Effects of infliximab treatment on rheumatoid synovial tissue.
Several studies have shown decreased synovial inflammation after treatment of patients with rheumatoid arthritis (RA) with infliximab. Recent data indicate that these effects can be detected as soon as 48 hours after first infusion. Although there are strong indications that infliximab exerts its effects in patients with Crohn's disease by induction of apoptosis in the gut, there are as yet no studies that convincingly show the same mechanism of action in RA. Conceivably, neutralization of tumor necrosis factor-alpha may be sufficient to induce clinical improvement in RA, even without induction of apoptosis at the site of inflammation. This hypothesis could explain the observation that both infliximab and etanercept are effective in RA, whereas apoptosis induction by infliximab might be required in Crohn's disease. Future studies should focus on the evaluation of apoptosis within the first 48 hours after initiation of therapy in RA to exclude the possibility that the effects occur very early after infliximab infusion.


Pinpointing retrovirus entry sites in cells expressing alternatively spliced receptor isoforms by single virus imaging.
The majority of viruses enter host cells via endocytosis. Current knowledge of viral entry pathways is largely based upon infectivity measurements following genetic and/or pharmacological interventions that disrupt vesicular trafficking and maturation. Imaging of single virus entry in living cells provides a powerful means to delineate viral trafficking pathways and entry sites under physiological conditions. Here, we visualized single avian retrovirus co-trafficking with markers for early (Rab5) and late (Rab7) endosomes, acidification of endosomal lumen and the resulting viral fusion measured by the viral content release into the cytoplasm. Virus-carrying vesicles either merged with the existing Rab5-positive early endosomes or slowly accumulated Rab5. The Rab5 recruitment to virus-carrying endosomes correlated with acidification of their lumen. Viral fusion occurred either in early (Rab5-positive) or intermediate (Rab5- and Rab7-positive) compartments. Interestingly, different isoforms of the cognate receptor directed virus entry from distinct endosomes. In cells expressing the transmembrane receptor, viruses preferentially entered and fused with slowly maturing early endosomes prior to accumulation of Rab7. By comparison, in cells expressing the GPI-anchored receptor, viruses entered both slowly and quickly maturing endosomes and fused with early (Rab5-positive) and intermediate (Rab5- and Rab7-positive) compartments. Since the rate of low pH-triggered fusion was independent of the receptor isoform, we concluded that the sites of virus entry are determined by the kinetic competition between endosome maturation and viral fusion. Our findings demonstrate the ability of this retrovirus to enter cells via alternative endocytic pathways and establish infection by releasing its content from distinct endosomal compartments.


Finding My Way: protocol of a randomised controlled trial evaluating an internet self-help program for cancer-related distress.
A cancer diagnosis elicits greater distress than any other medical diagnosis, and yet very few studies have evaluated the efficacy of structured online self-help therapeutic programs to alleviate this distress. This study aims to assess the efficacy over time of an internet Cognitive Behaviour Therapy (iCBT) intervention ('Finding My Way') in improving distress, coping and quality of life for individuals with a recent diagnosis of early stage cancer of any type. The study is a multi-site Randomised Controlled Trial (RCT) seeking to enrol 188 participants who will be randomised to either the Finding My Way Intervention or an attention-control condition. Both conditions are delivered online; with 6 modules released once per week, and an additional booster module released one month after program-completion. Participants complete online questionnaires on 4 occasions: at baseline (immediately prior to accessing the modules); post-treatment (immediately after program-completion); then three and six months later. Primary outcomes are general distress and cancer-specific distress, with secondary outcomes including Health-Related Quality of Life (HRQoL), coping, health service utilisation, intervention adherence, and user satisfaction. A range of baseline measures will be assessed as potential moderators of outcomes. Eligible participants are individuals recently diagnosed with any type of cancer, being treated with curative intent, aged over 18 years with sufficient English language literacy, internet access and an active email account and phone number. Participants are blinded to treatment group allocation. Randomisation is computer generated and stratified by gender. Compared to the few prior published studies, Finding My Way will be the first adequately powered trial to offer an iCBT intervention to curatively treated patients of heterogeneous cancer types in the immediate post-diagnosis/treatment period. If found efficacious, Finding My Way will assist with overcoming common barriers to face-to-face therapy in a cost-effective and accessible way, thus helping to reduce distress after cancer diagnosis and consequently decrease the cancer burden for individuals and the health system. Australian New Zealand Clinical Trials Registry ACTRN12613000001796 16.10.13.


Australian and New Zealand consensus statement on the management of lymphoma, chronic lymphocytic leukaemia and myeloma during the COVID-19 pandemic.
The COVID-19 pandemic poses a unique challenge to the care of patients with haematological malignancies. Viral pneumonia is known to cause disproportionately severe disease in patients with cancer, and patients with lymphoma, myeloma and chronic lymphocytic leukaemia are likely to be at particular risk of severe disease related to COVID-19. This statement has been developed by consensus among authors from Australia and New Zealand. We aim to provide supportive guidance to clinicians making individual patient decisions during the COVID-19 pandemic, in particular during periods that access to healthcare resources may be limited. General recommendations include those to minimise patient exposure to COVID-19, including the use of telehealth, avoidance of non-essential visits and minimisation of time spent by patients in infusion suites and other clinical areas. This statement also provides recommendations where appropriate in assessing indications for therapy, reducing therapy-associated immunosuppression and reducing healthcare utilisation in patients with specific haematological malignancies during the COVID-19 pandemic. Specific decisions regarding therapy of haematological malignancies will need to be individualised, based on disease risk, risks of immunosuppression, rates of community transmission of COVID-19 and available local healthcare resources.


Human tumour-associated macrophages differentiate into osteoclastic bone-resorbing cells.
Macrophages are commonly found within osteolytic secondary carcinomas in bone, but the manner in which these cells contribute to malignant bone resorption is uncertain. Macrophages isolated from primary breast carcinomas were co-cultured for up to 21 days with UMR 106 rat osteoblast-like cells on bone slices and glass coverslips in the presence and absence of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and human macrophage colony stimulating factor (M-CSF). Cell cultures were then assessed for the presence of phenotypic markers of macrophage and osteoclast differentiation. Isolated cells were negative for osteoclast markers including tartrate-resistant acid phosphatase (TRAP), vitronectin receptor (VNR), and the ability to carry our lacunar bone resorption, but were positive for CD11b and CD14, macrophage markers which are not present on osteoclasts. In 21-day co-cultures of breast carcinoma tumour-associated macrophages (TAMs) and UMR 106 cells, incubated in the presence of 1,25(OH)2D3 and M-CSF, numerous TRAP- and VNR-positive multinucleated cells capable of extensive lacunar resorption were formed. Contact with UMR 106 cells and the presence of 1,25(OH)2D3 and M-CSF were absolute requirements for differentiation of human breast carcinoma TAMs into mature functional osteoclasts. TAM-osteoclast differentiation may represent an important cellular mechanism of osteolysis in metastatic skeletal carcinomas.


Telomere length and the risk of atrial fibrillation: insights into the role of biological versus chronological aging.
Advanced age is the most important risk factor for atrial fibrillation (AF); however, the mechanism remains unknown. Telomeres, regions of DNA that shorten with cell division, are considered reliable markers of biological aging. We sought to examine the association between leukocyte telomere length (LTL) and incident AF in a large population-based cohort using direct LTL measurements and genetic data. To further explore our findings, we compared atrial cell telomere length and LTL in cardiac surgery patients. Mean LTL and the TERT rs2736100 single nucleotide polymorphism were assessed as predictors of incident AF in the Cardiovascular Health Study (CHS). Among the surgical patients, within subject comparison of atrial cell telomere length versus LTL was assessed. Among 1639 CHS participants, we observed no relationship between mean LTL and incident AF before and after adjustment for potential confounders (adjusted hazard ratio, 1.09; 95% confidence interval: 0.92-1.29; P=0.299); chronologic age remained strongly associated with AF in the same model. No association was observed between the TERT rs2736100 single nucleotide polymorphism and incident AF (adjusted hazard ratio: 0.95; 95% confidence interval: 0.88-1.04; P=0.265). In 35 cardiac surgery patients (26 with AF), atrial cell telomere length was longer than LTL (1.19 ± 0.20 versus 1.02 ± 0.25 [T/S ratio], P<0.001), a finding that remained consistent within the AF subgroup. Our study revealed no evidence of an association between LTL and incident AF and no evidence of relative atrial cell telomere shortening in AF. Chronological aging independent of biological markers of aging is the primary risk factor for AF.


Patterns of dental care utilization among patients with temporomandibular disorders.
To use data from a large health maintenance organization to specifically investigate dental utilization rates among patients with and without temporomandibular disorders (TMD). Subjects were enrolled in Kaiser Permanente Northwest between 1998 and 2003. Two age- and gender-matched controls were selected for each subject who had a TMD diagnosis during the study period. Dental treatment was categorized using Current Dental Terminology (CDT) codes. Overall dental utilization rates were calculated, as well as rates based on age, gender, categories of treatment, and periods before and after TMD diagnoses. These rates were analyzed with t tests. TMD subjects utilized significantly more dental services than comparison subjects overall and for several dental categories. The difference was between 10% to 20%, or about 1 additional dental procedure per year. A positive linear relationship existed between dental utilization rates and age, with a significant increase in utilization for each ascending age cohort. Females had higher dental utilization rates than males in TMD and non-TMD groups and in all categories of dentistry. After a TMD diagnosis, major differences in utilization were not found when compared to patterns of treatment prior to the diagnosis. TMD subjects utilized 10% to 20% more dental services than non-TMD subjects. Gender and age were important factors with increased utilization in females and older patients. TMD diagnoses did not affect dental utilization patterns, indicating that most TMD patients continue to seek routine dental care.


Identifying patients who require a change in their current acute migraine treatment: the Migraine Assessment of Current Therapy (Migraine-ACT) questionnaire.
Currently available measures of the efficacy of acute migraine medications are not frequently used in primary care. They may be too burdensome and complicated for routine use. To design and test a new, easy to use, 4-item assessment tool, the Migraine Assessment of Current Therapy (Migraine-ACT) questionnaire for use by clinicians, to quickly evaluate how a recently prescribed acute medication is working, and to identify patients who require a change of their current acute treatment. A 27-item Migraine-ACT questionnaire was developed by an international advisory board of headache specialists. Questions were formulated in four domains: headache impact, global assessment of relief, consistency of response and emotional response. All these are clinically important measures of migraine severity and treatment outcome. All questions were dichotomous and answered by yes or no. Patients (n = 185) attending secondary care headache clinics who were diagnosed with migraine according to International Headache Society criteria entered a multinational, prospective, observational study to investigate the test-retest reliability and construct validity of the 27-item Migraine-ACT. Patients completed the Migraine-ACT on two occasions, separated by a 1-week interval, and test-retest reliability was assessed by Pearson product moment and Spearman rank measures. Construct validity was assessed by correlating patients' answers to the 27-item Migraine-ACT with those to other questionnaires (individual domains and total scores) conceptually related to it; the Short-Form 36 quality of life questionnaire (SF-36), the Migraine Disability Assessment (MIDAS) questionnaire and the Migraine Therapy Assessment Questionnaire (MTAQ). Discriminatory t-tests were used to identify the four Migraine-ACT questions (one in each domain) which discriminated best between the domains of the SF36, MIDAS, and MTAQ. These four items constituted the final 4-item Migraine-ACT. The test-retest reliability of the 27 Migraine-ACT questions ranged from good to excellent, and correlation coefficients were highly significant for all items. The consistency of reporting the yes and no answers was also excellent. Correlations of Migraine-ACT items with SF-36 and MIDAS items and SF-36, MIDAS and MTAQ total scores indicated that the following were the most discriminating items, in the respective four domains, and constitute the final Migraine-ACT questionnaire: Consistency of response: Does your migraine medication work consistently, in the majority of your attacks? Global assessment of relief: Does the headache pain disappear within 2 h? Are you able to function normally within 2 h? Emotional response: Are you comfortable enough with your medication to be able to plan your daily activities? The 4-item Migraine-ACT was shown to be highly reliable (Spearman/Pearson measure r = 0.82). The individual questions, and the total 4-item Migraine-ACT score, showed good correlation with items of the SF-36, MIDAS and MTAQ questionnaires, particularly with the total MTAQ and SF-36 scores. The 4-item Migraine-ACT questionnaire is an assessment tool for use by primary care physicians to identify patients who require a change in their current acute migraine treatment. It is brief and simple to complete and score, and has demonstrated reliability, accuracy and simplicity. Migraine-ACT can therefore be recommended for everyday clinical use by clinicians.


Ethanol delays and reverses lysophosphatidylcholine-induced calcium overload in neonatal rat heart cells.
Increased lysophosphatidylcholine (LPC) production by the ischemic heart is associated with tissue damage. In vitro, LPC produces an increase in cytosolic [Ca2+], usually followed by cell contracture and lysis. Since ethanol reportedly protect cells during ischemia-reperfusion, we wished to determine whether ethanol could protect heart cells against LPC-induced Ca2+ overload. Newborn rat heart cells in culture were loaded with Fura-2 and [Ca2+]i recorded in individual cells. The presence of 22 or 44 mM ethanol increased the time required for 10 microM x L-palmitoyl-LPC to produce maximal Ca2+ accumulation from 8.4+/-0.4 min (n=47) to 21.1+/-2.1 x min (n=32; P<0.01) and 23.8+/-1.8 min (n=10; P<0.01) respectively. The onset of the [Ca2+]i increase could be reversed partially by the addition of ethanol (44 or 88 mM). After the addition of 22 mM ethanol, the cells retained the Fura-2 three times longer than under control conditions. Ethanol (88 mM) decreased the critical micelle concentration of LPC, thus decreasing the LPC monomer concentration in this solution. La3+ also protected the cells against LPC but no further protection was afforded by the addition of ethanol. Our results suggest that ethanol concentrations commonly found in the blood of social drinkers protect heart cells against the deleterious effect of LPC.


Binding of a chaperonin to the folding intermediates of lactate dehydrogenase.
When Bacillus stearothermophilus LDH dimer is incubated with increasing concentrations of the denaturant guanidinium chloride, three distinct unfolded states of the molecule are observed at equilibrium [Smith, C. J., et al. (1991) Biochemistry 30, 1028-1036]. The kinetics of LDH refolding are consistent with an unbranched progression through these states. The Escherichia coli chaperonin, GroEL, binds with high affinity to the completely denatured form and more weakly to the earliest folding intermediate, thus retarding the refolding process. A later structurally defined folding intermediate, corresponding to a molten globule form, is not bound by GroEL; neither is the inactive monomer. The complex between GroEL and denatured LDH is destabilized by the binding of magnesium/ATP (Mg/ATP) or by the nonhydrolyzable analogue adenylyl imidodiphosphate (AMP-PNP). From our initial kinetic data, we propose that GroEL exists in two interconvertible forms, one of which is stabilized by the binding of Mg/ATP but associates weakly with the unfolded protein. The other is destabilized by Mg/ATP and associates strongly with unfolded LDH. The relevance of these findings to the role of GroEL in vivo is discussed.


Comparative study on adsorption of perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) by different adsorbents in water.
Perfluorinated compounds (PFCs) are emerging environmental pollutants. Perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) are the two primary PFC contaminants that are widely found in water, particularly in groundwater. This study compared the adsorption behaviors of PFOS and PFOA on several commercially available adsorbents in water. The tested adsorbents include granular activated carbon (GAC: Filtrasorb 400), powdered activated carbon, multi-walled carbon nanotube (MCN), double-walled carbon nanotube, anion-exchange resin (AER: IRA67), non-ion-exchange polymer, alumina, and silica. The study demonstrated that adsorption is an effective technique for the removal of PFOS/PFOA from aqueous solutions. The kinetic tests showed that the adsorption onto AER reaches equilibrium rapidly (2 h), while it takes approximately 4 and 24 h to reach equilibrium for MCN and GAC, respectively. In terms of adsorption capacity, AER and GAC were identified as the most effective adsorbents to remove PFOS/PFOA from water. Furthermore, MCN, AER, and GAC proved to have high PFOS/PFOA removal efficiencies (≥98%). AER (IRA67) and GAC (Filtrasorb 400) were thus identified as the most promising adsorbents for treating PFOS/PFOA-contaminated groundwater at mg L(-1) level based on their equilibrium times, adsorption capacities, removal efficiencies, and associated costs.


SU-E-T-232: Proton Source Modeling for Geant4 Monte Carlo Simulations.
To investigate the effect of initial proton beam source placement, distribution and angle on the proton dose distribution in a therapeutic nozzle using Geant4. We performed Geant4 Monte Carlo simulations of a passively scattered proton treatment nozzle. Accurate geometry including all elements in the treatment room was used. Protons were generated just inside the vacuum pipe using one of two models. First, a standard two dimensional Gaussian distribution of proton starting position was used with a small random angle added to the initial direction. The size of the Gaussian distribution and the random angle were set to match measured beam spot size and angular spread at the exit window. Second, a point source of protons further back in the vacuum pipe with a small random angle was used. The distance of the point source to exit window and the random angle were set to match the spot size and angular deviation used for the Gaussian distribution. Depth dose curves and orthogonal beam profiles were examined to determine changes between the two models. Orthogonal beam profiles for large apertures showed changes of up to 6.5% between the two models with the point source showing much better agreement with measured data. Depth dose curves and orthogonal profiles for small apertures were unaffected. For large apertures, the average difference compared to measured data was of 1.9% and 0.7% and the max difference was 5.0% and 1.6% for Gaussian and point sources, respectively. The point source more realistically models the proton distribution in the vacuum pipe by correlating the proton position with the direction. For certain scattering setups and large apertures point source modeling is necessary to accurate match measured data with Monte Carlo simulations.


Modified Valenti Arthroplasty in Running and Jumping Athletes With Hallux Limitus/Rigidus: Analysis of One Hundred Procedures.
Despite hallux limitus/rigidus being a common condition, results of surgical procedures specifically pertaining to athletes are scarce. The results of 100 modified Valenti procedures, prospectively studied from January 2000 to June 2016 with an average 49.17 months of follow-up, are presented evaluating demographics, sport, time and ability to return to activity (RTA), decreased desired activity level, and need for additional surgery. Inclusion criteria included athletes who have exhausted conservative care without relief of daily pain, dorsiflexion <20°, and grade ≥2. Seventeen had grade 2, 79 had grade 3, and 4 had grade 4 disease. RTA for the 89 procedures where exact time could be determined was 9.25 weeks; however, 100% were confirmed to RTA to some degree. The RTA of dancers and runners (the largest portion of the cohort at 76) was around 8 weeks, whereas soccer players were the slowest at >16 weeks, which was significant. There was no other significant difference in RTA between sport, sex, or grade of hallux limitus/rigidus except for between runners and soccer players. Six patients (6%) stated a decreased desire to activity, although this was not a significant finding. The modified Valenti procedure is a safe and highly effective treatment for running and jumping athletes limited by hallux limitus/rigidus because 94% of patients were able to return to their desired level of activity.


Boosting Slow Oscillations during Sleep to Improve Memory Function in Elderly People: A Review of the Literature.
Sleep represents a crucial time window for the consolidation of memory traces. In this view, some brain rhythms play a pivotal role, first of all the sleep slow waves. In particular, the neocortical slow oscillations (SOs), in coordination with the hippocampal ripples and the thalamocortical spindles, support the long-term storage of the declarative memories. The aging brain is characterized by a disruption of this complex system with outcomes on the related cognitive functions. In recent years, the advancement of the comprehension of the sleep-dependent memory consolidation mechanisms has encouraged the development of techniques of SO enhancement during sleep to induce cognitive benefits. In this review, we focused on the studies reporting on the application of acoustic or electric stimulation procedures in order to improve sleep-dependent memory consolidation in older subjects. Although the current literature is limited and presents inconsistencies, there is promising evidence supporting the perspective to non-invasively manipulate the sleeping brain electrophysiology to improve cognition in the elderly, also shedding light on the mechanisms underlying the sleep-memory relations during healthy and pathological aging.


Neuronal pattern separation in the olfactory bulb improves odor discrimination learning.
Neuronal pattern separation is thought to enable the brain to disambiguate sensory stimuli with overlapping features, thereby extracting valuable information. In the olfactory system, it remains unknown whether pattern separation acts as a driving force for sensory discrimination and the learning thereof. We found that overlapping odor-evoked input patterns to the mouse olfactory bulb (OB) were dynamically reformatted in the network on the timescale of a single breath, giving rise to separated patterns of activity in an ensemble of output neurons, mitral/tufted (M/T) cells. Notably, the extent of pattern separation in M/T assemblies predicted behavioral discrimination performance during the learning phase. Furthermore, exciting or inhibiting GABAergic OB interneurons, using optogenetics or pharmacogenetics, altered pattern separation and thereby odor discrimination learning in a bidirectional way. In conclusion, we propose that the OB network can act as a pattern separator facilitating olfactory stimulus distinction, a process that is sculpted by synaptic inhibition.


Decaprenylphosphoryl-β-D-ribose 2'-epimerase from Mycobacterium tuberculosis is a magic drug target.
Tuberculosis is still a leading cause of death in developing countries and a resurgent disease in developed countries. The selection and soaring spread of Mycobacterium tuberculosis multidrug-resistant (MDR-TB) and extensively drug-resistant strains (XDR-TB) is a severe public health problem. Currently, there is an urgent need of new drugs for tuberculosis treatment, with novel mechanisms of action and, moreover, the necessity to identify new drug targets. Several enzymes involved in various metabolic processes have been described as potential targets for the development of new drugs. Recently, two different classes of most promising drugs, the benzothiazinones (BTZ) and the dinitrobenzamide derivatives (DNB), have been found to be highly active against M. tuberculosis, including XDR-TB strains. Interestingly, both drugs have the same target: the heteromeric decaprenylphosphoryl-β-D-ribose 2'-epimerase encoded by dprE1 (Rv3790) and dprE2 (Rv3791) genes, respectively. DprE1 and DprE2 are involved in the biosynthesis of D-arabinose and, in particular, they are essential to perform the transformation of decaprenylphosphoryl-D-ribose to decaprenylphosphoryl-D-arabinose, which is a substrate for arabinosyltransferases in the synthesis of the cell-envelope arabinogalactan and liporabinomannan polysaccharides of mycobacteria. Arabinogalactan is a fundamental component of the mycobacterial cell wall, which covalently binds the outer layer of mycolic acids to peptidoglycan. The heteromeric decaprenylphosphoryl-β-D-ribose 2'-epimerase thus represents a valid vulnerable antimycobacterial drug target which could result in "magic" for tuberculosis treatment.


Searching the Footprints of Pioneers on Neurology: A Bibliometric Analysis.
We identify the most cited articles that have influenced the clinical practices of neurologists. We first analyzed the top 100 cited articles published in 50 neurology journals with high impact factors. We collected all of the original articles on clinical neurology published in all 554 medical journals. The Institute for Scientific Information Web of Science search tools were used to identify the top 100 cited articles in the database of Journal Citation Reports since 1950, which were then manually reviewed to discover their contents. In the first part of analysis, the top 100 cited articles were all published in 17 journals, with 26 articles published in Neurology. The most frequent topic subject of neurodegeneration appeared in 40 articles. The second part of the analysis revealed that the top 100 cited articles were also all published in 17 journals, with 30 articles published in New England Journal of Medicine. In contrast to the first part of the analysis, stroke was the most frequent topic subject (in 38 articles). Our bibliometric analysis has yielded 2 detailed lists of the top 100 cited articles that were listed separately using different methods. This approach can provide information about the trends and academic achievements in the field of clinical neurology.


Effectiveness of a family nurse-led programme on accuracy of blood pressure self-measurement: A randomised controlled trial.
To evaluate the effectiveness of a Family Nurse Practitioner (FNP)-led programme on the degree of adherence of current recommendations on home blood pressure self-measurement (HBPM) as compared to routine care and management. HBPM plays an important role for monitoring hypertensive patients; however, patients' adherence to current guidelines is unsatisfactory. A nurse-led training programme in the community setting could be an effective strategy to achieve high level of patients' adherence to recommendations. A multicentre randomised controlled trial was carried out from September 2016 to September 2017. In total, 170 patients were randomly allocated into the intervention group (n = 83) and the usual care (n = 87). All participants received usual care (written and verbal information on HBPM recommendations); subjects in the intervention group also received 1-hour training session on how to correctly self-measure BP. Clinical trial registration was done (ClinicalTrials.gov.: NCT04681703). The CONSORT checklist for randomised controlled trials was used in this study. At baseline, the level of adherence to the recommendation was similar in the two groups (p < .05). After 1 month, the adherence significantly increased in the intervention group, where patients were more likely to measure BP at the same hour and from the same arm, in a quiet environment, with the back and uncovered arm supported and the legs uncrossed; recording BP more than once in each measurement session; keeping a diary of blood pressure measurements; use of the appropriate cuff and proper placement of the cuff; and resting for >5 min before performing the measurement (all p < .05). The FNP-led programme is effective in improving patients' adherence to guidelines on the correct technique to self-measure BP at home. This programme may be added to the existing interventions in the community setting or considered into specifically nurse-led hypertension management models.


Withdrawal of a novel-design duodenoscope ends outbreak of a VIM-2-producing Pseudomonas aeruginosa.
Infections are a recognized risk of endoscopic retrograde cholangiopancreatography (ERCP). This paper reports on a large outbreak of VIM-2-producing Pseudomonas aeruginosa that was linked to the use of a recently introduced duodenoscope with a specific modified design (Olympus TJF-Q180V). Epidemiological investigations and molecular typing were executed in order to identify the source of the outbreak. Audits on implementation of infection control measures were performed. Additional infection control strategies were implemented to prevent further transmission. The design and the ability to clean and disinfect the duodenoscope were evaluated, and the distal tip was dismantled. From January to April 2012, 30 patients with a VIM-2-positive P. aeruginosa were identified, of whom 22 had undergone an ERCP using a specific duodenoscope, the TJF-Q180V. This was a significant increase compared with the hospital-wide baseline level of 2 - 3 cases per month. Clonal relatedness of the VIM-2 P. aeruginosa was confirmed for all 22 cases and for the VIM-2 strain isolated from the recess under the forceps elevator of the duodenoscope. An investigational study of the new modified design, including the dismantling of the duodenoscope tip, revealed that the fixed distal cap hampered cleaning and disinfection, and that the O-ring might not seal the forceps elevator axis sufficiently. The high monthly number of cases decreased below the pre-existing baseline level following withdrawal of the TJF-Q180V device from clinical use. Duodenoscope design modifications may compromise microbiological safety as illustrated by this outbreak. Extensive pre-marketing validation of the reprocessability of any new endoscope design and stringent post-marketing surveillance are therefore mandatory.


BRain health and healthy AgeINg in retired rugby union players, the BRAIN Study: study protocol for an observational study in the UK.
Relatively little is known about the long-term health of former elite rugby players, or former sportspeople more generally. As well as the potential benefits of being former elite sportspersons, there may be potential health risks from exposures occurring during an individual's playing career, as well as following retirement. Each contact sport has vastly different playing dynamics, therefore exposing its players to different types of potential traumas. Current evidence suggests that these are not necessarily comparable in terms of pathophysiology, and their potential long-term adverse effects might also differ. There is currently limited but increasing evidence that poorer age-related and neurological health exists among former professional sportsmen exposed to repetitive concussions; however the evidence is limited on rugby union players, specifically. We present the protocol for a cross-sectional study to assess the association between self-reported history of concussion during a playing career, and subsequent measures of healthy ageing and neurological and cognitive impairment. We are recruiting a sample of approximately 200 retired rugby players (former Oxford and Cambridge University rugby players and members of the England Rugby International Club) aged 50 years or more, and collecting a number of general and neurological health-related outcome measures though validated assessments. Biomarkers of neurodegeneration (neurofilaments and tau) will be also be measured. Although the study is focusing on rugby union players specifically, the general study design and the methods for assessing neurological health are likely to be relevant to other studies of former elite sportspersons. The study has been approved by the Ethical Committee of London School of Hygiene and Tropical Medicine (reference: 11634-2). It is intended that results of this study will be published in peer-reviewed medical journals, communicated to participants, the general public and all relevant stakeholders.


Histone H4 lysine 20 monomethylation promotes transcriptional repression by L3MBTL1.
Lethal 3 malignant brain tumor 1 (L3MBTL1), a homolog of the Drosophila polycomb tumor suppressor l(3)mbt, contains three tandem MBT repeats (3xMBT) that are critical for transcriptional repression. We recently reported that the 3xMBT repeats interact with mono- and dimethylated lysines in the amino termini of histones H4 and H1b to promote methylation-dependent chromatin compaction. Using a series of histone peptides, we now show that the recognition of mono- and dimethylated lysines in histones H3, H4 and H1.4 (but not their trimethylated or unmodified counterparts) by 3xMBT occurs in the context of a basic environment, requiring a conserved aspartic acid (D355) in the second MBT repeat. Despite the broad range of in vitro binding, the chromatin association of L3MBTL1 mirrors the progressive accumulation of H4K20 monomethylation during the cell cycle. Furthermore, transcriptional repression by L3MBTL1 is enhanced by the H4K20 monomethyltransferase PR-SET7 (to which it binds) but not SUV420H1 (an H4K20 trimethylase) or G9a (an H3K9 dimethylase) and knockdown of PR-SET7 decreases H4K20me1 levels and the chromatin association of L3MBTL1. Our studies identify the importance of H4K20 monomethylation and of PR-SET7 for L3MBTL1 function.


The epidemiology and etiology of Perthes disease.
The incidence of Perthes disease varies markedly both between countries and within countries down to a local level. The disease is more common in white than in Asian or black African children. The disease is associated with deprivation; with a steep disease gradient across social class groups. This epidemiology alongside the lack of concordance in twins suggests a strong environmental etiology, with little evidence to suggest a genetic predisposition. Children are frequently short, with a growth pattern described as "rostral-sparing". A propensity to associated congenital anomalies suggests an intrauterine cause.


Gd(3+) complexes conjugated to Pittsburgh compound B: potential MRI markers of β-amyloid plaques.
In an effort towards the visualization of β-amyloid (Aβ) plaques by T1-weighted magnetic resonance imaging for detection of Alzheimer's disease, we report the synthesis and characterization of stable, noncharged Gd(3+) complexes of three different 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid monoamide derivatives conjugated to Pittsburgh compound B, a well-established marker of Aβ plaques. The ligands L1, L2, and L3 differ in the nature and size of the spacer linking the macrocyclic chelator and the Pittsburgh compound B targeting moiety, which affects their lipophilicity, the octanol-water partition coefficients of the complexes ranging from -0.15 to 0.32. Given their amphiphilic behavior, the complexes form micelles in aqueous solution (critical micellar concentration 1.00-1.49 mM). The parameters determining the relaxivity, including the water exchange rate and the rotational correlation times, were assessed for the monomeric and the micellar form by a combined (17)O NMR and (1)H nuclear magnetic relaxation dispersion (NMRD) study. They are largely influenced by the aggregation state and the hydrophobic character of the linkers. The analysis of the rotational dynamics for the aggregated state in terms of local and global motions using the Lipari-Szabo approach indicates highly flexible, large aggregates. On binding of the complexes to human serum albumin or to the amyloid peptide Aβ1-40 in solution, they undergo a fourfold and a twofold relaxivity increase, respectively (40 MHz). Proton relaxation enhancement studies confirmed moderate interaction of Gd(L1) and Gd(L3) with human serum albumin, with KA values ranging between 250 and 910 M(-1).


Can weather generation capture precipitation patterns across different climates, spatial scales and under data scarcity?
Stochastic weather generators can generate very long time series of weather patterns, which are indispensable in earth sciences, ecology and climate research. Yet, both their potential and limitations remain largely unclear because past research has typically focused on eclectic case studies at small spatial scales in temperate climates. In addition, stochastic multi-site algorithms are usually not publicly available, making the reproducibility of results difficult. To overcome these limitations, we investigated the performance of the reduced-complexity multi-site precipitation generator TripleM across three different climatic regions in the United States. By resampling observations, we investigated for the first time the performance of a multi-site precipitation generator as a function of the extent of the gauge network and the network density. The definition of the role of the network density provides new insights into the applicability in data-poor contexts. The performance was assessed using nine different statistical metrics with main focus on the inter-annual variability of precipitation and the lengths of dry and wet spells. Among our study regions, our results indicate a more accurate performance in wet temperate climates compared to drier climates. Performance deficits are more marked at larger spatial scales due to the increasing heterogeneity of climatic conditions.


Cross-talk between miR-29 and transforming growth factor-betas in trabecular meshwork cells.
To investigate the interactions between microRNA-29 (miR-29), a negative regulator of extracellular matrix (ECM), and transforming growth factors (TGF)β-1 and TGFβ-2. Changes in expression of the miR-29 family were analyzed by quantitative-PCR (Q-PCR) after treatment with TGFβ1 and TGFβ2 (1 ng/mL). TGFβ1 and TGFβ2 were evaluated at gene expression and protein levels by Q-PCR and ELISA, respectively, in human trabecular meshwork (HTM) cells transfected with miR-29b or scramble control. TGFβ1 promoter activity was analyzed using an adenovirus with the reporter SEAP. The effects of miR-29b and TGFβ2 on ECM gene expression were evaluated in cells transfected with miR-29b or scramble control and treated with TGFβ2, and the expression of ECM genes was analyzed by Q-PCR. TGFβ2 but not TGFβ1, downregulated the three members of the miR-29 family. Overexpression of miR-29b antagonized the effects of TGFβ2 on the expression of several ECM components. MiR-29b decreased the expression of TGFβ1 at the promoter, transcript, and protein levels but had only a minor effect on the expression of active TGFβ2. The inhibition of TGFβ1 by miR-29b was partially recovered after co-transfection with a plasmid-expressing bone morphogenetic protein 1. Results showed some level of crosstalk between TGFβs and miR-29. Specifically, the downregulation of miR-29 by TGFβ2 contributed to the induction of several ECM components by this cytokine in TM cells. This observation, together with the inhibitory effects of miR-29b on the expression of TGFβ1, suggests that the miR-29 family could play an important role in modulating TGFβs on the outflow pathway.


Salicylic acid is a systemic signal and an inducer of pathogenesis-related proteins in virus-infected tobacco.
Systemic induction of pathogenesis-related (PR) proteins in tobacco, which occurs during the hypersensitive response to tobacco mosaic virus (TMV), may be caused by a minimum 10-fold systemic increase in endogenous levels of salicylic acid (SA). This rise in SA parallels PR-1 protein induction and occurs in TMV-resistant Xanthi-nc tobacco carrying the N gene, but not in TMV-susceptible (nn) tobacco. By feeding SA to excised leaves of Xanthi-nc (NN) tobacco, we have shown that the observed increase in endogenous SA levels is sufficient for the systemic induction of PR-1 proteins. TMV infection became systemic and Xanthi-nc plants failed to accumulate PR-1 proteins at 32 degrees C. This loss of hypersensitive response at high temperature was associated with an inability to accumulate SA. However, spraying leaves with SA induced PR-1 proteins at both 24 and 32 degrees C. SA is most likely exported from the primary site of infection to the uninfected tissues. A computer model predicts that SA should move rapidly in phloem. When leaves of Xanthi-nc tobacco were excised 24 hr after TMV inoculation and exudates from the cut petioles were collected, the increase in endogenous SA in TMV-inoculated leaves paralleled SA levels in exudates. Exudation and leaf accumulation of SA were proportional to TMV concentration and were higher in light than in darkness. Different components of TMV were compared for their ability to induce SA accumulation and exudation: three different aggregation states of coat protein failed to induce SA, but unencapsidated viral RNA elicited SA accumulation in leaves and phloem. These results further support the hypothesis that SA acts as an endogenous signal that triggers local and systemic induction of PR-1 proteins and, possibly, some components of systemic acquired resistance in NN tobacco.


The first modern human dispersals across Africa.
The emergence of more refined chronologies for climate change and archaeology in prehistoric Africa, and for the evolution of human mitochondrial DNA (mtDNA), now make it feasible to test more sophisticated models of early modern human dispersals suggested by mtDNA distributions. Here we have generated 42 novel whole-mtDNA genomes belonging to haplogroup L0, the most divergent clade in the maternal line of descent, and analysed them alongside the growing database of African lineages belonging to L0's sister clade, L1'6. We propose that the last common ancestor of modern human mtDNAs (carried by "mitochondrial Eve") possibly arose in central Africa ~180 ka, at a time of low population size. By ~130 ka two distinct groups of anatomically modern humans co-existed in Africa: broadly, the ancestors of many modern-day Khoe and San populations in the south and a second central/eastern African group that includes the ancestors of most extant worldwide populations. Early modern human dispersals correlate with climate changes, particularly the tropical African "megadroughts" of MIS 5 (marine isotope stage 5, 135-75 ka) which paradoxically may have facilitated expansions in central and eastern Africa, ultimately triggering the dispersal out of Africa of people carrying haplogroup L3 ~60 ka. Two south to east migrations are discernible within haplogroup LO. One, between 120 and 75 ka, represents the first unambiguous long-range modern human dispersal detected by mtDNA and might have allowed the dispersal of several markers of modernity. A second one, within the last 20 ka signalled by L0d, may have been responsible for the spread of southern click-consonant languages to eastern Africa, contrary to the view that these eastern examples constitute relicts of an ancient, much wider distribution.


High-density electrode recordings reveal strong and specific connections between retinal ganglion cells and midbrain neurons.
The superior colliculus is a midbrain structure that plays important roles in visually guided behaviors in mammals. Neurons in the superior colliculus receive inputs from retinal ganglion cells but how these inputs are integrated in vivo is unknown. Here, we discovered that high-density electrodes simultaneously capture the activity of retinal axons and their postsynaptic target neurons in the superior colliculus, in vivo. We show that retinal ganglion cell axons in the mouse provide a single cell precise representation of the retina as input to superior colliculus. This isomorphic mapping builds the scaffold for precise retinotopic wiring and functionally specific connection strength. Our methods are broadly applicable, which we demonstrate by recording retinal inputs in the optic tectum in zebra finches. We find common wiring rules in mice and zebra finches that provide a precise representation of the visual world encoded in retinal ganglion cells connections to neurons in retinorecipient areas.


Genetic and metabolic status of NGF-deprived sympathetic neurons saved by an inhibitor of ICE family proteases.
Sympathetic neurons undergo programmed cell death (PCD) when deprived of NGF. We used an inhibitor to examine the function of interleukin-1 beta-converting enzyme (ICE) family proteases during sympathetic neuronal death and to assess the metabolic and genetic status of neurons saved by such inhibition. Bocaspartyl(OMe)-fluoromethylketone (BAF), a cell-permeable inhibitor of the ICE family of cysteine proteases, inhibited ICE and CPP32 (IC50 approximately 4 microM) in vitro and blocked Fas-mediated apoptosis in thymocytes (EC50 approximately 10 microM). At similar concentrations, BAF also blocked the NGF deprivation-induced death of rat sympathetic neurons in culture. Compared to NGF-maintained neurons, BAF-saved neurons had markedly smaller somas and maintained only basal levels of protein synthesis; readdition of NGF restored growth and metabolism. Although BAF blocked apoptosis in sympathetic neurons, it did not prevent the fall in protein synthesis or the increase in the expression of c-jun, c-fos, and other mRNAs that occur during neuronal PCD, implying that the ICE-family proteases function downstream of these events during PCD.NGF and BAF rescued sympathetic neurons with an identical time course, suggesting that NGF, in addition to inhibiting metabolic and genetic events associated with neuronal PCD, can act posttranslationally to abort apoptosis at a time point indistinguishable from the activation of cysteine proteases. Both poly-(ADP ribose) polymerase and pro-ICE and Ced-3 homolog-1 (ICH-1) appear to be cleaved in a BAF-inhibitable manner, although the majority of pro-CPP32 appears unchanged, suggesting that ICH-1 is activated during neuronal PCD. Potential implications of these findings for anti-apoptotic therapies are discussed.


Serum tube identification of Candida albicans.
The production of filaments (germ tubes) by cells of Candida albicans in serum tubes permits presumptive identification to be made within two to three hours. The proportion of yeast-like cells forming filaments is progressively decreased with increasing cell concentration. The test is effective over a comparatively wide range of temperatures and using different types and concentrations of sera.


Transplantation in the treatment of paralysis agitans (Parkinson's disease).
Over the past 3 years, there has been great interest in transplantation therapy in the treatment of Parkinson's disease. Following the impressive results reported by Madrazo in the spring of 1987, more than 350 cases of adrenal medullary implantation have been performed worldwide. There has been a significant reduction in "off" time and an increase in "on" time without chorea in 40% of patients having this procedure. The duration of effect is 1 year in half of these cases, with the other half (20% of all patients) still demonstrating significant improvement 3 years after the procedure. The mechanism of the bilateral beneficial improvement is unknown. The survival of adrenal medullary tissue has not been demonstrated at autopsy. It is thought that the mechanism of improvement involves either regenerative sprouting of the remaining dopamine producing neurons as a consequence of the release of neurotrophic factors or an interruption of the striatal pallidal output inhibitory influence of the basal ganglia on the thalamus (or both). Fetal mesencephalic implantation has also been attempted in more than 100 cases worldwide. The improvements when seen are not any more dramatic than those following the best results of adrenal medullary implantation. Graft survival has not been proved; it remains a possibility that interruption of the putamino-subthalamic pallidal pathway or a trophic influence of the tissue provides an alleviation in parkinsonism. The ethical controversy, need for long-term immunosuppression, and difficulty with obtaining tissue of the appropriate age and delivering the appropriate quantity to the putamen have made this technique less than adequate.(ABSTRACT TRUNCATED AT 250 WORDS)


Functional and molecular differences between voltage-gated K+ channels of fast-spiking interneurons and pyramidal neurons of rat hippocampus.
We have examined gating and pharmacological characteristics of somatic K+ channels in fast-spiking interneurons and regularly spiking principal neurons of hippocampal slices. In nucleated patches isolated from basket cells of the dentate gyrus, a fast delayed rectifier K+ current component that was highly sensitive to tetraethylammonium (TEA) and 4-aminopyridine (4-AP) (half-maximal inhibitory concentrations <0.1 mM) predominated, contributing an average of 58% to the total K+ current in these cells. By contrast, in pyramidal neurons of the CA1 region a rapidly inactivating A-type K+ current component that was TEA-resistant prevailed, contributing 61% to the total K+ current. Both types of neurons also showed small amounts of the K+ current component mainly found in the other type of neuron and, in addition, a slow delayed rectifier K+ current component with intermediate properties (slow inactivation, intermediate sensitivity to TEA). Single-cell RT-PCR analysis of mRNA revealed that Kv3 (Kv3.1, Kv3.2) subunit transcripts were expressed in almost all (89%) of the interneurons but only in 17% of the pyramidal neurons. In contrast, Kv4 (Kv4.2, Kv4.3) subunit mRNAs were present in 87% of pyramidal neurons but only in 55% of interneurons. Selective block of fast delayed rectifier K+ channels, presumably assembled from Kv3 subunits, by 4-AP reduced substantially the action potential frequency in interneurons. These results indicate that the differential expression of Kv3 and Kv4 subunits shapes the action potential phenotypes of principal neurons and interneurons in the cortex.


The former preterm infant and risk of post-operative apnoea: recommendations for management.
The preterm infant presenting for anaesthesia during the first 6 months of life is a major anaesthetic challenge. One of the most serious post-operative complications is apnoea with or without bradycardia. For this review, we conducted a search of the current literature in order to formulate a set of evidence-based clinical guidelines to help clinicians in the management of the former preterm infant to avoid post-operative apnoea. Only a small number of patients have been enrolled into prospective, randomized, controlled studies. Based on the current literature, regional anaesthesia is strongly recommended, preferably neuraxial block, but general anaesthesia is also used and in this setting, opioids and muscle relaxants should be avoided. Infants with a post-conceptual age of less than 46 weeks should be admitted for continuous monitoring for at least 12 h post-operatively. In infants with a post-conceptual age (PCA) between 46 and 60 weeks, a careful assessment of the child is mandatory and 12 h of respiratory monitoring is recommended if the patient's history reveals episodes of apnoea at home, chronic lung disease (CLD), neurological disease or anaemia. The otherwise healthy infant could be scheduled for theatre as the first patient on the list and subsequently monitored in the post-anaesthetic care unit for 6 h. The risk of apnoea in former preterm infants can be further reduced by the administration of intravenous caffeine (10 mg/kg). All of these patients should be referred to a tertiary centre for anaesthesia and surgery.


Preprogrammed 2D folding of conformationally flexible oligoamides: foldamers with multiple turn elements.
Controlling the molecular conformation of oligomers on surfaces through noncovalent interactions symbolizes an important approach in the bottom-up patterning of surfaces with nanoscale precision. Here we report on the design, synthesis, and scanning tunneling microscopy (STM) investigation of linear oligoamides adsorbed at the liquid-solid interface. A new class of extended foldamers comprising as many as four turn elements based on a structural design "rule" adapted from a mimic foldamer was successfully synthesized. The self-assembly of these progressively complex oligomeric structures was scrutinized at the liquid-solid interface by employing STM. Submolecularly resolved STM images of foldamers reveal characteristic in-plane folding and self-assembly behavior of these conformationally flexible molecules. The complexity of the supramolecular architectures increases with increasing number of turn elements. The dissimilarity in the adsorption behavior of different foldamers is discussed qualitatively in light of enthalpic and entropic factors. The modular construction of these oligomeric foldamers with integrated functionalities provides a simple, efficient, and versatile approach to surface patterning with molecular precision.


Commonality but diversity in cancer gene fusions.
Recent findings of gene fusions in carcinomas recapitulate the discovery of chromosomal abnormalities in leukemias and sarcomas decades ago. A recurring feature of carcinoma gene fusions, in contrast to those in hematopoietic and mesenchymal malignancies, is that they result in aberrant cell signaling. This may reflect differences in the differentiation programs of these tissues.


Differential effects of beta-blockers on albuminuria in patients with type 2 diabetes.
Increases in the cardiovascular risk marker microalbuminuria are attenuated by blood pressure reduction using blockers of the renin-angiotensin system. Such changes in microalbuminuria have not been observed when beta-blockers are used. A prespecified secondary end point of the Glycemic Effects in Diabetes Mellitus Carvedilol-Metoprolol Comparison in Hypertensives (GEMINI) trial was to examine the effects of different beta-blockers on changes in albuminuria in the presence of renin-angiotensin system blockade. Participants with hypertension and type 2 diabetes were randomized to either metoprolol tartrate (n=737) or carvedilol (n=498) in blinded fashion after a washout period of all antihypertensive agents except for angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Blinded medication was titrated to achieve target blood pressure, with a-5 month follow-up period. The current analysis examined microalbuminuria, using spot urine albumin:creatinine, in participants who had values at screening and trial end. A greater reduction in microalbuminuria was observed for those randomized to carvedilol (-16.2%Delta; 95% confidence interval, -25.3, -5.9; P=0.003). Of those with normoalbuminuria at baseline, fewer progressed to microalbuminuria on carvedilol versus metoprolol (20 of 302 [6.6%] versus 48 of 431 [11.1%], respectively; P=0.03). Microalbuminuria development was not related to differences in blood pressure or achievement of blood pressure goal (68% carvedilol versus 67%, metoprolol). Presence of metabolic syndrome at baseline was the only independent predictor of worsening albuminuria throughout the study (P=0.004). Beta-blockers have differential effects on microalbuminuria in the presence of renin-angiotensin system blockade. These differences cannot be explained by effects on blood pressure or alpha1-antagonism but may relate to antioxidant properties of carvedilol.


Tuberculosis elimination in the countries of Europe and other industrialized countries.
The working group summarized the conclusions of the workshop with the intention of providing a guide for the preparation of national plans for tuberculosis elimination. The basic strategies that appear consistently effective are: 1. Direct government responsibility for diagnosis, treatment and prevention of tuberculosis (the government is responsible by law for assuring that tuberculosis is identified early, and that cure of the patients is achieved). 2. Maintenance (or development) of properly designed disease surveillance and a programme monitoring system. 3. Availability of specialized tuberculosis personnel at regional and provincial level, responsible for close monitoring of the diagnostic skills and patient prioritization in general health institutions. Regarding research it was felt that no immediate practical applications of new techniques in the diagnosis of mycobacterial diseases, in treatment, or in vaccination can be recommended, but that further basic research in the field of mycobacteria should be pursued and supported.


Spatial clustering of filarial transmission before and after a Mass Drug Administration in a setting of low infection prevalence.
BACKGROUND: In the global program for the elimination of lymphatic filariasis (LF) longitudinal assessment of the prevalence of microfilaremia and antigenemia is recommended to monitor the effect of mass treatment on transmission. Additional monitoring tools such as entomologic and antibody methods may be useful in identifying residual foci of infection. In this study, we characterized serologic markers of infection and exposure spatially both before and after mass treatment, in an area of initial low Wuchereria bancrofti infection prevalence. METHODS: Consenting persons in the sentinel community were tested for circulating microfilaria and antigen (by immunochromatographic test) before and after the 1st annual mass drug administration of diethylcarbamazine and albendazole. A cohort of 161 persons provided serum specimens both years that were tested for antifilarial IgG (1 and 4) antibody. Every house was mapped using a differential Global Positioning System; this information was linked to the serologic data. W. bancrofti infection in the mosquito vector was assessed with year-round collection. Multiple linear regression was used to investigate the influence of antigen-positive persons on the antifilarial antibody responses of antigen-negative neighbors. RESULTS: After mass treatment, decreases were observed in the sentinel site in the overall prevalence of antigen (10.4% to 6.3%) and microfilaremia (0.9 to 0.4%). Of the persons in the cohort that provided serum specimens both years, 79% received treatment. Antigen prevalence decreased from 15.0% to 8.7%. Among 126 persons who received treatment, antigen and antifilarial IgG1 prevalence decreased significantly (p = 0.002 and 0.001, respectively). Among 34 persons who did not receive treatment, antifilarial IgG1 prevalence increased significantly (p = 0.003). Average antifilarial IgG1 levels decreased in households with high treatment coverage and increased in households that refused treatment. Each 10-meter increase in distance from the residence of a person who was antigen-positive in 2000 was associated a 4.68 unit decrease in antifilarial IgG1 level in 2001, controlling for other factors (p = 0.04). DISCUSSION: Antifilarial antibody assays can be used as a measure of filarial exposure. Our results suggest that micro-scale spatial heterogeneity exists in LF exposure and infection. Treatment appeared to be associated with reduced exposure at the sub-community level, suggesting the need to achieve high and homogeneous coverage. Public health messages should note the benefits of having one's neighbors receive treatment with antifilarial drugs.


Human detoxification of perfluorinated compounds.
There has been no proven method thus far to accelerate the clearance of potentially toxic perfluorinated compounds (PFCs) in humans. PFCs are a family of commonly used synthetic compounds with many applications, including repelling oil and stains on furniture, clothing, carpets and food packaging, as well as in the manufacturing of polytetrafluoroethylene - a non-stick surfacing often used in cookware (e.g. Teflon(r)). Some PFCs remain persistent within the environment due to their inherent chemical stability, and are very slowly eliminated from the human body due, in part, to enterohepatic recirculation. Exposure to PFCs is widespread and some subpopulations, living in proximity to or working in fluorochemical manufacturing plants, are highly contaminated. PFC bioaccumulation has become an increasing public health concern as emerging evidence suggests reproductive toxicity, neurotoxicity and hepatotoxicity, and some PFCs are considered to be likely human carcinogens. A case history is presented where an individual with high concentrations of PFCs in serum provided: (1) sweat samples after use of a sauna; and (2) stool samples before and after oral administration of each of two bile acid sequestrants - cholestyramine (CSM) and saponin compounds (SPCs). Stool samples before and after use of a cation-exchange zeolite compound were also examined. PFCs found in serum were not detected in substantial quantities in sweat or in stool prior to treatment. Minimal amounts of perfluorooctanoic acid, but no other PFCs, were detected in stool after SPC use; minimal amounts of perfluorooctanesulfonate, but no other PFCs, were detected in stool after zeolite use. All PFC congeners found in serum were detected in stool after CSM use. Serum levels of all PFCs subsequently declined after regular use of CSM. Further study is required but this report suggests that CSM therapy may facilitate gastrointestinal elimination of some PFCs from the human body.


Mongolian gerbils learn to navigate in complex virtual spaces.
Virtual reality (VR) environments are increasingly used to study spatial navigation in rodents. So far behavioral paradigms in virtual realities have been limited to linear tracks or open fields. However, little is known whether rodents can learn to navigate in more complex virtual spaces. We used a VR setup with a spherical treadmill but no head-fixation, which permits animals not only to move in a virtual environment but also to freely rotate around their vertical body axis. We trained Mongolian gerbils to perform spatial tasks in virtual mazes of different complexity. Initially the animals learned to run back and forth between the two ends of a virtual linear track for food reward. Performance, measured as path length and running time between the virtual reward locations, improved to asymptotic performance within about five training sessions. When more complex mazes were presented after this training epoch, the animals generalized and explored the new environments already at their first exposure. In a final experiment, the animals also learned to perform a two-alternative forced choice task in a virtual Y-maze. Our data thus shows that gerbils can be trained to solve spatial tasks in virtual mazes and that this behavior can be used as a readout for psychophysical measurements.


US term stillbirth rates and the 39-week rule: a cause for concern?
More than a decade ago an obstetric directive called "the 39-week rule" sought to limit "elective" delivery, via labor induction or cesarean delivery, before 39 weeks 0 days of gestation. In 2010 the 39-week rule became a formal quality measure in the United States. The progressive adherence to the 39-week rule throughout the United States has caused a well-documented, progressive reduction in the proportion of term deliveries occurring during the early-term period. Because of the known association between increasing gestational age during the term period and increasing cumulative risk of stillbirth, however, there have been published concerns that the 39-week rule-by increasing the gestational age of delivery for a substantial number of pregnancies-might increase the rate of term stillbirth within the United States. Although adherence to the 39-week rule is assumed to be beneficial, its actual impact on the US rate of term stillbirth in the years since 2010 is unknown. To determine whether the adoption of the 39-week rule was associated with an increased rate of term stillbirth in the United States. Sequential ecological study, based on state data, of US term deliveries that occurred during a 7-year period bounded by 2007 and 2013. The patterns of the timing of both term childbirth and term stillbirth were determined for each state and for the United States as a whole. A total of 46 usable datasets were obtained (45 states and the District of Columbia). During the 7-year period, there was a continuous reduction in all geographic entities in the proportion of term deliveries that occurred before 39 weeks of gestation. The overall rate of term stillbirth, when we compared 2007-2009 with 2011-2013, increased significantly (1.103/1000 vs 1.177/1000, RR 1.067, 95% confidence interval 1.038-1.096). Furthermore, during the 7-year period, the increase in the rate of US term stillbirth appeared to be continuous (estimated slope: 0.0186/1000/year, 95% confidence interval 0.002-0.035). Assuming 3.5 million term US births per year, and given 6 yearly "intervals" with this rate increase, it is possible that more than 335 additional term stillbirths occurred in the United States in 2013 as compared with 2007. In addition, during the 7-year period, there was a progressive shift in the timing of delivery from the 40th week to the 39th week. Absent this confounding factor, the magnitude of association between the adoption of the 39-week rule and the increase in rate of term stillbirth might have been greater. Between 2007 and 2013 in the United States, the adoption of the 39-week rule caused a progressive reduction in the proportion of term births occurring before the 39th week of gestation. During the same interval the United States experienced a significant increase in its rate of term stillbirth. This study raises the possibility that the 39-week rule may be causing unintended harm. Additional studies of the actual impact of the adoption of the 39-week rule on major childbirth outcomes are urgently needed. Pressures to enforce the 39-week rule should be reconsidered pending the findings of such studies.


Molecular characterization of sarcomatoid clear cell renal cell carcinoma unveils new candidate oncogenic drivers.
Sarcomatoid clear-cell renal cell carcinomas (sRCC) are associated with dismal prognosis. Genomic alterations associated with sarcomatoid dedifferentiation are poorly characterized. We sought to define the genomic landscape of sRCC and uncover potentially actionable therapeutic targets. We assessed the genomic landscape of sRCC using targeted panel sequencing including patients with microdissected sarcomatoid and epithelial components. Along with common genomic alterations associated with clear-cell histology, we found that Hippo was one of the most frequently altered pathways in these tumours. Hippo alterations were differentially enriched in sRCC compared to non-sRCC. Functional analysis showed that Hippo members mutations were associated with higher nuclear accumulation of YAP/TAZ, core effectors of the Hippo pathway. In a NF2-mutant sRCC model, YAP1 knockdown and NF2 reconstitution suppressed cell proliferation, tumour growth and invasion, both in vitro and in vivo. Overall, we show that Hippo pathway alterations are a feature of sRCC, and enable the exploration of the Hippo pathway as a novel potential therapeutic target.


Multiple lineages of lice pass through the K-Pg boundary.
For modern lineages of birds and mammals, few fossils have been found that predate the Cretaceous-Palaeogene (K-Pg) boundary. However, molecular studies using fossil calibrations have shown that many of these lineages existed at that time. Both birds and mammals are parasitized by obligate ectoparasitic lice (Insecta: Phthiraptera), which have shared a long coevolutionary history with their hosts. Evaluating whether many lineages of lice passed through the K-Pg boundary would provide insight into the radiation of their hosts. Using molecular dating techniques, we demonstrate that the major louse suborders began to radiate before the K-Pg boundary. These data lend support to a Cretaceous diversification of many modern bird and mammal lineages.


Apoptotic phosphorylation of histone H2B is mediated by mammalian sterile twenty kinase.
DNA in eukaryotic cells is associated with histone proteins; hence, hallmark properties of apoptosis, such as chromatin condensation, may be regulated by posttranslational histone modifications. Here we report that phosphorylation of histone H2B at serine 14 (S14) correlates with cells undergoing programmed cell death in vertebrates. We identify a 34 kDa apoptosis-induced H2B kinase as caspase-cleaved Mst1 (mammalian sterile twenty) kinase. Mst1 can phosphorylate H2B at S14 in vitro and in vivo, and the onset of H2B S14 phosphorylation is dependent upon cleavage of Mst1 by caspase-3. These data reveal a histone modification that is uniquely associated with apoptotic chromatin in species ranging from frogs to humans and provide insights into a previously unrecognized physiological substrate for Mst1 kinase. Our data provide evidence for a potential apoptotic "histone code."


Gamete types, sex determination and stable equilibria of all-hybrid populations of diploid and triploid edible frogs (Pelophylax esculentus).
Triploid individuals often play a key role in speciation by hybridization. An understanding of the gamete types (ploidy and genomic content) and stability of hybrid populations with triploid individuals is therefore of importance for exploring the role of hybridization in evolution. The all-hybrid populations of the edible frog, Pelophylax esculentus, are unique in their composition and genetic dynamics: Diploid (genotype LR) and triploid (LLR and LRR) hybrids depend on each other's different gamete contributions for successful reproduction and maintenance of the populations, as the parental genotypes P. lessonae (LL) and P. ridibundus (RR) are absent among adults. This study provides data and interpretations on gamete types and sex determination that are essential for understanding the function, evolutionary potential and threats of this intriguing system. Dissection of metamorphs from a crossing experiment confirmed that sex determination is an XX-XY system with the Y confined to the L genome. From microsatellite analysis of parents and offspring from the crossings, gamete frequencies could be deduced: Triploids of both sexes mostly made haploid gametes with the genome they had in double dose, however LLR females also made approximately 10% LL gametes by automixis. LR frogs showed much variation in their gamete production. In LRR-rich populations, their LR sperm production was sufficiently high (22%) to explain the observed proportion of LRR males, the formation of which has not previously been understood. A model was constructed to calculate equilibrium genotype proportions for different population types on the basis of the gamete proportions found. These equilibria agreed well with empirical literature data. If population differentiation with respect to genotype proportions is really driven by gamete patterns, as strongly suggested by the present study, all-hybrid populations constitute not one, but several intrinsically different breeding systems. Tetraploidization could occur if the survival or fertility of both males and females increased. Whether introduction of hybrid or parental species individuals would threaten the all-hybrid populations cannot be predicted without further knowledge on the mechanisms behind non-hybrid inviability, but at least R genomes with Y factor are predicted to be invasive, if introduced, and could bring the populations to collapse.


Self-harm and depression in women with urinary incontinence: a record-linkage study.
To investigate the association between self-harm and urinary incontinence (UI), and between depression and UI, in women. The incidence of self-harm in women with UI is not well documented. We analysed a statistical database that includes hospital contact data for UI and for self-harm and depression. We calculated rate ratios for self-harm and depression in a cohort of women admitted for UI, and rate ratios for UI in cohorts of women admitted with self-harm or depression, compared with a control cohort. After admission for UI, self-harm was significantly high in young women (aged < 45 years: rate ratio 1.73, 95% confidence intervals 1.37-2.14) but not in older women. Depression was associated with UI in all age groups, e.g. after admission for depression the rate ratio for UI within 5 years was 1.46 (1.33-1.75); and for UI at > or = 5 years after admission for depression, it was 1.20 (1.05-1.35). Young women with UI are at risk of self-harm. For all age groups studied, depression was more common in women with UI than in others. Depression might be a consequence of UI, but the increase in risk at long intervals before admission with UI suggests that they might share underlying causal mechanisms.


Spi-1/PU.1 activates transcription through clustered DNA occupancy in erythroleukemia.
Acute leukemias are characterized by deregulation of transcriptional networks that control the lineage specificity of gene expression. The aberrant overexpression of the Spi-1/PU.1 transcription factor leads to erythroleukemia. To determine how Spi-1 mechanistically influences the transcriptional program, we combined a ChIP-seq analysis with transcriptional profiling in cells from an erythroleukemic mouse model. We show that Spi-1 displays a selective DNA-binding that does not often cause transcriptional modulation. We report that Spi-1 controls transcriptional activation and repression partially through distinct Spi-1 recruitment to chromatin. We revealed several parameters impacting on Spi-1-mediated transcriptional activation. Gene activation is facilitated by Spi-1 occupancy close to transcriptional starting site of genes devoid of CGIs. Moreover, in those regions Spi-1 acts by binding to multiple motifs tightly clustered and with similar orientation. Finally, in contrast to the myeloid and lymphoid B cells in which Spi-1 exerts a physiological activity, in the erythroleukemic cells, lineage-specific cooperating factors do not play a prevalent role in Spi-1-mediated transcriptional activation. Thus, our work describes a new mechanism of gene activation through clustered site occupancy of Spi-1 particularly relevant in regard to the strong expression of Spi-1 in the erythroleukemic cells.


High Operator and Hospital Volume Are Associated With a Decreased Risk of Death and Stroke After Carotid Revascularization: A Systematic Review and Meta-analysis.
To examine the association between operator or hospital volume and procedural outcomes of carotid revascularization. Operator and hospital volume have been proposed as determinants of outcome after carotid endarterectomy (CEA) or carotid artery stenting (CAS). The magnitude and clinical relevance of this relationship are debated. We systematically searched PubMed and EMBASE until August 21, 2017. The primary outcome was procedural (30 days, in-hospital, or perioperative) death or stroke. Obtained or estimated risk estimates were pooled with a generic inverse variance random-effects model. We included 87 studies. A decreased risk of death or stroke following CEA was found for high compared to low operator volume with a pooled adjusted odds ratio (OR) of 0.50 (95% confidence interval [CI] 0.28-0.87; 3 cohorts), and a pooled unadjusted relative risk (RR) of 0.59 (95% CI 0.42-0.83; 9 cohorts); for high compared to low hospital volume with a pooled adjusted OR of 0.62 (95% CI 0.42-0.90; 5 cohorts), and a pooled unadjusted RR of 0.68 (95% CI 0.51-0.92; 9 cohorts). A decreased risk of death or stroke after CAS was found for high compared to low operator volume with an adjusted OR of 0.43 (95% CI 0.20-0.95; 1 cohort), and an unadjusted RR of 0.50 (95% CI 0.32-0.79; 1 cohort); for high compared to low hospital volume with an adjusted OR of 0.46 (95% CI 0.26-0.80; 1 cohort), and no significant decreased risk in a pooled unadjusted RR of 0.72 (95% CI 0.49-1.06; 2 cohorts). We found a decreased risk of procedural death and stroke after CEA and CAS for high operator and high hospital volume, indicating that aiming for a high volume may help to reduce procedural complications. This systematic review has been registered in the international prospective registry of systematic reviews (PROSPERO): CRD42017051491.


Could a policy of provision of hip protectors to elderly nursing home residents result in cost savings in acute hip fracture care? The case of Ontario, Canada.
Hip fractures are an important problem in nursing homes. Hip protectors are external devices that decrease the risk of hip fracture in elderly nursing home residents. We estimated the overall healthcare cost savings from a hypothetical strategy of provision of hip protectors to elderly nursing home residents in Ontario, Canada. In a recent meta-analysis, we determined that a strategy of provision of hip protectors decreases the risk of hip fracture in nursing home residents. Our objective was to determine whether the provision of hip protectors to all Ontario nursing home residents aged > or =65 years could result in cost savings, stemming from reductions in initial hospitalizations for hip fracture. We conducted a cost analysis from a Ministry of Health perspective (one year cycle length). The efficacy of the intervention was estimated from a meta-analysis of randomized controlled trials. A strategy of provision of hip protectors to all 60,775 elderly Ontario nursing home residents could result in an overall mean cost savings of 6.0 million Canadian dollars in one year (95% credibility interval, -26.4 million, 39.7 million), with a probability of cost savings of 0.63 (assuming no additional labor costs). In sensitivity analyses, decreasing hip protector price increased cost savings, whereas additional labor expenditures for application for hip protectors decreased cost savings. In conclusion, if hip protectors can be provided to elderly Ontario nursing home residents without additional labor expenditures, there is a reasonable probability that such a strategy may result in healthcare cost savings.


Effect of enamel surface treatment on the bond strength of metallic brackets in rebonding process.
Bond failure after rebonding for newly placed brackets can be reduced by appropriate enamel surface treatment. This in vitro study investigated the effect of two enamel surface treatments on the bond strength of metallic brackets in the rebonding process. After debonding the brackets and removing the residual adhesive on the enamel surface of 50 upper premolar teeth, the teeth were divided into two equal groups. In the first group, the enamel surface was etched with phosphoric acid 37 per cent, and in the second group, the teeth were sandblasted prior to acid etching. After bonding of the new brackets, the shear bond strength (SBS), probability of bond failures, and adhesive remnant index (ARI) were determined and compared with the t-test, Weibull analysis, and chi-square test. Mean SBS in both groups did not differ significantly (P = 0.081). Most bond failures occurred with ARI scores of 2 and 3, and the difference between the two groups was statistically significant (P < 0.001). Weibull analysis showed that for a given stress, the probability of failure differed between groups. Enamel surface preparation with sandblasting prior to acid etching did not significantly improve SBS in bracket rebonding and left more residual adhesive remnants on the enamel surface.


Glucocorticoid with cyclophosphamide for paraquat-induced lung fibrosis.
Paraquat is an effective and widely used herbicide but is also a lethal poison. In many developing countries paraquat is widely available and inexpensive, making poisoning prevention difficult. However most of the people who become poisoned from paraquat have taken it as a means of suicide.Standard treatment for paraquat poisoning both prevents further absorption and reduces the load of paraquat in the blood through haemoperfusion or haemodialysis. The effectiveness of standard treatments is extremely limited.The immune system plays an important role in exacerbating paraquat-induced lung fibrosis. Immunosuppressive treatment using glucocorticoid and cyclophosphamide in combination is being developed and studied. To assess the effects of glucocorticoid with cyclophosphamide on mortality in patients with paraquat-induced lung fibrosis. The most recent search was run on the 15th April 2014. We searched the Cochrane Injuries Group's Specialised Register, The Cochrane Library, Ovid MEDLINE(R), Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid OLDMEDLINE(R), Embase Classic+Embase (Ovid), ISI WOS (SCI-EXPANDED, SSCI, CPCI-S & CPSI-SSH), trials registries, Chinese databases (, , ) and reference lists. RCTs were included in this review. All patients were to receive standard care, plus the intervention or control. The intervention was glucocorticoid with cyclophosphamide in combination versus a control of a placebo, standard care alone or any other therapy in addition to standard care. The mortality risk ratio (RR) and 95% confidence interval (CI) was calculated for each study on an intention-to-treat basis. Data for all-cause mortality at final follow-up were summarised in a meta-analysis using a fixed-effect model. This systematic review includes three trials with a combined total of 164 participants who had moderate to severe paraquat poisoning. Patients who received glucocorticoid with cyclophosphamide in addition to standard care had a lower risk of death at final follow-up than those receiving standard care only (RR 0.72; 95% CI 0.59 to 0.89). Based on the findings of three small RCTs of moderate to severely poisoned patients, glucocorticoid with cyclophosphamide in addition to standard care may be a beneficial treatment for patients with paraquat-induced lung fibrosis. To enable further study of the effects of glucocorticoid with cyclophosphamide for patients with moderate to severe paraquat poisoning, hospitals may provide this treatment as part of an RCT with allocation concealment.


Dexamethasone intravitreal implant in patients with macular edema related to branch or central retinal vein occlusion twelve-month study results.
To evaluate the safety and efficacy of 1 or 2 treatments with dexamethasone intravitreal implant (DEX implant) over 12 months in eyes with macular edema owing to branch or central retinal vein occlusion (BRVO or CRVO). Two identical, multicenter, prospective studies included a randomized, 6-month, double-masked, sham-controlled phase followed by a 6-month open-label extension. We included 1256 patients with vision loss owing to macular edema associated with BRVO or CRVO. At baseline, patients received DEX implant 0.7 mg (n = 421), DEX implant 0.35 mg (n = 412), or sham (n = 423) in the study eye. At day 180, patients could receive DEX implant 0.7 mg if best-corrected visual acuity (BCVA) was <84 letters or retinal thickness was >250 μm. The primary outcome for the open-label extension was safety; BCVA was also evaluated. At day 180, 997 patients received open-label DEX implant. Except for cataract, the incidence of ocular adverse events was similar in patients who received their first or second DEX implant. Over 12 months, cataract progression occurred in 90 of 302 phakic eyes (29.8%) that received 2 DEX implant 0.7 mg injections versus 5 of 88 sham-treated phakic eyes (5.7%); cataract surgery was performed in 4 of 302 (1.3%) and 1 of 88 (1.1%) eyes, respectively. In the group receiving two 0.7-mg DEX implants (n = 341), a ≥ 10-mmHg intraocular pressure (IOP) increase from baseline was observed in (12.6% after the first treatment, and 15.4% after the second). The IOP increases were usually transient and controlled with medication or observation; an additional 10.3% of patients initiated IOP-lowering medications after the second treatment. A ≥ 15-letter improvement in BCVA from baseline was achieved by 30% and 32% of patients 60 days after the first and second DEX implant, respectively. Among patients with macular edema owing to BRVO or CRVO, single and repeated treatment with DEX implant had a favorable safety profile over 12 months. In patients who qualified for and received 2 DEX implant injections, the efficacy and safety of the 2 implants were similar with the exception of cataract progression. Proprietary or commercial disclosure may be found after the references.


Cannabidiol reduces withdrawal symptoms in nicotine-dependent rats.
Cannabidiol (CBD) reduces craving in animal models of alcohol and cocaine use and is known to modulate nicotinic receptor function, suggesting that it may alleviate symptoms of nicotine withdrawal. However, preclinical evaluation of its efficacy is still lacking. The goal of this study was to test the preclinical efficacy of a chronic CBD treatment in reducing nicotine dependence using measures of withdrawal symptoms including somatic signs, hyperalgesia, and weight gain during acute and protracted abstinence. Male and female Wistar rats were made dependent on nicotine using osmotic minipumps (3.15 mg/kg/day) for 2 weeks, after which minipumps were removed to induce spontaneous withdrawal. Three groups received CBD injections at doses of 7.5, 15, and 30 mg/kg/day for 2 weeks, starting 1 week into chronic nicotine infusion. The control groups included rats with nicotine minipumps that received vehicle injections of sesame oil instead of CBD; rats implanted with saline minipumps received sesame oil injections (double vehicle) or the highest dose of CBD 30 mg/kg/day. Throughout the experiment, serum was collected for determination of CBD and nicotine concentrations, mechanical sensitivity threshold and withdrawal scores were measured, and body weight was recorded. CBD prevented rats from exhibiting somatic signs of withdrawal and hyperalgesia during acute and protracted abstinence. There was no dose-response observed for CBD, suggesting a ceiling effect at the doses used and the potential for lower effective doses of CBD. The saline minipump group did not show either somatic signs of withdrawal or hyperalgesia during acute and protracted abstinence, and the highest dose of CBD used (30 mg/kg/day) did not alter these results. This preclinical study suggests that using CBD as a strategy to alleviate the withdrawal symptoms upon nicotine cessation may be beneficial.


The association between the incidence of postmenopausal breast cancer and concentrations at street-level of nitrogen dioxide and ultrafine particles.
There is scant information as to whether traffic-related air pollution is associated with the incidence of breast cancer. Nitrogen dioxide (NO2) and ultrafine particles (UFPs, <0.1µm), are two pollutants that capture intra-urban variations in traffic-related air pollution and may also be associated with incidence. We conducted a population-based, case-control study of street-level concentrations of NO2 and UFPs and incident postmenopausal breast cancer in Montreal, Canada. Incident cases were identified between 2008 and 2011 from all but one hospital that treated breast cancer in the Montreal area. Population controls were identified from provincial electoral lists of Montreal residents and frequency-matched to cases using 5-year age groups. Concentrations of NO2 and UFPs were estimated using two separate land-use regression models. Exposures were assigned to residential locations at the time of recruitment, and we identified residential histories of women who had lived in these residences for 10 years or more. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression models adjusting for individual-level and ecological covariates. We assessed the functional form of NO2 and UFP exposures using natural cubic splines. We found that the functional form of the response functions between incident postmenopausal breast cancer and concentrations of NO2 and UFPs were consistent with linearity. For NO2, we found increasing risks of breast cancer for all subjects combined and stronger associations when analyses were restricted to those women who had lived at their current address for 10 years or more. Specifically, the OR, adjusted for personal covariates, per increase in the interquartile range (IQR=3.75 ppb) of NO2 was 1.08 (95%CI: 0.92-1.27). For women living in their homes for 10 years or more, the adjusted OR was 1.17 (95%CI: 0.93-1.46; IQR=3.84 ppb); for those not living at that home 10 years before the study, it was 0.93 (95%CI: 0.64, 1.36; IQR=3.65 ppb). For UFPs, the ORs were lower than for NO2, with little evidence of association in any of the models or sub-analyses and little variability in the ORs (about 1.02 for an IQR of ~3500cm-3). On the other hand, we found higher ORs amongst cases with positive oestrogen and progesterone receptor status; namely for NO2, the OR was 1.13 (95%CI: 0.94-1.35) and for UFPs it was 1.05 (95%CI: 0.96-1.14). Our findings suggest that exposure to ambient NO2 and UFPs may increase the risk of incident postmenopausal breast cancer especially amongst cases with positive oestrogen and progesterone receptor status.


Early extubation is associated with reduced length of stay and improved outcomes after elective aortic surgery in the Vascular Quality Initiative.
Timing of extubation after open aortic procedures varies across hospitals. This study was designed to examine extubation timing and determine its effect on length of stay (LOS) and respiratory complications after elective open aortic surgery. We studied extubation timing for 7171 patients undergoing elective open abdominal aortic aneurysm repair (2687 [37.5%]) or suprainguinal bypass for aortoiliac occlusive disease (4484 [62.5%]) from October 2010 to April 2015 in hospitals participating in the Vascular Quality Initiative (VQI). Our primary outcome was prolonged LOS (>7 days), and the secondary outcome was respiratory complications (pneumonia or reintubation). The association between extubation timing and outcomes was assessed using multivariable logistic regression mixed-effects models that adjusted for confounding factors at the patient and procedure level. A variable importance analysis was conducted using a chi-pie framework to identify factors contributing to the variability of extubation timing. The 7171 patients undergoing abdominal aortic surgery were a mean age of 65.4 (standard deviation, 10.2) years, and 63% were male. Extubation occurred (1) in the operating room (76.3%), (2) <12 hours (10.9%), (3) 12 to 24 hours (7.2%), or (4) >24 hours (5.6%) after surgery. Hospitals in the top quartile for case volume had the highest percentage of patients extubated in the operating room (82.8%). Patients least likely to be extubated in the operating room were older, more likely to have chronic obstructive pulmonary disease, require vasopressors, have higher estimated blood loss (EBL), and longer procedure times. After adjustment for patient, procedure, and institutional factors, delayed extubation was associated with prolonged LOS (<12 hours: odds ratio [OR], 1.4; 95% confidence interval [CI], 1.2-1.7; 12-24 hours: OR, 2.1; 95% CI, 1.7-2.7; >24 hours: OR, 5.3; 95% CI, 4.0-6.9), and pulmonary complications (<12 hours: OR, 1.9; 95% CI, 1.4-2.6; 12-24 hours: OR, 2.6; 95% CI, 1.8-3.6; >24 hours: OR, 9.6; 95% CI, 7.1-13.0) compared with those extubated in the operating room. Subset analysis of patients extubated in the operating room or <12 hours showed that extubation out of the operating room was associated with prolonged LOS (OR, 1.4; 95% CI, 1.2-1.7) and pulmonary complications (OR, 1.8; 95% CI, 1.3-2.5). The variable importance analysis demonstrated that EBL (26%) and procedure time (24%) accounted for half of the variation in extubation timing. Extubation in the operating room is associated with shorter LOS and morbidity after open aortic surgery. EBL, procedure time, and center variation account for variability in extubation timing. These data advocate for standardized perioperative respiratory care to reduce variation, improve outcomes, and reduce LOS.


Quinacrine upregulates p21/p27 independent of p53 through autophagy-mediated downregulation of p62-Skp2 axis in ovarian cancer.
We have previously shown that the anti-malarial compound Quinacrine (QC) inhibits ovarian cancer (OC) growth by modulating autophagy. In the present study we extended these studies to identify the molecular pathways regulated by QC to promote apoptosis independent of p53 status in OC. QC exhibited strong anti-cancer properties in OC cell lines in contrast to other anti-malarial autophagy inhibiting drugs. QC treatment selectively upregulated cell cycle inhibitor p21, and downregulated F box protein Skp2 and p62/SQSTM1 expression independent of p53 status. Genetic downregulation of key autophagy protein ATG5 abolished QC-mediated effects on both cell cycle protein p21/Skp2 as well as autophagic cargo protein p62. Furthermore, genetic silencing of p62/SQSTM1 resulted in increased sensitivity to QC-mediated apoptosis, downregulated Skp2 mRNA and increased accumulation of p21 expression. Likewise, genetic knockdown of Skp2 resulted in the upregulation of p21 and p27 and increased sensitivity of OC cells to QC treatment. In contrast, transient overexpression of exogenous p62-HA plasmid rescued the QC-mediated Skp2 downregulation indicating the positive regulation of Skp2 by p62. Collectively, these data indicate that QC-mediated effects on cell cycle proteins p21/Skp2is autophagy-dependent and p53-independent in high grade serious OC cells.


Predicting and Assessing Work Performance of People with Limited Work Capacity (LWC): A Multi-Wave, Multi-Source Study.
Purpose Occupational integration is vital for the health of all people, also for people with Limited Work Capacity (LWC). Therefore, participation in regular work is a legal right for people that are restricted in their work capacity due to a disability and/or lack sufficient education. Full and effective integration is dependent on the person-job fit, and adequate vocational support should focus on meeting performance standards, as is common practice in traditional personnel selection and development programmes. Despite the huge amount of valid instruments for personnel selection and development, these tests are not suitable people with LWC. Recently, an instrument was developed for assessment and development purposes specifically for this target group. That study provided evidence for reliability and dimensionality this instrument. In our study, we add criterion-related measures to this instrument to demonstrate that assessment at T1 predict performance at T2, thus validating the instrument. Method We conducted a four-source data study, two sources for independent and two for outcome variables, to test the predictive validity of this instrument in a multi-wave setup. Results This study largely supports the validity of the instrument in predicting work behaviour and task performance of people with LWC. More specific, when measures are tailored to this target group, this group is able to predict their work behaviour and task performance accurately just like the general population. Conclusion We conclude that this instrument contributes to science, vocational support practices, and the personal and professional development of people with LWC, which is required for sustainable work.


Bladder herniation after transpubic urethroplasty.
We report 2 cases of bladder hernia following repair of complex posterior urethral strictures by transpubic bulboprostatic anastomosis and omentoplasty. One patient was treated successfully by repair of the defect with a synthetic mesh. The presence of concomitant pubic diastasis is thought to be a contributing factor, as well as the use of omentum to fill the dead space.