Origin of Saturn's rings and inner moons by mass removal from a lost Titan-sized satellite.
The origin of Saturn's rings has not been adequately explained. The current rings are more than 90 to 95 per cent water ice, which implies that initially they were almost pure ice because they are continually polluted by rocky meteoroids. In contrast, a half-rock, half-ice mixture (similar to the composition of many of the satellites in the outer Solar System) would generally be expected. Previous ring origin theories invoke the collisional disruption of a small moon, or the tidal disruption of a comet during a close passage by Saturn. These models are improbable and/or struggle to account for basic properties of the rings, including their icy composition. Saturn has only one large satellite, Titan, whereas Jupiter has four large satellites; additional large satellites probably existed originally but were lost as they spiralled into Saturn. Here I report numerical simulations of the tidal removal of mass from a differentiated, Titan-sized satellite as it migrates inward towards Saturn. Planetary tidal forces preferentially strip material from the satellite's outer icy layers, while its rocky core remains intact and is lost to collision with the planet. The result is a pure ice ring much more massive than Saturn's current rings. As the ring evolves, its mass decreases and icy moons are spawned from its outer edge with estimated masses consistent with Saturn's ice-rich moons interior to and including Tethys.


Mechanisms of failure and survival of total femoral endoprosthetic replacements.
The aim of this study was to evaluate the prosthesis characteristics and associated conditions that may modify the survival of total femoral endoprosthetic replacements (TFEPR). In all, 81 patients treated with TFEPR from 1976 to 2017 were retrospectively evaluated and failures were categorized according to the Henderson classification. There were 38 female patients (47%) and 43 male patients (53%) with a mean age at diagnosis of 43 years (12 to 86). The mean follow-up time was 10.3 years (0 to 31.7). A survival analysis was performed followed by univariate and multivariate Cox regression to identify independent implant survival factors. The revision-free survival of the implant was 71% at five years and 63.3% at ten years. Three prostheses reached 15 years without revision. The mean Musculoskeletal Tumor Society score in the group was 26 (23 to 28). The mechanisms of failure were infection in 18%, structural failures in 6%, tumour progression in 5%, aseptic loosening in 2%, and soft-tissue failures in 1%. Prostheses used for primary reconstruction after oncological resections had lower infection rates than revision implants (8% vs 25%; p = 0.001). The rates of infection in silver-coated and non-silver-coated prosthesis were similar (17.4% vs 19.%; p = 0.869). The incidence of hip dislocation was 10%. Rotating hinge prosthesis had a lower failure rate than fixed hinge prosthesis (5.3% vs 11%). After Cox regression, the independent factors associated with failures were the history of previous operations (hazard ratio (HR) 3.7; p = 0.041), and the associated arthroplasty of the proximal tibia (HR 3.8; p = 0.034). At last follow-up, 11 patients (13%) required amputation. TFEPR offers a reliable reconstruction option for massive bone loss of the femur, with a good survival when the prosthesis is used as a primary implant. The use of a rotating hinge at the knee and dual mobility bearing at the hip may be adequate to reduce the risk of mechanical and soft-tissue failures. Infection remains the main concern and there is insufficient evidence to support the routine use of silver-coated endoprosthesis. Cite this article: Bone Joint J 2019;101-B:522-528.


Cobalt co-catalysis for cross-electrophile coupling: diarylmethanes from benzyl mesylates and aryl halides.
The nickel-catalyzed cross-coupling of aryl halides with alkyl radicals derived from alkyl halides has recently been extended to couplings with carbon radicals generated by a co-catalyst. In this study, a new co-catalyst, cobalt phthalocyanine (Co(Pc)), is introduced and demonstrated to be effective for coupling substrates not prone to homolysis. This is because Co(Pc) reacts with electrophiles by an SN2 mechanism instead of by the electron-transfer or halogen abstraction mechanisms previously explored. Studies demonstrating the orthogonal reactivity of (bpy)Ni and Co(Pc), applying this selectivity to the coupling of benzyl mesylates with aryl halides, and the adaptation of these conditions to the less reactive benzyl phosphate ester and an enantioconvergent reaction are presented.


Evaluation of the immune response in mice infected with Mycobacterium marinum.
Foot pad infection of mice with Mycobacterium marinum carried out with a view to comparing the immune response on the humoral level of such mice, with that observed previously in mice infected with M. leprae, indicated that there was a similarity in terms of the first appearance and proliferation of immunocytes and the time at which the peak and decline in the antibody-producing cells occurred. The significant difference appeared to be in the immunoglobulin G response, which was absent in the M. leprae infected mice, but occurred simultaneously with the immunoglobulin M response at a high level, both during a primary and after a secondary challenge administered 15 days post-primary infection in the M. marinum infected mice. Further confirmation was obtained through additional studies on the specific immunoglobulin levels and determination of both immunoglobulin M and immunoglobulin G antibodies by hemagglutination. Although the growth temperature requirement of the two organisms and their ability to initiate infection in areas of the body with lower temperatures are similar, it is suggested that the type of infection induced by each one of these species in the mouse may disallow the serious consideration of the M. marinum infection model as a possible alternative experimental model for studying the role of host immunity to M. leprae infections in mice.


Underpricing, underperformance and overreaction in initial public offerings: Evidence from investor attention using online searches.
Online activity of Internet users has proven very useful in modeling various phenomena across a wide range of scientific disciplines. In our study, we focus on two stylized facts or puzzles surrounding the initial public offerings (IPOs) - the underpricing and the long-term underperformance. Using the Internet searches on Google, we proxy the investor attention before and during the day of the offering to show that the high attention IPOs have different characteristics than the low attention ones. After controlling for various effects, we show that investor attention still remains a strong component of the high initial returns (the underpricing), primarily for the high sentiment periods. Moreover, we demonstrate that the investor attention partially explains the overoptimistic market reaction and thus also a part of the long-term underperformance.


The efficacy of escalating and fixed contingency management reinforcement on illicit drug use in opioid-dependent pregnant women.
OBJECTIVES: Contingency management (CM), long known to be efficacious in the treatment of substance-dependent men and women, has also been found to be efficacious for substance-dependent pregnant women. However, the specific CM reinforcement parameters in the special population of opioid-dependent pregnant women have been less fully and systematically studied. The Drug Abuse Incentive Systems (DAISY) study, a randomized controlled trial (RCT) of opioid-dependent pregnant patients, found that escalating reinforcement was not superior to a fixed reinforcement CM schedule after a 13-week intervention. To further examine CM's reinforcement parameters in this population, this study aims to test the hypothesis that there is an early treatment response showing an escalating reinforcement schedule to be significantly more efficacious than a fixed schedule after 5 weeks of intervention in opioid-dependent pregnant patients. METHODS: Nine measures of opioid and cocaine abstinence among fixed and escalating CM schedule participants in the DAISY RCT (N=90) were compared over the initial 5 weeks of the intervention. RESULTS: No statistically significant difference in the opioid and cocaine abstinence measures was found between escalating and fixed conditions after 5 weeks (14 opportunities for each participant to leave a urine sample). The mean (SD) number of drug negative urine samples was 8.1 (4.5) and 7.4 (4.3), for escalating and fixed groups, respectively (p=0.46). CONCLUSIONS: These results further the scientific knowledge regarding CM treatment in opioid-dependent pregnant women by supporting the finding that the escalating and fixed CM schedules produce similar amounts of drug negatives urine samples early in treatment.


Perceived responsibility in juvenile obsessive-compulsive disorder: an experimental manipulation.
Investigated the role of responsibility in obsessive-compulsive disorder (OCD) in juveniles with the disorder. This study experimentally manipulated perceived responsibility during a behavioral avoidance task (BAT) and examined the effects on levels of perceived probability and severity of harm, distress, ritualizing, and avoidance. Further, the association between OCD severity, anxiety, and depression with cognitive perceptions of threat was investigated. Finally, this study examined whether cognitive-behavioral treatment (CBT) would decrease ratings across all measures during a BAT. Results indicated that the manipulation successfully inflated responsibility, however this did not lead to increased ratings of distress or of probability or severity of harm. Anxiety was negatively correlated with responsibility; however, there were no significant correlations between depression and the cognitive variables. Following CBT, there were significant reductions across measures during the BAT.


Early postoperative feeding and abdominal gynaecological surgery.
Since the 1990s, the traditional postoperative feeding protocol has been challenged for patients who have undergone major abdominal gynaecological surgery, and value of extended delays in commencing oral intake has been questioned. This review aims to determine whether early rather than delayed postoperative feeding following major abdominal gynaecological surgery has an impact upon recovery as measured by length of hospital stay. The Cochrane Library, Embase, CINAHL and Medline were searched for randomized controlled trials (RCTs) which compared early postoperative oral intake with delayed (traditional) postoperative oral intake for patients who had undergone major abdominal gynaecological surgery. Three RCTs were identified and available for consideration. Although study quality was variable, they suggest that early postoperative feeding appears to be safe and well tolerated after most abdominal gynaecological surgery and leads to a considerable reduction in hospital stay of approximately one day. However, patients' preference and costs remain unclear. Therefore, further well-designed studies are needed to identify the comprehensive effectiveness of early postoperative feeding protocol.


Effects of Soy-derived diets on plasma and liver lipids, glucose tolerance, and longevity in normal, long-lived and short-lived mice.
We examined the effects of diets based on a low isoflavone or a high isoflavone soy protein isolates in normal, growth-hormone receptor knockout and Ames dwarf, and Prop 1 (df) mice that are hypoinsulinemic, insulin-sensitive, and exceptionally long-lived, as well as in growth hormone transgenic mice that are hyperinsulinemic, insulin-resistant, dyslipidemic, and short-lived. Soybean diets tended to normalize plasma cholesterol levels in dwarf and transgenic mice, while low isoflavone diet reduced plasma triglycerides in most of the examined genotypes. The effects of low isoflavone and high isoflavone diets on the levels of free and esterified cholesterol in the liver were strongly genotype-dependent. Fasting blood glucose levels were reduced and glucose tolerance improved by both low isoflavone and high isoflavone diets in growth hormone-transgenic mice and in their normal siblings. Glucose tolerance was also improved by high-isoflavone diet in growth hormone receptor knockout mice. Lifespan was increased by low isoflavone diet in normal mice from two of the examined stocks. High isoflavone diet increased lifespan in normal animals from one line, but reduced lifespan of normal mice from a different line. We conclude that dietary soy protein intake can improve plasma and hepatic lipid profiles, reduce fasting glucose, enhance capacity for glucose tolerance, and prolong life, but all of these effects are strongly genotype-dependent.


Identifying Cardiovascular Disease Risk Factors in Adults with Explainable Artificial Intelligence.
The aim of this study was to evaluate the relationship between risk factors causing cardiovascular diseases and their importance with explainable machine learning models. In this retrospective study, multiple databases were searched, and data on 11 risk factors of 70 000 patients were obtained. Data included risk factors highly associated with cardiovascular disease and having/not having any cardiovascular disease. The explainable prediction model was constructed using 7 machine learning algorithms: Random Forest Classifier, Extreme Gradient Boost Classifier, Decision Tree Classifier, KNeighbors Classifier, Support Vector Machine Classifier, and GaussianNB. Receiver operating characteristic curve, Brier scores, and mean accuracy were used to assess the model's performance. The interpretability of the predicted results was examined using Shapley additive description values. The accuracy, area under the curve values, and Brier scores of the Extreme Gradient Boost model (the best prediction model for cardiovascular disease risk factors) were calculated as 0.739, 0.803, and 0.260, respectively. The most important risk factors in the permutation feature importance method and explainable artificial intelligence-Shapley's explanations method are systolic blood pressure (ap_hi) [0.1335 ± 0.0045 w (weight)], cholesterol (0.0341 ± 0.0022 w), and age (0.0211 ± 0.0036 w). The created explainable machine learning model has become a successful clinical model that can predict cardiovascular patients and explain the impact of risk factors. Especially in the clinical setting, this model, which has an accurate, explainable, and transparent algorithm, will help encourage early diagnosis of patients with cardiovascular diseases, risk factors, and possible treatment options.


Immunogenetics and amyotrophic lateral sclerosis.
Immunological capability is to a substantial extent genetically determined. Because genetic linkage exists between histocompatibility gene loci and certain immune response gene loci, histocompatibility specificities can serve as indicators for the presence of particular inherited immunological traits. In man, certain HLA antigens seem to be associated with immunogenetic traits which result in altered susceptibility to disease with known or suspected viral or autoimmune etiologies. We have found an association between HLA-A3 and "classic" cases of ALS. The A3 antigen was present in 49% of these cases, but not in the more chronic or benign form of the disease. Five out of six "benign" cases carried HLA-B12, suggesting perhaps the presence of a trait conferring resistance to the disease. Epidemiological surveys provide evidence both for and against a correlation between the incidence of ALS and that of HLA-A3 in various population groups. Because of the multiplicity of immune response genes, susceptibility or resistance to ALS in different populations may depend on different immune response genes. The association of a disease with selected HLA antigens or phenotypes might be suggestive of a viral-allergic etiology. Evidence that bears on this hypothesis has been reviewed.


Shared humanity, awareness of socio-economic privilege, and classism during the pandemic as predictors of supporting equal socio-economic policies.
The coronavirus pandemic has caused unemployment to skyrocket, exposed the longstanding inequalities in health care services and working conditions, and mainly affected the poor in different parts of the world. In the current study, we focus on social identity and social class-related factors that are critical during the pandemic to gain insights into what predicts support for policies favoring economic equality in the post-pandemic period. We argue that to the extent that individuals 1) identify with all humanity during the pandemic, 2) are aware of their socio-economic status-based privilege, 3) do not hold classist attitudes, they would support policies favoring economic equality. In Study 1, survey data from 1212 participants in Turkey were analyzed by means of hierarchical linear regression analysis. The findings showed that stronger identification with all humanity, higher awareness of socio-economic status-based privilege, and less endorsement of classist attitudes predict more support for socio-economic equality policies in the post-pandemic period, after controlling for socio-demographic and socio-political characteristics of participants. Study 2 (N = 212) replicated the findings in a different context, namely the U.S. Our findings extend previous studies by showing the importance of a global identity, such as shared human identity, in the ongoing and potentially in the aftermath of the pandemic. In addition, our findings highlight the joint contributions of socio-economic factors such as classist attitudes and awareness of class-based privilege to the support for socio-economic policies.


A complex equilibrium among partially unfolded conformations in monomeric transthyretin.
Aggregation of transthyretin (TTR) is known to be linked to the development of systemic and localized amyloidoses. It also appears that TTR exerts a protective role against aggregation of the Aβ peptide, a process linked to Alzheimer's disease. In vitro, both processes correlate with the ability of TTR to populate a monomeric state, yet a complete description of the possible conformational states populated by monomeric TTR in vitro at physiological pH is missing. Using an array of biophysical methods and kinetic tests, we show that once monomers of transthyretin are released from the tetramer, equilibrium is established between a set of conformational states possessing different degrees of disorder. A molten globular state appears in equilibrium with the fully folded monomer, whereas an off-pathway species accumulates transiently during refolding of TTR. These two conformational ensembles are distinct in terms of structure, kinetics, and their pathways of formation. Further subpopulations of the protein fold differently because of the occurrence of proline isomerism. The identification of conformational states unrevealed in previous studies opens the way for further characterization of the amyloidogenicity of TTR and its protective role in Alzheimer's disease.


Tubular proteinuria in patients with HNF1α mutations: HNF1α drives endocytosis in the proximal tubule.
Hepatocyte nuclear factor 1α (HNF1α) is a transcription factor expressed in the liver, pancreas, and proximal tubule of the kidney. Mutations of HNF1α cause an autosomal dominant form of diabetes mellitus (MODY-HNF1A) and tubular dysfunction. To gain insights into the role of HNF1α in the proximal tubule, we analyzed Hnf1a-deficient mice. Compared with wild-type littermates, Hnf1a knockout mice showed low-molecular-weight proteinuria and a 70% decrease in the uptake of β2-microglobulin, indicating a major endocytic defect due to decreased expression of megalin/cubilin receptors. We identified several binding sites for HNF1α in promoters of Lrp2 and Cubn genes encoding megalin and cubilin, respectively. The functional interaction of HNF1α with these promoters was shown in C33 epithelial cells lacking endogenous HNF1α. Defective receptor-mediated endocytosis was confirmed in proximal tubule cells from these knockout mice and could be rescued by transfection of wild-type but not mutant HNF1α. Transfection of human proximal tubule HK2 cells with HNF1α was able to upregulate megalin and cubilin expression and to increase endocytosis of albumin. Low-molecular-weight proteinuria was consistently detected in individuals with HNF1A mutations compared with healthy controls and patients with non-MODY-HNF1A diabetes mellitus. Thus, HNF1α plays a key role in the constitutive expression of megalin and cubilin, hence regulating endocytosis in the proximal tubule of the kidney. These findings provide new insight into the renal phenotype of individuals with mutations of HNF1A.


Defect-Engineered Charge Transfer in a PtCu/PrxCe1-xO2 Carbon-Free Catalyst for Promoting the Methanol Oxidation and Oxygen Reduction Reactions.
Platinum (Pt) and Pt-based alloys have been extensively studied as efficient catalysts for both the anode and cathode of direct methanol fuel cells (DMFC). Defect engineering has been revealed to be practicable in tuning the charge transfer between Pt and transition metals/supports, which leads to the charge density rearrangement and facilitates the electrocatalytic performance. Herein, Pr-doped CeO2 nanocubes were used as the noncarbon support of a PtCu catalyst. The concentration and structure of oxygen vacancy (Vo) defects were engineered by Pr doping. Besides the Vo monomer, the oxygen vacancy with a linear structure is also observed, leading to the one-dimensional PtCu. The Vo concentration shows the volcanic scenario as Pr increased. Accordingly, the activities of PtCu/PrxCe1-xO2 toward methanol oxidation and oxygen reduction reactions exhibit the volcanic scenario. PtCu/Pr0.15Ce0.85O2 exhibits the optimal catalytic performance with the specific activity 3.57 times higher than that of Pt/C toward MOR and 1.34 times higher toward ORR. The MOR and ORR mass activities of PtCu/Pr0.15Ce0.85O2 reached 1.05 and 0.12 A·mg-1, which are 3.09 and 0.92 times the values of Pt/C, respectively. The abundant Vo afforded surplus electrons, which tailored the electron transfer between PtCu and PrxCe1-xO2, leading to enhanced catalytic performance of PtCu/PrxCe1-xO2. DFT calculations on PtCu/Pr0.15Ce0.85O2 revealed that Pr doping reduced the band gap of CeO2 and lowered the overpotential.


A Carboxyl Ester Lipase (CEL) Mutant Causes Chronic Pancreatitis by Forming Intracellular Aggregates That Activate Apoptosis.
Patients with chronic pancreatitis (CP) frequently have genetic risk factors for disease. Many of the identified genes have been connected to trypsinogen activation or trypsin inactivation. The description of CP in patients with mutations in the variable number of tandem repeat (VNTR) domain of carboxyl ester lipase (CEL) presents an opportunity to study the pathogenesis of CP independently of trypsin pathways. We tested the hypothesis that a deletion and frameshift mutation (C563fsX673) in the CEL VNTR causes CP through proteotoxic gain-of-function activation of maladaptive cell signaling pathways including cell death pathways. HEK293 or AR42J cells were transfected with constructs expressing CEL with 14 repeats in the VNTR (CEL14R) or C563fsX673 CEL (CEL maturity onset diabetes of youth with a deletion mutation in the VNTR (MODY)). In both cell types, CEL MODY formed intracellular aggregates. Secretion of CEL MODY was decreased compared with that of CEL14R. Expression of CEL MODY increased endoplasmic reticulum stress, activated the unfolded protein response, and caused cell death by apoptosis. Our results demonstrate that disorders of protein homeostasis can lead to CP and suggest that novel therapies to decrease the intracellular accumulation of misfolded protein may be successful in some patients with CP.


Cross-cultural variation in blood pressure: a quantitative analysis of the relationships of blood pressure to cultural characteristics, salt consumption and body weight.
This study has analyzed the relationships of cross-cultural variation in blood pressure to cultural characteristics, salt consumption and body weight. The data used were blood pressures for adults in 84 groups, ratings of cultural characteristics (based on anthropological data and made by raters who had no knowledge of the blood pressure data) and, where available, salt consumption and body mass index (weight/height2). Blood pressures were higher and the slopes of blood pressure with age were greater in groups which had greater involvement in a money economy, more economic competition, more contact with people of different culture or beliefs, and more unfulfilled aspirations for a return to traditional beliefs and values. Blood pressures were also higher in groups for which the predominant family type was a nuclear or father-absent family, as opposed to an extended family. For Negroes, groups who were descended from slaves had higher blood pressures than other groups. The correlations between blood pressures and involvement in a money economy were substantial and significant even after controlling for level of salt consumption and, for men, also after controlling for body mass index. For men there were also significant partial correlations between blood pressure and salt consumption, controlling for type of economy. For women there were significant partial correlations between blood pressure and body mass index, controlling for type of economy. In conclusion, cross-cultural variation in blood pressure appears to be due to multiple factors. One contributory factor appears to be psychosocial stress due to cultural disruption, including the disruption of cooperative relationships and traditional cultural patterns which frequently occurs during economic modernization. In addition, both the protective effects of very low salt consumption in some groups and differences in body weight appear to contribute to cross-cultural variation in blood pressure.


Progress in Integrative Biomaterial Systems to Approach Three-Dimensional Cell Mechanotransduction.
Mechanotransduction between cells and the extracellular matrix regulates major cellular functions in physiological and pathological situations. The effect of mechanical cues on biochemical signaling triggered by cell-matrix and cell-cell interactions on model biomimetic surfaces has been extensively investigated by a combination of fabrication, biophysical, and biological methods. To simulate the in vivo physiological microenvironment in vitro, three dimensional (3D) microstructures with tailored bio-functionality have been fabricated on substrates of various materials. However, less attention has been paid to the design of 3D biomaterial systems with geometric variances, such as the possession of precise micro-features and/or bio-sensing elements for probing the mechanical responses of cells to the external microenvironment. Such precisely engineered 3D model experimental platforms pave the way for studying the mechanotransduction of multicellular aggregates under controlled geometric and mechanical parameters. Concurrently with the progress in 3D biomaterial fabrication, cell traction force microscopy (CTFM) developed in the field of cell biophysics has emerged as a highly sensitive technique for probing the mechanical stresses exerted by cells onto the opposing deformable surface. In the current work, we first review the recent advances in the fabrication of 3D micropatterned biomaterials which enable the seamless integration with experimental cell mechanics in a controlled 3D microenvironment. Then, we discuss the role of collective cell-cell interactions in the mechanotransduction of engineered tissue equivalents determined by such integrative biomaterial systems under simulated physiological conditions.


Long-term Safety of Treatment with Autologous Mesenchymal Stem Cells in Patients with Radiation-Induced Xerostomia: Primary Results of the MESRIX Phase I/II Randomized Trial.
Mesenchymal stem/stromal cell therapy may reduce radiation-induced xerostomia. We investigated the long-term safety of autologous adipose tissue-derived mesenchymal stem/stromal cell (ASC) injections into the submandibular glands. An investigator-initiated, randomized, single-center, placebo-controlled trial. Previous patients with oropharyngeal squamous cell carcinoma with radiation-induced xerostomia were randomly (1:1) allocated to receive a 2.8 million ASCs/cm3 injection or placebo in both submandibular glands and followed for a minimum of 2 years. The primary endpoint was number of serious adverse events (SAE). Secondary endpoints included whole saliva flow rates and xerostomia-related symptoms. Data analysis was based on the intention-to-treat population using repeated measures mixed-effects linear models. Thirty-three patients were randomized; 30 patients were treated (ASC group, n = 15; placebo group, n = 15). Long-term safety data were collected from all 30 patients. During follow-up, 6 of 15 (40%) of the ASC-treated patients versus 5 of 15 (33%) of the placebo patients experienced an SAE; no SAEs appeared to be treatment related. Unstimulated whole saliva flow rate increased to 0.20 and 0.16 mL/minute in the ASC and placebo group, respectively, yielding a 0.05 mL/minute (95% confidence interval: 0.00-0.10; P = 0.051) difference between groups. Patient-reported xerostomia symptoms diminished according to a decreased xerostomia questionnaire summary score of 35.0 and 45.1, respectively [-10.1 (-18.1 to -2.2); P = 0.013]. Three of the visual analog scale xerostomia measures indicated clinical benefit following use of ASC. Our data show that ASC therapy is safe with a clinically relevant effect on xerostomia-related symptoms. Confirmation in larger randomized controlled trials is warranted.


Polymerase chain reaction identification of microorganisms in previously root-filled teeth in a South Korean population.
A large body of evidence indicates that microorganisms are the primary causative agents of endodontic treatment failures. This study intended to assess the occurrence of nine putative endodontic pathogens in root-filled teeth associated with periradicular lesions in a South Korean population using a culture-independent molecular approach. Fourteen root-filled teeth with persistent periradicular diseases were selected for retreatment. After removal of the root canal filling, the canals were sampled, and a polymerase chain reaction assay using taxon-specific oligonucleotide primers was used for microbial detection. Bacteria were present in all cases, as revealed by amplification using ubiquitous 16S rDNA primers. The most frequently detected taxon was Enterococcus faecalis (64%), followed by Streptococcus spp. (21%) and Tannerella forsythensis (14%). The results of this study using a highly sensitive identification method are concurrent with those from other geographical locations using diverse identification methods in that E. faecalis is the main species found in cases of root-filled teeth associated with periradicular lesions.


Cochlear Efferent Innervation Is Sparse in Humans and Decreases with Age.
The mammalian cochlea is innervated by two cholinergic feedback systems called the medial olivocochlear (MOC) and lateral olivocochlear (LOC) pathways, which send control signals from the brainstem back to the outer hair cells and auditory-nerve fibers, respectively. Despite countless studies of the cochlear projections of these efferent fibers in animal models, comparable data for humans are almost completely lacking. Here, we immunostained the cochlear sensory epithelium from 23 normal-aging humans (14 males and 9 females), 0-86 years of age, with cholinergic markers to quantify the normal density of MOC and LOC projections, and the degree of age-related degeneration. In younger ears, the MOC density peaks in mid-cochlear regions and falls off both apically and basally, whereas the LOC innervation peaks near the apex. In older ears, MOC density decreases dramatically, whereas the LOC density does not. The loss of MOC feedback may contribute to the age-related decrease in word recognition in noise; however, even at its peak, the MOC density is lower than in other mammals, suggesting the MOC pathway is less important for human hearing.SIGNIFICANCE STATEMENT The cochlear epithelium and its sensory innervation are modulated by the olivocochlear (OC) efferent pathway. Although the medial OC (MOC) reflex has been extensively studied in humans, via contralateral sound suppression, the cochlear projections of these cholinergic neurons have not been described in humans. Here, we use immunostaining to quantify the MOC projections to outer hair cells and lateral OC (LOC) projections to the inner hair cell area in humans 0-89 years of age. We show age-related loss of MOC, but not LOC, innervation, which likely contributes to hearing impairments, and a relative paucity of MOC terminals at all ages, which may account for the relative weakness of the human MOC reflex and the difficulty in demonstrating a robust functional role in human experiments.


IL-6 promoter polymorphism -174 is associated with new-onset diabetes after transplantation.
New-onset diabetes after transplantation (NODAT) is a serious complication of transplantation. This study tested whether IL-6 production capacity may influence the development of NODAT in two different groups of patients. The occurrence of NODAT was analyzed with respect to IL-6 gene promoter polymorphism at position -174 (G-->C) and other relevant risk factors retrospectively in 217 renal transplant recipients and prospectively in 132. A linear increase in both circulating IL-6 (P = 0.09) and C-reactive protein (an indicator of basal IL-6 secretion; P = 0.03) concentrations from the CC genotype to the GG genotype was observed. In the multivariate model, the CC genotype was associated with a decreased risk for NODAT compared with the GG genotype in the two cohorts. Homeostasis Model Assessment for Insulin Resistance also revealed lesser insulin sensitivity in the GG carriers than in the CC carriers (2.15 +/- 2 versus 1.32 +/- 1.03; P = 0.03). Subgroup analysis showed that the influence of IL-6 gene promoter polymorphism on the development of NODAT was restricted mostly to overweight patients. These results highly suggest that IL-6 production capacity influences the development of NODAT and that diabetes-inducing drug administration should be limited in overweight patients who carry the GG genotype.


Trends of Oncological Quality of Robotic Gastrectomy for Gastric Cancer in the United States.
Robotic gastrectomy (RG) has been increasingly used for treatment of gastric cancer in the United States. However, it is unknown if there has been a nationwide improvement of short-term safety outcomes and oncological quality metrics over time. We used the National Cancer Database to identify patients who underwent major gastrectomy from 2010 through 2018. The short-term safety outcomes and oncological metrics were compared between cases of open gastrectomy (OG), laparoscopic gastrectomy (LG), and RG. We also compared the indications and outcomes of RG between the three periods (2010 - 2012, 2013 - 2015, and 2016 - 2018). Of the 22,445 patients included, 1,867 (8%) underwent RG. Number of RG continued to increase from only 37 cases performed in 2010 to 412 cases performed in 2018. The number of lymph nodes (LNs) examined (OG, 16; LG, 17; and RG, 19) and the R0 rate (OG, 88%; LG, 92%; and RG 94%) were better for RG than for OG or LG (P < 0.001). In the RG group, the number of LNs examined (first period, 15; third period, 18; P < 0.001), R0 rate (first period, 88.6%; third period, 91.1%; P < 0.001), length of hospital stay (first period, 9 days; third period, 8 days; P < 0.001), 30-day readmission rate (first period, 10.1%; third period, 7.9%; P < 0.001), and 90-day mortality (first period, 7.3%; third period, 6.0%; P = 0.003) continued to improve cohort over time. The ratio of the robotic cases performed in academic institutions gradually increased (first period, 48.6%; third period, 54.3%; P < 0.001). In multivariable analyses, RG was associated with more than 15 LNs being examined (OR, 1.49; 95% CI, 1.34 - 1.65; P < 0.001). The indications for RG appeared expanding to include more advanced stage, high comorbidity, and patients who underwent preoperative therapy. RG has been increasingly performed in the past decade. Although its indication was expanded to include more advanced tumors, we found that the oncological quality metrics and safety outcomes of RG have improved over time and were better than those of OG or LG.


A hydrostatic weighing method using total lung capacity and a small tank.
The purpose of this study was to establish the validity and reliability of a hydrostatic weighing method using total lung capacity (measuring vital capacity with a respirometer at the time of weighing) the prone position, and a small oblong tank. The validity of the method was established by comparing the TLC prone (tank) method against three hydrostatic weighing methods administered in a pool. The three methods included residual volume seated, TLC seated and TLC prone. Eighty male and female subjects were underwater weighed using each of the four methods. Validity coefficients for per cent body fat between the TLC prone (tank) method and the RV seated (pool), TLC seated (pool) and TLC prone (pool) methods were .98, .99 and .99, respectively. A randomised complete block ANOVA found significant differences between the RV seated (pool) method and each of the three TLC methods with respect to both body density and per cent body fat. The differences were negligible with respect to HW error. Reliability of the TLC prone (tank) method was established by weighing twenty subjects three different times with ten-minute time intervals between testing. Multiple correlations yielded reliability coefficients for body density and per cent body fat values of .99 and .99, respectively. It was concluded that the TLC prone (tank) method is valid, reliable and a favourable method of hydrostatic weighing.


Polymorphism in genes that influence sperm displacement.
Paternity of offspring of multiply inseminated females is in many organisms highly skewed, with an advantage generally going to the male that most recently mated. Variation in sperm competitive ability can result in strong natural selection, and one expects that a gene that offers an advantage in sperm displacement would, all else being equal, be rapidly fixed, leaving low equilibrium levels of variability in sperm competition. However, empirical studies have demonstrated genetic variation in sperm displacement, begging the question of how this variation can be maintained. Here we develop a population genetic model to find conditions that maintain polymorphism in alleles that influence sperm displacement. We consider a one-locus model in which allelic variants have pleiotropic effects on fecundity and mating ability in addition to sperm displacement. This model can admit more than one stable polymorphism, and we find conditions for protected polymorphism. Induced overdominance is not necessary for stable polymorphism. These results have direct bearing on the observed variation in the ability of resident sperm to defend against displacement.


Generation and characterization of recombinant vascular targeting agents from hybridoma cell lines.
Vascular targeting agents (VTAs) can be produced by linking antibodies or antibody fragments directed against endothelial cell markers to effector moieties. So far, it has been necessary to produce the components of VTAs (antibody, antibody fragment, linker, and effector) separately and, subsequently, to conjugate them by biochemical reactions. We devised a cloning and expression system to allow rapid generation of recombinant VTAs from hybridoma cell lines. The VTAs consist of a single chain Fv antibody fragment as a targeting moiety and either truncated Pseudomonas exotoxin (resulting in immunotoxins) or truncated human tissue factor (resulting in coaguligands) as effectors. The system was applied to generate recombinant immunotoxins and coaguligands directed against endoglin, vascular endothelial growth factor (VEGF):VEGF receptor (VEGFR) complex and vascular cell adhesion molecule 1 (VCAM-1). The fusion proteins exhibited similar functional activity to analogous biochemical constructs. This is the first report to describe the generation and characterization of recombinant coaguligands.


Local adenosine receptor blockade accentuates the sympathetic responses to fatiguing exercise.
The role adenosine plays in evoking the exercise pressor reflex in humans remains controversial. We hypothesized that localized forearm adenosine receptor blockade would attenuate muscle sympathetic nerve activity (MSNA) responses to fatiguing handgrip exercise in humans. Blood pressure (Finometer), heart rate, and MSNA from the peroneal nerve were assessed in 11 healthy young volunteers during fatiguing isometric handgrip, postexercise circulatory occlusion (PECO), and passive muscle stretch during PECO. The protocol was performed before and after adenosine receptor blockade by local infusion of 40 mg aminophylline in saline via forearm Bier block (regional intravenous anesthesia). In the second experiment, the same amount of saline was infused via the Bier block. After aminophylline, the MSNA and blood pressure responses to fatiguing handgrip, PECO, and passive stretch (all P < 0.05) were significantly greater than during the control condition. Saline Bier block had no similar effects on the MSNA and blood pressure responses. These data suggest that adenosine receptor antagonism in the exercising muscles may accentuate sympathetic activation during fatiguing exercise.


Transposable elements reveal the impact of introgression, rather than transposition, in Pisum diversity, evolution, and domestication.
The genetic structure and evolutionary history of the genus Pisum were studied exploiting our germplasm collection to compare the contribution of different mechanisms to the generation of diversity. We used sequence-specific amplification polymorphism (SSAP) markers to assess insertion site polymorphism generated by a representative of each of the two major groups of LTR-containing retrotransposons, PDR1 (Ty1/copia-like) and Cyclops (Ty3/gypsy-like), together with Pis1, a member of the En/Spm transposon superfamily. The analysis of extended sets of the four main Pisum species, P. fulvum, P. elatius, P. abyssinicum, and P. sativum, together with the reference set, revealed a distinct pattern of the NJ (Neighbor-Joining) tree for each basic lineage, which reflects the different evolutionary history of each species. The SSAP markers showed that Pisum is exceptionally polymorphic for an inbreeding species. The patterns of phylogenetic relationships deduced from different transposable elements were in general agreement. The retrotransposon-derived markers gave a clearer separation of the main lineages than the Pis1 markers and were able to distinguish the truly wild form of P. elatius from the antecedents of P. sativum. There were more species-specific and unique PDR1 markers than Pis1 markers in P. fulvum and P. elatius, pointing to PDR1 activity during speciation and diversification, but the proportion of these markers is low. The overall genetic diversity of Pisum and the extreme polymorphism in all species, except P. abyssinicum, indicate a high contribution of recombination between multiple ancestral lineages compared to transposition within lineages. The two independently domesticated pea species, P. abyssinicum and P. sativum, arose in contrasting ways from the common processes of hybridization, introgression, and selection without associated transpositional activity.


Effect of Usual Medical Care Plus Chiropractic Care vs Usual Medical Care Alone on Pain and Disability Among US Service Members With Low Back Pain: A Comparative Effectiveness Clinical Trial.
It is critically important to evaluate the effect of nonpharmacological treatments on low back pain and associated disability. To determine whether the addition of chiropractic care to usual medical care results in better pain relief and pain-related function when compared with usual medical care alone. A 3-site pragmatic comparative effectiveness clinical trial using adaptive allocation was conducted from September 28, 2012, to February 13, 2016, at 2 large military medical centers in major metropolitan areas and 1 smaller hospital at a military training site. Eligible participants were active-duty US service members aged 18 to 50 years with low back pain from a musculoskeletal source. The intervention period was 6 weeks. Usual medical care included self-care, medications, physical therapy, and pain clinic referral. Chiropractic care included spinal manipulative therapy in the low back and adjacent regions and additional therapeutic procedures such as rehabilitative exercise, cryotherapy, superficial heat, and other manual therapies. Coprimary outcomes were low back pain intensity (Numerical Rating Scale; scores ranging from 0 [no low back pain] to 10 [worst possible low back pain]) and disability (Roland Morris Disability Questionnaire; scores ranging from 0-24, with higher scores indicating greater disability) at 6 weeks. Secondary outcomes included perceived improvement, satisfaction (Numerical Rating Scale; scores ranging from 0 [not at all satisfied] to 10 [extremely satisfied]), and medication use. The coprimary outcomes were modeled with linear mixed-effects regression over baseline and weeks 2, 4, 6, and 12. Of the 806 screened patients who were recruited through either clinician referrals or self-referrals, 750 were enrolled (250 at each site). The mean (SD) participant age was 30.9 (8.7) years, 175 participants (23.3%) were female, and 243 participants (32.4%) were nonwhite. Statistically significant site × time × group interactions were found in all models. Adjusted mean differences in scores at week 6 were statistically significant in favor of usual medical care plus chiropractic care compared with usual medical care alone overall for low back pain intensity (mean difference, -1.1; 95% CI, -1.4 to -0.7), disability (mean difference, -2.2; 95% CI, -3.1 to -1.2), and satisfaction (mean difference, 2.5; 95% CI, 2.1 to 2.8) as well as at each site. Adjusted odd ratios at week 6 were also statistically significant in favor of usual medical care plus chiropractic care overall for perceived improvement (odds ratio = 0.18; 95% CI, 0.13-0.25) and self-reported pain medication use (odds ratio = 0.73; 95% CI, 0.54-0.97). No serious related adverse events were reported. Chiropractic care, when added to usual medical care, resulted in moderate short-term improvements in low back pain intensity and disability in active-duty military personnel. This trial provides additional support for the inclusion of chiropractic care as a component of multidisciplinary health care for low back pain, as currently recommended in existing guidelines. However, study limitations illustrate that further research is needed to understand longer-term outcomes as well as how patient heterogeneity and intervention variations affect patient responses to chiropractic care. ClinicalTrials.gov Identifier: NCT01692275.


Using video modeling and reinforcement to teach perspective-taking skills to children with autism.
We evaluated video modeling and reinforcement for teaching perspective-taking skills to 3 children with autism using a multiple baseline design. Video modeling and reinforcement were effective; however, only 2 children were able to pass an untrained task, indicating limited generalization. The findings suggest that video modeling may be an effective technology for teaching perspective taking if researchers can continue to develop strategies for enhancing the generalization of these new skills.


Mycophenolate mofetil pharmacokinetic monitoring in pediatric kidney transplant recipients.
This open-label, longitudinal, long-term study of de novo pediatric renal transplant recipients was designed to investigate the pharmacokinetics (PK) of mycophenolic acid (MPA) and its possible interaction with cyclosporine (CsA). Thirty-four children on an immunosuppressive regimen of CsA, prednisone, and mycophenolate mofetil (MMF, 300-400 mg/m2 twice daily) were investigated at 6, 30, 180, and 360 days after transplantation. Considerable interindividual variability in the areas under the concentration curve (AUC(0-12)) of MPA was observed during the follow-up, although the dose of MMF remained the same over the same time. Predose levels (C0) increased significantly during the first 6 months after transplantation: C0 at 6 and 180 days after transplantation was 0.8 +/- 0.6 and 1.9 +/- 1.1 microg/mL (P < .0001). A significant time-dependent increase in the AUC of MPA was also observed during the first 6 posttransplant months: AUC(0-12) at 6 and 180 days after transplantation was 23.3 +/- 10.8 and 40 +/- 11.6 mg*h/L (P = .003). MPA concentrations 3 and 4 hours after MMF intake were the individual time points that best correlated with the full MPA AUC (r = 0.8 and 0.79; P < .001). The abbreviated MPA AUC (0-4 hours) correlated reasonably with the full AUC (r = 0.87; P < .001). Finally, a significant reduction in CsA dose during the first 6 posttransplant months (P < .001) matched the significant increases in both MPA C0 and full MPA AUC, thus demonstrating the interaction of the 2 immunosuppressive drugs. These observations suggest the need for therapeutic drug monitoring when adjusting the dose of MMF in children.


Engraftment of bone marrow and fetal liver cells after in utero transplantation in MDX mice.
In utero hematopoietic stem cell transplantation (IUHSCTx) has been experimentally or clinically effective only in circumstances in which there is a survival advantage for donor cells. A survival advantage exists for normal muscle cells in muscular dystrophy. Because hematopoietic and mesenchymal stem cells may have the capacity to differentiate into muscle cells, the authors hypothesized that in utero bone marrow (BM) or fetal liver (FL) stem cell transplantation may be used to treat muscular dystrophy. Time-dated 14-day-gestation fetal muscular dystrophy mice (mdx) were injected intraperitoneally with 1 to 5 x 10(6) BM or FL cells per fetus from Rosa26 donor mice (transgenic for lacZ). Four weeks after birth, peripheral blood from the pups was analyzed for hematopoietic chimerism by using fluorescence-activated cell sorting (FACS) for the Ly-9.1 marker. Chimeric mice (6 BM and 2 FL recipients) were sacrificed at 12 to 14 months of age, muscles were stained with X-gal, and analyzed by 1- to 2-microm plastic sections. Polymerase chain reaction (PCR) for lacZ was performed in other organs to determine systemic engraftment. At the time of death, all animals that were chimeric at 4 weeks continued to show hematopoietic chimerism of 0.2% to 9% by FACS. Engrafted donor cells were found in multiple sections from hindlimb skeletal muscles, diaphragms, and hearts from both BM and FL recipients. These cells had incorporated into the host muscles, and their morphology was consistent with myogenic differentiation. PCR of BM, liver, spleen, thymus, kidney, and lung for lacZ was positive in multiple animals. IUHSCTx leads to widespread engraftment of donor cells in multiple muscle compartments of hematopoietic chimeras. The advantage for normal myocytes offered in the mdx model allows engraftment and myogenic differentiation of transplanted BM or FL cells by morphology at a relatively higher frequency in muscle relative to other tissues, without the need for host conditioning. Because muscular dystrophy now can be detected early in gestation, such a strategy may offer a future alternative in the clinical treatment of this disease.


N-acetyl-beta-D-glucosaminidase assay in urine: urea inhibition.
Urea inhibition of urinary N-acetyl-beta-D-glucosaminidase (NAG) was examined with human isoenzymes and total enzyme in urine. The fluorometric substrate 4-methylumbelliferyl-N-acetyl-beta-D-glucosaminide (MUNAG) and the colorimetric substrate m-cresolsulfonphthaleinyl-N-acetyl-beta-D-glucosaminide (MCPNAG) were used to determine substrate kinetics and apparent urea inhibition kinetics. Apparent KmS of 0.47 (MUNAG) and 0.35 mmol/L (MCPNAG) for human NAG isoenzyme A and 0.46 (MUNAG) and 0.30 mmol/L (MCPNAG) for human NAG isoenzyme B were determined. Apparent Kis of approximately 100 mmol/L for urea inhibition of both isoenzymes in either substrate and apparent Kis of 79 (MUNAG) and 91 mmol/L (MCPNAG) for NAG in dilute urine samples were found. The potential for urea inhibition at physiological concentrations of urea and at normal assay dilutions therefore exists. Inhibition at these dilutions was minimal when substrate concentrations of 2 x Km or greater were used, but the substrate MUNAG at 1/2 x Km gave the highest sensitivity and lower blanks and allowed better quantitation of low activity samples. Within-run CVs of 3.2% with MUNAG and 10% with MCPNAG were found for low activity samples.


First evidence of an extensive Acheulean large cutting tool accumulation in Europe from Porto Maior (Galicia, Spain).
We describe a European Acheulean site characterised by an extensive accumulation of large cutting tools (LCT). This type of Lower Paleolithic assemblage, with dense LCT accumulations, has only been found on the African continent and in the Near East until now. The identification of a site with large accumulations of LCTs favours the hypothesis of an African origin for the Acheulean of Southwest Europe. The lithic tool-bearing deposits date back to 293-205 thousand years ago. Our chronological findings confirm temporal overlap between sites with clear "African" Acheulean affinities and Early Middle Paleolithic sites found elsewhere in the region. These complex technological patterns could be consistent with the potential coexistence of different human species in south-western Europe during the Middle Pleistocene.


Measurement of the affinity of melittin for zwitterionic and anionic membranes using immobilized lipid biosensors.
The binding of melittin to zwitterionic dimyristyphosphatidylcholine (DMPC) and anionic dimyristylphosphatidylglycerol (DMPG) was analysed using two different immobilized model membrane systems. The first system used surface plasmon resonance (SPR), which monitors the real-time binding of peptides to an immobilized hybrid bilayer. SPR experiments reflected a stronger binding of melittin for DMPG than for DMPC, while kinetic analysis suggested the existence of at least two distinct binding steps. The second lipid biosensor system involved an immobilized phospholipid monolayer covalently attached to a microporous silica surface. The binding of melittin to the immobilized monolayer was then monitored using dynamic elution chromatography with varied methanol concentrations to analyse the binding of melittin to DMPC and DMPG. The nonlinear binding behaviour observed for melittin with the phosphatidylcholine (PC) and phosphatidylglycerol (PG) monolayers compared with the linear retention plots and Gaussian peak shapes observed for the control molecule demonstrated that melittin undergoes significant conformational and orientational changes upon binding to the immobilized PC and PG ligands. The dependence of log k' on per cent methanol also demonstrated a bimodal interaction whereby hydrophobic forces predominated at higher temperatures and methanol concentrations, while other forces, presumably electrostatic in nature, also made a contribution to the affinity of the peptides for the lipid monolayer, particularly at lower temperatures. The complementary use of these two lipid biosensors thus allows the role of hydrophobic and electrostatic forces in peptide-membrane interactions to be studied.


Cancer control in small island nations: from local challenges to global action.
Cancer is a leading cause of death in small island nations and is forecast to increase substantially over the coming years. Governments, regional agencies, and health services of these nations face daunting challenges, including small and fragile economies, unequal distribution of resources, weak or fragmented health services, small population sizes that make sustainable workforce and service development problematic, and the unavailability of specialised cancer services to large parts of the population. Action is required to prevent large human and economic costs relating to cancer. This final Series paper highlights the challenges and opportunities for small island nations, and identifies ways in which the international community can support efforts to improve cancer control in these settings. Our recommendations focus on funding and investment opportunities to strengthen cancer-related health systems to improve sharing of technical assistance for research, surveillance, workforce, and service development, and to support small island nations with policy changes to reduce the consumption of commodities (eg, tobacco and unhealthy food products) that increase cancer risk.


Palatal configuration in complete bilateral cleft lip and palate infants before and after cheiloplasty.
The purpose of this study was to analyze the three-dimensional configuration of the premaxilla, vomer, and lateral segments in bilateral cleft lip and palate (BCLP) infants and to investigate the early changes in the configuration following one- and two-stage cheiloplasty. This study consisted of 10 complete BCLP infants. One-stage operations were performed in five patients according to Manchester's method at 4 months of age. Two-stage operations were done for the remaining five patients using a triangular flap according to Tennison's method, at 4 and 8 months of age. Serial plaster models before and after the cheiloplasty were measured with a computer-controlled, highly accurate, contact-type measuring apparatus. Temporal changes in the configuration and form of the premaxilla were observed using an automatic superimposition method. The inclination and deviation of the vomer were evaluated using an approximation technique to a straight line with least squares. The distance between the lateral segments and a three-dimensional coordinate of the incisal point were also measured. The following differences in palatal configuration between the one- and two-stage cheiloplasties were observed: 1) In the two-stage group, the premaxilla shifted toward the cleft edge where the cheiloplasty was performed in both first- and second-stage operations. After the two-stage operation, the premaxilla did not shift greatly, and the premaxilla in cases 4 and 5 shifted downward and toward the cleft edge of the lateral segments where the first operation was performed. Protrusion of the premaxilla remained in the two-stage group. 2) In the one-stage group, the premaxilla in case 4 descended downward and backward without twisting or bending. The premaxilla of the other patients descended downward with twisting and bending. 3) Patients in the two-stage group had a stronger tendency toward medial collapse of the lateral segments than did those in the one-stage group.


Emergence of Carbapenemase-Producing Enterobacteriaceae, South-Central Ontario, Canada1.
We analyzed population-based surveillance data from the Toronto Invasive Bacterial Diseases Network to describe carbapenemase-producing Enterobacteriaceae (CPE) infections during 2007-2015 in south-central Ontario, Canada. We reviewed patients' medical records and travel histories, analyzed microbiologic and clinical characteristics of CPE infections, and calculated incidence. Among 291 cases identified, New Delhi metallo-β-lactamase was the predominant carbapenemase (51%). The proportion of CPE-positive patients with prior admission to a hospital in Canada who had not received healthcare abroad or traveled to high-risk areas was 13% for patients with oxacillinase-48, 24% for patients with New Delhi metallo-β-lactamase, 55% for patients with Klebsiella pneumoniae carbapenemase, and 67% for patients with Verona integron-encoded metallo-β-lactamase. Incidence of CPE infection increased, reaching 0.33 cases/100,000 population in 2015. For a substantial proportion of patients, no healthcare abroad or high-risk travel could be established, suggesting CPE acquisition in Canada. Policy and practice changes are needed to mitigate nosocomial CPE transmission in hospitals in Canada.


Effect of different types of Tai Chi exercise programs on the rate of change in bone mineral density in middle-aged adults at risk of osteoporosis: a randomized controlled trial.
To evaluate three Tai Chi (TC) exercise programs as intervention measures to compare their effects on improving rate of change in bone mineral density (BMD) in elderly individuals with osteoporosis (OP) and to propose the optimal exercise duration. A randomized controlled trial (RCT) was conducted to identify study participants based on inclusion and exclusion criteria. Due to subject attrition, the number of participants analyzed decreased from 60 to 49. These participants were divided into four groups: 24-style TC Chuan group (24TCCG) (n = 13, 7 males/6 females), TC Kung Fu Fan group (TCKFFG) (n = 12, 5 males/7 females), TC Softball group (TCSBG) (n = 11, 6 males/5 females), and a control group (CG) (n = 13, 6 males/7 females). Except for the control group, each group received different TC exercise programs four times a week for 60 min per session, lasting for 16 weeks. BMD was measured using dual-energy X-ray absorptiometry (DXA) at the L2-L4 lumbar vertebrae, Ward's triangle, femoral neck, and greater trochanter. The rate of change of BMD was calculated using the formula. Compared with CG, all three TC groups showed significant improvements in BMD changes (P < 0.05), but their effects on the improvement of femoral neck and greater tuberosity BMD change rates were similar (P > 0.05). In addition, compared to the other exercise regimens, 24TCCG demonstrated more significant improvements in BMD at the L2-L4 lumbar vertebrae region and exhibited a more pronounced improvement in Ward's triangle BMD after only 8 weeks (P < 0.05). Short-term (≤ 4 weeks) TCKFFG was more effective than TCSBG in enhancing femoral neck BMD (P < 0.05). However, statistical significance was not found (P > 0.05) in all other cases. These three TC exercise programs have similar positive effects on the BMD of the femoral neck and greater trochanter. However, compared with other exercise schemes, 24TCC showed a more significant improvement in BMD of the L2-L4 lumbar vertebrae region after just 8 weeks, as well as a more pronounced improvement in BMD of Ward's triangle. In terms of improving femoral neck BMD, TCKFF was found to be more effective than TCSB in less than 4 weeks. This study provides evidence for the effectiveness of TC exercise in improving BMD and preventing OP in the middle-aged and elderly high-risk population.


Mitochondrial DNA evolution in mice.
This study extends knowledge of mitochondrial DNA (mtDNA) diversity in mice to include 208 animals belonging to eight species in the subgenus Mus. Highly purified mtDNA from each has been subjected to high-resolution restriction mapping with respect to the known sequence of one mouse mtDNA. Variation attributed to base substitutions was encountered at about 200 of the 300 cleavage sites examined, and a length mutation was located in or near the displacement loop. The variability of different functional regions in this genome was as follows, from least to most: ribosomal RNA, transfer RNA, known proteins, displacement loop and unidentified reading frames. --Phylogenetic analysis confirmed the utility of the Sage and Marshall revision of mouse classification, according to which there are at least four species of commensal mice and three species of aboriginal mice in the complex that was formerly considered to be one species. The most thoroughly studied of these species is Mus domesticus, the house mouse of Western Europe and the Mediterranean region, which is the mitochondrial source of all 50 of the laboratory strains examined and of the representatives of wild house mice introduced by Europeans to North and South America during the past few hundred years. --The level of mtDNA variation among wild representatives of M. domesticus is similar to that for the Eastern European house mouse (M. musculus) and several other mammalian species. By contrast, among the many laboratory strains that are known or suspected to stem from the pet mouse trade, there is little interstrain variation, most strains having the "old inbred" type of domesticus mtDNA, whose frequency in the 145 wild mice examined is low, about 0.04. Also notable is the apparent homogeneity of mtDNA in domesticus races that have fixed six or more fused chromosomes and the close relationship of some of these mtDNAs to those of karyotypically normal mice. --In addition, this paper discusses fossil and other evidence for the view that in mice, as in many other mammals, the average rate of point mutational divergence in mtDNA is 2-4% per million years. From this, it is estimated that the commensal association between mice and our ancestors began more than a million years ago, i.e., at an early stage in the evolution of Homo erectus.


Driving ability after a stroke: evaluation and recovery.
The ability to drive after a stroke has been recognised by many authors as a sign of independence and it is closely associated with proper social reintegration. However, it remains unclear how the driving ability of an individual who has suffered a stroke should be evaluated, and by whom. Neurorehabilitation can produce improvements in patients who have suffered a stroke, and patients may therefore be able to resume driving at the end of an appropriate neurorehabilitation programme. The aim of this article is to present a literature review in order to highlight current evidence regarding methods for assessing driving ability and therapeutic methods applied in order to recover a patient's ability to drive. A literature search was performed in different databases for the period between 1993 and 2011. Studies were analysed individually based on methods for assessing driving ability and neurorehabilitation measures. If there are any doubts regarding stroke patients' ability to drive, patients should be assessed appropriately. The proper way to assess these patients according to the literature is by employing a multidisciplinary evaluation to determine who is able to take a road test. Neurorehabilitation exercises currently in use may be able to improve driving ability in stroke patients.


Myosin heavy chain messenger RNA and protein isoform transitions during cardiac hypertrophy. Interaction between hemodynamic and thyroid hormone-induced signals.
Expression of the cardiac myosin isozymes is regulated during development, by hormonal stimuli and hemodynamic load. In this study, the levels of expression of the two isoforms (alpha and beta) of myosin heavy chain (MHC) during cardiac hypertrophy were investigated at the messenger RNA (mRNA) and protein levels. In normal control and sham-operated rats, the alpha-MHC mRNA predominated in the ventricular myocardium. In response to aortic coarctation, there was a rapid induction of the beta-MHC mRNA followed by the appearance of comparable levels of the beta-MHC protein in parallel to an increase in the left ventricular weight. Administration of thyroxine to coarctated animals caused a rapid deinduction of beta-MHC and induction of alpha-MHC, both at the mRNA and protein levels, despite progression of left ventricular hypertrophy. These results suggest that the MHC isozyme transition during hemodynamic overload is mainly regulated by pretranslational mechanisms, and that a complex interplay exists between hemodynamic and hormonal stimuli in MHC gene expression.


Reflections on Dr Henderson of Perth's case of impracticable labour: an early case (1820) in which the caesarean operation was performed.
The rediscovery of a female pelvis with features characteristic of osteomalacia stimulated an enquiry into the clinical history of the woman involved. It was established that she died in 1820, aged 30. Despite being severely debilitated and confined to bed for some years with increasing skeletal deformities, she became pregnant, and in due course laboured unsuccessfully for about 102 hours. An elective caesarean section was performed, but she died some hours later, though her daughter survived and was appropriately christened Caesar Anna. This represents one of the earliest cases in which the caesarean operation was performed where the full obstetric history was carefully recorded by the obstetrician involved, Dr. Henderson of Perth. The case was clearly considered important, and in 1836 engravings of this pelvis were used to illustrate Professor Hamilton's "Practical Observations of Various Subjects Related to Midwifery". Such cases are now of great rarity in the developed world.


Intracranial pulsatility is associated with regional brain volume in elderly individuals.
Excessive intracranial pulsatility is thought to damage the cerebral microcirculation, causing cognitive decline in elderly individuals. We investigated relationships between brain structure and measures related to intracranial pulsatility among healthy elderly. Thirty-seven stroke-free, non-demented individuals (62-82 years of age) were included. We assessed brain structure, invasively measured cerebrospinal fluid (CSF) pulse pressure, and magnetic resonance-quantified arterial and CSF flow pulsatility, as well as arterial pulse pressure. Using both multivariate partial least squares and ordinary regression analyses, we identified a significant pattern of negative relationships between the volume of several brain regions and measures of intracranial pulsatility. The strongest relationships concerned the temporal lobe cortex and hippocampus. These findings were also coherent with observations of positive relationships between intracranial pulsatility and ventricular volume. In conclusion, elderly subjects with high intracranial pulsatility display smaller brain volume and larger ventricles, supporting the notion that excessive cerebral arterial pulsatility harms the brain. This calls for research investigating altered intracranial cardiac-related pulsatile stress as a potential risk factor that may cause or worsen the prognosis in subjects developing cognitive impairment and dementia.


Automatic quantitative radiometric assay of bacterial metabolism.
In a two-compartment scintillation vial, suspensions of bacteria were cultured with 1 muCi of [U-14C] glucose and the released 14C02 was measured continuously, cumulatively, and automatically in a liquid-scintillation counter modified to maintain sample temperature at 37 degrees C. We could follow the metabolism of bacterial populations through their early phase of exponential growth with good precision. The data were obtained conveniently, with use of conventional reagents, glassware, and counting equipment. From analysis of the exponential portion of the curves for cumulative activity vs. time, we could measure cell replication rate precisely in units of time. The resulting values were demonstrably independent of some common experimental variables, including the number of bacteria in the inoculum and counting system sensitivity. Sensitivity of the bacteria to antibiotics was measured to within a few percent by noting the relative prolongation of replication time in the presence of those inhibitors. The digital data from the scintillation counter are susceptible to on- or off-line computer analysis, thus providing the prospect for a totally-automated analytical system. The method shows promise for the mechanized quantitative analysis of bacterial growth, and its inhibition.


Development of genetic diversity, differentiation and structure over 500 years in four ponderosa pine populations.
Population history plays an important role in shaping contemporary levels of genetic variation and geographic structure. This is especially true in small, isolated range-margin populations, where effects of inbreeding, genetic drift and gene flow may be more pronounced than in large continuous populations. Effects of landscape fragmentation and isolation distance may have implications for persistence of range-margin populations if they are demographic sinks. We studied four small, disjunct populations of ponderosa pine over a 500-year period. We coupled demographic data obtained through dendroecological methods with microsatellite data to discern how and when contemporary levels of allelic diversity, among and within-population levels of differentiation, and geographic structure, arose. Alleles accumulated rapidly following initial colonization, demonstrating proportionally high levels of gene flow into the populations. At population sizes of approximately 100 individuals, allele accumulation saturated. Levels of genetic differentiation among populations (F(ST) and Jost's D(est)) and diversity within populations (F(IS)) remained stable through time. There was no evidence of geographic genetic structure at any time in the populations' history. Proportionally, high gene flow in the early stages of population growth resulted in rapid accumulation of alleles and quickly created relatively homogenous genetic patterns among populations. Our study demonstrates that contemporary levels of genetic diversity were formed quickly and early in population development. How contemporary genetic diversity accumulates over time is a key facet of understanding population growth and development. This is especially relevant given the extent and speed at which species ranges are predicted to shift in the coming century.


Examining the Relationship Between Mental Skills and Grit in Senior Olympic Athletes.
Given the challenge of consistent physical activity among aging adults, it is important to find ways to increase physical activity levels in this population. Participants in the Senior Olympic Games may extend their sport participation through the use of mental skills. This study examined the relationship between mental skills use by Senior Olympic Games participants and their grit, or passion and perseverance, toward a long-term goal. The participants in the Arizona Senior Olympic Games (n = 304) completed an online survey of mental skills use (Athletic Coping Skills Inventory) and grit (Grit Scale-Short). Based on the ongoing validity and reliability issues of the Grit Scale-Short, two regression models were examined, with consistency of interests (passion) and perseverance of effort (perseverance) as dependent variables. After controlling for age and sex, mental skills accounted for 15.2% of the variance in consistency of interests and 13.1% of the variability in perseverance of effort. The results are discussed in light of the findings.


Position specificity in the genus Coreomyces (Laboulbeniomycetes, Ascomycota).
To study position specificity in the insect-parasitic fungal genus Coreomyces (Laboulbeniaceae, Laboulbeniales), we sampled corixid hosts (Corixidae, Heteroptera) in southern Scandinavia. We detected Coreomyces thalli in five different positions on the hosts. Thalli from the various positions grouped in four distinct clusters in the resulting gene trees, distinctly so in the ITS and LSU of the nuclear ribosomal DNA, less so in the SSU of the nuclear ribosomal DNA and the mitochondrial ribosomal DNA. Thalli from the left side of abdomen grouped in a single cluster, and so did thalli from the ventral right side. Thalli in the mid-ventral position turned out to be a mix of three clades, while thalli growing dorsally grouped with thalli from the left and right abdominal clades. The mid-ventral and dorsal positions were found in male hosts only. The position on the left hemelytron was shared by members from two sister clades. Statistical analyses demonstrate a significant positive correlation between clade and position on the host, but also a weak correlation between host sex and clade membership. These results indicate that sex-of-host specificity may be a non-existent extreme in a continuum, where instead weak pREFERENCES for one host sex may turn out to be frequent.


Transition to Grandparenthood and Subjective Well-Being in Older Europeans: A Within-Person Investigation Using Longitudinal Data.
The transition to grandparenthood, that is the birth of the first grandchild, is often assumed to increase the subjective well-being of older adults; however, prior studies are scarce and have provided mixed results. Investigation of the associations between grandparenthood and subjective well-being, measured by self-rated life satisfaction, quality of life scores, and depressive symptoms, used the longitudinal Survey of Health, Ageing and Retirement in Europe from 13 countries, including follow-up waves between 2006 and 2015 (n = 64,940 person-observations from 38,456 unique persons of whom 18,207 had two or more measurement times). Both between-person and within-person (or fixed-effect) regression models were executed, where between-person associations represent results across individuals, that is, between grandparents and non-grandparents; within-person associations represent an individual's variation over time, that is, they consider whether the transition to grandparenthood increases or decreases subjective well-being. According to the between-person models, both grandmothers and grandfathers reported higher rate of life satisfaction and quality of life than non-grandparents. Moreover, grandmothers reported fewer depressive symptoms than women without grandchildren. The within-person models indicated that entry into grandmotherhood was associated with both improved quality of life scores and improved life satisfaction. These findings are discussed with reference to inclusive fitness theory, parental investment theory, and the grandmother hypothesis.


Preparation and testing of bevacizumab radioimmunoconjugates with Bismuth-213 and Bismuth-205/Bismuth-206.
Bevacizumab, a humanized anti-VEGF monoclonal antibody has shown promise in various clinical trials. We report the development and testing of Bi-213 (an alpha-emitting radionuclide) labeled bevacizumab for in vitro and in vivo studies using two different chelators viz cDTPA and CHX-A''. The developed labeling method showed high labeling yields of 93.6% and 89.7% for cDTPA and CHX-A'' respectively and the results were reproducible. The in vitro and in vivo stability tests were carried out using Bi-213 and long half-life Bismuth isotope (Bi-205/Bi-206) for pharmacokinetics. The in vitro results showed remarkable stability of the radiolabeled bevacizumab regardless of the chelator. The in vivo pharmacokinetics studies however, showed that the uptake and retention of cDTPA-bevacizumab was significantly higher in kidneys (p-value 0.02) and lower in liver and spleen (p-value <0.0001 and 0.0009 respectively). The values for the two conjugates compared well in blood but the longer term data for CHX-A'' conjugate showed slow clearance resulting in a significantly longer blood half-life of the product (211 hours compared to 4 hours for cDTPA-bevacizumab). Preliminary in vivo results showed increased efficacy of the combination therapy compared to bevacizumab only. The tumor area (mm(2)) decreased from 24.8 +/- 3.6 and 12.8 +/- 1.7 for 1 and 3 mg/kg cold bevacizumab only to 6.5 +/- 0.7 and 7.5 +/- 4.8 when single dose of 333 MBq/kg of (213)Bi-bevacizumab was administered as combination therapy. In conclusion it can be said that stable radiolabeled bevacizumab conjugates can be prepared with Bi-213 with either chelators used. The shorter blood half-life with cDTPA-bevacizumab may not be a major concern with Bi-213 as its own half-life is 46 minutes only. The combination therapy proved superior to bevacizumab alone therapy, a phenomenon that can be particularly useful in cancers where bevacizumab alone has shown limited success like prostate cancer.


Sustaining secondary school nursing practice in Australia: a qualitative study.
This interpretive descriptive, qualitative study explored secondary school nurses' perceptions of factors that impact on their role and their views on how their role can be best supported. Nine secondary school nurses from four Department of Human Services regions in Victoria, Australia, participated in semistructured, in-depth interviews. Purposive sampling was used, with participants required to have a minimum of 2 years' experience as secondary school nurses. Data were thematically analyzed, revealing a complex and challenging role. The findings identified key factors necessary to support quality practice. All stakeholders need a shared understanding of the purpose and principles underpinning the secondary school nurse role and the nurse's professional obligations. Knowledge and experience are required that recognize the breadth and depth necessary for secondary school nurses to work effectively within their scope of practice. The adoption of a model of critical companionship is recommended to provide facilitated reflection on practice as a support mechanism for the role.


Effect of a media intervention on hepatitis B screening among Vietnamese Americans.
Objective: There is a lack of controlled studies of community-wide interventions to increase screening for hepatitis B (HBV) among Asian Americans, particularly Vietnamese Americans, who disproportionately suffer from HBV-related illnesses. The objective of our study was to develop, implement, and evaluate the effectiveness of a media campaign to promote HBV screening among Vietnamese Americans.Design: We designed and implemented a three-year media campaign promoting HBV screening among Vietnamese Americans. Evaluation consisted of cross-sectional pre- and post-intervention population-based telephone surveys of Vietnamese Americans adults age 18-64 who spoke English or Vietnamese and lived in the Northern California (intervention) or Greater Washington, D.C. (comparison) communities in 2007 or 2011. Statistical analysis was completed in 2012. The main outcome was self-report of HBV testing, defined as participants answering 'Yes' to the question: 'Have you ever had a blood test to check for hepatitis B?'Results: The sample sizes at pre- and post-intervention were 1,704 and 1,666, respectively. Both communities reported increased exposure to HBV-related booklets, radio and television advertisements, and websites. Only the intervention community reported increased exposure to newspaper elements. HBV screening increased in both communities (intervention: 65.3% to 73.1%, p < 0.01, comparison: 57.7% to 66.0%, p < 0.01). In multivariable analyses, there was no intervention effect. In both communities, exposure to media elements (Odds Ratio 1.26 [95% Confidence Interval: 1.21, 1.31] for each additional element) was significantly associated with screening.Conclusions: Among Vietnamese Americans in 2 large communities, HBV screening rates were sub-optimal. Screening increased in both the intensive media intervention and comparison communities, and exposure to HBV-related media messages was associated with increased screening. Efforts to address HBV screening among Vietnamese Americans should include mass media messaging.


Effects of Intra-Base Pair Proton Transfer on Dissociation and Singlet Oxygenation of 9-Methyl-8-Oxoguanine-1-Methyl-Cytosine Base-Pair Radical Cations.
8-Oxoguanosine is the most common oxidatively generated base damage and pairs with complementary cytidine within duplex DNA. The 8-oxoguanosine-cytidine lesion, if not recognized and removed, not only leads to G-to-T transversion mutations but renders the base pair being more vulnerable to the ionizing radiation and singlet oxygen (1 O2 ) damage. Herein, reaction dynamics of a prototype Watson-Crick base pair [9MOG ⋅ 1MC]⋅+ , consisting of 9-methyl-8-oxoguanine radical cation (9MOG⋅+ ) and 1-methylcystosine (1MC), was examined using mass spectrometry coupled with electrospray ionization. We first detected base-pair dissociation in collisions with the Xe gas, which provided insight into intra-base pair proton transfer of 9MOG⋅+ ⋅ 1MC ← → ${{\stackrel{ {\rightarrow} } { {\leftarrow} } } }$ [9MOG - HN1 ]⋅ ⋅ [1MC+HN3' ]+ and subsequent non-statistical base-pair separation. We then measured the reaction of [9MOG ⋅ 1MC]⋅+ with 1 O2 , revealing the two most probable pathways, C5-O2 addition and HN7 -abstraction at 9MOG. Reactions were entangled with the two forms of 9MOG radicals and base-pair structures as well as multi-configurations between open-shell radicals and 1 O2 (that has a mixed singlet/triplet character). These were disentangled by utilizing approximately spin-projected density functional theory, coupled-cluster theory and multi-referential electronic structure modeling. The work delineated base-pair structural context effects and determined relative reactivity toward 1 O2 as [9MOG - H]⋅>9MOG⋅+ >[9MOG - HN1 ]⋅ ⋅ [1MC+HN3' ]+ ≥9MOG⋅+ ⋅ 1MC.


Comparing the performance of linear and nonlinear principal components in the context of high-dimensional genomic data integration.
Linear principal component analysis (PCA) is a widely used approach to reduce the dimension of gene or miRNA expression data sets. This method relies on the linearity assumption, which often fails to capture the patterns and relationships inherent in the data. Thus, a nonlinear approach such as kernel PCA might be optimal. We develop a copula-based simulation algorithm that takes into account the degree of dependence and nonlinearity observed in these data sets. Using this algorithm, we conduct an extensive simulation to compare the performance of linear and kernel principal component analysis methods towards data integration and death classification. We also compare these methods using a real data set with gene and miRNA expression of lung cancer patients. First few kernel principal components show poor performance compared to the linear principal components in this occasion. Reducing dimensions using linear PCA and a logistic regression model for classification seems to be adequate for this purpose. Integrating information from multiple data sets using either of these two approaches leads to an improved classification accuracy for the outcome.


Aqueous humor outflow facility by tonography does not change with body position.
Intraocular pressure (IOP) varies with body position and previous research has indicated that most, but not all, of the variation in IOP is due to changes in episcleral venous pressure (EVP). Positional changes in other aqueous humor dynamic parameters may contribute to the change in IOP. The purpose of this study was to investigate the variation of aqueous humor outflow facility with body position changes. Healthy volunteers, aged 24 to 45 years old, were recruited for this study. Constant weight tonography was performed using a modified electronic Schiotz tonometer in two positions: seated position, 70 degrees from horizontal with neck extended until the cornea was level with floor; and supine position. A minimum of 30 minutes was allowed between the two measurements. Tonography data were fitted to second order polynomials and values for the initial steady state IOP and the outflow facility were determined using standard tables and normograms. IOP was measured using pneumatonometry. Forty-two eyes from 21 subjects were studied. IOP in the sitting and supine positions were 17.8 +/- 1.7 mm Hg and 19.9 +/- 1.6 mm Hg, respectively, and were significantly different (P < 0.001). The mean outflow facility in the sitting and supine positions were 0.30 +/- 0.31 microL/mL/mm Hg and 0.28 +/- 0.09 microL/mL/mm Hg, respectively, and were not significantly different (P = 0.37). Aqueous humor outflow facility measured with electronic Schiotz tonography does not vary significantly between the supine and sitting positions.


Impact of Comorbidity on Symptoms and Quality of Life Among Patients Being Treated for Breast Cancer.
Cancer patients often have other noncancer medical conditions. Presence of comorbidities negatively affects cancer survival. The aim of this study was to investigate comorbidity, risk factors for comorbidity, and how comorbidity was associated with symptoms and quality of life in patients being treated for breast cancer. One hundred and one breast cancer chemotherapy outpatients completed this study. Comorbid conditions, weight, height, and smoking status were identified by chart review. Symptoms and quality of life were self-reported using psychometrically sound instruments. Log-linear regression analyses with age as the covariate examined impact of ethnicity, body mass index (BMI), and smoking on comorbidities. Approximately 84% of the participants had 1 or more comorbid conditions. Adjusting for age, number of comorbidities differed by BMI (P = .000); the obese group had significantly more comorbidities than the normal and overweight groups. The interaction between BMI and smoking was significant (P = .047). The obese participants who smoked had significantly more comorbidities compared with those who were obese but did not smoke (P = .001). More comorbid conditions were associated with greater pain (P < .05) and poorer sleep quality (P < .05). Comorbidity significantly correlated with symptoms and functional aspects of quality of life (P < .01 and P < .05, respectively). A greater number of comorbidities was associated with lower physical and role functioning and worse fatigue, dyspnea, appetite loss, and nausea and vomiting (all P < .05). Comorbidity exerts negative impacts on symptoms and quality of life. Weight and smoking status are strong determinants of breast cancer comorbidity. Personalized care planning, weight management, and smoking cessation may lead to better cancer outcomes.


Hepatocellular carcinoma patients are advantaged in the current liver transplant allocation system.
Patients with hepatocellular carcinoma (HCC) within Milan criteria receive priority on the liver transplant waiting list (WL) and compete with non-HCC patients. Dropout from the WL is an indirect measure of transplant access. Competing risks (CR) evaluation of dropout for HCC and non-HCC patients has not previously been reported. Patients listed between 16 March 2005 and 30 June 2008 were included. Probability of dropout was estimated using a CR technique as well as a Cox model for time to dropout. Overall, non-HCC patients had a higher dropout rate from the WL than HCC patients (p < 0.0001). This was reproducible throughout all regions. In Cox regression, tumor size, model for end-stage liver disease (MELD) score and alpha fetoprotein (AFP) were associated with increased dropout risk. Multivariable analysis with CR showed that MELD score and AFP, were most influential in predicting dropout for HCC patients. The index of concordance for predicting dropout with the CR was 0.70. HCC patients appear to be advantaged in the current allocation scheme based on lower dropout rates without regard to geography. A continuous score incorporating MELD, AFP and tumor size may help to prioritize HCC patients to better equate dropout rates with non-HCC patients and equalize access.


CREB-binding [corrected] protein interacts with the homeodomain protein Cdx2 and enhances transcriptional activity.
Cdx2 encodes for a homeodomain protein that is expressed in intestinal epithelial cells. The Cdx2 protein triggers intestinal differentiation in cell lines and is necessary for maintenance of the intestinal phenotype in mice. CBP (cAMP response element-binding protein) is a transcriptional co-activator that interacts with many transcription factors and components of the basal transcriptional machinery. In this study, we demonstrate that CBP is markedly induced upon differentiation of the Caco-2 intestinal cell line and augments Cdx2-dependent transcriptional activity. Cdx2 interacts with the amino-terminal domain of CBP, and the two proteins coexist in vivo within the same nuclear protein complex. Moreover, expression of the CBP domain that interacts with Cdx2 acts as a dominant-negative inhibitor of transcriptional activation by Cdx2. These findings demonstrate a direct interaction between an intestinal homeodomain protein and CBP and suggest that CBP participates in the network of transcriptional proteins that direct intestinal differentiation.


Off-label use of second-generation antipsychotic agents among elderly nursing home residents.
This study examined off-label and evidence-based use of second-generation antipsychotic agents among elderly nursing home residents and factors associated with off-label use. This study involved a retrospective, cross-sectional analysis of data from the 2004 National Nursing Home Survey (NNHS). The sample included nursing home residents 65 years and older who received second-generation antipsychotic agents. This study used an indication-based definition of off-label use established by the U.S. Food and Drug Administration (FDA). Evidence-based use included FDA-approved indications and indications for which the Agency of Healthcare Research and Quality found at least moderate strength of evidence of effectiveness. Descriptive statistics were used to examine the prevalence of off-label and evidence-based use. Multiple logistic regression was used to examine the patient and facility factors associated with off-label use of second-generation antipsychotics. According to the 2004 NNHS, 308,990 (23.5%) elderly nursing home residents received at least one second-generation antipsychotic agent. Of those using second-generation antipsychotics, 86.3% received them for off-label indications and 56.9% received them for an evidence-based use. Multivariate analysis found that age (> or =75 years), self-pay for nursing home care, diagnosis of dementia, and residing in a nonprofit nursing home were positively associated with off-label use, whereas receiving Medicaid benefits was negatively associated with such use. Although second-generation antipsychotics were frequently used for off-label indications, most of the usage was evidence based among elderly nursing home residents. However, the high level of non-evidence-based use combined with recent safety and efficacy data suggests an urgent need to address the evidence base for this vulnerable population.


A thiolate anion buried within the hydrocarbon ruler perturbs PagP lipid acyl chain selection.
The Escherichia coli outer membrane phospholipid:lipid A palmitoyltransferase PagP exhibits remarkable selectivity because its binding pocket for lipid acyl chains excludes those differing in length from palmitate by a solitary methylene unit. This narrow detergent-binding hydrophobic pocket buried within the eight-strand antiparallel beta-barrel is known as the hydrocarbon ruler. Gly88 lines the acyl chain binding pocket floor, and its substitution can raise the floor to correspondingly shorten the selected acyl chain. An aromatic exciton interaction between Tyr26 and Trp66 provides an intrinsic spectroscopic probe located immediately adjacent to Gly88. The Gly88Cys PagP enzyme was engineered to function as a dedicated myristoyltransferase, but the mutant enzyme instead selected both myristoyl and pentadecanoyl groups, was devoid of the exciton, and displayed a 21 degrees C reduction in thermal stability. We now demonstrate that the structural perturbation results from a buried thiolate anion attributed to suppression of the Cys sulfhydryl group pK(a) from 9.4 in aqueous solvent to 7.5 in the hydrocarbon ruler microenvironment. The Cys thiol is sandwiched at the interface between a nonpolar and a polar beta-barrel interior milieu, suggesting that local electrostatics near the otherwise hydrophobic hydrocarbon ruler pocket serve to perturb the thiol pK(a). Neutralization of the Cys thiolate anion by protonation restores wild-type exciton and thermal stability signatures to Gly88Cys PagP, which then functions as a dedicated myristoyltransferase at pH 7. Gly88Cys PagP assembled in bacterial membranes recapitulates lipid A myristoylation in vivo. Hydrocarbon ruler-exciton coupling in PagP thus reveals a thiol-thiolate ionization mechanism for modulating lipid acyl chain selection.


Viral pathogenesis of a nephrotropic infectious bronchitis virus isolated from commercial pullets.
Infectious bronchitis was diagnosed in 3-to-4-week-old pullets from an outbreak in a commercial flock in California. The disease was characterized by head swelling, watery discharge from the eyes and nostrils, and urates in kidneys. Mortality ranged from 1.8% to 12.5% per week. The isolation of a coronavirus from a suspension of pooled kidneys from clinically ill chickens at the fifth passage in 10-day-old chicken embryos, gross and histologic renal lesions, and seroconversion by enzyme-linked immunosorbent assay in inoculated birds suggested that the virus isolated was a nephrotrophic strain of infectious bronchitis virus (IBV). The virus isolate was found to be a previously unrecognized serotype, based on virus neutralization tests performed in embryonated chicken eggs. Nephropathogenicity of the IBV isolate was confirmed by inoculation of the viral isolate into specific-pathogen-free chicks and demonstration of renal lesions. The isolation of nephrotropic strains of IBV has not been reported previously from poultry in California.


Carbamylation-dependent activation of T cells: a novel mechanism in the pathogenesis of autoimmune arthritis.
The posttranslational modification of proteins has the potential to generate neoepitopes that may subsequently trigger immune responses. The carbamylation of lysine residues to form homocitrulline may be a key mechanism triggering inflammatory responses. We evaluated the role of carbamylation in triggering immune responses and report a new role for this process in the induction of arthritis. Immunization of mice with homocitrulline-containing peptides induced chemotaxis, T cell activation, and Ab production. The mice also developed erosive arthritis following intra-articular injection of peptides derived from homocitrulline and citrulline. Adoptive transfer of T and B cells from homocitrulline-immunized mice into normal recipients induced arthritis, whereas systemic injection of homocitrulline-specific Abs or intra-articular injection of homocitrulline-Ab/citrulline-peptide mixture did not. Thus, the T cell response to homocitrulline-derived peptides, as well as the subsequent production of anti-homocitrulline Abs, is critical for the induction of autoimmune reactions against citrulline-derived peptides and provides a novel mechanism for the pathogenesis of arthritis.