DNA Methylation Dynamics of Germinal Center B Cells Are Mediated by AID.
Changes in DNA methylation are required for the formation of germinal centers (GCs), but the mechanisms of such changes are poorly understood. Activation-induced cytidine deaminase (AID) has been recently implicated in DNA demethylation through its deaminase activity coupled with DNA repair. We investigated the epigenetic function of AID in vivo in germinal center B cells (GCBs) isolated from wild-type (WT) and AID-deficient (Aicda(-/-)) mice. We determined that the transit of B cells through the GC is associated with marked locus-specific loss of methylation and increased methylation diversity, both of which are lost in Aicda(-/-) animals. Differentially methylated cytosines (DMCs) between GCBs and naive B cells (NBs) are enriched in genes that are targeted for somatic hypermutation (SHM) by AID, and these genes form networks required for B cell development and proliferation. Finally, we observed significant conservation of AID-dependent epigenetic reprogramming between mouse and human B cells.


Differential healing response attributed to culprit lesions of patients with acute coronary syndromes and stable coronary artery after implantation of drug-eluting stents: an optical coherence tomography study.
Pathology studies have shown delayed arterial healing in culprit lesions of patients with acute coronary syndrome (ACS) compared with stable coronary artery disease (CAD) after placement of drug-eluting stents (DES). It is unknown whether similar differences exist in-vivo during long-term follow-up. Using optical coherence tomography (OCT), we assessed differences in arterial healing between patients with ACS and stable CAD five years after DES implantation. A total of 88 patients comprised of 53 ACS lesions with 7864 struts and 35 stable lesions with 5298 struts were suitable for final OCT analysis five years after DES implantation. The analytical approach was based on a hierarchical Bayesian random-effects model. OCT endpoints were strut coverage, malapposition, protrusion, evaginations and cluster formation. Uncovered (1.7% vs. 0.7%, adjusted p=0.041) or protruding struts (0.50% vs. 0.13%, adjusted p=0.038) were more frequent among ACS compared with stable CAD lesions. A similar trend was observed for malapposed struts (1.33% vs. 0.45%, adj. p=0.072). Clusters of uncovered or malapposed/protruding struts were present in 34.0% of ACS and 14.1% of stable patients (adj. p=0.041). Coronary evaginations were more frequent in patients with ST-elevation myocardial infarction compared with stable CAD patients (0.16 vs. 0.13 per cross section, p=0.027). Uncovered, malapposed, and protruding stent struts as well as clusters of delayed healing may be more frequent in culprit lesions of ACS compared with stable CAD patients late after DES implantation. Our observational findings suggest a differential healing response attributable to lesion characteristics of patients with ACS compared with stable CAD in-vivo.


Key factors leading to reduced recruitment and retention of health professionals in remote areas of Ghana: a qualitative study and proposed policy solutions.
The ability of many countries to achieve national health goals such as the Millennium Development Goals remains hindered by inadequate and poorly distributed health personnel, including doctors. The distribution of doctors in Ghana is highly skewed, with a majority serving in two major metropolitan areas (Accra and Kumasi), and inadequate numbers in remote and rural districts. Recent policies increasing health worker salaries have reduced migration of doctors out of Ghana, but made little difference to distribution within the country. This qualitative study was undertaken to understand how practicing doctors and medical leaders in Ghana describe the key factors reducing recruitment and retention of health professionals into remote areas, and to document their proposed policy solutions. In-depth interviews were carried out with 84 doctors and medical leaders, including 17 regional medical directors and deputy directors from across Ghana, and 67 doctors currently practicing in 3 regions (Greater Accra, Brong Ahafo, and Upper West); these 3 regions were chosen to represent progressively more remote distances from the capital of Accra. All participants felt that rural postings must have special career or monetary incentives given the loss of locum (i.e. moonlighting income), the higher workload, and professional isolation of remote assignments. Career 'death' and prolonged rural appointments were a common fear, and proposed policy solutions focused considerably on career incentives, such as guaranteed promotion or a study opportunity after some fixed term of service in a remote or hardship area. There was considerable stress placed on the need for rural doctors to have periodic contact with mentors through rural rotation of specialists, or remote learning centers, and reliable terms of appointment with fixed end-points. Also raised, but given less emphasis, were concerns about the adequacy of clinical equipment in remote facilities, and remote accommodations. In-depth discussions with doctors suggest that while salary is important, it is career development priorities that are keeping doctors in urban centers. Short-term service in rural areas would be more appealing if it were linked to special mentoring and/or training, and led to career advancement.


Cathepsin L and Arg/Lys aminopeptidase: a distinct prohormone processing pathway for the biosynthesis of peptide neurotransmitters and hormones.
Peptide neurotransmitters and hormones are synthesized as protein precursors that require proteolytic processing to generate smaller, biologically active peptides that are secreted to mediate neurotransmission and hormone actions. Neuropeptides within their precursors are typically flanked by pairs of basic residues, as well as by monobasic residues. In this review, evidence for secretory vesicle cathepsin L and Arg/Lys aminopeptidase as a distinct proteolytic pathway for processing the prohormone proenkephalin is presented. Cleavage of prohormone processing sites by secretory vesicle cathepsin L occurs at the NH2-terminal side of dibasic residues, as well as between the dibasic residues, resulting in peptide intermediates with Arg or Lys extensions at their NH2-termini. A subsequent Arg/Lys aminopeptidase step is then required to remove NH2-terminal basic residues to generate the final enkephalin neuropeptide. The cathepsin L and Arg/Lys aminopeptidase prohormone processing pathway is distinct from the proteolytic pathway mediated by the subtilisin-like prohormone convertases 1/3 and 2 (PC1/3 and PC2) with carboxypeptidase E/H. Differences in specific cleavage sites at paired basic residue sites distinguish these two pathways. These two proteolytic pathways demonstrate the increasing complexity of regulatory mechanisms for the production of peptide neurotransmitters and hormones.


1,8-Diamidocarbazoles: an easily tuneable family of fluorescent anion sensors and transporters.
The synthesis, structure and anion recognition properties of an extensive, rationally designed series of bisamide derivatives of 1,8-diaminocarbazole and 1,8-diamino-3,6-dichlorocarbazole are described. Despite simple structures and the presence of only three hydrogen bond donors, such compounds are remarkably strong and selective receptors for oxyanions in DMSO + 0.5%H2O. Owing to their carbazole fluorophore, they are also sensitive turn-on fluorescent sensors for H2PO4- and AcO-, with a more than 15-fold increase in fluorescence intensity upon binding. Despite relatively weak chloride affinity, some of the diamidocarbazoles have also been shown, for the first time, to be very active chloride transporters through lipid bilayers. The binding, sensing and transport properties of these receptors can be easily modulated by the usually overlooked variations in the length and degree of branching of their alkyl side arms. Overall, this study demonstrates that the 1,8-diamidocarbazole binding unit is a very promising and synthetically versatile platform for the development of fluorescent sensors and transporters for anions.


Characterization of the metabolic phenotypes of Cushing's syndrome and growth hormone deficiency: a study of body composition and energy metabolism.
A comparison of the severity and distribution of perturbations in body composition and their relationship to energy metabolism in glucocorticoid excess and GH deficiency (GHD) has not been undertaken before. The aim of this study was to investigate the impact of Cushing's syndrome (CS) and GHD on whole and regional body composition and energy metabolism. Cross-sectional study design. Eighteen subjects with CS (12 women, aged = 41.5 +/- 3.0 years, 24-h urinary free cortisol = 1601 +/- 361 nmol/day, normal < 300 nmol/day), 22 subjects with GHD (14 women, age = 42.9 +/- 2.9 years) and 18 normal subjects (11 women, age = 46.8 +/- 2.8 years). Lean body mass (LBM), fat mass (FM) and regional body composition were assessed by dual-energy X-ray absorptiometry (DEXA). Resting energy expenditure (REE) and fat oxidation (Fox) were assessed by indirect calorimetry. Mean percentage FM was significantly greater by 30% in CS (P = 0.002) and 22% in GH-deficient subjects (P = 0.014) than in normal subjects. LBM was significantly lower by 15% in CS (P = 0.002) and 11% in GHD (P = 0.013). In CS, the proportion of lean tissue in the limbs was 12% less than in normal (P = 0.001) and GH-deficient subjects (P = 0.0005). Truncal fat represented a greater proportion of total FM in CS (52.5 +/- 1.8%vs. 46.9 +/- 1.3%, P = 0.014) than in normal subjects, but not in GHD. REE and Fox, corrected for LBM, were significantly lower in GHD (P < 0.02 for both vs. normal) but not in CS. FM was higher and LBM lower in both CS and GHD. However, there is a greater abnormality of regional body composition in patients with CS who exhibit a lower limb lean mass and a greater truncal fat. Reduced REE and Fox contribute to increased adiposity in GHD. As REE and Fox are not perturbed in CS, other mechanisms must explain the marked gain in truncal and total fat.


Pharmacokinetic study of enclosed hemoglobin and outer lipid component after the administration of hemoglobin vesicles as an artificial oxygen carrier.
The hemoglobin vesicle (HbV) is an artificial oxygen carrier that encapsulates a concentrated Hb solution in lipid vesicles (liposomes). The pharmacokinetic properties of HbV were investigated in mice and rats. With use of HbV in which the internal Hb was labeled with (125)I ((125)I-HbV) and cell-free (125)I-Hb, it was found that encapsulation of Hb increased the half-life by 30 times, accompanied by decreased distribution in both the liver and kidney. The half-life of HbV was increased, and the uptake clearance for the liver and spleen were decreased with increasing doses of HbV. In an in vitro study, the specific uptake and degradation of HbV in RAW 264.7 cells were found, but this was not the case for parenchymal and endothelial cells. The pharmacokinetics of HbV components (internal Hb and liposomal lipid) were also investigated using (125)I-HbV and (3)H-HbV (liposomal cholesterol was radiolabeled with tritium-3). The time courses for the plasma concentration curves of (125)I-HbV, (3)H-HbV, and iron derived from HbV suggest that HbV maintain an intact structure in the blood circulation up to 24 h after injection. (125)I-HbV and (3)H-HbV were distributed mainly to the liver and spleen. Internal Hb disappeared from both the liver and spleen 5 days after injection, and the liposomal cholesterol disappeared at approximately 14 days. Internal Hb was excreted into the urine and cholesterol into feces via biliary excretion. These results suggest that the HbV has a reasonable blood retention and metabolic and excretion performance and could be used as an oxygen carrier.


Crystal structures of YkuI and its complex with second messenger cyclic Di-GMP suggest catalytic mechanism of phosphodiester bond cleavage by EAL domains.
Cyclic di-GMP (c-di-GMP) is a ubiquitous bacterial second messenger that is involved in the regulation of cell surface-associated traits and the persistence of infections. Omnipresent GGDEF and EAL domains, which occur in various combinations with regulatory domains, catalyze c-di-GMP synthesis and degradation, respectively. The crystal structure of full-length YkuI from Bacillus subtilis, composed of an EAL domain and a C-terminal PAS-like domain, has been determined in its native form and in complex with c-di-GMP and Ca(2+). The EAL domain exhibits a triose-phosphate isomerase-barrel fold with one antiparallel beta-strand. The complex with c-di-GMP-Ca(2+) defines the active site of the putative phosphodiesterase located at the C-terminal end of the beta-barrel. The EAL motif is part of the active site with Glu-33 of the motif being involved in cation coordination. The structure of the complex allows the proposal of a phosphodiesterase mechanism, in which the divalent cation and the general base Glu-209 activate a catalytic water molecule for nucleophilic in-line attack on the phosphorus. The C-terminal domain closely resembles the PAS-fold. Its pocket-like structure could accommodate a yet unknown ligand. YkuI forms a tight dimer via EAL-EAL and trans EAL-PAS-like domain association. The possible regulatory significance of the EAL-EAL interface and a mechanism for signal transduction between sensory and catalytic domains of c-di-GMP-specific phosphodiesterases are discussed.


Thin grating couplers for integrated optics: an experimental and theoretical study.
A detailed account is given of the practical and theoretical aspects of grating or periodic couplers. Such couplers are used to launch light into thin film optical waveguides. The theoretical description stresses considerations of reciprocity. A Green's function formulation is used to calculate the radiated fields occurring when a guided wave is incident upon a grating coupler. Experiments were performed on grating couplers, formed in photoresist on top of thin film waveguides of 7059 glass deposited on glass of lower refractive index. Measurements of the coupling length and proportion of power in the various beams are presented as a function of the grating period for waveguides supporting one and many modes. Good agreement is found between the theoretical and experimental results. The methods used in the fabrication of the gratings are discussed in detail, and guidelines for the design of grating couplers are given.


Expert Consensus Statement on the Perioperative Management of Adult Patients Undergoing Head and Neck Surgery and Free Tissue Reconstruction From the Society for Head and Neck Anesthesia.
The perioperative care of adult patients undergoing free tissue transfer during head and neck surgical (microvascular) reconstruction is inconsistent across practitioners and institutions. The executive board of the Society for Head and Neck Anesthesia (SHANA) nominated specialized anesthesiologists and head and neck surgeons to an expert group, to develop expert consensus statements. The group conducted an extensive review of the literature to identify evidence and gaps and to prioritize quality improvement opportunities. This report of expert consensus statements aims to improve and standardize perioperative care in this setting. The Modified Delphi method was used to evaluate the degree of agreement with draft consensus statements. Additional discussion and collaboration was performed via video conference and electronic communication to refine expert opinions and to achieve consensus on key statements. Thirty-one statements were initially formulated, 14 statements met criteria for consensus, 9 were near consensus, and 8 did not reach criteria for consensus. The expert statements reaching consensus described considerations for preoperative assessment and optimization, airway management, perioperative monitoring, fluid management, blood management, tracheal extubation, and postoperative care. This group also examined the role for vasopressors, communication, and other quality improvement efforts. This report provides the priorities and perspectives of a group of clinical experts to help guide perioperative care and provides actionable guidance for and opportunities for improvement in the care of patients undergoing free tissue transfer for head and neck reconstruction. The lack of consensus for some areas likely reflects differing clinical experiences and a limited available evidence base.


Restoring Resolution in Biological Solid-State NMR under Conditions of Off-Magic-Angle Spinning.
Spin-state-selective excitation (S3E) experiments allow the selection of individual transitions in a coupled two spin system. We show that in the solid state, the dipole-dipole interaction (DD) between (15)N and (1)H in a (1)H-(15)N bond and the chemical shift anisotropy (CSA) of (15)N in an amide moiety mutually cancel each other for a particular multiplet component at high field, when the sample is spun off the magic angle (Arctan [√2] = 54.74°). The accuracy of the adjustment of the spinning angle is crucial in conventional experiments. We demonstrate that for S3E experiments, the requirement to spin the sample exactly at the magic angle is not mandatory. Applications of solid state NMR in narrow bore magnets will be facilitated where the adjustment of the magic angle is often difficult. The method opens new perspectives for the development of schemes to determine distances and to quantify dynamics in the solid state.


Using evolutionary demography to link life history theory, quantitative genetics and population ecology.
1. There is a growing number of empirical reports of environmental change simultaneously influencing population dynamics, life history and quantitative characters. We do not have a well-developed understanding of links between the dynamics of these quantities. 2. Insight into the joint dynamics of populations, quantitative characters and life history can be gained by deriving a model that allows the calculation of fundamental quantities that underpin population ecology, evolutionary biology and life history. The parameterization and analysis of such a model for a specific system can be used to predict how a population will respond to environmental change. 3. Age-stage-structured models can be constructed from character-demography associations that describe age-specific relationships between the character and: (i) survival; (ii) fertility; (iii) ontogenetic development of the character among survivors; and (iv) the distribution of reproductive allocation. 4. These models can be used to calculate a wide range of useful biological quantities including population growth and structure; terms in the Price equation including selection differentials; estimates of biometric heritabilities; and life history descriptors including generation time. We showcase the method through parameterization of a model using data from a well-studied population of Soay sheep Ovis aries. 5. Perturbation analysis is used to investigate how the quantities listed in summary point 4 change as each parameter in each character-demography function is altered. 6. A wide range of joint dynamics of life history, quantitative characters and population growth can be generated in response to changes in different character-demography associations; we argue this explains the diversity of observations on the consequences of environmental change from studies of free-living populations. 7. The approach we describe has the potential to explain within and between species patterns in quantitative characters, life history and population dynamics.


From the most fleeting of glimpses: on the time course for the extraction of distance information.
An observer's visual perception of the absolute distance between his or her position and an object is based on multiple sources of information that must be extracted during scene viewing. Research has not yet discovered the viewing duration observers need to fully extract distance information, particularly in navigable real-world environments. In a visually directed walking task, participants showed a sensitive response to distance when they were given 9-ms glimpses of floor- and eye-level targets. However, sensitivity to distance decreased markedly when targets were presented at eye level and angular size was rendered uninformative. Performance after brief viewing durations was characterized by underestimation of distance, unless the brief-viewing trials were preceded by a block of extended-viewing trials. The results indicate that experience plays a role in the extraction of information during brief glimpses. Even without prior experience, the extraction of useful information is virtually immediate when the cues of angular size or angular declination are informative for the observer.


Examination of type material of two species of Litomosoides (Filarioidea: Onchocercidae), parasites from bats; taxonomic consequences.
Type material of Litomosoides hamletti Sandground, 1934 from Glossophaga soricina soricina in Brazil and L. penai Jiménez-Quirós & Arroyo, 1960 from Carollia perspicillata azteca in Costa Rica, was examined. The morphology of the spicules shows that these species belong to the carinii group. Their synonymy with L. guiterasi Pérez Vigueras, 1934, from Artibeus jamaicensis yucatanicus in Cuba, does not appear justified because they are distinct in several characters (body length, width of female, size and shape of buccal cavity and capsule, shape of right spicule). L. hamletti is a valid species; L. penai is closely related to it and is considered to be a sub-species, L. hamletti penai Jiménez-Quirós & Arroyo, 1960. The material recovered from Glossophaga spp., previously assigned to L. guiterasi by several authors, is identified as L. h. hamletti. L. guiterasi appears to be closely related to L. chandleri Esslinger, 1973; L. chitwoodi n. sp. (= Litomosoides sp. Chitwood, 1938) seems close to these species; all three are parasites of Artibeus spp.


Bancroftian filariasis: the patterns of filarial-specific immunoglobulin G1 (IgG1), IgG4, and circulating antigens in an endemic community of northeastern Tanzania.
The profile of filarial-specific immunoglobulin G1 (IgG1), IgG4, and Wuchereria bancrofti-specific circulating antigen (Og4C3) was analyzed in individuals one year of age and older in a community with high endemicity for Bancroftian filariasis. The overall microfilarial (mf) prevalence in the examined population was 29%. Fifty-one percent of the population were positive for IgG1 (39% among mf-positive individuals and 63% among mf-negative individuals), whereas 90% were positive for IgG4 (97% among mf-positives and 87% among mf-negatives). The levels of IgG1 and IgG4 were clearly related to mf status and age, but they were unrelated to sex, intensity of microfilaremia, or chronic clinical manifestations. The mean level of IgG1 was significantly higher among amicrofilaremic than among microfilaremic individuals, and it was significantly higher in younger than in older persons. The highest mean IgG4 level was seen in young microfilaremic children, where the level was significantly higher than that in amicrofilaremic children of the same age group and that of older individuals irrespective of mf status. For those 10 years of age and older, the difference in mean level of IgG4 between microfilaremic and amicrofilaremic individuals was not significant. The prevalence of positivity for circulating antigens was 28% in the 1-4-year-old age group, and it increased gradually to 84% in the 50-59-year-old age group (average of 55% for all examined). When analyzed in relation to circulating antigen status, the difference in antibody levels between microfilaremic and amicrofilaremic adults decreased for IgG1 but increased for IgG4, indicating that the IgG1 levels were more related to mf status than to infection status, whereas the IgG4 levels were more related to infection status than to mf status.


Comparing illicit drug use in 19 European cities through sewage analysis.
The analysis of sewage for urinary biomarkers of illicit drugs is a promising and complementary approach for estimating the use of these substances in the general population. For the first time, this approach was simultaneously applied in 19 European cities, making it possible to directly compare illicit drug loads in Europe over a 1-week period. An inter-laboratory comparison study was performed to evaluate the analytical performance of the participating laboratories. Raw 24-hour composite sewage samples were collected from 19 European cities during a single week in March 2011 and analyzed for the urinary biomarkers of cocaine, amphetamine, ecstasy, methamphetamine and cannabis using in-house optimized and validated analytical methods. The load of each substance used in each city was back-calculated from the measured concentrations. The data show distinct temporal and spatial patterns in drug use across Europe. Cocaine use was higher in Western and Central Europe and lower in Northern and Eastern Europe. The extrapolated total daily use of cocaine in Europe during the study period was equivalent to 356 kg/day. High per capita ecstasy loads were observed in Dutch cities, as well as in Antwerp and London. In general, cocaine and ecstasy loads were significantly elevated during the weekend compared to weekdays. Per-capita loads of methamphetamine were highest in Helsinki and Turku, Oslo and Budweis, while the per capita loads of cannabis were similar throughout Europe. This study shows that a standardized analysis for illicit drug urinary biomarkers in sewage can be applied to estimate and compare the use of these substances at local and international scales. This approach has the potential to deliver important information on drug markets (supply indicator).


2017 Position Paper of the Italian Society for Cardiovascular Prevention (SIPREC) for an Updated Clinical Management of Hypercholesterolemia and Cardiovascular Risk: Executive Document.
The benefits achieved by implementing cardiovascular prevention strategies in terms of reduced incidence of atherosclerotic diseases and mortality are accepted, worldwide. In particular, the clinical management of hypercholesterolemia has a fundamental role for all preventive strategies, both in primary and secondary prevention, at each stage of cardiovascular risk. Since the net clinical benefit of lipid-lowering therapy largely depends on baseline individual cardiovascular risk profile, the assessment of individual risk is essential to establish type and intensity of both preventive and therapeutic strategies. Thus, the real challenge in a setting of clinical practice is not only to identify whom to treat among individuals at low-to-moderate risk, but mostly how much and how long to treat high or very-high risk patients. This manuscript, which reflects concepts and positions that have been published in a more extensive document of the Italian Society for Cardiovascular Prevention (SIPREC), deals with the diagnostic and therapeutic management of patients with dyslipidaemia, with an evidence-based approach adapted and updated from recent guidelines of the European Society of Cardiology and very recent results of randomized clinical trials. The purpose is to suggest a multidimensional and integrated actions aimed at eliminating or minimizing the impact of cardiovascular diseases and their related disabilities and mortality in patients with hypercholesterolemia.


Chromatin Dynamics in the Regulation of CFTR Expression.
The contribution of chromatin dynamics to the regulation of human disease-associated loci such as the cystic fibrosis transmembrane conductance regulator (CFTR) gene has been the focus of intensive experimentation for many years. Recent technological advances in the analysis of transcriptional mechanisms across the entire human genome have greatly facilitated these studies. In this review we describe the complex machinery of tissue-specific regulation of CFTR expression, and put earlier observations in context by incorporating them into datasets generated by the most recent genomics methods. Though the gene promoter is required for CFTR expression, cell-type specific regulatory elements are located elsewhere in the gene and in flanking intergenic regions. Probably within its own topological domain established by the architectural proteins CTCF and cohesin, the CFTR locus utilizes chromatin dynamics to remodel nucleosomes, recruit cell-selective transcription factors, and activate intronic enhancers. These cis-acting elements are then brought to the gene promoter by chromatin looping mechanisms, which establish long-range interactions across the locus. Despite its complexity, the CFTR locus provides a paradigm for elucidating the critical role of chromatin dynamics in the transcription of individual human genes.


Community genetics: resource addition has opposing effects on genetic and species diversity in a 150-year experiment.
We used the Park Grass Experiment, begun in 1856, to test alternative hypotheses about the relationship between genetic diversity and plant species diversity. The niche variation hypothesis predicts that populations with few interspecific competitors and hence broader niches are expected to contain greater genetic diversity. The coexistence hypothesis predicts that genetic diversity within species favours coexistence among species and therefore species and genetic diversity should be positively correlated. Amplified Fragment Length Polymorphism (AFLP) markers were used to measure the genetic diversity of populations of Anthoxanthum odoratum growing in 10 plots of differing species richness that lie along resource and soil pH gradients. Genetic diversity in A. odoratum was positively correlated with the number of resources added to a plot, but not correlated with species richness. However, separate analyses have shown a negative correlation between resource addition and species richness at Park Grass and elsewhere, so genetic and species diversity appear to respond in opposite directions.


Elicitation of the Swallowing Reflex by Esophageal Stimulation in Healthy Subjects: An Evaluation Using High-Resolution Manometry.
The purposes of this human study using high-resolution manometry were to verify whether the swallowing reflex can be evoked by intra-esophageal fluid injection and whether the reflex latency and manometric variables differ depending on the injected location, amount, or speed. Ten healthy individuals participated in this study. The tip of the intranasal catheter for injection was placed at 5 cm (upper), 10 cm (upper-middle), 15 cm (lower-middle), or 20 cm (lower) from the distal end of the upper esophageal sphincter (UES). An intra-esophageal injection of 3 mL or 10 mL of thickened water was administered and controlled at 3 mL/s or 10 mL/s. Latencies from the start of the injection to the onset of UES relaxation were compared regarding injection locations, amounts, and rates. Manometric variables of intra-esophageal injection and voluntary swallowing were compared. The latency became shorter when the upper region was injected. Latency after the 10-mL injection was shorter than that after the 3-mL injection (p < 0.01) when faster injection (10 mL/s) was used. Faster injection induced shorter latency (p < 0.01) when a larger volume (10 mL) was injected. Pre-maximum and post-maximum UES pressures during voluntary swallowing or during spontaneous swallowing when injecting the upper esophageal region were significantly higher than spontaneous swallowing at other regions (p < 0.01). Intra-esophageal fluid injection induces the swallowing reflex in humans. The most effective condition for inducing the swallowing reflex involved a larger fluid amount with a faster injection rate in the upper esophagus.


Role of membrane glycoproteins in the interaction of blood platelets with the vessel wall--the study on platelet adhesion to in vitro cultured subendothelial matrix.
Adhesion of platelets to the subendothelium is an essential step in hemostasis and thrombosis. Several receptors for adhesive macromolecules have been identified on platelets and are included in the integrin family. To clarify the role of platelet membrane glycoproteins in the interaction of platelets with the subendothelium, 51Cr-labeled platelet adhesion assay and antibody-blocking experiments were performed by using in vitro cultured subendothelium under the static condition. The platelet adhesion in this assay was inhibited by anti-GPIa (VLA-2), GPIc (VLA-5) and -GPIc'-(VLA-6) antibodies, while anti-GPIb and -GPIIb/IIIa antibodies had no effect. Platelets from the patients with Glanzmann's thrombasthenia could also attach to the subendothelium, whereas those from a patient whose platelets lacked GPIa failed to attach to the extracellular matrix (ECM). The monoclonal antibodies against fibronectin and laminin which recognized the cell binding domain of these molecules inhibited the platelet adhesion when they were pre-treated with ECM. Furthermore, antibody-blocking experiments revealed that the percent inhibition by the combination of anti-GPIa, -GPIc and -GPIc' antibodies used herein was approximately 75%. They did not completely inhibit the attachment. These results suggest that the interactions of collagen, fibronectin and laminin with their receptors on platelets are involved in the mechanism of platelet adhesion to subendothelium.


Mortality of Italian lead smelter workers.
The purpose of this study was to evaluate the health consequences of employment in the lead-smelting industry. A mortality study of 1388 workers and laborers in production and maintenance departments was conducted in an Italian lead-smelting plant. The vital status of cohort members was determined from 1950 to 1992. Standardized mortality ratios were calculated for specific causes of death on the basis of national and regional reference rates. The relative risk for selected causes of death was also modeled as a function of age, calendar period, latency, and duration of employment with Poisson regression analysis. A significant 4.5-fold excess mortality from pneumoconiosis and other diseases of the respiratory system was observed, but the risk of pneumoconiosis did not show a significant trend by duration of employment. Mortality from all cancers, stomach cancer, and lung cancer was lower than expected. The standardized mortality ratios for genitourinary diseases and kidney cancer were not significantly elevated, but the Poisson regression analysis showed that both risks increased significantly by duration of employment. These findings provide limited evidence that long-term employment in lead-smelting plants increases the risk of genitourinary diseases and kidney cancer. The observed increase in mortality from pneumoconiosis and other diseases of the respiratory system was more likely related to silica exposure in other workplaces.


Sick bats stay home alone: fruit bats practice social distancing when faced with an immunological challenge.
Along with its many advantages, social roosting imposes a major risk of pathogen transmission. How social animals reduce this risk is poorly documented. We used lipopolysaccharide challenge to imitate bacterial infection in both a captive and a free-living colony of an extremely social, long-lived mammal-the Egyptian fruit bat. We monitored behavioral and physiological responses using an arsenal of methods, including onboard GPS to track foraging, acceleration sensors to monitor movement, infrared video to record social behavior, and blood samples to measure immune markers. Sick-like (immune-challenged) bats exhibited an increased immune response, as well as classic illness symptoms, including fever, weight loss, anorexia, and lethargy. Notably, the bats also exhibited behaviors that would reduce pathogen transfer. They perched alone and appeared to voluntarily isolate themselves from the group by leaving the social cluster, which is extremely atypical for this species. The sick-like individuals in the open colony ceased foraging outdoors for at least two nights, thus reducing transmission to neighboring colonies. Together, these sickness behaviors demonstrate a strong, integrative immune response that promotes recovery of infected individuals while reducing pathogen transmission inside and outside the roost, including spillover events to other species, such as humans.


Measuring the role of psychological inflexibility in Trichotillomania.
Psychological Inflexibility (PI) is a construct that has gained recent attention as a critical theoretical component of Acceptance and Commitment Therapy (ACT). PI is typically measured by the Acceptance and Action Questionnaire-II (AAQ-II). However, the AAQ-II has shown questionable reliability in clinical populations with specific diagnoses, leading to the creation of content-specific versions of the AAQ-II that show stronger psychometric properties in their target populations. A growing body of the literature suggests that PI processes may contribute to hair pulling, and the current study sought to examine the psychometric properties and utility of a Trichotillomania-specific version of the AAQ-II, the AAQ-TTM. A referred sample of 90 individuals completed a battery of assessments as part of a randomized clinical trial of Acceptance-Enhanced Behavior Therapy for Trichotillomania. Results showed that the AAQ-TTM has two intercorrelated factors, adequate reliability, concurrent validity, and incremental validity over the AAQ-II. Furthermore, mediational analysis between emotional variables and hair pulling outcomes provides support for using the AAQ-TTM to measure the therapeutic process. Implications for the use of this measure will be discussed, including the need to further investigate the role of PI processes in Trichotillomania.


Reliability and concurrent validity of knee angle measurement: smart phone app versus universal goniometer used by experienced and novice clinicians.
The use of goniometers to measure joint angles is a key part of musculoskeletal practice. Recently smartphone goniometry applications have become available to clinicians. This study examined the intra- and inter-measurer reliability of novice and experienced clinicians and the concurrent validity of assessing knee range of motion using a smartphone application (the Knee Goniometer App (Ockendon(©))) (KGA) and a standard universal goniometer (UG). Three clinicians, each with over seven years' experience as musculoskeletal physiotherapists and three final year physiotherapy students, measured 18 different knee joint angles three times, using both the universal goniometer and the smartphone goniometric application. The universal goniometer and the smartphone goniometric application were reliable in repeated measures of knee flexion angles (average Concordance Correlation Coefficient (CCC) > 0.98) with both experienced clinicians and final year physiotherapy students (average CCCs > 0.96). There were no significant differences in reliability between the experienced and the novice practitioners for either device. Agreement between the universal goniometer and smartphone goniometric application measurements was also high for all examiners with average CCCs all above 0.96. The Standard Error of Measurement ranged between 1.56° (0.52-2.66) for the UG and 0.62° (0.29-1.27) for the KGA. The universal goniometer and the smartphone goniometric application were reliable in repeated measures of knee flexion angles. Smaller error of measurement values for the smartphone goniometric application might indicate superiority for assessment where clinical situations demand greater precision of knee range of motion.


Nitric oxide modulates cardiomyocyte pH control through a biphasic effect on sodium/hydrogen exchanger-1.
When activated, Na+/H+ exchanger-1 (NHE1) produces some of the largest ionic fluxes in the heart. NHE1-dependent H+ extrusion and Na+ entry strongly modulate cardiac physiology through the direct effects of pH on proteins and by influencing intracellular Ca2+ handling. To attain an appropriate level of activation, cardiac NHE1 must respond to myocyte-derived cues. Among physiologically important cues is nitric oxide (NO), which regulates a myriad of cardiac functions, but its actions on NHE1 are unclear. NHE1 activity was measured using pH-sensitive cSNARF1 fluorescence after acid-loading adult ventricular myocytes by an ammonium prepulse solution manoeuvre. NO signalling was manipulated by knockout of its major constitutive synthase nNOS, adenoviral nNOS gene delivery, nNOS inhibition, and application of NO-donors. NHE1 flux was found to be activated by low [NO], but inhibited at high [NO]. These responses involved cGMP-dependent signalling, rather than S-nitros(yl)ation. Stronger cGMP signals, that can inhibit phosphodiesterase enzymes, allowed [cAMP] to rise, as demonstrated by a FRET-based sensor. Inferring from the actions of membrane-permeant analogues, cGMP was determined to activate NHE1, whereas cAMP was inhibitory, which explains the biphasic regulation by NO. Activation of NHE1-dependent Na+ influx by low [NO] also increased the frequency of spontaneous Ca2+ waves, whereas high [NO] suppressed these aberrant forms of Ca2+ signalling. Physiological levels of NO stimulation increase NHE1 activity, which boosts pH control during acid-disturbances and results in Na+-driven cellular Ca2+ loading. These responses are positively inotropic but also increase the likelihood of aberrant Ca2+ signals, and hence arrhythmia. Stronger NO signals inhibit NHE1, leading to a reversal of the aforementioned effects, ostensibly as a potential cardioprotective intervention to curtail NHE1 overdrive.


Different localizations and cellular behaviors of leiomodin and tropomodulin in mature cardiomyocyte sarcomeres.
Leiomodin (Lmod) is a muscle-specific F-actin-nucleating protein that is related to the F-actin pointed-end-capping protein tropomodulin (Tmod). However, Lmod contains a unique ∼150-residue C-terminal extension that is required for its strong nucleating activity. Overexpression or depletion of Lmod compromises sarcomere organization, but the mechanism by which Lmod contributes to myofibril assembly is not well understood. We show that Tmod and Lmod localize through fundamentally different mechanisms to the pointed ends of two distinct subsets of actin filaments in myofibrils. Tmod localizes to two narrow bands immediately adjacent to M-lines, whereas Lmod displays dynamic localization to two broader bands, which are generally more separated from M-lines. Lmod's localization and F-actin nucleation activity are enhanced by interaction with tropomyosin. Unlike Tmod, the myofibril localization of Lmod depends on sustained muscle contraction and actin polymerization. We further show that Lmod expression correlates with the maturation of myofibrils in cultured cardiomyocytes and that it associates with sarcomeres only in differentiated myofibrils. Collectively, the data suggest that Lmod contributes to the final organization and maintenance of sarcomere architecture by promoting tropomyosin-dependent actin filament nucleation.


Absence of functioning alpha-adrenergic receptors in mature canine coronary collaterals.
To determine if mature coronary collateral vascular smooth muscle contains functioning alpha-adrenergic receptors, we studied 13 dogs, 6-10 months after circumflex ameroid occlusion. Regional myocardial blood flow was measured with radioactive microspheres in a blood-perfused heart preparation at constant aortic pressure (80 mm Hg). Normal zone resistance was calculated as aortic pressure divided by normal zone flow, and transcollateral resistance was calculated as aortic pressure minus circumflex pressure distal to the ameroid constrictor divided by coronary collateral flow. Flow and resistance were measured during adenosine vasodilation before and during graded doses of a constant infusion of the alpha-adrenergic agonist methoxamine (n = 6) or the alpha 2-adrenergic agonist clonidine (n = 7). In the hearts that received methoxamine, normal zone resistance increased from a control of 0.29 +/- 0.06 to 0.39 +/- 0.06 mm Hg X min/ml per 100 g (resistance units) during infusion of 10(-5)M methoxamine (p less than 0.05). In contrast transcollateral resistance averaged 0.24 +/- 0.02 resistance units under control conditions and did not change during methoxamine infusion. In the hearts that received clonidine, normal zone resistance averaged 0.24 +/- 0.03 resistance units and increased to 0.39 +/- 0.07 resistance units (p less than 0.05) with the highest dose of clonidine administered (10(-5) M). Transcollateral resistance averaged 0.17 +/- 0.03 resistance units during control conditions and did not change with clonidine infusion. In separate studies isometric tension development by the left anterior descending and coronary collateral vessels was examined in organ baths. The left anterior descending coronary artery demonstrated dose-dependent constriction to phenylephrine (peak response 22 +/- 5% of the response to 100 mM KCl). Clonidine produced weak constrictor responses in the left anterior descending coronary artery (5 +/- 2.5% maximal KCl response). In contrast, neither phenylephrine nor clonidine produced responses in mature collaterals. We also examined responses of mature collateral vessels to nonadrenergic agonists. In the vascular ring preparation the mature collaterals developed tension in the presence of KCl (2.3 +/- 0.9 g), prostaglandin F2 alpha (16 +/- 18% of the KCl responses), and vasopressin (90 +/- 30% of the KCl response). In adenosine-vasodilated hearts, pharmacologic doses of vasopressin caused a two-fold increase in transcollateral resistance. Thus, these studies performed on intact hearts and isolated vascular rings demonstrate that mature coronary collaterals do not contain functioning alpha-adrenergic receptors.(ABSTRACT TRUNCATED AT 400 WORDS)


Structure based identification and characterization of flavonoids that disrupt human papillomavirus-16 E6 function.
Expression and function of the human papillomavirus (HPV) early protein 6 (E6) is necessary for viral replication and oncogenesis in cervical cancers. HPV E6 targets the tumor suppressor protein p53 for degradation. To achieve this, "high-risk" HPV E6 proteins bind to and modify the target specificity of the ubiquitin ligase E6AP (E6 associated protein). This E6-dependent loss of p53 enables the virus to bypass host cell defenses and facilitates virally induced activation of the cell cycle progression during viral replication. Disruption of the interaction between E6 and E6AP and stabilization of p53 should decrease viability and proliferation of HPV positive cells. A new in vitro high-throughput binding assay was developed to assay binding between HPV-16 E6 and E6AP and to identify compounds that inhibit this interaction. The compound luteolin emerged from the screen and a library of novel flavones based on its structure was synthesized and characterized using this in vitro binding assay. The compounds identified in this study disrupt the E6/E6AP interaction, increase the levels of p53 and p21(Cip1/Waf1), and decrease proliferation of HPV positive cell lines. The new class of flavonoid E6 inhibitors displays a high degree of specificity for HPV positive cells. Docking analyses suggest that these compounds bind in a hydrophobic pocket at the interface between E6 and E6AP and mimic the leucines in the conserved α-helical motif of E6AP. The activity and specificity of these compounds represent a promising new lead for development as an antiviral therapy in the treatment of HPV infection and cervical cancer.


Sources of dietary fluoride intake in 6-7-year-old English children receiving optimally, sub-optimally, and non-fluoridated water.
Due to increased consumption of pre-packaged drinks, tap water may no longer be the principal source of water intake and consequently fluoride intake. Little is known about the importance of solid foods as fluoride sources and how the relative contribution of foods/drinks to fluoride intake is affected by residing in fluoridated or non-fluoridated areas. This study investigated the relative contributions of different dietary sources to dietary fluoride intake and compared this in children residing in optimally artificially fluoridated, sub-optimally artificially fluoridated, and non-fluoridated areas. Thirty-three healthy children aged 6 years were recruited from fluoridated and non-fluoridated communities and categorised into three groups based on fluoride content of home tap water: optimally fluoridated (< or =0.7 mgF/L), sub-optimally fluoridated (> or =0.3 to < or =0.7 mgF/L) and non-fluoridated (50.3 mgF/L) drinking water. A 3-day dietary diary collected dietary information. Samples of foods/drinks consumed were collected and analyzed for fluoride content. Drinks provided 59%, 55% and 32% of dietary fluoride intake in optimally, sub-optimally and non-fluoridated areas respectively. Tap water, fruit squashes and cordials (extremely sweet non-alcoholic fruit flavoured drink concentrates) prepared with tap water, as well as cooked rice, pasta and vegetables were important sources of fluoride in optimally and sub-optimally fluoridated areas. Carbonated soft drinks and bread were the most important contributors to dietary fluoride intake in the non-fluoridated area. The main contributory sources to dietary fluoride differ between fluoridated and non-fluoridated areas. Estimating total fluoride intake from levels of fluoride in tap water alone is unlikely to provide a reliable quantitative measure of intake. Studies monitoring dietary fluoride exposure should consider intake from all foods and drinks.


Rapid Assembly of Colloidal Crystals under Laser Illumination on a GeSbTe Substrate.
Optical techniques have been actively studied for manipulating nano- to microsized objects. However, long-range attraction and rapid transport of particles within thin quasi-two-dimensional systems are difficult because of the weak thermophoretic forces. Here, we introduce an experimental system that can rapidly generate quasi-two-dimensional colloidal crystals in deionized water, sandwiched between two hard plates. When a pulsed laser is irradiated on a chalcogenide phase-change material spattered on one side of the plates, the induced Marangoni-like flow causes a colloidal self-assembly in the order of tens of micrometers within the laser spot, with a transport velocity of a few tens of micrometers per second. This is due to the large thermal gradient induced by chalcogenide characteristics of high laser absorption and low thermal conductivity, and a strong hydrodynamic slip flow at the hydrophobic chalcogenide interface. Moreover, the colloidal crystals exhibit various lattice structures, depending on the laser intensity and chamber distance. For a certain range of the chamber distance, the colloidal crystal phases can be alternated by tuning the laser intensity in real time. Our system forms and deforms quasi-two-dimensional colloidal crystals at an on-demand location on a GeSbTe substrate.


Dietary Inflammatory Index and Risk of Colorectal Adenoma Recurrence: A Pooled Analysis.
No studies have evaluated the association between the dietary inflammatory index (DII) and colorectal adenoma recurrence. DII scores were calculated from a baseline food frequency questionnaire. Participants (n = 1727) were 40-80 years of age, enrolled in two Phase III clinical trials, who had ≥1 colorectal adenoma(s) removed within 6 months of study registration, and a follow-up colonoscopy during the trial. Multiple logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs). No statistically significant associations were found between DII and odds of colorectal adenoma recurrence [ORs (95% CIs) = 0.93 (0.73, 1.18) and 0.95 (0.73, 1.22)] for subjects in the second and third DII tertiles, respectively, compared to those in the lowest tertile (Ptrend = 0.72). No associations were found for recurrent colorectal adenoma characteristics, including advanced recurrent adenomas, large size, villous histology, or anatomic location. While our study did not support an association between a proinflammatory diet and colorectal adenoma recurrence, future studies are warranted to elucidate the role of a proinflammatory diet on the early stages of colorectal carcinogenesis.


Indigenous knowledge, use and on-farm management of enset (Ensete ventricosum (Welw.) Cheesman) diversity in Wolaita, Southern Ethiopia.
Ensete ventricosum (Welw.) Cheesman is a major food security crop in Southern Ethiopia, where it was originally domesticated and during millennia became pivotal crop around which an entire farming system has developed. Although its cultivation is highly localized, the enset-based farming system provides sustenance to more than 20 million people. Precise ethnobotanical information of intra-specific enset diversity and local knowledge on how communities maintain, manage and benefit from enset genetic resources is imperative for the promotion, conservation and improvement of this crop and its farming system. This study was conducted in Southern Ethiopia among the Wolaita 'enset culture' community. The research sample consisted of 270 households from 12 Kebeles (villages) representing three agro-ecological ranges. By establishing Participatory Rural Appraisal (PRA) based interactions and applying ethnobotanical interviewing methods of free-listing and open-ended questionnaires, information on the use and management of enset diversity, and its associated folk-biosystematics, food traditions and material culture was collected and analyzed. While enset agriculture is seen as cultural heritage and identity for the Wolaita, enset intra-specific diversity holds scenic, prestige and symbolic values for the household. In the present study we recorded 67 enset landraces under cultivation, and through a comprehensive literature review we identified 28 landraces reported from other areas of Wolaita, but not encountered in our survey. Landraces, identified using 11 descriptors primarily related to agro-morphological traits, are named after perceived places of origin, agro-morphological characteristics and cooking quality attributes. Folk classification of enset is based on its domestication status, 'gender', agro-ecological adaptability and landrace suitability for different food and other uses (fiber, feed, medicinal). Enset as a food crop is used to prepare 10 different dishes in Wolaita, 8 of which are exclusively prepared using enset, and their consumption ranges from daily staple to specialty food in festive occasions and ceremonies. On-farm landrace diversity and richness is guided by household needs; its dynamics is managed through regular propagation, harvesting restrain, control of landrace composition and arrangement in the enset homegardens. This study reported on the knowledge system, socio-cultural process and community practices that drive the maintenance of intra-specific on-farm enset diversity in Wolaita, Southern Ethiopia. The information is crucial for developing community based complementary in situ and ex situ conservation strategies to foster conservation of enset genetic resources and associated indigenous knowledge system.


Multipole expansion of Bessel and Gaussian beams for Mie scattering calculations.
Multipole expansions of Bessel and Gaussian beams, suitable for use in Mie scattering calculations, are derived. These results allow Mie scattering calculations to be carried out considerably faster than existing methods, something that is of particular interest for time evolution simulations where large numbers of scattering calculations must be performed. An analytic result is derived for the Bessel beam that improves on a previously published expression requiring the evaluation of an integral. An analogous expression containing a single integral, similar to existing results quoted, but not derived, in literature, is derived for a Gaussian beam, valid from the paraxial limit all the way to arbitrarily high numerical apertures.


The Use of Evaluation Panels During the Development of a Digital Intervention for Veterans Based on Cognitive Behavioral Therapy for Insomnia: Qualitative Evaluation Study.
Individuals enrolling in the Veterans Health Administration frequently report symptoms consistent with insomnia disorder. Cognitive behavioral therapy for insomnia (CBT-I) is a gold standard treatment for insomnia disorder. While the Veterans Health Administration has successfully implemented a large dissemination effort to train providers in CBT-I, the limited number of trained CBT-I providers continues to restrict the number of individuals who can receive CBT-I. Digital mental health intervention adaptations of CBT-I have been found to have similar efficacy as traditional CBT-I. To help address the unmet need for insomnia disorder treatment, the VA commissioned the creation of a freely available, internet-delivered digital mental health intervention adaptation of CBT-I known as Path to Better Sleep (PTBS). We aimed to describe the use of evaluation panels composed of veterans and spouses of veterans during the development of PTBS. Specifically, we report on the methods used to conduct the panels, the feedback they provided on elements of the course relevant to user engagement, and how their feedback influenced the design and content of PTBS. A communications firm was contracted to recruit 3 veteran (n=27) and 2 spouse of veteran (n=18) panels and convene them for three 1-hour meetings. Members of the VA team identified key questions for the panels, and the communications firm prepared facilitator guides to elicit feedback on these key questions. The guides provided a script for facilitators to follow while convening the panels. The panels were telephonically conducted, with visual content displayed via remote presentation software. The communications firm prepared reports summarizing the panelists' feedback during each panel meeting. The qualitative feedback described in these reports served as the raw material for this study. The panel members provided markedly consistent feedback on several elements of PTBS, including recommendations to emphasize the efficacy of CBT-I techniques; clarify and simplify written content as much as possible; and ensure that content is consistent with the lived experiences of veterans. Their feedback was congruent with previous studies on the factors influencing user engagement with digital mental health interventions. Panelist feedback influenced multiple course design decisions, including reducing the effort required to use the course's sleep diary function, making written content more concise, and selecting veteran testimonial videos that emphasized the benefits of treating chronic insomnia symptoms. The veteran and spouse evaluation panels provided useful feedback during the design of PTBS. This feedback was used to make concrete revisions and design decisions consistent with existing research on improving user engagement with digital mental health interventions. We believe that many of the key feedback messages provided by these evaluation panels could prove useful to other digital mental health intervention designers.


Systematic review and meta-analysis of the effect of SGLT-2 inhibitors on microvascular outcomes in patients with type 2 diabetes: a review protocol.
Sodium glucose cotransporter 2 (SGLT-2) inhibitors are a relatively new drug-class of glucose-lowering medications. Several trials and systematic reviews have demonstrated their beneficial effect on some macrovascular outcomes. Their effect on microvascular outcomes has been reported as positive in several trials, however, their effect remains uncertain. Therefore, we report the protocol of a systematic review and meta-analysis aimed at determining the effect of SGLT-2 inhibitors regarding patient-important and surrogate microvascular outcomes in patients with type 2 diabetes. A comprehensive search will be conducted to find eligible articles from each database's earliest inception to November 2017. These databases will include Ovid, MEDLINE, EMBASE, Web of Science, and Scopus. We will search for randomized controlled trials (RCTs) that compare any of the SGLT-2 inhibitors with any other active treatment or placebo assessing microvascular outcomes in either their primary or secondary outcomes. Reviewers working independently and in duplicate will review all abstracts, and full-text manuscripts for eligibility, and will systematically extract the data and will assess the risk of bias in the included studies. Random-effects models will also be used. The results of the systematic review will be disseminated via publication in a peer-reviewed journal regardless of outcome and will be presented at relevant conferences. The data we will use do not include individual patient data, so ethical approval is not required PROSPERO REGISTRATION NUMBER: CRD42017076460.


Inference for optimal dynamic treatment regimes using an adaptive m-out-of-n bootstrap scheme.
A dynamic treatment regime consists of a set of decision rules that dictate how to individualize treatment to patients based on available treatment and covariate history. A common method for estimating an optimal dynamic treatment regime from data is Q-learning which involves nonsmooth operations of the data. This nonsmoothness causes standard asymptotic approaches for inference like the bootstrap or Taylor series arguments to breakdown if applied without correction. Here, we consider the m-out-of-n bootstrap for constructing confidence intervals for the parameters indexing the optimal dynamic regime. We propose an adaptive choice of m and show that it produces asymptotically correct confidence sets under fixed alternatives. Furthermore, the proposed method has the advantage of being conceptually and computationally much simple than competing methods possessing this same theoretical property. We provide an extensive simulation study to compare the proposed method with currently available inference procedures. The results suggest that the proposed method delivers nominal coverage while being less conservative than alternatives. The proposed methods are implemented in the qLearn R-package and have been made available on the Comprehensive R-Archive Network (http://cran.r-project.org/). Analysis of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study is used as an illustrative example.


Similarities and differences in the associations between patient safety culture dimensions and self-reported outcomes in two different cultural settings: a national cross-sectional study in Palestinian and Belgian hospitals.
To investigate the relationships between patient safety culture (PSC) dimensions and PSC self-reported outcomes across different cultures and to gain insights in cultural differences regarding PSC. Observational, cross-sectional study. Ninety Belgian hospitals and 13 Palestinian hospitals. A total of 2836 healthcare professionals matched for profession, tenure and working hours. The validated versions of the Belgian and Palestinian Hospital Survey on Patient Safety Culture were used. An exploratory factor analysis was conducted. Reliability was tested using Cronbach's alpha (α). In this study, we examined the specific predictive value of the PSC dimensions and its self-reported outcome measures across different cultures and countries. Hierarchical regression and bivariate analyses were performed. Eight PSC dimensions and four PSC self-reported outcomes were distinguished in both countries. Cronbach's α was α≥0.60. Significant correlations were found between PSC dimensions and its self-reported outcome (p value range <0.05 to <0.001). Hierarchical regression analyses showed overall perception of safety was highly predicted by hospital management support in Palestine (β=0.16, p<0.001) and staffing in Belgium (β=0.24, p<0.001). The frequency of events was largely predicted by feedback and communication in both countries (Palestine: β=0.24, p<0.001; Belgium: β=0.35, p<0.001). Overall grade for patient safety was predicted by organisational learning in Palestine (β=0.19, p<0.001) and staffing in Belgium (β=0.19, p<0.001). Number of events reported was predicted by staffing in Palestine (β=-0.20, p<0.001) and feedback and communication in Belgium (β=0.11, p<0.01). To promote patient safety in Palestine and Belgium, staffing and communication regarding errors should be improved in both countries. Initiatives to improve hospital management support and establish constructive learning systems would be especially beneficial for patient safety in Palestine. Future research should address the association between safety culture and hard patient safety measures such as patient outcomes.


The effects of delayed auditory and visual feedback on speech production.
Monitoring the sensory consequences of articulatory movements supports speaking. For example, delaying auditory feedback of a speaker's voice disrupts speech production. Also, there is evidence that this disruption may be decreased by immediate visual feedback, i.e., seeing one's own articulatory movements. It is, however, unknown whether delayed visual feedback affects speech production in fluent speakers. Here, the effects of delayed auditory and visual feedback on speech fluency (i.e., speech rate and errors), vocal control (i.e., intensity and pitch), and speech rhythm were investigated. Participants received delayed (by 200 ms) or immediate auditory feedback, while repeating sentences. Moreover, they received either no visual feedback, immediate visual feedback, or delayed visual feedback (by 200, 400, and 600 ms). Delayed auditory feedback affected fluency, vocal control, and rhythm. Immediate visual feedback had no effect on any of the speech measures when it was combined with delayed auditory feedback. Delayed visual feedback did, however, affect speech fluency when it was combined with delayed auditory feedback. In sum, the findings show that delayed auditory feedback disrupts fluency, vocal control, and rhythm and that delayed visual feedback can strengthen the disruptive effect of delayed auditory feedback on fluency.


Poly(vinyl alcohol) Hydrogels Reinforced with Nanocellulose for Ophthalmic Applications: General Characteristics and Optical Properties.
Globally, uncorrected refractive errors are one of the main causes of visual impairment, and contact lenses form an important part of modern day eye care and culture. Several hydrogels with varying physicochemical properties are in use to manufacture soft contact lenses. Hydrogels are generally too soft and reinforcement with appropriate materials is desirable to achieve high water content without compromising mechanical properties. In this study, we have developed a highly transparent macroporous hydrogel with water content >90%, by combining poly(vinyl alcohol) with nanocellulose. Furthermore, the results show that the composite hydrogel has refractive index close to that of water and very good UV-blocking properties.


Central nervous system delivery of the antipsychotic olanzapine induces hepatic insulin resistance.
Olanzapine (OLZ) is an atypical antipsychotic whose clinical efficacy is hampered by side effects including weight gain and diabetes. Recent evidence shows that OLZ alters insulin sensitivity independent of changes in body weight and composition. The present study addresses whether OLZ-induced insulin resistance is driven by its central actions. Sprague-Dawley rats received an intravenous (OLZ-IV group) or intracerebroventricular (OLZ-ICV group) infusion of OLZ or vehicle. Glucose kinetics were assessed before (basal period) and during euglycemic-hyperinsulinemic clamp studies. OLZ-IV caused a transient increase in glycemia and a higher rate of glucose appearance (R(a)) in the basal period. During the hyperinsulinemic clamp, the glucose infusion rate (GIR) required to maintain euglycemia and the rate of glucose utilization (R(d)) were decreased in OLZ-IV, whereas endogenous glucose production (EGP) rate was increased compared with vehicle-IV. Consistent with an elevation in EGP, the OLZ-IV group had higher hepatic mRNA levels for the enzymes glucose-6-phosphatase and phosphoenolpyruvate carboxykinase. Phosphorylation of hypothalamic AMP-activated protein kinase (AMPK) was increased in OLZ-IV rats compared with controls. Similarly, an intracerebroventricular infusion of OLZ resulted in a transient increase in glycemia as well as a higher R(a) in the basal period. During the hyperinsulinemic period, OLZ-ICV caused a decreased GIR, an increased EGP, but no change in R(d). Furthermore, OLZ-ICV rats had increased hepatic gluconeogenic enzymes and elevated hypothalamic neuropeptide-Y and agouti-related protein mRNA levels. Acute central nervous system exposure to OLZ induces hypothalamic AMPK and hepatic insulin resistance, pointing to a hypothalamic site of action for the metabolic dysregulation of atypical antipsychotics.


Laparoscopic assistance for primary transanal pull-through in Hirschsprung's disease: a systematic review and meta-analysis.
To compare outcomes following totally transanal endorectal pull-through (TTERPT) versus pull-through with any form of laparoscopic assistance (LAPT) for infants with uncomplicated Hirschsprung's disease. Systematic review and meta-analysis. Five hospitals with a paediatric surgical service. 405 infants with uncomplicated Hirschsprung's disease. TTERPT versus LAPT. mortality, postoperative enterocolitis, faecal incontinence, constipation, unplanned laparotomy or stoma formation, and injury to abdominal viscera. Haemorrhage requiring transfusion of blood products, abscess formation, intestinal obstruction, intestinal ischaemia, enteric fistula formation, urinary incontinence or retention, impotency and duration of procedure. Five eligible studies comprising 405 patients were identified from 2107 studies. All studies were retrospective case series, with variability in outcome assessment quality and length of follow-up. Operative duration was 50.29 min shorter with TTERPT (95% CI 39.83 to 60.74, p<0.00001). There were no significant differences identified between TTERPT and LAPT for incidence of postoperative enterocolitis (OR=0.78, 95% CI 0.44 to 1.38, p=0.39), faecal incontinence (OR=0.44, 95% CI 0.09 to 2.20, p=0.32) or constipation (OR=0.84, 95% CI 0.32 to 2.17, p=0.71). This meta-analysis did not find any evidence to suggest a higher rate of enterocolitis, incontinence or constipation following TTERPT compared with LAPT. Further long-term comparative studies and multicentre data pooling are needed to determine whether a purely transanal approach offers any advantages over a laparoscopically assisted approach to rectosigmoid Hirschsprung's disease. PROSPERO registry- CRD42013005698.


Effectiveness of a Third Dose of mRNA Vaccines Against COVID-19-Associated Emergency Department and Urgent Care Encounters and Hospitalizations Among Adults During Periods of Delta and Omicron Variant Predominance - VISION Network, 10 States, August 2021-January 2022.
Estimates of COVID-19 mRNA vaccine effectiveness (VE) have declined in recent months (1,2) because of waning vaccine induced immunity over time,* possible increased immune evasion by SARS-CoV-2 variants (3), or a combination of these and other factors. CDC recommends that all persons aged ≥12 years receive a third dose (booster) of an mRNA vaccine ≥5 months after receipt of the second mRNA vaccine dose and that immunocompromised individuals receive a third primary dose.† A third dose of BNT162b2 (Pfizer-BioNTech) COVID-19 vaccine increases neutralizing antibody levels (4), and three recent studies from Israel have shown improved effectiveness of a third dose in preventing COVID-19 associated with infections with the SARS-CoV-2 B.1.617.2 (Delta) variant (5-7). Yet, data are limited on the real-world effectiveness of third doses of COVID-19 mRNA vaccine in the United States, especially since the SARS-CoV-2 B.1.1.529 (Omicron) variant became predominant in mid-December 2021. The VISION Network§ examined VE by analyzing 222,772 encounters from 383 emergency departments (EDs) and urgent care (UC) clinics and 87,904 hospitalizations from 259 hospitals among adults aged ≥18 years across 10 states from August 26, 2021¶ to January 5, 2022. Analyses were stratified by the period before and after the Omicron variant became the predominant strain (>50% of sequenced viruses) at each study site. During the period of Delta predominance across study sites in the United States (August-mid-December 2021), VE against laboratory-confirmed COVID-19-associated ED and UC encounters was 86% 14-179 days after dose 2, 76% ≥180 days after dose 2, and 94% ≥14 days after dose 3. Estimates of VE for the same intervals after vaccination during Omicron variant predominance were 52%, 38%, and 82%, respectively. During the period of Delta variant predominance, VE against laboratory-confirmed COVID-19-associated hospitalizations was 90% 14-179 days after dose 2, 81% ≥180 days after dose 2, and 94% ≥14 days after dose 3. During Omicron variant predominance, VE estimates for the same intervals after vaccination were 81%, 57%, and 90%, respectively. The highest estimates of VE against COVID-19-associated ED and UC encounters or hospitalizations during both Delta- and Omicron-predominant periods were among adults who received a third dose of mRNA vaccine. All unvaccinated persons should get vaccinated as soon as possible. All adults who have received mRNA vaccines during their primary COVID-19 vaccination series should receive a third dose when eligible, and eligible persons should stay up to date with COVID-19 vaccinations.


Phenotypic changes of adult porcine mesenchymal stem cells induced by prolonged passaging in culture.
The in vitro culture of porcine bone marrow-derived mesenchymal stem cells (MSCs) was used for the investigation of adult stem cell biology. Isolated porcine MSCs possessed the ability to proliferate extensively in an antioxidants-rich medium containing 5% fetal bovine serum (FBS). Greater than 40 serial MSC passages and 100 cell population doublings have been recorded for some MSC batches. Early and late passage MSCs were defined here as those cultures receiving less than 5 trypsin passages and more than 15 trypsin passages, respectively. Consistent with their robust ability to proliferate, both the early and late passage MSCs expressed the cell-cycle promoting enzyme p34cdc2 kinase. Late MSCs, however, exhibited certain features reminiscent of cellular aging such as actin accumulation, reduced substrate adherence, and increased activity of lysosomal acid beta-galactosidase. Early MSCs retained the multipotentiality capable of chondrogenic, osteogenic, and adipogenic differentiation upon induction in vitro. In contrast, late MSCs were only capable of adipogenic differentiation, which was greatly enhanced at the expense of the osteochondrogenic potential. Along with these changes in multipotentiality, late MSCs expressed decreased levels of the bone morphogenic protein (BMP-7) and reduced activity of alkaline phosphatase. Late MSCs also exhibited attenuated synthesis of the hematopoietic cytokines granulocyte colony-stimulating factor (G-CSF), leukemia inhibitory factor (LIF), and stem cell factor (SCF). The long-term porcine MSC culture, thus, provides a model system to study the molecular interplay between multiple MSC differentiation cascades in the context of cellular aging.


Modulation of Antibacterial, Antioxidant, and Anti-Inflammatory Properties by Drying of Prunus domestica L. Plum Juice Extracts.
The consumption of plums in a fresh form is seasonal, therefore the transformation of plum juice extracts into powdered form is a good alternative for its longer availability throughout the year. The drying process can moderate the physical and chemical properties of the plum extracts, thus, this study examined the changes in biological activity, i.e., antibacterial, antioxidant, and anti-inflammatory properties moderated by freeze, vacuum, and spray drying. It was suggested that the drying processes and the applied parameters might moderate the content of polyphenolic compounds in the powders, which influence the different levels of growth inhibition against the foodborne pathogens (17% to 58% of inhibition), demonstrating a strain-dependent effect. These powders could also induce cellular protection against oxidative stress by preventing intracellular reactive oxygen species (ROS) accumulation (23% to 37% of reduction), but the level of antioxidant capacity may be determined by the conditions applied during the drying process. Moreover, plum extract powders exhibited a greater anti-inflammatory capacity (24% to 39% of inhibition), which would be influenced both, by the type of treatment used and by the temperature used in each treatment. The results demonstrate that the selection of the drying method can be an effective tool for modulating the composition, physical, and bioactive properties of plum extracts powders.


[Dose reduction of conventional antipsychotics: does it reduce tardive dyskinesia?].
The first step in the treatment of tardive dyskinesia is to reduce the dose of antipsychotics. The view sometimes expressed in general practice is that, initially, dose reduction exacerbates tardive dyskinesia, which is an effect that can be explained on theoretical grounds. However, it is apparent from published scientific research that dose reduction of conventional antipsychotics tends to improve tardive dyskinesia rather than exacerbate it.


Topology-Matching Design of an Influenza-Neutralizing Spiky Nanoparticle-Based Inhibitor with a Dual Mode of Action.
In this study, we demonstrate the concept of "topology-matching design" for virus inhibitors. With the current knowledge of influenza A virus (IAV), we designed a nanoparticle-based inhibitor (nano-inhibitor) that has a matched nanotopology to IAV virions and shows heteromultivalent inhibitory effects on hemagglutinin and neuraminidase. The synthesized nano-inhibitor can neutralize the viral particle extracellularly and block its attachment and entry to the host cells. The virus replication was significantly reduced by 6 orders of magnitude in the presence of the reverse designed nano-inhibitors. Even when used 24 hours after the infection, more than 99.999 % inhibition is still achieved, which indicates such a nano-inhibitor might be a potent antiviral for the treatment of influenza infection.


[Ill-being and well-being: searching for biological correlates].
The aim of the present study is to describe the relationship between psychological well-being, ill-being and biological correlates on a sample of Italian blood donors. Particularly, specific correlations with biological correlates were analysed. Sample consisted of 58 blood donors. Biological parameters were assessed using the usual blood analyses. Psychological well-being, ill-being and stress were assessed respectively with the Psychological Well-Being scale (PWB), the Symptom Questionnaire (SQ), and the Psychosocial Index (PSI). Pearson Correlations were computed between these scores and biological indexes. A significant positive correlation between different scales of SQ and PSI and platelets was found, while the same parameter showed a significant negative correlation with the Environmental Mastery subscale (PWB). Results add clues to the growing literature concerning the link between health and well-being. Particularly, platelets data confirms previous literature on the relationship with the distress measures, but in this study it also displays an unexpected correlation with a well being dimension (Environmental Mastery).


Early discontinuation and non-adherence to adjuvant hormonal therapy are associated with increased mortality in women with breast cancer.
Despite the benefit of adjuvant hormonal therapy (HT) on mortality among women with breast cancer (BC), many women are non-adherent with its use. We investigated the effects of early discontinuation and non-adherence to HT on mortality in women enrolled in Kaiser Permanente of Northern California (KPNC). We identified women diagnosed with hormone-sensitive stage I-III BC, 1996-2007, and used automated pharmacy records to identify prescriptions and dates of refill. We categorized patients as having discontinued HT early if 180 days elapsed from the prior prescription. For those who continued, we categorized patients as adherent if the medication possession ratio was ≥80%. We used Cox proportional hazards models to estimate the association between discontinuation and non-adherence with all-cause mortality. Among 8,769 women who filled at least one prescription for HT, 2,761 (31%) discontinued therapy. Of those who continued HT, 1,684 (28%) were non-adherent. During a median follow-up of 4.4 years, 813 women died. Estimated survival at 10 years was 80.7% for women who continued HT versus 73.6% for those who discontinued (P < 0.001). Of those who continued, survival at 10 years was 81.7 and 77.8% in women who adhered and non-adhered, respectively (P < 0.001). Adjusting for clinical and demographic variables, both early discontinuation (HR 1.26, 95% CI 1.09-1.46) and non-adherence (HR 1.49, 95% CI 1.23-1.81), among those who continued, were independent predictors of mortality. Both early discontinuation and non-adherence to HT were common and associated with increased mortality. Interventions to improve continuation of and adherence to HT may be critical to improve BC survival.


Practice Bulletin No. 165 Summary: Prevention and Management of Obstetric Lacerations at Vaginal Delivery.
Lacerations are common after vaginal birth. Trauma can occur on the cervix, vagina, and vulva, including the labial, periclitoral, and periurethral regions, and the perineum. Most of these lacerations do not result in adverse functional outcomes. Severe perineal lacerations, extending into or through the anal sphincter complex, although less frequent, are more commonly associated with increased risk of pelvic floor injury, fecal and urinary incontinence, pain, and sexual dysfunction with symptoms that may persist or be present many years after giving birth. The purpose of this document is to provide evidence-based guidelines for the prevention, identification, and repair of obstetric lacerations and for episiotomy.


Multispectral Optical Tweezers for Biochemical Fingerprinting of CD9-Positive Exosome Subpopulations.
Extracellular vesicles (EVs), including exosomes, are circulating nanoscale particles heavily implicated in cell signaling and can be isolated in vast numbers from human biofluids. Study of their molecular profiling and materials properties is currently underway for purposes of describing a variety of biological functions and diseases. However, the large, and as yet largely unquantified, variety of EV subpopulations differing in composition, size, and likely function necessitates characterization schemes capable of measuring single vesicles. Here we describe the first application of multispectral optical tweezers (MS-OTs) to single vesicles for molecular fingerprinting of EV subpopulations. This versatile imaging platform allows for sensitive measurement of Raman chemical composition (e.g., variation in protein, lipid, cholesterol, nucleic acids), coupled with discrimination by fluorescence markers. For exosomes isolated by ultracentrifugation, we use MS-OTs to interrogate the CD9-positive subpopulations via antibody fluorescence labeling and Raman spectra measurement. We report that the CD9-positive exosome subset exhibits reduced component concentration per vesicle and reduced chemical heterogeneity compared to the total purified EV population. We observed that specific vesicle subpopulations are present across exosomes isolated from cell culture supernatant of several clonal varieties of mesenchymal stromal cells and also from plasma and ascites isolated from human ovarian cancer patients.


The emotional toll of spousal morbidity and mortality.
Spouse caregivers have an increased risk of mental and physical illness during caregiving and widowhood. The authors sought to evaluate whether partners of an ill spouse have a higher likelihood of developing mental health or substance abuse (MHSA) disorders than partners who have healthy spouses, accounting for both spousal illness and death. The authors used Medicare claims from 1993-2001 for 474,228 married couples. The authors used Cox models to determine the effect of spouse illness on partner MHSA diagnosis, controlling for demographic and clinical characteristics. A wife's hospitalization increased the husband's risk of MHSA diagnosis by 1.29 (95% confidence interval [CI]: 1.28-1.29) and his risk of depression by 1.49 (95% CI: 1.48-1.51). A husband's hospitalization increased the risk of a wife's MHSA diagnosis by 1.33 (95% CI: 1.32-1.33) and her risk of depression by 1.41 (95% CI: 1.39-1.42). A wife's death increased the risk of the husband's MHSA diagnosis by 1.12 (95% CI: 1.11-1.13) and increased his risk of depression by 1.49 (95% CI: 1.46-1.51). A husband's death increased the risk of the wife's MHSA diagnosis by 1.14 (95% CI: 1.14-1.15) and increased her risk of depression by 1.41 (95% CI: 1.39-1.42). Spouse hospitalizations and spouse death independently increase the risk for partner MHSA and depression diagnoses. These findings can identify which individuals are at greatest risk for emotional distress and should be targeted for interventions to relieve caregiver burden that can arise separately and additively from both spousal illness and death.


Computational capabilities of graph neural networks.
In this paper, we will consider the approximation properties of a recently introduced neural network model called graph neural network (GNN), which can be used to process-structured data inputs, e.g., acyclic graphs, cyclic graphs, and directed or undirected graphs. This class of neural networks implements a function tau(G,n) is an element of IR(m) that maps a graph G and one of its nodes n onto an m-dimensional Euclidean space. We characterize the functions that can be approximated by GNNs, in probability, up to any prescribed degree of precision. This set contains the maps that satisfy a property called preservation of the unfolding equivalence, and includes most of the practically useful functions on graphs; the only known exception is when the input graph contains particular patterns of symmetries when unfolding equivalence may not be preserved. The result can be considered an extension of the universal approximation property established for the classic feedforward neural networks (FNNs). Some experimental examples are used to show the computational capabilities of the proposed model.


Factors Associated with Knowledge of Evacuation Routes and Having an Emergency Backpack in Individuals Affected by a Major Earthquake in Piura, Peru.
Information on the prevention of earthquakes in Peru, a high-risk country, is still emerging. We determined the frequency and factors associated with knowledge of evacuation routes and the use of emergency backpacks in people affected by a major earthquake. A cross-sectional study using secondary data was conducted from August-December 2021 on people that experienced the 6.1 magnitude earthquake that occurred in Piura, Peru on 30 July 2021. The outcome was self-reported knowledge of evacuation routes and the use of emergency backpacks. The association with self-reported earthquake preparation training, use of sources of information on earthquakes, and sociodemographic variables was investigated. A total of 69.5% of participants knew evacuation routes, and 46.3% had an emergency backpack. A higher frequency of knowledge of evacuation routes was associated with previous training (PR: 1.47; 95% CI: 1.15-1.87), use of the media (PR: 1.35; 95% CI: 1.06-1.72), having received information from the COEN (PR: 1.19; 95% CI: 1.02-1.40), and with a greater number of household members (PR: 1.03; 95% CI: 1.01-1.06). There is a high frequency of knowledge of evacuation routes among participants. However, basic notions of prevention culture are still needed. This research contributes to policy development on earthquake preparation at the community level.


Risk factors for suboptimal antiretroviral therapy adherence in HIV-infected adolescents in Gaborone, Botswana: a pilot cross-sectional study.
Little is known about factors associated with suboptimal antiretroviral treatment (ART) adherence among adolescents in Sub-Saharan Africa. Our objective was to determine the level of ART adherence and predictors of non-adherence among human immunodeficiency virus (HIV)-infected adolescents at the Botswana-Baylor Children's Clinical Centre of Excellence in Gaborone, Botswana. In a cross-sectional study, 82 HIV-infected adolescents receiving ART and their caregivers were administered a structured questionnaire. The patient's clinical information was retrieved from medical records. Outcome measures included excellent pill count ART adherence (>95%) and virologic suppression (HIV viral load <400 copies/mL). Multivariate logistic regression analysis was performed to identify independent predictors of ART non-adherence. The overall median (interquartile range) ART adherence was 99% (96.5-100) (N = 82). Seventy-six percent of adolescents had excellent pill count ART adherence levels and 94% achieved virologic suppression. Male adolescents made up 65% of the non-adherent group (P = 0.02). Those who displayed suboptimal ART adherence were more likely to report having ever missed ART doses due to failure to pick up medication at the pharmacy (30.0% versus 9.7%, P = 0.03). In the multivariate logistic regression model, male sex (odds ratio [OR] 3.29, 95% confidence interval [CI] 1.13-9.54; P = 0.03) was the only factor which was independently associated with suboptimal ART adherence. A high proportion of HIV-infected adolescents studied had excellent ART adherence and virologic suppression, with male adolescents at higher risk of suboptimal adherence than females. Further research to investigate how sex relates to suboptimal adherence may aid in the design of targeted intervention strategies.


Physical fitness in postmenopausal women with fibromyalgia.
The purpose of this study was to compare physical fitness and health-related quality-of-life between twenty-three postmenopausal women with fibromyalgia (age 58 +/- 3 years) and eleven healthy women (58 +/- 5 years). Aerobic fitness and isometric force of different muscle groups were measured. Functional performance was assessed by walking and stair-climbing times. Symptoms were assessed by visual analog scale and quality-of-life by RAND-36 questionnaire. Women with fibromyalgia had significantly lower isometric force in bilateral leg extensors (1285 vs. 1898 N), unilateral knee extensors (414 vs. 502 N) and flexors (197 vs. 235 N) than healthy women, but no differences were observed in forces of the trunk and upper extremities. Maximal workload in the aerobic test (130 vs. 151 W), functional performance and quality-of-life were lower in women with fibromyalgia and they reported more symptoms than healthy subjects, while maximal oxygen uptake did not differ between the groups. A lower maximal load in the aerobic test suggests the patients' unsatisfactory ability to stand physical loading and resist overall fatigue. Moreover, fatigue rather than pain was the main factor to decrease the quality-of-life in women with fibromyalgia. Additional efforts should be addressed to strength training, when planning health promotion and rehabilitation programs in fibromyalgia.


APACHE II and ISS scores as predictors of nosocomial infections in trauma patients.
Nosocomial infections affect more than 2 million patients annually in the United States at a cost of $4.5 billion. The aim of this study is to identify the role of the APACHE II score and the Injury Severity Scale (ISS) as independent predictors of nosocomial infections in trauma patients admitted to the intensive care unit (ICU). A retrospective chart review of 113 trauma patients admitted to the ICU was conducted by an infectious disease physician. Demographic data and incidence of nosocomial infections were recorded. Multivariate logistic regression analysis was used to determine variables that are predictive of the occurrence of nosocomial infections. Presence or absence of intubation, ICU length of stay, APACHE II score, and ISS were related to the presence of infections; however, only the ICU length of stay was an independent predictor of a nosocomial infection, with an odds ratio of 1.81. By linear regression, 17% of the variance in the ICU duration of stay was a result of the APACHE II score in patients with a score >/=5. APACHE II score and ISS score were not good predictors of the incidence of nosocomial infections in trauma patients admitted to the ICU, but the APACHE II score has a modest correlation with the duration of stay in the ICU. A stratified cohort study could identify the subset of patients for which the APACHE II score predicts a prolonged stay in the ICU, thus an increased risk of infection.


Using maximum weight to redefine body mass index categories in studies of the mortality risks of obesity.
The high prevalence of disease and associated weight loss at older ages limits the validity of prospective cohort studies examining the association between body mass index (BMI) and mortality. I examined mortality associated with excess weight using maximum BMI-a measure that is robust to confounding by illness-induced weight loss. Analyses were carried out on US never-smoking adults ages 50-84 using data from the National Health and Nutrition Examination Surveys (1988-1994 and 1999-2004) linked to the National Death Index through 2006. Cox models were used to estimate hazard ratios for mortality according to BMI at time of survey and at maximum. Using maximum BMI, hazard ratios for overweight (BMI, 25.0-29.9 kg/m2), obese class 1 (BMI, 30.0-34.9 kg/m2) and obese class 2 (BMI, 35.0 kg/m2 and above) relative to normal weight (BMI, 18.5-24.9 kg/m2) were 1.28 (95% confidence interval [CI], 0.89-1.84), 1.67 (95% CI, 1.15-2.40), and 2.15 (95% CI, 1.47-3.14), respectively. The corresponding hazard ratios using BMI at time of survey were 0.98 (95% CI, 0.77-1.24), 1.18 (95% CI, 0.91-1.54), and 1.31 (95% CI, 0.95-1.81). The percentage of mortality attributable to overweight and obesity among never-smoking adults ages 50-84 was 33% when assessed using maximum BMI. The comparable figure obtained using BMI at time of survey was substantially smaller at 5%. The discrepancy in estimates is explained by the fact that when using BMI at time of survey, the normal category combines low-risk stable-weight individuals with high-risk individuals that have experienced weight loss. In contrast, only the low-risk stable-weight group is categorized as normal weight using maximum BMI. Use of maximum BMI reveals that estimates based on BMI at the time of survey may substantially underestimate the mortality burden associated with excess weight in the US.


Endothelial function and soluble endoglin in smokers with heart failure.
Although cigarette smoking is a risk factor for heart failure (HF), smokers with HF have lower mortality rates during/following hospitalization compared to nonsmokers. We examined vascular endothelial function in chronic smokers and nonsmokers with HF as it relates to this smoker's paradox. Smokers with HF will have attenuated endothelial dysfunction compared to non-smokers with HF. Brachial artery flow-mediated dilation (FMD), a measure of conduit vessel endothelial function, was measured in 33 smoking and nonsmoking patients with HF vs controls. In addition, soluble endoglin (sEng), a circulating mediator of endothelial function, was measured in a separate group of 36 smoking and nonsmoking patients with HF vs controls. FMD was significantly lower in smokers without HF compared to the nonsmokers without HF (P < 0.05). FMD was significantly higher in smokers with HF vs nonsmokers with HF (P < 0.05) and did not differ from values seen in nonsmokers without HF (P > 0.05). There were no differences in sEng between smokers and nonsmokers without HF (P > 0.05). sEng was lower in smokers with HF vs nonsmokers with HF (P < 0.05) and did not differ from values seen in nonsmokers without HF (P > 0.05). Smokers with HF had higher brachial FMD and lower sEng than nonsmokers with HF, and values were comparable to nonsmokers without HF. These findings offer novel insight into the smoker's paradox and suggest that improved short-term outcome in patients hospitalized with HF may in part be mediated by preservation of vascular endothelial function in this setting.


Node-Based Learning of Multiple Gaussian Graphical Models.
We consider the problem of estimating high-dimensional Gaussian graphical models corresponding to a single set of variables under several distinct conditions. This problem is motivated by the task of recovering transcriptional regulatory networks on the basis of gene expression data containing heterogeneous samples, such as different disease states, multiple species, or different developmental stages. We assume that most aspects of the conditional dependence networks are shared, but that there are some structured differences between them. Rather than assuming that similarities and differences between networks are driven by individual edges, we take a node-based approach, which in many cases provides a more intuitive interpretation of the network differences. We consider estimation under two distinct assumptions: (1) differences between the K networks are due to individual nodes that are perturbed across conditions, or (2) similarities among the K networks are due to the presence of common hub nodes that are shared across all K networks. Using a row-column overlap norm penalty function, we formulate two convex optimization problems that correspond to these two assumptions. We solve these problems using an alternating direction method of multipliers algorithm, and we derive a set of necessary and sufficient conditions that allows us to decompose the problem into independent subproblems so that our algorithm can be scaled to high-dimensional settings. Our proposal is illustrated on synthetic data, a webpage data set, and a brain cancer gene expression data set.