Local ablative procedures designed to destroy squamous-cell carcinoma.
In a series of experiments in dogs, the bronchial mucosa was either excised or destroyed prior to closure of a bronchial stump following a lobectomy or the reanastomosis of a divided bronchus. The experiments were designed to simulate the clinical situation in which focal areas of squamous-cell carcinoma in situ in the bronchial margin would be managed by local ablation of the mucosa rather than by excision of additional bronchus. The experiments demonstrated that the bronchial mucosa is not necessary for bronchial healing. They also demonstrated that functionally and morphologically normal bronchial epithelium regenerates across the denuded bronchus. The source of this regenerated epithelium appears to be the submucosal glands which remain in the bronchial wall after a variety of local ablative procedures. Since our clinical experience has demonstrated that these submucosal glands frequently contain small foci of squamous-cell carcinoma in situ, we have concluded that either excision or thermal destruction of the bronchial mucosa has very limited clinical application and should be considered only in patients who cannot tolerate excision of more than one lobe of the lung.


Fine-tuning of Smad protein function by poly(ADP-ribose) polymerases and poly(ADP-ribose) glycohydrolase during transforming growth factor β signaling.
Initiation, amplitude, duration and termination of transforming growth factor β (TGFβ) signaling via Smad proteins is regulated by post-translational modifications, including phosphorylation, ubiquitination and acetylation. We previously reported that ADP-ribosylation of Smads by poly(ADP-ribose) polymerase 1 (PARP-1) negatively influences Smad-mediated transcription. PARP-1 is known to functionally interact with PARP-2 in the nucleus and the enzyme poly(ADP-ribose) glycohydrolase (PARG) can remove poly(ADP-ribose) chains from target proteins. Here we aimed at analyzing possible cooperation between PARP-1, PARP-2 and PARG in regulation of TGFβ signaling. A robust cell model of TGFβ signaling, i.e. human HaCaT keratinocytes, was used. Endogenous Smad3 ADP-ribosylation and protein complexes between Smads and PARPs were studied using proximity ligation assays and co-immunoprecipitation assays, which were complemented by in vitro ADP-ribosylation assays using recombinant proteins. Real-time RT-PCR analysis of mRNA levels and promoter-reporter assays provided quantitative analysis of gene expression in response to TGFβ stimulation and after genetic perturbations of PARP-1/-2 and PARG based on RNA interference. TGFβ signaling rapidly induces nuclear ADP-ribosylation of Smad3 that coincides with a relative enhancement of nuclear complexes of Smads with PARP-1 and PARP-2. Inversely, PARG interacts with Smads and can de-ADP-ribosylate Smad3 in vitro. PARP-1 and PARP-2 also form complexes with each other, and Smads interact and activate auto-ADP-ribosylation of both PARP-1 and PARP-2. PARP-2, similar to PARP-1, negatively regulates specific TGFβ target genes (fibronectin, Smad7) and Smad transcriptional responses, and PARG positively regulates these genes. Accordingly, inhibition of TGFβ-mediated transcription caused by silencing endogenous PARG expression could be relieved after simultaneous depletion of PARP-1. Nuclear Smad function is negatively regulated by PARP-1 that is assisted by PARP-2 and positively regulated by PARG during the course of TGFβ signaling.


Environmental Effects on Glycophorin A Folding and Structure Examined through Molecular Simulations.
The human erythrocyte sialoglycoprotein glycophorin A (GpA) has been used extensively in experiment and simulations as a model of transmembrane helix-dimer formation, emphasizing the critical role of specific residue-residue interactions between helices in dimer stability. While the tertiary dimer structure is modulated by the hydrophobic lipid bilayer environment, we show that interactions of GpA with ordered interfacial water are commensurate to intrahelical forces. The role of lipid-water interface in stabilizing transmembrane proteins is not yet understood; however, dramatic water reordering in the presence of the transmembrane domains is observed from simulations and is possibly measurable by experiment. Interfacial interactions including anisotropic interactions with the polar headgroups might favor parallel association of transmembrane helices. To quantify forces capable of disrupting the GpA dimer, we generate folding/unfolding intermediates by replacement of the lipid bilayer with water, eliminating not only the native hydrophobic environment but also the native interfacial water region. Dramatic changes in the secondary, helical structures occur, with a transition from i,i+4 α-helix to i,i+5 π-helix and concomitant perturbation of the tertiary structure. Enforcing the native α-helix secondary structure by soft dihedral restraints restores the native tertiary structure, in essence substituting for the lack of the lipid-water interface. We suggest that differentiation between interactions within the lipid bilayer, including interactions with lipid headgroups and interfacial water can enrich our understanding of the thermodynamic stability of transmembrane domains.


Analysis of survival in pediatric high-grade brainstem gliomas: A population-based study.
The purpose of this study was to use the National Cancer Institutes' Surveillance, Epidemiology, and End Results (SEER) database to perform a large-scale analysis of brainstem anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM). Use of the SEER database gave us a larger sample size of this rare tumor type, allowing for the analysis of the relationship between prognostic factors and survival. We selected pediatric patients (<18 years old) from the SEER database with histologically confirmed diagnoses of primary high-grade gliomas (World Health Organization Grade III/IV) of the brainstem. In univariate and multivariate analysis, we analyzed the relationship between demographic (age, gender, race, diagnosis date), histologic (AA, GBM), and treatment (surgery, radiation) factors on survival. In our cohort of 124 patients, those with AA had a median survival of 13 months and those with GBM 9 months. Higher-grade tumors were associated with statistically significantly increased mortality (hazard ratio [HR]: 1.74, confidence intervals [CIs]: 1.17-2.60). Surgical intervention was associated with a significantly lower mortality, either alone (HR: 0.14, CI: 0.04-0.5) or in combination with radiation (HR: 0.35, CI: 0.15-0.82). Radiation therapy alone was significantly associated with decreased mortality within the first 9 months after diagnosis but not with overall mortality. No demographic characteristics were significantly associated with mortality. Outcome remains poor in the pediatric high-grade brainstem glioma population. Survival is correlated with lower-grade tumor histology, radiation therapy only in the first 9 months after diagnosis, and surgical resection.


Homoharringtonine: an effective new natural product in cancer chemotherapy.
Homoharringtonine (HHT) is a cytotoxic alkaloid isolated from the evergreen tree cephalotaxus harringtonia native to the southern provinces of China. The principal mechanism of action of HHT is the inhibition of protein synthesis in a dose- and time-dependent manner by acting on the ribosomes of cancer cells. It blocks the progression of cells from G1 phase into S phase and from G2 phase into M phase. It is synergestic or additive in vitro with AraC, amsacrine, actinomycin D and dexamethasone. Clinical studies have indicated that HHT is effective in treating acute myeloid leukemia (AML), chronic myeloid leukemia (CML) and myelodysplastic syndrome (MDS), but not acute lymphoblastic leukemia (ALL) and solid tumors. The dose limiting toxicities are hypotention and myelosuppression. Homoharringtonine has relatively mild extramedullary toxicities and no anthracycline-like cardiac toxicity, which make it a suitable candidate for the treatment of aged patients. Pharmacological studies indicate that HHT belongs to the category of multidrug resistance (MDR)-related drugs. The cells resistant to HHT are cross-resistant to anthracycline, vinca alkaloids, mitoxantrone, but not cis-platine and AraC. Multiple mechanisms, including the sequential emergence of overexpression of multidrug resistance-associated protein (MRP) and MDR1 genes, are involved in the cross-resistance of tumor cells to HHT.


Biochemical toxicology and suicide in Ireland: a laboratory study.
Biochemical toxicology in suicides provides a template to improve preventive interventions in cases of suicide. The menu for biochemical toxicological analysis in coroners' cases is not prescriptive in Ireland or in the United Kingdom. The aim of the study was to confirm that reliance on the results of an immunoassay screen for drugs of abuse and common analgesics in order to select samples for compound confirmation by gas chromatography-mass spectrometry is likely to understate the potential role of drugs in suicide. Blood and urine samples were analyzed using enzyme immunoassay, alcohols by gas chromatography and urines were screened by Bio-Rad's Rapid Emergency Drug Identification (REMEDi) system. Laboratory data from analysis of 132 cases of suicide, including 101 cases of hanging revealed that 83 % were male confirming suicide as a male epidemic. Overall, alcohol was a factor in 57 %, benzodiazepines in 26 %, cannabinoids in 11 %, opioids in 19.7 %, sympathomimetics in 7.5 %, cocaine in 4.5 %, antidepressants 22 %, antipsychotics in 10 %, hypnotics in 5 %, and antihistamines in 4 % of these cases. Screening compounds in cases of hanging and other suicides should extend beyond the narrow focus of alcohol and illicit drugs to include a wide spectrum of psychoactive and other compounds as a standard procedure. The wide range of licit and illicit compounds found in these cases reflects current experience and dictates the necessity for chromatographic screening with mass spectroscopy confirmation in all cases as best practice.


Quantification of Competitive Game Demands of NCAA Division I College Football Players Using Global Positioning Systems.
The aim of the present study was to examine the competitive physiological movement demands of National Collegiate Athletic Association (NCAA) Division I college football players using portable global positioning system (GPS) technology during games and to examine positional groups within offensive and defensive teams, to determine if a player's physiological requirements during games are influenced by playing position. Thirty-three NCAA Division I Football Bowl Subdivision football players were monitored using GPS receivers with integrated accelerometers (GPSports) during 12 regular season games throughout the 2014 season. Individual data sets (n = 295) from players were divided into offensive and defensive teams and subsequent position groups. Movement profile characteristics, including total, low-intensity, moderate-intensity, high-intensity, and sprint running distances (m), sprint counts, and acceleration and deceleration efforts, were assessed during games. A one-way ANOVA and post-hoc Bonferroni statistical analysis were used to determine differences in movement profiles between each position group within offensive and defensive teams. For both offensive and defensive teams, significant (p ≤ 0.05) differences exist between positional groups for game physical performance requirements. The results of the present study identified that wide receivers and defensive backs completed significantly (p ≤ 0.05) greater total distance, high-intensity running, sprint distance, and high-intensity acceleration and deceleration efforts than their respective offensive and defensive positional groups. Data from the present study provide novel quantification of position-specific physical demands of college football games and support the use of position-specific training in the preparation of NCAA Division I college football players for competition.


Findings from an exploration of a social network intervention to promote diet quality and health behaviours in older adults with COPD: a feasibility study.
Diet quality in older people with chronic obstructive pulmonary disease (COPD) is associated with better health and lung function. Social factors, such as social support, social networks and participation in activities, have been linked with diet quality in older age. A social network tool-GENIE (Generating Engagement in Network Involvement)-was implemented in a COPD community care context. The study aimed to assess the feasibility of the GENIE intervention to promote diet quality and other health behaviours in COPD. Twenty-two community-dwelling older adults with COPD were recruited from a local COPD service. Participants were offered usual care or the GENIE intervention. Process evaluation methods were used to assess intervention implementation, context and mechanisms of impact; these included observations of patient interactions with the intervention, documented in observational field notes and in films of a patient group discussion. Diet quality was assessed by food frequency questionnaire; 'prudent' diet scores were used to describe diet quality at baseline and at 3-month follow-up. Change in diet quality was expressed per month, from baseline to follow-up. Feasibility data showed that the GENIE intervention could be implemented in this sample of community-living older people. The intervention was acceptable to clinicians and older people with COPD, especially for those with less severe disease, when facilitated appropriately and considering the levels of literacy of participants. There was no significant change in diet quality in the intervention group over the follow-up period (median change in prudent diet score per month (interquartile range (IQR), 0.03 (- 0.24-0.07)), whereas an overall fall in diet quality was observed in the control group (- 0.15 (- 0.24-0.03)). The process evaluation findings suggest that this intervention is feasible and acceptable to both patients and clinicians. Although the sample size achieved in this study was small, findings suggest that the intervention may have a protective effect against declines in diet quality, and other health behaviours, in an older COPD population. Findings from this feasibility study indicate that further evaluation of the GENIE intervention is warranted in a larger study, with a longer follow-up. ClinicalTrials.gov, NCT02935452. NIH U.S. National Library of Medicine. Registered 17 October 2016.


Deep conservation of bivalve nacre proteins highlighted by shell matrix proteomics of the Unionoida Elliptio complanata and Villosa lienosa.
The formation of the molluscan shell nacre is regulated to a large extent by a matrix of extracellular macromolecules that are secreted by the shell-forming tissue, the mantle. This so-called 'calcifying matrix' is a complex mixture of proteins, glycoproteins and polysaccharides that is assembled and occluded within the mineral phase during the calcification process. Better molecular-level characterization of the substances that regulate nacre formation is still required. Notable advances in expressed tag sequencing of freshwater mussels, such as Elliptio complanata and Villosa lienosa, provide a pre-requisite to further characterize bivalve nacre proteins by a proteomic approach. In this study, we have identified a total of 48 different proteins from the insoluble matrices of the nacre, 31 of which are common to both E. complanata and V. lienosa A few of these proteins, such as PIF, MSI60, CA, shematrin-like, Kunitz-like, LamG, chitin-binding-containing proteins, together with A-, D-, G-, M- and Q-rich proteins, appear to be analogues, if not true homologues, of proteins previously described from the pearl oyster or the edible mussel nacre matrices, thus forming a remarkable list of deeply conserved nacre proteins. This work constitutes a comprehensive nacre proteomic study of non-pteriomorphid bivalves that has enabled us to describe the molecular basis of a deeply conserved biomineralization toolkit among nacreous shell-bearing bivalves, with regard to proteins associated with other shell microstructures, with those of other mollusc classes (gastropods, cephalopods) and, finally, with other lophotrochozoans (brachiopods).


Evaluation of white-tailed deer (Odocoileus virginianus) as natural sentinels for Anaplasma phagocytophilum.
Anaplasma phagocytophilum, the causative agent of human granulocytotropic anaplasmosis, can infect white-tailed deer (WTD; Odocoileus virginianus), and this species is a crucial host for adult Ixodes scapularis, the primary vector of A. phagocytophilum. The goal of this study was to determine the geographic distribution of A. phagocytophilum among WTD across a 19 state region and to evaluate the utility of WTD as natural sentinels. Serologic testing using the indirect fluorescent antibody (IFA) assay was conducted on WTD serum samples and molecular and xenodiagnostic tests were performed to confirm serologic results. The surveillance system was assessed through examination of vital attributes including WTD age and gender associations with serologic status, sample size adequacy for accurate infection status classification, and presence of the vector, I. scapularis. Six hundred thirty-three of 2,666 (24%) WTD in 17 states tested positive for antibodies (>or=128) when tested by IFA assay. Testing for p44 and/or 16S rRNA gene targets identified 73 (16%) PCR positive WTD among 458 animals tested, all of which originated from seropositive populations. Attempts to culture A. phagocytophilum from WTD were unsuccessful; however, xenodiagnostic mice inoculated with blood from 3 WTD became infected. Seroprevalence did not differ by deer age or gender; however, WTD<or=0.75 years old had a higher prevalence of PCR positivity. Using seroprevalence data, a sample size of 6-9 animals per population was projected to be adequate for identifying seropositive populations. The presence of I. scapularis was significantly associated with A. phagocytophilum antibodies in WTD. Collectively, the results of this study demonstrate that WTD would be suitable natural sentinels for this emerging zoonotic pathogen.


Predictors of quality of life in hemodialysis patients.
Quality of Life (QoL) is a consistent and powerful predictor that affects the out-come in end-stage renal disease (ESRD) patients on dialysis. This study was undertaken to identify the factors that might predict QoL scores among ESRD patients on hemodialysis (HD). The study was conducted at three HD units in Saudi Arabia from January 2007 to January 2008. We studied 100 HD patients (53 males and 47 females) and used the SF-36 and KDQoL-SF forms covering six domains of QoL, namely physical, emotional, social, illness impact, medical and financial satisfaction, and overall general health. The mean age of the study patients was 47.5 ± 13.8 years and the mean duration of dialysis was 77.2 ± 75.5 months. The QoL scores were 45.8 ± 17.1 for general health, 53.1 ± 32.0 for physical QoL, 50.5 ± 14.8 for emotional QoL, 54.9 ± 18.1 for social QoL, 46.5 ± 13.7 for illness impact, and 45.9 ± 12.2 for the medical and financial domain. The total QoL score was 49.5 ± 13.7. The male patients had statistically significantly reduced QoL and younger patients had better QoL scores. The QoL scores revealed a decreasing trend with decreasing level of education; they were elevated among employed patients. Multiple linear regression analysis demonstrated that age, dialysis duration, and male sex were negative predictors of QoL score. We conclude from our study that QoL is reduced in all the health domains of HD patients. Older age, male gender, unemployment, and duration of dialysis adversely affected the QoL scores. Adequate management of some of these factors could influence patient outcomes.


Meiotic recombination involving heterozygous large insertions in Saccharomyces cerevisiae: formation and repair of large, unpaired DNA loops.
Meiotic recombination in Saccharomyces cerevisiae involves the formation of heteroduplexes, duplexes containing DNA strands derived from two different homologues. If the two strands of DNA differ by an insertion or deletion, the heteroduplex will contain an unpaired DNA loop. We found that unpaired loops as large as 5.6 kb can be accommodated within a heteroduplex. Repair of these loops involved the nucleotide excision repair (NER) enzymes Rad1p and Rad10p and the mismatch repair (MMR) proteins Msh2p and Msh3p, but not several other NER (Rad2p and Rad14p) and MMR (Msh4p, Msh6p, Mlh1p, Pms1p, Mlh2p, Mlh3p) proteins. Heteroduplexes were also formed with DNA strands derived from alleles containing two different large insertions, creating a large "bubble"; repair of this substrate was dependent on Rad1p. Although meiotic recombination events in yeast are initiated by double-strand DNA breaks (DSBs), we showed that DSBs occurring within heterozygous insertions do not stimulate interhomologue recombination.


Transfer of liraglutide from blood to cerebrospinal fluid is minimal in patients with type 2 diabetes.
Treatment with liraglutide leads to weight loss. We investigated whether blood-to-cerebrospinal fluid (CSF) transfer of liraglutide occurs, and if so, whether it associates with clinical weight loss following liraglutide treatment in humans. We performed lumbar puncture and blood sampling in eight patients with type 2 diabetes (mean (range)): age 63 (54-79) years; actual body weight: 90 (75-118) kg treated with 1.8 mg liraglutide for 14 (5-22) months and with a treatment-induced weight loss of 8.4 (7-11) kg. We measured liraglutide in plasma and CSF with a radioimmunoassay specific for the N-terminus of the GLP-1 moiety of liraglutide. Mean plasma liraglutide was 31 (range: 21-63) nmol l(-1). The mean CSF-liraglutide concentration was 6.5 (range: 0.9-13.9) pmol l(-1). Ratio of CSF: plasma-liraglutide concentrations was 0.02 (range: 0.07-0.002)% and plasma liraglutide did not correlate with CSF-liraglutide levels (P=0.67). Body weight loss tended to correlate with plasma-liraglutide levels (P=0.06), but not with CSF-liraglutide levels (P=0.69). In conclusion, we measured very low concentrations of liraglutide in CSF, and the levels of CSF liraglutide did not correlate with the actual clinical weight loss in these patients. The amount of liraglutide in plasma tended to correlate with the clinical weight loss.


Cost-effectiveness of pembrolizumab with axitinib as first-line treatment for advanced renal cell carcinoma.
Pembrolizumab/axitinib significantly prolonged overall survival (OS) and progression-free survival (PFS), and increased objective response rate versus sunitinib in the phase III trial KEYNOTE-426 among previously untreated patients with advanced renal cell carcinoma (RCC). This study assessed the cost-effectiveness of pembrolizumab/axitinib versus other first-line treatments of advanced RCC from a US public healthcare payer perspective. A partitioned survival model with three states (progression-free, progressed, death) evaluated lifetime costs and quality-adjusted life-years (QALYs) for pembrolizumab/axitinib and other first-line regimens: sunitinib, pazopanib and avelumab/axitinib in the overall population; and sunitinib, cabozantinib and nivolumab/ipilimumab in the subgroup with intermediate/poor prognostic risk. Costs of treatments, adverse events and medical resources were estimated. OS, PFS and treatment duration were extrapolated using parametric models fitted to KEYNOTE-426 data and hazard ratios from network meta-analyses. Utilities were derived through mixed-effects regressions of KEYNOTE-426 EuroQol-5 Dimensions-3 Levels data. In the overall population, pembrolizumab/axitinib was associated with incremental cost-effectiveness ratios (ICERs) of $95,725/QALY versus sunitinib and $128,210/QALY versus pazopanib, and was dominant (lower cost, higher effectiveness) versus avelumab/axitinib, with incremental QALY gains of 2.73, 2.40 and 1.80 versus these therapies, respectively. In the intermediate/poor-risk subgroup, base-case ICERs for pembrolizumab/axitinib were $101,030/QALY versus sunitinib, $6989/QALY versus cabozantinib, and $130,934/QALY versus nivolumab/ipilimumab, with incremental QALY gains of 2.62, 1.78 and 1.06 versus these therapies. In this economic evaluation, pembrolizumab/axitinib was associated with higher life expectancy and QALYs and, based on typical willingness-to-pay thresholds of $150,000-$180,000/QALY, was found cost-effective versus other first-line treatments for advanced RCC in the US.


3D motion of DNA-Au nanoconjugates in graphene liquid cell electron microscopy.
Liquid-phase transmission electron microscopy (TEM) can probe and visualize dynamic events with structural or functional details at the nanoscale in a liquid medium. Earlier efforts have focused on the growth and transformation kinetics of hard material systems, relying on their stability under electron beam. Our recently developed graphene liquid cell technique pushed the spatial resolution of such imaging to the atomic scale but still focused on growth trajectories of metallic nanocrystals. Here, we adopt this technique to imaging three-dimensional (3D) dynamics of soft materials instead, double strand (dsDNA) connecting Au nanocrystals as one example, at nanometer resolution. We demonstrate first that a graphene liquid cell can seal an aqueous sample solution of a lower vapor pressure than previously investigated well against the high vacuum in TEM. Then, from quantitative analysis of real time nanocrystal trajectories, we show that the status and configuration of dsDNA dictate the motions of linked nanocrystals throughout the imaging time of minutes. This sustained connecting ability of dsDNA enables this unprecedented continuous imaging of its dynamics via TEM. Furthermore, the inert graphene surface minimizes sample-substrate interaction and allows the whole nanostructure to rotate freely in the liquid environment; we thus develop and implement the reconstruction of 3D configuration and motions of the nanostructure from the series of 2D projected TEM images captured while it rotates. In addition to further proving the nanoconjugate structural stability, this reconstruction demonstrates 3D dynamic imaging by TEM beyond its conventional use in seeing a flattened and dry sample. Altogether, we foresee the new and exciting use of graphene liquid cell TEM in imaging 3D biomolecular transformations or interaction dynamics at nanometer resolution.


A wireless ECG smart sensor for broad application in life threatening event detection.
A single channel wireless, wearable ECG smart sensor has been developed for long-term monitoring of patients at risk of life-threatening cardiac arrhythmias. The battery-operated sensor can be applied in virtually any orientation on the upper left quadrant of the chest, and monitors patient health continuously for up to three days. An embedded microcontroller calculates heart rate and monitors the ECG signal for life-threatening arrhythmias, which are transmitted wirelessly to a central server and relayed to a respondent device. Tests on human subjects demonstrated signal amplitude from the closely-spaced smart sensor electrodes to be one-half that of the best vector from traditional limb lead placement. Tests with motion and muscle artifact showed superior noise immunity by the smart sensor as compared to a state-of-the-art telemetry monitor.


Crucial Conversations: An interprofessional learning opportunity for senior healthcare students.
Clinical errors due to human mistakes are estimated to result in 400,000 preventable deaths per year. Strategies to improve patient safety often rely on healthcare workers' ability to speak up with concerns. This becomes difficult during critical decision-making as a result of conflicting opinions and power differentials, themes underrepresented in many interprofessional initiatives. These elements are prominent in our interprofessional initiative, namely Crucial Conversations. We sought to evaluate this initiative as an interprofessional learning (IPL) opportunity for pre-licensure senior healthcare students, as a way to foster interprofessional collaboration, and as a method of empowering students to vocalise their concerns. The attributes of this IPL opportunity were evaluated using the Points for Interprofessional Education Score (PIPES). The University of the West of England Interprofessional Questionnaire was administered before and after the course to assess changes in attitudes towards IPL, relationships, interactions, and teamwork. Crucial Conversations strongly attained the principles of interprofessional education on the PIPES instrument. A total of 38 volunteers completed the 16 hours of training: 15 (39%) medical rehabilitation, 10 (26%) medicine, 7 (18%) pharmacy, 5 (13%) nursing, and 1 (2%) dentistry. Baseline attitude scores were positive for three of the four subscales, all of which improved post-intervention. Interprofessional interactions remained negative possibly due to the lack of IPL opportunities along the learning continuum, the hidden curriculum, as well as the stereotyping and hierarchical structures in today's healthcare environment preventing students from maximising the techniques learned by use of this interprofessional initiative.


Association of Informal Clinical Integration of Physicians With Cardiac Surgery Payments.
To reduce inefficiency and waste associated with care fragmentation, many current programs target greater clinical integration among physicians. However, these programs have led to only modest Medicare spending reductions. Most programs focus on formal integration, which often bears little resemblance to actual physician interaction patterns. To examine how physician interaction patterns vary between health systems and to assess whether variation in informal integration is associated with care delivery payments. National Medicare data from January 1, 2008, through December 31, 2011, identified 253 545 Medicare beneficiaries (aged ≥66 years) from 1186 health systems where Medicare beneficiaries underwent coronary artery bypass grafting (CABG) procedures. Interactions were mapped between all physicians who treated these patients-including primary care physicians and surgical and medical specialists-within a health system during their surgical episode. The level of informal integration was measured in these networks of interacting physicians. Multivariate regression models were fitted to evaluate associations between payments for each surgical episode made on a beneficiary's behalf and the level of informal integration in the health system where the patient was treated. The informal integration level of a health system. Price-standardized total surgical episode and component payments. The total 253 545 study participants included 175 520 men (69.2%; mean [SD] age, 74.51 [5.75] years) and 78 024 women (34.3%; 75.67 [5.91] years). One beneficiary of the 253 545 participants did not have sex information. The low level of informal clinical integration included 84 598 patients (33.4%; mean [SD] age, 75.00 [5.93] years); medium level, 84 442 (33.30%; 74.94 [5.87] years); and high level, 84 505 (33.34%; 74.66 [5.72] years) (P < .001). Informal integration levels varied across health systems. After adjusting for patient, health-system, and community factors, higher levels of informal integration were associated with significantly lower total episode and component payments (β coefficients for informal integration were -365.87 [95% CI, -451.08 to -280.67] for total episode payments, -182.63 [-239.80 to -125.46] for index hospitalization, -43.13 [-55.53 to -30.72] for physician services, -74.48 [-103.45 to -45.51] for hospital readmissions, and -62.04 [-88.00 to -36.07] for postacute care; P < .001 for each association). When beneficiaries were treated in health systems with higher informal integration, the greatest savings of lower estimated payments were from hospital readmissions (13.0%) and postacute care services (5.8%). Informal integration is associated with lower spending. Although most programs that seek to promote clinical integration are focused on health systems' formal structures, policy makers may also want to address informal integration.


Small RNA sequencing reveals miR-642a-3p as a novel adipocyte-specific microRNA and miR-30 as a key regulator of human adipogenesis.
In severe obesity, as well as in normal development, the growth of adipose tissue is the result of an increase in adipocyte size and numbers, which is underlain by the stimulation of adipogenic differentiation of precursor cells. A better knowledge of the pathways that regulate adipogenesis is therefore essential for an improved understanding of adipose tissue expansion. As microRNAs (miRNAs) have a critical role in many differentiation processes, our study aimed to identify the role of miRNA-mediated gene silencing in the regulation of adipogenic differentiation. We used deep sequencing to identify small RNAs that are differentially expressed during adipogenesis of adipose tissue-derived stem cells. This approach revealed the un-annotated miR-642a-3p as a highly adipocyte-specific miRNA. We then focused our study on the miR-30 family, which was also up-regulated during adipogenic differentiation and for which the role in adipogenesis had not yet been elucidated. Inhibition of the miR-30 family blocked adipogenesis, whilst over-expression of miR-30a and miR-30d stimulated this process. We additionally showed that both miR-30a and miR-30d target the transcription factor RUNX2, and stimulate adipogenesis via the modulation of this major regulator of osteogenesis. Overall, our data suggest that the miR-30 family plays a central role in adipocyte development. Moreover, as adipose tissue-derived stem cells can differentiate into either adipocytes or osteoblasts, the down-regulation of the osteogenesis regulator RUNX2 represents a plausible mechanism by which miR-30 miRNAs may contribute to adipogenic differentiation of adipose tissue-derived stem cells.


Endothelial cells and the electrical and mechanical responses of the rabbit coronary artery to 5-hydroxytryptamine.
The influence of endothelial cells on the response of smooth muscle in the rabbit coronary artery to 5-hydroxytryptamine (5-HT) was investigated with intracellular microelectrode and mechanical methods. Recent work has suggested that 5-HT stimulates the release of a smooth muscle relaxing factor from endothelial cells, which will reduce the direct constrictor action of 5-HT on the artery wall. In arteries with intact endothelial cells, 5-HT (10(-8) to 10(-4) M) produced dose-dependent depolarization of muscle cells in the inner part of the media. Hyperpolarization to 5-HT was not observed, even with 1 microM ketanserin (a 5-HT2 receptor antagonist) present to reduce its direct action on the smooth muscle. After removal of the endothelium 5-HT produced similar sized depolarization, but the graded depolarization was now often accompanied by rhythmical oscillations in membrane potential. Isolated, perfused arteries with an intact endothelium were insensitive to the constrictor action of 5-HT and at wall tensions similar to that in vivo did not show dilatation, even with ketanserin present. Small dilator responses to 5-HT could be recorded in the presence of increased tone to K-rich saline (30 mM). After removal of the endothelium, the mechanical responsiveness greatly increased and 5-HT produced large constrictor responses. The findings suggest that an endothelial-released factor protects the coronary artery from 5-HT which reaches it from the intimal surface and that this protective role could in part be due to inhibition of rhythmical electrical activity in the smooth muscle.


Dry olive leaf extract counteracts L-thyroxine-induced genotoxicity in human peripheral blood leukocytes in vitro.
The thyroid hormones change the rate of basal metabolism, modulating the consumption of oxygen and causing production of reactive oxygen species, which leads to the development of oxidative stress and DNA strand breaks. Olive (Olea europaea L.) leaf contains many potentially bioactive compounds, making it one of the most potent natural antioxidants. The objective of this study was to evaluate the genotoxicity of L-thyroxine and to investigate antioxidative and antigenotoxic potential of the standardized oleuropein-rich dry olive leaf extract (DOLE) against hydrogen peroxide and L-thyroxine-induced DNA damage in human peripheral blood leukocytes by using the comet assay. Various concentrations of the extract were tested with both DNA damage inducers, under two different experimental conditions, pretreatment and posttreatment. Results indicate that L-thyroxine exhibited genotoxic effect and that DOLE displayed protective effect against thyroxine-induced genotoxicity. The number of cells with DNA damage, was significantly reduced, in both pretreated and posttreated samples (P < 0.05). Comparing the beneficial effect of all tested concentrations of DOLE, in both experimental protocols, it appears that extract was more effective in reducing DNA damage in the pretreatment, exhibiting protective role against L-thyroxine effect. This feature of DOLE can be explained by its capacity to act as potent free radical scavenger.


FM-AFM constant height imaging and force curves: high resolution study of DNA-tip interactions.
Interaction of the atomic force microscopy (AFM) tip with the sample can be invasive for soft samples. Frequency Modulation (FM) AFM is gentler because it allows scanning in the non-contact regime where only attractive forces exist between the tip and the sample, and there is no sample compression. Recently, FM-AFM was used to resolve the atomic structure of single molecules of pentacene and of carbon nanotubes. We are testing similar FM-AFM-based approaches to study biological samples. We present FM-AFM experiments on dsDNA deposited on 3-aminopropyltriethoxysilane modified mica in ultra high vacuum. With flexible samples such as DNA, the substrate flatness is a sub-molecular resolution limiting factor. Non-contact topographic images of DNA show variations that have the periodicity of the right handed helix of B-form DNA - this is an unexpected result as dehydrated DNA is thought to assume the A-form structure. Frequency shift maps at constant height allow working in the non-monotonic frequency shift range, show a rich contrast that changes significantly with the tip-sample separation, and show 0.2 to 0.4 nm size details on DNA. Frequency shift versus distance curves acquired on DNA molecules and converted in force curves show that for small molecules (height < 2.5 nm), there is a contribution to the interaction force from the substrate when the tip is on top of the molecules. Our data shine a new light on dehydrated and adsorbed DNA behavior. They show a longer tip-sample interaction distance. These experiments may have an impact on nanotechnological DNA applications in non-physiological environments such as DNA based nanoelectronics and nanotemplating.


Three-Dimensional Carbon Allotropes Comprising Phenyl Rings and Acetylenic Chains in sp+sp(2) Hybrid Networks.
We here identify by ab initio calculations a new type of three-dimensional (3D) carbon allotropes that consist of phenyl rings connected by linear acetylenic chains in sp+sp(2) bonding networks. These structures are constructed by inserting acetylenic or diacetylenic bonds into an all sp(2)-hybridized rhombohedral polybenzene lattice, and the resulting 3D phenylacetylene and phenyldiacetylene nets comprise a 12-atom and 18-atom rhombohedral primitive unit cells in the symmetry, which are characterized as the 3D chiral crystalline modification of 2D graphyne and graphdiyne, respectively. Simulated phonon spectra reveal that these structures are dynamically stable. Electronic band calculations indicate that phenylacetylene is metallic, while phenyldiacetylene is a semiconductor with an indirect band gap of 0.58 eV. The present results establish a new type of carbon phases and offer insights into their outstanding structural and electronic properties.


INvestigational Vertebroplasty Efficacy and Safety Trial (INVEST): a randomized controlled trial of percutaneous vertebroplasty.
The treatment of painful osteoporotic vertebral compression fractures has historically been limited to several weeks of bed rest, anti-inflammatory and analgesic medications, calcitonin injections, or external bracing. Percutaneous vertebroplasty (the injection of bone cement into the fractured vertebral body) is a relatively new procedure used to treat these fractures. There is increasing interest to examine the efficacy and safety of percutaneous vertebroplasty and to study the possibility of a placebo effect or whether the pain relief is from local anesthetics placed directly on the bone during the vertebroplasty procedure. Our goal is to test the hypothesis that patients with painful osteoporotic vertebral compression fractures who undergo vertebroplasty have less disability and pain at 1 month than patients who undergo a control intervention. The control intervention is placement of local anesthesia near the fracture, without placement of cement. One hundred sixty-six patients with painful osteoporotic vertebral compression fractures will be recruited over 5 years from US and foreign sites performing the vertebroplasty procedure. We will exclude patients with malignant tumor deposit (multiple myeloma), tumor mass or tumor extension into the epidural space at the level of the fracture. We will randomly assign participants to receive either vertebroplasty or the control intervention. Subjects will complete a battery of validated, standardized measures of pain, functional disability, and health related quality of life at baseline and at post-randomization time points (days 1, 2, 3, and 14, and months 1, 3, 6, and 12). Both subjects and research interviewers performing the follow-up assessments will be blinded to the randomization assignment. Subjects will have a clinic visit at months 1 and 12. Spine X-rays will be obtained at the end of the study (month 12) to determine subsequent fracture rates. Our co-primary outcomes are the modified Roland score and pain numerical rating scale at 1 month. Although extensively utilized throughout North America for palliation of pain, vertebroplasty still has not undergone rigorous study. The study outlined above represents the first randomized, controlled study that can account for a placebo effect in the setting of vertebroplasty. Current Controlled Trials ISRCTN81871888.


Progression of patterns (POP): a machine classifier algorithm to identify glaucoma progression in visual fields.
We evaluated Progression of Patterns (POP) for its ability to identify progression of glaucomatous visual field (VF) defects. POP uses variational Bayesian independent component mixture model (VIM), a machine learning classifier (MLC) developed previously. VIM separated Swedish Interactive Thresholding Algorithm (SITA) VFs from a set of 2,085 normal and glaucomatous eyes into nine axes (VF patterns): seven glaucomatous. Stable glaucoma was simulated in a second set of 55 patient eyes with five VFs each, collected within four weeks. A third set of 628 eyes with 4,186 VFs (mean ± SD of 6.7 ± 1.7 VFs over 4.0 ± 1.4 years) was tested for progression. Tested eyes were placed into suspect and glaucoma categories at baseline, based on VFs and disk stereoscopic photographs; a subset of eyes had stereophotographic evidence of progressive glaucomatous optic neuropathy (PGON). Each sequence of fields was projected along seven VIM glaucoma axes. Linear regression (LR) slopes generated from projections onto each axis yielded a degree of confidence (DOC) that there was progression. At 95% specificity, progression cutoffs were established for POP, visual field index (VFI), and mean deviation (MD). Guided progression analysis (GPA) was also compared. POP identified a statistically similar number of eyes (P > 0.05) as progressing compared with VFI, MD, and GPA in suspects (3.8%, 2.7%, 5.6%, and 2.9%, respectively), and more eyes than GPA (P = 0.01) in glaucoma (16.0%, 15.3%, 12.0%, and 7.3%, respectively), and more eyes than GPA (P = 0.05) in PGON eyes (26.3%, 23.7%, 27.6%, and 14.5%, respectively). POP, with its display of DOC of progression and its identification of progressing VF defect pattern, adds to the information available to the clinician for detecting VF progression.


In vitro synergism of colistin in combination with N-acetylcysteine against Acinetobacter baumannii grown in planktonic phase and in biofilms.
To investigate the potential synergism of colistin in combination with N-acetylcysteine against Acinetobacter baumannii strains grown in planktonic phase or as biofilms. Sixteen strains were investigated, including nine colistin-susceptible (MIC range 0.5-1 mg/L) and seven colistin-resistant (MIC range 16-256 mg/L) strains. Synergism of colistin in combination with N-acetylcysteine was investigated by chequerboard assays. The activity of colistin/N-acetylcysteine combinations was further evaluated by time-kill assays with planktonic cultures (three colistin-resistant strains and one colistin-susceptible strain) and by in vitro biofilm models (three colistin-resistant and three colistin-susceptible strains). Chequerboard assays revealed a relevant synergism of colistin/N-acetylcysteine combinations with all colistin-resistant strains, whereas no synergism was observed with colistin-susceptible strains. Time-kill assays showed a concentration-dependent potentiation of colistin activity by N-acetylcysteine against colistin-resistant strains, with eradication of the culture by combinations of N-acetylcysteine at 8000 mg/L plus colistin at 2 or 8 mg/L. A static effect during the first 8 h of incubation was demonstrated with the colistin-susceptible strain exposed to 0.25 × MIC colistin plus 8000 mg/L N-acetylcysteine. A remarkable antibiofilm synergistic activity of 8 mg/L colistin plus 8000 mg/L N-acetylcysteine was demonstrated with all colistin-resistant and colistin-susceptible strains. The effects were greater with colistin-resistant strains (marked reduction of viable biofilm cells was observed at sub-MIC colistin concentrations). N-acetylcysteine, at concentrations achievable by topical administration, was shown to revert the colistin-resistant phenotype in A. baumannii, and to exert a relevant activity against biofilms of colistin-susceptible and colistin-resistant A. baumannii strains.


Real or bogus: Predicting susceptibility to phishing with economic experiments.
We present a lab-in-the-field experiment to demonstrate how individual behavior in the lab predicts their ability to identify phishing attempts. Using the business and finance staff members from a large public university in the U.S., we find that participants who are intolerant of risk, more curious, and less trusting commit significantly more errors when evaluating interfaces. We also replicate prior results on demographic correlates of phishing vulnerability, including age, gender, and education level. Our results suggest that behavioral characteristics such as intolerance of risk, curiosity, and trust can be used to predict individual ability to identify phishing interfaces.


Strontium ranelate inhibits key factors affecting bone remodeling in human osteoarthritic subchondral bone osteoblasts.
In osteoarthritis (OA) the progression of cartilage degeneration has been associated with remodeling of the subchondral bone. Human OA subchondral bone osteoblasts were shown to have an abnormal phenotype and altered metabolism leading to an abnormal resorptive process. Bone resorption is suggested to occur, at least in part, through the increased levels of two proteolytic enzymes, MMP-2 and MMP-9, and RANKL, which are mainly produced by osteoblasts. In this study, we investigated in human OA subchondral bone osteoblasts the modulatory effect of strontium ranelate on the above key factors. Human subchondral bone osteoblasts were cultured in a medium containing 0.1, 1 and 2 mM of strontium ranelate for 18 h for mRNA and 72 h for protein determination. The effect of strontium ranelate was evaluated on the expression (qPCR) of MMP-2, MMP-9, OPG, RANKL (total), RANKL-1, and RANKL-3, on the production of OPG (ELISA), membranous RANKL (flow cytometry), and MT1-MMP, ADAM17, and ADAM19 (Western blot). After incubation of osteoblasts with pre-osteoclasts (i.e., differentiated human peripheral blood mononuclear cells), the resorbed surface was measured using a sub-micron synthetic calcium phosphate thin film. Firstly, the expression levels of MMP-2, MMP-9, OPG, and RANKL were determined in normal and OA subchondral bone osteoblasts. As expected, the gene expression of MMP-9 and RANKL were not detectable in normal cells, whereas MMP-2 was very low but detectable and OPG demonstrated high gene expression. Further experiments looking at the effect of strontium ranelate on expression levels, except for OPG, were performed only on the OA subchondral bone osteoblasts. In OA cells, the expression levels of MMP-2 and MMP-9 were significantly decreased by strontium ranelate at 1mM (p≤0.005, p≤0.02, respectively) and 2 mM (p≤0.003, p≤0.007), and for MMP-9 only at 0.1 mM (p≤0.05). In normal cells, the expression of OPG was increased with strontium ranelate at 2 mM, and in OA both the expression (p≤0.02) and synthesis (p≤0.002) of OPG were significantly increased with strontium ranelate at 1 and 2 mM. RANKL (total) as well as the isoforms RANKL-1 and RANKL-3 were significantly increased by strontium ranelate at 1 and 2 mM. Of note, it is known that the different RANKL isoforms differentially regulate RANKL membranous localization: RANKL-3, in contrast to RANKL-1, prevents such membranous localization. This is reflected by the significant (p≤0.02) reduction in the level of membranous RANKL by strontium ranelate at 2 mM. This latter finding was not likely to be related to a proteolytic cleavage of membranous RANKL, as the enzymes known to cleave it, MT1-MMP, ADAM17 and ADAM19, were unaffected by strontium ranelate. In addition, OA osteoblasts treated with strontium ranelate induced a significant (p≤0.002) decrease in resorbed surface at the three tested concentrations. This study provides new insights into the mode of action of strontium ranelate on the metabolism of human OA subchondral bone osteoblasts. These data suggest that strontium ranelate may exert a positive effect on OA pathophysiology by inhibiting, in these cells, the synthesis of key factors leading to bone resorption, a feature associated with the OA process.


Visual training in hemianopia alters neural activity in the absence of behavioural improvement: a pilot study.
Damage to the primary visual cortex (V1) due to stroke often results in permanent loss of sight affecting one side of the visual field (homonymous hemianopia). Some rehabilitation approaches have shown improvement in visual performance in the blind region, but require a significant time investment. Seven patients with cortical damage performed 400 trials of a motion direction discrimination task daily for 5 days. Three patients received anodal transcranial direct current stimulation (tDCS) during training, three received sham stimulation and one had no stimulation. Each patient had an assessment of visual performance and a functional magnetic resonance imaging (fMRI) scan before and after training to measure changes in visual performance and cortical activity. No patients showed improvement in visual function due to the training protocol, and application of tDCS had no effect on visual performance. However, following training, the neural response in motion area hMT+ to a moving stimulus was altered. When the stimulus was presented to the sighted hemifield, activity decreased in hMT+ of the damaged hemisphere. There was no change in hMT+ response when the stimulus was presented to the impaired hemifield. There was a decrease in activity in the inferior precuneus after training when the stimulus was presented to either the impaired or sighted hemifield. Preliminary analysis of tDCS data suggested that anodal tDCS interacted with the delivered training, modulating the neural response in hMT+ in the healthy side of the brain. Training can affect the neural responses in hMT+ even in the absence of change in visual performance.


ERAP1 association with ankylosing spondylitis is attributable to common genotypes rather than rare haplotype combinations.
We investigated the proposal that ankylosing spondylitis (AS) is associated with unusual ERAP1 genotypes. ERAP1 haplotypes were constructed for 213 AS cases and 46 rheumatoid arthritis controls using family data. Haplotypes were generated from five common ERAP1 single nucleotide polymorphisms (SNPs)-rs2287987 (M349V), rs30187 (K528R), rs10050860 (D575N), rs17482078 (R725Q), and rs27044 (Q730E). Haplotype frequencies were compared using Fisher's exact test. ERAP1 haplotypes imputed from the International Genetics of AS Consortium (IGAS) Immunochip study were also studied. In the family study, we identified only four common ERAP1 haplotypes ("VRNQE," "MKDRQ," "MRDRE," and "MKDRE") in both AS cases and controls apart from two rare (<0.5%) previously unreported haplotypes. There were no examples of the unusual ERAP1 haplotype combination ("*001/*005") previously reported by others in 53% of AS cases. As expected, K528-bearing haplotypes were increased in the AS family study (AS 43% vs. control 35%), due particularly to an increase in the MKDRQ haplotype (AS 35% vs. control 25%, P = 0.01). This trend was replicated in the imputed Immunochip data for the two K528-bearing haplotypes MKDRQ (AS 33% vs. controls 27%, P = 1.2 × 10-24) and MKDRE (AS 8% vs. controls 7%, P = 0.004). The ERAP1 association with AS is therefore predominantly attributable to common ERAP1 haplotypes and haplotype combinations.


Genetic variation in sodium-dependent vitamin C transporters SLC23A1 and SLC23A2 and risk of advanced colorectal adenoma.
Previous observational studies suggest that vitamin C may reduce risk of colorectal cancer. Vitamin C transport is facilitated by membrane bound sodium-dependent transporters, SVCT1 (encoded by SLC23A1) and SVCT2 (encoded by SLC23A2). To investigate if common genetic variants in these two genes are associated with risk of colorectal tumor development, we conducted a case-control study of 656 Caucasian advanced distal colorectal adenoma cases and 665 Caucasian sigmoidoscopy-negative controls nested within the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. The analysis of common single nucleotide polymorphisms in SLC23A1 revealed no association. For SLC23A2, overall, there was no association with haplotypes, but two SNPs located in intron 8 and exon 11 could be associated (odds ratio = 0.49, 95% confidence interval = 0.25-0.95 for haplotype G-C vs. haplotype C-C). The findings should be confirmed in follow-up studies, and further investigation is required to probe the functional basis of this finding.


Detecting cervical cancer by quantitative promoter hypermethylation assay on cervical scrapings: a feasibility study.
Current morphology-based cervical cancer screening is associated with significant false-positive and false-negative results. Tumor suppressor gene hypermethylation is frequently present in cervical cancer. It is unknown whether a cervical scraping reflects the methylation status of the underlying epithelium, and it is therefore unclear whether quantitative hypermethylation specific PCR (QMSP) on cervical scrapings could be used as a future screening method augmenting the current approach. Cervical scrapings and paired fresh frozen cervical tissue samples were obtained from 53 cervical cancer patients and 45 controls. All scrapings were morphologically scored and analyzed with QMSP for the genes APC, DAPK, MGMT, and GSTP1. To adjust for DNA input, hypermethylation ratios were calculated against DNA levels of a reference gene. Hypermethylation ratios of paired fresh frozen tissue samples and scrapings of cervical cancer patients and controls were strongly related (Spearman correlation coefficient, 0.80 for APC, 0.98 for DAPK, and 0.83 for MGMT; P < 0.001). More cervical cancer patients than controls were DAPK positive (P < 0.001). When cutoff levels for ratios were defined to be above the highest ratio observed in controls, QMSP in cervical scrapings identified 32 (67%) of 48 cervical cancer patients. This feasibility study demonstrates that QMSP on cervical scrapings holds promise as a new diagnostic tool for cervical cancer. The addition of more genes specifically methylated in cervical cancer will further improve the assay.


Efficacy of conjugated linoleic acid for reducing fat mass: a meta-analysis in humans.
Conjugated linoleic acid (CLA) has been shown to be an effective supplement for reducing fat mass in animals, whereas results in humans have been inconsistent. This is a meta-analysis of human studies in which CLA was provided as a dietary supplement to test its efficacy in reducing fat mass. We searched the PubMed database (National Library of Medicine, Bethesda, MD) and references from the resulting search to identify studies in which CLA was provided to humans in randomized, double-blinded, placebo-controlled trials and in which body composition was assessed by using a validated technique. We identified 18 eligible studies. Of these, 3 were single-isomer studies, and results comparing CLA isomers were inconclusive. We compared the length of treatment by using studies in which a mixture of purified isomers were used and those in which purified trans-10,cis-12 isomers were used. This comparison indicated that the effect of CLA was linear for up to 6 mo and then slowly approached an asymptote at 2 y. An analysis of the dose effect indicated that fat loss compared with placebo was -0.024 kg x g CLA(-1) x wk(-1) (P=0.03). After adjustment to the median dose of 3.2 g CLA/d, CLA was effective and produced a reduction in fat mass for the CLA group alone (0.05 +/- 0.05 kg/wk; P<0.001) and for the CLA group compared with placebo (0.09 +/- 0.08 kg/wk; P<0.001) Given at a dose of 3.2 g/d, CLA produces a modest loss in body fat in humans.


A 4-alkyl-substituted analogue of guaiacol shows greater repellency to savannah tsetse (Glossina spp.).
The responses of Glossina morsitans morsitans Westwood to guaiacol (2-methoxyphenol), a mild repellent constituent of bovid odors, and seven analogues comprising 2-methoxyfuran, 2,4-dimethylphenol, 2-methoxy-4-methylphenol (4-methylguaiacol), 4-ethyl-2-methoxyphenol (4-ethylguaiacol), 4-allyl-2-methoxyphenol (4-allylguaiacol; eugenol), 3,4-methylenedioxytoluene, and 3,4-dimethoxystyrene were compared in a two-choice wind tunnel. The 4-methyl-substituted derivative (2-methoxy-4-methylphenol) was found to elicit stronger repellent responses from the flies compared with guaiacol. None of the other analogues showed significant repellent effects on flies. 4-Methylguaiacol, guaiacol, and eugenol (which was included because of previous reports of its repellency against a number of arthropods) were further evaluated in the field with wild populations of predominantly Glossina pallidipes Austen. The presence of guaiacol or eugenol near odor-baited traps caused some nonsignificant reduction in the number of tsetse catches at relatively high release rates (approximately 50 mg/hr). In contrast, the 4-methyl derivative at three different release rates (2.2, 4.5, and 9.0 mg/hr) reduced trap catches of baited traps in a dose-response manner. At 10 mg/hr release rate, it reduced the catches of baited and unbaited traps by approximately 80 and approximately 70%, respectively. In addition, the compound not only reduced the number of tsetse attracted to natural ox odor (approximately 80%), but also had an effect on their feeding responses, reducing the proportion that fed on an ox by more than 80%. Our study shows that the presence of a methyl substituent at the 4-position of guaiacol enhances the repellency of the molecule to savannah tsetse and suggests that 4-methylguaiacol may represent a promising additional tool in the arsenal of techniques in trypanosomiasis control.


Hypothermia During Partial Nephrectomy for Patients with Renal Tumors: A Randomized Controlled Trial.
Surgeons induce renal hypothermia during partial nephrectomy to preserve kidney function, without strong evidence of benefit. This trial examined the effectiveness and safety of renal hypothermia during partial nephrectomy. We conducted a parallel randomized controlled trial of hypothermia versus no hypothermia (control group) during partial nephrectomy at 6 academic hospitals. Eligible patients had a planned open partial nephrectomy for the treatment of a renal tumor. During surgery, after clamping the renal hilum, patients were randomized to the intervention or control arm in a 1:1 ratio using permuted blocks of variable lengths (2 and 4), stratified by institution, using a computer-based program. Surgeons and study coordinators were masked to treatment allocation until the renal hilum was clamped. Overall glomerular filtration rates were determined before, and 1-year after, surgery. The primary outcome was measured glomerular filtration rate (mGFR) assessed by the plasma clearance of 99mTc-DTPA. The trial (NCT01529658) was designed with 90% power to detect a minimal clinically important difference in mGFR of 10 ml/minute/1.73 m2 at a 5% significance level. Of the 184 patients randomized, hypothermia and control patients had similar baseline mean mGFR (87.1 vs 81.0 ml/minute/1.73 m2). One hundred and sixty-one (79 hypothermia, 82 control) were alive with primary outcome data 1 year after surgery. The change in mGFR 1 year after surgery was -6.6 ml/minute/1.73 m2 in the hypothermia group and -7.8 ml/minute/1.73 m2 in the control group (mean difference 1.2 ml/minute/1.73 m2, 95% CI -3.3 to 5.6). Operated-kidney change in mGFR was similar between groups (-5.8 vs -6.3 ml/minute/1.73 m2; mean difference 0.5 ml/minute/1.73 m2, 95% CI -2.9 to 3.8). No clinically significant difference in the mGFR was observed when patients were stratified by pre-planned subgroups. Renal hypothermia did not impact the secondary outcomes of surgical complications and patient reported quality of life. Renal hypothermia during partial nephrectomy does not preserve kidney function in patients with normal or mildly impaired renal function.


Survey of microbial contamination and characterization of Escherichia coli in kiwifruit orchards in Shaanxi, China, 2013.
The aim of the study was to survey three foodborne pathogens in kiwifruit orchards as a continuous monitoring program. A total of 193 samples were collected from 11 kiwifruit orchards in Shaanxi province in October 2013. Among the 193 samples, 68 Escherichia coli isolates were recovered, while no Staphylococcus aureus and Salmonella was recovered. All E. coli isolates were characterized by antimicrobial susceptibility testing, detection of virulence genes, and the ability to produce biofilm formation. The isolates were further examined by random amplified polymorphic DNA (RAPD) analysis. E. coli isolates displayed resistance most frequently to tetracycline (48.5%). Two E. coli isolates (2.9%) were positive for the eae gene (the intimin gene). All E. coli isolates lacked the ability to make biofilm formation. Multilocus sequence typing analysis demonstrated that one isolate in kiwifruit orchards shared the same sequence type with a human clinical isolate. RAPD results showed a close relationship among E. coli isolates from fresh fruit, fallen fruit, soil, air, and irrigation water. This study could provide a further understanding of microbial contamination in kiwifruit orchards based on our previous study and help growers take appropriate measures for prevention.


Transfundal stent placement for treatment of complex basilar tip aneurysm: technical note.
We describe a case where a complex unruptured basilar tip aneurysm was treated with a unique method of stent-assisted coil embolization. The aneurysm was considered to have a complex anatomy since both the left posterior cerebral artery and left superior cerebellar artery originated from the dome of the aneurysm. Also, the right posterior cerebral artery was incorporated in the aneurysm neck and needed to be protected prior to coil embolization. This case describes placement of a stent across the span of the aneurysm fundus in order to preserve the two branches arising from it, and the aneurysm dome was coiled without any complication. Using modifications of existing strategies for stent-assisted coil embolization, the aneurysm was treated without any complications and all of the vessels at risk were preserved.


Comparative analysis of regulatory elements between Escherichia coli and Klebsiella pneumoniae by genome-wide transcription start site profiling.
Genome-wide transcription start site (TSS) profiles of the enterobacteria Escherichia coli and Klebsiella pneumoniae were experimentally determined through modified 5' RACE followed by deep sequencing of intact primary mRNA. This identified 3,746 and 3,143 TSSs for E. coli and K. pneumoniae, respectively. Experimentally determined TSSs were then used to define promoter regions and 5' UTRs upstream of coding genes. Comparative analysis of these regulatory elements revealed the use of multiple TSSs, identical sequence motifs of promoter and Shine-Dalgarno sequence, reflecting conserved gene expression apparatuses between the two species. In both species, over 70% of primary transcripts were expressed from operons having orthologous genes during exponential growth. However, expressed orthologous genes in E. coli and K. pneumoniae showed a strikingly different organization of upstream regulatory regions with only 20% identical promoters with TSSs in both species. Over 40% of promoters had TSSs identified in only one species, despite conserved promoter sequences existing in the other species. 662 conserved promoters having TSSs in both species resulted in the same number of comparable 5' UTR pairs, and that regulatory element was found to be the most variant region in sequence among promoter, 5' UTR, and ORF. In K. pneumoniae, 48 sRNAs were predicted and 36 of them were expressed during exponential growth. Among them, 34 orthologous sRNAs between two species were analyzed in depth, and the analysis showed that many sRNAs of K. pneumoniae, including pleiotropic sRNAs such as rprA, arcZ, and sgrS, may work in the same way as in E. coli. These results reveal a new dimension of comparative genomics such that a comparison of two genomes needs to be comprehensive over all levels of genome organization.


Ptf1a determines GABAergic over glutamatergic neuronal cell fate in the spinal cord dorsal horn.
Mutations in the human and mouse PTF1A/Ptf1a genes result in permanent diabetes mellitus and cerebellar agenesis. We show that Ptf1a is present in precursors to GABAergic neurons in spinal cord dorsal horn as well as the cerebellum. A null mutation in Ptf1a reveals its requirement for the dorsal horn GABAergic neurons. Specifically, Ptf1a is required for the generation of early-born (dI4, E10.5) and late-born (dIL(A), E12.5) dorsal interneuron populations identified by homeodomain factors Lhx1/5 and Pax2. Furthermore, in the absence of Ptf1a, the dI4 dorsal interneurons trans-fate to dI5 (Lmx1b(+)), and the dIL(A) to dIL(B) (Lmx1b(+);Tlx3(+)). This mis-specification of neurons results in a complete loss of inhibitory GABAergic neurons and an increase in the excitatory glutamatergic neurons in the dorsal horn of the spinal cord by E16.5. Thus, Ptf1a function is essential for GABAergic over glutamatergic neuronal cell fates in the developing spinal cord, and provides an important genetic link between inhibitory and excitatory interneuron development.


Host-parasite coevolution in a multilocus gene-for-gene system.
This paper examines a mathematical model for the coevolution of parasite virulence and host resistance under a multilocus gene-for-gene interaction. The degrees of parasite virulence and host resistance show coevolutionary cycles for sufficiently small costs of virulence and resistance. Besides these coevolutionary cycles of a longer period, multilocus genotype frequencies show complex fluctuations over shorter periods. All multilocus genotypes are maintained within host and parasite classes having the same number of resistant/virulent alleles and their frequencies fluctuate with approximately equally displaced phases. If either the cost of virulence or the number of resistance loci is larger then a threshold, the host maintains the static polymorphism of singly (or doubly or more, depending on the cost of resistance) resistant genotypes and the parasite remains universally avirulent. In other words, host polymorphism can prevent the invasion of any virulent strain in the parasite. Thus, although assuming an empirically common type of asymmetrical gene-for-gene interaction, both host and parasite populations can maintain polymorphism in each locus and retain complex fluctuations. Implications for the red queen hypothesis of the evolution of sex and the control of multiple drug resistance are discussed.


Cost-Effectiveness of Initiating Pharmacological Treatment in Stage One Hypertension Based on 10-Year Cardiovascular Disease Risk: A Markov Modeling Study.
Antihypertensive drug treatment is cost-effective for adults at high risk of developing cardiovascular disease (CVD). However, the cost-effectiveness in people with stage 1 hypertension (140-159 mm Hg systolic blood pressure) at lower CVD risk remains unclear. The objective was to establish the 10-year CVD risk threshold where initiating antihypertensive drug treatment for primary prevention in adults, with stage 1 hypertension, becomes cost-effective. A lifetime horizon Markov model compared antihypertensive drug versus no treatment, using a UK National Health Service perspective. Analyses were conducted for groups ranging between 5% and 20% 10-year CVD risk. Health states included no CVD event, CVD and non-CVD death, and 6 nonfatal CVD morbidities. Interventions were compared using cost-per-quality-adjusted life-years. The base-case age was 60, with analyses repeated between ages 40 and 75. The model was run separately for men and women, and threshold CVD risk assessed against the minimum plausible risk for each group. Treatment was cost-effective at 10% CVD risk for both sexes (incremental cost-effectiveness ratio £10 017/quality-adjusted life-year [$14 542] men, £8635/QALY [$12 536] women) in the base-case. The result was robust in probabilistic and deterministic sensitivity analyses but was sensitive to treatment effects. Treatment was cost-effective for men regardless of age and women aged >60. Initiating treatment in stage 1 hypertension for people aged 60 is cost-effective regardless of 10-year CVD risk. For other age groups, it is also cost-effective to treat regardless of risk, except in younger women.


Biofidelity Evaluation of the THOR and Hybrid III 50th Percentile Male Frontal Impact Anthropomorphic Test Devices.
The objective of this study is to present a quantitative comparison of the biofidelity of the THOR and Hybrid III 50th percentile male ATDs. Quantitative biofidelity was assessed using NHTSA's Biofidelity Ranking System in a total of 21 test conditions, including impacts to the head, face, neck, upper thorax, lower oblique thorax, upper abdomen, lower abdomen, femur, knee, lower leg, and whole-body sled tests to evaluate upper body kinematics and thoracic response under frontal and frontal oblique restraint loading. Biofidelity Ranking System scores for THOR were better (lower) than Hybrid III in 5 of 7 body regions for internal biofidelity and 6 of 7 body regions for external biofidelity. Nomenclature is presented to categorize the quantitative results, which show overall good internal and external biofidelity of the THOR compared to the good (internal) and marginal (external) biofidelity of the Hybrid III. The results highlight the excellent internal and external biofidelity of the THOR thorax.


Collision dynamics of polyatomic molecules containing carbon rings at low temperatures.
We explore the collision dynamics of complex hydrocarbon molecules (benzene, coronene, adamantane, and anthracene) containing carbon rings in a cold buffer gas of (3)He. For benzene, we present a comparative analysis of the fully classical and fully quantum calculations of elastic and inelastic scattering cross sections at collision energies between 1 and 10 cm(-1). The quantum calculations are performed using the time-independent coupled channel approach and the coupled-states approximation. We show that the coupled-states approximation is accurate at collision energies between 1 and 20 cm(-1). For the classical dynamics calculations, we develop an approach exploiting the rigidity of the carbon rings and including low-energy vibrational modes without holonomic constraints. Our results illustrate the effect of the molecular shape and the vibrational degrees of freedom on the formation of long-lived resonance states that lead to low-temperature clustering.


Unusual domain movement in a multidomain protein in the presence of macromolecular crowders.
Domain movements play a fundamental and critical role in the specific biological function that multidomain proteins have evolved to perform. A significant amount of research has been carried out to investigate the effects of macromolecular crowding agents, mostly on single domain proteins, thereby furthering our appreciation for the crowding phenomenon. However similar studies on proteins having multiple domains are relatively scarce. Using the plasma protein human serum albumin (HSA) as the protein of interest, we have probed the influence of dextran based crowding agents (Dextran 6, Dextran 40, and Dextran 70) on the relative movements of domains I and II using FRET, with Trp-214 in domain II acting as the donor and acrylodan (Ac) covalently attached to Cys-34 of domain I as the acceptor. Amongst the higher molecular weight crowders, while both Dextran 70 and Dextran 40 induced a significant decrease in the distance between the aforesaid domains, however for the latter macromolecular crowder (Dextran 40), beyond 50 g L(-1), no change in domain separation was observed even up to concentrations of 175 g L(-1). On the other hand, contrary to our expectations, Dextran 6, having the highest packing density by virtue of it being the smallest crowding agent used, provided an asymmetric excluded volume which resulted in forced elongation of HSA along the Trp-Ac FRET axis. Additionally both chemical and thermal studies performed at varying concentrations of the chemical denaturant, urea, reveal unusual movements of the two domains, an aspect that can have important implications with regard to HSA being an avid transporter of fatty acids, with the binding of latter being known to invoke appreciable domain displacements. We hypothesise that we see a distinct crossover from entropy dominated depletion effects in the case of Dextran 6 to significant enthalpic contribution for Dextran 70 with Dextran 40 lying midway between these two crowders, having characteristics of both.


Weight gain and incident obesity among male snus users.
Snus is a moist smokeless tobacco product which has recently reached beyond its original market of Scandinavia. Snus is now being increasingly used in both the United States and South Africa. The effect of snus use on weight is unknown. This study has therefore investigated the relationship between the use of snus, weight gain (≥5%) and the incidence of obesity (body mass index ≥30 kg/m(2)). The study participants (n = 9,954 males living in Stockholm County, Sweden) were recruited in 2002 and reassessed in 2007. Tobacco use was categorized according to information obtained in both the baseline and follow-up surveys. Outcomes were assessed by comparing self-reported weight and body mass index between the baseline and follow-up surveys. Stable current snus use (according to both surveys), compared to never having used any kind of tobacco, seemed to be associated with both weight gain (odds ratio = 1.31, 95% confidence interval: 1.04-1.65) and incident obesity (odds ratio = 1.93, 95% confidence interval: 1.13-3.30) after adjustment for age, baseline weight, alcohol consumption, physical activity, education, consumption of fruit and berries, and the frequency of having breakfast. No associations with incident obesity or weight gain were seen for stable former users of snus (according to both surveys) or among men who quit or began using snus during follow-up. These data suggest that the use of snus is moderately associated with weight gain and incident obesity among men.


Smiling enemies: Young children better recall mean individuals who smile.
Remembering whether a person is cooperative is essential in social interactions. It has been shown that adults have better memory of a person who showed an incongruence between emotional expression and expected behavior (e.g., smiling while stealing). To examine whether children would show similar emotional incongruity effects, we examined 70 children aged 5 or 6 years. They obtained coins that could be exchanged later for rewards (stickers) by answering quiz questions. Then, they participated in the coin collection game where individual persons with smiling or angry expressions appeared one at a time on a computer monitor. These same individuals then either gave coins to or took coins away from the children, leading to congruent (smiling giver and angry taker) and incongruent (smiling taker and angry giver) conditions. After the game, children needed to choose between two faces to indicate which one previously appeared in the game. Participants recognized faces better under the incongruent conditions. In particular, the smiling taker was recognized significantly better than the angry taker, whereas no difference was observed for the smiling and angry givers. Evidently, 5- and 6-year-olds better remember individuals whose facial expression or appearance is incongruent with their expected behavior.


New horizons: the management of hypertension in people with dementia.
The optimal management of hypertension in people with dementia is uncertain. This review explores if people with dementia experience greater adverse effects from antihypertensive medications, if cognitive function is protected or worsened by controlling blood pressure (BP) and if there are subgroups of people with dementia for whom antihypertensive therapy is more likely to be harmful. Robust evidence is scant, trials of antihypertensive medications have generally excluded those with dementia. Observational data show changes in risk association over the life course, with high BP being a risk factor for cognitive decline in mid-life, while low BP is predictive in later life. It is therefore possible that excessive BP lowering in older people with dementia might harm cognition. From the existing literature, there is no direct evidence of benefit or harm from treating hypertension in people with dementia. So what practical steps can the clinician take? Assess capacity, establish patient preferences when making treatment decisions, use ambulatory monitoring to thoroughly assess BP, individualise and consider deprescribing where side effects (e.g. hypotension) outweigh the benefits. Future research might include pragmatic randomised trials of targeted deprescribing, which include patient-centred outcome measures to help support decision-making and studies to address mechanistic uncertainties.


Overdominant epistatic loci are the primary genetic basis of inbreeding depression and heterosis in rice. II. Grain yield components.
The genetic basis underlying inbreeding depression and heterosis for three grain yield components of rice was investigated in five interrelated mapping populations using a complete RFLP linkage map, replicated phenotyping, and the mixed model approach. The populations included 254 F(10) recombinant inbred lines (RILs) derived from a cross between Lemont (japonica) and Teqing (indica), two backcross (BC) and two testcross populations derived from crosses between the RILs and the parents plus two testers (Zhong413 and IR64). For the yield components, the RILs showed significant inbreeding depression and hybrid breakdown, and the BC and testcross populations showed high levels of heterosis. The average performance of the BC or testcross hybrids was largely determined by heterosis. The inbreeding depression values of individual RILs were negatively associated with the heterosis measurements of the BC or testcross hybrids. We identified many epistatic QTL pairs and a few main-effect QTL responsible for >65% of the phenotypic variation of the yield components in each of the populations. Most epistasis occurred between complementary loci, suggesting that grain yield components were associated more with multilocus genotypes than with specific alleles at individual loci. Overdominance was also an important property of most loci associated with heterosis, particularly for panicles per plant and grains per panicle. Two independent groups of genes appeared to affect grain weight: one showing primarily nonadditive gene action explained 62.1% of the heterotic variation of the trait, and the other exhibiting only additive gene action accounted for 28.1% of the total trait variation of the F(1) mean values. We found no evidence suggesting that pseudo-overdominance from the repulsive linkage of completely or partially dominant QTL for yield components resulted in the overdominant QTL for grain yield. Pronounced overdominance resulting from epistasis expressed by multilocus genotypes appeared to explain the long-standing dilemma of how inbreeding depression could arise from overdominant genes.


Studies on the origin of milk fat. A further study of bovine serum lipoproteins and an estimation of their contribution to milk fat.
1. Tritium-labelled palmitic acid combined in olive-oil triglycerides was introduced into the rumen of a lactating cow and the specific radioactivity of the lipids of milk and of the lipoproteins of both jugular and mammary venous serum was measured. 2. As previously found in a similar experiment with [(3)H]stearic acid, the specific radioactivity of the triglyceride fraction of the dextran sulphate-precipitable lipoproteins reached a maximum earlier and greater than that of the milk fat. 3. This fraction was the only lipid separated that had a significant arteriovenous difference in concentration, and is therefore identified as the main circulating lipid precursor of milk fat. 4. Although the non-esterified fatty acids showed no arteriovenous difference in concentration, they showed a negative difference in specific radioactivity that could have occurred only at the expense of the triglycerides of the precipitable lipoproteins. 5. The mean specific radioactivity of the triglycerides immediately after removal from the blood is calculated and shown to be very close in value to that of the corresponding fraction in mammary venous serum. 6. By comparison of the mean specific radioactivities of milk fat and of this precursor, its contribution is calculated as 36%. 7. This value is discussed with reference to the concentration of C(16) and C(18) fatty acids in milk fat and it is concluded that substantial amounts of these acids must have been derived from a source other than preformed circulating lipids.


Strain differences affect the induction of status epilepticus and seizure-induced morphological changes.
Genetic deficits have been discovered in human epilepsy, which lead to alteration of the balance between excitation and inhibition, and ultimately result in seizures. Rodents show similar genetic determinants of seizure induction. To test whether seizure-prone phenotypes exhibit increased seizure-related morphological changes, we compared two standard rat strains (Long-Evans hooded and Wistar) and two specially bred strains following status epilepticus. The special strains, namely the kindling-prone (FAST) and kindling-resistant (SLOW) strains, were selectively bred based on their amygdala kindling rate. Although the Wistar and Long-Evans hooded strains experienced similar amounts of seizure activity, Wistar rats showed greater mossy fiber sprouting and hilar neuronal loss than Long-Evans hooded rats. The mossy fiber system was affected differently in FAST and SLOW rats. FAST animals showed more mossy fiber granules in the naïve state, but were more resistant to seizure-induced mossy fiber sprouting than SLOW rats. These properties of the FAST strain are consistent with those observed in juvenile animals, further supporting the hypothesis that the FAST strain shares circuit properties similar to those seen in immature animals. Furthermore, the extent of mossy fiber sprouting was not well correlated with sensitivity to status epilepticus, but was positively correlated with the frequency of spontaneous recurrent seizures in the FAST rats only, suggesting a possible role for axonal sprouting in the development of spontaneous seizures in these animals. We conclude that genetic factors clearly affect seizure development and related morphological changes in both standard laboratory strains and the selectively bred seizure-prone and seizure-resistant strains.


Defensive symbionts.
Interactions in nature vary from competitive to neutral to symbiotic. An interesting case of symbiosis is seen when one organism provides protection to the other-a relationship termed 'defensive symbiosis'. Kayla King highlights this interesting type of relationship, which can be found throughout the tree of life.


Spatial Patterns of Extensively Drug-Resistant Tuberculosis Transmission in KwaZulu-Natal, South Africa.
Transmission is driving the global drug-resistant tuberculosis (TB) epidemic; nearly three-quarters of drug-resistant TB cases are attributable to transmission. Geographic patterns of disease incidence, combined with information on probable transmission links, can define the spatial scale of transmission and generate hypotheses about factors driving transmission patterns. We combined whole-genome sequencing data with home Global Positioning System coordinates from 344 participants with extensively drug-resistant (XDR) TB in KwaZulu-Natal, South Africa, diagnosed from 2011 to 2014. We aimed to determine if genomically linked (difference of ≤5 single-nucleotide polymorphisms) cases lived close to one another, which would suggest a role for local community settings in transmission. One hundred eighty-two study participants were genomically linked, comprising 1084 case-pairs. The median distance between case-pairs' homes was 108 km (interquartile range, 64-162 km). Between-district, as compared to within-district, links accounted for the majority (912/1084 [84%]) of genomic links. Half (526 [49%]) of genomic links involved a case from Durban, the urban center of KwaZulu-Natal. The high proportions of between-district links with Durban provide insight into possible drivers of province-wide XDR-TB transmission, including urban-rural migration. Further research should focus on characterizing the contribution of these drivers to overall XDR-TB transmission in KwaZulu-Natal to inform design of targeted strategies to curb the drug-resistant TB epidemic.


A classification of developmental activities of academic family medicine supported by federal grants.
Substantial funds have been awarded to academic departments of family medicine through the federal Establishment of Departments of Family Medicine grants program, initiated in 1980 under the Public Health Service Act. In 1989 the authors analyzed the successful grant applications in a sample of 61 institutions variously funded or re-funded for the grant cycles from 1980 through 1986 in order to classify the supported developmental activities. Three dimensions for explicating this activity emerged: (1) the functional area of the activity (e.g., curricular development); (2) the objectives of the activity (e.g., improving relevance of instruction); and (3) the strategies to be used to attain the objectives (e.g., addition of specialized faculty). This classification scheme provides a tentative but useful framework for characterizing departmental development.


The heart of darkness: growth and form of Trypanosoma brucei in the tsetse fly.
The first description of African trypanosomes was made over a century ago. The importance of the tsetse in transmission and cyclic development of trypanosomes was discovered soon afterwards, and has been the focus of numerous studies since. However, investigation of trypanosomes in tsetse flies requires high resource investment and unusual patience; hence, many facets of trypanosome biology in the tsetse remain to be characterised despite the long history of research. Here, current knowledge and questions about some of the developmental changes in trypanosomes that occur in tsetse flies are summarised, along with recent technical advances that can now be used to provide some answers.


Order-restricted semiparametric inference for the power bias model.
The power bias model, a generalization of length-biased sampling, is introduced and investigated in detail. In particular, attention is focused on order-restricted inference. We show that the power bias model is an example of the density ratio model, or in other words, it is a semiparametric model that is specified by assuming that the ratio of several unknown probability density functions has a parametric form. Estimation and testing procedures under constraints are developed in detail. It is shown that the power bias model can be used for testing for, or against, the likelihood ratio ordering among multiple populations without resorting to any parametric assumptions. Examples and real data analysis demonstrate the usefulness of this approach.


Impact of differential attrition on the association of education with cognitive change over 20 years of follow-up: the ARIC neurocognitive study.
Studies of long-term cognitive change should account for the potential effects of education on the outcome, since some studies have demonstrated an association of education with dementia risk. Evaluating cognitive change is more ideal than evaluating cognitive performance at a single time point, because it should be less susceptible to confounding. In this analysis of 14,020 persons from a US cohort study, the Atherosclerosis Risk in Communities (ARIC) Study, we measured change in performance on 3 cognitive tests over a 20-year period, from ages 48-67 years (1990-1992) through ages 70-89 years (2011-2013). Generalized estimating equations were used to evaluate the association between education and cognitive change in unweighted adjusted models, in models incorporating inverse probability of attrition weighting, and in models using cognitive scores imputed from the Telephone Interview for Cognitive Status for participants not examined in person. Education did not have a strong relationship with change in cognitive test performance, although the rate of decline was somewhat slower among persons with lower levels of education. Methods used to account for selective dropout only marginally changed these observed associations. Future studies of risk factors for cognitive impairment should focus on cognitive change, when possible, to allow for reduction of confounding by social or cultural factors.


A new method for estimating patient body weight using CT dose modulation data.
Body weight (BW) is a relevant metric in emergency care. However, visual/physical methods to estimate BW are unreliable. We have developed a method for estimating BW based on effective mAs (mAseff) from computed tomography (CT) dose modulation. The mAseff of CT examinations was correlated with the BW of 329 decedents. Linear regression analysis was used to calculate an equation for BW estimation based on the results of decedents with a postmortem interval (PMI) < 4 days (n = 240). The equation was applied to a validation group of 125 decedents. Pearson correlation and t-test statistics were used. We found an overall strong correlation between mAseff and BW (r = 0.931); r values ranged from 0.854 for decedents with PMI ≥ 4 days to 0.966 for those with PMI < 4 days; among the latter group, r was 0.974 for females and 0.960 for males and 0.969 in the presence and 0.966 in the absence of metallic implants (all correlations with p values < 0.001). The estimated BW was equal to 3.732 + (0.422 × mAseff) - (3.108 × sex index), where the sex index is 0 for males and 1 for females. The validation group showed a strong correlation (r = 0.969) between measured BW and the predicted BW, without significant differences overall (p = 0.119) as well as in female (p = 0.394) and in male decedents (p = 0.196). No outliers were observed. CT dose modulation is a rapid and reliable method for BW estimation with potential use in clinical practice, in particular in emergency settings.


Factors affecting the electronic ground state of low-spin iron(III) porphyrin complexes.
To determine the factors affecting the ground-state electron configuration of low-spin Fe(III) porphyrin complexes, we have examined the (1)H NMR, (13)C NMR, and EPR spectra of a series of low-spin bis-ligated Fe(III) porphyrin complexes [Fe(Por)L(2)](+/-), in which the positions of porphyrin substituents and the coordination ability of axial ligands are different. The seven porphyrins used in this study are meso-tetraalkylporphyrins (TRP: R is propyl, cyclopropyl, or isopropyl), meso-tetraphenylporphyrin (TPP), meso-tetrakis(2,3,4,5,6-pentafluorophenyl)porphyrin, and 5,10,15,20-tetraphenyl-2,3,7,8,12,13,17,18-octaalkylporphyrins (ORTPP: R is methyl or ethyl). The porphyrin cores of TRP are more or less S(4)-ruffled depending on the bulkiness of the alkyl substituents, while those of ORTPP are highly S(4)-saddled. Three types of axial ligands are examined which have the following characteristics in ligand field theory: they are (i) strong sigma-donating imidazole (HIm), (ii) strong sigma-donating and weak pi-accepting cyanide (CN(-)), and (iii) weak sigma-donating and strong pi-accepting tert-butyl isocyanide ((t)BuNC). In the case of the bis(HIm) complexes, only the isopropyl complex, [Fe(T(i)PrP)(HIm)(2)](+), has shown the less common (d(xz), d(yz))(4)(d(xy))(1) ground state; the other six complexes have exhibited the common (d(xy))(2)(d(xz), d(yz))(3) ground state. When the axial imidazole is replaced by cyanide, even the propyl and cyclopropyl complexes have shown the (d(xz), d(yz))(4)(d(xy))(1) ground state; the TPP and ORTPP complexes have still maintained the common (d(xy))(2)(d(xz), d(yz))(3) ground state. In the case of the bis((t)()BuNC) complexes, all the complexes have shown the (d(xz), d(yz))(4)(d(xy))(1) ground state. However, the contribution of the (d(xz), d(yz))(4)(d(xy))(1) state to the electronic ground state differs from complex to complex; the (d(xz), d(yz))(4)(d(xy))(1) contribution is the largest in [Fe(T(i)PrP)((t)()BuNC)(2)](+) and the smallest in [Fe(OETPPP)((t)BuNC)(2)](+). We have then examined the electronic ground state of low-spin [Fe(OEP)((t)BuNC)(2)](+) and [Fe(ProtoIXMe(2))((t)BuNC)(2)](+); OEP and ProtoIXMe(2) represent 2,3,7,8,12,13,17,18-octaethylporphyrin and protoporphyrin-IX dimethyl ester, respectively. These porphyrins have a(1u) HOMO in contrast to the other seven porphyrins that have a(2u) HOMO. The (13)C NMR and EPR studies have revealed that the contribution of the (d(xz), d(yz))(4)(d(xy))(1) state in these complexes is as small as that in [Fe(OETPP)((t)BuNC)(2)](+). On the basis of these results, we have concluded that the low-spin iron(III) porphyrins that have (i) strong axial ligands, (ii) highly saddle shaped porphyrin rings, (iii) porphyrins with a(1u) HOMO, and (iv) electron withdrawing substituents at the meso positions tend to maintain the common (d(xy))(2)(d(xz), d(yz))(3) ground state.


Midterm results of endovascular treatment of superficial femoral artery disease with biodegradable stents: single-center experience.
To assess the midterm efficacy of a biodegradable poly-l-lactic acid (PLLA) stent in the treatment of superficial femoral artery (SFA) occlusive disease. Between June 2009 and April 2011, 35 de novo SFA lesions were treated with 43 biodegradable stents. This nonrandomized, retrospective, single-center study included patients with moderate or severe claudication, lower-limb rest pain, or ischemic ulceration restricted to the toes; symptoms were classified as Rutherford category 2 (48.6%), 3 (37.1%), 4 (8.6%), or 5 (5.7%). The population included 28 men and had a mean age of 71 years (range, 51-81 y). Follow-up included clinical examination and color-flow duplex imaging. Mean follow-up was 38.3 months (range, 30-58 mo). Technical success was reported in all patients (100%). There were no intraoperative or immediate (< 30 d) complications.. During follow-up, one in-stent occlusion and seven in-stent restenoses occurred, all of which were successfully treated with percutaneous transluminal angioplasty. Primary and secondary patency rates were 77.1% and 97.1% at 24 and 36 months, respectively. No stent recoil or stent fracture was encountered. Late follow-up (> 12 mo) by ultrasound confirmed total reabsorption of the stent structures. Clinical improvement (ie, an upward shift of at least two Rutherford categories) was achieved in all 35 patients. Midterm results for biodegradable PLLA stents for atherosclerotic SFA lesions were associated with high technical success and secondary patency rates, without stent recoil and vessel remodeling.


"Where are you really from?": Asian Americans and identity denial.
Five studies investigate identity denial, the situation in which an individual is not recognized as a member of an important in-group. Asian Americans are seen as less American than other Americans (Study 1) and realize this is the case, although they do not report being any less American than White Americans (Studies 2A and 2B). Identity denial is a common occurrence in Asian Americans' daily lives (Study 3). They react to instances of identity denial by presenting American cultural knowledge and claiming greater participation in American practices (Studies 4 & 5). Identity denial furthers the understanding of group dynamics by capturing the experience of less prototypical group members who desire to have their common in-group identity recognized by fellow group members.