Revisiting the Origin of Nanopore Current Blockage for Volume Difference Sensing at the Atomic Level.
Changes in the nanopore ionic current during entry of a target molecule underlie the sensing capability and dominate the intensity and extent of applications of the nanopore approach. The volume exclusion model has been proposed and corrected to describe the nanopore current blockage. However, increasing evidence shows nonconformity with this model, suggesting that the ionic current within a nanopore should be entirely reconsidered. Here, we revisit the origin of nanopore current blockage from a theoretical perspective and propose that the noncovalent interactions between a nanopore and a target molecule affect the conductance of the solution inside the nanopore, leading to enhanced current blockage. Moreover, by considering the example of an aerolysin nanopore discriminating the cytosine DNA and methylcytosine DNA that differ by a single methyl group, we completely demonstrate, by nanopore experiments and molecular dynamics simulations, the essential nature of this noncovalent interaction for discrimination. Our conductance model suggests multiplicative effects of both volume exclusion and noncovalent interaction on the current blockage and provides a new strategy to achieve volume difference sensing at the atomic level with highly specific current events, which would promote the nanopore protein sequencing and its applications in real-life systems.


Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer.
Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 × 10(-8)) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for ∼11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction.


Doppler-derived strain and strain rate imaging assessment of right ventricular systolic function in adults late after tetralogy of Fallot repair: an observational study.
Tetralogy of Fallot (TOF) is the most common form of cyanotic congenital heart disease. Today, we are faced with an increasing number of patients with residual pulmonary regurgitation (PR) late after TOF repair. The right ventricular (RV) volumes and function are among the most important factors influencing clinical decision-making. Cardiac magnetic resonance (CMR) is the gold standard method for the quantitative assessment of the RV function; it is, however, expensive for routine clinical follow-up and sometimes is contraindicated. We sought to evaluate the RV systolic function via CMR and compare it with Doppler-derived strain(S) and strain rate (SR) imaging in patients with repaired TOF. In an observational cross-sectional study, 70 patients (22 women, mean age=22±4.9 years) late after TOF repair with severe PR were evaluated. Peak systolic strain and SR in the basal, mid, and apical segments of RV free wall (RVFW) were measured and compared with the RV function measured in the short-axis cine MR. Associations between RVEF and S/SR, investigated by ordinal logistic regression models. Significant association was observed between RV function and mean S of all the three segments of the RVFW segments [OR (CI95%): 1.17 (1.05-1.31)]. Association between RV function and mean SR of all the three segments of the RVFW segments was borderline significant [OR (CI95%): 1.7 (0.97-2.93)]. There was a significant correlation between the Doppler-derived mean strain of RVFW and the RV function measured by CMR in adults late after TOF repair. These quantitative methods improved the assessment of the RV function and served as an additional method to follow up patients with contraindications to CMR.


Cortical synapse loss in progressive supranuclear palsy.
Cortical synapse loss, the probable substrate of cognitive impairment in Alzheimer disease (AD), has not previously been evaluated in progressive supranuclear palsy (PSP). Hypothesizing that synapse loss would be greater in demented than non-demented PSP patients, we examined synaptophysin concentrations in 8 cases of PSP (5 demented and 3 nondemented cases). We found a decrease in mean synaptophysin concentration in these 8 cases in frontal, temporal, and parietal lobes, and in cerebellum, compared to the means in corresponding lobes of 16 controls. The decreases were similar to those in 28 cases of AD, but not as great. We determined synaptophysin concentration from motor cortex in only 4 of our PSP cases, 2 demented and 2 non-demented. The average concentrations in these 4 cases were lower than in AD motor cortex; both were lower than controls. When demented and non-demented PSP cases were compared, neocortical synaptophysin concentrations in non-demented PSP cases were lower than in demented cases. There appears to be a link between AD and PSP, in that synapse loss is found in both. However, the basis and significance of the prominent neocortical synapse loss in PSP, especially in non-demented subjects, remain to be explored.


SLiMDisc: short, linear motif discovery, correcting for common evolutionary descent.
Many important interactions of proteins are facilitated by short, linear motifs (SLiMs) within a protein's primary sequence. Our aim was to establish robust methods for discovering putative functional motifs. The strongest evidence for such motifs is obtained when the same motifs occur in unrelated proteins, evolving by convergence. In practise, searches for such motifs are often swamped by motifs shared in related proteins that are identical by descent. Prediction of motifs among sets of biologically related proteins, including those both with and without detectable similarity, were made using the TEIRESIAS algorithm. The number of motif occurrences arising through common evolutionary descent were normalized based on treatment of BLAST local alignments. Motifs were ranked according to a score derived from the product of the normalized number of occurrences and the information content. The method was shown to significantly outperform methods that do not discount evolutionary relatedness, when applied to known SLiMs from a subset of the eukaryotic linear motif (ELM) database. An implementation of Multiple Spanning Tree weighting outperformed two other weighting schemes, in a variety of settings.


Inflammation and Cholesterol as Predictors of Cardiovascular Events Among 13970 Contemporary High-Risk Patients With Statin Intolerance.
Background: Among patients treated with statin therapy to guideline-recommended cholesterol levels, residual inflammatory risk assessed by high-sensitivity C-reactive protein (hsCRP) is at least as strong a predictor of future cardiovascular events as is residual risk assessed by low-density lipoprotein cholesterol (LDLC). Whether these relationships are present among statin-intolerant patients with higher LDLC levels is uncertain but has implications for the choice of preventive therapies, including bempedoic acid, an agent that reduces both LDLC and hsCRP. Methods: The multinational CLEAR-Outcomes trial (Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen Outcomes Trial) randomly allocated 13970 statin-intolerant patients to 180 mg of oral bempedoic acid daily or matching placebo and followed them for a 4-component composite of incident myocardial infarction, stroke, coronary revascularization, or cardiovascular death, and for all-cause mortality. Quartiles of increasing baseline hsCRP and LDLC were assessed as predictors of future adverse events after adjustment for traditional risk factors and randomized treatment assignment. Results: Compared with placebo, bempedoic acid reduced median hsCRP by 21.6% and mean LDLC levels by 21.1% at 6 months. Baseline hsCRP was significantly associated with the primary composite end point of major cardiovascular events (highest versus lowest hsCRP quartile; hazard ratio [HR], 1.43 [95% CI, 1.24-1.65]), cardiovascular mortality (HR, 2.00 [95% CI, 1.53-2.61]), and all-cause mortality (HR, 2.21 [95% CI, 1.79-2.73]). By contrast, the relationship of baseline LDLC quartile (highest versus lowest) to future events was smaller in magnitude for the primary composite cardiovascular end point (HR, 1.19 [95% CI, 1.04-1.37]) and neutral for cardiovascular mortality (HR, 0.90 [95% CI, 0.70-1.17]) and all-cause mortality (HR, 0.95 [95% CI, 0.78-1.16]). Risks were high for those with elevated hsCRP irrespective of LDLC level. Bempedoic acid demonstrated similar efficacy in reducing cardiovascular events across all levels of hsCRP and LDLC. Conclusions: Among contemporary statin-intolerant patients, inflammation assessed by hsCRP predicted risk for future cardiovascular events and death more strongly than hyperlipidemia assessed by LDLC. Compared with placebo, bempedoic acid had similar efficacy for reducing cardiovascular risk across hsCRP and LDLC strata.


Placebo-controlled study in neuromyelitis optica-Ethical and design considerations.
To date, no treatment for neuromyelitis optica (NMO) has been granted regulatory approval, and no controlled clinical studies have been reported. To design a placebo-controlled study in NMO that appropriately balances patient safety and clinical-scientific integrity. We assessed the "standard of care" for NMO to establish the ethical framework for a placebo-controlled trial. We implemented measures that balance the need for scientific robustness while mitigating the risks associated with a placebo-controlled study. The medical or scientific community, patient organizations, and regulatory authorities were engaged early in discussions on this placebo-controlled study, and their input contributed to the final study design. The N-MOmentum study (NCT02200770) is a clinical trial that randomizes NMO patients to receive MEDI-551, a monoclonal antibody that depletes CD19+ B-cells, or placebo. The study design has received regulatory, ethical, clinical, and patient approval in over 100 clinical sites in more than 20 countries worldwide. The approach we took in the design of the N-MOmentum trial might serve as a roadmap for other rare severe diseases when there is no proven therapy and no established clinical development path.


Acute Myeloid Leukemia in Adolescents and Young Adults Treated in Pediatric and Adult Departments in the Nordic Countries.
Studies on adolescents and young adults with acute lymphoblastic leukemia suggest better results when using pediatric protocols for adult patients, while corresponding data for acute myeloid leukemia (AML) are limited. We investigated disease characteristics and outcome for de novo AML patients 10-30 years old treated in pediatric or adult departments. We included 166 patients 10-18 years of age with AML treated according to the pediatric NOPHO-protocols (1993-2009) compared with 253 patients aged 15-30 years treated in hematology departments (1996-2009) in the Nordic countries. The incidence of AML was 4.9/million/year for the age group 10-14 years, 6.5 for 15-18 years, and 6.9 for 19-30 years. Acute promyelocytic leukemia (APL) was more frequent in adults and in females of all ages. Pediatric patients with APL had similar overall survival as pediatric patients without APL. Overall survival at 5 years was 60% (52-68%) for pediatric patients compared to 65% (58-70%) for adult patients. Cytogenetics and presenting white blood cell count were the only independent prognostic factors for overall survival. Age was not an independent prognostic factor. No difference was found in outcome for AML patients age 10-30 years treated according to pediatric as compared to adult protocols.


Antibodies against Venom of the Snake Deinagkistrodon acutus.
Snake venom protein from Deinagkistrodon acutus (DA protein), one of the major venomous species in Taiwan, causes hemorrhagic symptoms that can lead to death. Although horse-derived antivenin is a major treatment, relatively strong and detrimental side effects are seen occasionally. In our study, yolk immunoglobulin (IgY) was purified from eggs, and DA protein was recognized using Western blotting and an enzyme-linked immunosorbent assay (ELISA), similar to therapeutic horse antivenin. The ELISA also indicated that specific IgY antibodies were elicited after the fifth booster, plateaued, and lasted for at least 3 months. To generate monoclonal single-chain variable fragment (scFv) antibodies, we used phage display technology to construct two libraries with short or long linkers, containing 6.24 × 10(8) and 5.28 × 10(8) transformants, respectively. After four rounds of biopanning, the eluted phage titer increased, and the phage-based ELISA indicated that the specific clones were enriched. Nucleotide sequences of 30 individual clones expressing scFv were analyzed and classified into four groups that all specifically recognized the DA venom protein. Furthermore, based on mass spectrometry, the scFv-bound protein was deduced to be snake venom metalloproteinase proteins. Most importantly, both IgY and mixed scFv inhibited the lethal effect in mice injected with the minimum lethal dosage of the DA protein. We suggest that together, these antibodies could be applied to the development of diagnostic agents or treatments for snakebite envenomation in the future.


Asthma and physical activity--a population based study results from the Swedish GA(2)LEN survey.
Having asthma has in previous reports been related to a lower physical activity level. At the same time the prevalence of asthma among elite athletes is high. The aim of this study was to investigate the association between physical activity level and asthma. A postal questionnaire was completed by 25,610 individuals in Sweden. Current asthma was defined as having had an asthma attack during the last 12 months or current use of asthma medication. The participants were asked how often and for how many hours a week they were physically active. In the population 1830 subjects (7.1%) had current asthma. There was no significant difference in the proportion of subjects that reported being inactive or slightly physically active between asthmatic and non-asthmatics (57 vs. 58%) while the proportion of subjects that were vigorously physically active (≥2 times a week and ≥7 h per week) was higher among the subjects with asthma (6.7 vs. 4.8%, p < 0.0001). Being vigorously physically active was independently related to current asthma (OR (95% CI)) 1.40 (1.11-1.77)), wheeze (1.39 (1.17-1.65)), wheeze and breathlessness (1.68 (1.38-2.04)), and wheezing without having a cold (1.39 (1.13-1.71)). The association between being vigorously physically active and wheeze was significantly stronger in women compared to men. There was no difference in the proportion of subjects with a reported low level of physical activity between asthmatics and non-asthmatics. Health care professionals should, however, be aware of the increased prevalence of asthma and asthma-related symptoms in vigorously physically active subjects.


Surfactant protein D (SP-D) counteracts the inhibitory effect of surfactant protein A (SP-A) on phospholipid secretion by alveolar type II cells. Interaction of native SP-D with SP-A.
The surfactant proteins SP-A and SP-D were obtained from rats given intratracheal instillation of silica. SP-D was isolated from the 33,000 g supernatant of rat bronchoalveolar lavage fluids, and we examined whether SP-D affects surfactant secretion by alveolar type II cells. Native SP-D affected neither basal secretion nor stimulated secretion by type II cells. However, native SP-D counteracted the inhibitory effect of SP-A on surfactant secretion in a concentration-dependent manner; however, SP-D failed to counteract the inhibitory effect of concanavalin A. The activity of SP-D was unaffected by inclusion of excess methyl alpha-mannoside. Excess native SP-D competed with 125I-SP-A for high-affinity binding to type II cells. Heat treatment of SP-D and antibody against SP-D both decreased SP-D activity. Butanol extraction of native SP-D was most effective at destroying SP-D activity and attenuated the ability of the protein to compete with labelled SP-A for binding to type II cells. The butanol-soluble fraction of SP-D possessed the ability to alter the inhibitory effect of SP-A to the same extent as native SP-D. Direct binding of 125I-SP-A on nitrocellulose sheets demonstrated that SP-A could bind native SP-D, but not butanol-extracted SP-D. We conclude that native SP-D alters SP-A activity in type II cells through interaction with it via SP-D-associated lipids.


Virulence properties of methicillin-susceptible Staphylococcus aureus food isolates encoding Panton-Valentine Leukocidin gene.
In this study, three Panton-Valentine Leukocidin gene carrying methicillin-susceptible Staphylococcus aureus (MSSA) strains (M1-AAG42B, PY30C-b and YF1B-b) were isolated from different food samples in Kesan-Edirne, Turkey. These strains were characterized on the basis of MLST type, spa type, virulence factor gene contents, antibiotic susceptibilities against 21 antibiotics and biofilm formation. The genetic relatedness of the strains was determined by PFGE. In addition, the complete gene sequences of lukS-PV and lukF-PV were also investigated. All strains were found to be susceptible to tested antibiotics and they were mecA negative. Three strains showed the same PFGE band pattern, ST152 clonal type and t355 spa type. In the detection of virulence factor genes, sea, seb, sec, sed, see, seg, seh, sei, sej, sek, sel, sem, sen, seo, sep, seq, seu, eta, etb, set1, geh and tst genes were not detected. All strains showed the positive results for alpha- and beta-haemolysin genes (hla and hlb), protease encoding genes (sspA, sspB and aur), lukE and lukD leukocidin genes (lukED). The strains were found to be non-biofilm formers. By this study, the virulence properties of the strains were described and this is one of the first reports regarding PVL-positive MSSA strains from food.


Extracellular and cytoplasmic domains of endoglin interact with the transforming growth factor-beta receptors I and II.
Endoglin is an auxiliary component of the transforming growth factor-beta (TGF-beta) receptor system, able to associate with the signaling receptor types I (TbetaRI) and II (TbetaRII) in the presence of ligand and to modulate the cellular responses to TGF-beta1. Endoglin cannot bind ligand on its own but requires the presence of the signaling receptors, supporting a critical role for the interaction between endoglin and TbetaRI or TbetaRII. This study shows that full-length endoglin interacts with both TbetaRI and TbetaRII, independently of their kinase activation state or the presence of exogenous TGF-beta1. Truncated constructs encoding either the extracellular or the cytoplasmic domains of endoglin demonstrated that the association with the signaling receptors occurs through both extracellular and cytoplasmic domains. However, a more specific mapping revealed that the endoglin/TbetaRI interaction was different from that of endoglin/TbetaRII. TbetaRII interacts with the amino acid region 437-558 of the extracellular domain of endoglin, whereas TbetaRI interacts not only with the region 437-558 but also with the protein region located between amino acid 437 and the N terminus. Both TbetaRI and TbetaRII interact with the cytoplasmic domain of endoglin, but TbetaRI only interacts when the kinase domain is inactive, whereas TbetaRII remains associated in its active and inactive forms. Upon association, TbetaRI and TbetaRII phosphorylate the endoglin cytoplasmic domain, and then TbetaRI, but not TbetaRII, kinase dissociates from the complex. Conversely, endoglin expression results in an altered phosphorylation state of TbetaRII, TbetaRI, and downstream Smad proteins as well as a modulation of TGF-beta signaling, as measured by the reporter gene expression. These results suggest that by interacting through its extracellular and cytoplasmic domains with the signaling receptors, endoglin might affect TGF-beta responses.


Unmetabolized folic acid in plasma is associated with reduced natural killer cell cytotoxicity among postmenopausal women.
Folic acid (FA) supplements and food fortification are used to prevent neural tube defects and to lower plasma homocysteine. Through exposure to food fortification and vitamin supplement use, large populations in the United States and elsewhere have an unprecedented high FA intake. We evaluated dietary and supplemental intakes of folate and FA in relation to an index of immune function, natural killer cell (NK) cytotoxicity, among 105 healthy, postmenopausal women. Among women with a diet low in folate (<233 microg/d), those who used FA-containing supplements had significantly greater NK cytotoxicity (P = 0.01). However, those who consumed a folate-rich diet and in addition used FA supplements > 400 microg/d had reduced NK cytotoxicity compared with those consuming a low-folate diet and no supplements (P = 0.02). Prompted by this observation, we assessed the presence of unmetabolized FA in plasma as a biochemical marker of excess FA. Unmetabolized folic acid was detected in 78% of plasma samples from fasting participants. We found an inverse relation between the presence of unmetabolized FA in plasma and NK cytotoxicity. NK cytotoxicity was approximately 23% lower among women with detectable folic acid (P = 0.04). This inverse relation was stronger among women >or= 60 y old and more pronounced with increasing unmetabolized FA concentrations (P-trend = 0.002). Because of the increased intake of FA in many countries, our findings highlight the need for further studies on the effect of long-term high FA intake on immune function and health.


Predictors of immigrant children's mental health in Canada: selection, settlement contingencies, culture, or all of the above?
A previous publication from the New Canadian Children and Youth Study, a national study of immigrant children and youth in Canada, showed a gradient of levels of emotional distress with children from Hong Kong (HK) at the most severe end, Filipino children at the least severe, and children from the People's Republic of China (PRC) in between. Based on the premise that country of origin can be regarded as an index for differing immigration trajectories, the current study examines the extent to which arrival characteristics, resettlement contingencies and cultural factors account for country of origin variations in immigrant children's mental health. Arrival characteristics included child's age at arrival, parental education, parental fluency in English or French, and assistance from family at arrival. Resettlement contingencies included parental mental health, intra-familial conflict, settlement stress, separations from parents and child's age when mother started working outside the home. Cultural factors included one-child family composition and parenting styles. A national survey of 2,031 families with at least one child between the ages of 4 and 6 or 11 and 13 from HK, the PRC and the Philippines was conducted with the Person Most Knowledgeable (PMK) in snowball-generated samples in 6 different cities across Canada. Predictors of the dependent variable, emotional problems (EP), were examined in a hierarchical block regression analysis. EP was regressed on ethnic and country of origin group in model 1; arrival characteristics were added in model 2; resettlement contingencies in model 3 and cultural factors in model 4. The final set of predictor variables accounted for 19.3 % of the variance in EP scores among the younger cohort and 23.2 % in the older. Parental human and social capital variables accounted for only a small amount of the overall variance in EP, but there were statistically significant inverse relationships between EP and PMK fluency in English or French. Settlement contingencies accounted for a significant increase in the explanatory power of the regression equation, net of the effects of country of origin and selection characteristics. This block of variables also accounted for the Filipino mental health advantage. Levels of parent's depression and somatization, harsh parenting, intrafamilial conflict, and resettlement stress each varied directly with levels of children's EP. Cultural variables made a significant contribution to explaining the variance in EP scores. Harsh parenting was significantly associated with increased levels of EP in both age groups, and supportive parenting was a mental health protective factor for younger children. Immigrant family human and social capital, according to which immigrants are selected for admission to Canada, play a relatively small role in determining children's mental health. These effects are overshadowed by resettlement contingencies and cultural influences. Concentrating on trying to find a formula to select the "right" immigrants while neglecting settlement and culture is likely to pay limited dividends for ensuring the mental health of children.


Etiologic heterogeneity among non-Hodgkin lymphoma subtypes: the InterLymph Non-Hodgkin Lymphoma Subtypes Project.
Non-Hodgkin lymphoma (NHL) comprises biologically and clinically heterogeneous subtypes. Previously, study size has limited the ability to compare and contrast the risk factor profiles among these heterogeneous subtypes. We pooled individual-level data from 17 471 NHL cases and 23 096 controls in 20 case-control studies from the International Lymphoma Epidemiology Consortium (InterLymph). We estimated the associations, measured as odds ratios, between each of 11 NHL subtypes and self-reported medical history, family history of hematologic malignancy, lifestyle factors, and occupation. We then assessed the heterogeneity of associations by evaluating the variability (Q value) of the estimated odds ratios for a given exposure among subtypes. Finally, we organized the subtypes into a hierarchical tree to identify groups that had similar risk factor profiles. Statistical significance of tree partitions was estimated by permutation-based P values (P NODE). Risks differed statistically significantly among NHL subtypes for medical history factors (autoimmune diseases, hepatitis C virus seropositivity, eczema, and blood transfusion), family history of leukemia and multiple myeloma, alcohol consumption, cigarette smoking, and certain occupations, whereas generally homogeneous risks among subtypes were observed for family history of NHL, recreational sun exposure, hay fever, allergy, and socioeconomic status. Overall, the greatest difference in risk factors occurred between T-cell and B-cell lymphomas (P NODE < 1.0×10(-4)), with increased risks generally restricted to T-cell lymphomas for eczema, T-cell-activating autoimmune diseases, family history of multiple myeloma, and occupation as a painter. We further observed substantial heterogeneity among B-cell lymphomas (P NODE < 1.0×10(-4)). Increased risks for B-cell-activating autoimmune disease and hepatitis C virus seropositivity and decreased risks for alcohol consumption and occupation as a teacher generally were restricted to marginal zone lymphoma, Burkitt/Burkitt-like lymphoma/leukemia, diffuse large B-cell lymphoma, and/or lymphoplasmacytic lymphoma/Waldenström macroglobulinemia. Using a novel approach to investigate etiologic heterogeneity among NHL subtypes, we identified risk factors that were common among subtypes as well as risk factors that appeared to be distinct among individual or a few subtypes, suggesting both subtype-specific and shared underlying mechanisms. Further research is needed to test putative mechanisms, investigate other risk factors (eg, other infections, environmental exposures, and diet), and evaluate potential joint effects with genetic susceptibility.


Persistent environmental pollutants and couple fecundity: the LIFE study.
Evidence suggesting that persistent environmental pollutants may be reproductive toxicants underscores the need for prospective studies of couples for whom exposures are measured. We examined the relationship between selected persistent pollutants and couple fecundity as measured by time to pregnancy. A cohort of 501 couples who discontinued contraception to become pregnant was prospectively followed for 12 months of trying to conceive or until a human chorionic gonadotrophin (hCG) test confirmed pregnancy. Couples completed daily journals on lifestyle and provided biospecimens for the quantification of 9 organochlorine pesticides, 1 polybrominated biphenyl, 10 polybrominated diphenyl ethers, 36 polychlorinated biphenyls (PCBs), and 7 perfluorochemicals (PFCs) in serum. Using Cox models for discrete time, we estimated fecundability odds ratios (FORs) and 95% CIs separately for each partner's concentrations adjusting for age, body mass index, serum cotinine, serum lipids (except for PFCs), and study site (Michigan or Texas); sensitivity models were further adjusted for left truncation or time off of contraception (≤ 2 months) before enrollment. The adjusted reduction in fecundability associated with standard deviation increases in log-transformed serum concentrations ranged between 18% and 21% for PCB congeners 118, 167, 209, and perfluorooctane sulfonamide in females; and between 17% and 29% for p,p´-DDE and PCB congeners 138, 156, 157, 167, 170, 172, and 209 in males. The strongest associations were observed for PCB 167 (FOR 0.79; 95% CI: 0.64, 0.97) in females and PCB 138 (FOR = 0.71; 95% CI: 0.52, 0.98) in males. In this couple-based prospective cohort study with preconception enrollment and quantification of exposures in both female and male partners, we observed that a subset of persistent environmental chemicals were associated with reduced fecundity.


Laparoscopic versus Open Roux-en-Y hepatojejunostomy for children with choledochal cysts: intermediate-term follow-up results.
Laparoscopic hepatojejunostomy (LH) for children with choledochal cysts (CDC) has been gaining popularity recently. However, its safety and efficacy remain unknown. The purpose of this study was to evaluate the intermediate-term results of LH for CDC children. We reviewed 218 patients who underwent LH between October 2001 and October 2009 and 200 patients who underwent open hepatojejunostomy (OH) between September 1993 and September 2001. Ultrasonography, upper gastrointestinal contrast studies, and laboratory tests were performed during the follow-up period. Age, operative blood loss, operative time, postoperative hospital stay, time to full feed, duration of drainage, postoperative complications, and perioperative laboratory tests were evaluated in both groups. The median follow-up periods of the LH and OH groups were 38 and 146 months, respectively. There was no significant difference in age between the two groups. Interestingly, the operative time of the LH group decreased significantly with increasing number of cases (P<0.01). The most recent operative time of the LH group did not differ from that of the OH group (3.04 vs. 2.95 h, P=0.557). The operative blood loss of the LH group was significantly less (P<0.001). The postoperative hospital stay, resumption of alimentation, and duration of drainage in the LH group were significantly shorter (P<0.001, respectively). Two of 218 (0.9%) LH patients developed bile leak. This was significantly less than 11 of 200 (5.5%) in the OH group (P<0.01). The morbidities of LH group were significantly lower than those of the OH group. Postoperative liver function tests and serum amylase levels normalized in both groups (P<0.001). Laparoscopic hepatojejunostomy is safe and effective. Its intermediate-term results are comparable to open surgery.


Akt-Girdin signaling in cancer-associated fibroblasts contributes to tumor progression.
PI3K-Akt signaling is critical for the development, progression, and metastasis of malignant tumors, but its role in the tumor microenvironment has been relatively little studied. Here, we report that the Akt substrate Girdin, an actin-binding protein that regulates cell migration, is expressed and activated by Akt phosphorylation in cancer-associated fibroblasts (CAF) and blood vessels within the tumor microenvironment. Lewis lung tumors grafted into mice defective in Akt-mediated Girdin phosphorylation (SA transgenic mice) exhibited a decrease in both CAF infiltration and tumor growth, compared with wild-type (WT) host control animals. Contrasting with the findings of other studies, we found that Akt-dependent phosphorylation of Girdin was not a rate-limiting step in the growth of endothelial cells. In addition, Lewis lung tumors displayed limited outgrowth when cotransplanted with CAF derived from tumor-bearing SA transgenic mice, compared with CAF derived from tumor-bearing WT mice. Collectively, our results revealed a role for Akt-mediated Girdin phosphorylation in CAF during tumor progression, highlighting the need to inhibit Akt function in both tumor cells and cells that comprise the tumor microenvironment.


Prolonged thromboprophylaxis with low molecular weight heparin for abdominal or pelvic surgery.
This an update of the review first published in 2009.Major abdominal and pelvic surgery carries a high risk of venous thromboembolism (VTE). The efficacy of thromboprophylaxis with low molecular weight heparin (LMWH) administered during the in-hospital period is well-documented, but the optimal duration of prophylaxis after surgery remains controversial. Some studies suggest that patients undergoing major abdominopelvic surgery benefit from prolongation of the prophylaxis up to 28 days after surgery. To evaluate the efficacy and safety of prolonged thromboprophylaxis with LMWH for at least 14 days after abdominal or pelvic surgery compared with thromboprophylaxis administered during the in-hospital period only in preventing late onset VTE. We performed electronic searches on 28 October 2017 in the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, LILACS and registered trials (Clinicaltrials.gov October 28, 2017 and World Health Organization International Clinical Trials Registry Platform (ICTRP) 28 October 2017). Abstract books from major congresses addressing thromboembolism were handsearched from 1976 to 28 October 2017, as were reference lists from relevant studies. We assessed randomized controlled clinical trials (RCTs) comparing prolonged thromboprophylaxis (≥ fourteen days) with any LMWH agent with placebo, or other methods, or both to thromboprophylaxis during the admission period only. The population consisted of persons undergoing abdominal or pelvic surgery for both benign and malignant pathology. The outcome measures included VTE (deep venous thrombosis (DVT) or pulmonary embolism (PE)) as assessed by objective means (venography, ultrasonography, pulmonary ventilation/perfusion scintigraphy, spiral computed tomography (CT) scan or autopsy). We excluded studies exclusively reporting on clinical diagnosis of VTE without objective confirmation. Review authors identified studies and extracted data. Outcomes were VTE (DVT or PE) assessed by objective means. Safety outcomes were defined as bleeding complications and mortality within three months after surgery. Sensitivity analyses were also performed with unpublished studies excluded, and with study participants limited to those undergoing solely open and not laparoscopic surgery. We used a fixed-effect model for analysis. We identified seven RCTs (1728 participants) evaluating prolonged thromboprophylaxis with LMWH compared with control or placebo. The searches resulted in 1632 studies, of which we excluded 1528. One hundred and four abstracts, eligible for inclusion, were assessed of which seven studies met the inclusion criteria.For the primary outcome, the incidence of overall VTE after major abdominal or pelvic surgery was 13.2% in the control group compared to 5.3% in the patients receiving out-of-hospital LMWH (Mantel Haentzel (M-H) odds ratio (OR) 0.38, 95% confidence interval (CI) 0.26 to 0.54; I2 = 28%; moderate-quality evidence).For the secondary outcome of all DVT, seven studies, n = 1728, showed prolonged thromboprophylaxis with LMWH to be associated with a statistically significant reduction in the incidence of all DVT (M-H OR 0.39, 95% CI 0.27 to 0.55; I2 = 28%; moderate-quality evidence).We found a similar reduction when analysis was limited to incidence in proximal DVT (M-H OR 0.22, 95% CI 0.10 to 0.47; I2 = 0%; moderate-quality evidence).The incidence of symptomatic VTE was also reduced from 1.0% in the control group to 0.1% in patients receiving prolonged thromboprophylaxis (M-H OR 0.30, 95% CI 0.08 to 1.11; I2 = 0%; moderate-quality evidence).No difference in the incidence of bleeding between the control and LMWH group was found, 2.8% and 3.4%, respectively (M-H OR 1.10, 95% CI 0.67 to 1.81; I2 = 0%; moderate-quality evidence).No difference in mortality between the control and LMWH group was found, 3.8% and 3.9%, respectively (M-H OR 1.15, 95% CI 0.72 to 1.84; moderate-quality evidence).Estimates of heterogeneity ranged between 0% and 28% depending on the analysis, suggesting low or unimportant heterogeneity. Prolonged thromboprophylaxis with LMWH significantly reduces the risk of VTE compared to thromboprophylaxis during hospital admittance only, without increasing bleeding complications or mortality after major abdominal or pelvic surgery. This finding also holds true for DVT alone, and for both proximal and symptomatic DVT. The quality of the evidence is moderate and provides moderate support for routine use of prolonged thromboprophylaxis. Given the low heterogeneity between studies and the consistent and moderate evidence of a decrease in risk for VTE, our findings suggest that additional studies may help refine the degree of risk reduction but would be unlikely to significantly influence these findings. This updated review provides additional evidence and supports the previous results reported in the 2009 review.


Apical entry and release of severe acute respiratory syndrome-associated coronavirus in polarized Calu-3 lung epithelial cells.
Severe acute respiratory syndrome (SARS), caused by a novel coronavirus (CoV) known as SARS-CoV, is a contagious and life-threatening respiratory illness with pneumocytes as its main target. A full understanding of how SARS-CoV would interact with lung epithelial cells will be vital for advancing our knowledge of SARS pathogenesis. However, an in vitro model of SARS-CoV infection using relevant lung epithelial cells is not yet available, making it difficult to dissect the pathogenesis of SARS-CoV in the lungs. Here, we report that SARS-CoV can productively infect human bronchial epithelial Calu-3 cells, causing cytopathic effects, a process reflective of its natural course of infection in the lungs. Indirect immunofluorescence studies revealed a preferential expression of angiotensin-converting enzyme 2 (ACE-2), the functional receptor of SARS-CoV, on the apical surface. Importantly, both ACE-2 and viral antigen appeared to preferentially colocalize at the apical domain of infected cells. In highly polarized Calu-3 cells grown on the membrane inserts, we found that cells exposed to virus through the apical rather than the basolateral surface showed high levels of viral replication. Progeny virus was released into the apical chamber at titers up to 5 logs higher than those recovered from the basolateral chambers of polarized cultures. Taken together, these results indicate that SARS-CoV almost exclusively entered and was released from the apical domain of polarized Calu-3 cells, which might provide important insight into the mechanism of transmission and pathogenesis of SARS-CoV.


A phase I trial of adenovector-mediated delivery of interleukin-2 (AdIL-2) in high-risk localized prostate cancer.
Preclinical studies demonstrate that intratumoral delivery of adenovirus expressing IL-2 eradicates pre-established tumors in mice and confers immune protection from rechallenge. To explore the activity of AdCAIL-2 in prostate cancer, a Phase I clinical trial was conducted in patients with localized disease and Gleason score >7 or prostate-specific antigen (PSA) >10 plus Gleason score 7. A total of 12 patients were injected 4 weeks prior to prostatectomy in a dose-escalation study at doses of 10(9), 5 x 10(9) and 10(10) PFU of virus. No dose-limiting toxicity was observed. Side effects included perineal discomfort, hematuria, flu-like symptoms in two patients and urinary hesitancy in one patient. Pathology demonstrated an inflammatory response consisting predominantly of CD3+CD8+ T lymphocytes with areas of tumor necrosis. Intracellular cytokine staining of tumor-infiltrating lymphocytes demonstrated increases in both gamma-interferon and IL-4 secreting T cells after vaccination. PSA levels fell in five of five evaluable patients treated at the lowest dose (mean decline of 33.3%, range 17-69%). At higher doses, PSA values initially increased after injection, then fell to baseline prior to surgery. This trial demonstrates the feasibility and safety of intraprostatic adenovector-mediated IL-2 gene delivery.


The relationship of speech intelligibility with hearing sensitivity, cognition, and perceived hearing difficulties varies for different speech perception tests.
Listeners vary in their ability to understand speech in noisy environments. Hearing sensitivity, as measured by pure-tone audiometry, can only partly explain these results, and cognition has emerged as another key concept. Although cognition relates to speech perception, the exact nature of the relationship remains to be fully understood. This study investigates how different aspects of cognition, particularly working memory and attention, relate to speech intelligibility for various tests. Perceptual accuracy of speech perception represents just one aspect of functioning in a listening environment. Activity and participation limits imposed by hearing loss, in addition to the demands of a listening environment, are also important and may be better captured by self-report questionnaires. Understanding how speech perception relates to self-reported aspects of listening forms the second focus of the study. Forty-four listeners aged between 50 and 74 years with mild sensorineural hearing loss were tested on speech perception tests differing in complexity from low (phoneme discrimination in quiet), to medium (digit triplet perception in speech-shaped noise) to high (sentence perception in modulated noise); cognitive tests of attention, memory, and non-verbal intelligence quotient; and self-report questionnaires of general health-related and hearing-specific quality of life. Hearing sensitivity and cognition related to intelligibility differently depending on the speech test: neither was important for phoneme discrimination, hearing sensitivity alone was important for digit triplet perception, and hearing and cognition together played a role in sentence perception. Self-reported aspects of auditory functioning were correlated with speech intelligibility to different degrees, with digit triplets in noise showing the richest pattern. The results suggest that intelligibility tests can vary in their auditory and cognitive demands and their sensitivity to the challenges that auditory environments pose on functioning.


Effects of high-oil corn on feedlot performance, carcass characteristics, fatty acid profiles, beef palatability, and retail case life traits of beef top loin steaks.
Our objective was to compare the effects of feeding steam-flaked, high-oil corn with normal steam-flaked corn to which yellow grease was added to equalize dietary fat on performance and carcass characteristics of finishing beef steers, and palatability, retail case life, and fatty acid composition of strip loins. Angus steers (n = 120; initial BW = 288 kg) were allotted to dietary treatments consisting of 1) normal mill-run, steam-flaked corn plus added fat (NMR) or 2) high-oil, steam-flaked corn (HOC) and assigned randomly to pens (12 pens/treatment with 5 steers/pen). Performance (ADG, DMI, and G:F) was measured over time, and cattle were shipped to a commercial abattoir for collection of carcass data after 165 d on feed. Carcass data were collected at 48 h postmortem on all carcasses, and 2 carcasses from each pen were selected randomly for collection of strip loins (IMPS #180A). At 14 d postmortem, 4 steaks (2.54 cm thick) were removed for retail display, trained sensory panel analysis, Warner-Bratzler shear force determination, and fatty acid analysis. Daily BW gain was greater (P = 0.03) and G:F was increased 8.4% (P = 0.01) for steers fed NMR compared with HOC, but DMI was not affected (P > 0.10) by treatment. No treatment differences were observed (P > 0.10) for HCW, 12th-rib fat, KPH, and yield grade. Marbling scores were greater (P = 0.01) for NMR than for HOC, and LM area tended (P = 0.07) to be greater in NMR than in HOC carcasses. The proportion of carcasses grading USDA Choice did not differ (P = 0.77) between treatments, but a greater (P = 0.04) proportion of carcasses graded in the upper two-thirds of Choice for NMR vs. HOC. Trained sensory panel traits and Warner-Bratzler shear force values did not differ between treatments (P > 0.10), and no differences (P > 0.10) were detected for purge loss or fatty acid composition. Overall, ADG and G:F were less and marbling score was decreased, but there were no differences between treatments in beef palatability, retail case life, or concentrations of fatty acids in strip loins.


Natural polymorphisms in human APOBEC3H and HIV-1 Vif combine in primary T lymphocytes to affect viral G-to-A mutation levels and infectivity.
The Vif protein of HIV-1 allows virus replication by degrading several members of the host-encoded APOBEC3 family of DNA cytosine deaminases. Polymorphisms in both host APOBEC3 genes and the viral vif gene have the potential to impact the extent of virus replication among individuals. The most genetically diverse of the seven human APOBEC3 genes is APOBEC3H with seven known haplotypes. Overexpression studies have shown that a subset of these variants express stable and active proteins, whereas the others encode proteins with a short half-life and little, if any, antiviral activity. We demonstrate that these stable/unstable phenotypes are an intrinsic property of endogenous APOBEC3H proteins in primary CD4+ T lymphocytes and confer differential resistance to HIV-1 infection in a manner that depends on natural variation in the Vif protein of the infecting virus. HIV-1 with a Vif protein hypo-functional for APOBEC3H degradation, yet fully able to counteract APOBEC3D, APOBEC3F, and APOBEC3G, was susceptible to restriction and hypermutation in stable APOBEC3H expressing lymphocytes, but not in unstable APOBEC3H expressing lymphocytes. In contrast, HIV-1 with hyper-functional Vif counteracted stable APOBEC3H proteins as well as all other endogenous APOBEC3s and replicated to high levels. We also found that APOBEC3H protein levels are induced over 10-fold by infection. Finally, we found that the global distribution of stable/unstable APOBEC3H haplotypes correlates with the distribution a critical hyper/hypo-functional Vif amino acid residue. These data combine to strongly suggest that stable APOBEC3H haplotypes present as in vivo barriers to HIV-1 replication, that Vif is capable of adapting to these restrictive pressures, and that an evolutionary equilibrium has yet to be reached.


Smoking cessation and related factors in middle-aged and older Chinese adults: Evidence from a longitudinal study.
There are more than 300 million smokers in China. This study aimed to evaluate the rate of smoking cessation, smoking relapse and related factors in middle-aged and older smokers in China. We performed a secondary analysis of data from China Health and Retirement Longitudinal Study (CHARLS) that recruited a nationally representative sample of adults aged 45 and older. Participants were 3708 smokers in 2011 who completed two waves of follow-up interviews in 2013 and 2015. Self-reported quit and relapse rates at follow-ups were estimated. Multiple logistic regressions were conducted to identify factors associated with smoking cessation and relapse. The overall quit rate was 8.5% (95% CI 7.7% - 9.5%) at the 2-year follow-up in 2013, and 16.6% (95% CI 15.5% - 17.9%) at the 4-year follow up. Smoking cessation in 2013 was associated with not living in the northeast region (p = 0.003), fewer cigarettes smoked daily (p <0.001), and longer time to the first cigarette in the morning (p<0.001). Smoking cessation in 2015 was associated with older age (p = 0.049), smoking initiation at age ≥20 years (p<0.001), longer time to the first cigarette in the morning (p<0.001), and self-perceived poor health (p<0.001). Of the 317 participants who stopped smoking in 2013, 13.3% (95% CI 9.9% - 17.5%) relapsed by 2015. Smoking relapse was associated with younger age (p = 0.025), shorter time to the first cigarette in the morning (p = 0.003), and self-perception of not poor health (p = 0.018). The overall quit rate was 8.5% at the 2-year follow up, and 16.6% at the 4-year follow up in the middle-aged and older smokers, but 13% of quitters returned to smoking in two years. Successful smoking cessation was associated with older age, lower nicotine dependence, and self-perceived poor health.


Balanced homodyne detection of Bragg microholograms in photopolymer for data storage.
Wavelength multiplexed holographic bit oriented memories are serious competitors for high capacity data storage systems. For data recording, two interfering beams are required whereas one of them should be blocked for readout in previously proposed systems. This makes the system complex. To circumvent this difficulty and make the device simpler, we validated an architecture for such memories in which the same two beams are used for recording and reading out. This balanced homodyne scheme is validated by recording holograms in a Lippmann architecture.


Non-Operative Management of Type 2 ERCP-Related Retroperitoneal Duodenal Perforations: A 9-Year Experience From a Single Center.
No consensus exists on treatment of endoscopic retrograde cholangiopancreatography (ERCP) -related, retroperitoneal duodenal perforations. The aim of this study is to determine the incidence of post-ERCP retroperitoneal periampullary (type 2) duodenal perforations and the clinical outcome of non-surgical management. Patients who underwent ERCP in our institution during the period from January 1, 2009 to December 31, 2017 were included. Any cases of retroperitoneal periampullary duodenal (type 2) perforation were identified. Relevant data (patient characteristics, indications, radiographic findings, time to diagnosis and surgery, surgical procedures, hospital stay and outcome) were retrospectively collected and reviewed. Results were compared to those from the existing literature. There were 24 patients with retroperitoneal type 2 duodenal perforation following 4,196 ERCPs were identified (24/4196, 0.57%) over the 9-year period. ERCP indications were: choledocholithiasis, obstructive jaundice and ampullectomy (ampullary adenoma). Diagnosis (aided by CT scan) was established within the first 12 h in the majority of patients (21/24, 87.5%) and intraprocedural in 3/24, (12.5%). Twelve patients (50%) with deteriorating clinical course were managed with CT-guided percutaneous drainage. Surgical intervention was required in two (8.3%). Overall mortality was 4.2%, 1/24 (one patient died after surgery). Retroperitoneal duodenal perforation is a rare and severe ERCP complication. However, conservative management is feasible in the majority of cases.


MO-B-218-01: Managing the Pediatric Patient's CT Dose: The Role of SSDE.
As many as 6 - 8 million CT scans are performed annually in the United States on pediatric patients. The majority of these CT scans are not performed in pediatric hospitals that specialize in addressing the unique requirements of pediatric imaging. Instead, most of these scans occur in adult hospitals, where pediatric CT scanning is a small fraction of the total caseload. Both adult and pediatric hospitals need a simple method that allows the management of the CT radiation dose received by each patient based on the patient's physical size. This lecture suggests some simple tools and techniques that the qualified medical physicist can introduce to an individual practice in an effort to properly manage CT doses. This lecture begins by exploring the unique challenges presented by the pediatric patient in the management of their radiation dose during CT scanning. This is followed by an explanation of the basic science behind the development of the Size Specific Dose Estimate (SSDE) in CT, the strengths and weaknesses of the method, and some sample calculations. The presentation concludes by exploring the clinical application of SSDE in the day to day management of the radiation dose during CT scanning of not only small pediatric patients, but also patients who are larger than the average size adult. 1. Understand the basic challenges associated with CT imaging of children. 2. Understand the basic science used to develop SSDE, its strengths and its limitations 3. Understand the application of SSDE in the clinic in the daily management of pediatric CT doses.


The radiographic evolution of radio frequency ablated renal tumors.
Radio frequency ablation (RFA) of renal tumors is a relatively new technology. Few groups are familiar with the posttreatment appearance of these lesions and how they differ from cryoablated renal masses. We describe the evolution of the appearance of these lesions on followup contrast enhanced (CE) computerized tomography (CT). A total of 64 consecutive renal tumors treated with RFA from April 2000 to September 2003 for which posttreatment CE-CT was done were included in this study. CE-CT was reviewed at 6 weeks, 3 months, 6 months and every 6 months thereafter to determine the characteristic features and evolution of these lesions. Renal tumors were treated with CT guided percutaneous (34), laparoscopic (28) or open (2) RFA. At a median followup of 13.7 months (range 6 weeks to 29 months) 62 RFA lesions demonstrated an absence of contrast enhancement on CE-CT. Treated endophytic tumors developed a low density, nonenhancing, wedge-shaped defect with fat infiltration seen between the ablated tissue and normal parenchyma. Treated exophytic tumors retained a configuration similar to that of the original with a lack of contrast enhancement and minimal shrinkage. Percutaneous treated lesions developed a peritumor scar or halo that demarcated ablated and nonablated tissue (perirenal fat). Persistent tumor was marked by contrast enhancement within the ablation borders of the original mass in 1 case, whereas tumor recurred after initial successful ablation with an enhancing nodule in 1. The radiographic features and evolution of radio frequency ablated renal tumors are unique. Successfully treated tumors demonstrated no contrast enhancement, minimal shrinkage and occasional retraction from normal parenchyma by fat infiltration.


Monophosphothreonyl extracellular signal-regulated kinases 1 and 2 (ERK1/2) are formed endogenously in intact cardiac myocytes and are enzymically active.
ERK1 and ERK2 (ERK1/2) are central to the regulation of cell division, growth and survival. They are activated by phosphorylation of the Thr- and the Tyr- residues in their Thr-Glu-Tyr activation loops. The dogma is that dually-phosphorylated ERK1/2 constitute the principal activities in intact cells. We previously showed that, in neonatal rat cardiac myocytes, endothelin-1 and phorbol 12-myristate 13-acetate (PMA) powerfully and rapidly (maximal at ~5 min) activate ERK1/2. Here, we show that dually-phosphorylated ERK1/2 rapidly (< 2 min) appear in the nucleus following stimulation with endothelin-1. We characterized the active ERK1/2 species in myocytes exposed to endothelin-1 or PMA using MonoQ FPLC. Unexpectedly, two peaks of ERK1 and two peaks of ERK2 activity were resolved using in vitro kinase assays. One of each of these represented the dually-phosphorylated species. The other two represented activities for ERK1 or ERK2 which were phosphorylated solely on the Thr- residue. Monophosphothreonyl ERK1/2 represented maximally ~30% of total ERK1/2 activity after stimulation with endothelin-1 or PMA, and their k(cat) values were estimated to be minimally ~30% of the dually-phosphorylated species. Appearance of monophosphothreonyl ERK1/2 was rapid but delayed in comparison with dually-phosphorylated ERK1/2. Of 10 agonists studied, endothelin-1 and PMA were most effective in terms of ERK1/2 activation and in stimulating the appearance of monophosphothreonyl and dually-phosphorylated ERK1/2. Thus, enzymically active monophosphothreonyl ERK1/2 are formed endogenously following activation of the ERK1/2 cascade and we suggest that monophosphothreonyl ERK1/2 arise by protein tyrosine phosphatase-mediated dephosphorylation of dually-phosphorylated ERK1/2.


The sleep of remitted bipolar outpatients: a controlled naturalistic study using actigraphy.
Several sleep laboratory studies suggest sleep abnormalities in bipolar disorder. However, this is the first study to compare remitted bipolar subjects with controls on actigraphic and subjective sleep parameters in a naturalistic setting over 5 nights. Nineteen subjects with Bipolar I Disorder and 19 age- and gender-matched healthy controls were included. Objective sleep parameters were estimated using wrist actigraphs. Subject-rated sleep diaries and mood ratings were also completed. Sleep data were averaged for each subject across nights, and raw score standard deviations were calculated as a measure of within-subject variability. Multivariate analyses of variance found significant group differences for both actigraphic (F(4,33)=3.80, P=0.012) and subjective measures (F(4,31)=3.18, P=0.027). Univariate analyses identified reliable differences in sleep onset latency (subjective), sleep duration (subjective), and variability of sleep duration and night wake time (actigraphic). Binary backward stepwise logistic regression demonstrated that a combination of three sleep measures correctly predicted disorder status in 84% of cases. Failure to match on sociodemographic and employment status is a limitation that may provide an alternative explanation for some findings. Furthermore, in the bipolar group 18 of 19 subjects were in receipt of psychotropic medication, compared to none of the healthy control group. Also, no information was recorded about family history of mental disorders in the control group. The study suggests that the sleep of remitted bipolar outpatients measured in naturalistic settings is characteristically different from controls: bipolar subjects sleep longer, report longer onset latencies, and display greater variability across nights.


Anticipation, teamwork and cognitive load: chasing efficiency during robot-assisted surgery.
Robot-assisted surgery (RAS) has changed the traditional operating room (OR), occupying more space with equipment and isolating console surgeons away from the patients and their team. We aimed to evaluate how anticipation of surgical steps and familiarity between team members impacted efficiency. We analysed recordings (video and audio) of 12 robot-assisted radical prostatectomies. Any requests between surgeon and the team members were documented and classified by personnel, equipment type, mode of communication, level of inconvenience in fulfilling the request and anticipation. Surgical team members completed questionnaires assessing team familiarity and cognitive load (National Aeronautics and Space Administration - Task Load Index). Predictors of team efficiency were assessed using Pearson correlation and stepwise linear regression. 1330 requests were documented, of which 413 (31%) were anticipated. Anticipation correlated negatively with operative time, resulting in overall 8% reduction of OR time. Team familiarity negatively correlated with inconveniences. Anticipation ratio, per cent of requests that were non-verbal and total request duration were significantly correlated with the console surgeons' cognitive load (r=0.77, p=0.006; r=0.63, p=0.04; and r=0.70, p=0.02, respectively). Anticipation and active engagement by the surgical team resulted in shorter operative time, and higher familiarity scores were associated with fewer inconveniences. Less anticipation and non-verbal requests were also associated with lower cognitive load for the console surgeon. Training efforts to increase anticipation and team familiarity can improve team efficiency during RAS.


Increases in eotaxin-positive cells in induced sputum from atopic asthmatic subjects after inhalational allergen challenge.
Eosinophils are believed to be critical proinflammatory cells in airway mucosal damage in asthma. Eotaxin is a C-C chemokine with selective activity for eosinophils and basophils. Previous studies have shown increased expression of eotaxin in the airways of asthmatics at baseline. We aimed to investigate eotaxin expression during the late-phase reaction to allergen inhalation in atopic asthmatics. Sputum induction was performed before and 24 h after inhalational allergen challenge in atopic asthmatics, and eotaxin protein was detected immunocytochemically. Thirteen patients with a mean decrease in forced expiratory volume in 1 s of 28% (+/-1.5) during the early asthmatic reaction, and 39% (+/-4.7) during the late asthmatic reaction produced sufficient sputum for study. The percentage of eosinophils in sputum was increased 24 h after allergen challenge (P<0.004), and eosinophil percentages in sputum after challenge correlated with the magnitude of the late-phase reaction (r=0.56, P=0.05). The percentage of eotaxin-positive cells increased from 12.6% (range 2-43.8) to 24.3% (8.1-47.1, P<0.005). Allergen-induced increases in eotaxin-positive cells correlated with increases in eosinophils (r=0.63, P<0.01). These findings suggest that eotaxin may contribute to allergen-induced recruitment of eosinophils to the airway in asthmatic subjects.


A review of production methods of carbon nanotube and graphene thin films for electrothermal applications.
Electrothermal materials transform electric energy into heat due to the Joule effect. To date, resistive wires made of heavy metal alloys have primarily been used as the heat source in many appliances surrounding us. Recent discoveries in the field of carbon nanostructures revealed that they can offer a spectrum of advantages over the traditional materials. We review the production methods of thin films composed of carbon nanotubes or graphene and depict how they can be used as conductive coatings for electrothermal applications. We screen all reports from the field up to now and highlight the features of designed nanoheaters. A particular focus is placed on the analysis of general findings of how to tune their electrothermal properties, why carbon nanostructure devices operate the way they do and in what aspects they are superior to the currently available materials on the market.


Development and optimization of a novel PLGA-Levan based drug delivery system for curcumin, using a quality-by-design approach.
This study aimed to develop a PLGA, Levan-based drug delivery system (DDS) of Curcumin using a quality-by-design (QbD) approach to reveal how formulation parameters affect the critical quality attributes (CQAs) of this DDS and to present an optimal design. First, a risk assessment was conducted to determine the impact of various process parameters on the CQAs of the DDS (i.e., average particle size, ZP, encapsulation efficiency and polydispersity index). Plackett-Burman design revealed that potential risk factors were Levan molecular weight, PLGA amount and acetone amount. Then, the optimization of the DDS was achieved through a Box-Behnken Design. The optimum formulation was prepared using low molecular weight Levan (134 kDa), 51.51 mg PLGA and 10 ml acetone. The model was validated and the optimized formulation was further characterized using different physic-chemical methods. The study resulted in the most stable NP with a spherical and uniform shape and physical stability tests indicated its stability for at least 60 days at room temperature. In conclusion, this study was an effort for developing a DDS which solubilizes Curcumin in clinically applicable concentrations.


Assessment of the structure of the Hospital Anxiety and Depression Scale in musculoskeletal patients.
Research suggests there is a high prevalence of anxiety and depression amongst patients with chronic musculoskeletal pain, which can influence the effectiveness of rehabilitation programs. It is therefore important for clinicians involved in musculoskeletal rehabilitation programs to consider screening patients for elevated levels of anxiety and depression and to provide appropriate counselling or treatment where necessary. The HADS has been used as a screening tool for assessment of anxiety and depression in a wide variety of clinical groups. Recent research however has questioned its suitability for use with some patient groups due to problems with dimensionality and the behaviour of individual items. The aim of this study is to assess the underlying structure and psychometric properties of the HADS among patients attending musculoskeletal rehabilitation. Data was obtained from 296 patients attending an outpatient musculoskeletal pain clinic. The total sample was used to identify the proportion of patients with elevated levels of anxiety and depression. Half the sample (n = 142) was used for exploratory factor analysis (EFA), with the holdout sample (n = 154) used for confirmatory factor analysis (CFA) to explore the underlying structure of the scale. A substantial proportion of patients were classified as probable cases on the HADS Anxiety subscale (38.2%) and HADS Depression subscale (30.1%), with the sample recording higher mean HADS subscales scores than many other patient groups (breast cancer, end-stage renal disease, heart disease) reported in the literature. EFA supported a two factor structure (representing anxiety and depression) as proposed by the scale's authors, however item 7 (an anxiety item) failed to load appropriately. Removing Item 7 resulted in a clear two factor solution in both EFA and CFA. The high levels of anxiety and depression detected in this sample suggests that screening for psychological comorbidity is important in musculoskeletal rehabilitation settings. It is necessary for clinicians who are considering using the HADS as a screening tool to first assess its suitability with their particular patient group. Although EFA and CFA supported the presence of two subscales representing anxiety and depression, the results with this musculoskeletal sample suggest that item 7 should be removed from the anxiety subscale.


Unidirectional single-mode Nd:YAG laser with a planar semimonolithic ring cavity.
Unidirectional single-mode operation of a diode-pumped Nd:YAG laser with a planar semimonolithic ring cavity has been demonstrated at 1064 nm. The semimonolithic cavity consists of a laser active medium placed in a magnetic field, a crystal quartz plate, and an output coupling mirror, which form an optical diode by acting as a Faraday rotator, a reciprocal polarization rotator, and a partial polarizer, respectively. A single-mode output power of 155 mW and a slope efficiency of 17% were obtained with a 1.2-W diode laser at 809 nm. A laser linewidth of less than 100 kHz is inferred from a beat note frequency spectrum between two identical laser systems and continuous tuning to greater than 2 GHz was observed.


The Placement of Post-pyloric Feeding Tubes Using DRX-Revolution Mobile X-Ray System in an ICU. A Case Series.
Enteral nutrition is crucial for ensuring that critically ill patients have a proper intake of food, water, and medicine. Methods to ensure this requirement should be initiated as early as possible. The use of PPF has several advantages compared to the use of a nasogastric feeding tube. In the present paper, the cases of three critically ill patients with a nonfunctional gastrointestinal system on admission to ICU, are detailed. Enteral feeding through a nasogastric tube by prokinetic agent therapy had been unsuccessful. The bedside placement of a post-pyloric feeding tube by the DRX-Revolution X-ray system is described.


Changes in parahippocampal white matter integrity in amnestic mild cognitive impairment: a diffusion tensor imaging study.
In the present study, changes in the parahippocampal white matter (PWM), in the region that includes the perforant path, were investigated, in vivo, in 14 individuals with amnestic mild cognitive impairment (aMCI) compared to 14 elderly controls with no cognitive impairment (NCI). For this purpose, (1) volumetry; (2) diffusion tensor imaging (DTI) derived measures of mean diffusivity (MD) and fractional anisotropy (FA); and (3) tractography were used. In addition, regression models were utilized to examine the association of PWM measurements with memory decline. The results from this study confirm previous findings in our laboratory and others, showing that compared to controls, individuals with aMCI have PWM volume loss. In addition to volume reduction, participants with aMCI demonstrated a significant increase in MD, but no difference in FA, both in the PWM region and in fibers modeled to pass through the PWM region. Further, the DTI metric of MD was associated with declarative memory performance, suggesting it may be a sensitive marker for memory dysfunction. These results indicate that there is general tissue loss and degradation (decreased volume; increased MD) in individuals with aMCI compared to older people with normal cognitive function. However, the microstructural organization of remaining fibers, as determined by measures of anisotropic diffusion, is not significantly different from that of controls.


Efficacy and Safety of Bcl-2 Inhibitor Venetoclax in Hematological Malignancy: A Systematic Review and Meta-Analysis of Clinical Trials.
Background: B-cell leukemia/lymphoma-2 (BCL-2) protein is an important part of apoptotic pathway, which is overexpressed in chronic lymphocytic leukemia cells, non-Hodgkin lymphoma cells, and myeloma cells. Venetoclax (ABT-199/GDC-0199) is a highly selective bioavailable inhibitor of BCL-2 protein, which is more effective and less valid against BCL-xL in BCL2-dependent leukemia and lymphoma cell. Method: We searched PubMed database using retrieval keyword venetoclax, ABT-199, or GDC-0199 and investigated the data of the involved articles. Considering variability in different studies, the overall response rate was collected to assess the efficacy. Meanwhile, adverse events (AEs) were summarized, and event rates were calculated to assess the safety. Results: When patients were treated with venetoclax monotherapy, the most common AEs were nausea, diarrhea, neutropenia, fatigue and thrombocytopenia, and neutropenia. In addition, thrombocytopenia, anemia, febrile neutropenia, and leukopenia appeared more common and are considered as the severe AEs (defined as grade ≥ 3 AEs). Although the occurrence of thrombocytopenia was relatively high, it was not the most severe type. When compared with patients treated with venetoclax and other drugs, nausea, diarrhea, and thrombocytopenia were still the most common AEs occurrence in the patients of all the grade. The overall event rate was 73%, which is quite satisfactory. Conclusion: Venetoclax is a mild and efficient drug in treating advanced hematological malignancy, which can be specially fit for the chronic lymphocytic leukemia patients with del[17p], and AEs are well tolerable. Few tumor lysis syndrome occurred after taking the drugs. The AEs aroused by venetoclax, and the combination is well tolerable. Therefore, the use of venetoclax monotherapy or its combination with other therapies is desirable in hematological malignancy.


Investigating individual differences in children's real-time sentence comprehension using language-mediated eye movements.
Individual differences in children's online language processing were explored by monitoring their eye movements to objects in a visual scene as they listened to spoken sentences. Eleven skilled and 11 less-skilled comprehenders were presented with sentences containing verbs that were either neutral with respect to the visual context (e.g., Jane watched her mother choose the cake, where all of the objects in the scene were choosable) or supportive (e.g., Jane watched her mother eat the cake, where the cake was the only edible object). On hearing the supportive verb, the children made fast anticipatory eye movements to the target object (e.g., the cake), suggesting that children extract information from the language they hear and use this to direct ongoing processing. Less-skilled comprehenders did not differ from controls in the speed of their anticipatory eye movements, suggesting normal sensitivity to linguistic constraints. However, less-skilled comprehenders made a greater number of fixations to target objects, and these fixations were of a duration shorter than those observed in the skilled comprehenders, especially in the supportive condition. This pattern of results is discussed in terms of possible processing limitations, including difficulties with memory, attention, or suppressing irrelevant information.


Sudden Cardiac Death and Post Cardiac Arrest Syndrome. An Overview.
A satisfactory neurologic outcome is the key factor for survival in patients with sudden cardiac death (SCD), however this is highly dependent on the haemodynamic status. Short term cardiopulmonary resuscitation and regained consciousness on the return of spontaneous circulation (ROSC) is indicative of a better prognosis. The evaluation and treatment of SCD triggering factors and of underlying acute and chronic diseases will facilitate prevention and lower the risk of cardiac arrest. Long term CPR and a prolonged unconscious status after ROSC, in the Intensive Care Units or Coronary Care Units, indicates the need for specific treatment and supportive therapy including efforts to prevent hyperthermia. The prognosis of these patients is unpredictable within the first seventy two hours, due to unknown responses to therapeutic management and the lack of specific prognostic factors. Patients in these circumstances require the highest level of intensive care and aetiology driven treatment without any delay, independently of their coma state. Current guidelines sugest the use of multiple procedures in arriving at a diagnosis and prognosis of these critical cases.


Enhanced luminous efficacy in phosphor-converted white vertical light-emitting diodes using low index layer.
We demonstrated improved luminous efficacy for GaN-based vertical light emitting diodes (VLEDs) employing a low index layer composed of silicon dioxide (SiO(2)) on the top surface. Three-dimensional ðnite-difference time-domain simulations for the fabricated VLED chip show that the penetration ratio of the emitted/reflected light into the VLED chip decreased by approximately 20% compared to a normal VLED chip. This result is in good agreement with an empirical study stating that white VLEDs having a SiO(2) layer exhibit an 8.1% higher luminous efficacy than white VLEDs with no layer at an injection current of 350 mA. Photons penetrating into the VLED chip, which become extinct in the VLED chip, are reflected from the SiO(2) layer due to the index contrast between the SiO(2) layer and epoxy resin containing phosphor, with no degradation of the light-extraction efficiency of the VLED chip. As such, this structure can contribute to the enhancement of the luminous efficacy of VLEDs.


Social Cognition and White Matter: Connectivity and Cooperation.
Humans are highly social animals whose survival and well-being depend on their capacity to cooperate in complex social settings. Advances in anthropology and psychology have demonstrated the importance of cooperation for enhancing social cohesion and minimizing conflict. The understanding of social behavior is informed by the notion of social cognition, a set of mental operations including emotion perception, mentalizing, and empathy. The social brain hypothesis posits that the mammalian brain has enlarged over evolution to meet the challenges of social life, culminating in a large human brain well adapted for social cognition. The structures subserving social cognition are mainly located in the frontal and temporal lobes, and although gray matter is critical, social cognition also requires white matter. Whereas the social brain hypothesis assumes that brain enlargement has been driven by neocortical expansion, cerebral white matter has expanded even more robustly than the neocortex, coinciding with the emergence of social cognition. White matter expansion is most evident in the frontal and temporal lobes, where it enhances connectivity between regions critical for social cognition. Myelination has, in turn, conferred adaptive social advantages by enabling prompt empathic concern for offspring and by strengthening networks that support cooperation and the related capacities of altruism and morality. Social cognition deficits related to myelinated tract involvement occur in many disorders, including stroke, Binswanger disease, traumatic brain injury, multiple sclerosis, glioma, and behavioral variant frontotemporal dementia. The contribution of white matter to social cognition can be conceptualized as the enhancement of cooperation through brain connectivity.


Recruiting and retaining family caregivers to a randomized controlled trial on mindfulness-based stress reduction.
Caregivers for a family member with dementia experience chronic long-term stress that may benefit from new complementary therapies such as mindfulness-based stress reduction. Little is known however, about the challenges of recruiting and retaining family caregivers to research on mind-body based complementary therapies. Our pilot study is the first of its kind to successfully recruit caregivers for a family member with dementia to a randomized controlled pilot study of mindfulness-based stress reduction. The study used an array of recruitment strategies and techniques that were tailored to fit the unique features of our recruitment sources and employed retention strategies that placed high value on establishing early and ongoing communication with potential participants. Innovative recruitment methods including conducting outreach to health plan members and generating press coverage were combined with standard methods of community outreach and paid advertising. We were successful in exceeding our recruitment goal and retained 92% of the study participants at post-intervention (2 months) and 90% at 6 months. Recruitment and retention for family caregiver interventions employing mind-body based complementary therapies can be successful despite many challenges. Barriers include cultural perceptions about the use and benefit of complementary therapies, cultural differences with how the role of family caregiver is perceived, the use of group-based designs requiring significant time commitment by participants, and travel and respite care needs for busy family caregivers.


[Visceral leishmaniasis and HIV infection: the diagnostic and therapeutic problems].
We present the case of an HIV-seropositive drug addict patient whose seropositivity was unknown until admission to hospital, where he presented with a clinical picture of fever splenomegaly and weight loss. A diagnosis of visceral leishmaniasis was established. We stress the diagnostic difficulties well expressed in the need to repeat the bone marrow aspirate to detect the presence of leishmanias. The lack of response to conventional antimonial therapy is discussed as well as the role of pentamidine as an alternative therapy.


A Bigger Picture: Organismal Function at the Nexus of Development, Ecology, and Evolution: An Introduction to the Symposium.
Over the past 40 years of research, two perspectives have dominated the study of ecomorphology at ontogenetic and evolutionary timescales. For key anatomical complexes (e.g., feeding apparatus, locomotor systems, sensory structures), morphological changes during ontogeny are often interpreted in functional terms and linked to their putative importance for fitness. Across larger timescales, morphological transformations in these complexes are examined through character stability or mutability during cladogenesis. Because the fittest organisms must pass through ontogenetic changes in size and shape, addressing transformations in morphology at different time scales, from life histories to macroevolution, has the potential to illuminate major factors contributing to phenotypic diversity. To date, most studies have relied on the assumption that organismal form is tightly constrained by the adult niche. Although this could be accurate for organisms that rapidly reach and spend a substantial portion of their life history at the adult phenotype (e.g., birds, mammals), it may not always hold true for species that experience substantial growth after one or more major fitness filters during their ontogeny (e.g., some fishes, reptiles). In such circumstances, examining the adult phenotype as the primary result of selective processes may be erroneous as it likely obscures the developmental configuration of morphology that was most critical to early survival. Given this discrepancy-and its potential to mislead interpretations of how selection may shape a taxon's phenotype-this symposium addresses the question: how do we identify such ontogenetic "inertia," and how do we integrate developmental information into our phylogenetic, ecological, and functional interpretations of complex phenotypes?


Cerebral atherosclerosis in Japanese. Part 5: relationship between cholesterol deposition and glycosaminoglycans.
Concentrations of various lipids and glycosaminoglycans (GAG) in the intima of the grossly normal and atherosclerotic cerebral arteries were compared with those of the aorta and coronary arteries. The lowest percentage of esterified cholesterol (EC) in total cholesterol, and of chondroitin sulfate-4/6 (CS-4/6) in total glycosaminoglycans and the highest percentage of heparin sulfate (HS) in total GAG are the characteristic features of the normal intima of normal cerebral arteries when compared with those in the aorta and coronary artery. In the cerebral arterial intimas, but not in the aorta or coronary arteries, there was a significant positive correlation between contents of EC and percentage and total content of CS-4/6. Atherogenesis in cerebral arteries is discussed in comparison to that of the aorta and coronary vessels.


Whole genome sequence of the Treponema pallidum subsp. endemicum strain Iraq B: A subpopulation of bejel treponemes contains full-length tprF and tprG genes similar to those present in T. p. subsp. pertenue strains.
Treponema pallidum subsp. endemicum (TEN) is the causative agent of endemic syphilis (bejel). Until now, only a single TEN strain, Bosnia A, has been completely sequenced. The only other laboratory TEN strain available, Iraq B, was isolated in Iraq in 1951 by researchers from the US Centers for Disease Control and Prevention. In this study, the complete genome of the Iraq B strain was amplified as overlapping PCR products and sequenced using the pooled segment genome sequencing method and Illumina sequencing. Total average genome sequencing coverage reached 3469×, with a total genome size of 1,137,653 bp. Compared to the genome sequence of Bosnia A, a set of 37 single nucleotide differences, 4 indels, 2 differences in the number of tandem repetitions, and 18 differences in the length of homopolymeric regions were found in the Iraq B genome. Moreover, the tprF and tprG genes that were previously found deleted in the genome of the TEN Bosnia A strain (spanning 2.3 kb in length) were present in a subpopulation of TEN Iraq B and Bosnia A microbes, and their sequence was highly similar to those found in T. p. subsp. pertenue strains, which cause the disease yaws. The genome sequence of TEN Iraq B revealed close genetic relatedness between both available bejel-causing laboratory strains (i.e., Iraq B and Bosnia A) and also genetic variability within the bejel treponemes comparable to that found within yaws- or syphilis-causing strains. In addition, genetic relatedness to TPE strains was demonstrated by the sequence of the tprF and tprG genes found in subpopulations of both TEN Iraq B and Bosnia A. The loss of the tprF and tprG genes in most TEN microbes suggest that TEN genomes have been evolving via the loss of genomic regions, a phenomenon previously found among the treponemes causing both syphilis and rabbit syphilis.


Alcohol exposure and outcomes in trauma patients.
To determine the injury patterns, complications, and mortality after alcohol consumption in trauma patients. The Trauma Registry at an American College of Surgeons (ACS) level I center was queried for all patients with a toxicology screen admitted between 1st January 2002 and 31st December 2005. Alcohol-positive (AP) patients were matched to control patients who had a completely negative screen (AN) using age, gender, mechanism, Injury Severity Score (ISS), head Abbreviated Injury Scale (AIS), chest AIS, abdominal AIS, and extremity AIS. Injuries and outcomes were compared between the groups. As many as 5,317 patients had toxicology data, of which 471 (8.9%) had a positive alcohol screen (AP). A total of 386 AP patients were then matched to 386 control (AN) patients. The AP group had a significantly higher mortality than the AN group overall (23 vs. 13%; p < 0.001), and by ISS stratification: ISS < 16 (6 vs. 0.4%; p < 0.001), ISS 16-25 (53 vs. 28%; p = 0.01), and ISS > 25 (90 vs. 67%; p = 0.01). AP patients had a higher incidence of admission systolic blood pressure < 90 (18 vs. 10%; p < 0.001) and Glasgow Coma Scale (GCS) score ≤ 8 (25 vs. 17%; p = 0.002). AN patients had a significantly higher incidence of hemopneumothorax (11 vs. 7%; p = 0.03), while AP patients had a higher incidence of cardiac arrest (8 vs. 3%; p = 0.004). There was no difference in intensive care unit (ICU) and hospital length of stay. In a mixed population of trauma patients, an AP screen is associated with an increased incidence of admission hypotension and depressed GCS score. In this case-matched study, alcohol exposure appeared to increase mortality after injury.


Neuroreflexotherapy for non-specific low-back pain.
Among the wide range of therapeutic alternatives proposed for the management of low-back pain (LBP), a less widely used technique from Spain, called neuroreflexotherapy (NRT) has claimed to show very favourable results, mainly in patients with chronic low-back pain. The aim of this review was to systematically assess the effectiveness of NRT for the treatment of non-specific LBP in adult patients, aged 16 to 65 years. A secondary objective was to compare NRT with other conventional interventions. We searched the Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE to October 1, 2002. Only randomised controlled trials (RCTs) of NRT for the treatment of patients with a clinical diagnosis of non-specific LBP were included. Two reviewers independently selected trials and extracted data using pre-designed forms. Because the outcome variables were not assessed in a homogenous way, it was not possible to pool the results to obtain an estimate of global effect, as initially planned. Three RCT were included, with a total of 125 subjects randomised to the control groups and 148 subjects receiving active NRT. Neuroreflexotherapy was the same in all three trials, while the control groups received sham-NRT in two trials and standard care in one. Two trials studied patients with chronic LBP, the third studied patients with a mix of chronic and sub-acute LBP. Clinical outcomes were measured in the short-term (15 to 60 days) in all three trials; in one trial, resource utilization was measured after one year. Individuals who received active NRT showed statistically significantly better outcomes than the control groups for measures of pain, degree of mobility, disability, medication use, consumption of resources and costs. No significant differences were observed for quality of life measures. Side effects were more frequently reported in the control groups during short-term follow-up, with no major side effects reported by those receiving active NRT. NRT appears to be a safe and effective intervention for the treatment of chronic non-specific LBP. The efficacy is less clear for sub-acute LBP. However, these results are limited to three trials conducted by a small number of specifically trained and experienced clinicians, in a limited geographical location. No data are available on the ease and time-frame needed to achieve that level of expertise. RCTs by other practitioners, in other locations, that replicate the effects reported in this review are needed before recommending a broader practice.


Severe pulmonary toxicity after myeloablative conditioning using total body irradiation: an assessment of risk factors.
To assess factors associated with severe pulmonary toxicity after myeloablative conditioning using total body irradiation (TBI) followed by allogeneic stem cell transplantation. A total of 101 adult patients who underwent TBI-based myeloablative conditioning for hematologic malignancies at Duke University between 1998 and 2008 were reviewed. TBI was combined with high-dose cyclophosphamide, melphalan, fludarabine, or etoposide, depending on the underlying disease. Acute pulmonary toxicity, occurring within 90 days of transplantation, was scored using Common Terminology Criteria for Adverse Events version 3.0. Actuarial overall survival and the cumulative incidence of acute pulmonary toxicity were calculated via the Kaplan-Meier method and compared using a log-rank test. A binary logistic regression analysis was performed to assess factors independently associated with acute severe pulmonary toxicity. The 90-day actuarial risk of developing severe (Grade 3-5) pulmonary toxicity was 33%. Actuarial survival at 90 days was 49% in patients with severe pulmonary toxicity vs. 94% in patients without (p < 0.001). On multivariate analysis, the number of prior chemotherapy regimens was the only factor independently associated with development of severe pulmonary toxicity (odds ratio, 2.7 per regimen). Severe acute pulmonary toxicity is prevalent after TBI-based myeloablative conditioning regimens, occurring in approximately 33% of patients. The number of prior chemotherapy regimens appears to be an important risk factor.


The effect of tumour shrinkage on biologically effective dose, and possible implications for fractionated high dose rate brachytherapy.
A method for incorporating a tumour shrinkage factor into linear-quadratic (LQ) brachytherapy equations is proposed. When there is a significant degree of ongoing shrinkage throughout a course of brachytherapy, and when the sources are centrally situated within the tumour volume, the biologically effective dose (BED) to the tumour will be higher than that which is calculated with standard equations. Although the analytical method initially assumes that shrinkage is exponential with time, it is shown that the modified equations (for both high and low dose rate brachytherapy) are essentially analogous to existing BED equations, but with the addition of a simple linear time-dependent factor. In this article, which concentrates on the implications for fractionated high dose-rate brachytherapy, it is demonstrated that increasing the time interval between fractions will only improve the BED in some cases, the conditions for which may be identified in terms of the ratio K/z, where K is the daily dose required to combat tumour repopulation and z is the daily linear shrinkage rate. In the absence of predictive assay techniques, or where there is doubt as to whether or not the radiobiological conditions favour an increase in the interval between each dose delivery, relatively close spacing (i.e. acceleration) of brachytherapy fractions appears to be the most prudent option.


Performance of On-Call Radiology Residents in Interpreting Total Spine MRI Studies for the Detection of Spinal Cord Compression or Cauda Equina Compression.
OBJECTIVE. Accurate diagnosis of spinal cord compression (SCC) or cauda equina compression (CEC) is important in the emergency setting so management decisions may be made promptly. The purpose of this study is to evaluate the performance of on-call radiology residents in interpreting total spine MRI studies for the detection of SCC or CEC. MATERIALS AND METHODS. On-call radiology residents' preliminary interpretation of total spine MRI studies performed over a period of two and half years were evaluated. Agreements and disagreements were determined for SCC (defined as severe spinal stenosis with compression of the spinal cord and lack of surrounding CSF), CEC (defined as > 75% narrowing of the lumbar canal and lack of CSF in the thecal sac), and the presence of other significant findings that might impact clinical management. Studies with true-positive, true-negative, false-positive, and false-negative findings were identified. RESULTS. SCC or CEC was present in 72 of the 295 studies with preliminary interpretations done by on-call residents. The sensitivity and specificity for detecting SCC or CEC were 93.1% and 98.2%, respectively. Sensitivity was higher for 3rd- and 4th-year residents (97.7%) than for 2nd-year residents (86.2%). Other significant findings were present in 34 of the 295 studies. The overall sensitivity and specificity for the detection of other significant findings were 85.3% and 100.0%, respectively. The level of training did not affect the detection of other significant findings. CONCLUSION. The overall sensitivity of on-call radiology residents' interpretation of total spine MR images for the detection of SCC or CEC was high, improving with their level of training. However, residents' sensitivity was slightly less for the detection of other significant findings. Resident performance can be further improved with focused training and the use of a preliminary interpretation template.


The Cerebral Palsy Kinematic Assessment Tool (CPKAT): feasibility testing of a new portable tool for the objective evaluation of upper limb kinematics in children with cerebral palsy in the non-laboratory setting.
Efficacy of treatment to improve upper-limb activity of children with cerebral palsy (CP) is typically evaluated outside clinical/laboratory environments through functional outcome measures (e.g. ABILHAND kids). This study evaluates CPKAT, a new portable laptop-based tool designed to objectively measure upper-limb kinematics in children with CP. Seven children with unilateral CP (2 females; mean age 10 years 2 months (SD 2 years 3 months), median age 9 years 6 months, range 6 years 5 months, MACS II-IV) were evaluated on copying, tracking and tracing tasks at their homes using CPKAT. CPKAT recorded parameters relating to spatiotemporal hand movement: path length, movement time, smoothness, path accuracy and root mean square error. The Wilcoxon signed ranks test explored whether CPKAT could detect differences between the affected and less-affected limb. CPKAT detected intra-limb differences for movement time and smoothness (aiming), and path length (tracing). No intra-limb tracking differences were found, as hypothesised. These findings are consistent with other studies showing that movements of the impaired upper limb in unilateral CP are slower and less smooth. CPKAT provides a potential solution for home-based assessment of upper limb kinematics in children with CP to supplement other measures and assess functional intervention outcomes. Further validation is required. Implications for Rehabilitation This paper demonstrates the feasibility of evaluating upper limb kinematics in home using CPKAT, a portable laptop-based evaluation tool. We found that CPKAT is easy to set-up and use in home environments and yields useful kinematic measures of upper limb function. CPKAT can complement less responsive patient reported or subjectively evaluated functional measures for a more complete evaluation of children with cerebral palsy. Thus, CPKAT can help guide a multi-disciplinary team to more effective intervention and rehabilitation for children with cerebral palsy.


Syndemic vulnerability, sexual and injection risk behaviors, and HIV continuum of care outcomes in HIV-positive injection drug users.
Limited investigations have been conducted on syndemics and HIV continuum of care outcomes. Using baseline data from a multi-site, randomized controlled study of HIV-positive injection drug users (n = 1,052), we examined whether psychosocial factors co-occurred, and whether these factors were additively associated with behavioral and HIV continuum of care outcomes. Experiencing one type of psychosocial problem was significantly (p < 0.05) associated with an increased odds of experiencing another type of problem. Persons with 3 or more psychosocial problems were significantly more likely to report sexual and injection risk behaviors and were less likely to be adherent to HIV medications. Persons with 4 or more problems were less likely to be virally suppressed. Reporting any problems was associated with not currently taking HIV medications. Our findings highlight the association of syndemics not only with risk behaviors, but also with outcomes related to the continuum of care for HIV-positive persons.