaican adolescents are at risk of T2D and CVD. Family history of disease and anthropometric measures identified more participants at risk than did the blood measures. Jamaican adolescent females reported more risk factors for T2D and CVD as compared to males. Collection of this type of data was feasible within the school settings. All data were collected in 1 day per school. Intervention measures are needed to educate Jamaican adolescents to reduce overweight and subsequently the risk factors.


Harnessing the power of light to treat staphylococcal infections focusing on MRSA.
Methicillin-resistant Staphylococcus aureus (MRSA) has become the most important drug-resistant microbial pathogen in countries throughout the world. Morbidity and mortality due to MRSA infections continue to increase despite efforts to improve infection control measures and to develop new antibiotics. Therefore alternative antimicrobial strategies that do not give rise to development of resistance are urgently required. A group of therapeutic interventions has been developed in the field of photomedicine with the common theme that they rely on electromagnetic radiation with wavelengths between 200 and 1000 nm broadly called "light". These techniques all use simple absorption of photons by specific chromophores to deliver the killing blow to microbial cells while leaving the surrounding host mammalian cells relatively unharmed. Photodynamic inactivation uses dyes called photosensitizers (PS) that bind specifically to MRSA cells and not host cells, and generate reactive oxygen species including singlet oxygen and singlet oxygen upon illumination. Sophisticated molecular strategies to target the PS to MRSA cells have been designed. Ultraviolet C radiation can damage microbial DNA without unduly harming host DNA. Blue light can excite endogenous porphyrins and flavins in MRSA cells that are not present in host cells. Near-infrared lasers can interfere with microbial membrane potentials without raising the temperature of the tissue. Taken together these innovative approaches towards harnessing the power of light suggest that the ongoing threat of MRSA may eventually be defeated.


Resolvin D1 prevents smoking-induced emphysema and promotes lung tissue regeneration.
Emphysema is an irreversible disease that is characterized by destruction of lung tissue as a result of inflammation caused by smoking. Resolvin D1 (RvD1), derived from docosahexaenoic acid, is a novel lipid that resolves inflammation. The present study tested whether RvD1 prevents smoking-induced emphysema and promotes lung tissue regeneration. C57BL/6 mice, 8 weeks of age, were randomly divided into four groups: control, RvD1 only, smoking only, and smoking with RvD1 administration. Four different protocols were used to induce emphysema and administer RvD1: mice were exposed to smoking for 4 weeks with poly(I:C) or to smoking only for 24 weeks, and RvD1 was injected within the smoking exposure period to prevent regeneration or after completion of smoking exposure to assess regeneration. The mean linear intercept and inflammation scores were measured in the lung tissue, and inflammatory cells and cytokines were measured in the bronchoalveolar lavage fluid. Measurements of mean linear intercept showed that RvD1 significantly attenuated smoking-induced lung destruction in all emphysema models. RvD1 also reduced smoking-induced inflammatory cell infiltration, which causes the structural derangements observed in emphysema. In the 4-week prevention model, RvD1 reduced the smoking-induced increase in eosinophils and interleukin-6 in the bronchoalveolar lavage fluid. In the 24-week prevention model, RvD1 also reduced the increased neutrophils and total cell counts induced by smoking. RvD1 attenuated smoking-induced emphysema in vivo by reducing inflammation and promoting tissue regeneration. This result suggests that RvD1 may be useful in the prevention and treatment of emphysema.


Spectroscopic methodologies and molecular docking studies on the interaction of the soluble guanylate cyclase stimulator riociguat with human serum albumin.
Interaction of riociguat with human serum albumin (HSA) is extremely important in understanding the drug's disposition and efficiency. In the current study, the binding of riociguat to HSA was explored using spectroscopic methods and molecular docking. The quenching constant, the binding constant, the number of binding sites, thermodynamic parameters, and the secondary structure of protein were determined. A fluorescence study revealed that riociguat quenched HSA fluorescence via static quenching with a binding constant of 1.55 × 104 L mol-1 at 298 K. The calculated thermodynamic parameters indicated that the binding process was spontaneous and that the main interaction force was hydrophobic interaction. Site marker competitive binding experiments and molecular docking studies suggested that riociguat was inserted into the subdomain IIA (site I) of HSA. Alterations in the protein secondary structure after drug complexation were predicted. Results indicated that the protein a-helix structure increased with an increasing concentration of riociguat. This indicated that a riociguat-HSA complex was formed and that the protein secondary structure was altered by the addition of riociguat.


Deaths of teenagers in car crashes: a child death review.
MVCs are a leading cause of death and disability for teenagers. In Wales, a child death review process has been established to carry out thematic reviews of deaths; this approach is believed to highlight opportunities for prevention that individual case review could not. Cases were 13-year-old to 17-year-old Welsh residents who died as car drivers or passengers between 1 January 2006 and 31 December 2010. An expert panel was convened to review these cases. 28 MVCs occurred and 34 13-17 year olds died; 24 males, 10 females. 51 vehicles were involved; 23 driven by 17-year-old to 19-year-old males. 19 of the 28 MVCs occurred between 21:00 and 05:00. The risk factors identified were consistent with global research on MVC deaths and injuries to teenagers. However, there is a lack of effective interventions to tackle these in the UK. It is recommended that the implementation of Graduated Driver Licensing is considered.


The Monty Hall problem revisited: Autonomic arousal in an inverted version of the game.
The asymmetry of autonomic arousal for potential losses and gains was assessed by the galvanic skin response (GSR) of participants playing classic and inverted versions of the Monty Hall problem (MHP). In both versions, the prize remained the same (a pen valued at £10 for the right answer), but in the modified version, prizes were received prior to choosing the door. Both experimental groups showed increased levels of GSR while completing the task, demonstrating increased autonomic arousal during the game. However, a robust difference in GSR was detected between classic and inverted versions of the MHP, thus demonstrating the differing autonomic arousal involved in deciding between the alternatives presented by the game. Participants experienced a stronger autonomic response when they could lose the prize than when they could win the prize. This experiment presents the first demonstration of this effect on the MHP. The stronger autonomic arousal for the inverted task may indicate a stronger emotional reaction and/or greater attentional focus than for the standard version of the task. These data demonstrate that potential losses increase arousal in more complex tasks than is typically shown.


GiSAO.db: a database for ageing research.
Age-related gene expression patterns of Homo sapiens as well as of model organisms such as Mus musculus, Saccharomyces cerevisiae, Caenorhabditis elegans and Drosophila melanogaster are a basis for understanding the genetic mechanisms of ageing. For an effective analysis and interpretation of expression profiles it is necessary to store and manage huge amounts of data in an organized way, so that these data can be accessed and processed easily. GiSAO.db (Genes involved in senescence, apoptosis and oxidative stress database) is a web-based database system for storing and retrieving ageing-related experimental data. Expression data of genes and miRNAs, annotation data like gene identifiers and GO terms, orthologs data and data of follow-up experiments are stored in the database. A user-friendly web application provides access to the stored data. KEGG pathways were incorporated and links to external databases augment the information in GiSAO.db. Search functions facilitate retrieval of data which can also be exported for further processing. We have developed a centralized database that is very well suited for the management of data for ageing research. The database can be accessed at https://gisao.genome.tugraz.at and all the stored data can be viewed with a guest account.


Polarization switching and polarization mode hopping in quantum dot vertical-cavity surface-emitting lasers.
We show experimentally that polarization mode hopping in quantum dot vertical cavity surface emitting lasers (VCSELs) takes place between nonorthogonal elliptically polarized modes. In contrast to quantum well VCSELs the average dwell time decreases with injection current. This decrease is by 8 orders of magnitude: from seconds to nanoseconds and is achieved without any modifications of the VCSEL internal anisotropies. The observed scaling happens in a range of currents as wide as 8 times the threshold value.


Egg chemoattractants moderate intraspecific sperm competition.
Interactions among eggs and sperm are often assumed to generate intraspecific variation in reproductive fitness, but the specific gamete-level mechanisms underlying competitive fertilization success remain elusive in most species. Sperm chemotaxis-the attraction of sperm by egg-derived chemicals-is a ubiquitous form of gamete signaling, occurring throughout the animal and plant kingdoms. The chemical cues released by eggs are known to act at the interspecific level (e.g., facilitating species recognition), but recent studies have suggested that they could have roles at the intraspecific level by moderating sperm competition. Here, we exploit the experimental tractability of a broadcast spawning marine invertebrate to test this putative mechanism of gamete-level sexual selection. We use a fluorescently labeled mitochondrial dye in mussels to track the real-time success of sperm as they compete to fertilize eggs, and provide the first direct evidence in any species that competitive fertilization success is moderated by differential sperm chemotaxis. Furthermore, our data are consistent with the idea that egg chemoattractants selectively attract ejaculates from genetically compatible males, based on relationships inferred from both nuclear and mitochondrial genetic markers. These findings for a species that exhibits the ancestral reproductive strategy of broadcast spawning have important implications for the numerous species that also rely on egg chemoattractants to attract sperm, including humans, and have potentially important implications for our understanding of the evolutionary cascade of sexual selection.


Bioactive nanoengineered hydrogels for bone tissue engineering: a growth-factor-free approach.
Despite bone's impressive ability to heal after traumatic injuries and fractures, a significant need still exists for developing strategies to promote healing of nonunion defects. To address this issue, we developed collagen-based hydrogels containing two-dimensional nanosilicates. Nanosilicates are ultrathin nanomaterials with a high degree of anisotropy and functionality that results in enhanced surface interactions with biological entities compared to their respective three-dimensional counterparts. The addition of nanosilicates resulted in a 4-fold increase in compressive modulus along with an increase in pore size compared to collagen-based hydrogels. In vitro evaluation indicated that the nanocomposite hydrogels are capable of promoting osteogenesis in the absence of any osteoinductive factors. A 3-fold increase in alkaline phosphatase activity and a 4-fold increase in the formation of a mineralized matrix were observed with the addition of the nanosilicates to the collagen-based hydrogels. Overall, these results demonstrate the multiple functions of nanosilicates conducive to the regeneration of bone in nonunion defects, including increased network stiffness and porosity, injectability, and enhanced mineralized matrix formation in a growth-factor-free microenvironment.


Review of Neoadjuvant Chemotherapy Alone in Locally Advanced Rectal Cancer.
Currently, the standard management of locally advanced rectal cancer (LARC) is neoadjuvant chemoradiotherapy followed by resection. Despite the significant improvement in local recurrence, survival benefits are not gained due to distant failure and radiotherapy-associated toxicity. Compliance to adjuvant chemotherapy after preoperative chemoradiotherapy is also poor. Neoadjuvant chemotherapy alone followed by surgery may be an alternative. The objective of this review is to determine the efficacy of neoadjuvant chemotherapy alone in operable LARC. Electronic databases searched (from database inception-December 2013) were Medline, PubMed, Embase, Scopus, Cochrane library, and the Clinical Trials Register. Specific journals were also hand searched. The selection criteria were studies published in English investigating stage II-III non-metastatic rectal cancer patients treated with neoadjuvant chemotherapy (oral, intravenous or rectal route) followed by curative resection. The primary outcome measure was tumour response. Secondary outcome measures included acute toxicity, operative morbidity, R0 resection, local recurrence, overall survival (OS) and disease-free survival (DFS). One randomised phase III trial, six single-arm phase II trials and one retrospective case series study were eligible for inclusion. Six studies administered fluoropyrimidine-based multiple agent regimens and two studies administered fluorouracil-based monotherapy. The studies with multiple agents and stronger chemotherapy regimens (intravenous and/or oral) followed by delayed surgery showed better tumour response rates. The overall objective response rate was good and ranged from 62.5 to 93.7 %. Pathological complete response ranged from 3.8 to 33.3 %. The R0 resection and compliance rates were also high ranging from 90 to 100 % and 72 to 100 %, respectively. Grade 3-4 toxicities ranged from 2.3 to 39 %. Four- to 5-year OS and DFS ranged from 67.2 to 91 % and 60.5 to 84 %, respectively. This review demonstrates that neoadjuvant chemotherapy could be affectively administered in LARC and could provide a good alternative to chemoradiotherapy in moderate-risk rectal cancers without compromising short- and long-term outcomes.


Association between BRAF (V600E) mutation and clinicopathological features of papillary thyroid carcinoma: a Brazilian single-centre case series.
We aimed to investigate the prevalence of the BRAF (V600E) mutation in consecutive cases of papillary thyroid carcinoma (PTC) in patients diagnosed and treated at the Hospital Sao Rafael (Salvador, BA, Brazil) and evaluate its association with clinical and pathological characteristics of PTC. We retrospectively enrolled in the study a total of 43 consecutive PTC patients who underwent total thyroidectomy. We performed DNA extraction from formalin-fixed paraffin-embedded (FFPE) tumour tissue samples. Polymerase chain reaction (PCR) and direct sequencing were used to determine BRAF (V600E) mutation status. Univariate and multivariate logistic regression analyses were employed to identify independent associations. The prevalence of BRAF (V600E) mutation was 65.1% (28/43). A high frequency of older patients (p value: 0.004) was observed among the BRAF-mutated PTC group and, in contrast, a low frequency of concurrent Hashimoto's thyroiditis (HT) (p value: 0.011) was noted. Multivariate analysis confirmed that older age (OR: 1.15; 95% CI: 1.00 - 1.33; p value: 0.047) and HT (OR: 0.05; 95% CI: 0.006-0.40; p value: 0.005) were independent factors associated with BRAF (V600E) mutation. We found a high prevalence of BRAF (V600E) mutation in PTC cases. Older age and no concurrent HT were independently associated with BRAF (V600E) mutation.


Outcomes of Surgery in Peyronie's Disease Following Intralesional Collagenase Clostridium Histolyticum Injections.
To explore the potential hurdles surgeons may encounter when preforming surgical correction of penile curvature in patients with Peyronie's Disease following intralesional collagenase clostridium histolyticum injections. Although limited data exists, retrospective analysis of surgeon experiences in surgical treatment of refractory penile curvature in patients with Peyronie's disease appears to not result in more post-operative complications and may only slightly increase intra-operative difficulty. As the use of intralesional collagenase clostridium histolyticum continues to increase and patients who demonstrate persistent curvature despite treatment seek further management, the role of investigating the feasibility of surgery demonstrates significant importance. Although limited data exists, it appears that surgery following intralesional collagenase clostridium histolyticum is safe without added post-operative complications. At the present time, however, further data on intra-operative findings and post-operative outcomes remain necessary, and as the use of this intralesional therapy continues to rise, further information should become readily available.


Elements of integrated care approaches for older people: a review of reviews.
The World Health Organization (WHO) recently proposed an Integrated Care for Older People approach to guide health systems and services in better supporting functional ability of older people. A knowledge gap remains in the key elements of integrated care approaches used in health and social care delivery systems for older populations. The objective of this review was to identify and describe the key elements of integrated care models for elderly people reported in the literature. Review of reviews using a systematic search method. A systematic search was performed in MEDLINE and the Cochrane database in June 2017. Reviews of interventions aimed at care integration at the clinical (micro), organisational/service (meso) or health system (macro) levels for people aged ≥60 years were included. Non-Cochrane reviews published before 2015 were excluded. Reviews were assessed for quality using the Assessment of Multiple Systematic Reviews (AMSTAR) 1 tool. Fifteen reviews (11 systematic reviews, of which six were Cochrane reviews) were included, representing 219 primary studies. Three reviews (20%) included only randomised controlled trials (RCT), while 10 reviews (65%) included both RCTs and non-RCTs. The region where the largest number of primary studies originated was North America (n=89, 47.6%), followed by Europe (n=60, 32.1%) and Oceania (n=31, 16.6%). Eleven (73%) reviews focused on clinical 'micro' and organisational 'meso' care integration strategies. The most commonly reported elements of integrated care models were multidisciplinary teams, comprehensive assessment and case management. Nurses, physiotherapists, general practitioners and social workers were the most commonly reported service providers. Methodological quality was variable (AMSTAR scores: 1-11). Seven (47%) reviews were scored as high quality (AMSTAR score ≥8). Evidence of elements of integrated care for older people focuses particularly on micro clinical care integration processes, while there is a relative lack of information regarding the meso organisational and macro system-level care integration strategies.


Genomic insights into bifidobacteria.
Since the discovery in 1899 of bifidobacteria as numerically dominant microbes in the feces of breast-fed infants, there have been numerous studies addressing their role in modulating gut microflora as well as their other potential health benefits. Because of this, they are frequently incorporated into foods as probiotic cultures. An understanding of their full interactions with intestinal microbes and the host is needed to scientifically validate any health benefits they may afford. Recently, the genome sequences of nine strains representing four species of Bifidobacterium became available. A comparative genome analysis of these genomes reveals a likely efficient capacity to adapt to their habitats, with B. longum subsp. infantis exhibiting more genomic potential to utilize human milk oligosaccharides, consistent with its habitat in the infant gut. Conversely, B. longum subsp. longum exhibits a higher genomic potential for utilization of plant-derived complex carbohydrates and polyols, consistent with its habitat in an adult gut. An intriguing observation is the loss of much of this genome potential when strains are adapted to pure culture environments, as highlighted by the genomes of B. animalis subsp. lactis strains, which exhibit the least potential for a gut habitat and are believed to have evolved from the B. animalis species during adaptation to dairy fermentation environments.


Types of social participation and psychological distress in Japanese older adults: A five-year cohort study.
The most effective type of social participation against psychological distress in older adults is not well documented. The aim of this study was to examine whether different types of social participation are associated with changes in psychological distress level in older men and women in Japan. Two thousand seven hundred community-dwelling older adults (aged 65-74 years, 50% women) were randomly selected from the resident registry of three cities. Of these, participants who reported social participation and psychological distress level in the baseline survey in 2010 were followed up. Psychological distress was evaluated based on K6 scales at baseline and follow-up (in 2015). Social participation level was examined using question items from the National Health and Nutrition Survey in Japan. Exploratory factor analysis was used to derive the underlying factor structure. Multiple linear regression analysis was used to examine the association between social participation and changes in psychological distress level after adjusting for covariates stratified by both gender and age group or living arrangement. Data from 825 community-dwelling older adults (45.3% women) were analyzed. Social participation was categorized into two types using factor analysis: community involvement (volunteer activities, community events, clubs for the elderly) and individual relationship (friendship, communication with family and friends, hobbies). During the 5-year follow-up, 29.5% of participants reported a deterioration in psychological distress. Higher community involvement was independently associated with lower risk of psychological distress for older women (β = 0.099, p = 0.047), whereas there were no associations with individual relationship for either gender. Furthermore, in older women living with others, higher community involvement was also associated with lower risk of psychological distress (β = 0.110, p = 0.048). Community involvement provides older women with mental health benefits regardless of individual relationship level. Promoting community involvement may be an effective strategy for healthy mental aging.


Liquorice and glycyrrhetinic acid increase DHEA and deoxycorticosterone levels in vivo and in vitro by inhibiting adrenal SULT2A1 activity.
The mineralocorticoid effects of liquorice are mediated by the inhibitory effects of one of its active components glycyrrhetinic acid on 11β-hydroxysteroid dehydrogenase type 2. However, liquorice is reputed to have many medicinal properties and also contains a number of other potentially biologically active compounds. Here we have investigated the wider effects of oral liquorice on steroidogenesis focussing particularly on possible inhibitory effects of glycyrrhetinic acid on adrenal sulfotransferase activity. Salivary steroids were profiled by ELISA in groups of normal male and female volunteers after consuming either liquorice-containing or non-liquorice-containing confectionary for one week. Cortisol and cortisone levels reflected expected inhibition of 11β-hydroxysteroid dehydrogenase type 2 by glycyrrhetinic acid. Salivary aldosterone was decreased but deoxycorticosterone, dehydroepiandrosterone and testosterone were increased. To assess whether glycyrrhetinic acid directly affected steroidogenesis, free and conjugated steroids were measured in incubates of adrenocortical H295 cells, firstly, in the presence or absence of forskolin and secondly, with radiolabeled deoxycorticosterone or dehydroepiandrosterone. Glycyrrhetinic acid inhibited cortisone and enhanced cortisol synthesis consistent with 11β-hydroxysteroid dehydrogenase type 2 inhibition. Basal and forskolin-stimulated syntheses of deoxycorticosterone and dehydroepiandrosterone conjugates were also inhibited in a dose-dependent manner; glycyrrhetinic acid inhibited the conjugation of deoxycorticosterone and dehydroepiandrosterone with IC50 values of 7 μM. Inhibition of deoxycorticosterone and dehydroepiandrosterone conjugation was apparent within 4 h of starting glycyrrhetinic acid treatment and was not associated with changes in the expression of SULT 2A1 mRNA. SULT2A1 encodes the enzyme sulfotransferase 2A1 which is responsible for the sulfonation of deoxycorticosterone and dehydroepiandrosterone as well as pregnenolone and 17-hydroxypregnenolone in human adrenal glands. We suggest that the glycyrrhetinic acid constituent of liquorice increases circulating and thereby, salivary levels of unconjugated deoxycorticosterone and dehydroepiandrosterone by inhibiting their conjugation at source within the adrenal cortex. This effect may contribute to the mineralocorticoid actions of glycyrrhetinic acid and gives substance to claims that liquorice also has androgenic properties.


Additive contribution of HLA class I alleles in the immune control of HIV-1 infection.
Previous studies have identified a central role for HLA-B alleles in influencing control of HIV infection. An alternative possibility is that a small number of HLA-B alleles may have a very strong impact on HIV disease outcome, dominating the contribution of other HLA alleles. Here, we find that even following the exclusion of subjects expressing any of the HLA-B class I alleles (B*57, B*58, and B*18) identified to have the strongest influence on control, the dominant impact of HLA-B alleles on virus set point and absolute CD4 count variation remains significant. However, we also find that the influence of HLA on HIV control in this C-clade-infected cohort from South Africa extends beyond HLA-B as HLA-Cw type remains a significant predictor of virus and CD4 count following exclusion of the strongest HLA-B associations. Furthermore, there is evidence of interdependent protective effects of the HLA-Cw*0401-B*8101, HLA-Cw*1203-B*3910, and HLA-A*7401-B*5703 haplotypes that cannot be explained solely by linkage to a protective HLA-B allele. Analysis of individuals expressing both protective and detrimental alleles shows that even the strongest HLA alleles appear to have an additive rather than dominant effect on HIV control at the individual level. Finally, weak but significant frequency-dependent effects in this cohort can be detected only by looking at an individual's combined HLA allele frequencies. Taken together, these data suggest that although individual HLA alleles, particularly HLA-B, can have a strong impact, HIV control overall is likely to be influenced by the additive effect of some or all of the other HLA alleles present.


Superlubricity between MoS2 Monolayers.
The ultralow friction between atomic layers of hexagonal MoS2 , an important solid lubricant and additive of lubricating oil, is thought to be responsible for its excellent lubricating performances. However, the quantitative frictional properties between MoS2 atomic layers have not been directly tested in experiments due to the lack of conventional tools to characterize the frictional properties between 2D atomic layers. Herein, a versatile method for studying the frictional properties between atomic-layered materials is developed by combining the in situ scanning electron microscope technique with a Si nanowire force sensor, and the friction tests on the sliding between atomic-layered materials down to monolayers are reported. The friction tests on the sliding between incommensurate MoS2 monolayers give a friction coefficient of ≈10-4 in the regime of superlubricity. The results provide the first direct experimental evidence for superlubricity between MoS2 atomic layers and open a new route to investigate frictional properties of broad 2D materials.


High-speed terahertz reflection three-dimensional imaging using beam steering.
High-speed terahertz (THz) reflection three-dimensional (3D) imaging is demonstrated using electronically-controlled optical sampling (ECOPS) and beam steering. ECOPS measurement is used for scanning an axial range of 7.8 mm in free space at 1 kHz scan rate while a transverse range of 100 × 100 mm(2) is scanned using beam steering instead of moving an imaging target. Telecentric f-θ lenses with axial and non-axial symmetry have been developed for beam steering. It is experimentally demonstrated that the non-axially symmetric lens has better characteristics than the axially symmetric lens. The total scan time depends on the number of points in a transverse range. For example, it takes 40 s for 200 × 200 points and 10 s for 100 × 100 points. To demonstrate the application of the imaging technique to nondestructive testing, THz 3D tomographic images of a glass fiber reinforced polymer sample with artificial internal defects have been acquired using the lenses for comparison.


Time course of contrast enhancement patterns after Gd-BOPTA in correlation to myocardial infarction and viability: a feasibility study.
Our objective was to analyze contrast enhancement patterns (CEP) and their time course after myocardial infarction (MI) following injection of Gd-BOPTA in correlation with recovery of regional function. Seven patients with subacute MI (18 +/- nine days) were examined before, as well as three and six (n = six) months after, revascularization of the infarct-related artery. Regional wall motion abnormalities were assessed by cine-MRI, and repetitive images of one representative slice were acquired up to 45 minutes after 0.05 mmol/kg Gd-BOPTA using a T1-w TSE-sequence. Two patients showed mid-wall/subendocardial, one patient subendocardial enhancement of MI associated with mechanical improvement after revascularization. Three patients without improvement revealed a mid-wall hypoenhanced zone within the first five minutes after injection, which was unchanged at follow-up. One patient with partial functional improvement showed transmural enhancement and a mid-wall hypoenhanced zone in adjacent areas. With this feasibility study, we concluded that mid-wall and/or subendocardial enhancement after Gd-BOPTA was associated with viable myocardium, whereas detection of microvascular obstruction correlating with scar formation is suggested by mid-wall hypoenhancement within the first five minutes after injection.


Drunk and disorganised: relationships between bar characteristics and customer intoxication in European drinking environments.
Preventing alcohol-related harm in drinking environments is a growing international priority. Factors relating to the physical, social and staffing environments in bars can contribute to increased alcohol consumption and harm. Understanding the relationships between such factors and intoxication in European drinking environments is critical to developing appropriate interventions. We undertook a quantitative observational study in 60 bars in four European cities, in The Netherlands, Slovenia, Spain and the UK (n = 237 observational visits). Using a structured observational schedule, researchers recorded characteristics of the bar environment and rated customer intoxication levels. All physical bar characteristics showed associations with intoxication before interactions between them were controlled for. Hierarchical modelling found significant independent associations between intoxication and use of plastic glassware, promotion of non-alcoholic drinks (often energy drinks), permissive environments, poor washroom facilities, the presence of a dance floor, customer sexual activity/competitiveness and later observational time. Findings suggest that prevention efforts should focus on raising and enforcing managerial standards in bars. While harm reduction measures such as plastic glassware are often promoted for high risk bars, such measures are inadequate to address public health concerns and insufficient to demonstrate social responsibility.


Gender differences in pain levels before and after treatment: a prospective outcomes study on 3,900 Swiss patients with musculoskeletal complaints.
Current studies comparing musculoskeletal pain levels between the genders focus on a single point in time rather than measuring change over time. The purpose of this study is to compare pain levels between males and females before and after treatment. Eleven different patient cohorts (3,900 patients) included in two prospective outcome databases collected pain data at baseline and 1 month after treatment. Treatments were either imaging-guided therapeutic injections or chiropractic therapy. The Mann-Whitney U test was used to calculate differences in numerical rating scale (NRS) median scores between the genders for both time points in all 11 cohorts. Females reported significantly higher baseline pain scores at 4 of the 11 sites evaluated (glenohumeral (p = 0.015), subacromial (p = 0.002), knee (p = 0.023) injections sites and chiropractic low back pain (LBP) patients (p = 0.041)). However, at 1 month after treatment there were no significant gender differences in pain scores at any of the extremity sites. Only the chiropractic LBP patients continued to show higher pain levels in females at 1 month. In these 11 musculoskeletal sites evaluated before and after treatment, only 3 extremity sites and the chiropractic LBP patients showed significantly higher baseline pain levels in females. At 1 month after treatment only the LBP patients had significant gender differences in pain levels. Gender evaluation of change in pain over time is likely to be more clinically important than an isolated pain measurement for certain anatomical sites.


Multidrug resistance protein gene expression in Trichoplusia ni caterpillars.
Many insect species exhibit pesticide-resistant phenotypes. One of the mechanisms capable of contributing to resistance is the overexpression of multidrug resistance (MDR) transporter proteins. Here we describe the cloning of three genes encoding MDR proteins from Trichoplusia ni: trnMDR1, trnMDR2 and trnMDR3. Real-time quantitative PCR (qPCR) detected trnMDR mRNA in the whole nervous system, midgut and Malpighian tubules of final instar T. ni caterpillars. To test whether these genes are upregulated in response to chemical challenge in this insect, qPCR was used to compare trnMDR mRNA levels in unchallenged insects with those of insects fed the synthetic pyrethroid, deltamethrin. Only limited increases were detected in a single gene, trnMDR2, which is the most weakly expressed of the three MDR genes, suggesting that increased multidrug resistance of this type is not a significant part of the response to deltamethrin exposure.


Comparison of the body compositions in obese and nonobese individuals: Can learning body compositions motivate losing weight?
Obesity is one of the leading preventable causes of death worldwide. To compare body compositions in obese and nonobese individuals. This cross-sectional study constituted of 428 individuals. Body compositions were determined using the Tanita. Of all the participants, 300 (70.1%) were female. The prevalence of overweight and obesity was 30.8% and 47.7%, respectively. Having low educational level, female gender, not working, being married, and nonsmoker significantly increased more in obese than nonobese (P < 0.001). Total body water, visceral fat accumulation, body mass index, resting metabolic rate, fat-free mass, bone mass, and muscle mass were significantly higher in obese when compared to those with nonobese (P < 0.001). Thirteen percent of the participants were thinking of changing their diet and lifestyle to lose weight at the beginning. After learning their body compositions, the rate increased to 60% who decided to modify their lifestyle and asked for help to lose weight. This behavior change was significant in especially the overweighted participants (P = 0.025). The changes in body composition are associated with obesity and increased risk for certain cancers, cardiovascular disease, type 2 diabetes mellitus. Learning the health risks can motivate losing weight. Multicentered studies can be illuminating different cultural factors about obesity.


An Exploration of the Impact of Non-Dependent Parental Drinking on Children.
To examine the impact of non-dependent parental drinking on UK children aged 10-17. Cross-sectional survey of UK parents and their children in 2017 (administered to one parent in a household, then their child, totaling 997 adults and 997 children), providing linked data on parental drinking from parent and child perspectives. The survey included measures of parents' alcohol consumption and drinking motivations (both reported by parents) and children's exposure to their parent's drinking patterns and children's experiences of negative outcomes following their parent's drinking (both reported by children), plus sociodemographic measures. Logistic regression analysis indicates a significant positive association between parental consumption level and children reporting experiencing negative outcomes. Witnessing a parent tipsy or drunk and having a parent who reported predominantly negative drinking motives were also associated with increased likelihood of children reporting experiencing negative outcomes. Age was also associated, with older children less likely to report experiencing negative outcomes following their parent's drinking. Findings suggest levels of and motivations for parental drinking, as well as exposure to a parent tipsy or drunk, all influence children's likelihood of experiencing negative outcomes.


Definition of the Minimal Contents for the Molecular Simulation of the Yeast Cytoplasm.
The cytoplasm is a densely packed environment filled with macromolecules with hindered diffusion. Molecular simulation of the diffusion of biomolecules under such macromolecular crowding conditions requires the definition of a simulation cell with a cytoplasmic-like composition. This has been previously done for prokaryote cells (E. coli) but not for eukaryote cells such as yeast as a model organism. Yeast proteomics datasets vary widely in terms of cell growth conditions, the technique used to determine protein composition, the reported relative abundance of proteins, and the units in which abundances are reported. We determined that the gene ontology profiles of the most abundant proteins across these datasets are similar, but their abundances vary greatly. To overcome this problem, we chose five mass spectrometry proteomics datasets that fulfilled the following criteria: high internal consistency, consistency with published experimental data, and freedom from GFP-tagging artifacts. Using these datasets, the contents of a simulation cell containing a single 80S ribosome were defined, such that the macromolecular density and the mass ratio of ribosomal-to-cytoplasmic proteins were consistent with experiment and chosen datasets. Finally, multiple tRNAs were added, consistent with their experimentally-determined number in the yeast cell. The resulting composition can be readily used in molecular simulations representative of yeast cytoplasmic macromolecular crowding conditions to characterize a variety of phenomena, such as protein diffusion, protein-protein interactions and biological processes such as protein translation.


Influence of Substrate in Roll-to-roll Coated Nanographite Electrodes for Metal-free Supercapacitors.
Due to the high electric conductivity and large surface area of nanographites, such as graphene and graphite nanoplatlets, these materials have gained a large interest for use in energy storage devices. However, due to the thin flake geometry, the viscosity of aqueous suspensions containing these materials is high even at low solids contents. This together with the use of high viscosity bio-based binders makes it challenging to coat in a roll-to-roll process with sufficient coating thickness. Electrode materials for commercial energy storage devices are often suspended by organic solvents at high solids contents and coated onto metal foils used as current-collectors. Another interesting approach is to coat the electrode onto the separator, to enable large-scale production of flat cell stacks. Here, we demonstrate an alternative, water-based approach that utilize slot-die coating to coat aqueous nanographite suspension with nanocellulose binder onto the paper separator, and onto the current collector as reference, in aqueous metal-free supercapacitors. The results show that the difference in device equivalent series resistance (ESR) due to interfacial resistance between electrode and current collector was much lower than expected and thus similar or lower compared to other studies with a aqueous supercapacitors. This indicates that electrode coated paper separator substrates could be a promising approach and a possible route for manufacturing of low-cost, environmentally friendly and metal-free energy storage devices.


Novel approaches to lupus drug discovery using stem cell therapy. Role of mesenchymal-stem-cell-secreted factors.
Patients with systemic lupus erythematosus (SLE) are at increased risk for premature death, particularly among young adults, and present dilemmas regarding drug efficacy versus toxicity. Novel therapeutic strategies have included the use of mesenchymal stem cell (MSC) therapies that are promising but still have limitations. In several disease models, it has become apparent that MSCs do not necessarily replace diseased tissues but rather exert complex paracrine effects that are mediated by their extracellular-secreted products. In this review, the authors highlight the data on MSC treatment of SLE and related mechanisms of actions. This data includes the recent evidence that MSC-secreted factors such as extracellular microvesicles (MVs) are important mediators of MSC therapy. Among MVs, the authors delineate the role of exosomes as triggers of regenerative effects in target cells, mediated by transfer of proteins, mRNAs or microRNAs. The authors also outline some of the biological and regulatory restraints encountered by MSC therapy, in contrast to the potential advantages of MSC-derived exosomes as new therapeutic tools in SLE. There is concern about reproducible data on the use of MSC therapy in rheumatic diseases and specifically SLE. Although most experts consider MSCs to be safe, there are still worries over donor variability, immune-mediated rejection, culture-induced senescence, loss of functional properties and genetic instability or eventual malignant transformation. MSC-released factors could avoid most limiting factors associated with cell therapy and are therefore expected to provide a new and safe therapeutic option at an affordable cost.


Reality of Gastric Cancer in Young Patients: The Importance and Difficulty of the Early Diagnosis, Prevention and Treatment.
Gastric cancer usually arises in middle-aged to older patients, and is rarely found in younger patients. The clin-ical characteristics, etiology, prognosis, preventive methods and treatment of gastric cancer in young patients have not been fully investigated because of its low prevalence. In this review, we discuss the current under-standing and clinical problems associated with gastric cancer in young patients. Helicobacter pylori (H. pylori), which is a major cause of gastric cancer, especially in older populations, is closely associated with gastric cancer in young patients as well as in older patients. Gastric cancer in young patients tends to be diagnosed at an advanced stage with alarm symptoms. However, young patients with advanced gastric cancer tend to have a favorable general condition and organ function, so they can tolerate intensive systematic chemotherapy. Unfortunately, the prognosis of gastric cancer in young patients with an advanced stage is not favorable. We should not take this rare disease lightly, given its poor prognosis if patients are diagnosed at an unresectable stage. The evaluation of the H. pylori infection status and performance of H. pylori eradication therapy to prevent gastric cancer in young patients as well as the development of more intensive chemotherapy regimens for unre-sectable gastric cancer in young patients are warranted.


Ultrafast charge separation in a photoreactive rhenium-appended porphyrin assembly monitored by picosecond transient infrared spectroscopy.
Rhenium(bipyridine)(tricarbonyl)(picoline) units have been linked covalently to tetraphenylmetalloporphyrins of magnesium and zinc via an amide bond between the bipyridine and one phenyl substituent of the porphyrin. The resulting complexes, abbreviated as [Re(CO)(3)(Pic)Bpy-MgTPP][OTf] and [Re(CO)(3)(Pic)Bpy-ZnTPP][OTf], exhibit no signs of electronic interaction between the Re(CO)(3)(bpy) units and the metalloporphyrin units in their ground states. However, emission spectroscopy reveals solvent-dependent quenching of porphyrin emission on irradiation into the long-wavelength absorption bands localized on the porphyrin. The characteristics of the excited states have been probed by picosecond time-resolved absorption (TRVIS) spectroscopy and time-resolved infrared (TRIR) spectroscopy in nitrile solvents. The presence of the charge-separated state involving electron transfer from MgTPP or ZnTPP to Re(bpy) is signaled in the TRIR spectra by a low-frequency shift in the nu(CO) bands of the Re(CO)(3) moiety similar to that observed by spectroelectrochemical reduction. Long-wavelength excitation of [Re(CO)(3)(Pic)Bpy-MTPP][OTf] results in characteristic TRVIS spectra of the S(1) state of the porphyrin that decay with a time constant of 17 ps (M = Mg) or 24 ps (M = Zn). The IR bands of the CS state appear on a time scale of less than 1 ps (Mg) or ca. 5 ps (Zn) and decay giving way to a vibrationally excited (i.e., hot) ground state via back electron transfer. The IR bands of the precursors recover with a time constant of 35 ps (Mg) or 55 ps (Zn). The short lifetimes of the charge-transfer states carry implications for the mechanism of reaction in the presence of triethylamine.


Marine phytoplankton temperature versus growth responses from polar to tropical waters--outcome of a scientific community-wide study.
"It takes a village to finish (marine) science these days" Paraphrased from Curtis Huttenhower (the Human Microbiome project) The rapidity and complexity of climate change and its potential effects on ocean biota are challenging how ocean scientists conduct research. One way in which we can begin to better tackle these challenges is to conduct community-wide scientific studies. This study provides physiological datasets fundamental to understanding functional responses of phytoplankton growth rates to temperature. While physiological experiments are not new, our experiments were conducted in many laboratories using agreed upon protocols and 25 strains of eukaryotic and prokaryotic phytoplankton isolated across a wide range of marine environments from polar to tropical, and from nearshore waters to the open ocean. This community-wide approach provides both comprehensive and internally consistent datasets produced over considerably shorter time scales than conventional individual and often uncoordinated lab efforts. Such datasets can be used to parameterise global ocean model projections of environmental change and to provide initial insights into the magnitude of regional biogeographic change in ocean biota in the coming decades. Here, we compare our datasets with a compilation of literature data on phytoplankton growth responses to temperature. A comparison with prior published data suggests that the optimal temperatures of individual species and, to a lesser degree, thermal niches were similar across studies. However, a comparison of the maximum growth rate across studies revealed significant departures between this and previously collected datasets, which may be due to differences in the cultured isolates, temporal changes in the clonal isolates in cultures, and/or differences in culture conditions. Such methodological differences mean that using particular trait measurements from the prior literature might introduce unknown errors and bias into modelling projections. Using our community-wide approach we can reduce such protocol-driven variability in culture studies, and can begin to address more complex issues such as the effect of multiple environmental drivers on ocean biota.


Viral SELEX reveals individual and cooperative roles of the C-box and G-box in HIV-2 replication.
The 5' UTR of HIV-2 genomic RNA contains signaling motifs that regulate specific steps of the replication cycle. Two motifs of interest are the C-box and the G-box. The C-box is found in the 5' untranslated region upstream of the primer binding site, while the G-box is found downstream from the major splice donor site, encompassing the gag start codon and flanking nucleotides. Together the C-box and the G-box form a long-range base-pairing interaction called the CGI. We and others have previously shown that formation of the CGI affects RNA dimerization in vitro and the positions of the C-box and the G-box are suggestive of potential roles of the CGI in other steps of HIV-2 replication. Therefore, we attempted to elucidate the role of the CGI using a viral SELEX approach. We constructed proviral DNA libraries containing randomized regions of the C-box or G-box paired with wild-type or mutant base-pairing partners. These proviral DNA libraries were transfected into COS-7 cells to produce viral libraries that were then used to infect permissive C8166 cells. The "winner" viruses were sequenced and further characterized. Our results demonstrate that there is strong selective pressure favoring viruses that can form a branched CGI. In addition, we show that the mutation of the C-box alone can enhance RNA encapsidation, and mutation of the G-box can alter the levels of Gag protein isoforms. These results suggest coordinated regulation of RNA translation, dimerization, and encapsidation during HIV-2 replication.


Encapsulation of proteins in hydrogel carrier systems for controlled drug delivery: influence of network structure and drug size on release rate.
Novel hydrogels based on hydroxyethyl starch modified with polyethylene glycol methacrylate (HES-P(EG)₆MA) were developed as delivery system for the controlled release of proteins. Since the drug release behavior is supposed to be related to the pore structure of the hydrogel network the pore sizes were determined by cryo-SEM, which is a mild technique for imaging on a nanometer scale. The results showed a decreasing pore size and an increase in pore homogeneity with increasing polymer concentration. Furthermore, the mesh sizes of the hydrogels were calculated based on swelling data. Pore and mesh size were significantly different which indicates that both structures are present in the hydrogel. The resulting structural model was correlated with release data for bulk hydrogel cylinders loaded with FITC-dextran and hydrogel microspheres loaded with FITC-IgG and FITC-dextran of different molecular size. The initial release depended much on the relation between hydrodynamic diameter and pore size while the long term release of the incorporated substances was predominantly controlled by degradation of the network of the much smaller meshes.


High level expression of p27(kip1) and cyclin D1 in some human breast cancer cells: inverse correlation between the expression of p27(kip1) and degree of malignancy in human breast and colorectal cancers.
The expression of cyclin-dependent kinase inhibitor p27(kip1) in human tumors and normal tissues was investigated using a panel of novel anti-p27(kip1) mAbs. An inverse correlation between expression of p27(kip1) and cell proliferation was generally observed after analyzing its expression in 25 different normal human tissues. In some highly proliferative human breast cancer cells, however, high level p27(kip1) expression was seen, indicating the existence of a mechanism by which some growing tumor cells may tolerate this inhibitor of cell cycle progression. Detailed studies demonstrated a correlation between the high level expression of p27(kip1) and cyclin D1 in human breast cancer cells. There was also an inverse correlation between the expression of p27(kip1) and the degree of tumor malignancy in human breast and colorectal cancers, indicating that p27(kip1) may be a useful prognostic marker in these cancers.


Detecting Dynamic Community Structure in Functional Brain Networks Across Individuals: A Multilayer Approach.
We present a unified statistical framework for characterizing community structure of brain functional networks that captures variation across individuals and evolution over time. Existing methods for community detection focus only on single-subject analysis of dynamic networks; while recent extensions to multiple-subjects analysis are limited to static networks. To overcome these limitations, we propose a multi-subject, Markov-switching stochastic block model (MSS-SBM) to identify state-related changes in brain community organization over a group of individuals. We first formulate a multilayer extension of SBM to describe the time-dependent, multi-subject brain networks. We develop a novel procedure for fitting the multilayer SBM that builds on multislice modularity maximization which can uncover a common community partition of all layers (subjects) simultaneously. By augmenting with a dynamic Markov switching process, our proposed method is able to capture a set of distinct, recurring temporal states with respect to inter-community interactions over subjects and the change points between them. Simulation shows accurate community recovery and tracking of dynamic community regimes over multilayer networks by the MSS-SBM. Application to task fMRI reveals meaningful non-assortative brain community motifs, e.g., core-periphery structure at the group level, that are associated with language comprehension and motor functions suggesting their putative role in complex information integration. Our approach detected dynamic reconfiguration of modular connectivity elicited by varying task demands and identified unique profiles of intra and inter-community connectivity across different task conditions. The proposed multilayer network representation provides a principled way of detecting synchronous, dynamic modularity in brain networks across subjects.


Error-free replicative bypass of (6-4) photoproducts by DNA polymerase zeta in mouse and human cells.
The ultraviolet (UV)-induced (6-4) pyrimidine-pyrimidone photoproduct [(6-4) PP] confers a large structural distortion in DNA. Here we examine in human cells the roles of translesion synthesis (TLS) DNA polymerases (Pols) in promoting replication through a (6-4) TT photoproduct carried on a duplex plasmid where bidirectional replication initiates from an origin of replication. We show that TLS contributes to a large fraction of lesion bypass and that it is mostly error-free. We find that, whereas Pol eta and Pol iota provide alternate pathways for mutagenic TLS, surprisingly, Pol zeta functions independently of these Pols and in a predominantly error-free manner. We verify and extend these observations in mouse cells and conclude that, in human cells, TLS during replication can be markedly error-free even opposite a highly distorting DNA lesion.


Phenotype fingerprinting suggests the involvement of single-genotype consortia in degradation of aromatic compounds by Rhodopseudomonas palustris.
Anaerobic degradation of complex organic compounds by microorganisms is crucial for development of innovative biotechnologies for bioethanol production and for efficient degradation of environmental pollutants. In natural environments, the degradation is usually accomplished by syntrophic consortia comprised of different bacterial species. This strategy allows consortium organisms to reduce efforts required for maintenance of the redox homeostasis at each syntrophic level. Cellular mechanisms that maintain the redox homeostasis during the degradation of aromatic compounds by one organism are not fully understood. Here we present a hypothesis that the metabolically versatile phototrophic bacterium Rhodopseudomonas palustris forms its own syntrophic consortia, when it grows anaerobically on p-coumarate or benzoate as a sole carbon source. We have revealed the consortia from large-scale measurements of mRNA and protein expressions under p-coumarate, benzoate and succinate degrading conditions using a novel computational approach referred as phenotype fingerprinting. In this approach, marker genes for known R. palustris phenotypes are employed to determine the relative expression levels of genes and proteins in aromatics versus non-aromatics degrading condition. Subpopulations of the consortia are inferred from the expression of phenotypes and known metabolic modes of the R. palustris growth. We find that p-coumarate degrading conditions may lead to at least three R. palustris subpopulations utilizing p-coumarate, benzoate, and CO2 and H2. Benzoate degrading conditions may also produce at least three subpopulations utilizing benzoate, CO2 and H2, and N2 and formate. Communication among syntrophs and inter-syntrophic dynamics in each consortium are indicated by up-regulation of transporters and genes involved in the curli formation and chemotaxis. The N2-fixing subpopulation in the benzoate degrading consortium has preferential activation of the vanadium nitrogenase over the molybdenum nitrogenase. This subpopulation in the consortium was confirmed in an independent experiment by consumption of dissolved nitrogen gas under the benzoate degrading conditions.


Consensus panel recommendation for incorporating lipoprotein-associated phospholipase A2 testing into cardiovascular disease risk assessment guidelines.
A consensus panel was formed to review the rapidly emerging literature on the vascular-specific inflammatory marker lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) and to update recommendations for the appropriate use of this novel biomarker in clinical practice. The recommendations of the panel build on guidelines of the Adult Treatment Panel III (ATP III) and the American Heart Association/Centers for Disease Control (AHA/CDC) for cardiovascular risk assessment. Consistent with the ATP III guideline recommendations for the use of inflammatory markers, Lp-PLA(2) is recommended as an adjunct to traditional risk assessment in patients at moderate and high 10-year risk. A simplified framework for traditional Framingham risk factor assessment is proposed. As a highly specific biomarker for vascular inflammation, elevated Lp-PLA(2) levels should prompt consideration of increasing the cardiovascular risk category from moderate to high or high to very high risk, respectively. Because intensification of lifestyle changes and low-density lipoprotein (LDL) cholesterol lowering is beneficial in high-risk patients, regardless of baseline LDL cholesterol levels, consideration should be given to lowering the LDL cholesterol target by 30 mg/dL (1 mg/dL = 0.02586 mmol/L) in patients with high levels of Lp-PLA(2). Lp-PLA(2) is recommended as a diagnostic test for vascular inflammation to better identify patients at high or very high risk who will benefit from intensification of lipid-modifying therapies. However, at this time Lp-PLA(2) cannot be recommended as a target of therapy.


Evaluating a Proof-of-Concept Approach of the German Health Telematics Infrastructure in the Context of Discharge Management.
Although national eHealth strategies have existed now for more than a decade in many countries, they have been implemented with varying success. In Germany, the eHealth strategy so far has resulted in a roll out of electronic health cards for all citizens in the statutory health insurance, but in no clinically meaningful IT-applications. The aim of this study was to test the technical and organisation feasibility, usability, and utility of an eDischarge application embedded into a laboratory Health Telematics Infrastructure (TI). The tests embraced the exchange of eDischarge summaries based on the multiprofessional HL7 eNursing Summary standard between a municipal hospital and a nursing home. All in all, 36 transmissions of electronic discharge documents took place. They demonstrated the technical-organisation feasibility and resulted in moderate usability ratings. A comparison between eDischarge and paper-based summaries hinted at higher ratings of utility and information completeness for eDischarges. Despite problems with handling the electronic health card, the proof-of-concept for the first clinically meaningful IT-application in the German Health TI could be regarded as successful.


Cultural transmission of enemy recognition: one function of mobbing.
There are at least ten suggested hypotheses for the function of mobbing predators by fish, birds, and mammals. Experiments with captive European black-birds support one of these-the "cultural transmission hypothesis." Perceiving a mobbing conspecific together with a novel, harmless bird induced blackbirds to mob the innocuous object. The mobbing response persisted during subsequent presentations of the novel bird alone, which was more effectively conditioned than an artificial control object. Enemy recognition could be culturally transmitted along a chain of at least six individuals.


Exploring Health Care Providers' Views About Initiating End-of-Life Care Communication.
Numerous factors impede effective and timely end-of-life (EOL) care communication. These factors include delays in communication until patients are seriously ill and/or close to death. Gaps in patient-provider communication negatively affect advance care planning and limit referrals to palliative and hospice care. Confusion about the roles of various health care providers also limits communication, especially when providers do not coordinate care with other health care providers in various disciplines. Although providers receive education regarding EOL communication and care coordination, little is known about the roles of all health care providers, including nonphysician support staff working with physicians to discuss the possibility of dying and help patients prepare for death. This study explores the perspectives of physicians, nurses, social workers, and chaplains on engaging seriously ill patients and families in EOL care communication. Qualitative data were from 79 (medical and nonmedical) providers practicing at 2 medical centers in Central Los Angeles. Three themes that describe providers' perceptions of their roles and responsibility in talking with seriously ill patients emerged: (1) providers' roles for engaging in EOL discussions, (2) responsibility of physicians for initiating and leading discussions, and (3) need for team co-management patient care. Providers highlighted the importance of beginning discussions early by having physicians lead them, specifically due to their medical training and need to clarify medical information regarding patients' prognosis. Although physicians are a vital part of leading EOL communication, and are at the center of communication of medical information, an interdisciplinary approach that involves nurses, social workers, and chaplains could significantly improve patient care.


Mitochondrial DNA mutations distinguish bilateral multifocal renal oncocytomas from familial Birt-Hogg-Dubé tumors.
Oncocytomas are mostly benign tumors characterized by accumulation of defective mitochondria, and in sporadic cases, are associated with disruptive mitochondrial DNA (mtDNA) mutations. However, the role mtDNA mutations have in renal tumors of Birt-Hogg-Dubé (BHD) patients and other renal oncocytomas with an apparent genetic component has not been investigated to date. Here we characterize the mitochondrial genome in different renal tumors and investigate the possibility of employing mtDNA sequencing analyses of biopsy specimens to aid in the differential diagnosis of oncocytomas. The entire mitochondrial genome was sequenced in 25 samples of bilateral and multifocal (BMF) renal oncocytomas, 30 renal tumors from BHD patients and 36 non-oncocytic renal tumors of different histologies as well as in biopsy samples of kidney tumors. mtDNA sequencing in BMF oncocytomas revealed that all tumors carry disruptive mutations, which impair the assembly of the NADH-ubiquinone oxidoreductase. Multiple tumors from a given BMF oncocytoma patient mainly harbor the same somatic mutation and the kidneys of these patients display diffuse oncocytosis. In contrast, renal oncocytomas of patients with BHD syndrome and renal tumors with different histologies do not show disruptive mtDNA mutations. Moreover, we demonstrate that it is feasible to amplify and sequence the entire mtDNA in biopsy specimens, and that these sequences are representative of the tumor DNA. These results show that pathogenic mtDNA mutations affecting complex I of the respiratory chain are strongly correlated with the oncocytoma phenotype in non-BHD-related renal tumors and that mtDNA sequences from biopsies are predictive of the tumor genotype. This work supports a role for mtDNA mutations in respiratory chain complexes as diagnostic markers for renal oncocytomas.


Evaluation of atopy among mouth-breathing pediatric patients referred for treatment to a tertiary care center.
A mouth breather is someone who uses his/her oral cavity as the main airway during breathing. This is a syndrome with several etiologies, but allergic rhinitis plays a key role due to its high prevalence. The aim of this study was to assess the presence of atopy among mouth-breathing patients referred to a tertiary care center in the metropolitan region of Belo Horizonte, Brazil. Cross-sectional, descriptive study carried out at Hospital das Clínicas of Universidade Federal de Minas Gerais. Patients aged 2 to 12 years, admitted between November 2002 and April 2004, were included. Parents or surrogates completed a comprehensive questionnaire, and patients were submitted to a skin test for inhalant allergens. A total of 140 patients participated in the study. Those with a positive result for at least one allergen were regarded as atopic. The statistical analyses were made using SPSS, with univariate analyses followed by logistic regression. Of 140 patients, 44.3% (62/140) obtained positive results on the allergic test. Mites were the most predominant allergens, with a positive rate of 100% among atopic patients. In the multivariate analysis, atopy was significantly associated with the male sex (p = 0.05), presence of asthma (p = 0.014), lower number of people sleeping in the same room with the patient (p = 0.005), absence of passive smoking (p = 0.005) and absence of sleep apnea (p = 0.003). The high prevalence of positive results on the allergic test highlights the importance of allergologic investigation in mouth-breathers, since allergy has specific treatments that may reduce morbidity in these patients when properly used.


Diagnosis of Gilbert's syndrome: role of reduced caloric intake test.
Reduction in caloric intake to 400 a day for 72 hours resulted in a significant increase in the plasma bilirubin concentration in patients with Gilbert's syndrome and in normal subjects. This was due to an increase in unconjugated pigment. There was no significant increase in the bilirubin concentration in patients with liver disease or haemolytic anaemia.The increase in unconjugated bilirubin was signficantly greater in Gilbert's syndrome than in normals but only when the initial bilirubin concentration was raised. It was usually seen within 24 hours of reducing the caloric intake. An increase of 100% or more suggests that unconjugated hyperbilirubinaemia is due to Gilbert's syndrome. In the normal subjects the unconjugated bilirubin level did not exceed 1.0 mg/100 ml.The increase in unconjugated bilirubin concentration on reducing the caloric intake may be due to decreased hepatic bilirubin uridine diphosphate glucuronyl transferase activity, which was shown to be present in seven rats starved for 72 hours. The effect of a 400 calorie diet for 24 hours on the unconjugated bilirubin level may distinguish Gilbert's syndrome from other causes of unconjugated hyperbilirubinaemia.


In vitro fertilization and multiple pregnancies: an evidence-based analysis.
The objective of this health technology policy assessment was to determine the clinical effectiveness and cost-effectiveness of IVF for infertility treatment, as well as the role of IVF in reducing the rate of multiple pregnancies. TARGET POPULATION AND CONDITION Typically defined as a failure to conceive after a year of regular unprotected intercourse, infertility affects 8% to 16% of reproductive age couples. The condition can be caused by disruptions at various steps of the reproductive process. Major causes of infertility include abnormalities of sperm, tubal obstruction, endometriosis, ovulatory disorder, and idiopathic infertility. Depending on the cause and patient characteristics, management options range from pharmacologic treatment to more advanced techniques referred to as assisted reproductive technologies (ART). ART include IVF and IVF-related procedures such as intra-cytoplasmic sperm injection (ICSI) and, according to some definitions, intra-uterine insemination (IUI), also known as artificial insemination. Almost invariably, an initial step in ART is controlled ovarian stimulation (COS), which leads to a significantly higher rate of multiple pregnancies after ART compared with that following natural conception. Multiple pregnancies are associated with a broad range of negative consequences for both mother and fetuses. Maternal complications include increased risk of pregnancy-induced hypertension, pre-eclampsia, polyhydramnios, gestational diabetes, fetal malpresentation requiring Caesarean section, postpartum haemorrhage, and postpartum depression. Babies from multiple pregnancies are at a significantly higher risk of early death, prematurity, and low birth weight, as well as mental and physical disabilities related to prematurity. Increased maternal and fetal morbidity leads to higher perinatal and neonatal costs of multiple pregnancies, as well as subsequent lifelong costs due to disabilities and an increased need for medical and social support. IVF was first developed as a method to overcome bilateral Fallopian tube obstruction. The procedure includes several steps: (1) the woman's egg is retrieved from the ovaries; (2) exposed to sperm outside the body and fertilized; (3) the embryo(s) is cultured for 3 to 5 days; and (4) is transferred back to the uterus. IFV is considered to be one of the most effective treatments for infertility today. According to data from the Canadian Assisted Reproductive Technology Registry, the average live birth rate after IVF in Canada is around 30%, but there is considerable variation in the age of the mother and primary cause of infertility. An important advantage of IVF is that it allows for the control of the number of embryos transferred. An elective single embryo transfer in IVF cycles adopted in many European countries was shown to significantly reduce the risk of multiple pregnancies while maintaining acceptable birth rates. However, when number of embryos transferred is not limited, the rate of IVF-associated multiple pregnancies is similar to that of other treatments involving ovarian stimulation. The practice of multiple embryo transfer in IVF is often the result of pressures to increase success rates due to the high costs of the procedure. The average rate of multiple pregnancies resulting from IVF in Canada is currently around 30%. An alternative to IVF is IUI. In spite of reported lower success rates of IUI (pregnancy rates per cycle range from 8.7% to 17.1%) it is generally attempted before IVF due to its lower invasiveness and cost. Two major drawbacks of IUI are that it cannot be used in cases of bilateral tubal obstruction and it does not allow much control over the risk of multiple pregnancies compared with IVF. The rate of multiple pregnancies after IUI with COS is estimated to be about 21% to 29%. Ontario Health Insurance Plan Coverage Currently, the Ontario Health Insurance Plan covers the cost of IVF for women with bilaterally blocked Fallopian tubes only, in which case it is funded for 3 cycles, excluding the cost of drugs. The cost of IUI is covered except for preparation of the sperm and drugs used for COS. DIFFUSION OF TECHNOLOGY: According to Canadian Assisted Reproductive Technology Registry data, in 2004 there were 25 infertility clinics across Canada offering IVF and 7,619 IVF cycles performed. In Ontario, there are 13 infertility clinics with about 4,300 IVF cycles performed annually. ROYAL COMMISSION REPORT ON REPRODUCTIVE TECHNOLOGIES: The 1993 release of the Royal Commission report on reproductive technologies, Proceed With Care, resulted in the withdrawal of most IVF funding in Ontario, where prior to 1994 IVF was fully funded. Recommendations of the Commission to withdraw IVF funding were largely based on findings of the systematic review of randomized controlled trials (RCTs) published before 1990. The review showed IVF effectiveness only in cases of bilateral tubal obstruction. As for nontubal causes of infertility, there was not enough evidence to establish whether IVF was effective or not. Since the field of reproductive technology is constantly evolving, there have been several changes since the publication of the Royal Commission report. These changes include: increased success rates of IVF; introduction of ICSI in the early 1990's as a treatment for male factor infertility; and improved embryo implantation rates allowing for the transfer of a single embryo to avoid multiple pregnancies after IVF. STUDIES AFTER THE ROYAL COMMISSION REPORT: REVIEW STRATEGY THREE SEPARATE LITERATURE REVIEWS WERE CONDUCTED IN THE FOLLOWING AREAS: clinical effectiveness of IVF, cost-effectiveness of IVF, and outcomes of single embryo transfer (SET) in IVF cycles. CLINICAL EFFECTIVENESS OF IVF: RCTs or meta-analyses of RCTs that compared live birth rates after IVF versus alternative treatments, where the cause of infertility was clearly stated or it was possible to stratify the outcome by the cause of infertility.COST EFFECTIVENESS OF IVF: All relevant economic studies comparing IVF to alternative methods of treatment were reviewedOUTCOMES OF IVF WITH SET: RCTs or meta-analyses of RCTs that compared live birth rates and multiple birth rates associated with transfer of single versus double embryos.OVID MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, Cochrane Library, the International Agency for Health Technology Assessment database, and websites of other health technology assessment agencies were searched using specific subject headings and keywords to identify relevant studies. COMPARATIVE CLINICAL EFFECTIVENESS OF IVF: Overall, there is a lack of well composed RCTs in this area and considerable diversity in both definition and measurement of outcomes exists between trials. Many studies used fertility or pregnancy rates instead of live birth rates. Moreover, the denominator for rate calculation varied from study to study (e.g. rates were calculated per cycle started, per cycle completed, per couple, etc...). Nevertheless, few studies of sufficient quality were identified and categorized by the cause of infertility and existing alternatives to IVF. The following are the key findings: A 2005 meta-analysis demonstrated that, in patients with idiopathic infertility, IVF was clearly superior to expectant management, but there were no statistically significant differences in live birth rates between IVF and IUI, nor between IVF and gamete-intra-Fallopian transfer.A subset of data from a 2000 study showed no significant differences in pregnancy rates between IVF and IUI for moderate male factor infertility.In patients with moderate male factor infertility, standard IVF was also compared with ICSI in a 2002 meta-analysis. All studies included in the meta-analysis showed superior fertilization rates with ICSI, and the pooled risk ratio for oocyte fertilization was 1.9 (95% Confidence Interval 1.4-2.5) in favour of ICSI. Two other RCTs in this area published after the 2002 meta-analysis had similar results and further confirmed these findings. There were no RCTs comparing IVF with ICSI in patients with severe male factor infertility, mainly because based on the expert opinion, ICSI might only be an effective treatment for severe male factor infertility. COST-EFFECTIVENESS OF IVF: Five economic evaluations of IVF were found, including one comprehensive systematic review of 57 health economic studies. The studies compared cost-effectiveness of IVF with a number of alternatives such as observation, ovarian stimulation, IUI, tubal surgery, varicocelectomy, etc... The cost-effectiveness of IVF was analyzed separately for different types of infertility. Most of the reviewed studies concluded that due to the high cost, IVF has a less favourable cost-effectiveness profile compared with alternative treatment options. Therefore, IVF was not recommended as the first line of treatment in the majority of cases. The only two exceptions were bilateral tubal obstruction and severe male factor infertility, where an immediate offer of IVF/ICSI might the most cost-effective option. CLINICAL OUTCOMES AFTER SINGLE VERSUS DOUBLE EMBRYO TRANSFER STRATEGIES OF IVF: Since the SET strategy has been more widely adopted in Europe, all RCT outcomes of SET were conducted in European countries. The major study in this area was a large 2005 meta-analysis, followed by two other published RCTs. All of these studies reached similar conclusions: Although a single SET cycle results in lower birth rates than a single double embryo transfer (DET) cycle, the cumulative birth rate after 2 cycles of SET (fresh + frozen-thawed embryos) was comparable to the birth rate after a single DET cycle (~40%).SET was associated with a significant reduction in multiple births compared with DET (0.8% vs. 33.1% respectively in the largest RCT). (ABSTRACT TRUNCATED)


Parents are interested in newborn genomic testing during the early postpartum period.
We surveyed parents to ascertain interest in newborn genomic testing and determine whether these queries would provoke refusal of conventional state-mandated newborn screening. After a brief genetics orientation, parents rated their interest in receiving genomic testing for their healthy newborn on a 5-point Likert scale and answered questions about demographics and health history. We used logistic regression to explore factors associated with interest in genomic testing and tracked any subsequent rejection of newborn screening. We queried 514 parents within 48 hours after birth while still in hospital (mean age (SD) 32.7 (6.4) years, 65.2% female, 61.2% white, 79.3% married). Parents reported being not at all (6.4%), a little (10.9%), somewhat (36.6%), very (28.0%), or extremely (18.1%) interested in genomic testing for their newborns. None refused state-mandated newborn screening. Married participants and those with health concerns about their infant were less interested in newborn genomic testing (P = 0.012 and P = 0.030, respectively). Degree of interest for mothers and fathers was discordant (at least two categories different) for 24.4% of couples. Interest in newborn genomic testing was high among parents of healthy newborns, and the majority of couples had similar levels of interest. Surveying parents about genomic sequencing did not prompt rejection of newborn screening.Genet Med 17 6, 501-504.