Prophylactic mastectomy: indications, options, and reconstructive alternatives.
Prophylactic mastectomy continues to be a controversial procedure as a preventive tool against breast cancer. Recent research and other scientific advances, however, have refocused attention on better risk estimation, evidence of efficacy, and improvements in reconstruction. The recently discovered genetic markers BRCA1 and BRCA2 have become increasingly important in determining risk; a BRCA1-positive patient's risk of developing breast cancer by the age of 65 is estimated at 50 percent to 80 percent. BRCA1- and BRCA2-positive breast cancers also tend to be higher grade and occur in younger women (making mammography less effective). Genetically linked breast cancers are usually estrogen receptor negative, making them less susceptible to chemoprevention. Various predictive models and recommendations by experts in the field are also available for today's clinicians to ascertain who should be genetically tested. The benefit of bilateral prophylactic mastectomy, although difficult to estimate, can be evaluated by looking at the incidence of breast cancer in studies of patients who have previously undergone prophylactic mastectomy. The estimated risk reduction from these studies is 80 percent to 95 percent. Similarly, life expectancy is believed to be increased from 2.9 to 5.3 years. The psychological benefits include a 70 percent rate of satisfaction and a decrease in emotional concern over developing breast cancer by 74 percent of women who underwent prophylactic mastectomy. Although reconstruction results may vary, most patients have been very satisfied and some may achieve cosmetic results that are better than their preoperative situation. Patient selection for specific types of reconstruction after prophylactic mastectomy and the decision to proceed should be based on surgical risk and the likelihood of a good outcome. The choice of mastectomy incision should consider the size of the breast, preexisting scars, patient risk factors, and the planned method and goal of reconstruction. The authors propose certain guidelines based on degree of ptosis and cup size when planning prophylactic mastectomies with reconstruction. In certain cases, a nipple-sparing mastectomy may provide cosmetic advantages that could outweigh the additional oncologic risk.


Resolving 1 million sensing points in an optimized differential time-domain Brillouin sensor.
A differential pulse-width pair (DPP) Brillouin distributed fiber sensor is implemented to achieve centimetric spatial resolution over distances of several kilometers. The presented scheme uses a scanning method in which the spectral separation between the two probe sidebands is kept constant, while the optical frequency of the pump is swept to scan the Brillouin spectral response. Experimental results show that this method avoids detrimental temporal distortions of the pump pulses, which in a standard implementation prevent the DPP method from operating over mid-to-long distances. Such a novel scanning procedure allows the resolving, for the first time in pure time-domain Brillouin sensors, of 1,000,000 sensing points, i.e., 1 cm spatial resolution over 10 km in a conventional acquisition time.


White paper on the promotion of an integrated risk assessment concept in European regulatory frameworks for chemicals.
The vision of a sustainable and safe use of chemicals to protect human health, preserve the environment and maintain the ecosystem requires innovative and more holistic approaches to risk assessment (RA) in order to better inform decision making. Integrated risk assessment (IRA) has been proposed as a solution to current scientific, societal and policy needs. It is defined as the mutual exploitation of environmental risk assessment (ERA) for human health risk assessment (HHRA) and vice versa in order to coherently and more efficiently characterize an overall risk to humans and the environment for better informing the risk analysis process. Extrapolating between species which are relevant for HHRA and ERA requires a detailed understanding of pathways of toxicity/modes of action (MoA) for the various toxicological endpoints. Significant scientific advances, changes in chemical legislation, and increasing environmental consciousness have created a favourable scientific and regulatory environment to develop and promote the concept and vision of IRA. An initial proof of concept is needed to foster the incorporation of IRA approaches into different chemical sectorial regulations and demonstrate their reliability for regulatory purposes. More familiarity and confidence with IRA will ultimately contribute to an overall reduction in in vivo toxicity testing requirements. However, significant progress will only be made if long-term support for MoA-related research is secured. In the short term, further exchange and harmonization of RA terminology, models and methodologies across chemical categories and regulatory agencies will support these efforts. Since societal values, public perceptions and cultural factors are of increasing importance for the acceptance of risk analysis and successful implementation of risk mitigation measures, the integration of socio-economic analysis and socio-behavioural considerations into the risk analysis process may help to produce a more effective risk evaluation and consideration of the risks and benefits associated with the use of chemicals.


Simulation study of high-dose-rate brachytherapy for early glottic cancer.
External beam radiation therapy (EBRT) is effective for early glottic cancers, with cure rates of ∼90% for T1 tumors. EBRT has strengths but also disadvantages including radiation to healthy tissues and duration of 5-7 weeks. With advances in laryngeal framework surgery, new devices can provide reliable, minimally invasive access to the larynx. Such devices could be modified to insert brachytherapy catheters. Brachytherapy could provide focused radiation while limiting dose to normal structures in the larynx and neck. As a preliminary step, we performed simulations comparing EBRT to high-dose-rate brachytherapy to assess if this approach could provide dosimetric advantage. One- and 2-catheter brachytherapy simulations were performed for 3 patients with T1 glottic carcinoma. Percentage of dose delivered to the target and adjacent structures was compared with conventional EBRT using 3D and intensity-modulated radiation therapy approaches. Percentage of structures exposed to 50% of the dose was lower for brachytherapy compared with 3D EBRT and intensity-modulated radiation therapy, particularly for the cricoid and contralateral arytenoid. Dose was also lower for the carotid-internal jugular vein complexes compared with 3D EBRT. Dose profiles did not differ significantly between 1- and 2-catheter simulations. Brachytherapy can decrease radiation to normal tissues including laryngeal cartilages and carotid-internal jugular vein complexes. Recent advancements allowing catheter placement may afford the potential to decrease radiation to healthy tissues with decreased treatment time. However, careful, stepwise evaluation of feasibility and outcomes in model systems is required before recommending this approach for such high cure rate cancers in humans.


Is pharmacologic care of chronic obstructive pulmonary disease consistent with the guidelines?
Chronic obstructive pulmonary disease (COPD) is a common chronic illness that affects an estimated 210 million people worldwide, including 12 million people in the United States. National and international guidelines for treatment of COPD recommend use of certain medications, especially bronchodilators and corticosteroids, but the extent to which these are used appropriately is largely unknown. The objective of this study was to determine the extent to which pharmacotherapy for COPD is consistent with guidelines. Individuals with COPD (N = 2272), enrolled for at least 2 years in a large midwestern managed care organization, were identified from medical claims data. Medications dispensed in 2003 were examined using National Drug Codes from dispensation records. Quality indictors, developed from guidelines, focused on (1) use of bronchodilators, (2) use of inhaled corticosteroids (ICS) for patients with frequent exacerbations, and (3) use of systemic corticosteroids for acute exacerbation of COPD (AE-COPD). A total of 2272 subjects aged 45 years or older with a diagnosis of COPD were identified. Seventy-two percent of subjects with COPD received at least 1 bronchodilator; 64% of subjects with frequent prior exacerbations (> or =3 in the past year) received ICS; and only 51% of subjects with AE-COPD during the study year received systemic corticosteroids. Although most patients received 1 or more respiratory medications recommended by the guidelines, there were gaps in care including limited use of systemic corticosteroids for AE-COPD and ICS for patients with frequent exacerbations. Greater use of appropriate medications could lead to improved health for patients with COPD.


Block copolymer synthesis by controlled/living radical polymerisation in heterogeneous systems.
Nanostructured soft materials open up new opportunities in material design and application, and block copolymer self-assembly is one particularly powerful phenomenon that can be exploited for their synthesis. The advent of controlled/living radical polymerisation (CLRP) has greatly simplified block copolymer synthesis, and versatility towards monomer types and polymer architectures across the different forms of CLRP has vastly expanded the range of functional materials accessible. CLRP-controlled synthesis of block copolymers has been applied in heterogeneous systems, motivated by the numerous process advantages and the position of emulsion polymerisation at the forefront of industrial latex synthesis. In addition to the inherent environmental advantages of heterogeneous routes, the incidence of block copolymer self-assembly within dispersed particles during polymerisation leads to novel nanostructured materials that offer enticing prospects for entirely new applications of block copolymers. Here, we review the range of block copolymers prepared by heterogeneous CLRP techniques, evaluate the methods applied to maximise purity of the products, and summarise the unique nanoscale morphologies resulting from in situ self-assembly, before discussing future opportunities within the field.


Can microsolvation effects be estimated from vacuum computations? A case-study of alcohol decomposition at the H2O/Pt(111) interface.
Converting biomass into sustainable chemicals and energy feed-stocks requires innovative heterogeneous catalysts, which are able to efficiently work under aqueous conditions. Computational chemistry is a key asset in the design of these novel catalysts, but it has to face two challenges: the large reaction networks and the potential role of hydration. They can be addressed using scaling relations such as Brønsted-Evans-Polanyi (BEP) and solvation models, respectively. In this study, we show that typical reaction and activation energies of alcohol decomposition on Pt(111) are not strongly modified by the inclusion of the water solvent as a continuum model. In contrast, adding a single water molecule strongly favours O-H and C-OH scission and it prevents C-O and to a lesser extent C-C scissions. The resulting BEP relationships partially reflect these changes induced by the solvent. Predicting Pt-catalysed alcohol decomposition in water should thus account for the influence of the solvent on thermodynamics and kinetics. In addition, we found that the reaction energies obtained in the presence of an explicit water molecule scale with the ones obtained in a vacuum. Hence, we reveal that vacuum computations in combination with corrections based on our linear regressions are able to capture the important H-bonding effect.


Absence of a radiation-induced first-cycle G1-S arrest in p53+ human tumor cells synchronized by mitotic selection.
It is well known that normal human diploid fibroblasts undergo a significant, p53-dependent arrest in the G1 phase of the cell cycle after exposure to ionizing radiation. The presence and magnitude of a G1 arrest in human tumor cell lines, however, has been controversial, particularly in cells derived from solid tumors and irradiated during exponential growth. To examine this question more precisely, we synchronized cells by mitotic selection and irradiated them in very early G1 prior to any of the described G1 checkpoints. Progression of cells from G1 into the S phase was monitored by autoradiographic measurement of cumulative labeling indices and by flow cytometric analysis. Three different human tumor cell lines confirmed as expressing normal p53 function were examined, i.e., lines derived from an adenocarcinoma of the colon (RKO), a breast cancer (MCF-7), and a squamous cell carcinoma (SCC61). Following irradiation with 4-8 Gy, there was a transient delay in progression from G1 into S phase, lasting approximately 2 h, and in two of the three cell lines (RKO and MCF-7), a small fraction of cells (5-8%) never entered the first S phase. Although there was no evidence for a prolonged G1 arrest, the expected G2 delay was observed in all three cell lines. When irradiated RKO cells were resynchronized at the next mitosis, approximately 30% of the cells did not enter the second S phase. This latter finding is consistent with earlier reports on the kinetics of radiation-induced reproductive failure in mammalian cells. These results indicate that cells derived from human solid tumors that express normal p53 may respond to irradiation quite differently than do normal cells in terms of G1 checkpoint control.


Hypnosis as a treatment of chronic widespread pain in general practice: a randomized controlled pilot trial.
Hypnosis treatment in general practice is a rather new concept. This pilot study was performed to evaluate the effect of a standardized hypnosis treatment used in general practice for patients with chronic widespread pain (CWP). The study was designed as a randomized control group-controlled study. Sixteen patients were randomized into a treatment group or a control group, each constituting eight patients. Seven patients in the treatment group completed the schedule. After the control period, five of the patients in the control group also received treatment, making a total of 12 patients having completed the treatment sessions. The intervention group went through a standardized hypnosis treatment with ten consecutive therapeutic sessions once a week, each lasting for about 30 minutes, focusing on ego-strengthening, relaxation, releasing muscular tension and increasing self-efficacy. A questionnaire was developed in order to calibrate the symptoms before and after the 10 weeks period, and the results were interpolated into a scale from 0 to 100, increasing numbers representing increasing suffering. Data were analyzed by means of T-tests. The treatment group improved from their symptoms, (change from 62.5 to 55.4), while the control group deteriorated, (change from 37.2 to 45.1), (p = 0,045). The 12 patients who completed the treatment showed a mean improvement from 51.5 to 41.6. (p = 0,046). One year later the corresponding result was 41.3, indicating a persisting improvement. The study indicates that hypnosis treatment may have a positive effect on pain and quality of life for patients with chronic muscular pain. Considering the limited number of patients, more studies should be conducted to confirm the results. The study was registered in ClinicalTrials.gov and released 27.08.07 Reg nr NCT00521807 Approval Number: 05032001.


QQS orphan gene regulates carbon and nitrogen partitioning across species via NF-YC interactions.
The allocation of carbon and nitrogen resources to the synthesis of plant proteins, carbohydrates, and lipids is complex and under the control of many genes; much remains to be understood about this process. QQS (Qua-Quine Starch; At3g30720), an orphan gene unique to Arabidopsis thaliana, regulates metabolic processes affecting carbon and nitrogen partitioning among proteins and carbohydrates, modulating leaf and seed composition in Arabidopsis and soybean. Here the universality of QQS function in modulating carbon and nitrogen allocation is exemplified by a series of transgenic experiments. We show that ectopic expression of QQS increases soybean protein independent of the genetic background and original protein content of the cultivar. Furthermore, transgenic QQS expression increases the protein content of maize, a C4 species (a species that uses 4-carbon photosynthesis), and rice, a protein-poor agronomic crop, both highly divergent from Arabidopsis. We determine that QQS protein binds to the transcriptional regulator AtNF-YC4 (Arabidopsis nuclear factor Y, subunit C4). Overexpression of AtNF-YC4 in Arabidopsis mimics the QQS-overexpression phenotype, increasing protein and decreasing starch levels. NF-YC, a component of the NF-Y complex, is conserved across eukaryotes. The NF-YC4 homologs of soybean, rice, and maize also bind to QQS, which provides an explanation of how QQS can act in species where it does not occur endogenously. These findings are, to our knowledge, the first insight into the mechanism of action of QQS in modulating carbon and nitrogen allocation across species. They have major implications for the emergence and function of orphan genes, and identify a nontransgenic strategy for modulating protein levels in crop species, a trait of great agronomic significance.


Comparative effects of clindamycin and lincomycin on end-plate currents and quantal content at the neuromuscular junction.
The pre- and postjunctional effects of the lincosamide antibiotics, clindamycin and lincomycin, were studied in voltage-clamped transected twitch fibers of costocutaneous muscles of garter snakes (species Thamnophis). Miniature end-plate currents and end-plate currents (EPCs) were recorded over a wide voltage range for each antibiotic. The amplitude and kinetics of these currents were studied and estimates of the quantal content of evoked transmitter release determined. High concentrations of clindamycin (2 X 10(-4) M) and lincomycin (2 X 10(-3) M) produced significant depression of EPC amplitude and a nonlinearity in the EPC-voltage relationships. The time constant of EPC decay was accelerated in clindamycin and the relationship between the time constant of EPC decay and membrane potential remained a single exponential function with a concentration-dependent loss of the voltage dependence. In contrast to clindamycin, lincomycin produced biphasic EPCs which consisted of two components, one faster and one slower than the control decay rate. The relative amplitude and decay rate of each component was both concentration and voltage dependent. Either increasing the concentration of lincomycin or membrane hyperpolarization decreased the amplitude ratio, iota slow/iota fast, and increased the ratio of the respective time constants, tau slow/tau fast. Clindamycin affected EPC decay amplitude and quantal content in the same concentration range, whereas lincomycin affected EPC decay at concentrations 20 times less than those required to reduce EPC amplitude and quantal content. These results suggest that the neuromuscular blocking effects of clindamycin involve both pre-and postjunctional sites, whereas the effects of lincomycin are primarily on the postjunctional receptor-channel complex.


Adiposity, physical activity and risk of diabetes mellitus: prospective data from the population-based HUNT study, Norway.
Physical activity may counteract the adverse effects of adiposity on cardiovascular mortality; however, the evidence of a similar effect on diabetes is sparse. This study examines whether physical activity may compensate for the adverse effect of adiposity on diabetes risk. The study population consisted of 38 231 individuals aged 20 years or more who participated in two consecutive waves of the prospective longitudinal Nord-Trøndelag Health Study in Norway: in 1984-1986 and in 1995-1997. A Poisson regression model with SEs derived from robust variance was used to estimate adjusted risk ratios of diabetes between categories of body mass index and physical activity. Risk of diabetes increased both with increasing body mass (Ptrend <0.001) and with decreasing physical activity level (Ptrend <0.001 in men and 0.01 in women). Combined analyses showed that men who were both obese and had low activity levels had a risk ratio of 17 (95% CI 9.52 to 30) compared to men who were normal weight and highly active, whereas obese men who reported high activity had a risk ratio of 13 (95% CI 6.92 to 26). Corresponding analysis in obese women produced risk ratios of 15 (95% CI 9.18 to 25) and 13 (95% CI 7.42 to 21) among women reporting low and high activity levels, respectively. This study shows that overweight and obesity are associated with a substantially increased risk of diabetes, particularly among those who also reported being physically inactive. High levels of physical activity were associated with a lower risk of diabetes within all categories of body mass index, but there was no clear evidence that being physically active could entirely compensate for the adverse effect of adiposity on diabetes risk.


Why are some books important (and others not)?
The book Why Are Some People Healthy and Others Not? The Determinants of Health of Populations represented a milestone in our evolving understanding of the determinants of population health. Building on Marc Lalonde's earlier A New Perspective on the Health of Canadians, it created a theoretical framework that could incorporate emerging evidence from a wide range of disciplines. Central to its authors' approach was the observation of heterogeneity, of the systematic differences in health observed when populations are partitioned on characteristics such as income, education, geographic region, etc. The universal observation of a social gradient, of a strong correlation between socio-economic class and health, led to a focus on how the social environment might influence health. Social position strongly influences both the stresses to which individuals are subject, and the resources available to cope with them. Furthermore, healthy and unhealthy responses to stress become "embedded", learned or conditioned both behaviourally and biologically, thus influencing health over the whole life course. The book's impact has been remarkable, not merely in academic citations but through its authors' subsequent work and strategic positions in Canadian health research organizations. The concept of "Population Health" has become part of our shared intellectual heritage.


External Beam, Brachytherapy, or Chemotherapy? Defining Adjuvant Therapy for Early-Stage and High- and High-Intermediate-Risk Endometrial Cancer.
The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice. A 54-year-old postmenopausal female with a history of stroke and carotid endarterectomy presented with 3 weeks of vaginal bleeding with passage of clots. Gynecologic exam revealed a 3-cm barrel-shaped cervix with friability at the os and no appreciable parametrial involvement. Cervical biopsy showed high-grade endometrioid adenocarcinoma. Pelvic magnetic resonance imaging demonstrated a 9.9-cm × 4.5-cm × 6.2-cm mass extending from the uterus to the cervix with greater than 50% myometrial invasion (MMI; Fig 1 ). Total laparoscopic hysterectomy, bilateral salpingo-oophorectomy, and pelvic lymphadenectomy revealed International Federation of Gynecology and Obstetrics (FIGO) stage II endometrial cancer: a 12-cm grade 3 endometrioid adenocarcinoma with 80% MMI and lymphovascular invasion (LVI) involving the outer half of the cervical stroma ( Fig 1 ), and without pelvic lymph node involvement.


Benefit-risk profile of cytoreductive drugs along with antiplatelet and antithrombotic therapy after transient ischemic attack or ischemic stroke in myeloproliferative neoplasms.
We analyzed 597 patients with myeloproliferative neoplasms (MPN) who presented transient ischemic attacks (TIA, n = 270) or ischemic stroke (IS, n = 327). Treatment included aspirin, oral anticoagulants, and cytoreductive drugs. The composite incidence of recurrent TIA and IS, acute myocardial infarction (AMI), and cardiovascular (CV) death was 4.21 and 19.2%, respectively at one and five years after the index event, an estimate unexpectedly lower than reported in the general population. Patients tended to replicate the first clinical manifestation (hazard ratio, HR: 2.41 and 4.41 for recurrent TIA and IS, respectively); additional factors for recurrent TIA were previous TIA (HR: 3.40) and microvascular disturbances (HR: 2.30); for recurrent IS arterial hypertension (HR: 4.24) and IS occurrence after MPN diagnosis (HR: 4.47). CV mortality was predicted by age over 60 years (HR: 3.98), an index IS (HR: 3.61), and the occurrence of index events after MPN diagnosis (HR: 2.62). Cytoreductive therapy was a strong protective factor (HR: 0.24). The rate of major bleeding was similar to the general population (0.90 per 100 patient-years). In conclusion, the long-term clinical outcome after TIA and IS in MPN appears even more favorable than in the general population, suggesting an advantageous benefit-risk profile of antithrombotic and cytoreductive treatment.


Risk Factors for Canine Osteoarthritis and Its Predisposing Arthropathies: A Systematic Review.
Osteoarthritis is a common clinical and pathological end-point from a range of joint disorders, that ultimately lead to structural and functional decline of the joint with associated lameness and pain. Increasing understanding of the risk factors associated with osteoarthritis will assist in addressing the significant threat it poses to the welfare of the dog population and implementing preventive measures. Presented here, is the first comprehensive systematic review and evaluation of the literature reporting risk factors for canine osteoarthritis. This paper aimed to systematically collate, review and critically evaluate the published literature on risk factors for canine osteoarthritis and its predisposing conditions such as developmental joint dysplasias, cruciate ligament degeneration, and patellar luxation. Peer-reviewed publications were systematically searched for both osteoarthritis and predisposing arthropathies on Web of Science and PubMed following PRISMA (2009) guidelines, using pre-specified combinations of keywords. Sixty-two papers met the inclusion criteria and were evaluated and graded on reporting quality. Identified risk factors included both modifiable factors (neuter status and body weight) for which intervention can potentially affect the risk of occurrence of osteoarthritis, and unmodifiable factors (sex, breed, and age) which can be used to identify individuals most "at risk." Osteoarthritis in dogs frequently develops from predisposing arthropathies, and therefore risk factors for these are also important to consider. Papers evaluated in this study were rated as medium to high-quality; gap analysis of the literature suggests there would be significant benefit from additional research into the interactions between and relative weighting of risk factors. There are a number of examples where research outcomes are conflicting such as age and sex; and further investigation into these factors would be beneficial to attain greater understanding of the nature of these risks. Comprehensively collating the published risk factors for osteoarthritis and its predisposing conditions offers opportunities to identify possible means for control and reduction within the population through preventative methods and control strategies. These factors are highlighted here, as well as current literature gaps where further research is warranted, to aid future research direction.


Aromatization of natural products by a specialized detoxification enzyme.
In plants, lineage-specific metabolites can be created by activities derived from the catalytic promiscuity of ancestral proteins, although examples of recruiting detoxification systems to biosynthetic pathways are scarce. The ubiquitous glyoxalase (GLX) system scavenges the cytotoxic methylglyoxal, in which GLXI isomerizes the α-hydroxy carbonyl in the methylglyoxal-glutathione adduct for subsequent hydrolysis. We show that GLXIs across kingdoms are more promiscuous than recognized previously and can act as aromatases without cofactors. In cotton, a specialized GLXI variant, SPG, has lost its GSH-binding sites and organelle-targeting signal, and evolved to aromatize cyclic sesquiterpenes bearing α-hydroxyketones to synthesize defense compounds in the cytosol. Notably, SPG is able to transform acetylated deoxynivalenol, the prevalent mycotoxin contaminating cereals and foods. We propose that detoxification enzymes are a valuable source of new catalytic functions and SPG, a standalone enzyme catalyzing complex reactions, has potential for toxin degradation, crop engineering and design of novel aromatics.


Motion detection using extended fractional Fourier transform and digital speckle photography.
Digital speckle photography is a useful tool for measuring the motion of optically rough surfaces from the speckle shift that takes place at the recording plane. A simple correlation based digital speckle photographic system has been proposed that implements two simultaneous optical extended fractional Fourier transforms (EFRTs) of different orders using only a single lens and detector to simultaneously detect both the magnitude and direction of translation and tilt by capturing only two frames: one before and another after the object motion. The dynamic range and sensitivity of the measurement can be varied readily by altering the position of the mirror/s used in the optical setup. Theoretical analysis and experiment results are presented.


Re-opening live events and large venues after Covid-19 'lockdown': Behavioural risks and their mitigations.
This article reviews the behavioural risks and possible mitigations for re-opening large venues for sports and music events when Covid-19 infection rates and hospitalizations begin to decline. We describe the key variables that we suggest will affect public behaviour relevant to the spread of the virus, drawing upon four sources: (1) relevant evidence and recommendations from the Scientific Pandemic Influenza Group on Behaviours produced for the Scientific Advisory Group for Emergencies (SAGE); (2) research evidence from non-pandemic conditions; (3) research on behaviour during the pandemic; and (4) relevant theory. We first outline some basic risks and a framework for understanding collective behaviour at live events. We then survey some trends in UK public behaviour observed over 2020 and how these might interact with the opening of live events and venues. We present a range of mitigation strategies, based on the framework for collective behaviour and on what is known about non-pharmaceutical (i.e. behavioural) interventions in relation to Covid-19.


Preferential binding of hot spot mutant p53 proteins to supercoiled DNA in vitro and in cells.
Hot spot mutant p53 (mutp53) proteins exert oncogenic gain-of-function activities. Binding of mutp53 to DNA is assumed to be involved in mutp53-mediated repression or activation of several mutp53 target genes. To investigate the importance of DNA topology on mutp53-DNA recognition in vitro and in cells, we analyzed the interaction of seven hot spot mutp53 proteins with topologically different DNA substrates (supercoiled, linear and relaxed) containing and/or lacking mutp53 binding sites (mutp53BS) using a variety of electrophoresis and immunoprecipitation based techniques. All seven hot spot mutp53 proteins (R175H, G245S, R248W, R249S, R273C, R273H and R282W) were found to have retained the ability of wild-type p53 to preferentially bind circular DNA at native negative superhelix density, while linear or relaxed circular DNA was a poor substrate. The preference of mutp53 proteins for supercoiled DNA (supercoil-selective binding) was further substantiated by competition experiments with linear DNA or relaxed DNA in vitro and ex vivo. Using chromatin immunoprecipitation, the preferential binding of mutp53 to a sc mutp53BS was detected also in cells. Furthermore, we have shown by luciferase reporter assay that the DNA topology influences p53 regulation of BAX and MSP/MST1 promoters. Possible modes of mutp53 binding to topologically constrained DNA substrates and their biological consequences are discussed.


Connexin mutation that causes dominant congenital cataracts inhibits gap junctions, but not hemichannels, in a dominant negative manner.
The connexin (Cx) 50, E48K, mutation is associated with a human dominant congenital cataract; however, the underlying molecular mechanism has not been characterized. The glutamate (E) residue at position 48 is highly conserved across animal species and types of connexins. When expressed in paired Xenopus oocytes, human (h) and chicken (ch) Cx50 E48K mutants showed no electrical coupling. In addition, this mutation acts in a dominant negative manner when paired hetero-typically or hetero-merically with wild-type Cx50, but has no such effect on Cx46, the other lens fiber connexin. A similar loss-of-function and dominant negative effect was observed using dye transfer assays in the same system. By using two different dye transfer methods, with two different tracer dyes, we found chCx50 E48K expressed in chicken lens embryonic fibroblast cells by retroviral infection similarly failed to induce dye coupling, and prevented wild-type chCx50 from forming functional gap junctions. In contrast to its effect on gap junctions, the E48K mutation has no effect on hemichannel activity when assayed using electrical conductance in oocytes, and mechanically induced dye uptake in cells. Cx50 is functionally involved in cell differentiation and lens development, and the E48K mutant promotes primary lens cell differentiation indistinguishable from wild-type chCx50, despite its lack of junctional channel function. Together the data show that mutations affecting gap junctions but not hemichannel function of Cx50 can lead to dominant congenital cataracts in humans. This clearly supports the model of intercellular coupling of fiber cells creating a microcirculation of nutrients and metabolites required for lens transparency.


Model system for the analysis of cell surface expression of human ABCA1.
The ABCA1 protein plays a pivotal role in reverse cholesterol transport, by mediating the generation of HDL particles and removing cellular cholesterol. Both the proper expression of ABCA1 in the plasma membrane and the internalization along with apoA-I are required for function. Therefore, we developed a model system to investigate the effect of clinically relevant drugs on the cell surface appearance of ABCA1. By retroviral transduction system, we established stable mammalian cell lines expressing functional and non-functional ABCA1 variants, tagged with an extracellular hemagglutinin epitope. After characterization of the expression, proper localization and function of different ABCA1 variants, we followed quantitatively their cell surface expression by immunofluorescent staining, using flow cytometry. As expected, we found increased cell surface expression of ABCA1 after treatment with a calpain inhibitor, and observed a strong decrease in plasma membrane ABCA1 expression upon treatment with a trans-Golgi transport inhibitor, Brefeldin A. We tested cholesterol level lowering drugs and other potential inhibitors of ABCA1. Here we demonstrate that ezetimibe affects ABCA1 cell surface expression only in the case of a functional ABCA1. Our model system allows a quantitative detection of cell surface expression of ABCA1, screening of substrates or specific inhibitors, and investigating transport regulation.


Genomic stability of pulmonary artery endothelial colony-forming cells in culture.
Pulmonary vascular remodeling, including proliferation and migration of pulmonary artery endothelial cells (PAEC), is a pathologic hallmark of pulmonary arterial hypertension (PAH). Multiple studies have shown evidence of increased levels of DNA damage and lineage-specific genetic changes in PAH lung vascular cells, suggesting increased genomic instability. Highly proliferative endothelial colony-forming cell (ECFC) clones can be isolated from PAEC. Here we utilized ECFC to track chromosomal copy number of 20 PAH and eight control clones across serial passages using genome-wide microarrays. All PAH clones were genomically stable for at least 20-22 population doublings. At very late passages, ECFC developed a highly aneuploid karyotype, but this was generally associated with senescence and was common to both PAH and controls. We also utilized ECFC to isolate the chromosomally abnormal cells from a mixed population of PAH PAEC. Analysis of PAEC harboring two different changes affecting chromosomes 1 and X demonstrated that both abnormalities were present in the same clone, indicating they originated in a common ancestral cell. In a second case, with a partial duplication of chromosome 17, clones carrying the duplication were more frequent at later passages than chromosomally normal clones from the same PAEC culture, suggesting the rearrangement may confer a proliferative advantage. Overall, this small study suggests that endothelial cells from PAH lungs are stable in culture, but that when chromosome abnormalities do occur, they may confer a selective advantage that allows expansion of the abnormal cell population and could contribute to lung vascular remodeling in vivo.


Economic Development and Forest Cover: Evidence from Satellite Data.
Ongoing deforestation is a pressing, global environmental issue with direct impacts on climate change, carbon emissions, and biodiversity. There is an intuitive link between economic development and overexploitation of natural resources including forests, but this relationship has proven difficult to establish empirically due to both inadequate data and convoluting geo-climactic factors. In this analysis, we use satellite data on forest cover along national borders in order to study the determinants of deforestation differences across countries. Controlling for trans-border geo-climactic differences, we find that income per capita is the most robust determinant of differences in cross-border forest cover. We show that the marginal effect of per capita income growth on forest cover is strongest at the earliest stages of economic development, and weakens in more advanced economies, presenting some of the strongest evidence to date for the existence of at least half of an environmental Kuznets curve for deforestation.


[Nalbuphine in pediatric anesthesia].
Efficient and safe pediatric perioperative pain therapy in the context of a multimodal pain therapy concept requires a slight to moderate opioid analgesic. Nalbuphine is a nearly ideal opioid for this purpose due to its unique pharmacological properties as a μ-receptor antagonist/κ-receptor agonist and a high safety profile. Nalbuphine is used clinically primarily in postoperative pain therapy administered as a bolus, continuous infusion and patient-controlled analgesia. Furthermore, it is administered in different regimens for pediatric diagnostic and interventional sedation.


An information-theoretic derivation of min-cut-based clustering.
Min-cut clustering, based on minimizing one of two heuristic cost functions proposed by Shi and Malik nearly a decade ago, has spawned tremendous research, both analytic and algorithmic, in the graph partitioning and image segmentation communities over the last decade. It is, however, unclear if these heuristics can be derived from a more general principle, facilitating generalization to new problem settings. Motivated by an existing graph partitioning framework, we derive relationships between optimizing relevance information, as defined in the Information Bottleneck method, and the regularized cut in a K-partitioned graph. For fast-mixing graphs, we show that the cost functions introduced by Shi and Malik can be well approximated as the rate of loss of predictive information about the location of random walkers on the graph. For graphs drawn from a generative model designed to describe community structure, the optimal information-theoretic partition and the optimal min-cut partition are shown to be the same with high probability.


Low-density lipoprotein nanoparticles as magnetic resonance imaging contrast agents.
Low-density lipoproteins (LDLs) are a naturally occurring endogenous nanoplatform in mammalian systems. These nanoparticles (22 nm) specifically transport cholesterol to cells expressing the LDL receptor (LDLR). Several tumors overexpress LDLRs presumably to provide cholesterol to sustain a high rate of membrane synthesis. Amphiphilic gadolinium (Gd)-diethylenetriaminepentaacetic acid chelates have been incorporated into the LDL to produce a novel LDLR-targeted magnetic resonance imaging (MRI) contrast agent. The number of Gd chelates per LDL particle ranged between 150 and 496 Gd(III). In vitro studies demonstrated that Gd-labeled LDL retained a similar diameter and surface charge as the native LDL particle. In addition, Gd-labeled LDL retained selective cellular binding and uptake through LDLR-mediated endocytosis. Finally, Gd-labeled LDLs exhibited significant contrast enhancement 24 hours after administration in nude mice with human hepatoblastoma G2 xenografts. Thus, Gd-labeled LDL demonstrates potential use as a targeted MRI contrast agent for in vivo tumor detection.


Aging and sleep deprivation induce the unfolded protein response in the pancreas: implications for metabolism.
Sleep disruption has detrimental effects on glucose metabolism through pathways that remain poorly defined. Although numerous studies have examined the consequences of sleep deprivation (SD) in the brain, few have directly tested its effects on peripheral organs. We examined several tissues in mice for induction of the unfolded protein response (UPR) following acute SD. In young animals, we found a robust induction of BiP in the pancreas, indicating an active UPR. At baseline, pancreata from aged animals exhibited a marked increase in a pro-apoptotic transcription factor, CHOP, that was amplified by SD, whereas BiP induction was not observed, suggesting a maladaptive response to cellular stress with age. Acute SD increased plasma glucose levels in both young and old animals. However, this change was not overtly related to stress in the pancreatic beta cells, as plasma insulin levels were not lower following acute SD. Accordingly, animals subjected to acute SD remained tolerant to a glucose challenge. In a chronic SD experiment, young mice were found to be sensitized to insulin and have improved glycemic control, whereas aged animals became hyperglycemic and failed to maintain appropriate plasma insulin concentrations. Our results show that both age and SD cooperate to induce the UPR in pancreatic tissue. While changes in insulin secretion are unlikely to play a major role in the acute effects of SD, CHOP induction in pancreatic tissues suggests that chronic SD may contribute to the loss or dysfunction of endocrine cells and that these effects may be exacerbated by normal aging.


Suppression and splitting of modulational instability sidebands in periodically tapered optical fibers because of fourth-order dispersion.
We study the modulational instability induced by periodic variations of group-velocity dispersion in the proximity of the zero dispersion point. Multiple instability peaks originating from parametric resonance coexist with the conventional modulation instability because of fourth-order dispersion, which in turn is suppressed by the oscillations of dispersion. Moreover, isolated unstable regions appear in the space of parameters because of imperfect phase matching. This confirms the dramatic effect of periodic tapering in the control and shaping of MI sidebands in optical fibers.


Coronary vasomotor function in infarcted and remote myocardium after primary percutaneous coronary intervention.
In patients with acute myocardial infarction (AMI), coronary vasomotor function is impaired in the myocardial territory supplied by the culprit artery and in remote myocardium supplied by angiographically normal vessels. The aim was to investigate the temporal evolution of coronary vasodilatory reserve in patients with AMI by use of [(15)O]H2O positron emission tomography, after successful percutaneous coronary intervention. 44 patients with AMI and successful revascularisation by percutaneous coronary intervention were included. Subjects were examined 1 week and 3 months after AMI with [(15)O]H2O positron emission tomography to assess the coronary flow reserve (CFR). CFR was defined as the ratio of myocardial blood flow (MBF) during hyperaemia and rest. Additionally, 45 age-matched and sex-matched subjects underwent similar scanning procedures and served as controls. At baseline, CFR averaged 1.81±0.66 in infarcted myocardium versus 2.51±0.81 in remote myocardium (p<0.01). In comparison, CFR in the control group averaged 4.16±1.45 (p=0.001 vs both). During follow-up, the CFR increased to 2.74±0.85 in infarcted myocardium (p<0.01), and to 2.85±0.70 in remote myocardium (p<0.01). This was predominantly due to an increase in hyperaemic MBF, from 1.62±0.54 mL/min/g to 2.19±0.68 mL/min/g in infarcted myocardium (p<0.001), and 2.17±0.54 mL/min/g to 2.60±0.65 mL/min/g in remote myocardium (p<0.001). CFR in infarcted and remote myocardium is impaired 1 week after AMI. After 3 months vasomotor function partially recovers. However, as compared with control patients, MBF remains impaired in culprit and reference territories in patients with AMI. NTR3164.


Vitamin D, obesity, and obesity-related chronic disease among ethnic minorities: a systematic review.
To assess the association between 25-hydroxyvitamin D (25[OH]D) status and obesity, cardiovascular diseases (CVDs), the metabolic syndrome, and type 2 diabetes mellitus (T2DM) in ethnic minorities. Databases searched were CINHAL with full text, Global Health, MEDLINE with full text, and PsycINFO from 1980 through 2010 (February). Studies were included if they 1) targeted immigrants from low- to high-income countries or ethnic minorities, 2) focused primarily on 25(OH)D and its relation to obesity, T2DM, and/or CVDs, and 3) were published in peer-reviewed journals. The influences of key confounders such as age, gender, and ethnicity on any observed relations were also assessed. Due to the heterogeneity of study characteristics, only a narrative synthesis was undertaken. Ethnic minorities had significantly higher rates of vitamin D insufficiency (25[OH]D <50 nmol/L; children 43.6-48.7% versus 10%; adults 30.3-53% versus 13.7-26%) than their white counterparts. None of the studies reported a prevalence of obesity stratified by ethnicity. There was evidence supporting links between vitamin D deficiency and obesity-related chronic diseases, with 14 of 14 studies reporting a statistically significant result with a measurement of obesity, four of five for T2DM, four of five for CVDs, and one of one for the metabolic syndrome. However, the strength of the association varied across ethnic groups depending on the index used to measure adiposity, T2DM, and CVDs. Because most of the included studies were cross-sectional and there were variations in outcome measurements, it was not possible to determine the relative contributions of obesity or vitamin D insufficiency to CVD risk and risk of T2DM or which is the initial driver It is possible both have a role to play. Further research specific to migrant populations using randomized controlled trials are required to establish whether causal links between 25(OH)D and obesity-related chronic disease exist, and whether vitamin D supplementation could be valuable in the prevention or treatment of obesity-related diseases.


Salmonella enterica Serovar Typhi in Bangladesh: Exploration of Genomic Diversity and Antimicrobial Resistance.
Typhoid fever, caused by Salmonella enterica serovar Typhi, is a global public health concern due to increasing antimicrobial resistance (AMR). Characterization of S Typhi genomes for AMR and the evolution of different lineages, especially in countries where typhoid fever is endemic such as Bangladesh, will help public health professionals to better design and implement appropriate preventive measures. We studied whole-genome sequences (WGS) of 536 S Typhi isolates collected in Bangladesh during 1999 to 2013 and compared those sequences with data from a recent outbreak in Pakistan reported previously by E. J. Klemm, S. Shakoor, A. J. Page, F. N. Qamar, et al. (mBio 9:e00105-18, 2018, https://doi.org/10.1128/mBio.00105-18), and a laboratory surveillance in Nepal reported previously by C. D. Britto, Z. A. Dyson, S. Duchene, M. J. Carter, et al. [PLoS Negl. Trop. Dis. 12(4):e0006408, 2018, https://doi.org/10.1371/journal.pntd.0006408]. WGS had high sensitivity and specificity for prediction of ampicillin, chloramphenicol, co-trimoxazole, and ceftriaxone AMR phenotypes but needs further improvement for prediction of ciprofloxacin resistance. We detected a new local lineage of genotype 4.3.1 (named lineage Bd) which recently diverged into a sublineage (named Bdq) containing qnr genes associated with high-level ciprofloxacin resistance. We found a ceftriaxone-resistant isolate with the blaCTX-M-15 gene and a genotype distinct from the genotypes of extensively drug-resistant (XDR) isolates from Pakistan. This result suggests a different source and geographical origin of AMR. Genotype 4.3.1 was dominant in all three countries but formed country-specific clusters in the maximum likelihood phylogenetic tree. Thus, multiple independent genetic events leading to ciprofloxacin and ceftriaxone resistance took place in these neighboring regions of Pakistan, Nepal, and Bangladesh. These independent mutational events may enhance the risk of global spread of these highly resistant clones. A short-term global intervention plan is urgently needed.IMPORTANCE Typhoid fever, caused by Salmonella enterica serovar Typhi, is responsible for an estimated burden of approximately 17 million new episodes per year worldwide. Adequate and timely antimicrobial treatment invariably cures typhoid fever. The increasing antimicrobial resistance (AMR) of S Typhi severely limits the treatment options. We studied whole-genome sequences (WGS) of 536 S Typhi isolates collected in Bangladesh between 1999 and 2013 and compared those sequences with data from a recent outbreak in Pakistan and a laboratory surveillance in Nepal. The analysis suggests that multiple ancestral origins of resistance against ciprofloxacin and ceftriaxone are present in three countries. Such independent genetic events and subsequent dissemination could enhance the risk of a rapid global spread of these highly resistant clones. Given the current treatment challenges, vaccination seems to be the most appropriate short-term intervention to reduce the disease burden of typhoid fever at a time of increasing AMR.


Synthesis, structure, and magnetic properties of three 1D chain complexes based on high-spin metal-cyanide clusters: [Mn(III)6M(III)] (M = Cr, Fe, Co).
On the basis of high-spin metal-cyanide clusters of Mn(III)(6)M(III) (M = Cr, Fe, Co), three one-dimensional (1D) chain complexes, [Mn(salen)](6)[Cr(CN)(6)](2)·6CH(3)OH·H(2)O (1), [Mn(5-CH(3))salen)](6)[Fe(CN)(6)](2)·2CH(3)CN·10H(2)O (2), and [Mn(5-CH(3))salen)](6)[Co(CN)(6)](2)·2CH(3)CN·10H(2)O (3) [salen = N,N'-ethylenebis(salicylideneiminato) dianion], have been synthesized and characterized structurally as well as magnetically. Complexes 2 and 3 are isomorphic but slightly different from complex 1. All three complexes contain a 1D chain structure which is comprised of alternating high-spin metal-cyanide clusters of [Mn(6)M](3+) and a bridging group [M(CN)(6)](3-) in the trans mode. Furthermore, the three complexes all exhibit extended 3D supramolecular networks originating from short intermolecular contacts. Magnetic investigation indicates that the coupling mechanisms are intrachain antiferromagnetic interactions for 1 and ferromagnetic interactions for 2, respectively. Complex 3 is a magnetic dilute system due to the diamagnetic nature of Co(III). Further magnetic investigations show that complexes 1 and 2 are dominated by the 3D antiferromagnetic ordering with T(N) = 7.2 K for 1 and 9.5 K for 2. It is worth noting that the weak frequency-dependent phenomenon of AC susceptibilities was observed in the low-temperature region in both 1 and 2, suggesting the presence of slow magnetic relaxations.


MicroRNA Signatures of Colonic Polyps on Screening and Histology.
Colorectal cancer and adenoma adjacent to cancer exhibit distinct microRNA (miRNA) alterations in an apparent mucosa-to-adenocarcinoma sequence. The pattern of microRNAs in screen-detected polyps in relation to histologic features and cancer risk has not been investigated. miRNA expression analysis was performed on normal mucosa (NM), hyperplastic polyps (HP), tubular adenomas (TA), tubulovillous adenomas or high-grade dysplasia (TVHG), and serrated polyps [sessile serrated adenoma/polyps (SSA/P) and traditional serrated adenomas (TSA)] in biopsy specimens from 109 patients undergoing screening/surveillance colonoscopy. Generalized linear models were used to identify differentially expressed miRNAs by histologic type and logistic regression to identify miRNA predictors of histopathology. False discovery rate (FDR) was used to control for multiple comparisons. We identified 99 miRNAs differing in at least one of five histopathologic groups (FDR ≤0.05). In a comparison of HPNM versus TVHG, the top most upregulated and downregulated miRNAs in HPNM included miR-145, -143, -107, -194, and -26a (upregulated), and miR-663, -1268, -320b, -1275, and -320b (downregulated; FDR P < 0.05). miR-145 and -619 showed high accuracy to discriminate low- from high-risk polyps without serrated histology (TVHG vs. HPNM + TA; CI, 95.6%), whereas miR-124, -143, and -30a showed high accuracy of separating high-risk polyps (TVHG + TSA) from low-risk polyps (HPNM + TA + SSA/P; CI, 96.0%). For TSAs, miR-125b and -199a were uniquely downregulated relative to HPNMs, and miR-335, -222, and -214 discriminated between non-serrated and serrated histology. Our data support the presence of colorectal cancer-associated miRNA alterations in screen-detected adenomas that may be useful for risk stratification for surveillance interval planning. Cancer Prev Res; 9(12); 942-9. ©2016 AACR.


Power of genetic association studies with fixed and random genotype frequencies.
When estimating the power of genetic association studies, the allele and genotype frequencies are often assumed to be known, and the numbers of individuals with each genotype are set equal to their expectations under Hardy-Weinberg equilibrium. In fact, both allele and genotype frequencies are unknown and thus random. It has previously been suggested that ignoring uncertainty in these parameters could lead to inflated power expectations. To overcome the problem, one can average power estimates over the distributions of unknown frequencies. We investigate the power-averaging method and find that, despite the intuitive appeal, it may not improve accuracy in practice, while significantly increasing computational time. For a fixed allele frequency, we show that the amount of overestimation diminishes rapidly with sample size and is completely negligible for N > 200. For an unknown frequency, the result of averaging depends on the genetic model, and may not always provide a more conservative estimate of power. We explore the effect of uncertainty in the factors that determine statistical power of association studies and propose a more economical approach to the power analysis.


Guidelines for community-based injury surveillance in rugby union.
The vast majority of rugby union ('rugby') participants are community-based players; however, the majority of injury surveillance studies reported relate to the elite, professional game. A potential reason for this dearth of studies could be the perceived difficulty of using the consensus statement for injury recording at the community level. The aim of this study was to identify areas where the consensus statement could be adapted for easier and more appropriate implementation within the community setting. Round-table discussion. All community-based injury surveillance issues were discussed during a 2-day facilitated round-table meeting, by an 11-person working group consisting of researchers currently active in rugby-related injury surveillance, sports medicine and sports science issues. The outcomes from the meeting were summarised in a draft guidance document that was then subjected to an extensive iterative review prior to producing methodological recommendations. Each aspect of the rugby-specific consensus statement was reviewed to determine whether it was feasible to implement the standards required in the context of non-elite rugby and the resources available within in a community setting. Final recommendations are presented within a community-based injury report form. It is recommended that whenever possible the rugby-specific consensus statement for injury surveillance studies be used: this paper presents an adapted report form that can be used to record injury surveillance information in community rugby if suitable medical support is not available.


The effects of increased intracortical remodeling on microcrack behaviour in compact bone.
The behaviour of microdamage in bone is related to its microstructural features and thus has an important role in tissue structural properties. However, it is not known how cracks behave in areas of increased intracortical remodeling. More remodeling creates wider variation in the properties of the primary microstructural features of cortical bone, namely osteons. This situation may occur after treatment involving parathyroid hormone or events such as menopause/ovariectomy. High turnover was modeled in this study by using ovariectomy (OVX) to induce surgical menopause in sheep. We hypothesized that osteon age would influence microcrack behaviour during propagation. Five fluorochrome dyes were administered intravenously at different time-points over 12 months post-OVX to label remodeling sites and all animals were then euthanized. Compact bone specimens (2x2x36 mm) were harvested from the right metatarsal. Samples were cyclically loaded to failure and then histological analyses were carried out. Cracks were categorized by length into three groups; short (<100 mum), intermediate (100-300 mum) and long (>300 mum). Numerical crack density (Cr.Dn) of long cracks was greater in controls compared with OVX. Controls also displayed a higher crack surface density (Cr.S.Dn) compared with OVX (p<0.05). The behaviour of short cracks did not differ between old and new osteons, but intermediate and long cracks preferentially stopped at newer osteons compared with older ones (p<0.05). This mechanism may have an important role in terms of prolonging fatigue life. We conclude that recently formed secondary osteons have a unique influence on propagating microcracks compared with older osteons. Therefore localized remodeling levels should be considered when studying microcrack behaviour in bone.


Adjunctive β2-agonists reverse neuromuscular involvement in murine Pompe disease.
Pompe disease has resisted enzyme replacement therapy with acid α-glucosidase (GAA), which has been attributed to inefficient cation-independent mannose-6-phosphate receptor (CI-MPR) mediated uptake. We evaluated β2-agonist drugs, which increased CI-MPR expression in GAA knockout (KO) mice. Clenbuterol along with a low-dose adeno-associated virus vector increased Rotarod latency by 75% at 4 wk, in comparison with vector alone (P<2×10(-5)). Glycogen content was lower in skeletal muscles, including soleus (P<0.01), extensor digitorum longus (EDL; P<0.001), and tibialis anterior (P<0.05) following combination therapy, in comparison with vector alone. Glycogen remained elevated in the muscles following clenbuterol alone, indicating an adjunctive effect with gene therapy. Elderly GAA-KO mice treated with combination therapy demonstrated 2-fold increased wirehang latency, in comparison with vector or clenbuterol alone (P<0.001). The glycogen content of skeletal muscle decreased following combination therapy in elderly mice (P<0.05). Finally, CI-MPR-KO/GAA-KO mice did not respond to combination therapy, indicating that clenbuterol's effect depended on CI-MPR expression. In summary, adjunctive β2-agonist treatment increased CI-MPR expression and enhanced efficacy from gene therapy in Pompe disease, which has implications for other lysosomal storage disorders that involve primarily the brain.


Mastery and self-esteem mediate the association between visual acuity and mental health: a population-based longitudinal cohort study.
With deteriorating eyesight, people often become dependent on others for many aspects of their daily lives. As a result, they feel less 'in control' and experience lower self-esteem. Lower sense of mastery and self-esteem are known to predict depression, but their roles in people with visual impairment have only marginally been investigated. Therefore, this study aimed to determine the influence of mastery and self-esteem on the relationship between visual acuity and mental health. A longitudinal cohort study was performed using data from the Longitudinal Aging Study Amsterdam (LASA), collected between 2001 and 2012. A community-based population of 2599 older adults were included, who were randomly selected from population registers. Outcomes of interest were the Pearlin Mastery Scale, Rosenberg Self-Esteem Scale, Center for Epidemiologic Studies - Depression scale and the Hospital Anxiety Depression Scale - Anxiety subscale. Linear mixed models were used to establish the association between visual acuity and mental health over time. Mean age was 72 years, 56% was female and 1.2% qualified as having low vision. Visual impairment was associated with a lower sense of mastery (β = - 0.477, p < 0.001), lower self-esteem (β = - 0.166, p = 0.008) and more depression (β = 0.235, p < 0.001). No significant association between visual acuity and anxiety was found. The relationship between visual acuity and depression was mediated by self-esteem (25%) and sense of mastery (79%). Vision loss was associated with depression. This association was mediated by self-esteem and sense of mastery. This provides us with new possibilities to identify, support and treat those at risk for developing depression by aiming to increase their self-esteem and sense of mastery.


Diagnostic delay in REM sleep behavior disorder (RBD).
REM sleep behavior disorder (RBD) is a parasomnia in which normal muscle atonia of REM sleep is lost. The aim of this study was to confirm if diagnostic delay exists in RBD and identify any contributing factors. A database was compiled of 49 patients with RBD seen at a tertiary referral center from 2005 to 2011 by retrospective review of referral letters and polysomnographic (PSG) reports. Patients with comorbid narcolepsy were excluded. A questionnaire was sent to investigate diagnostic delay, management, and comorbidities. Mean diagnostic delay was 8.7 ± 11 (median 4.5, IQR 1.75-11.75) years in 30 questionnaire responders. Common reasons for diagnostic delay included belief that symptoms were not serious enough to consult a doctor (59%), mild or infrequent occurrence of sleep behavior (56%), belief that symptoms may resolve (47%), and lack of knowledge of treatment options (47%). The bed partner was an important influence, with the decision to seek medical attention being made jointly by the patient and partner in 47%. This study has demonstrated the existence of significant diagnostic delay in RBD, mainly due to lack of understanding of the disorder and its treatment by patients and members of the medical profession.


A scoping review to assess the effects of virtual reality in medical education and clinical care.
Due to the challenges and restrictions posed by COVID-19 pandemic, technology and digital solutions played an important role in the rendering of necessary healthcare services, notably in medical education and clinical care. The aim of this scoping review was to analyze and sum up the most recent developments in Virtual Reality (VR) use for therapeutic care and medical education, with a focus on training medical students and patients. We identified 3743 studies, of which 28 were ultimately selected for the review. The search strategy followed the most recent Preferred Reporting Items for Systematic Reviews and Meta-Analysis for scoping review (PRISMA-ScR) guidelines. 11 studies (39.3%) in the field of medical education assessed different domains, such as knowledge, skills, attitudes, confidence, self-efficacy, and empathy. 17 studies (60.7%) focused on clinical care, particularly in the areas of mental health, and rehabilitation. Among these, 13 studies also investigated user experiences and feasibility in addition to clinical outcomes. Overall, the findings of our review reported considerable improvements in terms of medical education and clinical care. VR systems were also found to be safe, engaging, and beneficial by the studies' participants. There were huge variations in studies with respect to the study designs, VR contents, devices, evaluation methods, and treatment periods. In the future, studies may focus on creating definitive guidelines that can help in improving patient care further. Hence, there is an urgent need for researchers to collaborate with the VR industry and healthcare professionals to foster a better understanding of contents and simulation development.


Chilean regulations on metal-polluted soils: The need to advance from adapting foreign laws towards developing sovereign legislation.
Chile as a major international Cu producer faces serious soil contamination issues in mining areas. Currently Chile does not have any specific law governing the maximum permissible concentrations of metals in soils to protect ecosystems and human health. Chile heavily relies on the use of environmental laws of 14 foreign countries; the choice of the country depends on the similarity of its environmental conditions with those in Chile. In this study, we used an online database to compare the similarity of Chilean rocks to those in foreign countries. Likewise, we performed soil sampling and determined the background concentrations of Cu, As, Pb, and Zn in soils of the Aconcagua basin, the largest river basin in the Valparaiso Region of central Chile. The results showed that geochemical patterns in Chile have the greatest resemblance to New Zealand, Mexico, and Italy. The background Cu concentration in the Aconcagua basin (134 mg kg-1) exceeded the legislated limits of New Zealand (100 mg kg-1) and Italy (120 mg kg-1), whereas the background Zn concentration (200 mg kg-1) exceeded the legislated limit of Italy (150 mg kg-1). Due to the elevated natural abundance of Cu and Zn in Chile, international laws should not be applied in Chile for the assessment of soil contamination. In addition, we assessed ecological risk using the results of our previous studies obtained by analyzing native field-contaminated soils of the Valparaiso region. In the Aconcagua basin, Cu posed high risk for plants in 11% of the samples, whereas As posed high risk for earthworms in 48% of the samples. We suggest that future studies are required to search for other organisms that can serve as biomarkers of metal toxicity because our previous studies were limited to plants and earthworms. Importantly, As posed high risk to human health in 25% of the samples in our study. There is a need for future studies to demonstrate empirically an association between soil As and children's blood As in order to establish the national threshold values of soil As to protect human health. We conclude that there is an urgent need in Chile to advance from the current approach of adapting foreign laws to developing Chilean sovereign environmental legislation.


Advancing our understanding of religion and spirituality in the context of behavioral medicine.
Recognizing and understanding the potentially powerful roles that religiousness and spirituality (RS) may serve in the prevention and amelioration of disease, as well as symptom management and health related quality of life, significantly enhances research and clinical efforts across many areas of behavioral medicine. This article examines the knowledge established to date and suggests advances that remain to be made. We begin with a brief summary of the current knowledge regarding RS as related to three exemplary health conditions: (a) cardiovascular disease; (b) cancer; and, (c) substance abuse. We then focus on particular concerns for future investigations, emphasizing conceptual issues, possible mediators and moderators of relationships or effects, and methodology. Our discussion is framed by a conceptual model that may serve to guide and organize future investigations. This model highlights a number of important issues regarding the study of links between RS and health: (a) RS comprise many diverse constructs, (b) the mechanisms through which RS may influence health outcomes are quite diverse, and (c) a range of different types of health and health relevant outcomes may be influenced by RS. The multidimensional nature of RS and the complexity of related associations with different types of health relevant outcomes present formidable challenges to empirical study in behavioral medicine. These issues are referred to throughout our review and we suggest several solutions to the presented challenges in our summary. We end with a presentation of barriers to be overcome, along with strategies for doing so, and concluding thoughts.


Can pro-marriage policies work? An analysis of marginal marriages.
Policies to promote marriage are controversial, and it is unclear whether they are successful. To analyze such policies, one must distinguish between a marriage that is created by a marriage-promoting policy (marginal marriage) and a marriage that would have been formed even in the absence of a state intervention (average marriage). We exploit the suspension of a cash-on-hand marriage subsidy in Austria to examine the differential behavior of marginal and average marriages. The announcement of an impending suspension of this subsidy led to an enormous marriage boom among eligible couples that allows us to locate marginal marriages. Applying a difference-in-differences approach, we show that marginal marriages are surprisingly as stable as average marriages but produce fewer children, children later in marriage, and children who are less healthy at birth.


Detection of antineutrophil cytoplasmic antibodies in primary sclerosing cholangitis: a comparison of the alkaline phosphatase and immunofluorescent techniques.
The reported prevalence of antineutrophil cytoplasmic antibodies (ANCA) in primary sclerosing cholangitis (PSC) varies considerably (26-85%). Part of this may reflect methodological differences but part may reflect the differences in the patient groups analysed. To resolve this issue we compared the sensitivity and specificity of the immunoalkaline phosphatase (IALP) and immunofluorescence (IF) techniques in four different populations. Sera from four centres were tested blind on alcohol-fixed neutrophils using both techniques. USA: 14 PSC, 14 primary biliary cirrhosis (PBC); Sweden: 32 PSC, 3 autoimmune hepatitis (AIH), 14 PBC, 11 chronic liver disease; Norway: 32 PSC, 14 AIH, 13 PBC, 1 hepatitis C. Italy: 8 PSC, 14 PBC, 8 viral hepatitis. Thirty-six normal healthy volunteers from Oxford, together with positive and negative controls, were also tested. The healthy controls were all ANCA negative. The diagnostic sensitivity and specificity, respectively, of ANCA for PSC using the IALP technique for the different test sera were: USA 71% and 93%, Sweden 66% and 96%, Norway 69% and 46%, Italy 50% and 95%. The diagnostic sensitivity and specificity, respectively, of the IF technique on the same sera were: USA 50% and 86%, Sweden 56% and 86%, Norway 47% and 61%, Italy 50% and 91%. Overall, combining all four groups, detection of ANCA using the IALP technique gave a diagnostic sensitivity of 66% with a specificity of 74% for PSC. In contrast, the IF technique gave an overall diagnostic of only 51% (P = 0.044, compared with IALP) with a specificity of 73%. Although overall the IALP technique was more sensitive than IF, the differences in sensitivity and specificity between the two techniques did not reach statistical significance for any individual group. Furthermore, the small differences in sensitivity between the four groups using either technique were not significant. However, the IALP technique had greater specificity in the US, Swedish and Italian groups compared with the Norwegian group (P < 0.05) whereas no statistically significant differences in specificity were noted between the groups using the IF technique. This study shows that the IALP method of ANCA detection is at least as sensitive as IF for the serological diagnosis of PSC. Indeed, combining data from all four centres, the IALP technique was significantly more sensitive than IF. We therefore recommend the use of the IALP technique, which is also easier to interpret and does not require the use of a specialist fluorescent microscope. The lack of a wide variation in sensitivity between IALP and IF for any individual patient group reported in this study suggests that the previously reported regional differences in ANCA prevalence in PSC of between 26% and 85% may be patient, related, rather than due to ethnic or methodological differences in ANCA detection, perhaps reflecting possible disease heterogeneity within PSC, or case selection bias. Further studies are needed to investigate this intriguing possibility. Such differences, if confirmed, will need to be taken into account when assessing the use of ANCA as a serological marker of PSC.


Antimicrobial activity of the extracts and physalin D from Physalis alkekengi and evaluation of antioxidant potential of physalin D.
Physalis alkekengi L. (Solanaceae) is a popular plant in traditional European and Chinese folk medicine, and it has been reported to have many ethnopharmacological properties including antifungal, anti-cough, anti-inflammatory, analgesic, and febricide activities. Some active components from Physalis species have been investigated. However, no antimicrobial activity studies on extracts and physalins of P. alkekengi have been carried out. In this study, we attempted to identify the possible antimicrobial activities of the methanol extract from aerial parts of P. alkekengi and the dichloromethane extract from calyces of the plant. The extracts were tested against five Gram-positive and five Gram-negative bacteria and five Candida species by using disk diffusion and broth microdilution methods. The extracts were fractionated to isolate physalins using chromatographic techniques, and physalin D was isolated from the extracts. The structure of the compound was elucidated on the basis of (1)H-NMR spectroscopic study, and confirmed by comparison with a reference sample and literature data. Results indicated that all the extracts and physalin D were characterized by antibacterial action, especially against Gram-positive bacteria, with MIC values between 32 and 128 microg/mL. The methanol extract had moderate activity against fungi at MICs ranging from 128 to 512 microg/mL, but the dichloromethane extract and physalin D had low activity against fungi at MICs ranging from 256 to 512 microg/mL. Additionally, the antioxidant activity of physalin D was evaluated by qualitative DPPH (1,1-diphenyl-2-picrylhydrazyl) radical and TBA (thiobarbituric acid) assays. Physalin D showed low antioxidant activity with an IC(50) value of >or= 10 +/- 2.1.


Critical assessment of the research outcomes of European birth cohorts: linking environmental factors with non-communicable diseases.
The objective of this review paper was to stimulate collaborative discussions toward the development of a general concept of an open source protocol for a feasible and efficient longitudinal birth cohort study exploring non-communicable diseases (NCDs), their multifactorial etiology and relations between various risk factors. The present paper systematically reviews the design of existing birth cohorts in Europe containing environmental exposure data, and assesses a quantity and quality of their research outcomes as their potential to be an effective tool for studying non-communicable diseases and their risk factors. European birth cohorts with more than 3000 participants have been included in the study. A total number of scientific papers published in the internationally recognized journals and their impact factors and citation records were evaluated for all cohorts as surrogates for their efficiency to contribute to NCDs understanding and thus their prevention. The birth cohorts contributing most significantly to the NCD understanding shared common features: (i) study size between 10,000 and 15,000 mother-child pairs; (ii) repeated assessment of children from prenatal into adulthood; and (iii) availability of biological samples. Smaller cohorts and cohorts with a specific focus generated a lower number of publications; however, these often received considerably a higher number of citations. General cohort studies with 10,000-15,000 mother-child pairs allow a broader context interpretation, publish a higher number of articles, and often lead to the formation of infrastructures for 'spin-off (nested) studies'.


Disentangling sub-millisecond processes within an auditory transduction chain.
Every sensation begins with the conversion of a sensory stimulus into the response of a receptor neuron. Typically, this involves a sequence of multiple biophysical processes that cannot all be monitored directly. In this work, we present an approach that is based on analyzing different stimuli that cause the same final output, here defined as the probability of the receptor neuron to fire a single action potential. Comparing such iso-response stimuli within the framework of nonlinear cascade models allows us to extract the characteristics of individual signal-processing steps with a temporal resolution much finer than the trial-to-trial variability of the measured output spike times. Applied to insect auditory receptor cells, the technique reveals the sub-millisecond dynamics of the eardrum vibration and of the electrical potential and yields a quantitative four-step cascade model. The model accounts for the tuning properties of this class of neurons and explains their high temporal resolution under natural stimulation. Owing to its simplicity and generality, the presented method is readily applicable to other nonlinear cascades and a large variety of signal-processing systems.


Psychiatric disorders prior to amyotrophic lateral sclerosis.
It is recognized that neuropsychiatric conditions are overrepresented in amyotrophic lateral sclerosis (ALS) patient kindreds and psychiatric symptoms may precede the onset of motor symptoms. Using a hospital record linkage database, hospitalization with a diagnosis of schizophrenia, bipolar disorder, depression, or anxiety was significantly associated with a first diagnosis of ALS within the following year. This is likely to specifically reflect the clinicopathological overlap of ALS with frontotemporal dementia. A diagnosis of depression was significantly associated with a first record of ALS ≥5 years later, in keeping with growing evidence for major depressive disorder as an early marker of cerebral neurodegeneration. Ann Neurol 2016;80:935-938.


Proteomic Analysis of Infants Undergoing Cardiopulmonary Bypass Using Contemporary Ontological Tools.
Cardiopulmonary bypass (CPB) is essential for the repair of many congenital cardiac defects in infants but is associated with significant derangements in hemostasis and systemic inflammation. As a result, hemorrhagic complications and thrombosis are major challenges in the management of children requiring CPB or extracorporeal membrane oxygenation. Conventional clinical laboratory tests capture individual hemostatic derangements (low platelets, elevated fibrinogen) but fail to describe the complex, overlapping interactions among the various components of coagulation, including cellular interactions, contact activation, fibrinolysis, and inflammation. Given recent advances in analytic tools for identifying protein-protein interactions in the plasma proteome, we hypothesized that an unbiased proteomic analysis would help identify networks of interacting proteins for further investigation in pediatric CPB. Infants up to 1 y of age were enrolled. Plasma samples were collected at 0, 1, 4, and 24 h after CPB. Mass spectrometry was used to identify proteins undergoing changes in concentration after CPB, and STRING and ToppGene tools were used to identify biological networks. Two-dimensional difference gel electrophoresis identified changes in protein concentrations. Inflammatory markers were assessed by enzyme-linked immunosorbent assay at the same time points. Ten infants with cardiac anomalies requiring surgery and CPB were enrolled; no major complications were recorded (median age, 127.5 d; interquartile range, 181.25 d). Using two-dimensional difference gel electrophoresis, >1400 individual protein spots were observed, and 89 proteins demonstrated change in concentration >30% with P < 0.02 when comparing 1, 4, or 24 h to baseline. Among protein spots with significant changes in concentration after CPB, 29 were identified with mass spectrometry (33%). In our interrogation of functional associations among these differentially expressed proteins, our results were dominated by the acute phase response, coagulation, and cell signaling functional categories. Among cytokines analyzed by enzyme-linked immunosorbent assay, IL-2, IL-8, and IL-10 were elevated at 4 h but normalized by 24 h, whereas IL-6 was persistently elevated. Infants manifest a robust response to CPB that includes overlapping, complex pathways. Further investigation of interactions among immune, coagulation, and cell signaling systems may lead to novel therapeutics or biomarkers useful in the management of infants requiring CPB.


Epidemiologic Evidence That Excess Body Weight Increases Risk of Cervical Cancer by Decreased Detection of Precancer.
Purpose Obesity has been inconsistently linked to increased cervical cancer incidence and mortality; however, the effect of obesity on cervical screening has not been explored. We investigated the hypothesis that increased body mass might decrease detection of cervical precancer and increase risk of cervical cancer even in women undergoing state-of-the-art screening. Methods We conducted a retrospective cohort study of 944,227 women age 30 to 64 years who underwent cytology and human papillomavirus DNA testing (ie, cotesting) at Kaiser Permanente Northern California (January 2003 to December 2015). Body mass index was categorized as normal/underweight (< 25 kg/m2), overweight (25 to < 30 kg/m2), or obese (≥ 30 kg/m2). We estimated 5-year cumulative risks of cervical precancer and cancer by category of body mass index using logistic Weibull survival models. Results We observed lower risk of cervical precancer (n = 4,489) and higher risk of cervical cancer (n = 490) with increasing body mass index. Specifically, obese women had the lowest 5-year risk of precancer (0.51%; 95% CI, 0.48% to 0.54% v 0.73%; 95% CI, 0.70% to 0.76% in normal/underweight women; P trend < .001). In contrast, obese women had the highest 5-year risk of cancer (0.083%; 95% CI, 0.072% to 0.096% v 0.056%; 95% CI, 0.048% to 0.066% in normal/underweight women; P trend < .001). Results were consistent in subgroups defined by age (30 to 49 v 50 to 64 years), human papillomavirus status (positive v negative), and histologic subtype (glandular v squamous). Approximately 20% of cervical cancers could be attributed to overweight or obesity in the women in our study who underwent routine cervical screening. Conclusion In this large, screened population, overweight and obese women had an increased risk of cervical cancer, likely because of underdiagnosis of cervical precancer. Improvements in equipment and/or technique to assure adequate sampling and visualization of women with elevated body mass might reduce cervical cancer incidence.


Health literacy and informed decision making regarding colorectal cancer screening: a systematic review.
Making an informed decision about participation in colorectal cancer (CRC) screening may be challenging for invitees with lower health literacy skills. The aim of this systematic review is to explore to what extent the level of a person's health literacy is related to their informed decision making concerning CRC screening. We searched for peer-reviewed studies published between 1950 and May 2013 in MEDLINE, EMBASE, SciSearch and PsycINFO. Studies were included when health literacy was studied in relation to concepts underpinning informed decision making (awareness, risk perception, perceived barriers and benefits, knowledge, attitude, deliberation). The quality of the studies was determined and related to the study results. The search returned 2254 papers. Eight studies in total were included, among which seven focused on knowledge, four focused on attitudes or beliefs concerning CRC screening, and one focused on risk perception. The studies found either no association or a positive association between health literacy and concepts underpinning informed decision making. Some studies showed that higher health literacy was associated with more CRC screening knowledge and a more positive attitude toward CRC screening. The results of studies that obtained a lower quality score were no different than studies that obtained a higher quality score. In order to obtain more insight into the association between health literacy and informed decision making in CRC cancer screening, future research should study the multiple aspects of informed decision making in conjunction instead of single aspects.


Web tool for estimating the cancer hazard rates in aging.
A computational approach for estimating the overall, population, and individual cancer hazard rates was developed. The population rates characterize a risk of getting cancer of a specific site/type, occurring within an age-specific group of individuals from a specified population during a distinct time period. The individual rates characterize an analogous risk but only for the individuals susceptible to cancer. The approach uses a novel regularization and anchoring technique to solve an identifiability problem that occurs while determining the age, period, and cohort (APC) effects. These effects are used to estimate the overall rate, and to estimate the population and individual cancer hazard rates. To estimate the APC effects, as well as the population and individual rates, a new web-based computing tool, called the CancerHazard@Age, was developed. The tool uses data on the past and current history of cancer incidences collected during a long time period from the surveillance databases. The utility of the tool was demonstrated using data on the female lung cancers diagnosed during 1975-2009 in nine geographic areas within the USA. The developed tool can be applied equally well to process data on other cancer sites. The data obtained by this tool can be used to develop novel carcinogenic models and strategies for cancer prevention and treatment, as well as to project future cancer burden.


Prevalence of antifolate resistance mutations in Plasmodium falciparum isolates in Afghanistan.
Artesunate plus sulphadoxine-pyrimethamine (AS+SP) is now first-line treatment for Plasmodium falciparum infection in several south Asian countries, including Afghanistan. Molecular studies provide a sensitive means to investigate the current state of drug susceptibility to the SP component, and can also provide information on the likely efficacy of other potential forms of artemisinin-combination therapy. During the years 2007 to 2010, 120 blood spots from patients with P. falciparum malaria were obtained in four provinces of Afghanistan. PCR-based methods were used to detect drug-resistance mutations in dhfr, dhps, pfcrt and pfmdr1, as well as to determine copy number of pfmdr1. The majority (95.5%) of infections had a double mutation in the dhfr gene (C59R, S108N); no mutations at dhfr positions 16, 51 or 164 were seen. Most isolates were wild type across the dhps gene, but five isolates from the provinces of Kunar and Nangarhar in eastern Afghanistan had the triple mutation A437G / K540E / A581G; all five cases were successfully treated with three receiving AS+SP and two receiving dihydroartemisinin-piperaquine. All isolates showed the pfcrt SVNMT chloroquine resistance haplotype. Five of 79 isolates had the pfmdr1 N86Y mutation, while 52 had pfmdr1 Y184F; positions 1034, 1042 and 1246 were wild type in all isolates. The pfmdr1 gene was not amplified in any sample. This study indicates that shortly after the adoption of AS+SP as first-line treatment in Afghanistan, most parasites had a double mutation haplotype in dhfr, and a small number of isolates from eastern Afghanistan harboured a triple mutation haplotype in dhps. The impact of these mutations on the efficacy of AS+SP remains to be assessed in significant numbers of patients, but these results are clearly concerning since they suggest a higher degree of SP resistance than previously detected. Further focused molecular and clinical studies in this region are urgently required.


Magnetic forces produced by rectangular permanent magnets in static microsystems.
Finite element numerical simulations were carried out in 2D geometries to map the magnetic field and force distribution produced by rectangular permanent magnets as a function of their size and position with respect to a microchannel. A single magnet, two magnets placed in attraction and in repulsion have been considered. The goal of this work is to show where magnetic beads are preferentially captured in a microchannel. These simulations were qualitatively corroborated, in one geometrical case, by microscopic visualizations of magnetic bead plug formation in a capillary. The results show that the number of plugs is configuration dependent with: in attraction, one plug in the middle of the magnets; in repulsion, two plugs near the edges of the magnets; and with a single magnet, a plug close to the center of the magnet. The geometry of the magnets (h and l are the height and length of the magnets respectively) and their relative spacing s has a significant impact on the magnetic flux density. Its value inside a magnet increases with the h/l ratio. Consequently, bar magnets produce larger and more uniform values than flat magnets. The l/s ratio also influences the magnetic force value in the microchannel, both increasing concomitantly for all the configurations. In addition, a zero force zone in the middle appears in the attraction configuration as the l/s ratio increases, while with a single magnet, the number of maxima and minima goes from one to two, producing two focusing zones instead of only one.


Microsurgical resection of brainstem, thalamic, and basal ganglia angiographically occult vascular malformations.
To evaluate the clinical results for patients who underwent resection of angiographically occult vascular malformations (AOVMs) of the brainstem, thalamus, or basal ganglia, successfully resected after it exhibited rebleeding and presented to a pial surface. Between January 1990 and May 1998, 56 patients with 57 deep AOVMs underwent 63 operations, at Stanford University Medical Center, to treat AOVMs of the brainstem (42 AOVMs), thalamus (5 AOVMs), or basal ganglia (10 AOVMs). The surgical approach was suboccipital midline (27 operations), far lateral suboccipital (10 operations), transsylvian (9 operations), interhemispheric transcallosal or infracallosal (8 operations), infratentorial supracerebellar (6 operations), or subtemporal (3 operations). Four patients experienced recurrent bleeding from the same lesion after surgical resection, requiring a second operation. One patient required a planned second operation, using a different approach, to completely resect the lesion, and one patient underwent two surgical procedures to resect two separate brainstem AOVMs. One patient initially underwent exploration but not resection of her AOVM, because it did not present to a pial or ependymal surface. The AOVM was successfully resected after it exhibited rebleeding and presented to a pial surface. The immediate outcomes after surgery were unchanged for 31 patients (55%), worsened for 16 (29%), and improved for 9 (16%). The long-term outcomes were unchanged for 24 patients (43%), compared with their presenting grade, worse for 3 (5%), and improved for 29 (52%). Patients who had undergone previous radiotherapy or radiosurgery to treat these lesions experienced more difficult postoperative courses, and radiation necrosis was observed for two patients. AOVMs of the brainstem, thalamus, and basal ganglia can be safely removed, with a long-term neurological morbidity rate of only 5% and a complete lesion resection rate of 93% after the initial planned resection. The use of cranial base surgical approaches and intraoperative electrophysiological monitoring contributes to successful clinical outcomes.


Compensatory Enlargement of Ossabaw Miniature Swine Coronary Arteries in Diffuse Atherosclerosis.
Studies in human and non-human primates have confirmed the compensatory enlargement or positive remodeling (Glagov phenomenon) of coronary vessels in the presence of focal stenosis. To our knowledge, this is the first study to document arterial enlargement in a metabolic syndrome animal model with diffuse coronary artery disease (DCAD) in the absence of severe focal stenosis. Two different groups of Ossabaw miniature pigs were fed a high fat atherogenic diet for 4 months (Group I) and 12 months (Group II), respectively. Group I (6 pigs) underwent contrast enhanced computed tomographic angiography (CCTA) and intravascular ultrasound (IVUS) at baseline and after 4 months of high fat diet, whereas Group II (7 pigs) underwent only IVUS at 12 months of high fat diet. IVUS measurements of the left anterior descending (LAD), left circumflex (LCX) and right coronary (RCA) arteries in Group I showed an average increase in their lumen cross-sectional areas (CSA) of 25.8%, 11.4%, and 43.4%, respectively, as compared to baseline. The lumen CSA values of LAD in Group II were found to be between the baseline and 4 months values in Group I. IVUS and CCTA measurements showed a similar trend and positive correlation. Fractional flow reserve (FFR) was 0.91±0.07 at baseline and 0.93±0.05 at 4 months with only 2.2%, 1.6% and 1% stenosis in the LAD, LCX and RCA, respectively. The relation between percent stenosis and lumen CSA shows a classical Glagov phenomenon in this animal model of DCAD.


Acute effects of LSD on amygdala activity during processing of fearful stimuli in healthy subjects.
Lysergic acid diethylamide (LSD) induces profound changes in various mental domains, including perception, self-awareness and emotions. We used functional magnetic resonance imaging (fMRI) to investigate the acute effects of LSD on the neural substrate of emotional processing in humans. Using a double-blind, randomised, cross-over study design, placebo or 100 μg LSD were orally administered to 20 healthy subjects before the fMRI scan, taking into account the subjective and pharmacological peak effects of LSD. The plasma levels of LSD were determined immediately before and after the scan. The study (including the a priori-defined study end point) was registered at ClinicalTrials.gov before study start (NCT02308969). The administration of LSD reduced reactivity of the left amygdala and the right medial prefrontal cortex relative to placebo during the presentation of fearful faces (P<0.05, family-wise error). Notably, there was a significant negative correlation between LSD-induced amygdala response to fearful stimuli and the LSD-induced subjective drug effects (P<0.05). These data suggest that acute administration of LSD modulates the engagement of brain regions that mediate emotional processing.


Feasibility of mitral isthmus and left atrial roof linear lesions using an 8 mm tip cryoablation catheter.
Left atrial linear lesions are part of the ablation strategy for persistent atrial fibrillation. Radiofrequency (RF) energy is the standard energy modality. Pulmonary vein (PV) balloon cryoablation has similar success rates to RF energy but is unsuitable for linear lesions. This study assessed the feasibility and safety of left atrial linear lesions using an 8 mm tip cryoablation catheter. Consecutive patients undergoing left atrial ablation procedures for paroxysmal or persistent atrial fibrillation were studied. An 8 mm tip focal cryoablation catheter was used to create mitral isthmus and left atrial roof linear lesions and compared to a matched cohort undergoing RF ablation. A total of 21 patients (54 ± 11 years, 14 male), 15 undergoing de novo procedures using a dual console technique (simultaneous focal catheter and cryoballoon PV ablation) and 6 redo procedures (single console and focal catheter) were studied. Mitral isthmus ablation was successful in 19/21 (91%) with a mean total ablation time of 32.5 ± 2.9 minutes. Roof line ablation was successful in 18/19 with a mean ablation time of 15.6 ± 6.0 minutes. Success rates were similar but ablation times were longer than those in the matched RF group. Epicardial ablation in the coronary sinus was required less often with cryoablation (11/21 vs 17/21, P < 0.05). There were no complications. Left atrial linear lesions with an 8 mm tip cryoablation catheter are feasible and safe with a high acute success rate. The need for coronary sinus ablation is reduced. A dual console technique is possible. Long-term durability of linear lesions remains to be determined.