Mangiferin: a natural miracle bioactive compound against lifestyle related disorders.
The current review article is an attempt to explain the therapeutic potential of mangiferin, a bioactive compound of the mango, against lifestyle-related disorders. Mangiferin (2-β-D-glucopyranosyl-1,3,6,7-tetrahydroxy-9H-xanthen-9-one) can be isolated from higher plants as well as the mango fruit and their byproducts (i.e. peel, seed, and kernel). It possesses several health endorsing properties such as antioxidant, antimicrobial, antidiabetic, antiallergic, anticancer, hypocholesterolemic, and immunomodulatory. It suppresses the activation of peroxisome proliferator activated receptor isoforms by changing the transcription process. Mangiferin protects against different human cancers, including lung, colon, breast, and neuronal cancers, through the suppression of tumor necrosis factor α expression, inducible nitric oxide synthase potential, and proliferation and induction of apoptosis. It also protects against neural and breast cancers by suppressing the expression of matrix metalloproteinase (MMP)-9 and MMP-7 and inhibiting enzymatic activity, metastatic potential, and activation of the β-catenin pathway. It has the capacity to block lipid peroxidation, in order to provide a shielding effect against physiological threats. Additionally, mangiferin enhances the capacity of the monocyte-macrophage system and possesses antibacterial activity against gram-positive and gram-negative bacteria. This review summarizes the literature pertaining to mangiferin and its associated health claims.


Association of drusen deposition with choroidal intercapillary pillars in the aging human eye.
To determine the pattern of drusen accumulation with age and to investigate the initial sites of deposition and their relationship to choroidal capillaries in human donor eyes from the eye bank of Moorfields Eye Hospital. Wholemounted, hydrated preparations of the choriocapillaris and Bruch's membrane from donor eyes ranging from 42 to 95 years, with or without retinal pigment epithelium (RPE), were examined by conventional and confocal microscopy. Drusen were visualized by their autofluorescence. In all age groups studied autofluorescent drusen were present at the equator but were not found centrally where the vascular architecture is different, being tubular rather than a honeycomb pattern. Autofluorescing drusen were strongly associated with the lateral walls of the choriocapillaris (an area commonly known as the intercapillary pillars of the choriocapillaris (P = 0.028; Wilcoxon signed ranks test). Nonfluorescing drusen were occasionally seen centrally, but were not easily identified, and because of their large size, their localization with respect to capillary walls was not possible. These results strongly support the notion that autofluorescent drusen are not randomly distributed and have a specific spatial relationship to choroidal vessel walls. That equatorial drusen fluoresce, whereas central drusen do not, suggests that they may have different chemical compositions at the two sites and possibly different significance in age-related macular disease.


Expression of EphA2 is prognostic of disease-free interval and overall survival in surgically treated patients with renal cell carcinoma.
Whereas normally expressed at sites of cell-to-cell contact in adult epithelial tissues, recent studies have shown that the receptor tyrosine kinase EphA2 is overexpressed in numerous epithelial-type carcinomas, with the greatest level of EphA2 expression observed in metastatic lesions. In the current study, we have assessed EphA2 expression in archived renal cell carcinoma (RCC) tissues as it relates to patient disease course. Using specific anti-EphA2 monoclonal antibody 208 and immunohistochemistry, we evaluated EphA2 protein expression levels in RCC specimens surgically resected from 34 patients (including 30 conventional clear-cell RCC, 3 papillary, and 1 chromophobic RCC cases) resulting in clinical cures. Regardless of histopathologic subtype, RCC lesions expressing higher levels of EphA2 tended to be of a higher grade (P < 0.05) and larger (P = 0.093), more-highly-vascularized tumors (P = 0.005). Perhaps most notable, the degree of EphA2 overexpression (versus normal matched autologous kidney tissue) seemed predictive of short-term (<1 year) versus longer-term (> or =1 year) disease-free interval (P < 0.001) and of overall survival (P < 0.001) among the RCC patients evaluated. These data suggest that EphA2 expression level may serve as a useful prognostic tool in the clinical management of patients who have been successfully treated with surgery, but who are at greater risk for accelerated disease recurrence and who have a poorer prognosis.


Influence of Molecular Aggregation on Electron Transfer at the Perylene Diimide/Indium-Tin Oxide Interface.
Chemisorption of an organic monolayer to tune the surface properties of a transparent conductive oxide (TCO) electrode can improve the performance of organic electronic devices that rely on efficient charge transfer between an organic active layer and a TCO contact. Here, a series of perylene diimides (PDIs) was synthesized and used to study relationships between monolayer structure/properties and electron transfer kinetics at PDI-modified indium-tin oxide (ITO) electrodes. In these PDI molecules, one of the imide substituents is a benzene ring bearing a phosphonic acid (PA) and the other is a bulky aryl group that is twisted out of the plane of the PDI core. The size of the bulky aryl group and the substitution of the benzene ring bearing the PA were both varied, which altered the extent of aggregation when these molecules were absorbed as monolayer films (MLs) on ITO, as revealed by both attenuated total reflectance (ATR) and total internal reflection fluorescence spectra. Polarized ATR measurements indicate that, in these MLs, the long axis of the PDI core is tilted at an angle of 33-42° relative to the surface normal; the tilt angle increased as the degree of bulky substitution increased. Rate constants for electron transfer (ks,opt) between these redox-active modifiers and ITO were determined by potential-modulated ATR spectroscopy. As the degree of PDI aggregation was reduced, ks,opt declined, which is attributed to a reduction in the lateral electron self-exchange rate between adsorbed PDI molecules, as well as the heterogeneous conductivity of the ITO electrode surface. Photoelectrochemical measurements using a dissolved aluminum phthalocyanine as an electron donor showed that ITO modified with any of these PDIs is a more effective electron-collecting electrode than bare ITO.


Barriers to obstetric fistula treatment in low-income countries: a systematic review.
To identify the barriers faced by women living with obstetric fistula in low-income countries that prevent them from seeking care, reaching medical centres and receiving appropriate care. Bibliographic databases, grey literature, journals, and network and organisation websites were searched in English and French from June to July 2014 and again from August to November 2016 using key search terms and specific inclusion and exclusion criteria for discussion of barriers to fistula treatment. Experts provided recommendations for additional sources. Of 5829 articles screened, 139 were included in the review. Nine groups of barriers to treatment were identified: psychosocial, cultural, awareness, social, financial, transportation, facility shortages, quality of care and political leadership. Interventions to address barriers primarily focused on awareness, facility shortages, transportation, financial and social barriers. At present, outcome data, though promising, are sparse and the success of interventions in providing long-term alleviation of barriers is unclear. Results from the review indicate that there are many barriers to fistula treatment, which operate at the individual, community and national levels. The successful treatment of obstetric fistula may thus require targeting several barriers, including depression, stigma and shame, lack of community-based referral mechanisms, financial cost of the procedure, transportation difficulties, gender power imbalances, the availability of facilities that offer fistula repair, community reintegration and the competing priorities of political leadership.


Primary Cytomegalovirus Infection Significantly Impacts Circulating T Cells in Kidney Transplant Recipients.
Cytomegalovirus (CMV) infection profoundly affects the T cell compartment and is associated with alterations in T cell aging parameters and generation of cytotoxic CD4(+) CD28null T cells. Hence, the effect of a primary CMV infection post-kidney transplantation (KT) on the peripheral T cell compartment was examined. As aging parameters, we determined the T cell differentiation status, T cell receptor excision circle (TREC) content, CD31(+) naïve T cell numbers and relative telomere length (RTL) pre-KT and 12 months post-KT. CMV-seronegative KT recipients, receiving a kidney from a CMV-seropositive donor (D+/R-) were compared to D+/R+ KT recipients. Eleven out of the 22 D+/R- KT recipients had CMV viremia post-KT. They developed CMV-specific CD4(+) and CD8(+) T cells and their T cell compartment shifted towards a more differentiated memory phenotype with expansion of CD4(+) CD28null and CD8(+) CD28null cells. One year post-KT, the CD8(+) T cell count was almost doubled compared to nonviremic D+/R- and D+/R+ KT recipients. In addition, the RTL of the CD8(+) T cell was significantly lower and both the TREC content and CD31(+) naïve T cell numbers significantly decreased. Moreover, primary CMV infection was associated with a negative impact on glomerular filtration rate. In conclusion, primary CMV infection has a substantial impact on the number and phenotype of peripheral T cells and may negatively affect renal allograft function.


Dynamics of envelope evolution in clade C SHIV-infected pig-tailed macaques during disease progression analyzed by ultra-deep pyrosequencing.
Understanding the evolution of the human immunodeficiency virus type 1 (HIV-1) envelope during disease progression can provide tremendous insights for vaccine development, and simian-human immunodeficiency virus (SHIV) infection of non-human primate provides an ideal platform for such studies. A newly developed clade C SHIV, SHIV-1157ipd3N4, which was able to infect rhesus macaques, closely resembled primary HIV-1 in transmission and pathogenesis, was used to infect several pig-tailed macaques. One of the infected animals subsequently progressed to AIDS, whereas one remained a non-progressor. The viral envelope evolution in the infected animals during disease progression was analyzed by a bioinformatics approach using ultra-deep pyrosequencing. Our results showed substantial envelope variations emerging in the progressor animal after the onset of AIDS. These envelope variations impacted the length of the variable loops and charges of different envelope regions. Additionally, multiple mutations were located at the CD4 and CCR5 binding sites, potentially affecting receptor binding affinity, viral fitness and they might be selected at late stages of disease. More importantly, these envelope mutations are not random since they had repeatedly been observed in a rhesus macaque and a human infant infected by either SHIV or HIV-1, respectively, carrying the parental envelope of the infectious molecular clone SHIV-1157ipd3N4. Moreover, similar mutations were also observed from other studies on different clades of envelopes regardless of the host species. These recurring mutations in different envelopes suggest that there may be a common evolutionary pattern and selection pathway for the HIV-1 envelope during disease progression.


In vitro and in vivo influenza virus-inhibitory effects of viramidine.
Viramidine, the 3-carboxamidine derivative of ribavirin, was effective against a spectrum of influenza A (H1N1, H3N2 and H5N1) and B viruses in vitro, with the 50% effective concentration (EC50) ranging from 2 to 32 microg/ml. The mean 50% cytotoxic concentration (CC50) in the MDCK cells used in these experiments was 760 microg/ml. Ribavirin, run in parallel, had a similar antiviral spectrum, with EC50 values ranging from 0.6 to 5.5 microg/ml; the mean CC50 for ribavirin was 560 microg/ml. Oral gavage administrations of viramidine or ribavirin to mice infected with influenza A/NWS/33 (H1N1), A/Victoria/3/75 (H3N2), B/Hong Kong/5/72 or B/Sichuan/379/99 viruses were highly effective in preventing death, lessening decline in arterial oxygen saturation, inhibition of lung consolidation and reducing lung virus titers. The minimum effective dose of viramidine in these studies ranged from 15 to 31 mg/kg/day, depending upon the virus infection, when administered twice daily for 5 days beginning 4 h pre-virus exposure. The LD50 of the compound was 610 mg/kg/day. Ribavirin's minimum effective dose varied between 18 and 37.5 mg/kg/day with the LD50 determined to be 220 mg/kg/day. Viramidine's efficacy was also seen against an influenza A/NWS/33 (H1N1) virus infection in mice, when the compound was administered in the drinking water, the minimum effective dose being 100 mg/kg/day. Delay of the initiation of either viramidine or ribavirin therapy, using the approximate 1/3 LD50 dose of each, was protective as late as 48 h after exposure to the A/NWS/33 virus. While both compounds appear to have similar efficacy against influenza virus infections, when one considers the lesser toxicity, viramidine may warrant further evaluation as a possible therapy for influenza.


Correlation between intracoronary physiology and myocardial perfusion imaging in patients with severe aortic stenosis.
Aortic stenosis (AS) is frequently associated with coronary artery disease (CAD). However, the best tool to functionally assess CAD in AS remains undetermined. Fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) have never been validated in AS. FFR, iFR and stress single photon emission computed tomography (SPECT) were performed in a consecutive series of 28 patients with severe AS and 41 borderline coronary lesions during the work-up for valve replacement. Both FFR and iFR were correlated with an abnormal SPECT. At ROC analysis, FFR yielded an AUC = 0.91 with negative predictive value (NPV) = 95% in detecting ischemia according to SPECT. iFR showed significant worse agreement with myocardial perfusion imaging compared to FFR (59% vs 85%, p = 0.014). Specifically, a significant larger proportion of false positive measurements (negative SPECT and iFR < 0.89) was observed using iFR vs FFR: 39% vs 12%, p = 0.011. Using a pre-specified 0.82 cut-off, the iFR agreement with SPECT increased to 73%. FFR yielded a good correlation with SPECT and a high NPV in detecting ischemia-provoking lesions. iFR diagnostic metrics were inferior compared with FFR and improved adopting a lower ischemic threshold.


Isolation of base stabilized fluoroborylene and its radical cation.
Herein, we report the synthesis and characterization of the metal free low valent fluoroborylene [(Me-cAAC)2BF] (1) stabilized by cyclic (alkyl)(amino) carbene (cAAC). The fluoroborylene 1 is obtained by the reductive defluorination of Me-cAAC:BF3 with 2.0 equivalents of KC8 in the presence of 1.0 equivalent of Me-cAAC. Due to its highly electron rich nature, 1 underwent one-electron oxidation with 1.0 equivalent of lithium tetrakis(pentafluorophenyl)borate [LiB(C6F5)4] to form the radical cation [(Me-cAAC)2BF]˙+[B(C6F5)4]- (2). DFT studies suggested that the lone pair of electrons is localized on the boron atom in 1, which explains its unprecedented reactivity. Both compounds 1 and 2 were characterized by X-ray crystallography. The radical cation 2 was studied by EPR spectroscopy.


Barriers and facilitators to implementation of menu labelling interventions to support healthy food choices: a mixed methods systematic review protocol.
Menu labelling is continuing to gather public and legislative support as one of the potential environmental strategies for addressing the obesity pandemic. However, issues relating to implementation have been reported in countries where menu labelling has been introduced on a voluntary or mandatory basis. The aim of this mixed methods systematic review is to synthesise the empirical evidence on the barriers and facilitators to implementation of menu labelling interventions to support healthy food choices. This review will use the 'best fit' framework synthesis approach to synthesise qualitative, quantitative and mixed methods evidence. Peer-reviewed publications will be accessed through PubMed, EMBASE, CINAHL, PsycINFO, Web of Science and Scopus. Grey literature will be accessed through Google Scholar, OpenGrey, RIAN, EThOS, ProQuest, WorldCat, Networked Digital Library of Theses and Dissertations, Open Access Theses and Dissertations, and public health organisation websites. Screening reference lists, citation chaining and contacting authors of all included studies will be undertaken. There will be no restriction on menu labelling scheme or format, publication year or language; however, only primary research studies relevant to supply-side stakeholders will be eligible for inclusion. Study quality will be assessed using the Mixed Methods Appraisal Tool. At least two independent reviewers will perform study selection, data extraction and quality appraisal; if consensus is required, another independent reviewer will be consulted. A combination of deductive coding, using the Consolidated Framework for Implementation Research as the a priori framework, and inductive analysis, using secondary thematic analysis, will be used. The overall process will assist in the construction of a new evidence-based conceptual model regarding the implementation of menu labelling interventions. The new model will be assessed for bias and a sensitivity analysis performed. Given the growing consensus that a systemic, sustained portfolio of obesity prevention strategies, delivered at scale, is needed to address the obesity epidemic, greater understanding of the practical issues relating to implementation of such strategies is required. Findings from this review will be used to develop a set of best-practice guidelines to enhance the adoption, implementation and sustainability of menu labelling interventions across countries worldwide. PROSPERO CRD42017083306.


Insulin regulation of amino acid transport in mesenchymal cells from avian and mammalian tissues.
Insulin regulation of amino acid transport across the cell membrane was studied in a variety of mesenchymal cell directly isolated from avian and mammalian tissues or collected from confluent cultures. Transport activity of the principal systems of mediation in the presence and absence of insulin was evaluated by measuring the uptake of representative amino acids under conditions approaching initial entry rates. Insulin enhanced the transport rate of substrate amino acids from the A system(alpha-aminoisobutyric acid, L-proline, glycine, L-alanine and L-serine) in fibroblasts and osteoblasts from chick-embryo tissues, in mesenchymal cells (fibroblasts and smooth muscle cells) from immature rat uterus, in thymic lymphocytes from young rats and in chick-embryo fibroblasts from confluent secondary cultures. In these tissues, the uptake of amino acid substrates of transport systems L and Ly+ (L-leucine, L-phenylalanine, L-lysine) was not affected by the presence of the hormone. No insulin control of amino acid transport was detected in chick-embryo chondroblasts and rat peritoneal macrophages. These observations identify the occurrence of hormonal regulatory patterns of amino acid transport for different mesenchymal cells types and indicate that these properties emerge early during cell differentiation.


Impacts of 3 years of elevated atmospheric CO2 on rhizosphere carbon flow and microbial community dynamics.
Carbon (C) uptake by terrestrial ecosystems represents an important option for partially mitigating anthropogenic CO2 emissions. Short-term atmospheric elevated CO2 exposure has been shown to create major shifts in C flow routes and diversity of the active soil-borne microbial community. Long-term increases in CO2 have been hypothesized to have subtle effects due to the potential adaptation of soil microorganism to the increased flow of organic C. Here, we studied the effects of prolonged elevated atmospheric CO2 exposure on microbial C flow and microbial communities in the rhizosphere. Carex arenaria (a nonmycorrhizal plant species) and Festuca rubra (a mycorrhizal plant species) were grown at defined atmospheric conditions differing in CO2 concentration (350 and 700 ppm) for 3 years. During this period, C flow was assessed repeatedly (after 6 months, 1, 2, and 3 years) by (13) C pulse-chase experiments, and label was tracked through the rhizosphere bacterial, general fungal, and arbuscular mycorrhizal fungal (AMF) communities. Fatty acid biomarker analyses and RNA-stable isotope probing (RNA-SIP), in combination with real-time PCR and PCR-DGGE, were used to examine microbial community dynamics and abundance. Throughout the experiment the influence of elevated CO2 was highly plant dependent, with the mycorrhizal plant exerting a greater influence on both bacterial and fungal communities. Biomarker data confirmed that rhizodeposited C was first processed by AMF and subsequently transferred to bacterial and fungal communities in the rhizosphere soil. Over the course of 3 years, elevated CO2 caused a continuous increase in the (13) C enrichment retained in AMF and an increasing delay in the transfer of C to the bacterial community. These results show that, not only do elevated atmospheric CO2 conditions induce changes in rhizosphere C flow and dynamics but also continue to develop over multiple seasons, thereby affecting terrestrial ecosystems C utilization processes.


Screening of chemicals for human bioaccumulative potential with a physiologically based toxicokinetic model.
Human bioaccumulative potential is an important element in the risk assessment of chemicals. Due to the high number of synthetic chemicals, there exists the need to develop prioritisation strategies. The purpose of this study was to develop a predictive tool for human bioaccumulation risk assessment that incorporates not only the chemical properties of the compounds, but also the processes that tend to decrease the concentration of the compound such as metabolisation. We used a generic physiologically based toxicokinetic model that based on in vitro human liver metabolism data, minimal renal excretion and a constant exposure was able to assess the bioaccumulative potential of a chemical. The approach has been analysed using literature data on well-known bioaccumulative compounds and liver metabolism data from the ECVAM database and a subset of the ToxCast phase I chemical library-in total 94 compounds covering pharmaceuticals, plant protection products and industrial chemicals. Our results provide further evidence that partitioning properties do not allow for a reliable screening criteria for human chemical hazard. Our model, based on a 100% intestinal absorption assumption, suggests that metabolic clearance, plasma protein-binding properties and renal excretion are the main factors in determining whether bioaccumulation will occur and its amount. It is essential that in vitro metabolic clearance tests with metabolic competent cell lines as well as plasma protein-binding assays be performed for suspected bioaccumulative compounds.


Alteration of epithelial cell transferrin-iron homeostasis by Neisseria meningitidis and Neisseria gonorrhoeae.
Iron is an essential element for nearly all organisms. In mammals, iron is transported to body tissues by the serum glycoprotein transferrin. Transferrin-iron is internalized by binding to specific receptors followed by endocytosis. In vitro, Neisseria meningitidis and Neisseria gonorrhoeae can use iron from a variety of iron-containing compounds, including human transferrin. In vivo, transferrin is an important source of iron for N. gonorrhoeae: a mutant that is unable to bind and use transferrin-iron is unable to colonize the urethra of men or initiate disease at this site. As pathogenic Neisseria and its human host derive much of their iron from transferrin, we reasoned that a competition may exist between microbe and host epithelial cells for transferrin-iron at certain stages of infection. We therefore tested the hypothesis that N. meningitidis and N. gonorrhoeae may actively interfere with host transferrin-iron metabolism. We report that Neisseria-infected human epithelial cells have reduced levels of transferrin receptor messenger RNA and cycling transferrin receptors. The ability of infected cells to internalize transferrin receptor is also reduced. Finally, the relative distribution of surface and cycling transferrin receptors is altered in an infected cell. We conclude that Neisseria infection alters epithelial cell transferrin-iron homeostasis at multiple levels.


Enhanced insulin-stimulated activation of phosphatidylinositol 3-kinase in the liver of high-fat-fed rats.
Insulin receptor substrate (IRS)-1 and IRS-2, which mediate phosphatidylinositol (PI) 3-kinase activation, play essential roles in insulin-induced translocation of GLUT4 and in glycogen synthesis. In this study, we investigated the process of PI 3-kinase activation via binding with IRS-1 and -2 in liver, muscle, and fat of high-fat-fed rats, a model of insulin-resistant diabetes. In the liver of high-fat-fed rats, insulin increased the PI 3-kinase regulatory subunit p85alpha and the PI 3-kinase activities associated with IRS-1 3.6- and 2.4-fold, and with IRS-2, 4.7- and 3.0-fold, respectively, compared with those in control rats. The tyrosine phosphorylation levels of IRS-1 and IRS-2 were not significantly altered, however. In contrast with the liver, tyrosine phosphorylation levels and associated PI 3-kinase proteins and activities were decreased in the muscle and adipose tissue of high-fat-fed rats. Thus, high-fat feeding appears to cause insulin resistance in the liver by a mechanism different from the impaired PI 3-kinase activation observed in muscle and adipose tissue. Taking into consideration that hepatic PI 3-kinase activation is severely impaired in obese diabetic models such as Zucker fatty rats, it is possible that the mechanism by which a high-fat diet causes insulin resistance is quite different from that associated with obesity and overeating due to abnormality in the leptin system. This is the first report to show increased PI 3-kinase activation by insulin in an insulin-resistant diabetic animal model. These findings may be important for understanding the mechanism of insulin resistance in human NIDDM, since a high-fat diet is considered to be one of the major factors exacerbating insulin insensitivity in humans.


Self-reported knee joint instability is related to passive mechanical stiffness in medial knee osteoarthritis.
Self-reported knee joint instability compromises function in individuals with medial knee osteoarthritis and may be related to impaired joint mechanics. The purpose of this study was to evaluate the relationship between self-reported instability and the passive varus-valgus mechanical behaviour of the medial osteoarthritis knee. Passive varus-valgus angular laxity and stiffness were assessed using a modified isokinetic dynamometer in 73 participants with medial tibiofemoral osteoarthritis. All participants self-reported the absence or presence of knee instability symptoms and the degree to which instability affected daily activity on a 6-point likert scale. Forward linear regression modelling identified a significant inverse relationship between passive mid-range knee stiffness and symptoms of knee instability (r = 0.27; P < 0.05): reduced stiffness was indicative of more severe instability symptoms. Angular laxity and end-range stiffness were not related to instability symptoms (P > 0.05). Conceivably, a stiffer passive system may contribute toward greater joint stability during functional activities. Importantly however, net joint stiffness is influenced by both active and passive stiffness, and thus the active neuromuscular system may compensate for reduced passive stiffness in order to maintain joint stability. Future work is merited to examine the role of active stiffness in symptomatic joint stability.


Externalizing and self-medicating: Heterogeneity among repeat DUI offenders.
Despite significant reductions in Driving Under the Influence (DUI) in the United States during recent decades, DUI continues to be a major public health threat. The current study investigated the intersection of two domains known to influence DUI: criminal history and psychiatric comorbidity. DUI recidivists (N = 743) attending a court-mandated two-week inpatient DUI program completed a computerized mental health assessment as part of their intake to that program. Participants' criminal records were obtained 4-5 years after program attendance. This study identified three primary repeat DUI offender subtypes with distinct patterns of criminal behavior and psychiatric comorbidity: (Type I) those whose DUI emerges from a pattern of drinking to cope with mood and anxiety problems, (Type II) those whose DUI emerges as part of a larger pattern of externalizing and criminal behavior, and (Type III) those whose DUI offenses reflect more acute triggers and isolated episodes of excessive drinking. These findings suggest that current treatment models used in DUI programs are inadequate to address the heterogeneity in the population of DUI recidivists and that earlier and more comprehensive screening would allow for better targeting of resources to DUI offender subtypes.


Electromyogram-controlled assistive exercise for the motor recovery of shoulder in chronic hemiplegia: A pilot study.
Correct-active-repetitive exercise is important for the motor recovery in hemiplegics. The present study hypothesizes that the electromyogram (EMG)-controlled assistance of motion would be an effective implementation of the concept for the rehabilitation of the hemiplegic shoulder, even in chronic patients. This study aims to investigate the feasibility of the suggested method. The motor intention is derived from the EMG of the shoulder muscles and the shoulder movement (flexion and abduction) is assisted by an electro-mechanical system only when the motor intention (EMG amplitude) exceeded the threshold. Twelve patients in the chronic stage of stroke participated in this pilot study. The EMG-controlled assistive exercise lasts for two weeks, 20 min per day and 5 days a week. The active range of motion in both abduction and flexion increases significantly after the intervention (p < 0.01). The maximum torque increases in both directions, and the increase is significant in the abduction (p < 0.01). The Fugl-Myer motor assessment score is improved greatly in the shoulder-related items (p < 0.01), but neither in the shoulder-unrelated items of the upper extremity (p = 0.13) nor in the lower extremity items (p = 0.19). This pilot study demonstrates that EMG-controlled assistive exercise can improve shoulder motor functions related to selected muscles and the suggested method is promising for the motor recovery of the shoulder in chronic hemiplegia.


Screening and characterisation of antimicrobial properties of semisynthetic betulin derivatives.
Betulin (lup-20(29)-ene-3β, 28-diol) is a naturally occurring triterpene, which is found in substantial amounts from the outer bark of birch trees. A library of 51 structurally diverse semisynthetic betulin derivatives was screened against five bacterial strains, Enterobacter aerogenes, Escherichia coli, Enterococcus faecalis, Pseudomonas aeruginosa, Staphylococcus aureus and a fungal strain Candida albicans, using broth microdilution assays. Primary antimicrobial screening at 50 µM concentration led to the identification of five compounds showing antimicrobial properties (inhibition of growth by >70% against one or more microbial strains). According to the dose-response results, 28-O-(N-acetylanthraniloyl)betulin (compound 5) was the most active, showing MIC90 of 6.25 µM against two Gram-positive bacteria, E. faecalis and S. aureus. However, the activity of this compound was affected by albumin binding, which was demonstrated by the loss of activity in a host-pathogen co-culture assay as well as in the antibacterial assay in the presence of increased concentration of albumin. Furthermore, the effects on mammalian cells were evaluated by cytotoxicity assessment on hepatocyte cell culture after 24 h exposure to the compounds. Betulinic aldehyde (18), betulin-28-oxime (31) and hetero cycloadduct with acetoxy groups at carbon atoms 3 and 28 and ethyl substituent at the triazolo ring (43) displayed cytotoxicity towards hepatocytes, with IC50 values of 47, 25 and 16 µM, respectively. The IC50 value for 28-O-(N-acetylanthraniloyl)betulin (5) was 56 µM. The current study presents an insight into using betulin scaffold for developing derivatives with antibacterial potential, and furthermore the necessity of in-depth analysis of found actives through selectivity profiling and follow-up studies including in silico ADMET predictions.


Conjunctival scarring in trachoma is associated with the HLA-C ligand of KIR and is exacerbated by heterozygosity at KIR2DL2/KIR2DL3.
Chlamydia trachomatis is globally the predominant infectious cause of blindness and one of the most common bacterial causes of sexually transmitted infection. Infections of the conjunctiva cause the blinding disease trachoma, an immuno-pathological disease that is characterised by chronic conjunctival inflammation and fibrosis. The polymorphic Killer-cell Immunoglobulin-like Receptors (KIR) are found on Natural Killer cells and have co-evolved with the Human Leucocyte Antigen (HLA) class I system. Certain genetic constellations of KIR and HLA class I polymorphisms are associated with a number of diseases in which modulation of the innate responses to viral and intracellular bacterial pathogens is central. A sample of 134 Gambian pedigrees selected to contain at least one individual with conjunctival scarring in the F1 generation was used. Individuals (n = 830) were genotyped for HLA class I and KIR gene families. Family Based Association Tests and Case Pseudo-control tests were used to extend tests for transmission disequilibrium to take full advantage of the family design, genetic model and phenotype. We found that the odds of trachomatous scarring increased with the number of genome copies of HLA-C2 (C1/C2 OR = 2.29 BHP-value = 0.006; C2/C2 OR = 3.97 BHP-value = 0.0004) and further increased when both KIR2DL2 and KIR2DL3 (C2/C2 OR = 5.95 BHP-value = 0.006) were present. To explain the observations in the context of chlamydial infection and trachoma we propose a two-stage model of response and disease that balances the cytolytic response of KIR expressing NK cells with the ability to secrete interferon gamma, a combination that may cause pathology. The data presented indicate that HLA-C genotypes are important determinants of conjunctival scarring in trachoma and that KIR2DL2/KIR2DL3 heterozygosity further increases risk of conjunctival scarring in individuals carrying HLA-C2.


Serotonin-induced hypersensitivity via inhibition of catechol O-methyltransferase activity.
The subcutaneous and systemic injection of serotonin reduces cutaneous and visceral pain thresholds and increases responses to noxious stimuli. Different subtypes of 5-hydroxytryptamine (5-HT) receptors are suggested to be associated with different types of pain responses. Here we show that serotonin also inhibits catechol O-methyltransferase (COMT), an enzyme that contributes to modultion the perception of pain, via non-competitive binding to the site bound by catechol substrates with a binding affinity comparable to the binding affinity of catechol itself (K(i) = 44 μM). Using computational modeling, biochemical tests and cellular assays we show that serotonin actively competes with the methyl donor S-adenosyl-L-methionine (SAM) within the catalytic site. Binding of serotonin to the catalytic site inhibits the access of SAM, thus preventing methylation of COMT substrates. The results of in vivo animal studies show that serotonin-induced pain hypersensitivity in mice is reduced by either SAM pretreatment or by the combined administration of selective antagonists for β(2)- and β(3)-adrenergic receptors, which have been previously shown to mediate COMT-dependent pain signaling. Our results suggest that inhibition of COMT via serotonin binding contributes to pain hypersensitivity, providing additional strategies for the treatment of clinical pain conditions.


A practical "ABCDE" approach to the metabolic syndrome.
The metabolic syndrome comprises a cluster of risk factors for cardiovascular disease and type 2 diabetes mellitus that are due to abdominal obesity and insulin resistance. This increasingly important proinflammatory condition remains both underrecognized and undertreated. To aid physicians in their approach to the metabolic syndrome, we assessed and synthesized the literature on cardiovascular risk assessment and early intervention for risk reduction. We performed a comprehensive search of MEDLINE and the Cochrane database for peer-reviewed clinical studies published from January 1, 1988, to December 31, 2007, augmented by consultation with content experts. We used the search terms metabolic syndrome, abdominal obesity, waist circumference, insulin resistance, cardiovascular disease, prediabetes, diabetes, treatment, prevention, aspirin, hypertension, cholesterol, atherogenic dyslipidemia, lifestyle therapy, diet, and exercise. Criteria used for study review were controlled study design, English language, relevance to clinicians, and validity based on experimental design and appropriateness of conclusions. Although growing evidence supports early intervention in patients with the metabolic syndrome, many physicians do not recognize the risk associated with this condition and fail to initiate early treatment. A comprehensive management plan can be assembled through an "ABCDE" approach: "A" for assessment of cardiovascular risk and aspirin therapy, "B" for blood pressure control, "C" for cholesterol management, "D" for diabetes prevention and diet therapy, and "E" for exercise therapy. This ABCDE approach provides a practical and systematic framework for encouraging metabolic syndrome recognition and for implementing a comprehensive, evidence-based management plan for the reduction of cardiovascular risk.


Data compression in frequency-selective materials using frequency-swept excitation pulses.
We demonstrate the temporal compression of photon echoes in frequency-selective materials by application of frequency-swept excitation pulses. Experimental results in Pr(3+):Y(2)SiO(5) for two- and three-pulse photon echoes are presented and compared with theory. A possible application to temporal reduction of optical data streams is shown.


Use of the radial forearm microvascular free-flap graft for cranial base reconstruction.
Reconstruction of the cranial base after resection of complex lesions requires creation of both a vascularized barrier to cerebrospinal fluid (CSF) leakage and tailored filling of operative defects. The authors describe the use of radial forearm microvascular free-flap grafts to reconstruct skull base lesions, to fill small tissue defects, and to provide an excellent barrier against CSF leakage. Ten patients underwent 11 skull base procedures including placement of microvascular free-flap grafts harvested from the forearm and featuring the radial artery and its accompanying venae comitantes. Operations included six craniofacial, three lateral skull base, and two transoral procedures for various diseases. Excellent results were obtained, with no persistent CSF leaks, no flap failures, and no operative infections. One temporary CSF leak was easily repaired with flap repositioning, and at one flap donor site minor wound breakdown was observed. One patient underwent a second procedure for tumor recurrence and CSF leakage at a site distant from the original operation. Microvascular free tissue transfer reconstruction of skull base defects by using the radial forearm flap provides a safe, reliable, low-morbidity method for reconstructing the skull base and is ideally suited to "low-volume" defects.


A complex of Arabidopsis DRB proteins can impair dsRNA processing.
Small RNAs play an important role in regulating gene expression through transcriptional and post-transcriptional gene silencing. Biogenesis of small RNAs from longer double-stranded (ds) RNA requires the activity of dicer-like ribonucleases (DCLs), which in plants are aided by dsRNA binding proteins (DRBs). To gain insight into this pathway in the model plant Arabidopsis, we searched for interactors of DRB4 by immunoprecipitation followed by mass spectrometry-based fingerprinting and discovered DRB7.1. This interaction, verified by reciprocal coimmunoprecipitation and bimolecular fluorescence complementation, colocalizes with markers of cytoplasmic siRNA bodies and nuclear dicing bodies. In vitro experiments using tobacco BY-2 cell lysate (BYL) revealed that the complex of DRB7.1/DRB4 impairs cleavage of diverse dsRNA substrates into 24-nucleotide (nt) small interfering (si) RNAs, an action performed by DCL3. DRB7.1 also negates the action of DRB4 in enhancing accumulation of 21-nt siRNAs produced by DCL4. Overexpression of DRB7.1 in Arabidopsis altered accumulation of siRNAs in a manner reminiscent of drb4 mutant plants, suggesting that DRB7.1 can antagonize the function of DRB4 in siRNA accumulation in vivo as well as in vitro. Specifically, enhanced accumulation of siRNAs from an endogenous inverted repeat correlated with enhanced DNA methylation, suggesting a biological impact for DRB7.1 in regulating epigenetic marks. We further demonstrate that RNase three-like (RTL) proteins RTL1 and RTL2 cleave dsRNA when expressed in BYL, and that this activity is impaired by DRB7.1/DRB4. Investigating the DRB7.1-DRB4 interaction thus revealed that a complex of DRB proteins can antagonize, rather than promote, RNase III activity and production of siRNAs in plants.


Variation in radiographic protocols in paediatric interventional cardiology.
The aim of this work is to determine current radiographic protocols in paediatric interventional cardiology (IC) in the UK and Ireland. To do this we investigated which imaging parameters/protocols are commonly used in IC in different hospitals, to identify if a standard technique is used and illustrate any variation in practice. A questionnaire was sent to all hospitals in the UK and Ireland which perform paediatric IC to obtain information on techniques used in each clinical department and on the range of clinical examinations performed. Ethical and research governance approval was sought from the Office for Research Ethics Committees Northern Ireland and the individual trusts. A response rate of 79% was achieved, and a wide variation in technique was found between hospitals. The main differences in technique involved variations in the use of an anti-scatter grid and the use of additional filtration to the radiation beam, frame rates for digital acquisition and pre-programmed projections/paediatric specific programming in the equipment. We conclude that there is no standard protocol for carrying out paediatric IC in the UK or Ireland. Each hospital carries out the IC procedure according to its own local protocols resulting in a wide variation in radiation dose.


XIV. Cerebral ischemia: the role of thrombosis and of antithrombotic therapy. Study group on antithrombotic therapy.
A revival of interest in antithrombotic agents for the treatment of ischemic cerebrovascular disease has resulted in the widespread use of oral anticoagulants for the prophylaxis and therapy of the ischemic variety of stroke, and has generated enthusiasm for the use of platelet-suppressant agents such as aspirin, dipyridamole, and sulfinpyrazone. In delineating the several clinical types of focal ischemic disease and outlining the causes of cerebral ischemia and infarction, the study group considers the problems of data interpretation in the face of inconsistent terminology. The basic mechanisms of hemostasis and thrombogenesis are concisely detailed. Finally, the study group critically reviews extensive earlier reports of clinical trials of anticoagulants, platelet function suppressants, and thrombolytic agents, and reassesses according to present-day statistical standards the significance of the results. The information contained in this report should familiarize the reader with sufficient data to permit him to utilize antithrombotic agents under a variety of circumstances and to appreciate the contraindications and potential dangers in their use.


Quantum Dots Embedded in Graphene Nanoribbons by Chemical Substitution.
Bottom-up chemical reactions of selected molecular precursors on a gold surface can produce high quality graphene nanoribbons (GNRs). Here, we report on the formation of quantum dots embedded in an armchair GNR by substitutional inclusion of pairs of boron atoms into the GNR backbone. The boron inclusion is achieved through the addition of a small amount of boron substituted precursors during the formation of pristine GNRs. In the pristine region between two boron pairs, the nanoribbons show a discretization of their valence band into confined modes compatible with a Fabry-Perot resonator. Transport simulations of the scattering properties of the boron pairs reveal that they selectively confine the first valence band of the pristine ribbon while allowing an efficient electron transmission of the second one. Such band-dependent electron scattering stems from the symmetry matching between the electronic wave functions of the states from the pristine nanoribbons and those localized at the boron pairs.


Online information and support for carers of people with young-onset dementia: A multi-site randomised controlled pilot study.
The European RHAPSODY project sought to develop and test an online information and support programme for caregivers of individuals diagnosed with young onset dementia. The objectives were to assess user acceptability and satisfaction with the programme and to test outcome measures for a larger effectiveness study. A pilot randomised controlled trial in England, France, and Germany was conducted with 61 caregivers for adults with young onset Alzheimer's disease or frontotemporal degeneration. Evaluations at baseline, week 6, and week 12 assessed user acceptability and satisfaction. Use of the programme was measured from online back-end data. Qualitative feedback on user experiences was collected via semi-structured interviews. Measures of caregiver well-being (self-efficacy, stress, burden, frequency of patient symptoms, and caregiver reactions) were explored for use in a subsequent trial. Participants logged in online on average once a week over a 6-week period, consulting approximately 31% of programme content. Seventy percent of participants described the programme as useful and easy to use. Eighty-five percent expressed intent to use the resource in the future. Reductions in reported levels of stress and caregivers' negative reactions to memory symptoms were observed following use of the programme. Results indicated that the RHAPSODY programme was acceptable and useful to caregivers. The programme may be complementary to existing services in responding to the specific needs of families affected by young onset dementia. Distribution of the programme is underway in England, France, Germany, and Portugal.


Choroideremia associated with choroidal neovascularization treated with intravitreal bevacizumab.
To report a rare case of central vision loss in a patient with choroideremia. A retrospective, interventional case report. A 13-year-old male with history of choroideremia presented with subacute loss of central acuity in his left eye. Examination and diagnostic testing revealed subretinal fibrosis secondary to a choroidal neovascular membrane (CNVM). A trial of anti-vascular endothelial growth factor (VEGF) therapy with the injection of intravitreal bevacizumab was attempted. Mild improvements in acuity and anatomy were noted. Choroideremia is a rare hereditary choroidal dystrophy that predominantly affects males in the first and second decades of life. Visual acuity is usually spared until later in life. CNVM is a rare manifestation of choroideremia with only a handful of case reports presented in the literature. This case is unique in that it is the first reported case that received treatment with intravitreal anti-VEGF therapy.


Effect of Genetic Variation in CYP450 on Gonadal Impairment in a European Cohort of Female Childhood Cancer Survivors, Based on a Candidate Gene Approach: Results from the PanCareLIFE Study.
Female childhood cancer survivors (CCSs) carry a risk of therapy-related gonadal dysfunction. Alkylating agents (AA) are well-established risk factors, yet inter-individual variability in ovarian function is observed. Polymorphisms in CYP450 enzymes may explain this variability in AA-induced ovarian damage. We aimed to evaluate associations between previously identified genetic polymorphisms in CYP450 enzymes and AA-related ovarian function among adult CCSs. Anti-Müllerian hormone (AMH) levels served as a proxy for ovarian function in a discovery cohort of adult female CCSs, from the pan-European PanCareLIFE cohort (n = 743; age (years): median 25.8, interquartile range (IQR) 22.1-30.6). Using two additive genetic models in linear and logistic regression, nine genetic variants in three CYP450 enzymes were analyzed in relation to cyclophosphamide equivalent dose (CED) score and their impact on AMH levels. The main model evaluated the effect of the variant on AMH and the interaction model evaluated the modifying effect of the variant on the impact of CED score on log-transformed AMH levels. Results were validated, and meta-analysis performed, using the USA-based St. Jude Lifetime Cohort (n = 391; age (years): median 31.3, IQR 26.6-37.4). CYP3A4*3 was significantly associated with AMH levels in the discovery and replication cohort. Meta-analysis revealed a significant main deleterious effect (Beta (95% CI): -0.706 (-1.11--0.298), p-value = 7 × 10-4) of CYP3A4*3 (rs4986910) on log-transformed AMH levels. CYP2B6*2 (rs8192709) showed a significant protective interaction effect (Beta (95% CI): 0.527 (0.126-0.928), p-value = 0.01) on log-transformed AMH levels in CCSs receiving more than 8000 mg/m2 CED. Female CCSs CYP3A4*3 carriers had significantly lower AMH levels, and CYP2B6*2 may have a protective effect on AMH levels. Identification of risk-contributing variants may improve individualized counselling regarding the treatment-related risk of infertility and fertility preservation options.


Implications of human performance and perception under tonal noise conditions on indoor noise criteria.
This research investigated differences in task performance and perception under six non-time-varying ventilation-type background noise spectra with differing tonality. The results were related to five indoor noise criteria systems: noise criteria, balanced noise criteria, room criteria, room criteria mark II, and the A-weighted equivalent sound pressure level (L(Aeq)). These criteria systems are commonly used in the U.S. building industry, but concerns exist over whether they are appropriate for all noise situations. Thirty test subjects completed three types of performance tasks (typing, reasoning, and math) and answered questions about their perception of the indoor environment under each noise condition. Results showed that performance scores did not change significantly across the six noise conditions, but there were differences in subjective perception. For example, perception trends for tonality, annoyance, and distraction changed based on the frequency and prominence of discrete tones in noise. However, these perceptual changes were not fully reflected in the criteria level or spectral quality ratings. Additionally, task performance was related to subjective perception but not to criteria level predictions. As a result, the authors suggest that the current criteria should be modified to account for the frequency and prominence of tones in background noise.


Effectiveness of Written and Oral Specialty Certification Examinations to Predict Actions against the Medical Licenses of Anesthesiologists.
The American Board of Anesthesiology administers written and oral examinations for its primary certification. This retrospective cohort study tested the hypothesis that the risk of a disciplinary action against a physician's medical license is lower in those who pass both examinations than those who pass only the written examination. Physicians who entered anesthesiology training from 1971 to 2011 were followed up to 2014. License actions were ascertained via the Disciplinary Action Notification Service of the Federation of State Medical Boards. The incidence rate of license actions was relatively stable over the study period, with approximately 2 to 3 new cases per 1,000 person-years. In multivariable models, the risk of license actions was higher in men (hazard ratio = 1.88 [95% CI, 1.66 to 2.13]) and lower in international medical graduates (hazard ratio = 0.73 [95% CI, 0.66 to 0.81]). Compared with those passing both examinations on the first attempt, those passing neither examination (hazard ratio = 3.60 [95% CI, 3.14 to 4.13]) and those passing only the written examination (hazard ratio = 3.51 [95% CI, 2.87 to 4.29]) had an increased risk of receiving an action from a state medical board. The risk was no different between the latter two groups (P = 0.81), showing that passing the oral but not the written primary certification examination is associated with a decreased risk of subsequent license actions. For those with residency performance information available, having at least one unsatisfactory training record independently increased the risk of license actions. These findings support the concept that an oral examination assesses domains important to physician performance that are not fully captured in a written examination.


Chlorella viruses isolated in China.
Plaque-forming viruses of the unicellular, eucaryotic, exsymbiotic, Chlorella-like green algae strain NC64A, which are common in the United States, were also present in fresh water collected in the People's Republic of China. Seven of the Chinese viruses were examined in detail and compared with the Chlorella viruses previously isolated in the United States. Like the American viruses, the Chinese viruses were large polyhedra and sensitive to chloroform. They contained numerous structural proteins and large double-stranded DNA genomes of at least 300 kilobase pairs. Each of the DNAs from the Chinese viruses contained 5-methyldeoxycytosine, which varied from 12.6 to 46.7% of the deoxycytosine, and N6-methyldeoxyadenosine, which varied from 2.2 to 28.3% of the deoxyadenosine. Four of the Chinese virus DNAs hybridized extensively with DNA from the American virus PBCV-1, and three hybridized poorly.


Periodontal treatment in severe aplastic anemia.
Aplastic anemia (AA) is a rare hematologic disease characterized by hypo-cellular bone marrow. The clinical features include fatigue, increased bruising, and gingival bleeding caused by anemia, leukopenia, and thrombocytopenia. A patient with AA is at high risk for infection because of leukopenia. The risk of systemic infection is especially high in AA patients with severe local infections, including periodontitis. Accordingly, periodontal treatment should include antibiotic prophylaxis to reduce the risk of systemic infection. However, treatment of periodontitis in the AA patient is significantly complicated by the bleeding disorder. We present a case report of the successful periodontal treatment of an AA patient with spontaneous gingival bleeding. The patient was closely monitored for platelet and neutrophil counts before every treatment. The patient's platelet count was always under 10,000/microl. Therefore, it was necessary to increase platelet counts to over 25,000/microl by transfusion, after which subgingival scaling with anesthesia was performed. When the neutrophil count was less than 2,000/microl, local minocycline chemotherapy was applied to the pockets. Periodontal infection was monitored by detection of bacterial DNA and measurement of serum immunoglobulin (Ig) G titer against periodontal bacteria. Following the physical and chemical treatment, the gingival appearance improved dramatically and the spontaneous gingival bleeding disappeared. Moreover, the IgG titer against periodontal bacteria decreased to normal range and specific periodontal pathogens were no longer detectable in the tested pockets. We believe that the treatment strategy in the present report provides new sight into treatment planning for severely medically compromised patients.


Mindfulness training modifies cognitive, affective, and physiological mechanisms implicated in alcohol dependence: results of a randomized controlled pilot trial.
Mindfulness training may disrupt the risk chain of stress-precipitated alcohol relapse. In 2008, 53 alcohol-dependent adults (mean age = 40.3) recruited from a therapeutic community located in the urban southeastern U.S. were randomized to mindfulness training or a support group. Most participants were male (79.2%), African American (60.4%), and earned less than $20,000 annually (52.8%). Self-report measures, psychophysiological cue-reactivity, and alcohol attentional bias were analyzed via repeated measures ANOVA. Thirty-seven participants completed the interventions. Mindfulness training significantly reduced stress and thought suppression, increased physiological recovery from alcohol cues, and modulated alcohol attentional bias. Hence, mindfulness training appears to target key mechanisms implicated in alcohol dependence, and therefore may hold promise as an alternative treatment for stress-precipitated relapse among vulnerable members of society.


Health-related quality of life in Swedish pediatric burn patients and associations with burn and family characteristics.
Although many children with burns recover well and have a satisfying quality of life after the burn, some children do not adjust as well. Health-related quality of life (HRQoL) focuses on the impact health status has on quality of life. The aim of this study was to assess HRQoL with the American Burn Association/Shriners Hospitals for Children Burn Outcomes Questionnaire (BOQ) in a nationwide Swedish sample of children with burns 0.3-9.0 years after injury. Participants were parents (n=109) of children aged up to 18 years at the time of investigation who were treated at the Linköping or Uppsala Burn Center between 2000 and 2008. The majority of children did not have limitations in physical function and they did not seem to experience much pain. However, there were indications of psychosocial problems. Parents of preschool children reported most problems with the children's behavior and family disruption, whereas parents of children aged 5-18 years reported most problems with appearance and emotional health. There were mainly burn-related variables associated with suboptimal HRQoL in children aged 5-18 years, while family-related variables did not contribute as much.


Management of chronic spine-related conditions: consensus recommendations of a multidisciplinary panel.
Chronic spine-related conditions are very problematic in terms of treatment and indemnity costs, diagnostic complexity, and appropriate case management. Currently no chiropractic-directed guideline exists related to chiropractic management of the chronic spine pain patient. The purpose of this project was to develop a broad-based multidisciplinary consensus of medical and chiropractic clinical experts representing mainstream medical and chiropractic practice to produce a document designed to provide standardized parameters of care and documentation. Background materials were provided to the panelists prior to the consensus process and served as the basis for the 29 seed statements. Delphi rounds were conducted electronically, and the Nominal Group Panel was conducted via conference call. The RAND/UCLA methodology was used to reach consensus, which was considered present if both the median rating was 7 or higher and at least 80% of panelists rated the statement 7 or higher. Consensus was reached through a combination of Delphi rounds and Nominal Group Panel. Of 29 panelists, 5 were non-doctors of chiropractic. Specific recommendations regarding treatment, frequency and duration, as well as outcome assessment and contraindications for manipulation, were agreed upon by the panel. A multidisciplinary panel of experienced practitioners was able to reach a high level (80%) of consensus regarding specific aspects of the chiropractic approach to care for complex patients with chronic spine-related conditions, based on both the scientific evidence and their clinical experience.


The antimicrobial potential of cannabidiol.
Antimicrobial resistance threatens the viability of modern medicine, which is largely dependent on the successful prevention and treatment of bacterial infections. Unfortunately, there are few new therapeutics in the clinical pipeline, particularly for Gram-negative bacteria. We now present a detailed evaluation of the antimicrobial activity of cannabidiol, the main non-psychoactive component of cannabis. We confirm previous reports of Gram-positive activity and expand the breadth of pathogens tested, including highly resistant Staphylococcus aureus, Streptococcus pneumoniae, and Clostridioides difficile. Our results demonstrate that cannabidiol has excellent activity against biofilms, little propensity to induce resistance, and topical in vivo efficacy. Multiple mode-of-action studies point to membrane disruption as cannabidiol's primary mechanism. More importantly, we now report for the first time that cannabidiol can selectively kill a subset of Gram-negative bacteria that includes the 'urgent threat' pathogen Neisseria gonorrhoeae. Structure-activity relationship studies demonstrate the potential to advance cannabidiol analogs as a much-needed new class of antibiotics.


Parametric Oscillation, Frequency Mixing, and Injection Locking of Strongly Coupled Nanomechanical Resonator Modes.
We study locking phenomena of two strongly coupled, high quality factor nanomechanical resonator modes to a common parametric drive at a single drive frequency in different parametric driving regimes. By controlled dielectric gradient forces we tune the resonance frequencies of the flexural in-plane and out-of-plane oscillation of the high stress silicon nitride string through their mutual avoided crossing. For the case of the strong common parametric drive signal-idler generation via nondegenerate parametric two-mode oscillation is observed. Broadband frequency tuning of the very narrow linewidth signal and idler resonances is demonstrated. When the resonance frequencies of the signal and idler get closer to each other, partial injection locking, injection pulling, and complete injection locking to half of the drive frequency occurs depending on the pump strength. Furthermore, satellite resonances, symmetrically offset from the signal and idler by their beat note, are observed, which can be attributed to degenerate four-wave mixing in the highly nonlinear mechanical oscillations.


NLRC3 is an inhibitory sensor of PI3K-mTOR pathways in cancer.
NLRs (nucleotide-binding domain and leucine-rich repeats) belong to a large family of cytoplasmic sensors that regulate an extraordinarily diverse range of biological functions. One of these functions is to contribute to immunity against infectious diseases, but dysregulation of their functional activity leads to the development of inflammatory and autoimmune diseases. Cytoplasmic innate immune sensors, including NLRs, are central regulators of intestinal homeostasis. NLRC3 (also known as CLR16.2 or NOD3) is a poorly characterized member of the NLR family and was identified in a genomic screen for genes encoding proteins bearing leucine-rich repeats (LRRs) and nucleotide-binding domains. Expression of NLRC3 is drastically reduced in the tumour tissue of patients with colorectal cancer compared to healthy tissues, highlighting an undefined potential function for this sensor in the development of cancer. Here we show that mice lacking NLRC3 are hyper-susceptible to colitis and colorectal tumorigenesis. The effect of NLRC3 is most dominant in enterocytes, in which it suppresses activation of the mTOR signalling pathways and inhibits cellular proliferation and stem-cell-derived organoid formation. NLRC3 associates with PI3Ks and blocks activation of the PI3K-dependent kinase AKT following binding of growth factor receptors or Toll-like receptor 4. These findings reveal a key role for NLRC3 as an inhibitor of the mTOR pathways, mediating protection against colorectal cancer.


Clinical Approach to Supranuclear Brainstem Saccadic Gaze Palsies.
Failure of brainstem supranuclear centers for saccadic eye movements results in the clinical presence of a brainstem-mediated supranuclear saccadic gaze palsy (SGP), which is manifested as slowing of saccades with or without range of motion limitation of eye movements and as loss of quick phases of optokinetic nystagmus. Limitation in the range of motion of eye movements is typically worse with saccades than with smooth pursuit and is overcome with vestibular-ocular reflexive eye movements. The differential diagnosis of SGPs is broad, although acute-onset SGP is most often from brainstem infarction and chronic vertical SGP is most commonly caused by the neurodegenerative condition progressive supranuclear palsy. In this review, we discuss the brainstem anatomy and physiology of the brainstem saccade-generating network; we discuss the clinical features of SGPs, with an emphasis on insights from quantitative ocular motor recordings; and we consider the broad differential diagnosis of SGPs.


Sherlock 3CG(®) Tip Confirmation System for Placement of Peripherally Inserted Central Catheters: A NICE Medical Technology Guidance.
In current clinical practice, peripherally inserted central catheters (PICCs) are typically inserted using external anatomical measurements and a confirmatory chest X-ray, or using fluoroscopy. The Sherlock 3CG(®) Tip Confirmation System (TCS) allows magnetic tracking of the PICC tip during insertion and confirmation of the final location using ECG, meaning that most patients will not require a chest X-ray or fluoroscopy. The Sherlock 3CG(®) TCS was evaluated in 2014 by the UK National Institute for Health and Care Excellence (NICE) as part of the Medical Technologies Evaluation Programme. The company (C.R. Bard Ltd) identified four abstracts, one paper pending publication and questionnaire data from NHS users of the Sherlock 3CG(®) TCS. None of the evidence included a comparator arm. Placement accuracy of PICCs using the Sherlock 3CG(®) TCS where a chest X-ray was also used ranged from 79.5 to 100 %. The company reported that 9 out of 16 NHS centres that used the Sherlock 3CG(®) TCS were no longer using chest X-rays to routinely confirm PICC tip location. The evidence did not report the need for catheter repositioning, re-insertion, staff time savings, treatment delays, length of stay, quality of life outcomes or complications. The company's model found that the Sherlock 3CG(®) TCS was cost saving by GBP25.67 per patient compared to blind bedside PICC insertion. The External Assessment Centre (EAC) adapted the company's model to test alternative assumptions for nurse time, theatre cost, malposition rate and reinsertion method, and found that the Sherlock 3CG(®) TCS was cost incurring by GBP9.37 per patient compared to blind bedside PICC insertion. The use of the Sherlock 3CG(®) TCS in the UK NHS compared to blind PICC insertion using a confirmatory chest X-ray appears to hover around being cost neutral. Staff time and accuracy were key drivers in the model: evidence for these is sparse and the reality will vary in different situations. If evidence became available for outcomes after the initial insertion, such as replacement, complications and adverse events, the cost implications may change. The direction of this potential change is not known. NICE published guidance MTG24 in March 2015 recommending that the case for adoption of Sherlock 3CG(®) TCS was supported by the evidence.


Clinical impact of inflammation in dry eye disease: proceedings of the ODISSEY group meeting.
Dry eye disease (DED) is a common, multifactorial ocular condition with major impact on vision and quality of life. It is now well recognized that the pathophysiology of chronic DED can include a cycle of inflammation involving both innate and adaptive immune responses. Recently, in vitro/in vivo models have been used to obtain a better understanding of DED-related inflammatory processes at molecular/cellular levels although they do not truly reproduce the complex and chronic hallmarks of human DED. In clinical DED research, advanced techniques such as impression cytology, conjunctival biopsy, in vivo confocal microscopy and multiplex tear analyses have allowed an improved assessment of inflammation in DED patients. This was supported by the identification of reliable inflammatory markers including matrix metalloproteinase-9, human leucocyte antigen-DR or intercellular adhesion molecule-1 in tears and impression cytology samples. One of the current therapeutic strategies focuses on breaking the inflammatory cycle perpetuating the ocular surface disease, and preclinical/clinical research has led to the development of promising anti-inflammatory compounds. For instance, cyclosporine, already approved in the United States, has recently been authorized in Europe to treat DED associated with severe keratitis. In addition, other agents such as corticosteroids, doxycycline and essential fatty acids, through their anti-inflammatory properties, show encouraging results. We now have a clearer understanding of the inflammatory processes involved in DED, and there is hope that the still emerging preclinical/clinical findings will be translated into new and highly effective therapies for patients in the near future.


Glucuronidation of 2-arylpropionic acids pirprofen, flurbiprofen, and ibuprofen by liver microsomes.
Acylglucuronide formation from the 2-arylpropionic acids pirprofen, flurbiprofen, and ibuprofen, three nonsteroidal anti-inflammatory drugs (NSAIDs), was investigated in rat liver microsomes using an HPLC method and 14C-labeled UDP-glucuronic acid as co-substrate. Pirprofen was the best substrate of UDP-glucuronosyltransferase with a Vmax/Km of 45.4, as compared with 8.0 and 1.6 for flurbiprofen and ibuprofen, respectively. Glucuronidation of the drugs was significantly increased upon treatment of rats with phenobarbital; 3-methylcholanthrene or clofibrate failed to induce the activity. At the dose of 100 mg/kg body weight for 1, 3, and 5 days, pirprofen was unable to induce its own glucuronidation. However, this treatment caused a transient increase, after 1 day, of several isoform activities monitored with 4-nitrophenol, 1-naphthol, 4-methylumbelliferone, terpenes, and testosterone as substrates. After 3 and 5 days these activities were decreased, especially when glucuronidation of 4-nitrophenol and 4-methylumbelliferone was considered, glucuronidation of the terpenes cis-myrtanol, borneol, nopol, and of testosterone being similar to control values. By contrast to clofibrate, administration of pirprofen to rats decreased bilirubin UDP-glucuronosyltransferase in a time-dependent fashion with a maximal decrease of 59% after 5 days. Treatment of rats with pirprofen also decreased markedly the formation of flurbiprofen glucuronide. Comparison of NSAID glucuronidation between several species indicated that it was most potent in monkeys, dogs, and humans. Cats were also efficient in that respect. Gunn rats, which are genetically deficient in bilirubin glucuronidation, were able to form acylglucuronides from the drugs, thus indicating that these 2-arylpropionic acids were not substrates of the bilirubin isozyme.


Cancer biomarkers in human atherosclerotic lesions: detection of DNA adducts.
Since somatic mutations are suspected to contribute to the pathogenesis not only of cancer but also of atherosclerotic plaques, we measured DNA adducts in the smooth muscle layer of atherosclerotic lesions in abdominal aorta specimens taken at surgery from seven patients. DNA adducts were evaluated in three laboratories by means of different molecular dosimetry methods, including: (a) HPLC/fluorescence, which specifically identifies the DNA adducts of the anti-benzo(a)pyrene (BPDE) isomer; (b) two- and three-dimensional synchronous fluorescence spectrophotometries, which detect DNA adducts of BPDE and other reactive metabolites of polycyclic aromatic hydrocarbons; and (c) 32P postlabeling, which reveals the presence of a variety of types of DNA adducts. The HPLC/fluorescence method provided for the first time evidence for the presence of BPDE-DNA specific adducts in three of six specimens tested. Synchronous fluorescence spectrophotometry displayed broad areas of fluorescence in all seven specimens, thereby suggesting the occurrence not only of BDPE-DNA but also of other DNA adducts with similar fluorescence characteristics. All specimens were also positive at 32P postlabeling, which revealed multiple spots detectable following enrichment either with nuclease P1 or butanol, indicative of the presence of different aromatic DNA adducts. Thus, the data obtained by applying typical cancer biomarkers provide further support to the hypothesis that there may be similarities between the carcinogenic and the atherogenic processes, and in particular that genetic alterations caused by DNA-binding agents in the artery wall may be detected in atherosclerotic lesions.


Towards a complete physically based forecast model for underwater noise related to impact pile driving.
An approach for the prediction of underwater noise caused by impact pile driving is described and validated based on in situ measurements. The model is divided into three sub-models. The first sub-model, based on the finite element method, is used to describe the vibration of the pile and the resulting acoustic radiation into the surrounding water and soil column. The mechanical excitation of the pile by the piling hammer is estimated by the second sub-model using an analytical approach which takes the large vertical dimension of the ram into account. The third sub-model is based on the split-step Padé solution of the parabolic equation and targets the long-range propagation up to 20 km. In order to presume realistic environmental properties for the validation, a geoacoustic model is derived from spatially averaged geological information about the investigation area. Although it can be concluded from the validation that the model and the underlying assumptions are appropriate, there are some deviations between modeled and measured results. Possible explanations for the observed errors are discussed.


Simple group fMRI modeling and inference.
While many advanced mixed-effects models have been proposed and are used in fMRI, the simplest, ordinary least squares (OLS), is still the one that is most widely used. A survey of 90 papers found that 92% of group fMRI analyses used OLS. Despite the widespread use, this simple approach has never been thoroughly justified and evaluated; for example, the typical reference for the method is a conference abstract, (Holmes, A., Friston, K., 1998. Generalisability, random effects & population inference. NeuroImage 7 (4 (2/3)), S754, proceedings of Fourth International Conference on Functional Mapping of the Human Brain, June 7-12, 1998, Montreal, Canada.), which has been referenced over 400 times. In this work we fully derive the simplified method in a general setting and carefully identify the homogeneity assumptions it is based on. We examine the specificity (Type I error rate) of the OLS method under heterogeneity in the one-sample case and find that the OLS method is valid, with only slight conservativeness. Surprisingly, a Satterthwaite approximation for effective degrees of freedom only makes the method more conservative, instead of more accurate. While other authors have highlighted the inferior power of the OLS method relative to optimal mixed-effects methods under heterogeneity, we revisit these results and find the power differences very modest. While statistical methods that make the best use of the data are always to be preferred, software or other practical concerns may require the use of the simple OLS group modeling. In such cases, we find that group mean inferences will be valid under the null hypothesis and will have nearly optimal sensitivity under the alternative.


Epidemiology, risk factors, and clinical outcomes in severe microbial keratitis in South India.
Here, we report risk factors associated with outcome in severe bacterial keratitis (BK), fungal keratitis (FK), and Acanthamoeba keratitis (AK) in India. Prospective observational cohort study conducted in Aravind Eye Hospital, India. Adults presenting with severe microbial keratitis (MK) were enrolled (size ≥3 mm) and followed to 21 days post-enrolment. Ulcer clinical features were recorded at presentation. Outcomes by final visit were classified as good (completely healed or reduced infiltrate size) or poor (enlarged infiltrate size, perforated, or surgery performed). Of 252 participants with severe MK, 191 had FK, 18 had AK, 19 had BK, 4 had mixed BK/FK, and 20 were microbiologically negative. Median age was 50 years (interquartile range [IQR]: 37-60 years), 64% were male, 63% were agriculturalists, and 45% had no formal education. Corneal trauma occurred in 72%, and median symptom duration before presentation was 7 days (IQR: 5-15 days). Clinical features associated with FK were feathery margins (p < 0.001), raised profile (p = 0.039), or dry surface (p = 0.007). Hypopyon was more likely in BK (p = 0.001) and ring infiltrate in AK (p < 0.001). Ulcers with poor outcome (n = 106/214) were more likely to be larger (odds ratio [OR]: 1.63, 95% confidence interval [CI]: 1.30-2.05, p < 0.001), involve the posterior cornea at presentation (OR: 2.31, 95% CI: 1.16-4.59, p = 0.017), involve Aspergillus sp. (OR: 3.23, 95% CI: 1.26-8.25, p = 0.014), or occur in females (OR: 2.04, 95% CI: 1.03-4.04, p = 0.04). Even after treatment, 34% (n = 76/221) had severe visual impairment by the final visit. Severe MK occurred predominantly in agriculturalists post-corneal trauma and often had poor outcomes. Provision of community-based eyecare may allow earlier treatment and improve outcomes.


Multiple Sclerosis Mortality by Race/Ethnicity, Age, Sex, and Time Period in the United States, 1999-2015.
Multiple sclerosis (MS) carries high morbidity and shortens life span. While there is recent recognition of other US minority populations such as blacks and Hispanics being affected with MS, examination of MS-specific mortality trends by race/ethnicity has been lacking. To investigate MS mortality rates and trends in the United States by sex, age, and race/ethnicity. We used the Compressed Mortality data file for 1999-2015 in the Wide-ranging online Data for Epidemiological Research system developed by the Center for Disease Control and Prevention to calculate the age-adjusted (US 2000 standard population) and age-specific MS mortality rate (per 100,000) by race/ethnicity and sex over time. Five mutually exclusive racial/ethnic groups were included in the analysis: non-Hispanic (NH) white, NH black, NH Asian or Pacific Islander (API), NH American Indian or Alaska Native, and Hispanic. The average annual age-adjusted MS mortality rate was highest among NH whites (0.90 for males and 1.50 for females) immediately followed by NH blacks (0.75 for males and 1.42 for females), and lowest among APIs (0.05 for males and 0.12 for females). Statistically significant, increasing trend in age-adjusted MS mortality was observed during 1999-2015 among NH whites and NH blacks regardless of sex, more substantially in the latter. Age-specific MS mortality patterns showed NH blacks had the highest rate under age 55 and NH whites had the highest rate after that age point. For these 2 groups, MS mortality increased with age in both sexes and peaked at ages 55-64 for NH blacks and 65-74 for NH whites before declining substantially, while for Hispanic and API groups the risk plateaued after age 55. MS-specific mortality trends demonstrate distinctive differences by race/ethnicity and age. The observations that whites and females are more likely to die from MS is in line with the overall understanding that these groups are affected more by MS. However, the findings of blacks dying at an earlier age and having more substantially increasing mortality trends than whites suggest that MS burden weighs unequally by race. Further investigation into these trends may provide additional evidence into risk or protective factors within each group.


Inherent amplitude demodulation of an AC-EWOD (electrowetting on dielectric) droplet.
Recently, it has been shown that amplitude modulation (AM) in a wireless EWOD (electrowetting on dielectric) via magnetic induction facilitates the transmission of a low frequency message signal and then the oscillation of droplets at a low frequency. This process requires demodulation to recover the message signal from the high-frequency AM signal. As a key contribution, this paper theoretically and experimentally shows that the EWOD-actuated droplet has the inherent functionality of demodulation. That is, the EWOD droplet itself demodulates a supplied AM driving voltage, and as a result the contact angle of the droplet directly follows the message signal without any artificial demodulation circuit. A theoretical explanation of this inherent demodulation property is developed using a time-varying Lippmann-Young (LY) equation. In addition, experimental results are presented to substantiate the inherent demodulation functionality of an EWOD droplet.


Types of tobacco consumption and the oral microbiome in the United Arab Emirates Healthy Future (UAEHFS) Pilot Study.
Cigarette smoking alters the oral microbiome; however, the effect of alternative tobacco products remains unclear. Middle Eastern tobacco products like dokha and shisha, are becoming globally widespread. We tested for the first time in a Middle Eastern population the hypothesis that different tobacco products impact the oral microbiome. The oral microbiome of 330 subjects from the United Arab Emirates Healthy Future Study was assessed by amplifying the bacterial 16S rRNA gene from mouthwash samples. Tobacco consumption was assessed using a structured questionnaire and further validated by urine cotinine levels. Oral microbiome overall structure and specific taxon abundances were compared, using PERMANOVA and DESeq analyses respectively. Our results show that overall microbial composition differs between smokers and nonsmokers (p = 0.0001). Use of cigarettes (p = 0.001) and dokha (p = 0.042) were associated with overall microbiome structure, while shisha use was not (p = 0.62). The abundance of multiple genera were significantly altered (enriched/depleted) in cigarette smokers; however, only Actinobacillus, Porphyromonas, Lautropia and Bifidobacterium abundances were significantly changed in dokha users whereas no genera were significantly altered in shisha smokers. For the first time, we show that smoking dokha is associated to oral microbiome dysbiosis, suggesting that it could have similar effects as smoking cigarettes on oral health.


Photorelaxation of imidazole and adenine via electron-driven proton transfer along H2O wires.
Photochemically created πσ* states were classified among the most prominent factors determining the ultrafast radiationless deactivation and photostability of many biomolecular building blocks. In the past two decades, the gas phase photochemistry of πσ* excitations was extensively investigated and was attributed to N-H and O-H bond fission processes. However, complete understanding of the complex photorelaxation pathways of πσ* states in the aqueous environment was very challenging, owing to the direct participation of solvent molecules in the excited-state deactivation. Here, we present non-adiabatic molecular dynamics simulations and potential energy surface calculations of the photoexcited imidazole-(H2O)5 cluster using the algebraic diagrammatic construction method to the second-order [ADC(2)]. We show that electron driven proton transfer (EDPT) along a wire of at least two water molecules may lead to the formation of a πσ*/S0 state crossing, similarly to what we suggested for 2-aminooxazole. We expand on our previous findings by direct comparison of the imidazole-(H2O)5 cluster to non-adiabatic molecular dynamics simulations of imidazole in the gas phase, which reveal that the presence of water molecules extends the overall excited-state lifetime of the chromophore. To embed the results in a biological context, we provide calculations of potential energy surface cuts for the analogous photorelaxation mechanism present in adenine, which contains an imidazole ring in its structure.


Off-pump versus on-pump coronary artery bypass procedures:postoperative renal complications in an Asian population.
Diabetes and habitual smoking cause advanced coronary artery disease (CAD) in Asian patients at a younger age. No definite data exist as to whether off-pump (OPCAB) is better than conventional on-pump coronary artery bypass grafting (CCAB) in terms of postoperative renal complications. Thus, we aimed to compare the renal outcomes of on-pump and off-pump coronary artery bypass grafting (CABG) on our patients, which constituted a predominantly Asian population. A cohort of 395 patients following CCAB were compared with 293 patients who underwent OPCAB. Baseline demographics, comorbidities, intraoperative data, intensive care unit stay, number of grafts, New York Heart Association (NYHA) score, American Society of Anesthesiologists (ASA) score, EuroSCORE risk assessment model, and postoperative complications particularly renal, were collected and analysed. The off-pump group consisted of significantly older patients with higher Canadian Cardiovascular Society (CCS) and ASA scores. Additionally, the off-pump group involved a significantly greater number of smokers and chronic obstructive pulmonary disease (COPD) patients. Other demographic parameters were not different between the groups. Postoperative investigations showed a significantly elevated serum creatinine (100.3 +/- 42.5 vs 127.6 +/- 114.2 micromol/L; off-pump vs on-pump; P = 0.039) and urea levels (5.9 +/- 3.1 vs 10.6 +/- 15.6 mg/dL; off-pump vs on-pump; P = 0.006) in the on-pump group. Moreover, there was a high tendency towards a higher rate of renal dysfunction associated death in this group. OPCAB is a safe and equally efficient operative method compared to CCAB, and has a significant lower risk for postoperative renal complications as a treatment modality for surgical coronary revascularisation.


Childhood cancer in developing countries.
The problem of childhood cancer cannot be evaluated separately from developmental levels and states of health of the countries. Rapid increase in population, poverty, poor hygiene, lack of education, and multitude health problems impede the development of pediatric oncology and success of the management of childhood cancer in developing countries. More than 85% pediatric cancer cases occur in developing countries that use less than 5% of world resources. The rate will exceed 90% in the next two decades, due to the increase of youth population in favor of developing countries. Incidence rates, pathology, and clinical characteristics of various cancers seem different in developing and developed countries. Different environments, life styles, dietary habits, and hygienic conditions are the main reasons for those differences. Unprecedented changes in diagnostic techniques, treatment methods and supportive care have occurred during the last decades. Consequently, management has improved and the mortality rates have decreased. Most of the children with cancer living in developing countries could not profit from those advances in pediatric oncology because of the cost.


Free-space to single-mode collection efficiency enhancement using photonic lanterns.
We demonstrate single-mode collection efficiency enhancement for free space optical systems using a photonic lantern to collect scattered infrared light from diffuse objects at far- and near-field distances. A single-mode collection efficiency improvement of ∼8 dB is demonstrated in the near-field region relative to standard single-mode fiber. The insertion loss properties of the photonic lantern are also analyzed, and an additional insertion loss penalty is observed for near-field distances when the transmitted beam is collimated. The photonic lantern can be used for coherent detection systems such as light detection and ranging and free-space optical communication with improved collection efficiency and nearly perfect mode matching.


The microbial abundance dynamics of the paediatric oral cavity before and after sleep.
Objective: Microhabitats in the oral cavity differ in microbial taxonomy. However, abundance variations of bacterial and viral communities within these microhabitats are not fully understood. Aims and Hypothesis: To assess the spatial distribution and dynamics of the microbial abundances within 6 microhabitats of the oral cavity before and after sleep. We hypothesise that the abundance distributions of these microbial communities will differ among oral sites. Methods: Using flow cytometry, bacterial and virus-like particle (VLP) abundances were enumerated for 6 oral microhabitats before and after sleep in 10 healthy paediatric sleepers. Results: Bacterial counts ranged from 7.2 ± 2.8 × 105 at the palate before sleep to 1.3 ± 0.2 × 108 at the back of the tongue after sleep, a difference of 187 times. VLPs ranged from 1.9 ± 1.0 × 106 at the palate before sleep to 9.2 ± 5.0 × 107 at the back of the tongue after sleep, a difference of 48 times. Conclusion: The oral cavity is a dynamic numerically heterogeneous environment where microbial communities can increase by a count of 100 million during sleep. Quantification of the paediatric oral microbiome complements taxonomic diversity information to show how biomass varies and shifts in space and time.


A Review of Nutritional Requirements of Adults Aged ≥65 Years in the UK.
Appropriate dietary choices in later life may reduce the risk of chronic diseases and rate of functional decline, however, there is little well-evidenced age-specific nutritional guidance in the UK for older adults, making it challenging to provide nutritional advice. Therefore, the aim of this critical review was to propose evidence-based nutritional recommendations for older adults (aged ≥65 y). Nutrients with important physiological functions in older adults were selected for inclusion in the recommendations. For these nutrients: 1) recommendations from the UK Scientific Advisory Committee for Nutrition (SACN) reports were reviewed and guidance retained if recent and age-specific, and 2) a literature search conducted where SACN guidance was not sufficient to set or confirm recommendations for older adults, searching Web of Science up to March 2020. Data extracted from a total of 190 selected publications provided evidence to support age-specific UK recommendations for protein (1.2 g·kg-1·d-1), calcium (1000 mg·d-1), folate (400 μg·d-1), vitamin B-12 (2.4 μg·d-1), and fluid (1.6 L·d-1 women, 2.0 L·d-1 men) for those ≥65 y. UK recommendations for carbohydrates, free sugars, dietary fiber, dietary fat and fatty acids, sodium, and alcohol for the general population are likely appropriate for older adults. Insufficient evidence was identified to confirm or change recommendations for all other selected nutrients. In general, significant gaps in current nutritional research among older adults existed, which should be addressed to support delivery of tailored nutritional guidance to this age group to promote healthy aging.


Epilepsy, headache, and abdominal pain after shunt surgery for idiopathic normal pressure hydrocephalus: the INPH-CRasH study.
OBJECTIVE Adverse events related to shunt surgery are common and might have a negative effect on outcome in patients with idiopathic normal pressure hydrocephalus (INPH). The authors' objectives were to establish the frequencies of epilepsy, headache, and abdominal pain and determine their impact on patient quality of life (QOL), in long-term follow-up after shunt surgery for INPH. METHODS One hundred seventy-six shunt-treated patients with INPH (mean age 74 years) and 368 age- and sex-matched controls from the population were included. The mean follow-up time after surgery was 21 months (range 6-45 months). Each participant answered a questionnaire regarding present frequency and severity of headache and abdominal pain. Confirmed diagnoses of epilepsy and all prescriptions for antiepileptic drugs (AEDs) before and after shunt surgery for INPH were gathered from national registries. Equivalent presurgical and postsurgical time periods were constructed for the controls based on the date of surgery (the division date for controls is referred to as virtual surgery). All registry data covered a mean period of 6 years (range 3-8 years) before surgery/virtual surgery and 4 years (range 2-6 years) after surgery/virtual surgery. Provoked epileptic seizures were excluded. Patient QOL was assessed with the EuroQoL 5-dimension 5-level instrument. RESULTS Epilepsy was more common in shunt-treated patients with INPH than in controls (4.5% vs 1.1%, respectively; p = 0.023), as was treatment with AEDs (14.8% vs 7.3%, respectively; p = 0.010). No difference was found between the populations before surgery/virtual surgery (epilepsy, 2.3% [INPH] vs 1.1% [control], p = 0.280; AED treatment, 8.5% [INPH] vs 5.4% [control], p = 0.235). New-onset epilepsy and new AED treatment after surgery/virtual surgery were more common in INPH (epilepsy, 2.3% [INPH] vs 0.0% [control], p = 0.011; AED, 8.5% [INPH] vs 3.3% [control], p = 0.015). At follow-up, more patients with INPH than controls experienced headache several times per month or more often (36.1% vs 11.6%, respectively; p < 0.001). Patients with INPH and unilateral headache had more right-sided headaches than controls (p = 0.038). Postural headache was experienced by 16% (n = 27 of 169) of the patients with INPH. Twenty percent (n = 35) of the patients with INPH had persistent abdominal pain. Headache was not correlated to lower QOL. The study was underpowered to draw conclusions regarding QOL in patients with INPH who had epilepsy and abdominal pain, but the finding of no net difference in mean QOL indicates that no correlation between them existed. CONCLUSIONS Epilepsy, headache, and abdominal pain are common in long-term follow-up in patients after shunt surgery for INPH and are more common among patients with INPH than in the general population. All adverse events, including mild and moderate ones, should be considered during postoperative follow-ups and in the development of new methods for shunt placement.


Ascertainment of congenital malformations: a comparative study of two systems.
The aim was to compare the Office of Population Censuses and Surveys (OPCS) notification system for congenital malformation surveillance and the Liverpool Congenital Malformations Registry (LCMR) with respect to efficiency and uniformity of ascertainment, diagnostic accuracy, and overreporting of minor malformations. Manual matching of computer listings was done, using date of birth, sex, birthweight, and health district of residence. Maternal age was used to confirm the match. Data were collected in the English health districts of Liverpool, St Helens and Knowsley, Southport and Formby, South Sefton, and Wirral over the years 1980-1985. 1959 malformed children notified to OPCS and 2649 notified to LCMR were assessed. 35.5% of malformed children ascertained by LCMR within seven days of birth were not notified to OPCS; 35.7% of cases reported to OPCS were exclusions from the LCMR protocol as being trivial malformations according to EUROCAT (European Registry of Congenital Anomalies) guidelines. Misclassification was infrequent but in 11.2% of cases the additional malformations present were not notified to OPCS. Conditions readily diagnosed at birth, such as neural tube defects, exomphalos, and facial clefts, were well ascertained by OPCS but others such as oesophageal atresia and Down's syndrome were not. It is important that national surveillance of congenital malformations should continue. However, several modifications to the present OPCS monitoring system are necessary, including greater standardisation of data collection, the exclusion of trivial and clinically non-significant malformations, and the inclusion of data on therapeutic abortions performed for fetal abnormality. These issues are being addressed by OPCS.


Adsorbed poly(ethyleneoxide)-poly(propyleneoxide) copolymers on synthetic surfaces: spectroscopy and microscopy of polymer structures and effects on adhesion of skin-borne bacteria.
Poly(ethyleneoxide)-copoly(propyleneoxide) (PEO-PPO) polymer coatings were evaluated for their resistance to the attachment of the marker organism Serratia marcescens and the skin-borne bacteria Staphylococcus epidermidis. The copolymers were adsorbed onto poly(styrene) films-chosen as simplified physicochemical models of skin surfaces-and their surface characteristics probed by contact angle goniometry, attenuated total reflectance-Fourier transform infrared (ATR-FTIR), atomic force microscopy (AFM), and X-ray photoelectron spectroscopy (XPS). These functional surfaces were then presented to microbial cultures, bacterial attachment was assessed by fluorescence microscopy and AFM, and the structures of the polymer films examined again spectroscopically. Surface characterization data suggest that the adsorbed copolymer was partially retained at the surface and resisted bacterial attachment for 24 h. Quantitative evaluation of cell attachment was carried out by scintillation counting of (14)C-labeled microorganisms in conjunction with plate counts. The results show that a densely packed layer of PEO-PPO copolymer can reduce attachment of skin commensals by an order of magnitude, even when the coating is applied by a simple adsorptive process. The work supports the hypothesis that adhesion of microorganisms to biological substrates can be reduced if a pretreatment with an appropriate copolymer can be effected in vivo.