Testing a mobile mindful eating intervention targeting craving-related eating: feasibility and proof of concept.
Theoretically driven smartphone-delivered behavioral interventions that target mechanisms underlying eating behavior are lacking. In this study, we administered a 28-day self-paced smartphone-delivered intervention rooted in an operant conditioning theoretical framework that targets craving-related eating using mindful eating practices. At pre-intervention and 1-month post-intervention, we assessed food cravings among adult overweight or obese women (N = 104; M age = 46.2 ± 14.1 years; M BMI = 31.5 ± 4.5) using ecological momentary assessment via text message (SMS), self-reported eating behavior (e.g., trait food craving), and in-person weight. Seventy-eight participants (75.0%) completed the intervention within 7 months ('all completers'), and of these, 64 completed the intervention within 3 months ('timely completers'). Participants experienced significant reductions in craving-related eating (40.21% reduction; p < .001) and self-reported overeating behavior (trait food craving, p < .001; other measures ps < .01). Reductions in trait food craving were significantly correlated with weight loss for timely completers (r = .30, p = .020), this pattern of results was also evident in all completers (r = .22, p = .065). Taken together, results suggest that smartphone-delivered mindful eating training targeting craving-related eating may (1) target behavior that impacts a relative metabolic pathway, and (2) represent a low-burden and highly disseminable method to reduce problematic overeating among overweight individuals. ClinicalTrials.gov registration: NCT02694731.


CVSim: An Open-Source Cardiovascular Simulator for Teaching and Research.
CVSim is a lumped-parameter model of the human cardiovascular system that has been developed and used for research and for teaching quantitative physiology courses at MIT and Harvard Medical School since 1984. We present a brief historical background of lumped-parameter cardiovascular system models, followed by an overview of the development of the major versions of CVSim over a 25-year period in our laboratory. We describe the features and differences of four versions of CVSim that are freely available in open-source form via PhysioNet (http://physionet.org). These include a six-compartment cardiovascular model with an arterial baroreflex system, implemented in C for efficiency, with an X-based graphical user interface; a six-compartment model with a more extensive short-term regulatory system and incorporating resting physiologic perturbations, available as a stand-alone MATLAB application; and a pair of elaborated versions consisting of 6- and 21-compartment computational models implemented in C, with a separate and enhanced Java graphical user interface. We conclude with a discussion of the educational and research applications for which we have used CVSim.


Out in the Cold: Identification of Genomic Regions Associated With Cold Tolerance in the Biocontrol Fungus Clonostachys rosea Through Genome-Wide Association Mapping.
There is an increasing importance for using biocontrol agents in combating plant diseases sustainably and in the long term. As large scale genomic sequencing becomes economically viable, the impact of single nucleotide polymorphisms (SNPs) on biocontrol-associated phenotypes can be easily studied across entire genomes of fungal populations. Here, we improved a previously reported genome assembly of the biocontrol fungus Clonostachys rosea strain IK726 using the PacBio sequencing platform, which resulted in a total genome size of 70.7 Mbp and 21,246 predicted genes. We further performed whole-genome re-sequencing of 52 additional C. rosea strains isolated globally using Illumina sequencing technology, in order to perform genome-wide association studies in conditions relevant for biocontrol activity. One such condition is the ability to grow at lower temperatures commonly encountered in cryic or frigid soils in temperate regions, as these will be prevalent for protecting growing crops in temperate climates. Growth rates at 10°C on potato dextrose agar of the 53 sequenced strains of C. rosea were measured and ranged between 0.066 and 0.413 mm/day. Performing a genome wide association study, a total of 1,478 SNP markers were significantly associated with the trait and located in 227 scaffolds, within or close to (< 1000 bp distance) 265 different genes. The predicted gene products included several chaperone proteins, membrane transporters, lipases, and proteins involved in chitin metabolism with possible roles in cold tolerance. The data reported in this study provides a foundation for future investigations into the genetic basis for cold tolerance in fungi, with important implications for biocontrol.


Pancolitis with ischemic injury as a complication of immunosuppressive treatment in a patient with autoimmune hepatitis: a case report.
Ischemic colitis is a serious drug-induced adverse event. There are only few cases of immunosuppression-associated ischemic colitis described in the literature, but none with a pancolitis-like manifestation. We report the case of a 72-year-old female patient who developed a pancolitis with ischemic injury on immunosuppressive treatment with steroids and azathioprine for autoimmune hepatitis. The patient presented with massive rectal bleeding. Colonoscopy confirmed the diagnosis of pancolitis. The results of histological examination indicated drug-induced ischemic colitis involving the entire colon. This is the first case of ischemic pancolitis mimicking an inflammatory bowel disease (IBD) in a patient with immunosuppressive therapy.


Accessing heterogeneous sources of evidence to answer clinical questions.
The large and rapidly growing number of information sources relevant to health care, and the increasing amounts of new evidence produced by researchers, are improving the access of professionals and students to valuable information. However, seeking and filtering useful, valid information can be still very difficult. An online information system that conducts searches based on individual patient data can have a beneficial influence on the particular patient's outcome and educate the healthcare worker. In this paper, we describe the underlying model for a system that aims to facilitate the search for evidence based on clinicians' needs. This paper reviews studies of information needs of clinicians, describes principles of information retrieval, and examines the role that standardized terminologies can play in the integration between a clinical system and literature resources, as well as in the information retrieval process. The paper also describes a model for a digital library system that supports the integration of clinical systems with online information sources, making use of information available in the electronic medical record to enhance searches and information retrieval. The model builds on several different, previously developed techniques to identify information themes that are relevant to specific clinical data. Using a framework of evidence-based practice, the system generates well-structured questions with the intent of enhancing information retrieval. We believe that by helping clinicians to pose well-structured clinical queries and including in them relevant information from individual patients' medical records, we can enhance information retrieval and thus can improve patient-care.


Activating NK cell receptor expression/function (NKp30, NKp46, DNAM-1) during chronic viraemic HCV infection is associated with the outcome of combined treatment.
Specific NK cell killer inhibitory receptor (KIR):HLA haplotype combinations have been associated with successful clearance of acute and chronic HCV infection. Whether an imbalance of activating NK cell receptors also contributes to the outcome of treatment of chronic HCV infection, however, is not known. We studied peripheral NK cell phenotype and function in 28 chronically viraemic HCV genotype I treatment-naïve patients who underwent treatment with pegylated IFN-α and ribavirin. At baseline, chronically infected patients with sustained virological response (SVR) had reduced CD56(bright) CD16(+/-) cell populations, increased CD56(dull) CD16(+) NK cell proportions, and lower expression of NKp30, DNAM-1, and CD85j. Similarly, reduced NK cell IFN-γ production but increased degranulation was observed among nonresponding (NR) patients. After treatment, CD56(bright) CD16(+/-) NK cell numbers increased in both SVR and NR patients, with a parallel significant increase in activating NKp30 molecule densities in SVR patients only. In vitro experiments using purified NK cells in the presence of rIL-2 and IFN-α confirmed upregulation of NKp30 and also of NKp46 and DNAM-1 in patients with subsequent SVR. Thus, differences in patient NK cell receptor expression and modulation during chronic HCV-1 infection are associated with subsequent outcome of standard treatment. Individual activating receptor expression/function integrates with KIR:HLA genotype carriage to determine the clearance of HCV infection upon treatment.


Epidemiological and microbiological investigation of a large outbreak of monophasic Salmonella Typhimurium 4,5,12:i:- in schools associated with imported beef in Poitiers, France, October 2010.
An outbreak due to the emerging monophasic Salmonella Typhimurium 4,5,12:i:- occurred in four schools in Poitiers in October 2010. Food trace-back investigation led to the identification of beef burgers as the cause of the outbreak and their subsequent withdrawal. The Institute for Public Health Surveillance conducted a retrospective epidemiological investigation to assess the extent of the outbreak and describe cases. Self-administered questionnaires were completed by students and personnel attending each of the four schools affected. Clinical cases were defined as anyone having eaten at the school when the beef burgers were served and reporting diarrhoea or fever with at least one digestive symptom (nausea, vomiting or abdominal pain), within five days after the incriminated school meal or with unknown date of onset within a 15-day period after the incriminated school meal. Of 1,559 persons exposed, 554 clinical cases were identified corresponding to an overall attack rate of 35.5%. Of 554 clinical cases, a total of 286 (53%) sought medical care and 31 (6%) were hospitalised for more than 24 hours. This multi-school outbreak is one of the biggest food-borne outbreaks of monophasic Salmonella Typhimurium 4,5,12:i:- described in France. Prompt notification of cases and rapid identification and withdrawal of the incriminated batch of beef burgers was crucial to limit the extension of this outbreak.


Genetic diversity in two Plasmodium vivax protein ligands for reticulocyte invasion.
The interaction between Plasmodium vivax Duffy binding protein (PvDBP) and Duffy antigen receptor for chemokines (DARC) has been described as critical for the invasion of human reticulocytes, although increasing reports of P. vivax infections in Duffy-negative individuals questions its unique role. To investigate the genetic diversity of the two main protein ligands for reticulocyte invasion, PvDBP and P. vivax Erythrocyte Binding Protein (PvEBP), we analyzed 458 isolates collected in Cambodia and Madagascar from individuals genotyped as Duffy-positive. First, we observed a high proportion of isolates with multiple copies PvEBP from Madagascar (56%) where Duffy negative and positive individuals coexist compared to Cambodia (19%) where Duffy-negative population is virtually absent. Whether the gene amplification observed is responsible for alternate invasion pathways remains to be tested. Second, we found that the PvEBP gene was less diverse than PvDBP gene (12 vs. 33 alleles) but provided evidence for an excess of nonsynonymous mutations with the complete absence of synonymous mutations. This finding reveals that PvEBP is under strong diversifying selection, and confirms the importance of this protein ligand in the invasion process of the human reticulocytes and as a target of acquired immunity. These observations highlight how genomic changes in parasite ligands improve the fitness of P. vivax isolates in the face of immune pressure and receptor polymorphisms.


Sleep quality in individuals diagnosed with colorectal cancer: Factors associated with sleep disturbance as patients transition off treatment.
To identify patient characteristics associated with sleep disturbance and worsening of sleep in individuals diagnosed with localized colorectal cancer and assess heterogeneity in these relationships. Data were from the MY-Health study, a community-based observational study of adults diagnosed with cancer. Patient-Reported Outcomes Measurement Information System® Sleep Disturbance, Anxiety, Depression, Fatigue, and Pain Interference measures were administered. Participants self-reported demographics, comorbidities, and treatment information. Regression mixture and multiple regression models were used to evaluate the relationship between sleep disturbance and patient characteristics cross-sectionally at an average of 10 months after diagnosis (n = 613) as well as change in sleep disturbance over a 6-month period (n = 361). Pain, anxiety, fatigue, and the existence of multiple comorbid conditions had statistically significant relationships with sleep disturbance (B = 0.09, 0.22, 0.29, and 1.53, respectively; P < 0.05). Retirement (B = -2.49) was associated with sleep quality in the cross-sectional model. Worsening anxiety (B = 0.14) and fatigue (B = 0.20) were associated with worsening sleep disturbance, and more severe sleep disturbance 10 months after diagnosis (B = -0.21) was associated with improvement in sleep quality after diagnosis (P < 0.05). No evidence of latent subgroups of patients (heterogeneity) was present. Pain, anxiety, fatigue, employment, and comorbid conditions were associated with sleep disturbance, but regression coefficients were small (< |2.5|). Results suggest that screening for anxiety, depression, fatigue, or pain is not sufficient for identifying sleep disturbance. Given the negative consequences of sleep disturbance, sleep disturbance screening may be warranted.


Monitoring equity in vaccination coverage: A systematic analysis of demographic and health surveys from 45 Gavi-supported countries.
(1) To conduct a systematic analysis of inequalities in childhood vaccination coverage in Gavi-supported countries; (2) to comparatively assess alternative measurement approaches and how they may affect cross-country comparisons of the level of inequalities. Using the most recent Demographic and Health Surveys (2005-2014) in 45 Gavi-supported countries, we measured inequalities in vaccination coverage across seven dimensions of social stratification and of vulnerability to poor health outcomes. We quantified inequalities using pairwise comparisons (risk differences and ratios) and whole spectrum measures (slope and relative indices of inequality). To contrast measurement approaches, we pooled the estimates using random-effects meta-analyses, ranked countries by the magnitude of inequality and compared agreement in country ranks. At the aggregate level, maternal education, multidimensional poverty, and wealth index poverty were the dimensions associated with the largest inequalities. In 36 out of 45 countries, inequalities were substantial, with a difference in coverage of 10 percentage points or more between the top and bottom of at least one of these social dimensions. Important inequalities by child sex, child malnutrition and urban/rural residence were also found in a smaller set of countries. The magnitude of inequality and ranking of countries differed across dimension and depending on the measure used. Pairwise comparisons could not be estimated in certain countries. The slope and relative indices of inequality were estimated in all countries and produced more stable country rankings, and should thus facilitate more reliable international comparisons. Inequalities in vaccination coverage persist in a large majority of Gavi-supported countries. Inequalities should be monitored across multiple dimensions of vulnerability. Using whole spectrum measures to quantify inequality across multiple ordered social groups has important advantages. We illustrate these findings using an equity dashboard designed to support decision-making in the Sustainable Development Goals period.


Multicenter interrater and intrarater reliability in the endoscopic evaluation of velopharyngeal insufficiency.
To explore interrater and intrarater reliability (R (inter) and R (intra), respectively) of a standardized scale applied to nasoendoscopic assessment of velopharyngeal (VP) function, across multiple centers. Multicenter blinded R (inter) and R (intra) study. Eight academic tertiary care centers. Sixteen otolaryngologists from 8 centers. Raters estimated lateral pharyngeal and palatal movement on nasoendoscopic tapes from 50 different patients. Raters were asked to (1) estimate gap size during phonation and (2) note the presence of the Passavant ridge, a midline palatal notch on the nasal surface of the soft palate, and aberrant pulsations. Primary outcome measures were R (inter) and R (intra) coefficients for estimated gap size, lateral wall, and palatal movement; kappa coefficients for the Passavant ridge, a midline palatal notch on the nasal soft palate, and aberrant pulsations were also calculated. The R (inter) coefficients were 0.63 for estimated gap size, 0.41 for lateral wall movement, and 0.43 for palate movement; corresponding R (intra) coefficients were 0.86, 0.79, and 0.83, respectively. Interrater kappa values for qualitative features were 0.10 for the Passavant ridge; 0.48 for a notch on the nasal surface of the soft palate, 0.56 for aberrant pulsations, and 0.39 for estimation of gap size. In these data, there was good R (intra) and fair R (inter) when using the Golding-Kushner scale for rating VP function based on nasoendoscopy. Estimates of VP gap size demonstrate higher reliability coefficients than total lateral wall, mean palate estimates, and categorical estimate of gap size. The reliability of rating qualitative characteristics (ie, the presence of the Passavant ridge, aberrant pulsations, and notch on the nasal surface of the soft palate) is variable.


Learning from Japan: strengthening US emergency care and disaster response.
As Hurricane Katrina demonstrated in 2005, US health response systems for disasters-typically designed to handle only short-term mass-casualty events-are inadequately prepared for disasters that result in large-scale population displacements. Similarly, after the 2011 Great East Japan Earthquake, Japan found that many of its disaster shelters failed to meet international standards for long-term provision of basic needs and health care for the vulnerable populations that sought refuge in the shelters. Hospital disaster plans had not been tested and turned out to be inadequate, and emergency communication equipment did not function. We make policy recommendations that aim to improve US responses to mass-displacement disasters based on Japan's 2011 experience. First, response systems must provide for the extended care of large populations of chronically ill and vulnerable people. Second, policies should ensure that shelters meet or exceed international standards for the provision of food, water, sanitation, and privacy. Third, hospital disaster plans should include redundant communication systems and sufficient emergency provisions for both staff and patients. Finally, there must be routine drills for responses to mass-displacement disasters so that areas needing improvement can be uncovered before an emergency occurs.


Meta-analysis of Exercise Training on Vascular Endothelial Function in Cancer Survivors.
Cancer and cardiovascular disease (CVD) are leading causes of morbidity and mortality in the United States. Vascular endothelial dysfunction, an important contributor in the development of CVD, improves with exercise training in patients with CVD. However, the role of regular exercise to improve vascular function in cancer survivors remains equivocal. We performed a meta-analysis to determine the effect of exercise training on vascular endothelial function in cancer survivors. We searched PubMed (1975 to 2016), EMBASE CINAHL (1937 to 2016), OVID MEDLINE (1948 to 2016), and Cochrane Central Registry of Controlled Trials (1991 to 2016) using search terms: vascular function, endothelial function, flow-mediated dilation [FMD], reactive hyperemia, exercise, and cancer. Studies selected were randomized controlled trials of exercise training on vascular endothelial function in cancer survivors. We calculated pooled effect sizes and performed a meta-analysis. We identified 4 randomized controlled trials (breast cancer, n=2; prostate cancer, n=2) measuring vascular endothelial function by FMD (n=3) or reactive hyperemia index (n=1), including 163 cancer survivors (exercise training, n=82; control, n=81). Aerobic exercise training improved vascular function (n=4 studies; standardized mean difference [95% CI]=0.65 [0.33, 0.96], I2=0%; FMD, weighted mean difference [WMD]=1.28 [0.22, 2.34], I2=23.2%) and peak exercise oxygen uptake (3 trials; WMD [95% CI]=2.22 [0.83, 3.61] mL/kg/min; I2=0%). Our findings indicate that exercise training improves vascular endothelial function and exercise capacity in breast and prostate cancer survivors.


Symptom-based case definitions for COVID-19: Time and geographical variations for detection at hospital admission among 260,000 patients.
Case definitions are used to guide clinical practice, surveillance and research protocols. However, how they identify COVID-19-hospitalised patients is not fully understood. We analysed the proportion of hospitalised patients with laboratory-confirmed COVID-19, in the ISARIC prospective cohort study database, meeting widely used case definitions. Patients were assessed using the Centers for Disease Control (CDC), European Centre for Disease Prevention and Control (ECDC), World Health Organization (WHO) and UK Health Security Agency (UKHSA) case definitions by age, region and time. Case fatality ratios (CFRs) and symptoms of those who did and who did not meet the case definitions were evaluated. Patients with incomplete data and non-laboratory-confirmed test result were excluded. A total of 263,218 of the patients (42%) in the ISARIC database were included. Most patients (90.4%) were from Europe and Central Asia. The proportions of patients meeting the case definitions were 56.8% (WHO), 74.4% (UKHSA), 81.6% (ECDC) and 82.3% (CDC). For each case definition, patients at the extremes of age distribution met the criteria less frequently than those aged 30 to 70 years; geographical and time variations were also observed. Estimated CFRs were similar for the patients who met the case definitions. However, when more patients did not meet the case definition, the CFR increased. The performance of case definitions might be different in different regions and may change over time. Similarly concerning is the fact that older patients often did not meet case definitions, risking delayed medical care. While epidemiologists must balance their analytics with field applicability, ongoing revision of case definitions is necessary to improve patient care through early diagnosis and limit potential nosocomial spread.


Clustering of antimicrobial resistance outbreaks across bacterial species in the intensive care unit.
There are frequent reports of intensive care unit (ICU) outbreaks due to transmission of particular antibiotic-resistant bacteria. Less is known about the burden of outbreaks of resistance due to horizontal transfer of mobile genetic elements between species. Moreover, the potential of existing statistical software as a preliminary means for detecting such events has never been assessed. This study uses a software package to determine the burden of species and resistance outbreaks in 2 adjacent ICUs and to look for evidence of clustering of resistance outbreaks consistent with interspecies transmission of resistance elements. A retrospective analysis of data from 2 adjacent 15-bed adult ICUs between 2002 and 2009 was undertaken. Detection of bacterial species-groups and resistance outbreaks was conducted using SaTScan and WHONet-SaTScan software. Resampling and permutation methods were applied to investigate temporal clustering of outbreaks. Outbreaks occurred for 69% of bacterial species-groups (18/26), and resistance outbreaks were detected against 63% of antibiotics (10/16). Resistance outbreaks against 7 of 10 antibiotics were observed in multiple species-groups simultaneously and there was evidence of inter-species-group dependence for 4 of 7 antibiotics; background temporal changes in resistance did not explain the temporal aggregation of outbreaks in 3 of 7 antibiotics. Species outbreaks occurred for the majority of bacteria commonly identified in the ICU. There was evidence for frequent temporal clustering of resistance outbreaks consistent with interspecies transmission of resistance elements. Wider application of outbreak detection software combined with targeted sequencing of bacterial genomes is needed to understand the contribution of interspecies gene transfer to resistance emergence.


The association between global health training and underserved care: early findings from two longstanding tracks.
Global health tracks (GHTs) improve knowledge and skills, but their impact on career plans is unclear. The objective of this analysis was to determine whether GHT participants are more likely to practice in underserved areas than nonparticipants. In this retrospective cohort study, using the 2009 American Medical Association Masterfile, we assessed the practice location of the 480 graduates from 1980--2008 of two family medicine residencies-Residency 1 and Residency 2. The outcomes of interest were the percentage of graduates in health professional shortage areas (HPSAs), medically underserved areas (MUAs), rural areas, areas of dense poverty, or any area of underservice. Thirty-seven percent of Residency 1 participants and 20% of nonparticipants practiced in HPSAs; 69% of Residency 2 participants and 55.5% of nonparticipants practiced in areas of dense poverty. All other combined and within-residency differences were not statistically significant. These findings neither confirm nor refute the results of prior surveys suggesting that global health training is associated with increased interest in underserved care. Studies involving more GHTs and complimentary methods are needed to more precisely elucidate the impact of this training.


Biologics or tofacitinib for people with rheumatoid arthritis naive to methotrexate: a systematic review and network meta-analysis.
Biologic disease-modifying anti-rheumatic drugs (biologics) are highly effective in treating rheumatoid arthritis (RA), however there are few head-to-head biologic comparison studies. We performed a systematic review, a standard meta-analysis and a network meta-analysis (NMA) to update the 2009 Cochrane Overview. This review is focused on the adults with RA who are naive to methotrexate (MTX) that is, receiving their first disease-modifying agent. To compare the benefits and harms of biologics (abatacept, adalimumab, anakinra, certolizumab pegol, etanercept, golimumab, infliximab, rituximab, tocilizumab) and small molecule tofacitinib versus comparator (methotrexate (MTX)/other DMARDs) in people with RA who are naive to methotrexate. In June 2015 we searched for randomized controlled trials (RCTs) in CENTRAL, MEDLINE and Embase; and trials registers. We used standard Cochrane methods. We calculated odds ratios (OR) and mean differences (MD) along with 95% confidence intervals (CI) for traditional meta-analyses and 95% credible intervals (CrI) using a Bayesian mixed treatment comparisons approach for network meta-analysis (NMA). We converted OR to risk ratios (RR) for ease of interpretation. We also present results in absolute measures as risk difference (RD) and number needed to treat for an additional beneficial or harmful outcome (NNTB/H). Nineteen RCTs with 6485 participants met inclusion criteria (including five studies from the original 2009 review), and data were available for four TNF biologics (adalimumab (six studies; 1851 participants), etanercept (three studies; 678 participants), golimumab (one study; 637 participants) and infliximab (seven studies; 1363 participants)) and two non-TNF biologics (abatacept (one study; 509 participants) and rituximab (one study; 748 participants)).Less than 50% of the studies were judged to be at low risk of bias for allocation sequence generation, allocation concealment and blinding, 21% were at low risk for selective reporting, 53% had low risk of bias for attrition and 89% had low risk of bias for major baseline imbalance. Three trials used biologic monotherapy, that is, without MTX. There were no trials with placebo-only comparators and no trials of tofacitinib. Trial duration ranged from 6 to 24 months. Half of the trials contained participants with early RA (less than two years' duration) and the other half included participants with established RA (2 to 10 years). Biologic + MTX versus active comparator (MTX (17 trials (6344 participants)/MTX + methylprednisolone 2 trials (141 participants))In traditional meta-analyses, there was moderate-quality evidence downgraded for inconsistency that biologics with MTX were associated with statistically significant and clinically meaningful benefit versus comparator as demonstrated by ACR50 (American College of Rheumatology scale) and RA remission rates. For ACR50, biologics with MTX showed a risk ratio (RR) of 1.40 (95% CI 1.30 to 1.49), absolute difference of 16% (95% CI 13% to 20%) and NNTB = 7 (95% CI 6 to 8). For RA remission rates, biologics with MTX showed a RR of 1.62 (95% CI 1.33 to 1.98), absolute difference of 15% (95% CI 11% to 19%) and NNTB = 5 (95% CI 6 to 7). Biologics with MTX were also associated with a statistically significant, but not clinically meaningful, benefit in physical function (moderate-quality evidence downgraded for inconsistency), with an improvement of HAQ scores of -0.10 (95% CI -0.16 to -0.04 on a 0 to 3 scale), absolute difference -3.3% (95% CI -5.3% to -1.3%) and NNTB = 4 (95% CI 2 to 15).We did not observe evidence of differences between biologics with MTX compared to MTX for radiographic progression (low-quality evidence, downgraded for imprecision and inconsistency) or serious adverse events (moderate-quality evidence, downgraded for imprecision). Based on low-quality evidence, results were inconclusive for withdrawals due to adverse events (RR of 1.32, but 95% confidence interval included possibility of important harm, 0.89 to 1.97). Results for cancer were also inconclusive (Peto OR 0.71, 95% CI 0.38 to 1.33) and downgraded to low-quality evidence for serious imprecision. Biologic without MTX versus active comparator (MTX 3 trials (866 participants)There was no evidence of statistically significant or clinically important differences for ACR50, HAQ, remission, (moderate-quality evidence for these benefits, downgraded for imprecision), withdrawals due to adverse events,and serious adverse events (low-quality evidence for these harms, downgraded for serious imprecision). All studies were for TNF biologic monotherapy and none for non-TNF biologic monotherapy. Radiographic progression was not measured. In MTX-naive RA participants, there was moderate-quality evidence that, compared with MTX alone, biologics with MTX was associated with absolute and relative clinically meaningful benefits in three of the efficacy outcomes (ACR50, HAQ scores, and RA remission rates). A benefit regarding less radiographic progression with biologics with MTX was not evident (low-quality evidence). We found moderate- to low-quality evidence that biologic therapy with MTX was not associated with any higher risk of serious adverse events compared with MTX, but results were inconclusive for withdrawals due to adverse events and cancer to 24 months.TNF biologic monotherapy did not differ statistically significantly or clinically meaningfully from MTX for any of the outcomes (moderate-quality evidence), and no data were available for non-TNF biologic monotherapy.We conclude that biologic with MTX use in MTX-naive populations is beneficial and that there is little/inconclusive evidence of harms. More data are needed for tofacitinib, radiographic progression and harms in this patient population to fully assess comparative efficacy and safety.


[Blood pressure variability and stimulation tests: value of the Stroop word color conflict test].
To study the modifications of the BP and its short-term variability in hypertensives patients submitted at to a psychological stress test. Fourty nine hypertensive subjects (27 women and 22 men, aged 46 +/- 9, SBP 164 +/- 10, DBP 97 +/- 6 mmHg after a 15 days placebo run-in period) were studied. We used the original version of Stroop Word Color Conflict Test (SWCCT) to induce mental stress. Haemodynamic parameters (SBP, DBP, MPB and HR) were measured continuously by a non invasive method (Finapres) with data acquisition every 0.5 second allowing spectral analysis of SBP variability at rest, during and after SWCCT (FFT algorithm on 256 point time series Anapres 1.2). All haemodynamic parameters increased during stress test (p = 0.001). The mean value and the variability (V) of SBP standard deviation (SD) increased during SWCCT (p = 0.001 and p = 0.003 respectively). Two minutes after the test, SPB returned to the rest level, while the overall variability of SPB remained elevated (p = 0.007). Spectral analysis: the total area under the curve and the mid frequency component (MFC) (66-128 mHz) increased during and after SWCCT (p = 0.001). [table: see text] Short-term variability of SBP is increased in hypertensives when submitted to a SWCCT appears to induce sustained orthosympathetic stimulation as suggested by the increase of mid frequency component (Mayer waves).


Longitudinal Stability of Genetic and Environmental Influences on the Association between Diurnal Preference and Sleep Quality in Young Adult Twins and Siblings.
Overlapping genetic influences have been implicated in diurnal preference and subjective sleep quality. Our overall aim was to examine overlapping concurrent and longitudinal genetic and environmental effects on diurnal preference and sleep quality over ~5 years. Behavioral genetic analyses were performed on data from the longitudinal British G1219 study of young adult twins and nontwin siblings. A total of 1556 twins and siblings provided data on diurnal preference (Morningness-Eveningness Questionnaire) and sleep quality (Pittsburgh Sleep Quality Index) at time 1 (mean age = 20.30 years, SD = 1.76; 62% female), and 862 participated at time 2 (mean age = 25.30 years, SD = 1.81; 66% female). Preference for eveningness was associated with poorer sleep quality at both time points (r = 0.25 [95% confidence intervals {CIs} = 0.20-0.30] and r = 0.21 [CI = 0.15-0.28]). There was substantial overlap in the genetic influences on diurnal preference and sleep quality individually, across time (genetic correlations [rAs]: 0.64 [95% CI = 0.59-0.67] and 0.48 [95% CI = 0.42-.053]). There were moderate genetic correlations between diurnal preference and sleep quality concurrently and longitudinally (rAs = 0.29-0.60). Nonshared environmental overlap was substantially smaller for all cross-phenotype associations (nonshared environmental correlations (rEs) = -0.02 to 0.08). All concurrent and longitudinal associations within and between phenotypes were largely accounted for by genetic factors (explaining between 60% and 100% of the associations). All shared environmental effects were nonsignificant. Nonshared environmental influences played a smaller role on the associations between phenotypes (explaining between -0.06% and 40% of the associations). These results suggest that to some extent, similar genes contribute to the stability of diurnal preference and sleep quality throughout young adulthood but also that different genes play a part over this relatively short time frame. While there was evidence of genetic overlap between phenotypes concurrently and longitudinally, the possible emergence of new genetic factors (or decline of previously associated factors) suggests that molecular genetic studies focusing on young adults should consider more tightly specified age groups, given that genetic effects may be time specific.


Familial transitional cell carcinoma.
Bladder cancer is a common malignancy, and a frequent cause of urological consultation and surgical intervention. Except for smoking and certain occupational exposures, the etiology of bladder cancer is largely unknown. Although the majority of patients with bladder cancer do not have a family history of transitional cell carcinoma of the urinary tract, the study of familial transitional cell carcinoma may lead to knowledge of the pathogenesis of this disease. To evaluate the current understanding of familial transitional cell carcinoma, we reviewed the contemporary literature for case reports and epidemiological studies about this disease. Numerous case reports document the clustering of transitional cell carcinoma in families, several of which demonstrate an extremely early age at onset of disease, which argues in favor of a genetic component to familial transitional cell carcinoma. The results of large epidemiological studies also suggest the existence of familial transitional cell carcinoma, and first degree relatives appear to have an increased risk for disease by a factor of 2. Familial clustering of smoking does not appear to be the cause of this increased risk. Familial transitional cell carcinoma may be the result of a genetically transmitted predisposition to disease, at least in some affected families. Further studies are required to identify candidate genes that may be responsible for this form of bladder cancer.


Local dendritic activity sets release probability at hippocampal synapses.
The arrival of an action potential at a synapse triggers neurotransmitter release with a limited probability, p(r). Although p(r) is a fundamental parameter in defining synaptic efficacy, it is not uniform across all synapses, and the mechanisms by which a given synapse sets its basal release probability are unknown. By measuring p(r) at single presynaptic terminals in connected pairs of hippocampal neurons, we show that neighboring synapses on the same dendritic branch have very similar release probabilities, and p(r) is negatively correlated with the number of synapses on the branch. Increasing dendritic depolarization elicits a homeostatic decrease in p(r), and equalizing activity in the dendrite significantly reduces its variability. Our results indicate that local dendritic activity is the major determinant of basal release probability, and we suggest that this feedback regulation might be required to maintain synapses in their operational range.


Long-term outcome of vagus nerve stimulation therapy after failed epilepsy surgery.
Adequate control of intractable epilepsy continues to be a challenge. Little is known about the role of VNS therapy in intractable epilepsy in patients who failed to respond to surgical management. The objective of the present study is to determine the efficacy of vagus nerve stimulation therapy in patients with intractable epilepsy who have failed surgical and medical therapy. All the patients who had persistent seizures after cranial surgery who subsequently underwent vagus nerve stimulator (VNS) placement at our institution from 1998 to 2008 were included in the study. Thirty-seven consecutive patients were enrolled and followed for the outcome measures of seizure burden, anti-epileptic drug (AED) burden and quality of life (QoL). Minimum follow-up was 18 months. Overall, 24 (64.9%), 9 (24.3%), 4 (10.8%) patients reported less than 30%, between 30% and 60% and greater than 60% reduction in seizure frequency after VNS placement, respectively at a mean of 5 years follow-up period. Post-VNS anti-epileptic requirement exhibited a decreasing trend. 17 patients (45.9%) report an improvement in QoL (better or much better). VNS therapy in patients who have failed medical and surgical therapies only provides marginal improvement in seizure control but has greater likelihood to improve subjective QoL issues. In addition, VNS has the potential to reduce AED burden without adversely impacting seizure management. Given the low surgical risk of VNS placement, vagus nerve stimulation as a therapeutic modality should be individualized to achieve best clinical response and fewest side effects.


Concomitant Acute Hepatic Failure and Renal Failure Induced by Intravenous Amiodarone: A Case Report and Literature Review.
Hepatotoxicity caused by chronic oral amiodarone is well documented with around 15-20% incidence rate. However, acute liver failure due to intravenous (IV) amiodarone is rare clinical presentation with 3% incidence rate. Incidence of concomitant renal failure is even rarer. There is no full explanation for the underlying mechanism. Herein, we are presenting a rare case of concomitant acute hepatic failure and acute-on-chronic renal injury induced by use of IV amiodarone. A 67-year-old man with past medical history of coronary artery disease s/p coronary artery bypass graft (CABG), history of alcoholism, and chronic kidney disease stage 3 presented with chest pain for 1 week. In the emergency department (ED), he was found to have atrial flutter. Due to unresponsiveness to IV β-blocker and diltiazem, the patient was loaded with IV amiodarone and continued IV amiodarone drip. His liver function tests (LFTs) and renal functions at the time of administration of IV amiodarone were aspartate transaminase (AST) 176 (10 - 42 IU/L) and alanine transaminase (ALT) 208 (10 - 60 IU/L), international normalized ratio (INR) 1.39 (reference value 2 - 3), blood urea nitrogen (BUN) 37 (5 - 25 mg/dL), and creatinine 1.85. Sixteen hours later patient developed acute hepatic failure with AST 4,250 (reference value 10 - 42 IU/L), ALT 2,422 (10 - 60 IU/L), INR 2.28, and acute renal failure with creatinine of 3.2 mg/dL (0.44 - 1.0 mg/dL), and BUN of 44 mg/d (5 - 25 mg/dL). Patient was intubated due to acute hepatic encephalopathy and sent to intensive care unit (ICU). IV amiodarone was stopped immediately. All workup for other causes of acute hepatic failure came back negative. He was started on IV N-acetylcysteine and required hemodialysis for acute-on-chronic renal failure. LFTs peaked 72 h after discontinuation of amiodarone. Kidney functions started to improve 5 days after discontinuation of amiodarone and patient came off hemodialysis. Acute hepatic failure as result of IV amiodarone is a rare presentation; however, it has a high mortality. Risk factors include low ejection fraction, hepatic congestion and pre-existing hepatic dysfunction. No obvious underlying mechanism to this presentation has been fully explained. Acute renal failure can be associated with this presentation which is even rarer. Stopping IV amiodarone, administering N-acetylcysteine and good supportive care can lead to favorable outcome.


Non-cultured cell transplantation in an ovine model of non-ischemic heart failure.
Cell therapy may be a promising alternative or adjunct to current treatment modalities for ischemic heart failure. But little is known on the impact of myogenic cell transplantation in large animal models of non-ischemic cardiomyopathy. The aim of the present study was to explore whether an ovine model of toxin-induced heart disease could benefit from non-cultured skeletal muscle cell transplantation. Sequential intracoronary injections of doxorubicin (0.75 mg/kg) were carried out every 2 weeks until echocardiographic detection of myocardial dysfunction. Sheep were then randomly assigned to either non-cultured cell transplantation (n=8) or placebo injection (n=5). For the cell therapy group, a skeletal muscle biopsy (about 10 g) was explanted from each animal approximately 3h before grafting. After thoracotomy, 20 epicardial injections were carried out. The animals were assessed one last time before sacrifice, 2 months after the thoracotomy. Cells were tracked with cmDiI (red fluorescence) and characterized with immunohistochemistry with monoclonal antibodies to a fast skeletal isoform of myosin heavy chain. Two months after intramyocardial grafting, tissue Doppler imaging and conventional echocardiographic assessment of the groups showed a marked improvement in the non-cultured cell therapy group. Ejection fraction (EF) (p<0.05) as well as systolic endocardial velocities (p<0.01) improved versus the placebo group. CmDiI and skeletal myosin heavy chain expression was detected in all animals at 2 months after implantation confirming engraftment of skeletal muscle cells. In conclusion, our data indicate that non-cultured muscle cell transplantation is feasible and may translate into a functional benefit in an ovine model of dilated heart failure.


Desulfinylation of prop-2-enesulfinic acid: experimental results and mechanistic theoretical analysis.
The potential energy surfaces of the desulfinylation of prop-2-enesulfinic acid (13) in CH(2)Cl(2) solution at -15 degrees C have been explored by quantum calculations and analyzed with kinetic data obtained for the reaction in absence or presence of additives. Monomeric 13 adopts a preferred conformation with gauche S=O/sigma(C(1)-C(2) bond pairs and the O-H bond pointing toward C(3). It equilibrates with the more stable dimer (13)(2) (at -15 degrees C) formed by two O-H...O=S hydrogen bonds and in which the S=O/sigmaC(1)-C(2) are gauche also, but the SOH moieties are antiperiplanar with respect to sigma(C(1)-C(2)). Dimer (13)(2) undergoes desulfinylation into propene + SO(2) + 13 following a one-step, concerted mechanism. The preferred transition state is a six-membered, chairlike transition structure (C...S elongation and S-O...H...C(3) hydrogen transfer occur in concert) in which the S=O/sigma(C(1)-C(2)) bonds are gauche (S=O adopt pseudoaxial positions). There are at least 48 transition states, each one defining a different pathway, all with similar calculated free energies (DeltaG(double dagger) = 25.3-28.6 kcal/mol), which makes the bimolecular (autocatalyzed) retro-ene elimination of SO(2) competing (entropy factor) with a monomolecular process for which the transition state (calculated DeltaG(double dagger) = 24.3 kcal/mol) implies only one molecule of sulfinic acid. This agrees with the experimental rate law of the reaction which is first order in the concentration of dimer (13)(2). SO(2), CF(3)COOH, and BF(3) x Me(2)O do not catalyze the reaction. In the presence of an excess of BF(3) x Me(2)O the desulfinylation is completely inhibited due to the formation of a stable tetramolecular complex of type (CH(2)=CHCH(2)SO(2)H x BF(3))(2) (18), for which quantum calculations show that the S=O/sigma(C(1)-C(2)) bonds are antiperiplanar whereas the S-OH/sigma(C(1)-C(2)) bonds are gauche. Independently of the additive, the retro-ene eliminations of SO(2) are calculated to be concerted and have transition states adopting six-membered cyclic structures in which S=O and sigma(C(1)-C(2)) are gauche, the S=O interacting with the additive. Preliminary experiments suggested that the thermodynamically unfavored ene reaction of SO(2) with propene can occur at low temperature using 1 equiv of BF(3).


Cardiac troponin T and NT-proBNP as diagnostic and prognostic biomarkers of primary cardiac involvement and disease severity in systemic sclerosis: A prospective study.
The aim of our study was to define the role of high-sensitive cardiac troponin T (hs-cTnT) and NT-proBNP in identifying Systemic Sclerosis (SSc) patients with cardiac involvement and at higher risk of cardiac death. Plasma hs-cTnT and NT-proBNP concentrations were measured in 245 SSc-patients. hs-cTnT and NT-proBNP levels were higher in SSc-patients than in healthy controls. Hs-cTnT levels were higher than 0.014 ng/ml in 32.3% SSc-patients, while NT-proBNP was above 125 pg/ml in 31.8% of them, irrespective of classical cardiovascular risk factor and of pulmonary arterial hypertension. Elevated hs-cTnT and NT-proBNP were associated with diffuse skin involvement and directly correlated with the skin score. Patients with increased cardiac markers presented a lower left-ventricular ejection fraction (LVEF) and a higher rate of right bundle branch block (RBBB) on electrocardiogram (ECG) compared to patients with normal cardiac enzymes. During the follow-up, 12 SSc-patients experience a disease-related death; 9 of these were directly related to cardiac involvement (sudden cardiac death or heart failure) and the majority of them occurred among patients with increase of at least one cardiac biomarker. Long-term survival was worse in patients with increase of both cardiac biomarkers. Evaluation of hs-cTnT and NT-proBNP levels may provide a tool to screen non-invasively SSc-patients for heart involvement. A higher incidence of impaired systolic function, ECG abnormalities and a poor outcome in SSc-patients with elevated cardiac enzymes suggests that they may be valuable screening biomarkers to detect a cardiac damage at early stages and to improve risk stratification.


Identification and analysis of conserved cis-regulatory regions of the MEIS1 gene.
Meis1, a conserved transcription factor of the TALE-homeodomain class, is expressed in a wide variety of tissues during development. Its complex expression pattern is likely to be controlled by an equally complex regulatory landscape. Here we have scanned the Meis1 locus for regulatory elements and found 13 non-coding regions, highly conserved between humans and teleost fishes, that have enhancer activity in stable transgenic zebrafish lines. All these regions are syntenic in most vertebrates. The composite expression of all these enhancer elements recapitulate most of Meis1 expression during early embryogenesis, indicating they comprise a basic set of regulatory elements of the Meis1 gene. Using bioinformatic tools, we identify a number of potential binding sites for transcription factors that are compatible with the regulation of these enhancers. Specifically, HHc2:066650, which is expressed in the developing retina and optic tectum, harbors several predicted Pax6 sites. Biochemical, functional and transgenic assays indicate that pax6 genes directly regulate HHc2:066650 activity.


Magnetic resonance imaging of normal canine carpal ligaments.
Magnetic resonance imaging was conducted on previously frozen left carpi from six normal dogs using a 1.5 Tesla magnet in combination with a transmit/receive wrist coil. Three-millimeter thick T1-weighted spin-echo images and 1-mm thick T2*-weighted gradient-recalled 3-D images were obtained in dorsal and sagittal planes. Carpi were embedded, sectioned, and stained. Anatomic structures on the histologic sections were correlated with the MR images. All of the carpal ligaments plus the radioulnar articular disc and the palmar fibrocartilage were identified on MR images. The accessorio-quartile ligament, which had not been well described previously in dogs, was also identified. It originated on the accessory carpal bone and inserted on the fourth carpal bone. The T2*-weighted gradient echo imaging technique provided better images than T1-weighted technique, largely because thinner slices were possible (1 mm vs. 3 mm), resulting in less volume averaging of thin ligaments with surrounding structures. Although MRI is currently the imaging modality of choice to identify ligamentous injury in humans, further studies are needed to determine if abnormalities can be detected in canine carpal ligaments using MRI.


Psychophysiological effects of breathing instructions for stress management.
Stressed and tense individuals often are recommended to change the way they breathe. However, psychophysiological effects of breathing instructions on respiration are rarely measured. We tested the immediate effects of short and simple breathing instructions in 13 people seeking treatment for panic disorder, 15 people complaining of daily tension, and 15 controls. Participants underwent a 3-hour laboratory session during which instructions to direct attention to breathing and anti-hyperventilation instructions to breathe more slowly, shallowly, or both were given. Respiratory, cardiac, and electrodermal measures were recorded. The anti-hyperventilation instructions failed to raise end-tidal pCO(2) above initial baseline levels for any of the groups because changes in respiratory rate were compensated for by changes in tidal volume and vice versa. Paying attention to breathing significantly reduced respiratory rate and decreased tidal volume instability compared to the other instructions. Shallow breathing made all groups more anxious than did other instructions. Heart rate and skin conductance were not differentially affected by instructions. We conclude that simple and short instructions to alter breathing do not change respiratory or autonomic measures in the direction of relaxation, except for attention to breathing, which increases respiratory stability. To understand the results of breathing instructions for stress and anxiety management, respiration needs to be monitored physiologically.


Nationwide survey of refractory asthma with bronchiectasis by inflammatory subtypes.
Bronchiectasis and bronchiolitis are differential diagnoses of asthma; moreover, they are factors associated with worse asthma control. We determined clinical courses of bronchiectasis/bronchiolitis-complicated asthma by inflammatory subtypes as well as factors affecting them. We conducted a survey of refractory asthma with non-cystic fibrosis bronchiectasis/bronchiolitis in Japan. Cases were classified into three groups, based on the latest fractional exhaled NO (FeNO) level (32 ppb for the threshold) and blood eosinophil counts (320/µL for the threshold): high (type 2-high) or low (type 2-low) FeNO and eosinophil and high FeNO or eosinophil (type 2-intermediate). Clinical courses in groups and factors affecting them were analysed. In total, 216 cases from 81 facilities were reported, and 142 were stratified: 34, 40 and 68 into the type 2-high, -intermediate and -low groups, respectively. The frequency of bronchopneumonia and exacerbations requiring antibiotics and gram-negative bacteria detection rates were highest in the type 2-low group. Eighty-seven cases had paired latest and oldest available data of FeNO and eosinophil counts; they were analysed for inflammatory transition patterns. Among former type 2-high and -intermediate groups, 32% had recently transitioned to the -low group, to which relatively low FeNO in the past and oral corticosteroid use contributed. Lastly, in cases treated with moderate to high doses of inhaled corticosteroids, the frequencies of exacerbations requiring antibiotics were found to be higher in cases with more severe airway lesions and lower FeNO. Bronchiectasis/bronchiolitis-complicated refractory asthma is heterogeneous. In patients with sputum symptoms and low FeNO, airway colonisation of pathogenic bacteria and infectious episodes are common; thus, corticosteroids should be carefully used.


Soliton propagation through a disordered system: statistics of the transmission delay.
We have studied the soliton propagation through a segment containing random pointlike scatterers. In the limit of small concentration of scatterers when the mean distance between the scatterers is larger than the soliton width, a method has been developed for obtaining the statistical characteristics of the soliton transmission through the segment. The method is applicable for any classical particle traversing through a disordered segment with the given velocity transformation after each act of scattering. In the case of weak scattering and relatively short disordered segment the transmission time delay of a fast soliton is mostly determined by the shifts of the soliton center after each act of scattering. For sufficiently long segments the main contribution to the delay is due to the shifts of the amplitude and velocity of a fast soliton after each scatterer. Corresponding crossover lengths for both cases of light and heavy solitons have been obtained. We have also calculated the exact probability density function of the soliton transmission time delay for a sufficiently long segment. In the case of weak identical scatterers the latter is a universal function which depends on a sole parameter--the mean number of scatterers in a segment.


Is it always possible to determine a diagnosis? Prenatal ultrasonography, post mortem magnetic resonance, autopsy.
Pathological-anatomical autopsy is the gold standard for determining of foetal abnormalities, but in some cases its role is limited (pathology of central nervous system, in particular, in case of ventricular dilatation or developed autolysis). In pathology of central nervous system, where insufficiency of autopsy can occur, additional post mortem magnetic resonance imaging (MRI) is performed to determine type of malformation. In this case report, we would like to point out the fact that although all investigating methods including post mortem magnetic resonance and autopsy (incl. imunohistochemical tests) are used, this need not necessarily result in a clear diagnostic conclusion of the aborted foetus. Post mortem MRI visualized pathology: dilatation of both lateral ventricals, more in the left and, above all, a pathological focus parasagittaly on the right with haemorrhage and cystic component; it raised a suspicion on ependymoma. However imunohistochemical test did not give an unambiguous conclusion; therefore diagnosis based on MRI could not be uniquely verified.


Impaired vascular mechanotransduction in a transgenic mouse model of CADASIL arteriopathy.
CADASIL is an inherited small-vessel disease responsible for lacunar strokes and cognitive impairment. The disease is caused by highly stereotyped mutations in Notch3, the expression of which is highly restricted to vascular smooth muscle cells (VSMCs). The underlying vasculopathy is characterized by degeneration of VSMCs and the accumulation of granular osmiophilic material (GOM) and Notch3 protein within the cell surface of these cells. In this study, we assessed early functional changes related to the expression of mutant Notch3 in resistance arteries. Vasomotor function was examined in vitro in arteries from transgenic mice that express a mutant Notch3 in VSMC. Tail artery segments from transgenic and normal wild-type male mice were mounted on small-vessel arteriographs, and reactivity to mechanical (flow and pressure) forces and pharmacological stimuli were determined. Mice were studied at 10 to 11 months of age when VSMC degeneration, GOM deposits, and Notch3 accumulation were not yet present. Passive arterial diameter, contraction to phenylephrine, and endothelium-dependent relaxation to acetylcholine were unaffected in transgenic mice. By contrast, flow-induced dilation was significantly decreased and pressure-induced myogenic tone significantly increased in arteries from transgenic mice compared with wild-type mice. This is the first study to our knowledge providing evidence that mutant Notch3 impairs selectively the response of resistance arteries to flow and pressure. The data suggest an early role of vascular dysfunction in the pathogenic process of the disease.


Automated segmentation of retinal blood vessels in spectral domain optical coherence tomography scans.
The correct segmentation of blood vessels in optical coherence tomography (OCT) images may be an important requirement for the analysis of intra-retinal layer thickness in human retinal diseases. We developed a shape model based procedure for the automatic segmentation of retinal blood vessels in spectral domain (SD)-OCT scans acquired with the Spectralis OCT system. The segmentation procedure is based on a statistical shape model that has been created through manual segmentation of vessels in a training phase. The actual segmentation procedure is performed after the approximate vessel position has been defined by a shadowgraph that assigns the lateral vessel positions. The active shape model method is subsequently used to segment blood vessel contours in axial direction. The automated segmentation results were validated against the manual segmentation of the same vessels by three expert readers. Manual and automated segmentations of 168 blood vessels from 34 B-scans were analyzed with respect to the deviations in the mean Euclidean distance and surface area. The mean Euclidean distance between the automatically and manually segmented contours (on average 4.0 pixels respectively 20 µm against all three experts) was within the range of the manually marked contours among the three readers (approximately 3.8 pixels respectively 18 µm for all experts). The area deviations between the automated and manual segmentation also lie within the range of the area deviations among the 3 clinical experts. Intra reader variability for the experts was between 0.9 and 0.94. We conclude that the automated segmentation approach is able to segment blood vessels with comparable accuracy as expert readers and will provide a useful tool in vessel analysis of whole C-scans, and in particular in multicenter trials.


Prevalence, management, and outcomes of critically ill patients with prothrombin time prolongation in United Kingdom intensive care units.
Coagulopathy occurs frequently in critically ill patients, but its epidemiology, current treatment, and relation to patient outcome are poorly understood. We described the prevalence, risk factors, and treatment of prolongation of the prothrombin time in critically ill patients using the international normalized ratio to standardize data and explored its association with intensive care unit survival. Prospective multiple center observational cohort study. Twenty-nine adult intensive care units in the United Kingdom. All sequentially admitted patients over an 8-wk period. None. Prospective daily data were collected concerning prevalence, predefined risk factors, and treatment of coagulopathy throughout intensive care unit admission. Of 1923 intensive care unit admissions, 30% developed abnormal international normalized ratio values (defined as an international normalized ratio > 1.5). Most international normalized ratio abnormalities were minor and short-lived (73% of worst international normalized ratio values 1.6-2.5). Male sex, chronic liver disease, sepsis, warfarin therapy, increments in Acute Physiology and Chronic Health Evaluation II score, severity of renal and hepatic dysfunction, and red cell transfusions were all independent risk factors for international normalized ratio abnormalities (all p < .001). In all regression models, there was a strong independent association between abnormal international normalized ratio values and greater intensive care unit mortality (p < .0001), particularly when international normalized ratio increased after intensive care unit admission. Among patients with abnormal international normalized ratios, 33% received fresh-frozen plasma transfusions during their intensive care unit stay, but the pretransfusion international normalized ratio value varied widely. Fifty-one percent of fresh-frozen plasma treatments were to nonbleeding patients and 40% to nonbleeding patients whose international normalized ratio was normal or only modestly deranged (≤ 2.5). The dose of fresh-frozen plasma administered was highly variable (median dose 10.8 mL/kg (first, third quartile 7.2, 14.4; range, 2.4-41.1 mL/kg). Prothrombin time prolongation is prevalent in critically ill patients and is independently associated with greater intensive care unit mortality. Wide variation in fresh-frozen plasma treatment exists suggesting clinical uncertainty regarding best practice, particularly as a prophylactic treatment.


A multicenter total therapy strategy for de novo adult Philadelphia chromosome positive acute lymphoblastic leukemia patients: final results of the GIMEMA LAL1509 protocol.
The GIMEMA LAL1509 protocol, designed for adult (≥18-60 years) de novo Ph+ acute lymphoblastic leukemia patients, was based on a dasatinib plus steroids induction - with central nervous system prophylaxis - followed by dasatinib alone in patients in complete molecular response or chemotherapy and/or allogeneic transplantation in patients not reaching a complete molecular response. Sixty patients (median age 41.9 years) were enrolled: 33 were p190+, 18 p210+ and 9 p190/p210+. At the end of induction (day +85), 58 patients (97%) achieved a complete hematologic remission. No deaths in induction were recorded. Eleven patients (18.3%) obtained a complete molecular response. Among non-complete molecular responders (n=47), 22 underwent an allogeneic transplant. Seventeen hematologic relapses occurred (median 7 months, range 3-40.1), 13 during consolidation and 4 post-transplant. ABL1 mutations (5 T315I, 3 V299L, 1 E281K and 1 G254E) were found in 10/13 relapsed cases. With a median follow-up of 57.4 months (range: 4.2-75.6), overall survival and disease-free survival are 56.3% and 47.2%. A better diseasefree survival was observed in patients who obtained a molecular response at day +85 compared to cases who did not. The presence of additional copy number aberrations - IKZF1 plus CDKN2A/B and/or PAX5 deletions - was the most important unfavorable prognostic factor on overall and disease-free survival (p=0.005 and p=0.0008). This study shows that in adult Ph+ ALL long-term survivals can be achieved with a total-therapy strategy based on a chemo-free induction and, in complete molecular responders, also without further systemic chemotherapy. Finally, the screening of additional copy number aberrations should be included in the diagnostic work-up. EudraCT 2010-019119-39.


Merits of different anatomical landmarks for correct numbering of the lumbar vertebrae in lumbosacral transitional anomalies.
Anatomical landmarks and their relation to the lumbar vertebrae are well described in subjects with normal spine anatomy, but not for subjects with lumbosacral transitional vertebra (LSTV), in whom correct numbering of the vertebrae is challenging and can lead to wrong-level treatment. The aim of this study was to quantify the value of different anatomical landmarks for correct identification of the lumbar vertebra level in subjects with LSTV. After IRB approval, 71 subjects (57 ± 17 years) with and 62 without LSTV (57 ± 17 years), all with imaging studies that allowed correct numbering of the lumbar vertebrae by counting down from C2 (n = 118) or T1 (n = 15) were included. Commonly used anatomical landmarks (ribs, aortic bifurcation (AB), right renal artery (RRA) and iliac crest height) were documented to determine the ability to correctly number the lumbar vertebrae. Further, a tangent to the top of the iliac crests was drawn on coronal MRI images by two blinded, independent readers and named the 'iliac crest tangent sign'. The sensitivity, specificity and the interreader agreement were calculated. While the level of the AB and the RRA were found to be unreliable in correct numbering of the lumbar vertebrae in LSTV subjects, the iliac crest tangent sign had a sensitivity and specificity of 81 % and 64-88 %, respectively, with an interreader agreement of k = 0.75. While anatomical landmarks are not always reliable, the 'iliac crest tangent sign' can be used without advanced knowledge in MRI to most accurately number the vertebrae in subjects with LSTV, if only a lumbar spine MRI is available.


Molecular and immunological significance of chimpanzee major histocompatibility complex haplotypes for hepatitis C virus immune response and vaccination studies.
The chimpanzee is a critical animal model for studying cellular immune responses to infectious pathogens such as hepatitis B and C viruses, human immunodeficiency virus, and malaria. Several candidate vaccines and immunotherapies for these infections aim at the induction or enhancement of cellular immune responses against viral epitopes presented by common human major histocompatibility complex (MHC) alleles. To identify and characterize chimpanzee MHC class I molecules that are functionally related to human alleles, we sequenced 18 different Pan troglodytes (Patr) alleles of 14 chimpanzees, 2 of them previously unknown and 3 with only partially reported sequences. Comparative analysis of Patr binding pockets and binding assays with biotinylated peptides demonstrated a molecular homology between the binding grooves of individual Patr alleles and the common human alleles HLA-A1, -A2, -A3, and -B7. Using cytotoxic T cells isolated from the blood of hepatitis C virus (HCV)-infected chimpanzees, we then mapped the Patr restriction of these HCV peptides and demonstrated functional homology between the Patr-HLA orthologues in cytotoxicity and gamma interferon (IFN-gamma) release assays. Based on these results, 21 HCV epitopes were selected to characterize the chimpanzees' cellular immune response to HCV. In each case, IFN-gamma-producing T cells were detectable in the blood after but not prior to HCV infection and were specifically targeted against those HCV peptides predicted by Patr-HLA homology. This study demonstrates a close functional homology between individual Patr and HLA alleles and shows that HCV infection generates HCV peptides that are recognized by both chimpanzees and humans with Patr and HLA orthologues. These results are relevant for the design and evaluation of vaccines in chimpanzees that can now be selected according to the most frequent human MHC haplotypes.


Renal vascular reactivity in the young spontaneously hypertensive rat.
The renal resistance vessels of the mature spontaneously hypertensive rat (SHR) exhibit increased reactivity to vasoconstrictor agonists. This could be a cause or consequence of hypertension. We have compared vascular reactivity in isolated perfused kidneys from 46-day-old SHR and from normotensive control rats. The amplitude of responses in kidneys from the SHR to angiotensin II, barium chloride, or norepinephrine was not different from the control. Therefore, increased reactivity of the renal vascular smooth muscle cannot be an early pathogenic mechanism in spontaneous hypertension. Responses evoked by 5-hydroxytryptamine (serotonin) were of a greater amplitude in the SHR than in the control kidney. However, this difference was due to an interaction of serotonin with the sympathetic nerves, as it was abolished by treatment of the rats with 6-hydroxydopamine. Responses induced by electrical stimulation of the renal sympathetic nerves were also of greater amplitude in SHR than in control kidneys, both before and after the blockade of norepinephrine disposition mechanisms. Nerve stimulation evoked a greater efflux of endogenous norepinephrine from kidneys of the SHR than from those of control rats. Thus, the increased reactivity of the SHR kidney to renal nerve stimulation is due to an augmented release of endogenous norepinephrine. This could be an important factor in the early development of hypertension.


Are new neurons formed in the brains of adult mammals?
In an autoradiographic investigation, the production of brain lesions in rats was combined with intracranial injection of thymidine-H(3). Nuclei of numerous glia cells were found labeled in brain regions associated with the traumatized areas. In addition, some neurons and neuroblasts showed labeling, suggesting the possibility of proliferation of neurons in adult rats.


What about healthy participants? The improvement and deterioration of self-reported health at a 10-year follow-up of the Västerbotten Intervention Programme.
The Västerbotten Intervention Programme (VIP) addresses cardiovascular disease and diabetes in the middle-aged population of Västerbotten County, Sweden. Self-reported health (SRH) is one of the risk factors for both conditions. The aim of this study was to analyse the development patterns of SRH among the VIP participants. Cross-sectional data from 1990 to 2007 were used to analyse the prevalence of poor SRH among 101,396 VIP participants aged 40-60 years. Panel data were used to study the change in SRH among 25,695 persons aged 30-60 years, who participated in the VIP twice within a 10-year interval. Prevalence of poor SRH fluctuated between 1990 and 2007 in Västerbotten County. There was a temporary decline around 2000, with SRH continuously improving thereafter. The majority of panel participants remained in good SRH; over half of those with poor or fair SRH at baseline reported better SRH at follow-up. SRH declined in 19% of the panel participants, mostly among those who had good SRH at the baseline. The decline was common among both women and men, in all educational, age and marital status groups. The SRH improvement among those with poor and fair SRH at baseline suggests that VIP has been successful in addressing its target population. However, the deterioration of SRH among 21% of the individuals with good SRH at baseline is of concern. From a public health perspective, it is important for health interventions to address not only the risk group but also those with a healthy profile to prevent the negative development among the seemingly healthy participants.


Application of Nanoparticles and Nanomaterials in Thermal Ablation Therapy of Cancer.
Cancer is one of the major health issues with increasing incidence worldwide. In spite of the existing conventional cancer treatment techniques, the cases of cancer diagnosis and death rates are rising year by year. Thus, new approaches are required to advance the traditional ways of cancer therapy. Currently, nanomedicine, employing nanoparticles and nanocomposites, offers great promise and new opportunities to increase the efficacy of cancer treatment in combination with thermal therapy. Nanomaterials can generate and specifically enhance the heating capacity at the tumor region due to optical and magnetic properties. The mentioned unique properties of nanomaterials allow inducing the heat and destroying the cancerous cells. This paper provides an overview of the utilization of nanoparticles and nanomaterials such as magnetic iron oxide nanoparticles, nanorods, nanoshells, nanocomposites, carbon nanotubes, and other nanoparticles in the thermal ablation of tumors, demonstrating their advantages over the conventional heating methods.


Opening a Window into Reading Development: Eye Movements' Role Within a Broader Literacy Research Framework.
The cumulative body of eye movement research provides significant insight into how readers process text. The heart of this work spans roughly 40 years reflecting the maturity of both the topics under study and experimental approaches used to investigate reading. Recent technological advancements offer increased flexibility to the field providing the potential to more concertedly study reading and literacy from an individual differences perspective. Historically, eye movement research focused far less on developmental issues related to individual differences in reading; however, this issue and the broader change it represents signal a meaningful transition inclusive of individual differences. The six papers in this special issue signify the recent, increased attention to and recognition of eye movement research's transition to emphasize individual differences in reading while appreciating early contributions (e.g., Rayner, 1986) in this direction. We introduce these six papers and provide some historical context for the use of eye movement methodology to examine reading and context for the eye movement field's early transition to examining individual differences, culminating in future research recommendations.


Nonresponse bias in a mail survey of physicians.
With the increased pressure on survey researchers to achieve high response rates, it is critical to explore issues related to nonresponse. In this study, the authors examined the effects of nonresponse bias in a mail survey of physicians (N = 3,400). Because slightly more than one half of the sample did not respond to the survey, there was potential for bias if nonresponders differed significantly from responders with respect to key demographic and practice variables. They analyzed response status and timing of response with respect to five variables: gender, region, specialty, urbanicity, and survey length. The potential consequences of nonresponse bias on the survey estimates were then analyzed. Men were more likely to respond, as were physicians receiving a shorter questionnaire. Repeated follow-up attempts reduced gender response bias because male physicians were more likely to be early responders. Overall, higher response rates were not associated with lower response bias.


Predicting local and non-local effects of resources on animal space use using a mechanistic step selection model.
Predicting space use patterns of animals from their interactions with the environment is fundamental for understanding the effect of habitat changes on ecosystem functioning. Recent attempts to address this problem have sought to unify resource selection analysis, where animal space use is derived from available habitat quality, and mechanistic movement models, where detailed movement processes of an animal are used to predict its emergent utilization distribution. Such models bias the animal's movement towards patches that are easily available and resource-rich, and the result is a predicted probability density at a given position being a function of the habitat quality at that position. However, in reality, the probability that an animal will use a patch of the terrain tends to be a function of the resource quality in both that patch and the surrounding habitat.We propose a mechanistic model where this non-local effect of resources naturally emerges from the local movement processes, by taking into account the relative utility of both the habitat where the animal currently resides and that of where it is moving. We give statistical techniques to parametrize the model from location data and demonstrate application of these techniques to GPS location data of caribou (Rangifer tarandus) in Newfoundland.Steady-state animal probability distributions arising from the model have complex patterns that cannot be expressed simply as a function of the local quality of the habitat. In particular, large areas of good habitat are used more intensively than smaller patches of equal quality habitat, whereas isolated patches are used less frequently. Both of these are real aspects of animal space use missing from previous mechanistic resource selection models.Whilst we focus on habitats in this study, our modelling framework can be readily used with any environmental covariates and therefore represents a unification of mechanistic modelling and step selection approaches to understanding animal space use.


Probing the conformation of the ISWI ATPase domain with genetically encoded photoreactive crosslinkers and mass spectrometry.
We present a strategy for rapidly gaining structural information about a protein from crosslinks formed by genetically encoded unnatural amino acids. We applied it to ISWI, a chromatin remodeling enzyme involved in chromatin assembly, DNA replication and transcription. ISWI is part of the vast Snf2 family of helicase-related proteins, many of which constitute the catalytic cores of chromatin remodeling complexes. Structural information about this family is scarce, hampering our mechanistic understanding of chromatin remodeling. Making use of cells that harbor a special tRNA/aminoacyl-tRNA synthetase pair, several residues within the ATPase domain of ISWI were individually substituted with the UV-reactive unnatural amino acid p-benzoyl-p-phenylalanine. Intramolecular crosslinks could be mapped with amino acid precision by high resolution tandem mass spectrometry and the novel bioinformatic tool "Crossfinder." Most crosslinks were fully consistent with published crystal structures of ISWI-related ATPases. A subset of crosslinks, however, disagreed with the conformations previously captured in crystal structures. We built a structural model using the distance information obtained from the crosslinks and the structure of the closest crystallized relative, Chd1. The model shows the ATPase lobes strongly rotated against each other, a movement postulated earlier to be necessary to achieve a catalytically competent state. The minimal requirements for solubility and protein amounts make our approach ideal for studying structures and conformations of proteins that are not amenable to conventional structural techniques.


Ice: a new dosage form of an old drug.
Ice, which has been described as the drug of the 1990s, is a pure form of (+)methamphetamine hydrochloride; it is more dangerous because of its purity and because it can be inhaled. Taken by this route, the drug causes an effect similar to that from an intravenous dose, and much more intense than that from ingestion. The detailed mechanism of action differs from that of cocaine, but the overall stimulant effect of methamphetamine is similar. Methamphetamine effects, however, persist for hours, whereas cocaine effects are over in minutes. Ice is, therefore, just another agent for abuse by those seeking psychostimulation and, as with cocaine, compulsive abusers of amphetamines consume the drug repeatedly and continuously. Unlike cocaine, methamphetamine is a synthetic compound and is manufactured in illicit laboratories within the United States.


New Models of Pregnancy-Associated Hypertension.
Pregnancy-associated hypertensive disorders are leading causes of maternal and fetal mortality. These include: pre-pregnancy hypertension that persists throughout gestation (chronic/preexisting hypertension), de novo hypertension that is diagnosed after 20 weeks of gestation and resolves after birth (gestational hypertension), de novo hypertension that is diagnosed after 20 weeks of gestation with or without proteinuria and end-organ damage (preeclampsia and eclampsia), and chronic hypertension with superimposed preeclampsia during gestation. Preeclampsia is the most severe form of these disorders. Animal models have been developed by employing surgical, genetic, and pharmacological approaches in order to recapitulate the maternal symptoms of preeclampsia and other hypertensive disorders of pregnancy. The scope of this brief review is to present an up-to-date synthesis of our knowledge of experimental models of pregnancy-associated hypertensive disorders. Novel models, defined in this review as characterized within the last 5 years, will be described and critically discussed. In this review, we will also discuss established experimental models of pregnancy-associated hypertensive disorders in the context of their contribution to new advances in our knowledge about the pathophysiology of these disorders and potential therapeutics. Emphasis will be placed on animal models of preeclampsia; however, models of other hypertensive disorders in pregnancy will also be reviewed.


Nerve growth factor inhibits Na+/H+ exchange and formula absorption through parallel phosphatidylinositol 3-kinase-mTOR and ERK pathways in thick ascending limb.
In the medullary thick ascending limb, inhibiting the basolateral NHE1 Na(+)/H(+) exchanger with nerve growth factor (NGF) induces actin cytoskeleton remodeling that secondarily inhibits apical NHE3 and transepithelial HCO(3)(-) absorption. The inhibition by NGF is mediated 50% through activation of extracellular signal-regulated kinase (ERK). Here we examined the signaling pathway responsible for the remainder of the NGF-induced inhibition. Inhibition of HCO(3)(-) absorption was reduced 45% by the phosphatidylinositol 3-kinase (PI3K) inhibitors wortmannin or LY294002 and 50% by rapamycin, a specific inhibitor of mammalian target of rapamycin (mTOR), a downstream effector of PI3K. The combination of a PI3K inhibitor plus rapamycin did not cause a further reduction in the inhibition by NGF. In contrast, the combination of a PI3K inhibitor plus the MEK/ERK inhibitor U0126 completely eliminated inhibition by NGF. Rapamycin decreased NGF-induced inhibition of basolateral NHE1 by 45%. NGF induced a 2-fold increase in phosphorylation of Akt, a PI3K target linked to mTOR activation, and a 2.2-fold increase in the activity of p70 S6 kinase, a downstream effector of mTOR. p70 S6 kinase activation was blocked by wortmannin and rapamycin, consistent with PI3K, mTOR, and p70 S6 kinase in a linear pathway. Rapamycin-sensitive inhibition of NHE1 by NGF was associated with an increased level of phosphorylated mTOR in the basolateral membrane domain. These findings indicate that NGF inhibits HCO(3)(-) absorption in the medullary thick ascending limb through the parallel activation of PI3K-mTOR and ERK signaling pathways, which converge to inhibit NHE1. The results identify a role for mTOR in the regulation of Na(+)/H(+) exchange activity and implicate NHE1 as a possible downstream effector contributing to mTOR's effects on cell growth, proliferation, survival, and tumorigenesis.


Epigenetic changes in human model KMT2A leukemias highlight early events during leukemogenesis.
Chromosomal translocations involving KMT2A gene are one of the most common genetic alterations found in pediatric acute myeloid leukemias (AML) although the molecular mechanisms that initiate the disease remain incompletely defined. To elucidate these initiating events we have used a human model system of AML driven by the KMT2A-MLLT3 (KM3) fusion. More specifically, we investigated changes in DNA methylation, histone modifications, and chromatin accessibility at each stage of our model system and correlated these with expression changes. We observe the development of a profound hypomethylation phenotype in the early stages of leukemic transformation after KM3 addition along with loss of expression of stem cell associated genes along with skewed expression in other genes such as S100A8/9 implicated in leukemogenesis. In addition, early increases in the expression of the lysine demethylase KDM4B was functionally linked to these expression changes as well as other key transcription factors. Remarkably, our ATAC-seq data showed that there were relatively few leukemiaspecific changes and the vast majority corresponded to open chromatin regions and transcription factor clusters previously observed in other cell types. Integration of the gene expression and epigenetic changes revealed the adenylate cyclase gene ADCY9 as an essential gene in KM3-AML, and suggest the potential for autocrine signalling through the chemokine receptor CCR1 and CCL23 ligand. Together, our results suggest that KM3 induces subtle changes in the epigenome while co-opting the normal transcriptional machinery to drive leukemogenesis.


Biochemical and functional correlates of an increased membrane density of caveolae in hypertrophic rat urinary bladder.
Organ hypertrophy is often found to be associated with changes in the expression of caveolins and altered density of caveolae in the membrane. A plethora of signalling intermediaries are associated with caveolae and loss of caveolae has profound effects on contractility of the urinary bladder. We hypothesized that smooth muscle hypertrophy caused by bladder outflow obstruction (BOO) might lead to an altered caveola density with consequences for contractile regulation. Rat BOO for 6 weeks caused a 2.56-fold increase in the number of smooth muscle caveolae per μm membrane. No changes in the expression of caveolin-1 or cavin-1, normalized to β-actin were seen, but membrane area per unit muscle volume dropped to 0.346. Hypertrophy was associated with altered contraction in response to carbachol. The effect on contraction of cholesterol desorption, which disrupts lipid rafts and caveolae, was however not changed. Contraction in response to bradykinin resisted mβcd in control destrusor, but was inhibited by it after 6 weeks of obstruction. It is concluded that rat detrusor hypertrophy leads to an increased number of caveolae per unit membrane area. This change is due to a reduction of membrane area per volume muscle and it does not play a role for cholinergic activation, but promotes contraction in response to bradykinin after long-term obstruction.


A feedback loop between the androgen receptor and 6-phosphogluoconate dehydrogenase (6PGD) drives prostate cancer growth.
Alterations to the androgen receptor (AR) signalling axis and cellular metabolism are hallmarks of prostate cancer. This study provides insight into both hallmarks by uncovering a novel link between AR and the pentose phosphate pathway (PPP). Specifically, we identify 6-phosphogluoconate dehydrogenase (6PGD) as an androgen-regulated gene that is upregulated in prostate cancer. AR increased the expression of 6PGD indirectly via activation of sterol regulatory element binding protein 1 (SREBP1). Accordingly, loss of 6PGD, AR or SREBP1 resulted in suppression of PPP activity as revealed by 1,2-13C2 glucose metabolic flux analysis. Knockdown of 6PGD also impaired growth and elicited death of prostate cancer cells, at least in part due to increased oxidative stress. We investigated the therapeutic potential of targeting 6PGD using two specific inhibitors, physcion and S3, and observed substantial anti-cancer activity in multiple models of prostate cancer, including aggressive, therapy-resistant models of castration-resistant disease as well as prospectively collected patient-derived tumour explants. Targeting of 6PGD was associated with two important tumour-suppressive mechanisms: first, increased activity of the AMP-activated protein kinase (AMPK), which repressed anabolic growth-promoting pathways regulated by acetyl-CoA carboxylase 1 (ACC1) and mammalian target of rapamycin complex 1 (mTORC1); and second, enhanced AR ubiquitylation, associated with a reduction in AR protein levels and activity. Supporting the biological relevance of positive feedback between AR and 6PGD, pharmacological co-targeting of both factors was more effective in suppressing the growth of prostate cancer cells than single-agent therapies. Collectively, this work provides new insight into the dysregulated metabolism of prostate cancer and provides impetus for further investigation of co-targeting AR and the PPP as a novel therapeutic strategy.


Perceived Confidentiality Risks of Mobile Technology-Based Ecologic Momentary Assessment to Assess High-Risk Behaviors Among Rural Men Who Have Sex with Men.
Although men who have sex with men (MSM) within rural communities are disproportionately impacted by HIV, limited HIV research and programmatic resources are directed to these communities within the U.S. There is a need for improved behavioral data collection methods to obtain more detailed information on the relationship between rural environments, sexual behavior, and substance use. Utilization of mobile health (mHealth) technologies, such as ecologic momentary assessment (EMA), has been advocated for; however, limited research has evaluated its utility among rural MSM. Forty MSM residing in rural Oklahoma were recruited to complete in-depth interviews related to participating online/mobile-based HIV prevention research. Men described a willingness to participate in HIV and substance use studies that use EMA methodologies for data collection; however, they raised various research-related concerns. In particular, participants indicated potential privacy and confidentiality concerns related to the use of the mobile technology-based EMA in public and the storage of data by researchers. Given the varying degree of sexual orientation and substance use disclosure by participants, rural MSM were largely concerned with being inadvertently "outed" within their communities. Men described the various strategies they could employ to protect private information and methods to minimize research risk. Study findings suggest that EMA is an acceptable research methodology for use among rural MSM in the context of HIV and sexual health information, when privacy and confidentiality concerns are adequately addressed. Input from community members and stakeholders is necessary to identify potential areas of concerns for participants prior to data collection.


Integrative clustering reveals a novel split in the luminal A subtype of breast cancer with impact on outcome.
Breast cancer is a heterogeneous disease at the clinical and molecular level. In this study we integrate classifications extracted from five different molecular levels in order to identify integrated subtypes. Tumor tissue from 425 patients with primary breast cancer from the Oslo2 study was cut and blended, and divided into fractions for DNA, RNA and protein isolation and metabolomics, allowing the acquisition of representative and comparable molecular data. Patients were stratified into groups based on their tumor characteristics from five different molecular levels, using various clustering methods. Finally, all previously identified and newly determined subgroups were combined in a multilevel classification using a "cluster-of-clusters" approach with consensus clustering. Based on DNA copy number data, tumors were categorized into three groups according to the complex arm aberration index. mRNA expression profiles divided tumors into five molecular subgroups according to PAM50 subtyping, and clustering based on microRNA expression revealed four subgroups. Reverse-phase protein array data divided tumors into five subgroups. Hierarchical clustering of tumor metabolic profiles revealed three clusters. Combining DNA copy number and mRNA expression classified tumors into seven clusters based on pathway activity levels, and tumors were classified into ten subtypes using integrative clustering. The final consensus clustering that incorporated all aforementioned subtypes revealed six major groups. Five corresponded well with the mRNA subtypes, while a sixth group resulted from a split of the luminal A subtype; these tumors belonged to distinct microRNA clusters. Gain-of-function studies using MCF-7 cells showed that microRNAs differentially expressed between the luminal A clusters were important for cancer cell survival. These microRNAs were used to validate the split in luminal A tumors in four independent breast cancer cohorts. In two cohorts the microRNAs divided tumors into subgroups with significantly different outcomes, and in another a trend was observed. The six integrated subtypes identified confirm the heterogeneity of breast cancer and show that finer subdivisions of subtypes are evident. Increasing knowledge of the heterogeneity of the luminal A subtype may add pivotal information to guide therapeutic choices, evidently bringing us closer to improved treatment for this largest subgroup of breast cancer.


Mammary epithelial tubes elongate through MAPK-dependent coordination of cell migration.
Mammary branching morphogenesis is regulated by receptor tyrosine kinases (RTKs). We sought to determine how these RTK signals alter proliferation and migration to accomplish tube elongation in mouse. Both behaviors occur but it has been difficult to determine their relative contribution to elongation in vivo, as mammary adipocytes scatter light and limit the depth of optical imaging. Accordingly, we utilized 3D culture to study elongation in an experimentally accessible setting. We first used antibodies to localize RTK signals and discovered that phosphorylated ERK1/2 (pERK) was spatially enriched in cells near the front of elongating ducts, whereas phosphorylated AKT was ubiquitous. We next observed a gradient of cell migration speeds from rear to front of elongating ducts, with the front characterized by both high pERK and the fastest cells. Furthermore, cells within elongating ducts oriented both their protrusions and their migration in the direction of tube elongation. By contrast, cells within the organoid body were isotropically protrusive. We next tested the requirement for proliferation and migration. Early inhibition of proliferation blocked the creation of migratory cells, whereas late inhibition of proliferation did not block continued duct elongation. By contrast, pharmacological inhibition of either MEK or Rac1 signaling acutely blocked both cell migration and duct elongation. Finally, conditional induction of MEK activity was sufficient to induce collective cell migration and ductal elongation. Our data suggest a model for ductal elongation in which RTK-dependent proliferation creates motile cells with high pERK, the collective migration of which acutely requires both MEK and Rac1 signaling.


Identifying the Most Successful Procedures in Hip Arthroscopy.
Hip arthroscopy for femoral and acetabular pathologies has increased dramatically. However, there is little literature analyzing procedures as predictors of revision arthroscopy or arthroplasty. From February 2008 to November 2015, patients undergoing hip arthroscopy for a labral tear with minimum 2-year follow-up and between 18 and 60 years old were retrospectively reviewed. Those with previous surgeries, Tönnis grade greater than 1, and previous hip conditions were excluded. Follow-up was obtained for 1118 patients (1249 hips; 81.7%) with a mean age of 38.7 years (range, 18.0-60.0 years), mean body mass index of 26.4 kg/m2 (range, 16.3-48.9 kg/m2), and mean follow-up of 50.2 months (range, 24.0-111.9 months). A total of 122 (9.8%) patients converted to total hip arthroplasty (mean, 35.3 months; range, 1.4-95.2 months). Multivariate analysis for predictors of total hip arthroplasty found age at surgery (hazard ratio, 1.064/y; P<.05), body mass index (nonlinear; P<.05), labral debridement (HR, 1.558; P=.03), and notchplasty (HR, 2.128; P<.05), with trochanteric bursectomy (HR, 0.367; P<.05) identified as associated with higher survivorship. A total of 124 (9.9%) patients underwent revision hip arthroscopy at a mean of 21.7 months (range, 0.10-83.3 months). Multivariate analysis for predictors of revision surgery found workers' compensation (HR, 3.352; P<.05), capsular repair (HR, 1.950; P<.05), and femoral head microfracture (HR, 2.844; P=.04) to be significant, with age at date of surgery (HR, 0.973/y; P<.05) and femoral head chondroplasty (HR, 0.241; P=.05) associated with higher survivorship. Understanding risk factors for conversion to total hip arthroplasty or revision is paramount during discussions with patients. [Orthopedics. 2020;43(3):173-181.].