Drivers, dynamics, and control of emerging vector-borne zoonotic diseases.
Emerging vector-borne diseases are an important issue in global health. Many vector-borne pathogens have appeared in new regions in the past two decades, while many endemic diseases have increased in incidence. Although introductions and emergence of endemic pathogens are often considered to be distinct processes, many endemic pathogens are actually spreading at a local scale coincident with habitat change. We draw attention to key differences between dynamics and disease burden that result from increased pathogen transmission after habitat change and after introduction into new regions. Local emergence is commonly driven by changes in human factors as much as by enhanced enzootic cycles, whereas pathogen invasion results from anthropogenic trade and travel where and when conditions (eg, hosts, vectors, and climate) are suitable for a pathogen. Once a pathogen is established, ecological factors related to vector characteristics can shape the evolutionary selective pressure and result in increased use of people as transmission hosts. We describe challenges inherent in the control of vector-borne zoonotic diseases and some emerging non-traditional strategies that could be effective in the long term.


Changes in stable isotopes, lignin-derived phenols, and fossil pigments in sediments of Lake Biwa, Japan: implications for anthropogenic effects over the last 100 years.
We measured stable nitrogen (N) and carbon (C) isotope ratios, lignin-derived phenols, and fossil pigments in sediments of known ages to elucidate the historical changes in the ecosystem status of Lake Biwa, Japan, over the last 100 years. Stable N isotope ratios and algal pigments in the sediments increased rapidly from the early 1960s to the 1980s, and then remained relatively constant, indicating that eutrophication occurred in the early 1960s but ceased in the 1980s. Stable C isotope ratios of the sediment increased from the 1960s, but decreased after the 1980s to the present. This decrease in stable C isotope ratios after the 1980s could not be explained by annual changes in either terrestrial input or algal production. However, when the C isotope ratios were corrected for the Suess effect, the shift to more negative isotopic value in atmospheric CO(2) by fossil fuel burning, the isotopic value showed a trend, which is consistent with the other biomarkers and the monitoring data. The trend was also mirrored by the relative abundance of lignin-derived phenols, a unique organic tracer of material that originated from terrestrial plants, which decreased in the early 1960s and recovered to some degree in the 1980s. We detected no notable difference in the composition of lignin phenols, suggesting that the terrestrial plant composition did not change markedly. However, we found that lignin accumulation rate increased around the 1980s. These results suggest that although eutrophication has stabilized since the 1980s, allochthonous organic matter input has changed in Lake Biwa over the past 25 years.


Comparison of blood glucose management strategies to achieve control following cardiac surgery (computerized versus paper).
Blood glucose control can be time-consuming and difficult to achieve. We hypothesized that a computerized system to obtain glucose control would enable faster "time to target" and produce less variability in blood glucose levels. Patients who underwent cardiac surgery at a community hospital between January and December 2007 (n = 1131) with glucose control obtained under a paper protocol were compared with similar patients operated on between January and December 2008 (n = 769) whose glucose control was obtained with a computer-driven protocol. Glucose control was achieved in both groups. The computer group had less variability in glucose levels than the paper group. The mean time to target for the computer group was 3.5 (+/-1.3) hours. The time to target for the paper group was quite skewed; therefore, the median time to target was 6 hours. The computer-driven protocol achieved excellent glycemic control.


Correlated inter-domain motions in adenylate kinase.
Correlated inter-domain motions in proteins can mediate fundamental biochemical processes such as signal transduction and allostery. Here we characterize at structural level the inter-domain coupling in a multidomain enzyme, Adenylate Kinase (AK), using computational methods that exploit the shape information encoded in residual dipolar couplings (RDCs) measured under steric alignment by nuclear magnetic resonance (NMR). We find experimental evidence for a multi-state equilibrium distribution along the opening/closing pathway of Adenylate Kinase, previously proposed from computational work, in which inter-domain interactions disfavour states where only the AMP binding domain is closed. In summary, we provide a robust experimental technique for study of allosteric regulation in AK and other enzymes.


A novel integrated thermal-/membrane-based solar energy-driven hybrid desalination system: Concept description and simulation results.
In this paper, a hybrid desalination system consisting of vacuum membrane distillation (VMD) and adsorption desalination (AD) units, designated as VMD-AD cycle, is proposed. The synergetic integration of the VMD and AD is demonstrated where a useful effect of the AD cycle is channelled to boost the operation of the VMD process, namely the low vacuum environment to maintain the high pressure gradient across the microporous hydrophobic membrane. A solar-assisted multi-stage VMD-AD hybrid desalination system with temperature modulating unit is first designed, and its performance is then examined with a mathematical model of each component in the system and compared with the VMD-only system with temperature modulating and heat recovery units. The total water production and water recovery ratio of a solar-assisted 24-stage VMD-AD hybrid system are found to be about 21% and 23% higher, respectively, as compared to the VMD-only system. For the solar-assisted 24-stage VMD-AD desalination system having 150 m(2) of evacuated-tube collectors and 10 m(3) seawater storage tanks, both annual collector efficiency and solar fraction are close to 60%.


Resveratrol as a Multifunctional Topical Hypopigmenting Agent.
Melanin is produced in melanocytes and stored in melanosomes, after which it is transferred to keratinocytes and, thus, determines skin color. Despite its beneficial sun-protective effects, abnormal accumulation of melanin results in esthetic problems. A range of topical hypopigmenting agents have been evaluated for their use in the treatment of pigmentary disorders with varying degrees of success. Hydroquinone (HQ), which competes with tyrosine, is the main ingredient in topical pharmacological agents. However, frequent occurrence of adverse reactions is an important factor that limits its use. Thus, efforts to discover effective topical hypopigmenting agents with less adverse effects continue. Here, we describe the potential of resveratrol to function as an effective hypopigmenting agent based on its mechanism of action. Resveratrol is not only a direct tyrosinase inhibitor but an indirect inhibitor as well. Additionally, it can affect keratinocytes, which regulate the function of melanocytes. Resveratrol regulates the inflammatory process of keratinocytes and protects them from oxidative damage. In this way, it prevents keratinocyte-induced melanocyte stimulation. Furthermore, it has a rescuing effect on the stemness of interfollicular epidermal cells that can repair signs of photoaging in the melasma, a typical pigmentary skin disorder. Overall, resveratrol is a promising potent hypopigmenting agent.


Long-term effects of cerebral hypoperfusion on neural density and function using misery perfusion animal model.
We investigated the chronic effects of cerebral hypoperfusion on neuronal density and functional hyperemia using our misery perfusion mouse model under unilateral common carotid artery occlusion (UCCAO). Neuronal density evaluated 28 days after UCCAO using [(11)C]flumazenil-PET and histology indicated no neurologic deficit in the hippocampus and neocortex. CBF response to sensory stimulation was assessed using laser-Doppler flowmetry. Percentage changes in CBF response of the ipsilateral hemisphere to UCCAO were 18.4 ± 3.0%, 6.9 ± 2.8%, 6.8 ± 2.3% and 4.9 ± 2.4% before, and 7, 14 and 28 days after UCCAO, respectively. Statistical significance was found at 7, 14 and 28 days after UCCAO (P < 0.01). Contrary to our previous finding (Tajima et al. 2014) showing recovered CBF response to hypercapnia on 28 days after UCCAO using the same model, functional hyperemia was sustained and became worse 28 days after UCCAO.


Does screening for congenital cytomegalovirus at birth improve longer term hearing outcomes?
Currently, the diagnosis of congenital cytomegalovirus (cCMV) infection in most highly resourced countries is based on clinical suspicion alone. This means only a small proportion of cCMV infections are diagnosed. Identification, through either universal or targeted screening of asymptomatic newborns with cCMV, who would previously have gone undiagnosed, would allow for potential early treatment with antiviral therapy, ongoing audiological surveillance and early intervention if sensorineural hearing loss (SNHL) is identified. This paper systematically reviews published papers examining the potential benefits of targeted and universal screening for newborn infants with cCMV. We found that the treatment of these infants with antiviral therapy remains controversial, and clinical trials are currently underway to provide further answers. The potential benefit of earlier identification and intervention (eg, amplification and speech therapy) of children at risk of later-onset SNHL identified through universal screening is, however, clearer.


On the minimal risk threshold in research with children.
To protect children in research, procedures that are not administered in the medical interests of a child must be restricted. The risk threshold for these procedures is generally measured according to the concept of minimal risk. Minimal risk is often defined according to the risks of "daily life." But it is not clear whose daily life should serve as the baseline; that is, it is not clear to whom minimal risk should refer. Commentators in research ethics often argue that "minimal risk" should refer to healthy children or the subjects of the research. I argue that neither of these interpretations is successful. I propose a new interpretation in which minimal risk refers to children who are not unduly burdened by their daily lives. I argue that children are not unduly burdened when they fare well, and I defend a substantive goods account of children's welfare.


Efficacy of PD-1 Blockade Is Potentiated by Metformin-Induced Reduction of Tumor Hypoxia.
Blockade of the coinhibitory checkpoint molecule PD-1 has emerged as an effective treatment for many cancers, resulting in remarkable responses. However, despite successes in the clinic, most patients do not respond to PD-1 blockade. Metabolic dysregulation is a common phenotype in cancer, but both patients and tumors are metabolically heterogeneous. We hypothesized that the deregulated oxidative energetics of tumor cells present a metabolic barrier to antitumor immunity through the generation of a hypoxic microenvironment and that normalization of tumor hypoxia might improve response to immunotherapy. We show that the murine tumor lines B16 and MC38 differed in their ability to consume oxygen and produce hypoxic environments, which correlated with their sensitivity to checkpoint blockade. Metformin, a broadly prescribed type II diabetes treatment, inhibited oxygen consumption in tumor cells in vitro and in vivo, resulting in reduced intratumoral hypoxia. Although metformin monotherapy had little therapeutic benefit in highly aggressive tumors, combination of metformin with PD-1 blockade resulted in improved intratumoral T-cell function and tumor clearance. Our data suggest tumor hypoxia acts as a barrier to immunotherapy and that remodeling the hypoxic tumor microenvironment has potential to convert patients resistant to immunotherapy into those that receive clinical benefit. Cancer Immunol Res; 5(1); 9-16. ©2016 AACR.


Models of survivorship care provision in adult patients with haematological cancer: an integrative literature review.
Increasing numbers of haematology cancer survivors warrants identification of the most effective model of survivorship care to survivors from a diverse range of haematological cancers with aggressive treatment regimens. This review aimed to identify models of survivorship care to support the needs of haematology cancer survivors. An integrative literature review method utilised a search of electronic databases (CINAHL, Medline, PsycInfo, PubMed, EMBASE, PsycArticles, and Cochrane Library) for eligible articles (up to July 2014). Articles were included if they proposed or reported the use of a model of care for haematology cancer survivors. Fourteen articles were included in this review. Eight articles proposed and described models of care, and six reported the use of a range of survivorship models of care in haematology cancer survivors. No randomised controlled trials or literature reviews were found to have been undertaken specifically with this cohort of cancer survivors. There was variation in the models described and who provided the survivorship care. Due to the lack of studies evaluating the effectiveness of models of care, it is difficult to determine the best model of care for haematology cancer survivors. Many different models of care are being put into practice before robust research is conducted. Therefore, well-designed high-quality pragmatic randomised controlled trials are required to inform clinical practice.


A gene expression signature of epithelial tubulogenesis and a role for ASPM in pancreatic tumor progression.
Many patients with pancreatic ductal adenocarcinoma (PDAC) develop recurrent or metastatic diseases after surgery, so it is important to identify those most likely to benefit from aggressive therapy. Disruption of tissue microarchitecture is an early step in pancreatic tumorigenesis and a parameter used in pathology grading of glandular tumors. We investigated whether changes in gene expression during pancreatic epithelial morphogenesis were associated with outcomes of patients with PDAC after surgery. We generated architectures of human pancreatic duct epithelial cells in a 3-dimensional basement membrane matrix. We identified gene expression profiles of the cells during different stages of tubular morphogenesis (tubulogenesis) and of PANC-1 cells during spheroid formation. Differential expression of genes was confirmed by immunoblot analysis. We compared the gene expression profile associated with pancreatic epithelial tubulogenesis with that of PDAC samples from 27 patients, as well as with their outcomes after surgery. We identified a gene expression profile associated with tubulogenesis that resembled the profile of human pancreatic tissue with differentiated morphology and exocrine function. Patients with PDACs with this profile fared well after surgery. Based on this profile, we established a 6-28 gene tubulogenesis-specific signature that accurately determined the prognosis of independent cohorts of patients with PDAC (total n = 128; accuracy = 81.2%-95.0%). One gene, ASPM, was down-regulated during tubulogenesis but up-regulated in human PDAC cell lines and tumor samples; up-regulation correlated with patient outcomes (Cox regression P = .0028). Bioinformatic, genetic, biochemical, functional, and clinical correlative studies showed that ASPM promotes aggressiveness of PDAC by maintaining Wnt-β-catenin signaling and stem cell features of PDAC cells. We identified a gene expression profile associated with pancreatic epithelial tubulogenesis and a tissue architecture-specific signature of PDAC cells that is associated with patient outcomes after surgery.


Chromosomal transformation in Bacillus subtilis is a non-polar recombination reaction.
Natural chromosomal transformation is one of the primary driving forces of bacterial evolution. This reaction involves the recombination of the internalized linear single-stranded (ss) DNA with the homologous resident duplex via RecA-mediated integration in concert with SsbA and DprA or RecO. We show that sequence divergence prevents Bacillus subtilis chromosomal transformation in a log-linear fashion, but it exerts a minor effect when the divergence is localized at a discrete end. In the nucleotide bound form, RecA shows no apparent preference to initiate recombination at the 3'- or 5'-complementary end of the linear duplex with circular ssDNA, but nucleotide hydrolysis is required when heterology is present at both ends. RecA·dATP initiates pairing of the linear 5' and 3' complementary ends, but only initiation at the 5'-end remains stably paired in the absence of SsbA. Our results suggest that during gene transfer RecA·ATP, in concert with SsbA and DprA or RecO, shows a moderate preference for the 3'-end of the duplex. We show that RecA-mediated recombination initiated at the 3'- or 5'-complementary end might have significant implication on the ecological diversification of bacterial species with natural transformation.


Docosahexaenoic acid affects cell signaling by altering lipid rafts.
With 22 carbons and 6 double bonds docosahexaenoic acid (DHA) is the longest and most unsaturated fatty acid commonly found in membranes. It represents the extreme example of a class of important human health promoting agents known as omega-3 fatty acids. DHA is particularly abundant in retinal and brain tissue, often comprising about 50% of the membrane's total acyl chains. Inadequate amounts of DHA have been linked to a wide variety of abnormalities ranging from visual acuity and learning irregularities to depression and suicide. The molecular mode of action of DHA, while not yet understood, has been the focus of our research. Here we briefly summarize how DHA affects membrane physical properties with an emphasis on membrane signaling domains known as rafts. We report the uptake of DHA into brain phosphatidylethanolamines and the subsequent exclusion of cholesterol from the DHA-rich membranes. We also demonstrate that DHA-induced apoptosis in MDA-MB-231 breast cancer cells is associated with externalization of phosphatidylserine and membrane disruption ("blebbing"). We conclude with a proposal of how DHA incorporation into membranes may control cell biochemistry and physiology.


Situs Inversus with Levocardia and Congenitally Corrected Transposition of Great Vessels in a 35 year old Male: A Case report.
Situs inversus with levocardia and congenitally corrected transposition of the great arteries represents a relatively very rare congenital condition and most patients are diagnosed in infancy or early age. This case report describes a 35-year old man with congenitally corrected transposition of the great arteries which presented with a five month history of exertional dyspnea. A diagnosis was confirmed by transesophageal echocardiogram, showing situs inversus, levocardia, atrioventricular and ventriculoarterial discordance. He underwent physiologic repair, and was discharged thirty five days after the operation, in a good general condition. Although management of the corrected transposition of the great arteries patients remains controversial, the recommendation is that physiologic repair may be the procedure of choice for some patients, particularly complicated cases.


Long-term outcome of seropositive HIV patients with head and neck squamous cell carcinoma treated with radiation therapy and chemotherapy.
To report the outcome of radiation therapy (RT) +/- chemotherapy in HIV-seropositive patients with Head and Neck Squamous Cell Carcinoma (HNSCC). This is the largest single-Institution retrospective study to date, consisting of 73 HIV patients with HNSCC treated from January 1997-2010. The median age at RT, HIV diagnosis and the duration of patients being HIV seropositive were 51, 34, and 11 years, respectively. Seventy patients had SCC and one had submandibular salivary duct carcinoma. Stages I-II, III and IVA/B were: 22%, 27% and 51%, respectively. Primary cancer sites comprised the larynx (37%), oropharynx (32%), oral cavity (13%), hypopharynx (7%), nasopharynx (4%), unknown primary (MUP) (4%), nasal cavity (3%), and submandibular salivary duct (1%). All patients had an ECOG performance scale of ≤1 and were treated with RT +/- chemotherapy. Fifty patients (70%) were on highly active anti-retroviral therapy (HAART) during treatment, and the median CD4 count was 290 (range: 203-1142). Median dose of 70, 63, and 54 Gy were delivered to the gross disease, high-risk neck, and low-risk neck respectively. Median duration of treatment was 52 (range: 49-64) days. Twelve patients (17%) underwent neck dissection for N3 disease. After a median follow-up of 47 months (range: 7-140), the 4-year locoregional control (LRC) and overall survival (OS) were 69% and 55% respectively. Seven patients (10%) developed second primary sites within the first 5 years of completing RT (2 anal SCCs and 5 HNSCCs). The LRC for Stages III/IV larynx and oropharynx SCC (which represent the majority of the cohort) were 76% and 70%, respectively. Chemo/RT-related late toxicities were dysphagia of grade≤2, 3, and 4 found in 74%, 15% and 11% of patients, respectively. Hoarseness (grade 1) was reported in 10% of patients; no patient experienced grade ≥2. Xerostomia grade ≤2, and 3 was found in 77% and 23% of patients, respectively. A Chi-square test and univariate analysis showed statistically significant relationships between LRC and duration of RT (p<0.001), as well as positive trends for weight loss (<10%) and absence of second malignancy. Definitive RT +/- chemotherapy for HIV-seropositive patients with HNSCC appears to be less effective compared to the observed rates of LRC and OS of other HNSCC without HIV. Due to advances in the HAART which prolongs HIV patients' survival, it is extremely important to establish better treatment strategies to improve therapeutic ratio in this growing patient population.


Dietary choline requirements of women: effects of estrogen and genetic variation.
Choline is obtained from the diet and from the biosynthesis of phosphatidylcholine. Phosphatidylcholine is catalyzed by the enzyme phosphatidylethanolamine-N-methyltransferase (PEMT), which is induced by estrogen. Because they have lower estrogen concentrations, postmenopausal women are more susceptible to the risk of organ dysfunction in response to a low-choline diet. A common genetic polymorphism (rs12325817) in the PEMT gene can also increase this risk. The objective was to determine whether the risk of low choline-related organ dysfunction increases with the number of alleles of rs12325817 in premenopausal women and whether postmenopausal women (with or without rs12325817) treated with estrogen are more resistant to developing such symptoms. Premenopausal women (n = 27) consumed a choline-sufficient diet followed by a very-low-choline diet until they developed organ dysfunction (or for 42 d), which was followed by a high-choline diet. Postmenopausal women (n = 22) were placed on the same diets but were first randomly assigned to receive estrogen or a placebo. The women were monitored for organ dysfunction and plasma choline metabolites and were genotyped for rs12325817. A dose-response effect of rs12325817 on the risk of choline-related organ dysfunction was observed in premenopausal women: 80%, 43%, and 13% of women with 2, 1, or 0 alleles, respectively, developed organ dysfunction. Among postmenopausal women, 73% who received placebo but only 18% who received estrogen developed organ dysfunction during the low-choline diet. Because of their lower estrogen concentrations, postmenopausal women have a higher dietary requirement for choline than do premenopausal women. Choline requirements for both groups of women are further increased by rs12325817. This trial was registered at clinicaltrials.gov as NCT00065546.


Effect of long-term voluntary exercise wheel running on susceptibility to bacterial pulmonary infections in a mouse model.
Regular moderate exercise has been suggested to exert anti-inflammatory effects and improve immune effector functions, resulting in reduced disease incidence and viral infection susceptibility. Whether regular exercise also affects bacterial infection susceptibility is unknown. The aim of this study was to investigate whether regular voluntary exercise wheel running prior to a pulmonary infection with bacteria (P. aeruginosa) affects lung bacteriology, sickness severity and phagocyte immune function in mice. Balb/c mice were randomly placed in a cage with or without a running wheel. After 28 days, mice were intranasally infected with P. aeruginosa. Our study showed that regular exercise resulted in a higher sickness severity score and bacterial (P. aeruginosa) loads in the lungs. The phagocytic capacity of monocytes and neutrophils from spleen and lungs was not affected. Although regular moderate exercise has many health benefits, healthy mice showed increased bacterial (P. aeruginosa) load and symptoms, after regular voluntary exercise, with perseverance of the phagocytic capacity of monocytes and neutrophils. Whether patients, suffering from bacterial infectious diseases, should be encouraged to engage in exercise and physical activities with caution requires further research.


Berberine inhibits RANKL-induced osteoclast formation and survival through suppressing the NF-kappaB and Akt pathways.
Berberine, an isoquinoline alkaloid isolated from several medicinal plants, has been reported to possess anti-bacterial, anti-inflammatory and antitumor properties. Although berberine also inhibits osteoclastogenesis and bone resorption, the molecular machinery for its inhibitory effects remains unknown. This study focused on the suppressive effects of berberine on receptor activator of nuclear factor kappaB (NF-kappaB) ligand (RANKL)-induced osteoclastogenesis and survival. Berberine inhibited RANKL-mediated osteoclast formation and survival while having no cytotoxic effects on bone marrow macrophages or osteoblastic cells. Berberine attenuated RANKL-induced activation of NF-kappaB through inhibiting phosphorylation at the activation loop of IkappaBalpha kinase beta, phosphorylation and degradation of IkappaBalpha, and NF-kappaB p65 nuclear translocation. RANKL-induced Akt phosphorylation was strongly inhibited by berberine; however, neither monocyte/macrophage-colony stimulating factor (M-CSF)-induced nor insulin-induced Akt activation was inhibited by the drug. Under M-CSF- and RANKL-deprived condition, berberine increased the active form of caspase-3 in osteoclasts. By contrast, berberine did not potentiate the activation of caspase-3 in M-CSF-deprived bone marrow macrophages. These findings indicate that berberine inhibits osteoclast formation and survival through suppression of NF-kappaB and Akt activation and that both pathways in the osteoclast lineage are highly sensitive to berberine treatment.


Liver Transplantation during Pregnancy for Acute Liver Failure due to HBV Infection: A Case Report.
Acute hepatic failure during pregnancy is a life-threatening situation for the mother and fetus and might need a super-urgent liver transplantation. Many pregnancies with positive outcomes are reported after a previous liver transplantation before the pregnancy, but only a few of them are mentioned with transplantation during pregnancy. In these few cases, fetal outcome is mostly adverse. Experience with liver failure during pregnancy and its management is still deficient and needs to be approved. For sure, patients need to be treated in highly qualified centers in a multidisciplinary approach. We present a case of successful super-urgent liver transplantation during the second trimester of pregnancy after acute hepatic failure due to an acute hepatitis B infection with positive maternal and fetal outcome. Liver transplantation during pregnancy due to an acute liver failure can be a life-saving procedure for the mother and fetus. An early initiated maternal therapy with antiviral drugs and immunoglobulins seems to be safe and able to prevent fetal infection and immunosuppressive therapy after transplantation seems to be well tolerated. Nevertheless, fetal outcome differs widely and long-term outcome is deficiently known.


Vascular smooth muscle cell migration mediated by thrombin and urokinase receptor.
To determine whether thrombin directly modifies mobility of vascular smooth muscle cells (SMC), in Transwell systems (modified Boyden chambers), we exposed SMC to alpha-thrombin. In concentrations as low as 1 NIH U/ml, thrombin induced migration as well as proliferation of SMC. Inhibition of protein synthesis by cycloheximide (2 micrograms/ml) obviated thrombin's chemotactic effect. Neither gamma-thrombin nor D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone (PPACK)-inactivated alpha-thrombin (both used as controls) exerted a chemotactic effect. Concomitant hirudin or antithrombin III plus heparin inhibited chemotaxis by thrombin when added up to 2 h after addition of thrombin. alpha-Thrombin increased SMC synthesis of urokinase receptor (uPAR) and its cell surface expression as shown by metabolic labeling and immunoprecipitation as well as by flow cytometry. Thus alpha-thrombin, in concentrations thought to be present in vivo at sites of vascular injury, can stimulate not only proliferation but also migration of vascular SMC though a mechanism(s) possibly involving synthesis of uPAR, which is known to influence migration in diverse types of cells. Accordingly, both proliferation and migration dependent on thrombin may accelerate atherosclerosis, restenosis, or both after interventions such as angioplasty.


Genome-wide association analysis implicates the involvement of eight loci with response to tocilizumab for the treatment of rheumatoid arthritis.
Rheumatoid arthritis (RA) is an immune-mediated inflammatory disease affecting the joints. A heterogeneous response to available therapies demonstrates the need to identify those patients likely to benefit from a particular therapy. Our objective was to identify genetic factors associated with response to tocilizumab, a humanized monoclonal antibody targeting the interleukin (IL)-6 receptor, recently approved for treating RA. We report the first genome-wide association study on the response to tocilizumab in 1683 subjects with RA from six clinical studies. Putative associations were identified with eight loci, previously unrecognized as linked to the IL-6 pathway or associated with RA risk. This study suggests that it is unlikely that a major genetic determinant of response exists, and it illustrates the complexity of performing genome-wide association scans in clinical trials.


Sexual self-identification among behaviorally bisexual men in the midwestern United States.
Previous social and behavioral research on identity among bisexual men, when not subsumed within the category of men who have sex with men (MSM), has primarily focused on samples of self-identified bisexual men. Little is known about sexual self-identification among men who are behaviorally bisexual, regardless of sexual identity. Using qualitative data from 77 in-depth interviews with a diverse sample of behaviorally bisexual men (i.e., men who have had sex with at least one woman and at least one man in the past six months) from a large city in the Midwestern United States, we analyzed responses from a domain focusing on sexual self-identity and related issues. Overall, participants' sexual self-identification was exceptionally diverse. Three primary themes emerged: (1) a resistance to, or rejection of, using sexual self-identity labels; (2) concurrent use of multiple identity categories and the strategic deployment of multiple sexual identity labels; and (3) a variety of trajectories to current sexual self-identification. Based on our findings, we offer insights into the unique lived experiences of behaviorally bisexual men, as well as broader considerations for the study of men's sexuality. We also explore identity-related information useful for the design of HIV/STI prevention and other sexual health programs directed toward behaviorally bisexual men, which will ideally be variable and flexible in accordance with the wide range of diversity found in this population.


Poor performance in physical education - a risk factor for bully victimization. A case-control study.
Poor social skills are a risk factor for becoming bullied, which could explain why this frequently occurs to children with autism spectrum disorders (ASD) and attention-deficit hyperactivity disorder (ADHD). Poor social skills tend to coexist with clumsiness. According to a pilot study, poor performance in physical education (PE) was correlated with bully victimization. Sixty-nine healthy university students reported performance in PE and bully victimization in childhood. In addition, the participants responded to questionnaires for ADHD and ASDs to assess personality traits related to increased risk for bully victimization. Below average performance in PE was a risk factor of being bullied in school with an odds ratio of 3.6 [95% confidence interval: 1.23-10.5; p = 0.017]. Strong correlations between poor performance in PE and long duration of victimization (p = 0.007) and poor performance in PE and high frequency of victimization (p = 0.008) were found. Autistic traits were related to performance below average in PE. Poor motor skills are a strong risk factor for becoming bullied. Prevention programmes that identify, protect and empower the clumsy children could be an important step to avoid bullying of the most vulnerable children.


Adapting Aluminum-Doped Zinc Oxide for Electrically Conductive Membranes Fabricated by Atomic Layer Deposition.
The use of electrically conductive membranes has recently drawn great interest in water treatment as an approach to reduce biofouling. Most conductive membranes are made by binding nanoparticles (carbon nanotubes or graphene) to a polymeric membrane using additional polymers, but this method risks leaching these nanomaterials into the environment. A new approach was developed here based on producing an electrically conductive layer of aluminum-doped zinc oxide (AZO) by atomic layer deposition. The aqueous instability of AZO, which is a critical challenge for water applications, was solved by capping the AZO layer with an ultrathin (∼11 nm) TiO2 layer (AZO/TiO2). The combined film exhibited prolonged stability in water and had a low sheet resistance of 67 Ω/sq with a 120 nm-thick coating, while the noncapped AZO coating quickly deteriorated as shown by a large increase in membrane resistance. The AZO/TiO2 membranes had enhanced resistance to biofouling, with a 72% reduction in bacterial counts in the absence of an applied current due to its higher hydrophilicity than the bare polymeric membrane, and it achieved an additional 50% reduction in bacterial colonization with an applied voltage. The use of TiO2-capped AZO layers provides a new approach for producing conductive membranes using abundant materials, and it avoids the risk of releasing nanoparticles into the environment.


Chronic obstructive pulmonary disease (COPD) and erectile dysfunction (ED): Results of the BRED observational study.
Most patients with chronic obstructive pulmonary disease (COPD) share many risk factors and similar aetiological agents with erectile dysfunction (ED). Both conditions also cause serious interference with quality of life and sexual relationships. In general, ageing and chronic illness decrease sexual interest, sexual function, and testosterone levels. This observational study included 66 male patients referred to our centre with different grades of COPD. We studied the different correlations between COPD and ED. The data collected from each patient regarded the following features: demographic and social condition; smoking status; clinical status; spirometric measurements. In this group, COPD was diagnosed in 78.8% and ED was present in 83.3% with increased severity in presence of LUTS and nicotinism.


Impaired Cytotoxic CD8+ T Cell Response in Elderly COVID-19 Patients.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection induces a T cell response that most likely contributes to virus control in COVID-19 patients but may also induce immunopathology. Until now, the cytotoxic T cell response has not been very well characterized in COVID-19 patients. Here, we analyzed the differentiation and cytotoxic profile of T cells in 30 cases of mild COVID-19 during acute infection. SARS-CoV-2 infection induced a cytotoxic response of CD8+ T cells, but not CD4+ T cells, characterized by the simultaneous production of granzyme A and B as well as perforin within different effector CD8+ T cell subsets. PD-1-expressing CD8+ T cells also produced cytotoxic molecules during acute infection, indicating that they were not functionally exhausted. However, in COVID-19 patients over the age of 80 years, the cytotoxic T cell potential was diminished, especially in effector memory and terminally differentiated effector CD8+ cells, showing that elderly patients have impaired cellular immunity against SARS-CoV-2. Our data provide valuable information about T cell responses in COVID-19 patients that may also have important implications for vaccine development.IMPORTANCE Cytotoxic T cells are responsible for the elimination of infected cells and are key players in the control of viruses. CD8+ T cells with an effector phenotype express cytotoxic molecules and are able to perform target cell killing. COVID-19 patients with a mild disease course were analyzed for the differentiation status and cytotoxic profile of CD8+ T cells. SARS-CoV-2 infection induced a vigorous cytotoxic CD8+ T cell response. However, this cytotoxic profile of T cells was not detected in COVID-19 patients over the age of 80 years. Thus, the absence of a cytotoxic response in elderly patients might be a possible reason for the more frequent severity of COVID-19 in this age group than in younger patients.


Outcome of acute myeloid leukaemia in Nigeria: clinician's perspective.
The outcome of acute myeloid leukaemia (AML) has remained a major concern even in developed countries. In resource poor countries, it is envisaged that the outcome will be far worse because of late presentations, lack of appropriate diagnostic facilities and supportive care. However, data to validate this is lacking and many of these countries lack an effective cancer registry. This study determined the clinician's perspective of the outcome of care of AML patients in Nigeria and their attitudes to the care of these patients. Structured self-administered questionnaire was used to assess the clinician's perception of outcomes of care, contributory factors and attitude to care of AML patients. Ninety-eight percent of clinicians reported that the outcome of care was suboptimal; 73.3% and 90.6% of the clinicians reported having less than 31% of AML patients surviving induction and post-induction therapies, respectively. Sixty-six-point one percent (66.1%), 50% and 62.7% of the clinicians have never used immunophenotyping, cytogenetic or molecular studies, respectively, in the management of AML patients under their care. Access to blood components other than Red cells was low; 23.3% had access to apheresis platelets and 55% to fresh frozen plasma. Forty-six percent of clinicians will either give half dose of chemotherapy or offer only supportive care. This reported early death rate is three times higher than that reported in developed countries with only 9% likely to survive the first year of induction compared to about 32.9% in Ontario. Approximately 28 units of pooled or apheresis derived platelet may be required in course of therapy but just 10% of clinicians have access to platelet apheresis. Lack of diagnostic facilities, blood components and clinicians' attitudes are contributing factors to the extremely poor outcomes of patients with AML in Nigeria.


Immunoassay of fumonisins by a surface plasmon resonance biosensor.
A surface plasmon resonance (SPR) immunosensor is developed to determine concentrations of the mycotoxin, fumonisin B1 (FB1), in spiked samples. Polyclonal antibodies produced against FB1 are adsorbed onto a thin gold film substrate, which is coupled to a glass prism in the Kretschmann configuration. The output beam of a planar light-emitting diode is focused through the prism to excite SPR at the surface of the gold film. When a sample containing FB1 is added to a cell on the outside of the gold film, the angular profile of reflected light intensity shifts. This changes the resonance angle and the reflected beam intensity at a selected angle, both of which are proportional to the FB1 concentration. After optimization of the antibody overlayer, a detection limit of 50 ng/mL is obtained for the direct assay with an analysis time under 10 min. Multiple sample additions and large-volume sample circulation can be used with the high-affinity antibodies to achieve lower detection limits.


Molecular profiling of liver tumors: classification and clinical translation for decision making.
Hepatocellular carcinoma (HCC) is a complex disease with a dismal prognosis. Consequently, a translational approach is required to personalized clinical decision making to improve survival of HCC patients. Molecular signatures from cirrhotic livers and single nucleotide polymorphism have been linked with HCC occurrence. Identification of high-risk populations will be useful to design chemopreventive trials. In addition, molecular signatures derived from tumor and nontumor samples are associated with early tumor recurrence due to metastasis and late tumor recurrence due to de novo carcinogenesis after curative treatment, respectively. Identification of patients with a high risk of relapse will guide adjuvant randomized trials. The genetic landscape drawn by next-generation sequencing has highlighted the genomic diversity of HCC. Genetic drivers recurrently mutated belong to different signaling pathways including telomere maintenance, cell-cycle regulators, chromatin remodeling, Wnt/b-catenin, RAS/RAF/MAPK kinase, and AKT/mTOR pathway. These cancer genes will be ideally targeted by biotherapies as a paradigm of stratified medicine adapted to tumor biology.


The S-adenosylmethionine dependent O-methyltransferase PaMTH1: a longevity assurance factor protecting Podospora anserina against oxidative stress.
PaMTH1 is an O-methyltransferase catalysing the methylation of vicinal hydroxyl groups of polyphenols. The protein accumulates during ageing of Podospora anserina in both the cytosol and in the mitochondrial matrix. The construction and characterisation of a PaMth1 deletion strain provided additional evidence about the function of the protein in the protection against metal induced oxidative stress. Deletion of PaMth1 was found to lead to a decreased resistance against exogenous oxidative stress and to a shortened lifespan suggesting a role of PaMTH1 as a longevity assurance factor in a new molecular pathway involved in lifespan control.


A ketogenic diet affects brain volume and metabolome in juvenile mice.
Ketogenic diet (KD) is a high-fat and low-carbohydrate therapy for medically intractable epilepsy, and its applications in other neurological conditions, including those occurring in children, have been increasingly tested. However, how KD affects childhood neurodevelopment, a highly sensitive and plastic process, is not clear. In this study, we explored structural, metabolic, and functional consequences of a brief treatment of a strict KD (weight ratio of fat to carbohydrate plus protein is approximately 6.3:1) in naive juvenile mice of different inbred strains, using a multidisciplinary approach. Systemic measurements using magnetic resonance imaging revealed that unexpectedly, the volumes of most brain structures in KD-fed mice were about 90% of those in mice of the same strain but fed a standard diet. The reductions in volumes were nonselective, including different regions throughout the brain, the ventricles, and the white matter. The relative volumes of different brain structures were unaltered. Additionally, as KD is a metabolism-based treatment, we performed untargeted metabolomic profiling to explore potential means by which KD affected brain growth and to identify metabolic changes in the brain. We found that brain metabolomic profile was significantly impacted by KD, through both distinct and common pathways in different mouse strains. To explore whether the volumetric and metabolic changes induced by this KD treatment were associated with functional consequences, we recorded spontaneous EEG to measure brain network activity. Results demonstrated limited alterations in EEG patterns in KD-fed animals. In addition, we observed that cortical levels of brain-derived neurotrophic factor (BDNF), a critical molecule in neurodevelopment, did not change in KD-fed animals. Together, these findings indicate that a strict KD could affect volumetric development and metabolic profile of the brain in inbred juvenile mice, while global network activities and BDNF signaling in the brain were mostly preserved. Whether the volumetric and metabolic changes are related to any core functional consequences during neurodevelopment and whether they are also observed in humans need to be further investigated. In addition, our results indicate that certain outcomes of KD are specific to the individual mouse strains tested, suggesting that the physiological profiles of individuals may need to be examined to maximize the clinical benefit of KD.


Effects of natalizumab therapy on intrathecal antiviral antibody responses in MS.
To investigate the effects of natalizumab (NAT) treatment on intrathecally produced antiviral antibodies in MS. We performed a longitudinal, observational study analyzing both serum and CSF samples collected before and during NAT treatment for antibodies against measles, rubella, mumps, influenza, entero, herpes, and polyoma viruses, including JC polyomavirus (JCV) and its nearest homologue BK polyomavirus (BKV), and bacterial control antigens by ELISA to determine the antigen-specific CSF antibody index (CAI). CAI ≥1.5 indicated intrathecal synthesis of antigen-specific antibodies. Oligoclonal bands (OCBs) by isoelectric focusing and total IgG, IgM, and IgA by immunonephelometry were analyzed additionally. Intrathecal synthesis of JCV- and BKV-specific IgG was detected in 20% of patients with MS at baseline and was lost significantly more frequently during NAT treatment compared with other intrathecal antiviral and antibacterial antibody reactivities. Peripheral JCV- and BKV-specific antibody responses persisted, and no cross-reactivity between JCV- and BKV-specific CSF antibodies was found. Intrathecal production of antibodies against measles, rubella, and zoster antigens (MRZ reaction) was most prevalent and persisted (73.3% before vs 66.7% after 1 year of NAT therapy). CSF OCBs also persisted (93.3% vs 80.0%), but total CSF IgG and IgM levels declined significantly. These data indicate that JCV-specific antibodies are produced intrathecally in a minority of patients with MS, and NAT treatment affects the intrathecal humoral immune response against JCV relatively specifically compared with other neurotropic viruses. Further studies are needed to determine whether this effect translates to higher risk of progressive multifocal leukoencephalopathy development.


A disposable, canister-free negative-pressure wound therapy device proves feasible, but of inferior efficacy to conventional therapies for treating cutaneous wounds in dogs.
To assess the feasibility of a canister-free negative-pressure wound therapy (NPWT) device (PICO™ 1.6, Smith & Nephew Medical Ltd) and evaluate its effect on early phases of wound healing in canine experimental cutaneous wounds. 5 adult spayed female research Beagles. In a pilot experimental study, 1 full-thickness 2-cm X 2-cm cutaneous wound was surgically created on each hemithorax in each dog. Wounds were treated with either NPWT or a conventional wound dressing for 14 days. Bandage changes and wound evaluations were done at 7 time points. First macroscopic appearance of granulation tissue, smoothness of granulation tissue, and percentages of wound contraction and epithelialization were compared between treatments. Wounds were sampled at 3 time points for histopathologic analyses and semiquantitative scoring. NPWT dressings were well tolerated by all dogs. Complete seal of the dressing required the application of adhesive spray, and maintenance of the vacuum lessened over time. Self-limiting skin irritations appeared in all dogs and hampered the attainment of negative pressure. Granulation tissue developed faster and was more abundant in control wounds. Wound contraction, epithelialization, and fibroblast proliferation were greater in control wounds at the end of the study. This canister-free NPWT device is feasible but problematic in maintaining a vacuum, requiring frequent revisions of the dressing. Further studies are necessary to evaluate the effect of this device on early phases of wound healing. Its benefits in wound healing remain unknown.


Multi-Parameter Analysis of Biobanked Human Bone Marrow Stromal Cells Shows Little Influence for Donor Age and Mild Comorbidities on Phenotypic and Functional Properties.
Heterogeneous populations of human bone marrow-derived stromal cells (BMSC) are among the most frequently tested cellular therapeutics for treating degenerative and immune disorders, which occur predominantly in the aging population. Currently, it is unclear whether advanced donor age and commonly associated comorbidities affect the properties of ex vivo-expanded BMSCs. Thus, we stratified cells from adult and elderly donors from our biobank (n = 10 and n = 13, mean age 38 and 72 years, respectively) and compared their phenotypic and functional performance, using multiple assays typically employed as minimal criteria for defining multipotent mesenchymal stromal cells (MSCs). We found that BMSCs from both cohorts meet the standard criteria for MSC, exhibiting similar morphology, growth kinetics, gene expression profiles, and pro-angiogenic and immunosuppressive potential and the capacity to differentiate toward adipogenic, chondrogenic, and osteogenic lineages. We found no substantial differences between cells from the adult and elderly cohorts. As positive controls, we studied the impact of in vitro aging and inflammatory cytokine stimulation. Both conditions clearly affected the cellular properties, independent of donor age. We conclude that in vitro aging rather than in vivo donor aging influences BMSC characteristics.


Demographic Changes and the Challenge for a Healthy Ageing.
Demographic changes bring about a wide range of new research fields including policy topics, health, social welfare, work & productivity, urban & rural development, communication tools, and mobility. This new situation requires a new multi-disciplinary approach bringing together different research programs in order to provide solutions for the upcoming challenges. National Health services are now facing a huge shift in the population structure with a predominance of older generations in the total number of citizens. Good health is the most important factor to live independently in old age. A better understanding of ageing processes and the related "plasticity" of individual performance for environmental adaptation, the prevention for age-related illnesses and healthcare strategies are the basis for keeping very old people healthy and active throughout the course of their lives. We will face mainly the biological, cognitive and psychological dimensions of ageing. Afterwards, we will focus on the relationships linking various biological and lifestyle factors - such as nutrition - that are crucial to obtain a comprehensive picture of ageing and to promote preventing strategies against degenerative neurological diseases. Finally we will investigate which interventions - nutritional and physical - could help in keeping people healthy, in particular which factors could promote people's physical, social and psychological functional abilities and the systemic multilevel consequences induced by a healthy ageing.


A Ru-Ru pair housed in ruthenium phthalocyanine: the role of a "cage" architecture in the molecule coupling with the Ag(111) surface.
A number of studies have investigated the properties of monomeric and double-decker phthalocyanines (Pcs) adsorbed on metal surfaces, in view of applications in spintronics devices. In a combined experimental and theoretical study, we consider here a different member of the Pcs family, the (RuPc)2 dimer, whose structure is characterized by two paired up magnetic centers embedded in a double-decker architecture. For (RuPc)2 on Ag(111), we show that this architecture works as a preserving cage by shielding the Ru-Ru pair from a direct interaction with the surface atoms. In fact, while noticeable surface-to-molecule charge transfer occurs with the ensuing quenching of the molecular magnetic moment, such phenomena occur here in the absence of a direct Ru-Ag coupling or structural rearrangement, at variance with other Pcs and thanks to the above shielding effect. These unique properties of the (RuPc)2 architecture are expected to permit an easy control of the surface-to-molecule charge-transfer process as well as of the molecular magnetic properties, thus making the (RuPc)2 dimer a significant paradigm for innovative "cage" structures as well as a promising candidate for applications in spintronics nano or single-molecule devices.


Coupled attribute similarity learning on categorical data.
Attribute independence has been taken as a major assumption in the limited research that has been conducted on similarity analysis for categorical data, especially unsupervised learning. However, in real-world data sources, attributes are more or less associated with each other in terms of certain coupling relationships. Accordingly, recent works on attribute dependency aggregation have introduced the co-occurrence of attribute values to explore attribute coupling, but they only present a local picture in analyzing categorical data similarity. This is inadequate for deep analysis, and the computational complexity grows exponentially when the data scale increases. This paper proposes an efficient data-driven similarity learning approach that generates a coupled attribute similarity measure for nominal objects with attribute couplings to capture a global picture of attribute similarity. It involves the frequency-based intra-coupled similarity within an attribute and the inter-coupled similarity upon value co-occurrences between attributes, as well as their integration on the object level. In particular, four measures are designed for the inter-coupled similarity to calculate the similarity between two categorical values by considering their relationships with other attributes in terms of power set, universal set, joint set, and intersection set. The theoretical analysis reveals the equivalent accuracy and superior efficiency of the measure based on the intersection set, particularly for large-scale data sets. Intensive experiments of data structure and clustering algorithms incorporating the coupled dissimilarity metric achieve a significant performance improvement on state-of-the-art measures and algorithms on 13 UCI data sets, which is confirmed by the statistical analysis. The experiment results show that the proposed coupled attribute similarity is generic, and can effectively and efficiently capture the intrinsic and global interactions within and between attributes for especially large-scale categorical data sets. In addition, two new coupled categorical clustering algorithms, i.e., CROCK and CLIMBO are proposed, and they both outperform the original ones in terms of clustering quality on UCI data sets and bibliographic data.


Vietnam moves forward with harm reduction: an assessment of progress.
Historically, the response of the Vietnamese government to illicit drug use and HIV has been slow and ineffective. However, 2006 saw the government formally endorse harm reduction interventions. This paper examines the views of senior key informants inside Vietnam on the development of an advocacy strategy for harm reduction. Twenty-nine informants were interviewed across public health, public security, social affairs and other international bodies, including United Nations agencies and international non-governmental organisations. Challenges and barriers identified for harm reduction progress included: promoting a nationwide understanding and acceptance of harm reduction and the HIV Law; lack of skilled resources, training programmes and technical capacity; poor coverage of interventions; and gaps in the sharing of information. There is currently a government-led shift in Vietnam in the response to the prevailing HIV epidemic among drug users, but ensuring that the HIV Law can operate unhindered is critical. The implementation of a response to illicit drug use and HIV remains an enormous challenge. With appropriate technical education and training, ongoing advocacy, and a cohesive, coordinated multi-sectoral effort, the capacity of the government and community to adopt, support and promote measures to reduce HIV and other drug-related harms will be markedly strengthened.


Virtual Monoenergetic Imaging and Iodine Perfusion Maps Improve Diagnostic Accuracy of Dual-Energy Computed Tomography Pulmonary Angiography With Suboptimal Contrast Attenuation.
The aim of this study was to investigate the impact of virtual monoenergetic imaging (VMI+) and dual-energy computed tomography perfusion maps (DECT-PMs) on reader confidence and diagnostic accuracy in dual-energy computed tomography pulmonary angiography (DE-CTPA) studies with suboptimal contrast attenuation, compared with standard linearly blended reconstruction series. Dual-energy computed tomography pulmonary angiography examinations with suboptimal contrast attenuation of 68 patients with suspected pulmonary embolism (PE) were included in this institutional review board-approved retrospective study. Virtual monoenergetic imaging series at 40 keV, DECT-PM, and linearly blended images (M_0.6, 60% 90-kV spectrum) were reconstructed. Contrast-to-noise ratio and signal-to-noise ratio within the pulmonary trunk were calculated. Four independent radiologists assessed the presence of PE and their diagnostic confidence using 3 DE-CTPA reconstruction protocols: protocol 1, M_0.6 images; protocol 2, M_0.6 series and DECT-PM; and protocol 3, M_0.6, DECT-PM, and VMI+ series. Receiver operating characteristic (ROC) analysis was performed. Fourteen patients showed central and 29 segmental PE. Greater contrast-to-noise ratio and signal-to-noise ratio values were measured in VMI+ series at 40 keV in comparison to M_0.6 images (P < 0.001). Diagnostic accuracy for segmental PE detection was as follows: protocol 1 (69.1%); protocol 2 (86.8%); and protocol 3 (92.6%). Protocol 3 resulted in a significantly greater area under the curve for diagnosing segmental PE (0.991, P ≤ 0.033), compared with protocol 1 and 2 (0.897 and 0.951, respectively), and provided the highest diagnostic confidence (P < 0.001). A reconstruction protocol including 40-keV VMI+ series and DECT-PM improves reader confidence and diagnostic accuracy for segmental PE detection compared with standard M_0.6 images in DE-CTPA with suboptimal contrast attenuation.


Polarization and propagation characteristics of switchable first-order azimuthally asymmetric beam generated in dual-mode fiber.
We report here the controlled generation of a linearly polarized first-order azimuthally asymmetric beam (F-AAB) in a dual-mode fiber (DMF) by appropriate superposition of selectively excited zeroth-order vector modes that are doughnut-shaped azimuthally symmetric beams (D-ASBs). We first demonstrate continually switching polarization mode structures having an identical two-lobe intensity profile (i.e., intra-F-AAB conversion). Then, under a distinct launching state, we generate mode structures progressively toggling between the doughnut-shaped profile and two-lobe pattern having dissimilar polarization orientations (i.e., F-AAB to D-ASB conversion). Interestingly, a decentralized elliptical Gaussian beam possessing homogenous spatial polarization is obtained by enhancing the contribution of the fundamental mode (HE11/LP01) in selectively excited F-AAB. A smoothly varying azimuth of the input beam in this situation resulted in redistribution of transverse energy procuring a unique and exciting unconventional two-grain T-polarized beam having mutually orthogonal state of polarization (SOP). All of the above three were achieved under a given set of launching conditions (tilt/offset) of a Gaussian mode (TEM00) devised with changing SOP of the input beam. A strong modulation in the output beam characteristics was also observed with the variation in propagation distance (for a fixed input SOP) owing to the large difference in propagation constants of the participating modes (LP01 and one of the F-AABs). Finally, this particular study led to a design for a low-cost highly sensitive strain measuring device based on tracking the centroid movement of the output intensity pattern. Each of our experimentally observed intensity/polarization distributions is theoretically mapped on a one-to-one basis considering a linear superposition of appropriately excited LP basis modes of the waveguide toward a complete understanding of the polarization and mode propagation in the dual-mode structure.


Community-facility linkage models and maternal and infant health outcomes in Malawi's PMTCT/ART program: A cohort study.
In sub-Saharan Africa, 3 community-facility linkage (CFL) models-Expert Clients, Community Health Workers (CHWs), and Mentor Mothers-have been widely implemented to support pregnant and breastfeeding women (PBFW) living with HIV and their infants to access and sustain care for prevention of mother-to-child transmission of HIV (PMTCT), yet their comparative impact under real-world conditions is poorly understood. We sought to estimate the effects of CFL models on a primary outcome of maternal loss to follow-up (LTFU), and secondary outcomes of maternal longitudinal viral suppression and infant "poor outcome" (encompassing documented HIV-positive test result, LTFU, or death), in Malawi's PMTCT/ART program. We sampled 30 of 42 high-volume health facilities ("sites") in 5 Malawi districts for study inclusion. At each site, we reviewed medical records for all newly HIV-diagnosed PBFW entering the PMTCT program between July 1, 2016 and June 30, 2017, and, for pregnancies resulting in live births, their HIV-exposed infants, yielding 2,589 potentially eligible mother-infant pairs. Of these, 2,049 (79.1%) had an available HIV treatment record and formed the study cohort. A randomly selected subset of 817 (40.0%) cohort members underwent a field survey, consisting of a questionnaire and HIV biomarker assessment. Survey responses and biomarker results were used to impute CFL model exposure, maternal viral load, and early infant diagnosis (EID) outcomes for those missing these measures to enrich data in the larger cohort. We applied sampling weights in all statistical analyses to account for the differing proportions of facilities sampled by district. Of the 2,049 mother-infant pairs analyzed, 62.2% enrolled in PMTCT at a primary health center, at which time 43.7% of PBFW were ≤24 years old, and 778 (38.0%) received the Expert Client model, 640 (31.2%) the CHW model, 345 (16.8%) the Mentor Mother model, 192 (9.4%) ≥2 models, and 94 (4.6%) no model. Maternal LTFU varied by model, with LTFU being more likely among Mentor Mother model recipients (adjusted hazard ratio [aHR]: 1.45; 95% confidence interval [CI]: 1.14, 1.84; p = 0.003) than Expert Client recipients. Over 2 years from HIV diagnosis, PBFW supported by CHWs spent 14.3% (95% CI: 2.6%, 26.1%; p = 0.02) more days in an optimal state of antiretroviral therapy (ART) retention with viral suppression than women supported by Expert Clients. Infants receiving the Mentor Mother model (aHR: 1.24, 95% CI: 1.01, 1.52; p = 0.04) and ≥2 models (aHR: 1.44, 95% CI: 1.20, 1.74; p < 0.001) were more likely to undergo EID testing by age 6 months than infants supported by Expert Clients. Infants receiving the CHW and Mentor Mother models were 1.15 (95% CI: 0.80, 1.67; p = 0.44) and 0.84 (95% CI: 0.50, 1.42; p = 0.51) times as likely, respectively, to experience a poor outcome by 1 year than those supported by Expert Clients, but not significantly so. Study limitations include possible residual confounding, which may lead to inaccurate conclusions about the impacts of CFL models, uncertain generalizability of findings to other settings, and missing infant medical record data that limited the precision of infant outcome measurement. In this descriptive study, we observed widespread reach of CFL models in Malawi, with favorable maternal outcomes in the CHW model and greater infant EID testing uptake in the Mentor Mother model. Our findings point to important differences in maternal and infant HIV outcomes by CFL model along the PMTCT continuum and suggest future opportunities to identify key features of CFL models driving these outcome differences.


Awareness of epidural analgesia among pregnant women in Jeddah, Saudi Arabia.
Labor pain is one of the most severe forms of pain that women experience throughout their lifetime. Many pregnant women decide to have an epidural anesthesia to cope with labor pain. This study has focused on general awareness about epidural anesthesia among pregnant women in Jeddah, Saudi Arabia. This was a cross-sectional hospital-based study using a self-administered questionnaire, conducted in King Faisal Specialist Hospital and Research Center and International Medical Centre. The study was carried out from July to September 2016 and included all pregnant women who were having a routine antenatal care. They were asked about four main topics that tapped their knowledge on epidural anesthesia. A total of 384 questionnaires were returned and analyzed. Data were analyzed by SPSS version 21 using chi-square and multivariate logistic regression. According to multivariate logistic regression, women aged between 21-35 years were more likely to opt for an epidural anesthesia (EPA) than those aged less than 20 years, but women aged >35 years were less likely to select EPA, compared with women < 20 years old. Women who were previously exposed to EPA were 2.14 times more likely to prefer EPA during their current pregnancy than those who were not previously exposed (O.R 95% C.I: 1.123-3.66, p=0.006). Those who believed that EPA was commonly used by other women in the Kingdom were also 1.41 times more likely to report their preference to EPA (O.R 95% C.I: 1.15-1.74, p=0.001). This study demonstrates a lack of knowledge about EPA in certain countries but is better than in some other countries. In an aim to fill this gap, it is recommended that information about EPA must be given to all women during the antenatal visit either by the obstetrician, anesthetist, or through flyers and brochures.


Differential synthesis and replication of DNA in the Neurospora crassa slime mutant versus normal cells: role of carcinogens.
Small quantities of carcinogens, dl-ethionine, thiotepa, actinomycin D, and 1-(2-chloroethyl-3-cyclohexyl)-1-nitrosourea (CCNU) stimulated in vitro deoxyribonucleic acid (DNA) synthesis of the slime mutant of Neurospora crassa, while there was practically no effect on the DNA from the normal wild type 74A strain. All of these compounds caused increased strand separation in the mutant DNA of N. crassa, but no separation of normal DNA strands. The growth (in vivo tests) of the N. crassa slime mutant, but not its wild type, was markedly increased when nontoxic concentrations of one of the carcinogens (dl-ethionine) tested were present in the growth medium. These observations suggest that, unlike the wild type N. crassa, the slime mutant allows an excessive and unscheduled replication, indicating destabilized nature of its DNA.


Simultaneous Estimation of Vehicle Roll and Sideslip Angles through a Deep Learning Approach.
Presently, autonomous vehicles are on the rise and are expected to be on the roads in the coming years. In this sense, it becomes necessary to have adequate knowledge about its states to design controllers capable of providing adequate performance in all driving scenarios. Sideslip and roll angles are critical parameters in vehicular lateral stability. The later has a high impact on vehicles with an elevated center of gravity, such as trucks, buses, and industrial vehicles, among others, as they are prone to rollover. Due to the high cost of the current sensors used to measure these angles directly, much of the research is focused on estimating them. One of the drawbacks is that vehicles are strong non-linear systems that require specific methods able to tackle this feature. The evolution in Artificial Intelligence models, such as the complex Artificial Neural Network architectures that compose the Deep Learning paradigm, has shown to provide excellent performance for complex and non-linear control problems. In this paper, the authors propose an inexpensive but powerful model based on Deep Learning to estimate the roll and sideslip angles simultaneously in mass production vehicles. The model uses input signals which can be obtained directly from onboard vehicle sensors such as the longitudinal and lateral accelerations, steering angle and roll and yaw rates. The model was trained using hundreds of thousands of data provided by Trucksim® and validated using data captured from real driving maneuvers using a calibrated ground truth device such as VBOX3i dual-antenna GPS from Racelogic®. The use of both Trucksim® software and the VBOX measuring equipment is recognized and widely used in the automotive sector, providing robust data for the research shown in this article.


First Report of Verticillium Wilt of Ailanthus altissima in Virginia Caused by Verticillium nonalfalfae.
Ailanthus altissima (Mill.) Swingle, commonly known as tree-of-heaven, is an invasive tree species that has spread throughout the United States since its introduction in 1784 (2). During a survey in July 2009, approximately 1,100 A. altissima trees were observed at two locations in western Virginia (a roadside in Montgomery Co. and a wooded area adjacent to a railroad in Bedford Co.) exhibiting foliar wilt symptoms, defoliation, yellowish vascular discoloration, or death at an incidence of ~77%. Similar symptoms on A. altissima were reported in Roanoke, VA in the early 1930s and after 2005 in Pennsylvania, attributed to a Verticillium sp. (1,2). To identify the causal agent, discolored xylem tissue samples were excised from 10 symptomatic A. altissima trees at both locations, soaked in 1% NaOCl for 2 min, rinsed with sterilized distilled water for 5 min, and placed onto plum extract agar. Cultures were incubated in the dark at 22°C for 7 to 14 days. The resultant colonies (three to four per location) were subcultured and identified putatively as a Verticillium sp. closely related to Verticillium albo-atrum Reinke and Berthold (3), based on melanized, thick-walled, resting mycelia and phialides arranged in verticillate whorls that amassed round, oval-shaped conidia (5.1 ± 1.2 μm × 2.8 ± 0.4 μm, n = 100). Molecular identification of two fungal isolates (one per location) was determined by amplification of the protein coding genes elongation factor 1-alpha (EF), glyceraldehyde-3-phosphate dehydrogenase (GPD), and tryptophan synthase (TS), using PCR primers developed recently for Verticillium (3). A BLAST search on the edited contigs revealed 100% sequence similarity for all three protein coding genes among the two isolates and reference sequences of isolates PD592 (GenBank Accessions JN188227, JN188163, and JN188035 for EF, GPD, and TS, respectively) and VnAaPA140 (KC307764, KC307766, and KC307768 for EF, GPD, and TS, respectively) of the newly-proposed species, V. nonalfalfae (formerly V. albo-atrum). Aligned sequences from one representative isolate, VnAaVA2 (Bedford Co.), were deposited into GenBank as KC307758 (EF), KC307759 (GPD), and KC307760 (TS). To confirm pathogenicity to A. altissima, the two molecularly characterized isolates (one per location) were inoculated into 18 10-week old A. altissima stems that were grown in an environmental chamber at 24°C, 60% RH, and a 12-h photoperiod from seeds collected in Blacksburg, VA. A conidial suspension of each isolate was injected into each stem (0.1 ml of 1 × 108 CFU/ml/stem). All 36 seedlings inoculated with the proposed V. nonalfalfae isolates developed wilting of leaflets within 2 weeks post-inoculation (WPI), defoliation of leaflets by 6 WPI, and were dead by 9 WPI. Eighteen control seedlings were inoculated similarly with distilled water, and remained asymptomatic. Fungi resembling the proposed species V. nonalfalfae were reisolated from all inoculated stems except the control plants, and the species confirmed morphologically as described above. V. nonalfalfae is a recently proposed species that can infect a variety of plant species (3). To our knowledge, this is the first report of this proposed species on A. altissima in Virginia. New state reports of this pathogen on A. altissima are important for regulatory issues associated with using this pathogen as a potential biological control agent. References: (1) G. F. Gravatt and R. B. Clapper. Plant Dis. Rep. 16:96, 1932. (2) M. J. Schall and D. D. Davis. Plant Dis. 93:747, 2009. (3) P. Inderbitzin et al. PLoS ONE, 6, e28341, 2011.


Exploring the illness representations of people with psoriatic arthritis: a secondary analysis of focus group data.
PsA is an inflammatory arthritis associated with psoriasis, affecting the joints and connective tissue. According to the common-sense model (CSM), patients develop illness beliefs when faced with new symptoms, which determine their emotional and behavioural response to the condition. The CSM includes five beliefs: identity, consequence, cause, time line and control. These are important determinants of outcomes and have been shown to influence adherence to medication. A secondary analysis of eight focus groups held across five hospital sites and including 41 participants was undertaken. Participants were sampled for a range of phenotypes and domains of disease activity: men = 20 and women = 21; mean (s.d.): age = 58 (11.4) years; disease duration = 9 (8.3) years; and HAQ = 1 (0.7). The analysis provided evidence to support the existence of the five illness beliefs among patients with PsA and evidence that these representations affected the way patients engaged with their condition. The results showed that many participants experienced high levels of uncertainty in relationship to the illness representation. The role of external social and environmental factors was also shown to influence participants' illness representations and the way they made sense of their PsA. This research highlights a new theme of uncertainty within illness representations and how this impacts on the way in which people living with PsA manage their condition. A greater understanding of the uncertainty that patients might have about their condition and its treatment could provide clinicians with an opportunity to address misinformed illness representations.


Monensin does not consistently inhibit the spreading of normal or Duchenne fibroblasts on glass.
The spreading on glass of monensin-treated normal and Duchenne fibroblasts has been investigated with the intention of extending this approach to a study of the comparative spreading of these cells on differing substrata. Untreated normal and Duchenne fibroblasts varied considerably in their ability to spread on glass. The spreading properties of normal and DMD fibroblasts treated in four different ways were compared: (1) pre-incubated and plated without monensin; (2) pre-incubated with, but plated without monensin; (3) pre-incubated without, but plated with monensin; (4) pre-incubated and plated with monensin. The response to plating with monensin (and pre-incubation/plating with monensin) also varied from patient to patient, but no statistically significant differences in the degree of spreading between the four treatment groups were observed in pooled data for either normal or dystrophic fibroblasts. Our data thus do not substantiate the previous finding of Pizzey et al. (1984) that Duchenne fibroblasts spread less well than normal fibroblasts after pre-incubation or plating with monensin, and possible explanations for this are discussed. The observations made are, however, consistent with the recent report that dystrophin is effectively not expressed in fibroblasts, and with the idea that the abnormal behaviour of endomysial fibroblasts in Duchenne dystrophy is a secondary consequence of their proximity to degenerating muscle.


Music listening engages specific cortical regions within the temporal lobes: differences between musicians and non-musicians.
Music and speech are two of the most relevant and common sounds in the human environment. Perceiving and processing these two complex acoustical signals rely on a hierarchical functional network distributed throughout several brain regions within and beyond the auditory cortices. Given their similarities, the neural bases for processing these two complex sounds overlap to a certain degree, but particular brain regions may show selectivity for one or the other acoustic category, which we aimed to identify. We examined 53 subjects (28 of them professional musicians) by functional magnetic resonance imaging (fMRI), using a paradigm designed to identify regions showing increased activity in response to different types of musical stimuli, compared to different types of complex sounds, such as speech and non-linguistic vocalizations. We found a region in the anterior portion of the superior temporal gyrus (aSTG) (planum polare) that showed preferential activity in response to musical stimuli and was present in all our subjects, regardless of musical training, and invariant across different musical instruments (violin, piano or synthetic piano). Our data show that this cortical region is preferentially involved in processing musical, as compared to other complex sounds, suggesting a functional role as a second-order relay, possibly integrating acoustic characteristics intrinsic to music (e.g., melody extraction). Moreover, we assessed whether musical experience modulates the response of cortical regions involved in music processing and found evidence of functional differences between musicians and non-musicians during music listening. In particular, bilateral activation of the planum polare was more prevalent, but not exclusive, in musicians than non-musicians, and activation of the right posterior portion of the superior temporal gyrus (planum temporale) differed between groups. Our results provide evidence of functional specialization for music processing in specific regions of the auditory cortex and show domain-specific functional differences possibly correlated with musicianship.


Optimizing photon upconversion by decoupling excimer formation and triplet triplet annihilation.
Perylene is a promising annihilator candidate for triplet-triplet annihilation photon upconversion, which has been successfully used in solar cells and in photocatalysis. Perylene can, however, form excimers, reducing the energy conversion efficiency and hindering further development of TTA-UC systems. Alkyl substitution of perylene can suppress excimer formation, but decelerate triplet energy transfer and triplet-triplet annihilation at the same time. Our results show that mono-substitution with small alkyl groups selectively blocks excimer formation without severly compromising the TTA-UC efficiency. The experimental results are complemented by DFT calculations, which demonstrate that excimer formation is suppressed by steric repulsion. The results demonstrate how the chemical structure can be modified to block unwanted intermolecular excited state relaxation pathways with minimal effect on the preferred ones.


The cerebellum, sensitive periods, and autism.
Cerebellar research has focused principally on adult motor function. However, the cerebellum also maintains abundant connections with nonmotor brain regions throughout postnatal life. Here we review evidence that the cerebellum may guide the maturation of remote nonmotor neural circuitry and influence cognitive development, with a focus on its relationship with autism. Specific cerebellar zones influence neocortical substrates for social interaction, and we propose that sensitive-period disruption of such internal brain communication can account for autism's key features.


Combined use of bacteriophage K and a novel bacteriophage to reduce Staphylococcus aureus biofilm formation.
Biofilms are major causes of impairment of wound healing and patient morbidity. One of the most common and aggressive wound pathogens is Staphylococcus aureus, displaying a large repertoire of virulence factors and commonly reduced susceptibility to antibiotics, such as the spread of methicillin-resistant S. aureus (MRSA). Bacteriophages are obligate parasites of bacteria. They multiply intracellularly and lyse their bacterial host, releasing their progeny. We isolated a novel phage, DRA88, which has a broad host range among S. aureus bacteria. Morphologically, the phage belongs to the Myoviridae family and comprises a large double-stranded DNA (dsDNA) genome of 141,907 bp. DRA88 was mixed with phage K to produce a high-titer mixture that showed strong lytic activity against a wide range of S. aureus isolates, including representatives of the major international MRSA clones and coagulase-negative Staphylococcus. Its efficacy was assessed both in planktonic cultures and when treating established biofilms produced by three different biofilm-producing S. aureus isolates. A significant reduction of biofilm biomass over 48 h of treatment was recorded in all cases. The phage mixture may form the basis of an effective treatment for infections caused by S. aureus biofilms.


A population-health approach to characterizing migraine by comorbidity: Results from the Mindfulness and Migraine Cohort Study.
The heterogeneity of migraine has been reported extensively, with identified subgroups usually based on symptoms. Grouping individuals with migraine and similar comorbidity profiles has been suggested, however such segmentation methods have not been tested using real-world clinical data. To gain insights into natural groupings of patients with migraine using latent class analysis based on electronic health record-determined comorbidities. Retrospective electronic health record data analysis of primary-care patients at Sutter Health, a large open healthcare system in Northern California, USA. We identified migraine patients over a five-year time period (2015-2019) and extracted 29 comorbidities. We then applied latent class analysis to identify comorbidity-based natural subgroups. We identified 95,563 patients with migraine and found seven latent classes, summarized by their predominant comorbidities and population share: fewest comorbidities (61.8%), psychiatric (18.3%), some comorbidities (10.0%), most comorbidities - no cardiovascular (3.6%), vascular (3.1%), autoimmune/joint/pain (2.2%), and most comorbidities (1.0%). We found minimal demographic differences across classes. Our study found groupings of migraine patients based on comorbidity that have the potential to be used to guide targeted treatment strategies and the development of new therapies.


Arthritis health service utilization among the elderly: the role of urban-rural residence and other utilization factors.
To compare the impact of urban-rural residence and other factors on the utilization of any type of arthritis-related physician care and on rheumatologist utilization. A population-based random sample of adults 65 years of age or older with self-reported arthritis from 10 urban and 12 rural Iowa counties were surveyed by telephone interview. We estimated the arthritis prevalence and health service utilization in this sample and evaluated the effects of predisposing, enabling, and need factors on utilization and satisfaction. Health care utilization was defined as ever having visited specific types of providers for arthritis-related care. A total of 488 individuals participated: 227 from urban counties and 261 rural respondents. Urban respondents more commonly reported having received a diagnosis of osteoarthritis from their physicians but were less likely to report rheumatoid arthritis. A greater proportion of urban versus rural respondents had utilized any physician for arthritis care (50.7% versus 41.0%, P = 0.032) and had more often seen an orthopedist (18.1% versus 9.6%, P = 0.006) or general internist (18.5% versus 8.8%, P = 0.002). A diagnosis of rheumatoid arthritis, younger age, living with another person, higher income, and further distance from an arthritis provider were significantly associated with prior rheumatologist utilization. The strongest adjusted predictor of any physician visit for arthritis care was whether older adults drove themselves to their provider. For rheumatologist utilization, a diagnosis of rheumatoid arthritis and age were independently associated. The most striking finding was the consistent association of need factors (such as the desire for medical advice), joint swelling, and the presence of a diagnosis of rheumatoid arthritis with physician utilization. We identified significant urban-rural variations in factors both enabling and predisposing to arthritis care, although urban-rural status did not appear to independently influence arthritis physician utilization. In a rural state with a relatively small number of rheumatologists, deleterious enabling factors such as greater distance from the doctor and lack of supplemental insurance did not provide significant obstacles to either rheumatologist or generalist utilization.


Economic and Environmental Assessment of Seed and Rhizome Propagated Miscanthus in the UK.
Growth in planted areas of Miscanthus for biomass in Europe has stagnated since 2010 due to technical challenges, economic barriers and environmental concerns. These limitations need to be overcome before biomass production from Miscanthus can expand to several million hectares. In this paper, we consider the economic and environmental effects of introducing seed based hybrids as an alternative to clonal M. x giganteus (Mxg). The impact of seed based propagation and novel agronomy was compared with current Mxg cultivation and used in 10 commercially relevant, field scale experiments planted between 2012 and 2014 in the United Kingdom, Germany, and Ukraine. Economic and greenhouse gas (GHG) emissions costs were quantified for the following production chain: propagation, establishment, harvest, transportation, storage, and fuel preparation (excluding soil carbon changes). The production and utilization efficiency of seed and rhizome propagation were compared. Results show that new hybrid seed propagation significantly reduces establishment cost to below £900 ha-1. Calculated GHG emission costs for the seeds established via plugs, though relatively small, was higher than rhizomes because fossil fuels were assumed to heat glasshouses for raising seedling plugs (5.3 and 1.5 kg CO2 eq. C Mg [dry matter (DM)]-1), respectively. Plastic mulch film reduced establishment time, improving crop economics. The breakeven yield was calculated to be 6 Mg DM ha-1 y-1, which is about half average United Kingdom yield for Mxg; with newer seeded hybrids reaching 16 Mg DM ha-1 in second year United Kingdom trials. These combined improvements will significantly increase crop profitability. The trade-offs between costs of production for the preparation of different feedstock formats show that bales are the best option for direct firing with the lowest transport costs (£0.04 Mg-1 km-1) and easy on-farm storage. However, if pelleted fuel is required then chip harvesting is more economic. We show how current seed based propagation methods can increase the rate at which Miscanthus can be scaled up; ∼×100 those of current rhizome propagation. These rapid ramp rates for biomass production are required to deliver a scalable and economic Miscanthus biomass fuel whose GHG emissions are ∼1/20th those of natural gas per unit of heat.


Left atrial mechanical function and stiffness in patients with paroxysmal atrial fibrillation.
Abnormalities in the left atrial (LA) structure and function may develop in patients with paroxysmal atrial fibrillation (AF). We sought to determine the contribution of LA mechanical function, including LA stiffness, to AF by comparing patients with paroxysmal AF with normal control subjects, and to evaluate whether LA mechanical function and stiffness are related with the structural changes of LA. Sixty-four paroxysmal AF patients (57 ± 13 years, 59% male) were studied, using a speckle tracking echocardiography, and were compared with 34 age-, gender-, and left ventricular (LV) mass-matched controls (53 ± 14 years, 61% male). LA volume indices, expansion index for reservoir function, active emptying fraction for contractile function, mitral annular velocities, and global longitudinal LA strain were measured. The ratio of E/e' to LA strain was used as an index of LA stiffness. Patients with paroxysmal AF had similar LV volume indices, ejection fraction, and diastolic function, when compared with that of the normal controls. However, paroxysmal AF patients showed increased LA volume indices and decreased LA reservoir function, but similar contractile function. LA stiffness was increased in patients with paroxysmal AF than in the control subjects (0.40 ± 0.25 vs. 0.29 ± 0.10, p = 0.002), and was related with LA volume indices and reservoir function. Patients with paroxysmal AF have decreased LA reservoir function and increased stiffness, in comparison with that of the control subjects. LA stiffness was significantly related with LA volume indices and reservoir function. LA stiffness can be used for the assessment of LA function in patients with paroxysmal AF.


Phosphorus complexes of meso-triaryl-25-oxasmaragdyrins.
The aromatic PO2 complexes of meso-triaryl-25-oxasmaragdyrins were synthesized by treating the free base 25-oxasmaragdyrins with POCl3 in toluene/triethylamine at refluxing temperature. The complexes are stable and characterized by X-ray and different spectroscopic techniques. In these complexes, the phosphorus(V) ion was bound to two pyrrolic nitrogen atoms of the smaragdyrin macrocycle and two oxygen atoms in tetrahedral geometry. The X-ray structure revealed that the smaragdyrin macrocycle showed significant distortion upon insertion of a PO2 unit, and the phosphorus atom lies 1.339 Å above the mean plane defined by three meso-carbon atoms of the macrocycle. These complexes absorb strongly in the visible region and are 2.5 times more strongly fluorescent than free base 25-oxasmaragdyrins. The smaragdyrin macrocycle becomes electron-deficient upon complexation with a PO2 unit because these complexes are easier to reduce but difficult to oxidize compared to free base smaragdyrins. We designed and synthesized a covalently linked BODIPY-PO2-smaragdyrin dyad and demonstrated efficient energy transfer from the BODIPY unit to the PO2-smaragdyrin unit.


Social support, volunteering and health around the world: cross-national evidence from 139 countries.
High levels of social capital and social integration are associated with self-rated health in many developed countries. However, it is not known whether this association extends to non-western and less economically advanced countries. We examine associations between social support, volunteering, and self-rated health in 139 low-, middle- and high-income countries. Data come from the Gallup World Poll, an internationally comparable survey conducted yearly from 2005 to 2009 for those 15 and over. Volunteering was measured by self-reports of volunteering to an organization in the past month. Social support was based on self-reports of access to support from relatives and friends. We started by estimating random coefficient (multi-level) models and then used multivariate logistic regression to model health as a function of social support and volunteering, controlling for age, gender, education, marital status, and religiosity. We found statistically significant evidence of cross-national variation in the association between social capital variables and self-rated health. In the multivariate logistic model, self-rated health were significantly associated with having social support from friends and relatives and volunteering. Results from stratified analyses indicate that these associations are strikingly consistent across countries. Our results indicate that the link between social capital and health is not restricted to high-income countries but extends across many geographical regions regardless of their national-income level.


Diagnostic ability of macular nerve fiber layer thickness using new segmentation software in glaucoma suspects.
To assess the capacity of internal retinal layer thickness measurements made at the macula using new spectral-domain optical coherence tomography (OCT) software to distinguish between healthy subjects and those with suspected glaucoma. The diagnostic performance of such measurements also was compared with that of conventional peripapillary retinal nerve fiber layer (RNFL) thickness measurements. The study included 38 subjects with suspected glaucoma and 38 age-matched healthy subjects. In one randomly selected eye of each participant, thickness measurements at the level of the macula were made of the nerve fiber layer (mRNFL), the ganglion cell layer (GCL), and the ganglion cell complex (GCC; GCL + internal plexiform layer) through automated OCT segmentation. Peripapillary RNFL thickness (pRNFL) also was determined using the conventional scan. As the only variable showing intergroup variation, mRNFL in the glaucoma suspects was significantly thinner in the quadrants inner inferior (P = 0.003), inner temporal (P = 0.010), and outer inferior (P = 0.017). The variable best able to discriminate between the two groups was inner inferior mRNFL thickness, as indicated by an area below the receiver operating characteristic (ROC) curve of 0.742. Macular RNFL thickness measurements showed an improved diagnostic capacity over the other variables examined to distinguish between healthy subjects and glaucoma suspects.


3D proteochemometrics: using three-dimensional information of proteins and ligands to address aspects of the selectivity of serine proteases.
The high similarity between certain sub-pockets of serine proteases may lead to low selectivity of protease inhibitors. Therefore the application of proteochemometrics (PCM), which quantifies the relationship between protein/ligand descriptors and affinity for multiple ligands and targets simultaneously, is useful to understand and improve the selectivity profiles of potential inhibitors. In this study, protein field-based PCM that uses knowledge-based and WaterMap derived fields to describe proteins in combination with 2D (RDKit and MOE fingerprints) and 3D (4 point pharmacophoric fingerprints and GRIND) ligand descriptors was used to model the bioactivities of 24 homologous serine proteases and 5863 inhibitors in an integrated fashion. Of the multiple field-based PCM models generated based on different ligand descriptors, RDKit fingerprints showed the best performance in terms of external prediction with Rtest2 of 0.72 and RMSEP of 0.81. Further, visual interpretation of the models highlights sub-pocket specific regions that influence affinity and selectivity of serine protease inhibitors.


Health state descriptions to elicit stroke values: do they reflect patient experience of stroke?
To explore whether stroke health state descriptions used in preference elicitation studies reflect patients' experiences by comparing published descriptions with qualitative studies exploring patients' lived experience. Two literature reviews were conducted: on stroke health state descriptions used in direct preference elicitation studies and the qualitative literature on patients' stroke experience. Content and comparative thematic analysis was used to identify characteristics of stroke experience in both types of study which were further mapped onto health related quality of life (HRQOL) domains relevant to stroke. Two authors reviewed the coded text, categories and domains. We included 35 studies: seven direct preference elicitation studies and 28 qualitative studies on patients' experience. Fifteen coded categories were identified in the published health state descriptions and 29 in the qualitative studies. When mapped onto domains related to HRQOL, qualitative studies included a wider range of categories in every domain that were relevant to the patients' experience than health state descriptions. Variation exists in the content of health state descriptions for all levels of stroke severity, most critically with a major disjuncture between the content of descriptions and how stroke is experienced by patients. There is no systematic method for constructing the content/scope of health state descriptions for stroke, and the patient perspective is not incorporated, producing descriptions with major deficits in reflecting the lived experience of stroke, and raising serious questions about the values derived from such descriptions and conclusions based on these values.