A randomized study of oral nutritional support versus ad lib nutritional intake during chemotherapy for advanced colorectal and non-small-cell lung cancer.
One hundred ninety-two patients with previously untreated metastatic cancer (102 non-small-cell lung cancer [NSCLC]; 90 colorectal cancer) were randomized to receive either ad lib nutritional intake (control group) or specific nutritional intervention during a 12-week study period when chemotherapy was administered. Those patients randomized to nutritional interventions were counselled to take oral nutrients with caloric intake equal to 1.7 to 1.95 times their basal energy expenditure, depending on their pretreatment nutritional status ("standard" group). An augmented group was counselled to have a caloric intake equivalent to that of the standard group but with 25% of calories provided as protein and additional supplements of zinc and magnesium. Counselling increased caloric intake in both tumor types but reduced weight loss in the short term only for lung cancer patients. Ninety-three NSCLC patients were evaluable for tumor response to vindesine and cisplatin. Overall, only 20.4% of the patients responded, and there were no significant differences in response rates, median time to progression, or overall duration of survival between the nutrition intervention groups and the control group. The tumor response rate to time-sequenced 5-fluorouracil (5-FU) and methotrexate in the 81 evaluable patients with colorectal cancer was only 14.8%, and no significant differences in tumor response rates were noted between the three groups. Furthermore, the median time to progression and overall duration of survival were not different for the control, standard, and augmented groups. Nutritional interventions using dietary counselling had no impact on the percent of planned chemotherapy dose administered, the degree of toxicity experienced by patients, or the frequency of treatment delays. A multivariate prognostic factor analysis demonstrated that for lung cancer, the percent of weight loss, serum albumin concentration, and presence of liver metastases were significant (P less than .05) and independent prognostic variables for survival duration. For colorectal cancer, serum albumin, alkaline phosphatase, lactic dehydrogenase (LDH) levels, and percent targeted caloric intake (TCI) were significant independent predictors of survival duration.


Optimized negative staining: a high-throughput protocol for examining small and asymmetric protein structure by electron microscopy.
Structural determination of proteins is rather challenging for proteins with molecular masses between 40 - 200 kDa. Considering that more than half of natural proteins have a molecular mass between 40 - 200 kDa, a robust and high-throughput method with a nanometer resolution capability is needed. Negative staining (NS) electron microscopy (EM) is an easy, rapid, and qualitative approach which has frequently been used in research laboratories to examine protein structure and protein-protein interactions. Unfortunately, conventional NS protocols often generate structural artifacts on proteins, especially with lipoproteins that usually form presenting rouleaux artifacts. By using images of lipoproteins from cryo-electron microscopy (cryo-EM) as a standard, the key parameters in NS specimen preparation conditions were recently screened and reported as the optimized NS protocol (OpNS), a modified conventional NS protocol. Artifacts like rouleaux can be greatly limited by OpNS, additionally providing high contrast along with reasonably high-resolution (near 1 nm) images of small and asymmetric proteins. These high-resolution and high contrast images are even favorable for an individual protein (a single object, no average) 3D reconstruction, such as a 160 kDa antibody, through the method of electron tomography. Moreover, OpNS can be a high-throughput tool to examine hundreds of samples of small proteins. For example, the previously published mechanism of 53 kDa cholesteryl ester transfer protein (CETP) involved the screening and imaging of hundreds of samples. Considering cryo-EM rarely successfully images proteins less than 200 kDa has yet to publish any study involving screening over one hundred sample conditions, it is fair to call OpNS a high-throughput method for studying small proteins. Hopefully the OpNS protocol presented here can be a useful tool to push the boundaries of EM and accelerate EM studies into small protein structure, dynamics and mechanisms.


Association of Escherichia coli O157:H7 tir polymorphisms with human infection.
Emerging molecular, animal model and epidemiologic evidence suggests that Shiga-toxigenic Escherichia coli O157:H7 (STEC O157) isolates vary in their capacity to cause human infection and disease. The translocated intimin receptor (tir) and intimin (eae) are virulence factors and bacterial receptor-ligand proteins responsible for tight STEC O157 adherence to intestinal epithelial cells. They represent logical genomic targets to investigate the role of sequence variation in STEC O157 pathogenesis and molecular epidemiology. The purposes of this study were (1) to identify tir and eae polymorphisms in diverse STEC O157 isolates derived from clinically ill humans and healthy cattle (the dominant zoonotic reservoir) and (2) to test any observed tir and eae polymorphisms for association with human (vs bovine) isolate source. Five polymorphisms were identified in a 1,627-bp segment of tir. Alleles of two tir polymorphisms, tir 255 T>A and repeat region 1-repeat unit 3 (RR1-RU3, presence or absence) had dissimilar distributions among human and bovine isolates. More than 99% of 108 human isolates possessed the tir 255 T>A T allele and lacked RR1-RU3. In contrast, the tir 255 T>A T allele and RR1-RU3 absence were found in 55% and 57%, respectively, of 77 bovine isolates. Both polymorphisms associated strongly with isolate source (p < 0.0001), but not by pulsed field gel electrophoresis type or by stx1 and stx2 status (as determined by PCR). Two eae polymorphisms were identified in a 2,755-bp segment of 44 human and bovine isolates; 42 isolates had identical eae sequences. The eae polymorphisms did not associate with isolate source. Polymorphisms in tir but not eae predict the propensity of STEC O157 isolates to cause human clinical disease. The over-representation of the tir 255 T>A T allele in human-derived isolates vs the tir 255 T>A A allele suggests that these isolates have a higher propensity to cause disease. The high frequency of bovine isolates with the A allele suggests a possible bovine ecological niche for this STEC O157 subset.


Gene therapy: socioeconomic and ethical issues. A roundtable discussion.
Gene therapy research has the potential to revolutionize the way in which many human diseases are treated. Despite its enormous potential, roundtable panelists concluded that the field needs time to mature scientifically without pressure to develop a marketable therapeutic product. In addition, health care decision makers, physicians, and the lay public need to be educated on the future medical, economic, and ethical ramifications of gene therapy.


Host community structure and the maintenance of pathogen diversity.
Community structure has been widely identified as a feature of many real-world networks. It has been shown that the antigenic diversity of a pathogen population can be significantly affected by the contact network of its hosts; however, the effects of community structure have not yet been explored. Here, we examine the congruence between patterns of antigenic diversity in pathogen populations in neighbouring communities, using both a deterministic metapopulation model and individual-based formulations. We show that the spatial differentiation of the pathogen population can only be maintained at levels of coupling far lower than that necessary for the host populations to remain distinct. Therefore, identifiable community structure in host networks may not reflect differentiation of the processes occurring upon them and, conversely, a lack of genetic differentiation between pathogens from different host communities may not reflect strong mixing between them.


Evaluation of effects of ethyl alcohol and bismuth subsalicylate on gastric mucosal barrier in man.
The mucus-bicarbonate barrier provides the first line of defense against potentially harmful gastric luminal contents. Its integrity can be assessed in man by demonstrating the presence of a pH gradient across the mucus gel layer, from the acidified lumen to near-neutral pH at the mucosa. Our aim was, firstly, to assess the effects of ethyl alcohol and bismuth subsalicylate on the integrity of this lumen-to-mucosal pH gradient and, secondly, to evaluate whether pretreatment with bismuth subsalicylate would protect against any deleterious effects of ethyl alcohol. Ten healthy adults underwent two upper endoscopic procedures with microelectrode measurement of juxtamucosal pH gradients. At the first endoscopy, the effects of 30 ml of bismuth subsalicylate on the gradient was evaluated. At the second endoscopy, gradients were measured before and after luminal installation of 60 ml of ethyl alcohol (40% v/v) and following pretreatment with either 30 ml of bismuth subsalicylate or placebo. pH measurements were technically easy to perform and provided consistently reproducible results. A distinct juxtamucosal pH gradient (pH 4.0 +/- 0.2 units) was identified in all subjects in the basal state. Neither bismuth subsalicylate nor ethyl alcohol had a significant effect on these gradients. We conclude that a distinct pH gradient between gastric luminal fluid and the mucus gel layer can be readily demonstrated in man. Neither bismuth subsalicylate nor ethyl alcohol have a significant effect on this gradient.


The influence of a high dietary intake of purine-rich animal protein on urinary urate excretion and supersaturation in renal stone disease.
1. Eight recurrent renal stone-forming patients were housed in a metabolic ward and fed on a low (LPD) and a high (HPD) animal protein diet, which were isoenergetic. Metabolic studies were made after 2 weeks on each diet. 2. There was a 90% increase in urinary urate on HPD compared with LPD, whereas serum urate did not change consistently. 3. The urinary acid excretion increased by 200%, including a 100% increase in ammonium ion excretion. A fall in urine pH by 0.9 unit was also seen. 4. The calculated ion activities of the urines revealed a profound increase in the uric acid supersaturation, from undersaturation to supersaturation, and in some cases even surpassing the formation product ratio. The ammonium urate supersaturation also increased. The sodium urate supersaturation was unchanged, despite an induced natriuresis. 5. The risk of forming uric acid or ammonium urate crystals or stones in the urine was increased on a high protein diet, whereas the risk of forming sodium urate crystals was no greater than on a low protein diet. 6. As uric acid and ammonium urate crystals under certain conditions may adsorb a macromolecular fraction of the human urine, which inhibits calcium oxalate crystal growth, it is proposed that this mechanism, along with a decrease in urine pH, may also interfere with the inhibitory activity of calcium oxalate crystal growth and aggregation.


Clinical features and risk factors of creatine kinase elevations and myopathy associated with telbivudine.
With the extensive use of telbivudine, more and more studies reported its association with creatine kinase (CK) elevations and myopathy. However, clinical features of these adverse effects were poorly understood. The aim of the present study was to investigate the clinical features and risk factors of CK elevations and myopathy associated with telbivudine. The serum CK levels of 200 patients who were treated with telbivudine for chronic hepatitis B (CHB) between January 2007 and July 2010 were monitored and analysed along with clinical manifestations. The 3-year cumulative incidence of CK elevations and myopathy was 84.3% and 5%, respectively. CK elevations occurred more frequently in men than in women, and patients aged ≤45 years and with negative HBeAg had higher incidence of CK elevations. There was no difference in CK elevations among patients with different HBV DNA levels. Male, younger age and HBeAg negativity were independent predictors of CK elevations by multivariate Cox regression analysis. There was no association between the occurrence of myopathy and variables including age, sex, HBeAg and HBV DNA. No risk factors of myopathy were identified. CK elevations usually occurred 21 months after starting treatment, and most patients resolved spontaneously without interruption of telbivudine therapy except three patients who had to switch to other agents. In conclusion, CK elevations are common adverse reactions associated with telbivudine therapy, while myopathy is rare. Male, younger age and HBeAg negativity might be risk factors of CK elevations.


Impaired receptor-mediated endocytosis: its role in alcohol-induced apoptosis.
Hepatocyte apoptosis, inflammation, and fibrosis are prominent features of liver disease in general and of alcoholic liver injury in particular. Although the link between these processes remains unclear, one universal characteristic of liver injury is the induction of hepatocellular damage, which results in the generation of apoptotic bodies. Work from our laboratory over the last several years has studied the effect of ethanol administration on the process of apoptosis and a role for altered endocytosis in alcoholic apoptosis. We initially focused our research on the hepatocyte by examining endocytosis using the asialoglycoprotein receptor (ASGP-R) pathway as a model and we identified multiple ethanol-induced impairments in receptor function. We also showed that uptake of apoptotic bodies is impaired in hepatocytes isolated from ethanol-fed animals compared to controls, and that this impairment is linked to altered ASGP-R function. Recent work from our laboratory is examining a link between ethanol-impaired ASGP-R function, apoptotic body accumulation, and inflammation in the liver. We are particularly interested in data showing that factors produced by Kupffer cells incubated with apoptotic bodies can lead to production of tumor necrosis factor-alpha and interleukin-6, and that this effect is exacerbated in the setting of alcohol administration. In addition, we have preliminary data showing that media from Kupffer cell cultures incubated with apoptotic bodies can induce hepatocyte killing. The goal of our future work is to show that inadequate removal of apoptotic cells, in part via altered receptor-mediated endocytosis, plays a role in the course of pathogenesis of alcoholic liver injury.


Implementing international sexual counselling guidelines in hospital cardiac rehabilitation: development of the CHARMS intervention using the Behaviour Change Wheel.
Decreased sexual activity and sexual problems are common among people with cardiovascular disease, negatively impacting relationship satisfaction and quality of life. International guidelines recommend routine delivery of sexual counselling to cardiac patients. The Cardiac Health and Relationship Management and Sexuality (CHARMS) baseline study in Ireland found, similar to international findings, limited implementation of sexual counselling guidelines in practice. The aim of the current study was to develop the CHARMS multi-level intervention to increase delivery of sexual counselling by healthcare professionals. We describe the methods used to develop the CHARMS intervention following the three phases of the Behaviour Change Wheel approach: understand the behaviour, identify intervention options, and identify content and implementation options. Survey (n = 60) and focus group (n = 14) data from two previous studies exploring why sexual counselling is not currently being delivered were coded by two members of the research team to understand staff's capability, opportunity, and motivation to engage in the behaviour. All potentially relevant intervention functions to change behaviour were identified and the APEASE (affordability, practicability, effectiveness, acceptability, side effects and equity) criteria were used to select the most appropriate. The APEASE criteria were then used to choose between all behaviour change techniques (BCTs) potentially relevant to the identified functions, and these BCTs were translated into intervention content. The Template for Intervention Description and Replication (TIDieR) checklist was used to specify details of the intervention including the who, what, how and where of proposed intervention delivery. Providing sexual counselling group sessions by cardiac rehabilitation staff to patients during phase III cardiac rehabilitation was identified as the target behaviour. Education, enablement, modelling, persuasion and training were selected as appropriate intervention functions. Twelve BCTs, linked to intervention functions, were identified for inclusion and translated into CHARMS intervention content. This paper details the use of Behaviour Change Wheel approach to develop an implementation intervention in an under-researched area of healthcare provision. The systematic and transparent development of the CHARMS intervention will facilitate the evaluation of intervention effectiveness and future replication and contribute to the advancement of a cumulative science of implementation intervention design.


Application of new acute kidney injury biomarkers in human randomized controlled trials.
The use of novel biomarkers of acute kidney injury (AKI) in clinical trials may help evaluate treatments for AKI. Here we explore potential applications of biomarkers in simulated clinical trials of AKI using data from the TRIBE-AKI multicenter, prospective cohort study of patients undergoing cardiac surgery. First, in a hypothetical trial of an effective therapy at the time of acute tubular necrosis to prevent kidney injury progression, use of an indirect kidney injury marker such as creatinine compared to a new direct biomarker of kidney injury reduces the proportion of true acute tubular necrosis cases enrolled. The result is a lower observed relative risk reduction with the therapy, and lower statistical power to detect a therapy effect at a given sample size. Second, the addition of AKI biomarkers (interleukin-18 and NGAL) to clinical risk factors as eligibility criteria for trial enrollment in early AKI has the potential to increase the proportion of patients who will experience AKI progression and reduce trial cost. Third, we examine AKI biomarkers as outcome measures for the purposes of identifying therapies that warrant further testing in larger, multicenter, multi-country trials. In the hypothetical trial of lower cardiopulmonary bypass time to reduce the risk of postoperative AKI, the sample size required to detect a reduction in AKI is lower if new biomarkers are used to define AKI rather than serum creatinine. Thus, incorporation of new biomarkers of AKI has the potential to increase statistical power, decrease the sample size, and lower the cost of AKI trials.


Intradialytic Cardiac Magnetic Resonance Imaging to Assess Cardiovascular Responses in a Short-Term Trial of Hemodiafiltration and Hemodialysis.
Hemodynamic stress during hemodialysis (HD) results in recurrent segmental ischemic injury (myocardial stunning) that drives cumulative cardiac damage. We performed a fully comprehensive study of the cardiovascular effect of dialysis sessions using intradialytic cardiac magnetic resonance imaging (MRI) to examine the comparative acute effects of standard HD versus hemodiafiltration (HDF) in stable patients. We randomly allocated 12 patients on HD (ages 32-72 years old) to either HD or HDF. Patients were stabilized on a modality for 2 weeks before undergoing serial cardiac MRI assessment during dialysis. Patients then crossed over to the other modality and were rescanned after 2 weeks. Cardiac MRI measurements included cardiac index, stroke volume index, global and regional contractile function (myocardial strain), coronary artery flow, and myocardial perfusion. Patients had mean±SEM ultrafiltration rates of 3.8±2.9 ml/kg per hour during HD and 4.4±2.5 ml/kg per hour during HDF (P=0.29), and both modalities provided a similar degree of cooling. All measures of systolic contractile function fell during HD and HDF, with partial recovery after dialysis. All patients experienced some degree of segmental left ventricular dysfunction, with severity proportional to ultrafiltration rate and BP reduction. Myocardial perfusion decreased significantly during HD and HDF. Treatment modality did not influence any of the cardiovascular responses to dialysis. In conclusion, in this randomized, crossover study, there was no significant difference in the cardiovascular response to HDF or HD with cooled dialysate as assessed with intradialytic MRI.


Pseudogenization of the tooth gene enamelysin (MMP20) in the common ancestor of extant baleen whales.
Whales in the suborder Mysticeti are filter feeders that use baleen to sift zooplankton and small fish from ocean waters. Adult mysticetes lack teeth, although tooth buds are present in foetal stages. Cladistic analyses suggest that functional teeth were lost in the common ancestor of crown-group Mysticeti. DNA sequences for the tooth-specific genes, ameloblastin (AMBN), enamelin (ENAM) and amelogenin (AMEL), have frameshift mutations and/or stop codons in this taxon, but none of these molecular cavities are shared by all extant mysticetes. Here, we provide the first evidence for pseudogenization of a tooth gene, enamelysin (MMP20), in the common ancestor of living baleen whales. Specifically, pseudogenization resulted from the insertion of a CHR-2 SINE retroposon in exon 2 of MMP20. Genomic and palaeontological data now provide congruent support for the loss of enamel-capped teeth on the common ancestral branch of crown-group mysticetes. The new data for MMP20 also document a polymorphic stop codon in exon 2 of the pygmy sperm whale (Kogia breviceps), which has enamel-less teeth. These results, in conjunction with the evidence for pseudogenization of MMP20 in Hoffmann's two-toed sloth (Choloepus hoffmanni), another enamel-less species, support the hypothesis that the only unique, non-overlapping function of the MMP20 gene is in enamel formation.


Residual interfragmentary gap after intramedullary nailing of fragility fractures of the humeral diaphysis: short and midterm term results.
The purpose of this retrospective study was to evaluate the short and midterm radiological outcome with regards to bone healing, correlated with humeral shaft fractures treated with anterograde intramedullary nailing, when interfragmentary gap was significant. Here, we critically review our experience of short and midterm term results in over 65 year-old patients. Inclusion criteria in the study were: (1) patients over 65 years old (2) patients with displaced humeral mid shaft fractures (AO/OTA 12 A B C type fractures); (3) patients treated with closed reduction and internal fixation with intramedullary nail (Trigen Humeral Nail® Smith and Nephew) with at least two screws for proximal locking and one screw for distal locking; (4) residual interfragmentary gap, being considered significant any gap >6 mm (being 7 mm the minimum nail diameter available in our facility). Various factors were considered in our analysis: the size of the interfragmentary gap in both projections (also the mean of the measured gaps was calculated), the relationship between the greater and the mean interfragmentary gap and the second diameter measurement of the nail in the half distal part, the number of the screws in distal locking procedure, the use of a reaming procedure or not, the AO classification, the actual age at the time of surgery, the operating time, the nail second diameter as described before and its ratio with the measured residual gap. At 3 months follow-up, 4 patients showed radiographic healing (26,67%), 9 patients showed a visible callus (60%), with a total of 13 patients (86,67%) showing signs of normal recovery, the remaining 2 patient had insufficient callus formation (13,3%). At 6 months follow-up, 1 patient was missing (6,67%), although radiographic healing was already evident during the previous follow-up check, another one showed incomplete callus formation, the remaining 13 patients showed radiographic healing (86,67%), with a total of 14 patient considered healed at 6 months follow-up (93,33%). In conclusion, osteosynthesis with anterograde nail in geriatric patients appears to be a quite safe approach despite a great interfragmentary gap. After 6 months of treatment, callus formation and the overall clinical outcome were proven to be above satisfaction. (www.actabiomedica.it).


Third chronological supplement to the carcinogenic potency database: standardized results of animal bioassays published through December 1986 and by the National Toxicology Program through June 1987.
This paper is the third chronological supplement to the Carcinogenic Potency Database that first appeared in this journal in 1984. We report here results of carcinogenesis bioassays published in the general literature between January 1985 and December 1986, and in Technical Reports of the National Toxicology Program between June 1986 and June 1987. This supplement includes results of 337 long-term, chronic experiments of 121 compounds, and reports the same information about each experiment in the same plot format as the earlier papers, e.g., the species and strain of animal, the route and duration of compound administration, dose level, and other aspects of experimental protocol, histopathology, and tumor incidence, TD50 (carcinogenic potency) and its statistical significance, dose response, opinion of the author about carcinogenicity, and literature citation. The reader needs to refer to the 1984 publication for a guide to the plot of the database, a complete description of the numerical index of carcinogenic potency, and a discussion of the sources of data, the rationale for the inclusion of particular experiments and particular target sites, and the conventions adopted in summarizing the literature. The four plots of the database are to be used together as results published earlier are not repeated. In all, the four plots include results for approximately 4000 experiments on 1050 chemicals. Appendix 14 of this paper is an alphabetical index to all chemicals in the database and indicates which plot(s) each chemical appears in. A combined plot of all results from the four separate papers, that is ordered alphabetically by chemical, is available from the first author, in printed form or on computer tape or diskette.


Inferring stratified parasitoid dispersal mechanisms and parameters from coarse data using mathematical and Bayesian methods.
Biological invasions have movement at the core of their success. However, due to difficulties in collecting data, medium- and long-distance dispersal of small insects has long been poorly understood and likely to be underestimated. The agricultural release of parasitic hymenoptera, a group of wasps that are critical for biological pest control, represents a rare opportunity to study the spread of insects on multiple spatial scales. As these insects are typically less than 1 mm in size and are challenging to track individually, a first-time biocontrol release will provide a known spatial position and time of initial release for all individuals that are subsequently collected. In this paper, we develop and validate a new mathematical model for parasitoid wasp dispersal from point release, as in the case of biocontrol. The model is derived from underlying stochastic processes but is fully deterministic and admits an analytical solution. Using a Bayesian framework, we then fit the model to an Australian dataset describing the multi-scale wind-borne dispersal pattern of Eretmocerus hayati Zolnerowich & Rose (Hymenoptera: Aphelinidae). Our results confirm that both local movements and long-distance wind dispersal are significant to the movement of parasitoids. The model results also suggest that low velocity winds are the primary indicator of dispersal direction on the field scale shortly after release, and that average wind data may be insufficient to resolve long-distance movement given inherent nonlinearities and heterogeneities in atmospheric flows. The results highlight the importance of collecting wind data when developing models to predict the spread of parasitoids and other tiny organisms.


Murine models of premature ageing for the study of diet-induced immune changes: improvement of leucocyte functions in two strains of old prematurely ageing mice by dietary supplementation with sulphur-containing antioxidants.
Several immune functions are markers of health, biological age and predictors of longevity. A chronic oxidative and inflammatory state is the main cause of ageing and the immune system is involved in the rate of ageing. Thus, several murine models of premature ageing have been proposed owing to their early immunosenescence and oxidative stress, such as ovariectomised rats and mice, obese rats and anxious mice. In the last model, the most extensively studied by us, mice showing anxiety have an aged immune function and redox status as well as a shorter longevity in comparison with animals without anxiety of the same chronological age, being denominated prematurely ageing mice. A confirmation of the above is that the administration of diets supplemented with antioxidants improves the redox status and immune functions and increases the longevity of prematurely ageing mice. Antioxidant precursors of glutathione such as thioproline or N-acetylcysteine, which have a relevant role in ageing, have been the most widely investigated in adult prematurely ageing mice in our laboratory. In the present work, we have studied the effects of the ingestion for 5 weeks of a diet supplemented with 0·1% (w/w) thioproline+N-acetylcysteine on several functions of leucocytes from chronological old (69-73 weeks of age) prematurely ageing mice of two strains (Swiss and BALB/c). The results show an improvement of the immune functions, with their values becoming closer to those in adult animals (24±2 weeks). Thus, an adequate nutrition with antioxidants, even in aged subjects, could be a good strategy to retard ageing.


Diagnosis of liver fibrosis by transient elastography (FibroScan) and non-invasive methods in Crohn's disease patients treated with methotrexate.
Methotrexate is an effective treatment in Crohn's disease, which may induce liver fibrosis with high cumulative doses. Transient elastography (FibroScan, Echosens, Paris, France) is a new non-invasive rapid, allowing assessment of liver fibrosis by measurement of liver stiffness. A prospective study to evaluate liver fibrosis with FibroScan and non-invasive biochemical methods in Crohn's disease patients treated with methotrexate. Consecutive Crohn's disease patients had evaluation of liver fibrosis with non-invasive methods. Two subgroups of patients were compared: cumulative dose of methotrexate of more than 1500 mg (group 1) and naive for methotrexate (group 2). Liver biopsy was performed in patients with persistent liver enzyme abnormalities or FibroScan value >8.7 kPa. Fifty-four consecutive Crohn's disease patients were fully investigated (45 females, mean age 41 +/- 14 years). Median FibroScan values were similar in group 1 (n = 21) and in group 2 (n = 33), 5.5 and 4.5 kPa, respectively. FibroScan values were not correlated with the cumulative dose of methotrexate. In Crohn's disease patients treated with a high dose of methotrexate, significant liver fibrosis is rare and not accurately detected with liver enzymes abnormalities. FibroScan could be recommended and liver biopsy could be performed only with patients with high values and/or with chronic liver enzymes abnormalities.


A deficiency in the region homologous to human 17q21.33-q23.2 causes heart defects in mice.
Several constitutional chromosomal rearrangements occur on human chromosome 17. Patients who carry constitutional deletions of 17q21.3-q24 exhibit distinct phenotypic features. Within the deletion interval, there is a genomic segment that is bounded by the myeloperoxidase and homeobox B1 genes. This genomic segment is syntenically conserved on mouse chromosome 11 and is bounded by the mouse homologs of the same genes (Mpo and HoxB1). To attain functional information about this syntenic segment in mice, we have generated a 6.9-Mb deletion [Df(11)18], the reciprocal duplication [Dp(11)18] between Mpo and Chad (the chondroadherin gene), and a 1.8-Mb deletion between Chad and HoxB1. Phenotypic analyses of the mutant mouse lines showed that the Dp(11)18/Dp(11)18 genotype was responsible for embryonic or adolescent lethality, whereas the Df(11)18/+ genotype was responsible for heart defects. The cardiovascular phenotype of the Df(11)18/+ fetuses was similar to those of patients who carried the deletions of 17q21.3-q24. Since heart defects were not detectable in Df(11)18/Dp(11)18 mice, the haplo-insufficiency of one or more genes located between Mpo and Chad may be responsible for the abnormal cardiovascular phenotype. Therefore, we have identified a new dosage-sensitive genomic region that may be critical for normal heart development in both mice and humans.


Risk of cancer in relation to serum concentrations of selenium and vitamins A and E: matched case-control analysis of prospective data.
The independent and joint associations of serum selenium and vitamin A (retinol) and E (alpha tocopherol) concentrations with the risk of death from cancer were studied in 51 case-control pairs--that is, 51 patients with cancer, each paired with a control matched for age, sex, and smoking. Case-control pairs came from a random sample of some 12000 people aged 30-64 years resident in two provinces of eastern Finland who were followed up for four years. Patients who died of cancer during the follow up period had a 12% lower mean serum selenium concentration (p = 0.015) than the controls. The difference persisted when deaths from cancer in the first follow up year were excluded. The adjusted risk of fatal cancer was 5.8-fold (95% confidence interval 1.2-29.0) among subjects in the lowest tertile of selenium concentrations compared with those with higher values. Subjects with both low selenium and low alpha tocopherol concentrations in serum had an 11.4-fold adjusted risk. Among smoking men with cancer serum retinol concentrations were 26% lower than in smoking controls (p = 0.002). These data suggest that dietary selenium deficiency is associated with an increased risk of fatal cancer, that low vitamin E intake may enhance this effect, and that decreased vitamin or provitamin A intake contributes to the risk of lung cancer among smoking men with a low selenium intake.


Dairy product consumption and risk of type 2 diabetes in an elderly Spanish Mediterranean population at high cardiovascular risk.
The possible effects of dairy consumption on diabetes prevention remain controversial. The aim of this study was to investigate the association between the dairy consumption and type 2 diabetes (T2D) risk in an elderly Mediterranean population at high cardiovascular risk. We prospectively followed 3,454 non-diabetic individuals from the PREDIMED study. Dairy consumption was assessed at baseline and yearly using food frequency questionnaires and categorized into total, low-fat, whole-fat, and subgroups: milk, yogurt, cheeses, fermented dairy, concentrated full fat, and processed dairy. Hazard ratios (HRs) were calculated using Cox proportional hazards regression models. During a median follow-up of 4.1 years, we documented 270 incident T2D cases. After multivariate adjustment, total dairy product consumption was inversely associated with T2D risk [0.68 (95% CI 0.47-0.98); P-trend = .040]. This association appeared to be mainly attributed to low-fat dairy; the multivariate HRs (95% CIs) comparing the highest versus the lowest tertile consumption were 0.65 (0.45-0.94) for low-fat dairy products and 0.67 (0.46-0.95) for low-fat milk (both P-trend <.05). Total yogurt consumption was associated with a lower T2D risk [HR 0.60 (0.42-0.86); P-trend = .002]. An increased consumption of total low-fat dairy and total yogurt during the follow-up was inversely associated with T2D; HRs were 0.50 (0.29-0.85), 0.44 (0.26-0.75), and 0.55 (0.33-0.93), respectively. Substituting one serving/day of a combination of biscuits and chocolate and whole grain biscuits and homemade pastries for one serving/day of yogurt was associated with a 40 and 45% lower risk of T2D, respectively. No significant associations were found for the other dairy subgroups (cheese, concentrated full fat, and processed dairy products). A healthy dietary pattern incorporating a high consumption of dairy products and particularly yogurt may be protective against T2D in older adults at high cardiovascular risk.


Functional evolution of bacterial histone-like HU proteins.
Bacterial histone-like HU proteins are critical to maintenance of the nucleoid structure. In addition, they participate in all DNA-dependent functions, including replication, repair, recombination and gene regulation. In these capacities, their function is typically architectural, inducing a specific DNA topology that promotes assembly of higher-order nucleo-protein structures. Although HU proteins are highly conserved, individual homologs have been shown to exhibit a wide range of different DNA binding specificities and affinities. The existence of such distinct specificities indicates functional evolution and predicts distinct in vivo roles. Emerging evidence suggests that HU proteins discriminate between DNA target sites based on intrinsic flexure, and that two primary features of protein binding contribute to target site selection: The extent to which protein-mediated DNA kinks are stabilized and a network of surface salt-bridges that modulate interaction between DNA flanking the kinks and the body of the protein. These features confer target site selection for a specific HU homolog, they suggest the ability of HU to induce different DNA structural deformations depending on substrate, and they explain the distinct binding properties characteristic of HU homologs. Further divergence is evidenced by the existence of HU homologs with an additional lysine-rich domain also found in eukaryotic histone H1.


Trends in Unmet Need for Physician and Preventive Services in the United States, 1998-2017.
Improvements in insurance coverage and access to care have resulted from the Affordable Care Act (ACA). However, a focus on short-term pre- to post-ACA changes may distract attention from longer-term trends in unmet health needs, and the problems that persist. To identify changes from 1998 to 2017 in unmet need for physician services among insured and uninsured adults aged 18 to 64 years in the United States. Survey study using 20 years of data, from January 1, 1998, to December 31, 2017, from the Centers for Disease Control and Prevention Behavioral Risk Factor Surveillance System to identify trends in unmet need for physician and preventive services. The proportion of persons unable to see a physician when needed owing to cost (in the past year), having no routine checkup for those in whom a routine checkup was likely indicated (within 2 years), or failing to receive clinically indicated preventive services (in the recommended timeframe), overall and among subgroups defined by the presence of chronic illnesses and by self-reported health status. We estimated changes over time using logistic regression controlling for age, sex, race, Census region, employment status, and income. Among the adults aged 18 to 64 years in 1998 (n = 117 392) and in 2017 (n = 282 378) who responded to the Centers for Disease Control and Prevention Behavioral Risk Factors Surveillance System (mean age was 39.2 [95% CI, 39.0-39.3]; 50.3% were female; 65.9% were white), uninsurance decreased by 2.1 (95% CI, 1.6-2.5) percentage points (from 16.9% to 14.8%). However, the adjusted proportion unable to see a physician owing to cost increased by 2.7 (95% CI, 2.2-3.8) percentage points overall (from 11.4% to 15.7%, unadjusted); by 5.9 (95% CI, 4.1-7.8) percentage points among the uninsured (32.9% to 39.6%, unadjusted) and 3.6 (95% CI, 3.2-4.0) percentage points among the insured (from 7.1% to 11.5%, unadjusted). The adjusted proportion of persons with chronic medical conditions who were unable to see a physician because of cost also increased for most conditions. For example, an increase in the inability to see a physician because of cost for patients with cardiovascular disease was 5.9% (95% CI, 1.7%-10.1%), for patients with elevated cholesterol was 3.5% (95% CI, 2.5%-4.5%), and for patients with binge drinking was 3.1% (95% CI, 2.3%-3.3%). The adjusted proportion of chronically ill adults receiving checkups did not change. While the adjusted share of people receiving guideline-recommended cholesterol tests (16.8% [95% CI, 16.1%-17.4%]) and flu shots (13.2% [95% CI, 12.7%-13.8%]) increased, the proportion of women receiving mammograms decreased (-6.7% [95% CI, -7.8 to -5.5]). Despite coverage gains since 1998, most measures of unmet need for physician services have shown no improvement, and financial access to physician services has decreased.


The association of socioemotional problems with early sexual initiation.
Research on the association between socioemotional problems and early sexual initiation has not evaluated differences across types of problems, by gender, or by race or ethnicity. Data were analyzed for a sample derived from the Children of the National Longitudinal Surveys of Youth: 1,836 youth who were 10-11 years old at the 1992, 1994 and 1996 waves. Mothers' reports of their child's socioemotional problems at age 10-11 were assessed; sexual initiation before age 15 was assessed using youth self-reports. Logistic regression analyses estimated associations between socioemotional problems and early initiation; predicted probabilities and group differences were calculated using various regression techniques. Twenty-six percent of youth had had intercourse before turning 15, and their average level of each problem was higher than the level of those who had not. Both internalizing problems (e.g., depression and dependency) and externalizing problems (e.g., hyperactivity and antisocial behavior) were associated with early sexual initiation (odds ratios, 1.1 and 1.2, respectively), but only externalizing problems retained significance when both types were included in the model (1.2). Among specific problems, only hyperactivity and antisocial behavior were associated with early initiation (1.2 for each). Youth with a high level of externalizing problems had a higher predicted probability of having early sex than did those with a low level (0.28 vs. 0.21). Associations between socioemotional problems and early initiation did not differ by gender or by race or ethnicity. Interventions should be targeted at youth with externalizing problems, especially those who engage in antisocial or hyperactive behavior, in an effort to promote positive social interactions.


Effects of in utero and Postnatal Exposure to Secondhand Smoke on Lung Function by Gender and Asthma Status: The Seven Northeastern Cities (SNEC) Study.
Little information exists on whether gender or asthma status modifies the effects of secondhand smoke (SHS) exposure on lung function. To evaluate whether gender or asthma status modifies the association of SHS exposure with lung function. A total of 6,740 children (average 11.6 years) were recruited from 24 districts of 7 cities in northeast China in 2012. SHS exposure included exposure to environmental and maternal smoking both in utero and during early childhood (postnatal). Lung function was measured using electronic spirometers. Two-step regressions were used to analyze the association between SHS and lung function. In utero and postnatal exposure to SHS was independently associated with decreased lung function in both genders; however, this association was greater among males. For example, when exposed to maternal smoking during pregnancy, the adjusted odds ratio (aOR) for decreased forced vital capacity (FVC) was 6.46 (95% confidence interval [CI]: 2.58-16.17) among males, while only 2.16 (95% CI: 0.96-4.88) among females. More positive associations between SHS exposure and decreased lung function were detected among nonasthmatic compared with asthmatic children. Nonasthmatics had significantly larger deficits from in utero exposure to maternal smoking, which concerned decreased lung FVC function (aOR = 2.58, 95% CI: 1.28-5.21) and decreased lung forced expiratory volume in 1 s (FEV1) function (aOR = 2.32, 95% CI: 1.01-5.33). A similar pattern was also observed for the associations between SHS exposure and continuous pulmonary function test measurements. SHS exposure was associated with decreased lung function. Males and nonasthmatics seem to be more susceptible than their respective counterparts.


Indications and outcome of abdominal myomectomy in University of Maiduguri Teaching Hospital: Review of ten year.
Abdominal myomectomy is a common modality of treatment for large and symptomatic uterine fibroid in women who wish to retain their fertility. Though frequently performed the procedure may still be associated with complications. A retrospective review of all patients who had abdominal myomectomy from January 1999 to December 2008 at the University of Maiduguri Teaching Hospital. Information on the Sociodemographic characteristics, indication for the myomectomy, uterine size, pre and post operative packed cell volume (PCV), intraoperative findings, cadre of surgeon, duration of hospital stay and complications were obtained. The rate of abdominal myomectomy was 3.34%. Majority of the patients (79.8%) aged 30-49 years, and most (58.9%) were nulliparas. Abdominal mass (63.7%), menorrhagia (57.7%), and subfertility 55.2% were the leading indications for abdominal myomectomy. Complications were seen in 10.9% of the cases, 55.5 % of which were wound infections. Clinical and intra operative factors associated with complications included menorrhagia (P=0.003), estimated blood loss (EBL) ≥500mls (P=0.005) and post operative PCV of <30% (P=0.081). Complication rate after myomectomy was low with menorrhagia and EBL ≥ 500 mls being significantly associated with development of complication.


Determining the subcellular location of new proteins from microscope images using local features.
Evaluation of previous systems for automated determination of subcellular location from microscope images has been done using datasets in which each location class consisted of multiple images of the same representative protein. Here, we frame a more challenging and useful problem where previously unseen proteins are to be classified. Using CD-tagging, we generated two new image datasets for evaluation of this problem, which contain several different proteins for each location class. Evaluation of previous methods on these new datasets showed that it is much harder to train a classifier that generalizes across different proteins than one that simply recognizes a protein it was trained on. We therefore developed and evaluated additional approaches, incorporating novel modifications of local features techniques. These extended the notion of local features to exploit both the protein image and any reference markers that were imaged in parallel. With these, we obtained a large accuracy improvement in our new datasets over existing methods. Additionally, these features help achieve classification improvements for other previously studied datasets. The datasets are available for download at http://murphylab.web.cmu.edu/data/. The software was written in Python and C++ and is available under an open-source license at http://murphylab.web.cmu.edu/software/. The code is split into a library, which can be easily reused for other data and a small driver script for reproducing all results presented here. A step-by-step tutorial on applying the methods to new datasets is also available at that address. firstname.lastname@example.com Supplementary data are available at Bioinformatics online.


Reporting of life events over time: methodological issues in a longitudinal sample of women.
The number of life events reported by study participants is sensitive to the method of data collection and time intervals under consideration. Individual characteristics also influence reporting; respondents with poor mental health report more life events. Much current research on life events is cross-sectional. Data from a longitudinal study of women's health from 4 waves over a decade suggest that over time additional systematic biases in reporting life events occur. Inconsistency over time is due to both fall-off of reporting and telescoping. Intracategory variability and ambiguity of items, as well as respondent characteristics, also potentially contribute to response biases. Although some factors (e.g., item wording) are controllable, others (e.g., respondents' mental health) are not and must be factored into data analysis and interpretation.


Quality of life in survivors of colorectal carcinoma.
Colon carcinoma is a common malignancy that accounts for a substantial share of all cancer-related morbidity and mortality. However, little is known with regard to general and disease specific quality of life in survivors of colorectal carcinoma, particularly from community-based samples of cases across stage and survival times from diagnosis. Subjects with colorectal carcinoma were recruited from the National Cancer Institute's Surveillance, Epidemiology, and End Results cancer registry. Subjects completed two self-administered surveys: the Functional Assessment of Cancer Therapy Scales for Colorectal Cancer (FACT-C) and the Health Utilities Index (HUI) Mark III. One hundred seventy-three respondents (average age: 70.4 years, 71.4% female) completed the survey. In the first 3 years after diagnosis, quality of life was lower and varied substantially among respondents. After 3 years, respondents in all TNM stages of disease except Stage IV reported a relatively uniform and high quality of life. Pain, functional well-being, and social well-being were affected most substantially across all stages and times from diagnosis. Low income status was associated with worse outcomes for pain, ambulation, and social and emotional well-being. Only emotional well-being scores improved significantly over time in both surveys. Those individuals who achieve a long term remission from colorectal carcinoma may experience a relatively high quality of life, although deficits remain for several areas, particularly in those of low socioeconomic status. Sampling design may have excluded the most severely ill patients.


Mice carrying ubiquitin-specific protease 2 (Usp2) gene inactivation maintain normal sodium balance and blood pressure.
Ubiquitylation plays an important role in the control of Na⁺ homeostasis by the kidney. It is well established that the epithelial Na⁺ channel ENaC is regulated by the ubiquitin-protein ligase NEDD4-2, limiting ENaC cell surface expression and activity. Ubiquitylation can be reversed by the action of deubiquitylating enzymes (DUBs). One such DUB, USP2-45, was identified previously as an aldosterone-induced protein in the kidney and is also a circadian output gene. In heterologous expression systems, USP2-45 binds to ENaC, deubiquitylates it, and enhances channel density and activity at the cell surface. Because the role of USP2-45 in renal Na⁺ transport had not been studied in vivo, we investigated here the effect of Usp2 gene inactivation in this process. We demonstrate first that USP2-45 protein has a rhythmic expression with a peak at ZT12. Usp2-KO mice did not show any differences from wild-type littermates with respect to the diurnal control of Na⁺ or K⁺ urinary excretion and plasma levels either on a standard diet or after acute and chronic changes to low- and high-Na⁺ diets, respectively. Moreover, they had similar aldosterone levels on either a low- or high-Na⁺ diet. Blood pressure measurements using telemetry did not reveal variations compared with control mice. Usp2-KO mice did not display alterations in expression of genes involved in sodium homeostasis or the ubiquitin system, as evidenced by transcriptome analysis in the kidney. Our data suggest that USP2 does not play a primary role in the control of Na⁺ balance or blood pressure.


The nucleus: a highly organized but dynamic structure.
The nucleus in plants and animals is a highly structured organelle containing several well-defined subregions or suborganelles. These include the nucleolus, interphase chromosome territories and coiled bodies. We have visualized transcription sites in plants at both light- and electron-microscopy level by the incorporation of BrUTP. In the nucleolus many dispersed foci are revealed within the dense fibrillar component, each of which probably corresponds to a single gene copy. In the nucleoplasm there are also many dispersed foci of transcription, but not enough to correspond to one site per transcribed gene. We have shown that in wheat, and probably many other plant species, interphase chromosome territories are organized in a very regular way, with all the chromosomes in the Rabl configuration, all the centromeres clustered at the nuclear membrane and all the telomeres located at the nuclear membrane on the opposite side of the nucleus. However, despite this regular, polarized structure, there is no sign of polarization of transcription sites, or of any preferred location for them with respect to chromosome territorial boundaries. The nucleus is also highly dynamic. As an example, we have shown by the use of a green fluorescent protein fusion to the spliceosomal protein U2B" that coiled bodies move and coalesce within the nucleus, and may act as transport structures within the nucleus and nucleolus.


A facile grating approach towards broadband, wide-angle and high-efficiency holographic metasurfaces.
We analytically show that an incident light can be almost completely diffracted into the -1(st) order in wide-angle and broadband by suitably designed thin metallic nano-gratings with simple rectangular cross sections. Such extraordinary optical diffraction results from the excitation of localized cavity modes and exists even when the grating period is modulated in a broad range. By modulating the period with binary holography techniques, we can shape an incident wave into arbitrary wavefronts with near-unity conversion efficiencies. To show the efficacy of this approach, we demonstrate three reflection-type metasurfaces for achieving near-complete conversions from a Gaussian beam into a focused beam, Bessel beam, and vortex beam, respectively, with the complete suppression of the undesired specular reflection. Our findings provide a facile approach to build arbitrary wavefront-shaping metasurfaces with wide-angle, broadband, and high efficiency performance.


Readmission and Late Mortality After Critical Illness in Childhood.
Little is known about the ongoing mortality risk and healthcare utilization among U.S. children after discharge from a hospitalization involving ICU care. We sought to understand risks for hospital readmission and trends in mortality during the year following ICU discharge. Retrospective observational cohort study. This study was performed using administrative claims data from 2006-2013 obtained from the Truven Health Analytics MarketScan Database. We included all children in the dataset admitted to a U.S. ICU less than or equal to 18 years old. The primary outcome was nonelective readmission in the year following discharge. Risk of rehospitalization was determined using a Cox proportional hazards model. We identified 109,130 children with at least one ICU admission in the dataset. Over three quarters of the index ICU admissions (78.6%) had an ICU length of stay less than or equal to 3 days, and the overall index hospitalization mortality rate was 1.4%. In multivariate analysis, risk of nonelective readmission for children without cancer was higher with longer index ICU admission length of stay, younger age, and several chronic and acute conditions. By the end of the 1-year observation period, 36.0% of children with an index ICU length of stay greater than or equal to 14 days had been readmitted, compared with only 13.9% of children who had an index ICU length of stay equals to 1 day. Mortality in the year after ICU discharge was low overall (106 deaths per 10,000 person-years of observation) but was high among children with an initial index ICU admission length of stay greater than or equal to 14 days (599 deaths per 10,000 person-years). Readmission after ICU care is common. Further research is needed to investigate the potentially modifiable factors affecting likelihood of readmissions after discharge from the ICU. Although late mortality was relatively uncommon overall, it was 10-fold higher in the year after ICU discharge than in the general U.S. pediatric population.


3D SPECT/CT fusion using image data projection of bone SPECT onto 3D volume-rendered CT images: feasibility and clinical impact in the diagnosis of bone metastasis.
We developed a method of image data projection of bone SPECT into 3D volume-rendered CT images for 3D SPECT/CT fusion. The aims of our study were to evaluate its feasibility and clinical usefulness. Whole-body bone scintigraphy (WB) and SPECT/CT scans were performed in 318 cancer patients using a dedicated SPECT/CT systems. Volume data of bone SPECT and CT were fused to obtain 2D SPECT/CT images. To generate our 3D SPECT/CT images, colored voxel data of bone SPECT were projected onto the corresponding location of the volume-rendered CT data after a semi-automatic bone extraction. Then, the resultant 3D images were blended with conventional volume-rendered CT images, allowing to grasp the three-dimensional relationship between bone metabolism and anatomy. WB and SPECT (WB + SPECT), 2D SPECT/CT fusion, and 3D SPECT/CT fusion were evaluated by two independent reviewers in the diagnosis of bone metastasis. The inter-observer variability and diagnostic accuracy in these three image sets were investigated using a four-point diagnostic scale. Increased bone metabolism was found in 744 metastatic sites and 1002 benign changes. On a per-lesion basis, inter-observer agreements in the diagnosis of bone metastasis were 0.72 for WB + SPECT, 0.90 for 2D SPECT/CT, and 0.89 for 3D SPECT/CT. Receiver operating characteristic analyses for the diagnostic accuracy of bone metastasis showed that WB + SPECT, 2D SPECT/CT, and 3D SPECT/CT had an area under the curve of 0.800, 0.983, and 0.983 for reader 1, 0.865, 0.992, and 0.993 for reader 2, respectively (WB + SPECT vs. 2D or 3D SPECT/CT, p < 0.001; 2D vs. 3D SPECT/CT, n.s.). The durations of interpretation of WB + SPECT, 2D SPECT/CT, and 3D SPECT/CT images were 241 ± 75, 225 ± 73, and 182 ± 71 s for reader 1 and 207 ± 72, 190 ± 73, and 179 ± 73 s for reader 2, respectively. As a result, it took shorter time to read 3D SPECT/CT images than 2D SPECT/CT (p < 0.0001) or WB + SPECT images (p < 0.0001). 3D SPECT/CT fusion offers comparable diagnostic accuracy to 2D SPECT/CT fusion. The visual effect of 3D SPECT/CT fusion facilitates reduction of reading time compared to 2D SPECT/CT fusion.


Contractile arrest increases sarcoplasmic reticulum calcium uptake and SERCA2 gene expression in cultured neonatal rat heart cells.
We developed protocols with intact cultured neonatal rat myocytes to directly evaluate the function of the sarcoplasmic reticulum (SR) Ca-ATPase (or SERCA2), Na-Ca exchange (Na-CaX), and slow Ca transport systems (mitochondria and sarcolemmal Ca-ATPase). Spontaneously beating control cells were compared with cells cultured for 2 days in the presence of verapamil (verapamil-arrested cells, VA). Intracellular calcium (Cai) transients were measured by use of indo-1 during (1) spontaneous twitches, (2) contractures induced by rapid application of caffeine (CafC, with and without Nao), and (3) twitches induced by brief depolarizations with high [K]o solution (K-twitches). We also measured mRNA levels for the SR Ca-ATPase and Na-CaX in the same experimental preparations. The t1/2 for [Ca]i decline when both the SR Ca uptake and Na-CaX were prevented was the same for control and VA cells (approximately 20 seconds), indicating unaltered slow Ca transport systems. Similarly, there was no significant difference in the t1/2 of CafC when Na-CaX was the main mechanism responsible for [Ca]i decline (t1/2 approximately 1.5 seconds), indicating unaltered Na-CaX. Conversely, we found nearly a twofold increase in the rate of [Ca]i decline during K-twitches (control t1/2, 0.84 +/- 0.05 seconds; VA t1/2, 0.48 +/- 0.06 second; P < .001), indicating an increase in SR Ca-pumping activity in VA cells. This was also reflected by a 56% increase in the peak [Ca]i reached during CafC used to assess maximal SR Ca content (427 +/- 49 nmol/L in control versus 665 +/- 75 nmol/L in VA cells).(ABSTRACT TRUNCATED AT 250 WORDS)


Affinity resins as new tools for identifying target proteins of ascorbic acid.
l-Ascorbic acid (AA) has diverse physiological functions, but little is known about the functional mechanisms of AA. In this study, we synthesized two types of affinity resin on which AA is immobilized in a stable form to identify new AA-targeted proteins, which can provide important clues for elucidating unknown functional mechanisms of AA. To our knowledge, an affinity resin on which AA as a ligand is immobilized has not been prepared, because AA is very unstable and rapidly degraded in an aqueous solution. By using the affinity resins, cytochrome c (cyt c) was identified as an AA-targeted protein, and we showed that oxidized cyt c exhibits specific affinity for AA. These results suggest that two kinds of AA-affinity resin can be powerful tools to identify new target proteins of AA.


Parallel temperature dependence of contracture-associated enzyme release due to anoxia, 2,4-dinitrophenol (DNP), or caffeine and the calcium paradox.
Hypothermia during calcium-free perfusion of hearts protects them from injury caused by subsequent calcium repletion at 37 C (calcium paradox). Injury to calcium-free hearts is also associated with contracture caused by anoxia, 2,4-dinitrophenol (DNP), or caffeine. This study was done for the purpose of determining whether hypothermia during calcium-free perfusions protects hearts from contracture-associated injury. Langendorff-perfused rat hearts were studied in four experimental groups: I) Anoxia: Thirty minutes of anoxic perfusion at 37 C was followed by thirty minutes of anoxic calcium-free perfusion at 37-18 C. II) Calcium paradox: Five minutes of calcium-free perfusion at 37-18 C was followed by calcium repletion at 37 C. III, IVa) Caffeine or DNP: Five minutes of calcium-free perfusion at 37-18 C was followed by addition of 10 mM caffeine or 1 mM DNP in calcium-free medium at 37 C or, IVb) 1 mM DNP in calcium-free medium at 22 C. Injury was assessed by measurement of serial releases of creatine kinase (CK) in effluents and by cellular morphology. The results show that progressive hypothermia to 22 C during calcium-free perfusion periods produced a progressive reduction of CK release and morphologic evidence of injury due to anoxia, caffeine, or DNP, which closely paralleled protection of hearts from the calcium paradox. Protection from injury in all experimental groups was associated with preservation of sarcolemmal membrane integrity and prevention of cell separations at intercalated disk junctions. It is proposed that weakening of intercalated disks occurs during calcium-free perfusions and may be a cause of mechanical fragility of the sarcolemma. Hypothermia may protect hearts from contracture-associated injury by preserving the integrity of intercalated disk junctions during periods of extracellular calcium depletion.


Turbulence Visualization at the Terascale on Desktop PCs.
Despite the ongoing efforts in turbulence research, the universal properties of the turbulence small-scale structure and the relationships between small- and large-scale turbulent motions are not yet fully understood. The visually guided exploration of turbulence features, including the interactive selection and simultaneous visualization of multiple features, can further progress our understanding of turbulence. Accomplishing this task for flow fields in which the full turbulence spectrum is well resolved is challenging on desktop computers. This is due to the extreme resolution of such fields, requiring memory and bandwidth capacities going beyond what is currently available. To overcome these limitations, we present a GPU system for feature-based turbulence visualization that works on a compressed flow field representation. We use a wavelet-based compression scheme including run-length and entropy encoding, which can be decoded on the GPU and embedded into brick-based volume ray-casting. This enables a drastic reduction of the data to be streamed from disk to GPU memory. Our system derives turbulence properties directly from the velocity gradient tensor, and it either renders these properties in turn or generates and renders scalar feature volumes. The quality and efficiency of the system is demonstrated in the visualization of two unsteady turbulence simulations, each comprising a spatio-temporal resolution of 10244. On a desktop computer, the system can visualize each time step in 5 seconds, and it achieves about three times this rate for the visualization of a scalar feature volume.


Parental attitudes toward a diagnosis in children with unidentified multiple congenital anomaly syndromes.
One of the most common and unsatisfying situations encountered in medical genetics clinics is the child with multiple congenital anomalies (MCAs) suggestive of an underlying syndrome for whom it is not possible to make a definitive diagnosis. We undertook a qualitative, descriptive study to learn more about the ways in which the lack of a diagnosis affects parental coping and adjustment to their child's special needs. Semistructured interviews were conducted with 29 parents of 16 children born with an unidentified MCA syndrome. Interviews were based on a small number of open-ended questions, with follow-up probing, asking about parents' experiences with seeking a diagnosis, obtaining treatment and special services, explaining their child's problems to others, reproductive decision making, and support group participation. Transcripts of interviews were analyzed to identify the principal themes surrounding parents' beliefs about the significance of diagnostic information. The parents in this study had been aware of their child's anomalies for 2-23 years, and all had sought multiple evaluations to find a diagnosis. A majority of parents were still interested in identifying their child's syndrome, but most felt that their interest in a diagnosis had diminished over time, and some felt that there were benefits in not having this information. We identified six areas where parents claimed a diagnosis would have impact: labels, causes, prognosis, treatment, acceptance, and social support. Significant issues included obtaining special education services, anticipating the child's future and potential medical complications, life expectancy, recurrence risks, finding sources of social support, and ensuring that the child was receiving appropriate treatment. We conclude that the significance of diagnostic information is complex and varies for different parents. Providers should explore the underlying issues associated with a parental quest for a diagnosis in order to identify and address specific concerns. Published 2001 Wiley-Liss, Inc.


Fast diploidization in close mesopolyploid relatives of Arabidopsis.
Mesopolyploid whole-genome duplication (WGD) was revealed in the ancestry of Australian Brassicaceae species with diploid-like chromosome numbers (n = 4 to 6). Multicolor comparative chromosome painting was used to reconstruct complete cytogenetic maps of the cryptic ancient polyploids. Cytogenetic analysis showed that the karyotype of the Australian Camelineae species descended from the eight ancestral chromosomes (n = 8) through allopolyploid WGD followed by the extensive reduction of chromosome number. Nuclear and maternal gene phylogenies corroborated the hybrid origin of the mesotetraploid ancestor and suggest that the hybridization event occurred approximately 6 to 9 million years ago. The four, five, and six fusion chromosome pairs of the analyzed close relatives of Arabidopsis thaliana represent complex mosaics of duplicated ancestral genomic blocks reshuffled by numerous chromosome rearrangements. Unequal reciprocal translocations with or without preceeding pericentric inversions and purported end-to-end chromosome fusions accompanied by inactivation and/or loss of centromeres are hypothesized to be the main pathways for the observed chromosome number reduction. Our results underline the significance of multiple rounds of WGD in the angiosperm genome evolution and demonstrate that chromosome number per se is not a reliable indicator of ploidy level.


Barriers to the diagnosis and treatment of migraine: effects of sex, income, and headache features.
US Headache Consortium Guidelines state that persons with migraine with headache-related disability should receive certain acute treatments including migraine-specific and other medications. However, many eligible individuals do not receive these therapies. Individuals with migraine may experience barriers to receiving minimal appropriate care. We aimed to identify barriers to care in a population sample of individuals with episodic migraine. We assessed barriers at 3 levels: medical consultation, diagnosis, and acute pharmacologic therapy use and assessed the contribution of socioeconomic, demographic, and headache-specific variables to these barriers. We identified 3 steps that were minimally necessary to achieve guideline-defined appropriate acute pharmacologic therapy as: (1) consulting a prescribing health care professional; (2) receiving a migraine diagnosis; and (3) using migraine-specific or other appropriate acute treatments. We used data from the 2009 American Migraine Prevalence and Prevention study sample to identify persons with episodic migraine with unmet treatment needs, defined by a Migraine Disability Assessment Scale (MIDAS) score corresponding to Grade II (mild), III (moderate), or IV (severe) headache-related disability. We determined whether these individuals had consulted a health care professional for headache over the previous year, if they ever received a medical diagnosis of migraine from a health care professional, and whether they were currently using appropriate acute treatment for migraine (ie, a triptan, prescription non-steroidal anti-inflammatory drug, or an isometheptene-containing agent). We analyzed several socioeconomic, demographic, and headache-specific variables to determine if they were related to barriers in any of the 3 defined steps. Of 775 eligible participants with episodic migraine and headache-related disability, 45.5% (n = 353/775) had consulted health care professional for headache in the preceding year. Among those individuals, 86.7% (n = 306/353) reported receiving a medical diagnosis of migraine. Among the diagnosed consulters, 66.7% (204/306) currently used acute migraine-specific treatments. Only 204 (26.3%) individuals successfully completed all 3 steps. Multivariate logistic regression models revealed that the strongest predictors of current consulting for headache were having health insurance {odds ratio (OR) = 1.73 (95% confidence interval [CI], 1.07-2.79)}, high headache-related disability (OR = 1.06 [95% CI, 1.0-1.14] for a 10-point change in MIDAS score), and a high composite migraine symptom severity score (OR = 1.19 [95% CI, 1.05-1.36]). Among consulters, diagnosis was much more likely in women than men (OR = 4.25 [95% CI, 1.61-11.2]) and became increasingly likely with increasing average headache pain severity (OR = 1.44 [95% CI, 1.12-1.87]) and migraine symptom severity score. Among those who were diagnosed, annual household income was the strongest predictor of currently using guideline-defined appropriate acute treatment (OR = 1.44 [95% CI, 1.07-1.93]) followed by a 10-point change in MIDAS score (OR 1.16 [95% CI, 1.02-1.35]). Among persons with migraine in need of medical care (MIDAS Grade II or greater), only one quarter traversed the 3 steps we proposed to be necessary to achieving minimally appropriate care (consulting, diagnosis, and treatment/medication use). Health insurance status was an important predictor of consulting. Among consulters, women were far more likely to be diagnosed than men, suggesting that gender bias in diagnosis may be an important barrier for men. There were economic barriers related to use of appropriate prescription medications. Public health efforts should focus on improving consultation rates, particularly in the uninsured and diagnostic rates particularly in males with migraine.


Predictors of Expressive Language Change for Children with Autism Spectrum Disorder Receiving AAC-Infused Comprehensive Intervention.
Comprehensive interventions for children with autism spectrum disorder (ASD) often incorporate augmentative and alternative communication (AAC); however, variability in outcomes exists even among children who access similar intervention. This study investigated predictors of expressive language change for 48 children with ASD aged 31 to 67 months receiving AAC-infused intervention. The relationships between participants' initial responses to AAC and expressive language change were examined. Commonly reported predictors (IQ, chronological age, ASD symptomatology) did not significantly predict expressive language change. AAC factors (visual attention, object play, word learning) entered at Step 2 of a hierarchical multiple regression, explained an additional 42% of the variance. The findings provide preliminary data on child characteristics associated with expressive language changes within AAC-infused comprehensive interventions.


Evaluation and Validation of Assembling Corrected PacBio Long Reads for Microbial Genome Completion via Hybrid Approaches.
Despite the ever-increasing output of next-generation sequencing data along with developing assemblers, dozens to hundreds of gaps still exist in de novo microbial assemblies due to uneven coverage and large genomic repeats. Third-generation single-molecule, real-time (SMRT) sequencing technology avoids amplification artifacts and generates kilobase-long reads with the potential to complete microbial genome assembly. However, due to the low accuracy (~85%) of third-generation sequences, a considerable amount of long reads (>50X) are required for self-correction and for subsequent de novo assembly. Recently-developed hybrid approaches, using next-generation sequencing data and as few as 5X long reads, have been proposed to improve the completeness of microbial assembly. In this study we have evaluated the contemporary hybrid approaches and demonstrated that assembling corrected long reads (by runCA) produced the best assembly compared to long-read scaffolding (e.g., AHA, Cerulean and SSPACE-LongRead) and gap-filling (SPAdes). For generating corrected long reads, we further examined long-read correction tools, such as ECTools, LSC, LoRDEC, PBcR pipeline and proovread. We have demonstrated that three microbial genomes including Escherichia coli K12 MG1655, Meiothermus ruber DSM1279 and Pdeobacter heparinus DSM2366 were successfully hybrid assembled by runCA into near-perfect assemblies using ECTools-corrected long reads. In addition, we developed a tool, Patch, which implements corrected long reads and pre-assembled contigs as inputs, to enhance microbial genome assemblies. With the additional 20X long reads, short reads of S. cerevisiae W303 were hybrid assembled into 115 contigs using the verified strategy, ECTools + runCA. Patch was subsequently applied to upgrade the assembly to a 35-contig draft genome. Our evaluation of the hybrid approaches shows that assembling the ECTools-corrected long reads via runCA generates near complete microbial genomes, suggesting that genome assembly could benefit from re-analyzing the available hybrid datasets that were not assembled in an optimal fashion.


Cerebellar granule cells acquire a widespread predictive feedback signal during motor learning.
Cerebellar granule cells, which constitute half the brain's neurons, supply Purkinje cells with contextual information necessary for motor learning, but how they encode this information is unknown. Here we show, using two-photon microscopy to track neural activity over multiple days of cerebellum-dependent eyeblink conditioning in mice, that granule cell populations acquire a dense representation of the anticipatory eyelid movement. Initially, granule cells responded to neutral visual and somatosensory stimuli as well as periorbital airpuffs used for training. As learning progressed, two-thirds of monitored granule cells acquired a conditional response whose timing matched or preceded the learned eyelid movements. Granule cell activity covaried trial by trial to form a redundant code. Many granule cells were also active during movements of nearby body structures. Thus, a predictive signal about the upcoming movement is widely available at the input stage of the cerebellar cortex, as required by forward models of cerebellar control.


The Emergence of Social Capital in Low-Income Latino Elementary Schools.
Scholars suggest that racial/ethnic and class disparities in school-based social capital contribute to educational inequalities. Previous studies demonstrate that social capital (relations of trust, mutual expectations, and shared values) between parents and schools supports children's development. Yet we know little about the emergence of social capital, that is, the processes through which it develops. In this study, we explore mechanisms of social capital emergence in predominantly low-income Latino school communities. We draw data from an experimental study that manipulated social capital through an after-school family engagement program. Based on interviews and focus groups with participating parents, teachers, and program staff in two elementary schools, we identified four types of interactions that act as mechanisms of social capital emergence: (1) responsive communication; (2) reciprocal communication; (3) shared experiences; and (4) institutional linkage. The article connects these mechanisms to theoretically linked sources of social capital and discusses implications for theory and practice.


Molecular Profiling of Salivary Gland Intraductal Carcinoma Revealed a Subset of Tumors Harboring NCOA4-RET and Novel TRIM27-RET Fusions: A Report of 17 cases.
Intraductal carcinoma (IC) is the new World Health Organization designation for tumors previously called "low-grade cribriform cystadenocarcinoma" and "low-grade salivary duct carcinoma." The relationship of IC to salivary duct carcinoma is controversial, but they now are considered to be distinct entities. IC is a rare low-grade malignant salivary gland neoplasm with features similar to mammary atypical ductal hyperplasia or ductal carcinoma in situ, that shows diffuse S100 protein and mammaglobin positivity and is only partially defined genetically. (Mammary analogue) secretory carcinoma harboring ETV6-NTRK3, and in rare cases ETV6-RET fusion, shares histomorphologic and immunophenotypical features with IC. Recently, RET rearrangements and NCOA4-RET have been described in IC, suggesting a partial genetic overlap with mammary analogue secretory carcinoma. Here, we genetically characterize the largest cohort of IC to date to further explore this relationship. Seventeen cases of IC were analyzed by next-generation sequencing using the FusionPlex Solid Tumor kit (ArcherDX). Identified fusions were confirmed using fluorescence in situ hybridization break apart and, in some cases, fusion probes, and a reverse transcription polymerase chain reaction designed specifically to the detected breakpoints. All analyzed cases were known to be negative for ETV6 rearrangement by fluorescence in situ hybridization and for ETV6-NTRK3 fusion by reverse transcription polymerase chain reaction. Next-generation sequencing analysis detected a NCOA4-RET fusion transcript joining exon 7 or 8 of NCOA4 gene and exon 12 of RET gene in 6 cases of intercalated duct type IC; and a novel TRIM27-RET fusion transcript between exons 3 and 12 in 2 cases of salivary gland tumors displaying histologic and immunohistochemical features typical of apocrine IC. A total of 47% of IC harbored a fusion involving RET. In conclusion, we have confirmed the presence of NCOA4-RET as the dominant fusion in intercalated duct type IC. A novel finding in our study has been a discovery of a subset of IC patients with apocrine variant IC harboring a novel TRIM27-RET.


Early fate of exogenous promoters in E. coli.
Gene gain by horizontal gene transfer is a major pathway of genome innovation in bacteria. The current view posits that acquired genes initially need to be silenced and that a bacterial chromatin protein, H-NS, plays a role in this silencing. However, we lack direct observation of the early fate of a horizontally transferred gene to prove this theory. We combine sequencing, flow cytometry and sorting, followed by microscopy to monitor gene expression and its variability after large-scale random insertions of a reporter gene in a population of Escherichia coli bacteria. We find that inserted promoters have a wide range of gene-expression variability related to their location. We find that high-expression clones carry insertions that are not correlated with H-NS binding. Conversely, binding of H-NS correlates with silencing. Finally, while most promoters show a common level of extrinsic noise, some insertions show higher noise levels. Analysis of these high-noise clones supports a scenario of switching due to transcriptional interference from divergent ribosomal promoters. Altogether, our findings point to evolutionary pathways where newly-acquired genes are not necessarily silenced, but may immediately explore a wide range of expression levels to probe the optimal ones.


Effect of continuous intravenous oxycodone infusion in opioid-naïve cancer patients with dyspnea.
Dyspnea is among symptoms that decrease quality of life for terminal cancer patients. There are few reports of the positive effects of oxycodone for the treatment of dyspnea, and no studies have focused on opioid-naïve patients. This study aimed to determine the efficacy and safety of continuous intravenous oxycodone infusion for opioid-naïve cancer patients with dyspnea. Eligible patients were opioid-naïve cancer inpatients who received continuous oxycodone infusion as a treatment for dyspnea under the care of the palliative care team at Komaki City Hospital between November 2013 and December 2016. We retrospectively investigated the improvement of dyspnea following continuous oxycodone infusion from the medical records. This study included 19 patients, and the response rate to oxycodone infusion for dyspnea was 68.4%. Most participants were terminal cancer patients with performance status 3 or 4. Median survival of participants following continuous oxycodone infusion was 6 (range 1-377) days. No serious adverse events such as respiratory depression or somnolence were noted. Continuous oxycodone infusion could be a reasonable treatment option in the management of dyspnea in opioid-naïve cancer patients.


Identifying and characterizing a novel protein kinase STK35L1 and deciphering its orthologs and close-homologs in vertebrates.
The human kinome containing 478 eukaryotic protein kinases has over 100 uncharacterized kinases with unknown substrates and biological functions. The Ser/Thr kinase 35 (STK35, Clik1) is a member of the NKF 4 (New Kinase Family 4) in the kinome with unknown substrates and biological functions. Various high throughput studies indicate that STK35 could be involved in various human diseases such as colorectal cancer and malaria. In this study, we found that the previously published coding sequence of the STK35 gene is incomplete. The newly identified sequence of the STK35 gene codes for a protein of 534 amino acids with a N-terminal elongation of 133 amino acids. It has been designated as STK35L (STK35 long). Since it is the first of further homologous kinases we termed it as STK35L1. The STK35L1 protein (58 kDa on SDS-PAGE), but not STK35 (44 kDa), was found to be expressed in all human cells studied (endothelial cells, HeLa, and HEK cells) and was down-regulated after silencing with specific siRNA. EGFP-STK35L1 was localized in the nucleus and the nucleolus. By combining syntenic and gene structure pattern data and homology searches, two further STK35L1 homologs, STK35L2 (previously known as PDIK1L) and STK35L3, were found. All these protein kinase homologs were conserved throughout the vertebrates. The STK35L3 gene was specifically lost during placental mammalian evolution. Using comparative genomics, we have identified orthologous sets of these three protein kinases genes and their possible ancestor gene in two sea squirt genomes. We found the full-length coding sequence of the STK35 gene and termed it as STK35L1. We identified a new third STK35-like gene, STK35L3, in vertebrates and a possible ancestor gene in sea squirt genome. This study will provide a comprehensive platform to explore the role of STK35L kinases in cell functions and human diseases.


Handling uncertainty in economic evaluations of patient level data: a review of the use of Bayesian methods to inform health technology assessments.
Due to potential advantages (e.g., using all available evidence), Bayesian methods have been proposed to assist healthcare decision making. This review provides a detailed description of how Bayesian methods have been applied to economic evaluations of patient level data. The results serve both as a reference and as a means by which to examine the appropriate application of Bayesian methods to inform decision making. MEDLINE, EMBASE, and Cochrane Economic Evaluation databases were searched to identify studies, published up to November 2007, meeting three inclusion criteria: (i) the study conducted an economic evaluation, (ii) sampling uncertainty was incorporated using Bayesian methods, (iii) the likelihood function was informed by patient level data from a single source. Data were collected on key study characteristics (e.g., prior distribution, likelihood function, presentation of uncertainty). The search identified 366 potentially relevant studies, from which 103 studies underwent full-text review. Sixteen studies met the inclusion criteria. Half of the studies used uninformative priors; most studies incorporated the potential dependence between costs and effects, and presented cost-effectiveness acceptability curves. Results were sensitive to changes in the priors and likelihoods. Limited use of informative priors, among the included studies, gives policy makers little guidance on one of the main benefits of Bayesian methods, the ability to integrate all available evidence to capture the uncertainty inherent in decision making.


Prevalence of retinopathy in people with diabetes, impaired glucose tolerance, and normal glucose tolerance.
Recently, an international expert committee published new revised criteria for diagnosing diabetes. According to the new criteria, the 2-h glucose level for diabetes in the oral glucose tolerance test (OGTT) is the same as in the previous World Health Organization criteria, but the cut point for the fasting blood glucose level has been lowered to be equivalent to the 2-h OGTT level. Measurement of the fasting blood glucose level is preferred to the 2-h OGTT glucose level. The ability of the new cut point for fasting blood glucose to discriminate between those at a high and a low risk for retinopathy was tested in a population-based study The population consisted of all the 1,008 subjects (456 men) born in 1935 and living in a Finnish city A screening for type 2 diabetes was carried out in the first phase. All participants who were not on antidiabetic medication were invited for an OGTT in the second phase. A fasting blood glucose value was measured from the diabetic subjects on antidiabetic medication. In addition, measurements of serum cholesterol, HDL cholesterol, and triglycerides were made, and fundus photographs were taken. Altogether, 831 subjects (368 men) (82%) participated and constitute the eligible study population for the present analyses. Fundus photographs were available for 790 subjects (347 men) (95%). There were 28 subjects (3.5%) who had mild retinopathic changes in the fundus photographs. Retinopathic changes were associated with higher fasting blood glucose levels, but not with any of the other background factors. The prevalence of retinopathy was 10.2% (95% CI 4.8-18.5) in subjects with a fasting blood glucose of > or =6.1 mmol/l, while it was 2.6% (1.5-4.0) in those with a lower fasting blood glucose level. In the former group, a majority (seven of nine) of the subjects with retinopathy were previously diagnosed diabetic patients. Some cases of retinopathy were found regardless the level of glycemia, and measurement of the 2-h OGTT glucose levels did not increase information. The results of this population study give support to the use of fasting blood glucose levels in diagnosing type 2 diabetes. The lower limit of the highest decile of the fasting glucose level was 6.1 mmol/l, and it discriminated subjects at a high risk for retinopathy from those at a low risk. Because of the limited number of subjects with retinopathy in this study, the level of hyperglycemia associated with retinopathy cannot be estimated accurately.


What puts heart failure patients at risk for poor medication adherence?
Medication nonadherence is a major cause of hospitalization in patients with heart failure (HF), which contributes enormously to health care costs. We previously found, using the World Health Organization adherence dimensions, that condition and patient level factors predicted nonadherence in HF. In this study, we assessed a wider variety of condition and patient factors and interactions to improve our ability to identify those at risk for hospitalization. Medication adherence was measured electronically over the course of 6 months, using the Medication Event Monitoring System (MEMS). A total of 242 HF patients completed the study, and usable MEMS data were available for 218 (90.1%). Participants were primarily white (68.3%), male (64.2%), and retired (44.5%). Education ranged from 8-29 years (mean, 14.0 years; standard deviation, 2.9 years). Ages ranged from 30-89 years (mean, 62.8 years; standard deviation, 11.6 years). Analyses used adaptive methods based on heuristic searches controlled by cross-validation scores. First, individual patient adherence patterns over time were used to categorize patients in poor versus better adherence types. Then, risk factors for poor adherence were identified. Finally, an effective model for predicting poor adherence was identified based on identified risk factors and possible pairwise interactions between them. A total of 63 (28.9%) patients had poor adherence. Three interaction risk factors for poor adherence were identified: a higher number of comorbid conditions with a higher total number of daily medicines, older age with poorer global sleep quality, and fewer months since diagnosis of HF with poorer global sleep quality. Patients had between zero and three risk factors. The odds for poor adherence increased by 2.6 times with a unit increase in the number of risk factors (odds ratio, 2.62; 95% confidence interval, 1.78-3.86; P<0.001). Newly diagnosed, older HF patients with comorbid conditions, polypharmacy, and poor sleep are at risk for poor medication adherence. Interventions addressing these specific barriers are needed.


Women's Mobility and the Situational Conditions of Rape: Cases Reported to Hospitals.
A third of all rapes in Stockholm, the capital of Sweden, take place in public outdoor places. Yet, little is known about the events that precede this type of sexual offence and less about the situational context of rape. This study aims to improve the understanding of the nature of situational conditions that immediately precede events of rape. Using medical records of 147 rape victims during 2012 and 2013, we constructed time- and place-specific records of the places women traveled through or spent time at, the activities they engaged in, and the people they interacted with sequentially over the course of the day when they were raped. The analysis uses visualization tools (VISUAL-TimePAcTS), Geographical Information Systems, and conditional logistic regression to identify place-, context-, and social interaction-related factors associated with the onset of rape. Results for this sample of cases reported to hospitals show that being outdoors was not necessarily riskier for women when compared with indoor public settings; some outdoor environments were actually protective, such as streets. Being in a risky social context and engaging in a risky activity before the event was associated with an increased risk of rape, and the risk escalated over the day. Among those women who never drank alcohol, the results were similar to what was observed in the overall sample, which suggests that risky social interaction and risky activity made independent contributions to the risk of rape. The article finishes with suggestions for rape prevention.


Corticospinal responses following strength training: a systematic review and meta-analysis.
Strength training results in changes in skeletal muscle; however, changes in the central nervous system also occur. Over the last 15 years, non-invasive brain stimulation techniques, such as transcranial magnetic stimulation, have been used to study the neural adaptations to strength training. This review explored the hypothesis that the neural adaptations to strength training may be due to changes in corticospinal excitability and inhibition and, such changes, contribute to the gain in strength following strength training. A systematic review, according to PRISMA guidelines, identified studies by database searching, hand-searching and citation tracking between January 1990 and the first week of February 2017. Methodological quality of included studies was determined using the Downs and Black quality index. Data were synthesised and interpreted from meta-analysis. Nineteen studies investigating the corticospinal responses following strength training were included. Meta-analysis found that strength training increased strength [standardised mean difference (SMD) 0.84, 95% CI 0.55 to 1.13], decreased short-interval intracortical inhibition (SMD -1.00, 95% CI -1.84 to -0.17) and decreased the cortical silent period (SMD -0.66, 95% CI -1.00 to -0.32). Strength training had no effect on motor threshold (SMD -0.12, 95% CI -0.49 to 0.25), but a borderline effect for increased corticospinal excitability (SMD 0.27, 95% CI 0.00 to 0.54). In untrained healthy participants, the corticospinal response to strength training is characterised by reduced intracortical inhibition and cortical silent period duration, rather than changes in corticospinal excitability. These data demonstrate that strength training targets intracortical inhibitory networks within the primary motor cortex (M1) and corticospinal pathway, characterising an important neural adaptation to strength training.


Structure-induced switching of interpolymer adhesion at a solid-polymer melt interface.
Here we report a link between the interfacial structure and adhesive property of homopolymer chains physically adsorbed (i.e., via physisorption) onto solids. Polyethylene oxide (PEO) was used as a model and two different chain conformations of the adsorbed polymer were created on silicon substrates via the well-established Guiselin's approach: "flattened chains" which lie flat on the solid and are densely packed, and "loosely adsorbed polymer chains" which form bridges jointing up nearby empty sites on the solid surface and cover the flattened chains. We investigated the adhesion properties of the two different adsorbed chains using a custom-built adhesion testing device. Bilayers of a thick PEO overlayer on top of the flattened chains or loosely adsorbed chains were subjected to the adhesion test. The results revealed that the flattened chains do not show any adhesion even with the chemically identical free polymer on top, while the loosely adsorbed chains exhibit adhesion. Neutron reflectivity experiments corroborated that the difference in the interfacial adhesion is not attributed to the interfacial brodening at the free polymer-adsorbed polymer interface. Instead, coarse-grained molecular dynamics simulation results suggest that the tail parts of the loosely adsorbed chains act as "connector molecules", bridging the free chains and substrate surface and improving the interfacial adhesion. These findings not only shed light on the structure-property relationship at the interface, but also provide a novel approach for developing sticking/anti-sticking technologies through precise control of the interfacial polymer nanostructures.


The politics of local tobacco control.
Until the nonsmokers' rights movement, tobacco control activity was at the federal or state levels, which is where the tobacco industry dominates. Since the appearance of the nonsmokers' rights movement, progress in tobacco control has occurred primarily at the local level. In response to the success of this movement, the tobacco industry has developed "smokers' rights" groups and other tactics to fight local legislation. Several recent local campaigns in California illustrate these tactics. Tobacco control forces follow many paths, from sitting on the sidelines to making a serious commitment to smoking control legislation. Despite the tobacco industry's superior financial resources, the outcome of proposed local tobacco control legislation appears to depend on how seriously the health advocates mobilize in support of the local legislation. When the health community makes a serious commitment of time and resources, it wins. When it fails to make such a commitment, the tobacco industry prevails, more by default than by its superior financial resources.