Investigating clinical heterogeneity in systematic reviews: a methodologic review of guidance in the literature.
While there is some consensus on methods for investigating statistical and methodological heterogeneity, little attention has been paid to clinical aspects of heterogeneity. The objective of this study is to summarize and collate suggested methods for investigating clinical heterogeneity in systematic reviews. We searched databases (Medline, EMBASE, CINAHL, Cochrane Library, and CONSORT, to December 2010) and reference lists and contacted experts to identify resources providing suggestions for investigating clinical heterogeneity between controlled clinical trials included in systematic reviews. We extracted recommendations, assessed resources for risk of bias, and collated the recommendations. One hundred and one resources were collected, including narrative reviews, methodological reviews, statistical methods papers, and textbooks. These resources generally had a low risk of bias, but there was minimal consensus among them. Resources suggested that planned investigations of clinical heterogeneity should be made explicit in the protocol of the review; clinical experts should be included on the review team; a set of clinical covariates should be chosen considering variables from the participant level, intervention level, outcome level, research setting, or others unique to the research question; covariates should have a clear scientific rationale; there should be a sufficient number of trials per covariate; and results of any such investigations should be interpreted with caution. Though the consensus was minimal, there were many recommendations in the literature for investigating clinical heterogeneity in systematic reviews. Formal recommendations for investigating clinical heterogeneity in systematic reviews of controlled trials are required.


Five Misconceptions Related to Punctal Plugs in Dry Eye Management.
Punctal plugs are an effective treatment option for patients with aqueous-deficient dry eye refractory to topical medications. However, punctal plugs are not commonly used in clinical practice mainly because of various misconceptions, rather than clinical complications. We analyzed previous studies and present 5 misconceptions related to punctal plugs. The first and most important misconception is that ocular surface inflammation should be sufficiently controlled before punctal plug insertion. However, it is unclear how ocular surface inflammation can be sufficiently controlled in patients refractory to conventional topical medications. The second misconception is that silicone punctal plugs are made of nonabsorbable materials and, therefore, permanent. In fact, silicone plugs are reversible and can be easily removed if necessary. Therefore, depending on the specific type, nonabsorbable plugs may be classified as reversible or permanent. The third misconception is that punctal plugs disrupt normal tear drainage. However, punctal plugs maintain natural tears on the ocular surface for extended periods and reduce the frequency of artificial tear use. The fourth is that all punctal and canalicular plugs have similar effects. The efficacy and complication rates differ depending on plug types. The fifth misconception about punctal plugs is that they are effective only in aqueous-deficient dry eye disease. Many studies have reported that plugs are effective in a variety of ocular diseases and conditions. Understanding these 5 misconceptions may provide an opportunity to rethink the use of silicone punctal plugs in clinical practice.


Cell shape dynamics reveal balance of elasticity and contractility in peripheral arcs.
The mechanical interaction between adherent cells and their substrate relies on the formation of adhesion sites and on the stabilization of contractile acto-myosin bundles, or stress fibers. The shape of the cell and the orientation of these fibers can be controlled by adhesive patterning. On nonadhesive gaps, fibroblasts develop thick peripheral stress fibers, with a concave curvature. The radius of curvature of these arcs results from the balance of the line tension in the arc and of the surface tension in the cell bulk. However, the nature of these forces, and in particular the contribution of myosin-dependent contractility, is not clear. To get insight into the force balance, we inhibit myosin activity and simultaneously monitor the dynamics of peripheral arc radii and traction forces. We use these measurements to estimate line and surface tension. We found that myosin inhibition led to a decrease in the traction forces and an increase in arc radius, indicating that both line tension and surface tension dropped, but the line tension decreased to a lesser extent than surface tension. These results suggest that myosin-independent force contributes to tension in the peripheral arcs. We propose a simple physical model in which the peripheral arc line tension is due to the combination of myosin II contractility and a passive elastic component, while surface tension is largely due to active contractility. Numerical solutions of this model reproduce well the experimental data and allow estimation of the contributions of elasticity and contractility to the arc line tension.


Principal modes in multimode waveguides.
We generalize the concept of principal states of polarization and prove the existence of principal modes in multimode waveguides. Principal modes do not suffer from modal dispersion to first order of frequency variation and form orthogonal bases at both the input and the output ends of the waveguide. We show that principal modes are generally different from eigenmodes, even in uniform waveguides, unlike the special case of a single-mode fiber with uniform birefringence. The difference is most pronounced when different eigenmodes possess similar group velocities and when their field patterns vary as a function of frequency. This work may provide a new basis for analysis and control of dispersion in multimode fiber systems.


Genetic dysfunction of serotonin 2A receptor hampers response to antidepressant drugs: A translational approach.
Pharmacological studies have yielded valuable insights into the role of the serotonin 2A (5-HT2A) receptor in major depressive disorder (MDD) and antidepressant drugs (ADs) response. However, it is still unknown whether genetic variants in the HTR2A gene affect the therapeutic outcome of ADs and the mechanism underlying the regulation of such response remains poorly described. In this context, a translational human-mouse study offers a unique opportunity to address the possibility that variations in the HTR2A gene may represent a relevant marker to predict the efficacy of ADs. In a first part of this study, we investigated in depressed patients the effect of three HTR2A single nucleotide polymorphisms (SNPs), selected for their potential functional consequences on 5-HT2A receptor (rs6313, rs6314 and rs7333412), on response and remission rates after 3 months of antidepressant treatments. We also explored the consequences of the constitutive genetic inactivation of the 5-HT2A receptor (i.e. in 5-HT2A(-/-) mice) on the activity of acute and prolonged administration of SSRIs. Our clinical data indicate that GG patients for the rs7333412 SNP were less prone to respond to ADs than AA/AG patients. In the preclinical study, we demonstrated that the 5-HT2A receptor exerts an inhibitory influence on the neuronal activity of the serotonergic system after acute administration of SSRIs. However, while the chronic administration of the SSRIs escitalopram or fluoxetine elicited a progressive increased in the firing rate of 5-HT neurons in 5-HT2A(+/+) mice, it failed to do so in 5-HT2A(-/-) mutants. These electrophysiological impairments were associated with a decreased ability of the chronic administration of fluoxetine to stimulate hippocampal plasticity and to produce antidepressant-like activities. Genetic loss of the 5-HT2A receptor compromised the activity of chronic treatment with SSRIs, making this receptor a putative marker to predict ADs response.


Association study of a functional catechol-O-methyltransferase (COMT) Val108/158Met polymorphism and suicide attempts in patients with alcohol dependence.
Alcohol dependence is frequently associated with aggressive and suicidal behaviour. Genetic factors contribute to both behaviours. Candidate genes, related to suicide and aggression, include genes involved in serotonin, norepinephrine and dopamine pathways. The enzyme catechol-O-methyl transferase (COMT) degrades dopamine, epinephrine and norepinephrine. The functional polymorphism (COMT Val108/158Met) affects COMT activity, with the valine (Val) variant associated with higher and the methionine (Met) variant with lower COMT activity. This polymorphism is associated with aggressive and suicidal behaviour, but the literature data on this relationship is contradictory and inconsistent. The hypothesis of this study was that Met allele carriers with alcohol dependence will have a higher frequency of suicide attempts compared to other genotypes. Participants were 312 male and 81 female medication-free patients with alcohol dependence and 487 male and 122 female unrelated, non-suicidal medication-free Caucasian healthy subjects. Our results showed significant (χ2 test with standardized residuals) differences in the frequencies of COMT variants in all alcoholics, alcoholics with different comorbid diagnoses, and in male but not in female alcoholics, with or without suicide attempts. Male alcoholic suicide attempters, compared to male non-attempters, had the higher frequency of Met/Met genotype or Met allele, and significantly (Kruskal-Wallis ANOVA on ranks and Mann-Whitney test) higher aggression and depression scores. These results confirmed the associations between Met allele and aggressive behaviour or violent suicide attempts in various psychiatric diagnoses, and suggested that Met allele of the COMT Val108/158 Met might be used as an independent biomarker of suicidal behaviour across different psychopathologies.


Specific salt effects on thermophoresis of charged colloids.
We study the Soret effect of charged polystyrene particles as a function of temperature and electrolyte composition. As a main result we find that the Soret coefficient is determined by charge effects, and that non-ionic contributions are small. In view of the well-known electric-double layer interactions, our thermal field-flow fractionation data lead us to the conclusion that the Soret effect originates to a large extent from diffusiophoresis in the salt gradient and from the electrolyte Seebeck effect, both of which show strong specific-ion effects. Moreover, we find that thermophoresis of polystyrene beads is fundamentally different from proteins and aqueous polymer solutions, which show a strong non-ionic contribution.


Aptamer-based analysis: a promising alternative for food safety control.
Ensuring food safety is nowadays a top priority of authorities and professional players in the food supply chain. One of the key challenges to determine the safety of food and guarantee a high level of consumer protection is the availability of fast, sensitive and reliable analytical methods to identify specific hazards associated to food before they become a health problem. The limitations of existing methods have encouraged the development of new technologies, among them biosensors. Success in biosensor design depends largely on the development of novel receptors with enhanced affinity to the target, while being stable and economical. Aptamers fulfill these characteristics, and thus have surfaced as promising alternatives to natural receptors. This Review describes analytical strategies developed so far using aptamers for the control of pathogens, allergens, adulterants, toxins and other forbidden contaminants to ensure food safety. The main progresses to date are presented, highlighting potential prospects for the future.


AMPAR peptide values in blood of nonathletes and club sport athletes with concussions.
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) peptide, a product of the proteolytic degradation of AMPA receptors in healthy nonathletes and athletes with concussions, is assessed. The detection of AMPAR peptide in conjunction with neuropsychological testing and neuroimaging is undertaken. Persons (n = 124, 19-23 years) are enrolled in the pilot-blinded study according to approved Institutional Review Board protocols at Kennesaw State University and DeKalb Medical. AMPAR peptide plasma assay was performed using magnetic particles-enzyme-linked immunosorbent assay. All participants had neurocognitive tests (ImPACT); selected subjects with concussions were followed-up with magnetic resonance imaging and neurologic consultations. Athletes (n = 33) with clinically defined single or multiple concussions were compared to 91 age and gender matched controls without a history of concussion. AMPAR peptide values of 0.05-0.40 ng/mL for controls and 1.0-8.5 ng/mL for concussions are found. The biomarker sensitivity of 91% and a specificity of 92% (0.4 ng/mL cut off) to assess concussions are calculated. Poorer ImPACT scores correlated with abnormal levels of the biomarker. In athletes with multiple concussions, increased AMPAR peptide values (2.0-12.0 ng/mL) were associated with minor findings on magnetic resonance imaging. AMPAR peptide assay combined with ImPACT and neuroimaging is a promising tool for assessment of concussions. Additional clinical validation studies are required.


Dimerization of thiol-specific antioxidant and the essential role of cysteine 47.
Thiol-specific antioxidant (TSA) from yeast contains cysteine residues at amino acid positions 47 and 170 but is not associated with obvious redox cofactors. These two cysteines are highly conserved in a family of proteins that exhibit sequence identity of 23-98% with TSA. The roles of Cys-47 and Cys-170 in yeast TSA were investigated by replacing them individually with serine and expressing the mutant TSA proteins (RC47S and RC170S, respectively), as well as wild-type TSA (RWT), in Escherichia coli. Wild-type TSA purified from yeast (YWT) and RWT were both shown to exist predominantly as dimers, whereas RC47S and RC170S existed mainly as monomers under a denaturing condition. This observation suggests that the dimerization of YWT and RWT requires disulfide linkage of Cys-47 and Cys-170. The presence of the Cys-47-Cys-170 linkage in YWT was directly shown by isolation of dimeric tryptic peptides, one monomer of which contained Cys-47 and the other contained Cys-170. A small percentage of YWT, RWT, RC47S, and RC170S molecules formed dimers linked by Cys-47-Cys-47 or Cys-170-Cys-170 disulfide bonds. The antioxidant activity of the various TSA proteins was evaluated from their ability to protect glutamine synthetase against the dithiothreitol/Fe3+/O2 oxidation system. YWT, RWT, and RC170S were equally protective, whereas RC47S was completely ineffective. Thus, Cys-47, but not Cys-170, constitutes the site of oxidation by putative substrate.


Half-time analysis of the integrated Michaelis equation. Simulation and use of the half-time plot and its direct linear variant in the analysis of some alpha-chymotrypsin, papain- and fumarase-catalysed reactions.
Substitution of half-time parameters in the integrated form of the Michaelis-Menten equation for any enzyme-catalysed reaction yields an equation that gives a linear relationship between the half-time of the reaction and the substrate concentration at that point of the reaction. The logarithmic term of the integrated equation becomes a constant as a result of the substitution, which means that the use of the half-time plot of the equation requires calculation only of half-time and substrate-concentration values at various stages of the reaction. The half-time method is both simple and exact, being analogous to an [S(0)]/v(i) against [S(0)] plot. A direct linear form of the half-time plot has been devised that allows very simple estimation of Michaelis parameters and/or initial velocities from progress-curve data. This method involves no approximation and is statistically valid. Simulation studies have shown that linear-regression analysis of half-time plots provides unbiased estimates of the Michaelis parameters. Simulation of the effect of error in estimation of the product concentration at infinite time [P(infinity)] reveals that this is always a cause for concern, such errors being magnified approximately an order of magnitude in the estimate of the Michaelis constant. Both the half-time plot and the direct linear form have been applied to the analysis of a variety of experimental data. The method has been shown to produce excellent results provided certain simple rules are followed regarding criteria of experimental design. A set of rules has been formulated that, if followed, allows progress-curve data to be acquired and analysed in a reliable fashion. It is apparent that the use of modern spectrophotometers in carefully designed experiments allows the collection of data characterized by low noise and accurate [P(infinity)] estimates. [P(infinity)] values have been found, in the present work, to be precise to within +/-0.2% and noise levels have always been below 0.1% (signal-to-noise ratio approximately 1000). As a result of the considerations above, it is concluded that there is little to be feared with regard to the analysis of enzyme kinetics using complete progress curves, despite the generally lukewarm recommendations to be found in the literature. The saving in time, materials and experimental effort amply justify analysis of enzyme kinetics by progress-curve methods. Half-time plots linear to >/=90% of reaction have been obtained for some alpha-chymotrypsin-, papain- and fumarase-catalysed reactions.


Destruction of Claspin by SCFbetaTrCP restrains Chk1 activation and facilitates recovery from genotoxic stress.
We show that Claspin, an adaptor protein required for Chk1 activation, becomes degraded at the onset of mitosis. Claspin degradation was triggered by its interaction with, and ubiquitylation by, the SCFbetaTrCP ubiquitin ligase. This interaction was phosphorylation dependent and required the activity of the Plk1 kinase and the integrity of a betaTrCP recognition motif (phosphodegron) in the N terminus of Claspin. Uncoupling of Claspin from betaTrCP by mutating the conserved serines in Claspin's phosphodegron or by knocking down betaTrCP stabilized Claspin in mitosis, impaired Chk1 dephosphorylation, and delayed G2/M transition during recovery from cell cycle arrest imposed by DNA damage or replication stress. Moreover, the inability to degrade Claspin allowed partial reactivation of Chk1 in cells exposed to DNA damage after passing the G2/M transition. Our data suggest that degradation of Claspin facilitates timely reversal of the checkpoint response and delineates the period permissive for Chk1 activation during cell cycle progression.


Model-Based Recommendations for Optimal Surgical Placement of Epiretinal Implants.
A major limitation of current electronic retinal implants is that in addition to stimulating the intended retinal ganglion cells, they also stimulate passing axon fibers, producing perceptual 'streaks' that limit the quality of the generated visual experience. Recent evidence suggests a dependence between the shape of the elicited visual percept and the retinal location of the stimulating electrode. However, this knowledge has yet to be incorporated into the surgical placement of retinal implants. Here we systematically explored the space of possible implant configurations to make recommendations for optimal intraocular positioning of the electrode array. Using a psychophysically validated computational model, we demonstrate that better implant placement has the potential to reduce the spatial extent of axonal activation in existing implant users by up to ~55%. Importantly, the best implant location, as inferred from a population of simulated virtual patients, is both surgically feasible and is relatively stable across individuals. This study is a first step towards the use of computer simulations in patient-specific planning of retinal implant surgery.


Development, validation, and results of a measure of 30-day readmission following hospitalization for pneumonia.
Readmission following hospital discharge has become an important target of quality improvement. To describe the development, validation, and results of a risk-standardized measure of hospital readmission rates among elderly patients with pneumonia employed in federal quality measurement and efficiency initiatives. A retrospective cohort study using hospital and outpatient Medicare claims from 2005 and 2006. A total of 4675 hospitals in the United States. Medicare beneficiaries aged >65 years with a principal discharge diagnosis of pneumonia. None. Hospital-specific, risk-standardized 30-day readmission rates calculated as the ratio of predicted-to-expected readmissions, multiplied by the national unadjusted rate. Comparison of the areas under the receiver operating curve (ROC) and measurement of correlation coefficient in development and validation samples. The development sample consisted of 226,545 hospitalizations at 4675 hospitals, with an overall unadjusted 30-day readmission rate of 17.4%. The median risk-standardized hospital readmission rate was 17.3%, and the odds of readmission for a hospital one standard deviation above average was 1.4 times that of a hospital one standard deviation below average. Performance of the medical record and administrative models was similar (areas under the ROC curve 0.59 and 0.63, respectively) and the correlation coefficient of estimated state-specific standardized readmission rates from the administrative and medical record models was 0.96. Rehospitalization within 30 days of treatment for pneumonia is common, and rates vary across hospitals. A risk-standardized measure of hospital readmission rates derived from administrative claims has similar performance characteristics to one based on medical record review.


Identification of a Classical Mutant in the Industrial Host Aspergillus niger by Systems Genetics: LaeA Is Required for Citric Acid Production and Regulates the Formation of Some Secondary Metabolites.
The asexual filamentous fungus Aspergillus niger is an important industrial cell factory for citric acid production. In this study, we genetically characterized a UV-generated A. niger mutant that was originally isolated as a nonacidifying mutant, which is a desirable trait for industrial enzyme production. Physiological analysis showed that this mutant did not secrete large amounts of citric acid and oxalic acid, thus explaining the nonacidifying phenotype. As traditional complementation approaches to characterize the mutant genotype were unsuccessful, we used bulk segregant analysis in combination with high-throughput genome sequencing to identify the mutation responsible for the nonacidifying phenotype. Since A. niger has no sexual cycle, parasexual genetics was used to generate haploid segregants derived from diploids by loss of whole chromosomes. We found that the nonacidifying phenotype was caused by a point mutation in the laeA gene. LaeA encodes a putative methyltransferase-domain protein, which we show here to be required for citric acid production in an A. niger lab strain (N402) and in other citric acid production strains. The unexpected link between LaeA and citric acid production could provide new insights into the transcriptional control mechanisms related to citric acid production in A. niger. Interestingly, the secondary metabolite profile of a ΔlaeA strain differed from the wild-type strain, showing both decreased and increased metabolite levels, indicating that LaeA is also involved in regulating the production of secondary metabolites. Finally, we show that our systems genetics approach is a powerful tool to identify trait mutations.


Comparing fall detection methods in people with multiple sclerosis: A prospective observational cohort study.
Background Falls occur across the population but are more common, and have more negative sequelae, in people with multiple sclerosis (MS). Given the prevalence and impact of falls, accurate measures of fall frequency are needed. This study compares the sensitivity and false discovery rates of three methods of fall detection: the current gold standard, prospective paper fall calendars, real-time self-reporting and automated detection, the latter two from a novel body-worn device. Methods Falls in twenty-five people with MS were recorded for eight weeks with prospective fall calendars, real-time body-worn self-report, and an automated body-worn detector concurrently. Eligible individuals were adults with MS enrolled in a randomized controlled trial of a fall prevention intervention. Entry criteria were at least two falls or near-falls in the previous two months, Expanded Disability Status Scale ≤ 6.0, community dwelling, and no MS relapse in the previous month. The sensitivity (proportion of true falls detected) and false discovery rates (proportion of false reports generated) of the fall detection methods were compared. A true fall was a fall reported by at least two methods. A false report was a fall reported by only one method. The trial is registered on ClinicalTrials.gov (NCT02583386) and is closed. Results In the 1,276 person-days of fall counting with all three methods in use simultaneously there were 1344 unique fall events. Of these, 8.5% (114) were true falls and 91.5% (1230) were false reports. Fall calendars had the lowest sensitivity (0.614) and the lowest false discovery rate (0.067). The automated detector had the highest sensitivity (0.921) and the highest false discovery rate (0.919). All methods generated under one false report per day. There were no fall detection-related adverse events. Conclusion Fall calendars likely underestimate fall frequency by around 40%. The automated detector evaluated here misses very few falls but likely overestimates the number of falls by around one fall per day. Additional research is needed to produce an ideal fall detection and counting method for use in clinical and research applications. Funding United States Department of Veterans Affairs, Rehabilitations Research and Development Service.


Nanobiocatalyst advancements and bioprocessing applications.
The nanobiocatalyst (NBC) is an emerging innovation that synergistically integrates advanced nanotechnology with biotechnology and promises exciting advantages for improving enzyme activity, stability, capability and engineering performances in bioprocessing applications. NBCs are fabricated by immobilizing enzymes with functional nanomaterials as enzyme carriers or containers. In this paper, we review the recent developments of novel nanocarriers/nanocontainers with advanced hierarchical porous structures for retaining enzymes, such as nanofibres (NFs), mesoporous nanocarriers and nanocages. Strategies for immobilizing enzymes onto nanocarriers made from polymers, silicas, carbons and metals by physical adsorption, covalent binding, cross-linking or specific ligand spacers are discussed. The resulting NBCs are critically evaluated in terms of their bioprocessing performances. Excellent performances are demonstrated through enhanced NBC catalytic activity and stability due to conformational changes upon immobilization and localized nanoenvironments, and NBC reutilization by assembling magnetic nanoparticles into NBCs to defray the high operational costs associated with enzyme production and nanocarrier synthesis. We also highlight several challenges associated with the NBC-driven bioprocess applications, including the maturation of large-scale nanocarrier synthesis, design and development of bioreactors to accommodate NBCs, and long-term operations of NBCs. We suggest these challenges are to be addressed through joint collaboration of chemists, engineers and material scientists. Finally, we have demonstrated the great potential of NBCs in manufacturing bioprocesses in the near future through successful laboratory trials of NBCs in carbohydrate hydrolysis, biofuel production and biotransformation.


Frequent PD-L1 expression in testicular germ cell tumors.
Many testicular germ cell cancers are curable despite metastatic disease, but about 10-15% of patients fail cisplatin-based first-line treatment. Immunotherapy is considered as additional treatment approach for these patients. Inhibition of the interaction between Programmed Death Receptor 1 (PD-1) and Programmed Death Receptor Ligand 1 (PD-L1) enhances T-cell responses in vitro and mediates clinical antitumour activity. We analysed the expression of PD-L1 in testicular germ cell tumours to evaluate its potential as target for immunotherapeutic strategies. Immunohistochemistry was performed in 479 formalin-fixed paraffin-embedded specimens using a rabbit monoclonal antibody (E1L3N). The tissue microarray consisted of 208 pure seminomas, 121 non-seminomas, 20 intratubular germ cell neoplasia unclassified (IGCNU) and 20 specimens of non-neoplastic testicular tissue. Programmed Death Receptor Ligand-1 expression was found in 73% of all seminomas and in 64% of all non-seminomas. None of 20 IGCNU and none of 20 normal tissue specimens exhibited PD-L1 expression. PD-L1 positive stromal cells were only detected in seminomas, but not in non-seminomas. The anti PD-L1 antibody showed a pre-dominantly membranous staining pattern in testicular tumour cells, as well as expression in stromal cells. This frequent expression of PD-L1 in human testicular germ cell tumours suggests that patients with testicular germ cell tumours could profit from immunotherapeutic strategies using anti-PD1 and anti-PDL1 antibodies.


Thermodynamic and kinetic approaches for evaluation of monoclonal antibody - Lipoprotein interactions.
Two complementary instrumental techniques were used, and the data generated was processed with advanced numerical tools to investigate the interactions between anti-human apoB-100 monoclonal antibody (anti-apoB-100 Mab) and apoB-100 containing lipoproteins. Partial Filling Affinity Capillary Electrophoresis (PF-ACE) combined with Adsorption Energy Distribution (AED) calculations provided information on the heterogeneity of the interactions without any a priori model assumptions. The AED calculations evidenced a homogenous binding site distribution for the interactions. Quartz Crystal Microbalance (QCM) studies were used to evaluate thermodynamics and kinetics of the Low-Density Lipoprotein (LDL) and anti-apoB-100 Mab interactions. High affinity and selectivity were observed, and the emerging data sets were analysed with so called Interaction Maps. In thermodynamic studies, the interaction between LDL and anti-apoB-100 Mab was found to be predominantly enthalpy driven. Both techniques were also used to study antibody interactions with Intermediate-Density (IDL) and Very Low-Density (VLDL) Lipoproteins. By screening affinity constants for IDL-VLDL sample in a single injection we were able to distinguish affinity constants for both subpopulations using the numerical Interaction Map tool.


Operational response simulation tool for epidemics within refugee and IDP settlements: A scenario-based case study of the Cox's Bazar settlement.
The spread of infectious diseases such as COVID-19 presents many challenges to healthcare systems and infrastructures across the world, exacerbating inequalities and leaving the world's most vulnerable populations most affected. Given their density and available infrastructure, refugee and internally displaced person (IDP) settlements can be particularly susceptible to disease spread. In this paper we present an agent-based modeling approach to simulating the spread of disease in refugee and IDP settlements under various non-pharmaceutical intervention strategies. The model, based on the June open-source framework, is informed by data on geography, demographics, comorbidities, physical infrastructure and other parameters obtained from real-world observations and previous literature. The development and testing of this approach focuses on the Cox's Bazar refugee settlement in Bangladesh, although our model is designed to be generalizable to other informal settings. Our findings suggest the encouraging self-isolation at home of mild to severe symptomatic patients, as opposed to the isolation of all positive cases in purpose-built isolation and treatment centers, does not increase the risk of secondary infection meaning the centers can be used to provide hospital support to the most intense cases of COVID-19. Secondly we find that mask wearing in all indoor communal areas can be effective at dampening viral spread, even with low mask efficacy and compliance rates. Finally, we model the effects of reopening learning centers in the settlement under various mitigation strategies. For example, a combination of mask wearing in the classroom, halving attendance regularity to enable physical distancing, and better ventilation can almost completely mitigate the increased risk of infection which keeping the learning centers open may cause. These modeling efforts are being incorporated into decision making processes to inform future planning, and further exercises should be carried out in similar geographies to help protect those most vulnerable.


Mosquito larval habitats and public health implications in Abeokuta, Ogun State, Nigeria.
The larval habitats of mosquitoes were investigated in Abeokuta, Nigeria in order to determine the breeding sites of the existing mosquito fauna and its possible public health implications on the residents of the City. The habitats were sampled between August 2005 and July 2006 using plastic dippers and a pipette. The habitats were grouped as ground pools/ponds, gutters/open drains, tyres, domestic containers and treeholes/ leaf axils. Ten species of mosquitoes were encountered in the five habitats namely Mansonia africana, M. uniformis, Culex quinquefasciatus, Aedes aegypti, Ae. albopictus, Ae. vittatus, Cx tigripes, Anopheles gambiae s.l., An. funestus and Eretmapodite clnysogaster. Ae. aegypti bred in all the habitats sampled while Cx quinquefasciatus bred in four habitats except tree holes/leaf axils. An. gambiae s.l and Ae. albopictus occurred in three habitats while other species bred only in one or two habitats. Ground pools and domestic containers recorded the highest number of species followed by gutters/open drains. Tree holes/leaf axils was the least preferred habitat with the lowest number of species occurrence. However, statistical analysis revealed non-significant difference in species occurrence in the five habitats. The availability of the habitats to support the breeding of Aedes, Culex and Anopheles, which are known vectors of urban yellow fever, lymphatic filariasis and malaria suggest that the residents ofAbeokuta City are at risk of mosquito-borne diseases. It is important that residents of the City are enlighten on the environmental factors that contribute to mosquito breeding and that the Government should institute proper sanitation measures to reduce mosquito breeding sites.


Horizontal gene transfer in Histophilus somni and its role in the evolution of pathogenic strain 2336, as determined by comparative genomic analyses.
Pneumonia and myocarditis are the most commonly reported diseases due to Histophilus somni, an opportunistic pathogen of the reproductive and respiratory tracts of cattle. Thus far only a few genes involved in metabolic and virulence functions have been identified and characterized in H. somni using traditional methods. Analyses of the genome sequences of several Pasteurellaceae species have provided insights into their biology and evolution. In view of the economic and ecological importance of H. somni, the genome sequence of pneumonia strain 2336 has been determined and compared to that of commensal strain 129Pt and other members of the Pasteurellaceae. The chromosome of strain 2336 (2,263,857 bp) contained 1,980 protein coding genes, whereas the chromosome of strain 129Pt (2,007,700 bp) contained only 1,792 protein coding genes. Although the chromosomes of the two strains differ in size, their average GC content, gene density (total number of genes predicted on the chromosome), and percentage of sequence (number of genes) that encodes proteins were similar. The chromosomes of these strains also contained a number of discrete prophage regions and genomic islands. One of the genomic islands in strain 2336 contained genes putatively involved in copper, zinc, and tetracycline resistance. Using the genome sequence data and comparative analyses with other members of the Pasteurellaceae, several H. somni genes that may encode proteins involved in virulence (e.g., filamentous haemaggutinins, adhesins, and polysaccharide biosynthesis/modification enzymes) were identified. The two strains contained a total of 17 ORFs that encode putative glycosyltransferases and some of these ORFs had characteristic simple sequence repeats within them. Most of the genes/loci common to both the strains were located in different regions of the two chromosomes and occurred in opposite orientations, indicating genome rearrangement since their divergence from a common ancestor. Since the genome of strain 129Pt was ~256,000 bp smaller than that of strain 2336, these genomes provide yet another paradigm for studying evolutionary gene loss and/or gain in regard to virulence repertoire and pathogenic ability. Analyses of the complete genome sequences revealed that bacteriophage- and transposon-mediated horizontal gene transfer had occurred at several loci in the chromosomes of strains 2336 and 129Pt. It appears that these mobile genetic elements have played a major role in creating genomic diversity and phenotypic variability among the two H. somni strains.


Substance use disorders in prisoners: an updated systematic review and meta-regression analysis in recently incarcerated men and women.
The aims were to (1) estimate the prevalence of alcohol and drug use disorders in prisoners on reception to prison and (2) estimate and test sources of between study heterogeneity. Studies reporting the 12-month prevalence of alcohol and drug use disorders in prisoners on reception to prison from 1 January 1966 to 11 August 2015 were identified from seven bibliographic indexes. Primary studies involving clinical interviews or validated instruments leading to DSM or ICD diagnoses were included; self-report surveys and investigations that assessed individuals more than 3 months after arrival to prison were not. Random-effects meta-analysis and subgroup and meta-regression analyses were conducted. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. In total, 24 studies with a total of 18 388 prisoners across 10 countries were identified. The random-effects pooled prevalence estimate of alcohol use disorder was 24% [95% confidence interval (CI) = 21-27], with very high heterogeneity (I2 = 94%). These ranged from 16 to 51% in male and 10-30% in female prisoners. For drug use disorders, there was evidence of heterogeneity by sex, and the pooled prevalence estimate in male prisoners was 30% (95% CI = 22-38; I2 = 98%; 13 studies; range 10-61%) and, in female prisoners, was 51% (95% CI = 43-58; I2 = 95%; 10 studies; range 30-69%). On meta-regression, sources of heterogeneity included higher prevalence of drug use disorders in women, increasing rates of drug use disorders in recent decades, and participation rate. Substance use disorders are highly prevalent in prisoners. Approximately a quarter of newly incarcerated prisoners of both sexes had an alcohol use disorder, and the prevalence of a drug use disorder was at least as high in men, and higher in women.


Nearest-cell: a fast and easy tool for locating crystal matches in the PDB.
When embarking upon X-ray diffraction data collection from a potentially novel macromolecular crystal form, it can be useful to ascertain whether the measured data reflect a crystal form that is already recorded in the Protein Data Bank and, if so, whether it is part of a large family of related structures. Providing such information to crystallographers conveniently and quickly, as soon as the first images have been recorded and the unit cell characterized at an X-ray beamline, has the potential to save time and effort as well as pointing to possible search models for molecular replacement. Given an input unit cell, and optionally a space group, Nearest-cell rapidly scans the Protein Data Bank and retrieves near-matches.


Expression of non-TLR pattern recognition receptors in the spleen of BALB/c mice infected with Plasmodium yoelii and Plasmodium chabaudi chabaudi AS.
The spleen plays a crucial role in the development of immunity to malaria, but the role of pattern recognition receptors (PRRs) in splenic effector cells during malaria infection is poorly understood. In the present study, we analysed the expression of selected PRRs in splenic effector cells from BALB/c mice infected with the lethal and non-lethal Plasmodium yoelii strains 17XL and 17X, respectively, and the non-lethal Plasmodium chabaudi chabaudi AS strain. The results of these experiments showed fewer significant changes in the expression of PRRs in AS-infected mice than in 17X and 17XL-infected mice. Mannose receptor C type 2 (MRC2) expression increased with parasitemia, whereas Toll-like receptors and sialoadhesin (Sn) decreased in mice infected with P. chabaudi AS. In contrast, MRC type 1 (MRC1), MRC2 and EGF-like module containing mucin-like hormone receptor-like sequence 1 (F4/80) expression decreased with parasitemia in mice infected with 17X, whereas MRC1 an MRC2 increased and F4/80 decreased in mice infected with 17XL. Furthermore, macrophage receptor with collagenous structure and CD68 declined rapidly after initial parasitemia. SIGNR1 and Sn expression demonstrated minor variations in the spleens of mice infected with either strain. Notably, macrophage scavenger receptor (Msr1) and dendritic cell-associated C-type lectin 2 expression increased at both the transcript and protein levels in 17XL-infected mice with 50% parasitemia. Furthermore, the increased lethality of 17X infection in Msr1 -/- mice demonstrated a protective role for Msr1. Our results suggest a dual role for these receptors in parasite clearance and protection in 17X infection and lethality in 17XL infection.


Long-term physical activity in people with multiple sclerosis: exploring expert views on facilitators and barriers.
Purpose: To explore the views of experts on facilitators and barriers of long-term physical activity among people with multiple sclerosis living in different European countries.Methods: We conducted semi-structured telephone or face to face interviews with twelve multiple sclerosis and physical activity experts (scientists, practitioners, patient representatives) from five European countries. Interviews were audio-recorded, transcribed verbatim and analyzed using thematic analysis.Results: We identified 20 themes and categorized them into environmental and personal factors. The most frequently mentioned and intensively discussed themes were environmental factors. The themes were structured according to possible intervention level: organizational, interpersonal and intrapersonal level themes. Themes at the organizational level comprised availability, access and quality of exercise/physical activity options; health system characteristics like services and organization, health professionals and information provision. The interpersonal level comprised social support and peer support. Disease related factors were the most frequently mentioned intrapersonal level theme. In our study, more codes were obtained for environmental factors than for personal factors.Conclusions: The results suggested that environmental factors may need to be addressed in particular to increase long-term physical activity adherence. This study will inform the design of a survey questionnaire assessing possible barriers and facilitators among people with multiple sclerosis. Implications for rehabilitationLong-term physical activity among people with multiple sclerosis is subject to a number of modifiable determinants: personal and environmental factors.Multiple sclerosis exercise experts emphasized the importance of environmental factors on the organizational and interpersonal level.Future physical activity interventions should be guided by a social-ecological perspective.Addressing environmental and personal factors simultaneously to reach optimal long-term outcomes should be considered in future interventions.


Bubbles: a unifying framework for low-level statistical properties of natural image sequences.
Recently, different models of the statistical structure of natural images have been proposed. These models predict properties of biological visual systems and can be used as priors in Bayesian inference. The fundamental model is independent component analysis, which can be estimated by maximization of the sparsenesses of linear filter outputs. This leads to the emergence of principal simple cell properties. Alternatively, simple cell properties are obtained by maximizing the temporal coherence in natural image sequences. Taking account of the basic dependencies of linear filter outputs permit modeling of complex cells and topographic organization as well. We propose a unifying framework for these statistical properties, based on the concept of spatiotemporal activity "bubbles."A bubble means here an activation of simple cells (linear filters) that is contiguous both in space (the cortical surface) and in time.


Practical considerations for plant phylogenomics.
The past decade has seen a major breakthrough in our ability to easily and inexpensively sequence genome-scale data from diverse lineages. The development of high-throughput sequencing and long-read technologies has ushered in the era of phylogenomics, where hundreds to thousands of nuclear genes and whole organellar genomes are routinely used to reconstruct evolutionary relationships. As a result, understanding which options are best suited for a particular set of questions can be difficult, especially for those just starting in the field. Here, we review the most recent advances in plant phylogenomic methods and make recommendations for project-dependent best practices and considerations. We focus on the costs and benefits of different approaches in regard to the information they provide researchers and the questions they can address. We also highlight unique challenges and opportunities in plant systems, such as polyploidy, reticulate evolution, and the use of herbarium materials, identifying optimal methodologies for each. Finally, we draw attention to lingering challenges in the field of plant phylogenomics, such as reusability of data sets, and look at some up-and-coming technologies that may help propel the field even further.


Characterization of the natural variation in Arabidopsis thaliana metabolome by the analysis of metabolic distance.
Metabolite fingerprinting is widely used to unravel the chemical characteristics of biological samples. Multivariate data analysis and other statistical tools are subsequently used to analyze and visualize the plasticity of the metabolome and/or the relationship between those samples. However, there are limitations to these approaches for example because of the multi-dimensionality of the data that makes interpretation of the data obtained from untargeted analysis almost impossible for an average human being. These limitations make the biological information that is of prime importance in untargeted studies be partially exploited. Even in the case of full exploitation, current methods for relationship elucidation focus mainly on between groups variation and differences. Therefore, a measure that is capable of exploiting both between- and within-group biological variation would be of great value. Here, we examined the natural variation in the metabolome of nine Arabidopsis thaliana accessions grown under various environmental conditions and established a measure for the metabolic distance between accessions and across environments. This data analysis approach shows that there is just a minor correlation between genetic and metabolic diversity of the nine accessions. On the other hand, it delivers so far in Arabidopsis unexplored chemical information and is shown to be biologically relevant for resistance studies. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11306-011-0375-3) contains supplementary material, which is available to authorized users.


Management of biliary complications after liver transplantation.
Biliary tract complications after liver transplantation are common, and the evaluation of newer treatment options compared with standard surgical treatment is important. In 62 liver transplants performed in 55 adult patients, the biliary tract was reconstructed with choledochocholedochostomy (CC) in 52 (84%) and Roux-en-Y choledochojejunostomy (RYCJ) in 10 (16%). Seventeen biliary tract complications occurred in 16 patients (29%). The incidence of complications was the same after CC and RYCJ. Eight complications (47%) occurred within the first month and nine (53%) thereafter. Only 6 of 17 (35%) biliary tract complications required operation. One patient died of a biliary tract complication. No other allografts were lost due to biliary tract complications. Four patients transplanted at other centers were also treated, for a total of 21 biliary tract complications. Overall, there were nine bile leaks, eight bile duct strictures, two Roux loop hemorrhages, one choledocholithiasis, and one ampullary dyskinesia. Temporary or permanent stents were used successfully in seven of eight strictures. Five bile leaks were managed without operation. Nonsurgical management is appropriate for a selected majority of patients with late bile leaks, biliary tract strictures, or choledocholithiasis after liver transplantation.


Integrating population dynamics models and distance sampling data: a spatial hierarchical state-space approach.
Stochastic versions of Gompertz, Ricker, and various other dynamics models play a fundamental role in quantifying strength of density dependence and studying long-term dynamics of wildlife populations. These models are frequently estimated using time series of abundance estimates that are inevitably subject to observation error and missing data. This issue can be addressed with a state-space modeling framework that jointly estimates the observed data model and the underlying stochastic population dynamics (SPD) model. In cases where abundance data are from multiple locations with a smaller spatial resolution (e.g., from mark-recapture and distance sampling studies), models are conventionally fitted to spatially pooled estimates of yearly abundances. Here, we demonstrate that a spatial version of SPD models can be directly estimated from short time series of spatially referenced distance sampling data in a unified hierarchical state-space modeling framework that also allows for spatial variance (covariance) in population growth. We also show that a full range of likelihood based inference, including estimability diagnostics and model selection, is feasible in this class of models using a data cloning algorithm. We further show through simulation experiments that the hierarchical state-space framework introduced herein efficiently captures the underlying dynamical parameters and spatial abundance distribution. We apply our methodology by analyzing a time series of line-transect distance sampling data for fin whales (Balaenoptera physalus) off the U.S. west coast. Although there were only seven surveys conducted during the study time frame, 1991-2014, our analysis detected presence of strong density regulation and provided reliable estimates of fin whale densities. In summary, we show that the integrative framework developed herein allows ecologists to better infer key population characteristics such as presence of density regulation and spatial variability in a population's intrinsic growth potential.


Evaluating medical students' proficiency with a handheld ophthalmoscope: a pilot study.
Historically, testing medical students' skills using a handheld ophthalmoscope has been difficult to do objectively. Many programs train students using plastic models of the eye which are a very limited fidelity simulator of a real human eye. This makes it difficult to be sure that actual proficiency is attained given the differences between the various models and actual patients. The purpose of this article is to introduce a method of testing where a medical student must match a patient with his/her fundus photo, ensuring objective evaluation as well as developing skills on real patients which are more likely to transfer into clinical practice directly. Fundus photos from standardized patients (SPs) were obtained using a retinal camera and placed into a grid using proprietary software. Medical students were then asked to examine a SP and attempt to match the patient to his/her fundus photo in the grid. Of the 33 medical students tested, only 10 were able to match the SP's eye to the correct photo in the grid. The average time to correct selection was 175 seconds, and the successful students rated their confidence level at 27.5% (average). The incorrect selection took less time, averaging 118 seconds, yet yielded a higher student-reported confidence level at 34.8% (average). The only noteworthy predictor of success (p<0.05) was the student's age (p=0.02). It may be determined that there is an apparent gap in the ophthalmoscopy training of the students tested. It may also be of concern that students who selected the incorrect photo were more confident in their selections than students who chose the correct photo. More training may be necessary to close this gap, and future studies should attempt to establish continuing protocols in multiple centers.


Collaborative United Kingdom-Australasian study of cancer in patients treated with immunosuppressive drugs.
A collaborative study including centres in the United Kingdom, Australia, and New Zealand was instituted in 1970 to determine the incidence of cancer in patients treated for at least three months with azathioprine, cyclophosphamide, or chlorambucil. Follow-up of 3823 renal transplant recipients showed an almost 60-fold increase of non-Hodgkin's lymphoma together with an excess of squamous-cell skin cancer and mesenchymal tumours. A series of 1349 patients without transplants showed an excess of the same tumours, though to a less extent. These preliminary findings provide no clear evidence that immunosuppressive drugs produce the increased risk of most of the common cancers that might be expected from the simplest interpretation of impaired "immunosurveillance."


Improving patient safety and physician accountability using the hospital credentialing process.
The lack of systematic oversight of physician performance has led to some serious cases related to physician competence and behaviour. We are currently implementing a hospital-wide approach to improve physician oversight by incorporating it into the hospital credentialing process. Our proposed credentialing method involves four systems: (1) a system for monitoring and reporting clinical performance; (2) a system for evaluating physician behaviour; (3) a complaints management system; and (4) an administrative system for maintaining documentation. In our method, physicians are responsible for implementing an annual performance assessment program. The hospital will be responsible for the complaints management system and the system for collecting and reporting relevant health outcomes. Physicians and the hospital will share responsibility for monitoring professional behaviour. Medical leadership, effective governance, appropriate supporting information systems and adequate human resources are required for the program to be successful. Our program is proactive and will allow our hospital to enhance safety through a quality assurance framework and by complementing existing safety activities. Our program could be extended to non-hospital physicians through regional health or provider networks. Central licensing authorities could help to coordinate these programs on a province- or state-wide basis to ensure uniformity of standards and to avoid duplication of efforts.


Progressive hair loss and myocardial degeneration in rough coat mice: reduced lysyl oxidase-like (LOXL) in the skin and heart.
The rough coat (rc) is a spontaneous recessive mutation in mice. To identify the mutated gene, we have characterized the rc phenotype and initiated linkage mapping. The rc mice show growth retardation, cyclic and progressive hair loss, hyperplastic epidermis, abnormal hair follicles, cardiac muscle degeneration, and reduced amount of collagen and elastin in the skin and heart. The rc locus was mapped at 32.0 cM on chromosome 9, close to the loxl gene. Lysyl oxidase-like (LOXL) protein is a novel copper-containing amine oxidase that is required for the cross-linking of elastin and collagen in vitro. LOXL is expressed at high levels in the skin and heart, where the rc mice show strong phenotype. The expression pattern and the genetic proximity to rc suggested loxl as a potential candidate gene. In rc mice, the loxl mRNA was reduced in the skin and the LOXL protein in the heart, dermis, atrophic hair follicles, and sebaceous glands. No mutations, however, were identified within the coding region of loxl, and offspring from rc/rc and loxl null mice crossing were phenotypically normal. Based on these results, loxl appears non-allelic to rc. Heart- and skin-specific downregulation of LOXL in rc mice, however, may contribute to the extracellular matrix alterations and the rc phenotype.


Identification of SERPINA1 as single marker for papillary thyroid carcinoma through microarray meta analysis and quantification of its discriminatory power in independent validation.
Several DNA microarray based expression signatures for the different clinically relevant thyroid tumor entities have been described over the past few years. However, reproducibility of these signatures is generally low, mainly due to study biases, small sample sizes and the highly multivariate nature of microarrays. While there are new technologies available for a more accurate high throughput expression analysis, we show that there is still a lot of information to be gained from data deposited in public microarray databases. In this study we were aiming (1) to identify potential markers for papillary thyroid carcinomas through meta analysis of public microarray data and (2) to confirm these markers in an independent dataset using an independent technology. We adopted a meta analysis approach for four publicly available microarray datasets on papillary thyroid carcinoma (PTC) nodules versus nodular goitre (NG) from N2-frozen tissue. The methodology included merging of datasets, bias removal using distance weighted discrimination (DWD), feature selection/inference statistics, classification/crossvalidation and gene set enrichment analysis (GSEA). External Validation was performed on an independent dataset using an independent technology, quantitative RT-PCR (RT-qPCR) in our laboratory. From meta analysis we identified one gene (SERPINA1) which identifies papillary thyroid carcinoma against benign nodules with 99% accuracy (n = 99, sensitivity = 0.98, specificity = 1, PPV = 1, NPV = 0.98). In the independent validation data, which included not only PTC and NG, but all major histological thyroid entities plus a few variants, SERPINA1 was again markedly up regulated (36-fold, p = 1:3*10-10) in PTC and identification of papillary carcinoma was possible with 93% accuracy (n = 82, sensitivity = 1, specificity = 0.90, PPV = 0.76, NPV = 1). We also show that the extracellular matrix pathway is strongly activated in the meta analysis data, suggesting an important role of tumor-stroma interaction in the carcinogenesis of papillary thyroid carcinoma. We show that valuable new information can be gained from meta analysis of existing microarray data deposited in public repositories. While single microarray studies rarely exhibit a sample number which allows robust feature selection, this can be achieved by combining published data using DWD. This approach is not only efficient, but also very cost-effective. Independent validation shows the validity of the results from this meta analysis and confirms SERPINA1 as a potent mRNA marker for PTC in a total (meta analysis plus validation) of 181 samples.


Lung function increases with increasing level of physical activity in school children.
Little is known about the association between physical activity and lung function in childhood. We conducted a survey including parental reports of the child's participation in physical activity and measurements of lung function. The associations between physical activity and lung function were estimated by linear regression analysis adjusting for potential confounders in 2,537 children (9 to 10 years). Using the linear model in exploring the effect of physical activity on lung function with those who were physical active less than once a week as the reference category, showed that forced expiratory volume in 1 s (FEV1) was highest among those who were physical active > or = 4 times a week also when adjusting for potential confounders (p = .02). FEV1 increased with 70 ml. A similar pattern was present for forced vital capacity (FVC; p = .002). The present study suggested that lung function was highest in highly physical active children age 9 to 10 years. The implications are that exercise may influence lung function, but these findings need to be confirmed using a longitudinal study design.


Vaccination strategies for people living with inborn errors of metabolism in Brazil.
Through a literature review, make recommendations regarding immunizations in people living with Inborn Error of Metabolism (IEM) in Brazil, assess the possible impact on metabolic decompensations after immunization, and if this specific population may have an impaired immune response to vaccines. The MeSH Terms vaccination OR vaccine OR immunization associated with the term inborn error of metabolism AND recommendation were used in combination with search databases. Only articles published after 1990, in the languages English, Spanish, French or Portuguese, human-related were included. A total of 44 articles were included to make the following recommendations. Individuals with IEMs need to be up to date with their immunizations. Regarding which vaccines should be offered, children and adults should follow the routine immunization schedules locally available, including the COVID-19 vaccines. The only exception is the rotavirus vaccine for hereditary fructose intolerance. The benefit of immunization outweighs the very low risk of metabolic decompensation. Since not all patients will have an adequate immune response, measuring antibody conversion and titers is recommended CONCLUSIONS: All patients should receive age-appropriate immunizations in their respective schedules without delays. The only situation when vaccination may be contraindicated is with oral rotavirus vaccine in hereditary fructose intolerance. Monitoring the levels of antibodies should be done to detect any immune dysfunction or the necessity for boosters. A personalized immunization schedule is ideal for patients with IEMs. The reference organizations could improve their recommendations to address all IEMs, not only some of them.


Guidelines for the management of the foot health problems associated with rheumatoid arthritis.
Rheumatoid arthritis (RA) as a chronic systemic disease, commonly affects the feet, impacting negatively on patients' quality of life. Specialist podiatrists have a prime role to play in the assessment and management of foot and ankle problems within this patient group. However, it has been identified that in many areas there is no specialist podiatry service, with many patients being managed by non-specialist podiatrists. Therefore, the North West Clinical Effectiveness Group for the Foot in Rheumatic Diseases (NWCEG) identified the need to develop 'practitioner facing' guidelines for the management of specific foot health problems associated with RA. Members of a guideline development group from the NWCEG each reviewed the evidence for specific aspects of the assessment and management of foot problems. Where evidence was lacking, 'expert opinion' was obtained from the members of the NWCEG and added as a consensus on current and best practice. An iterative approach was employed, with the results being reviewed and revised by all members of the group and external reviewers before the final guideline document was produced. The management of specific foot problems (callus, nail pathology, ulceration) and the use of specific interventions (foot orthoses, footwear, patient education, steroid injection therapy) are detailed and standards in relation to each are provided. A diagrammatic screening pathway is presented, with the aim of guiding non-specialist podiatrists through the complexity of assessing and managing those patients with problems requiring input from a specialist podiatrist and other members of the rheumatology multidisciplinary team. This pragmatic approach ensured that the guidelines were relevant and applicable to current practice as 'best practice', based on the available evidence from the literature and consensus expert opinion. These guidelines provide both specialist and non-specialist podiatrists with the essential and 'gold standard' aspects of managing people with RA-related foot problems.


Comparative efficiency analysis of fiber-array and conventional beam director systems in volume turbulence.
The performance of two prominent laser beam projection system types is analyzed through wave-optics numerical simulations for various atmospheric turbulence conditions, propagation distances, and adaptive optics (AO) mitigation techniques. Comparisons are made between different configurations of both a conventional beam director (BD) using a monolithic-optics-based Cassegrain telescope and a fiber-array BD that uses an array of densely packed fiber collimators. The BD systems considered have equal input power and aperture diameters. The projected laser beam power inside the Airy size disk at the target plane is used as the performance metric. For the fiber-array system, both incoherent and coherent beam combining regimes are considered. We also present preliminary results of side-by-side atmospheric beam projection experiments over a 7-km propagation path using both the AO-enhanced beam projection system with a Cassegrain telescope and the coherent fiber-array BD composed of 21 densely packed fiber collimators. Both wave-optics numerical simulation and experimental results demonstrate that, for similar system architectures and turbulence conditions, coherent fiber-array systems are more efficient in mitigation of atmospheric turbulence effects and generation of a hit spot of the smallest possible size on a remotely located target.


[18F]fluorodeoxyglucose uptake in neonatal acute lung injury measured by positron emission tomography.
The objective of this study was to evaluate positron emission tomography (PET) of [18F]fluorodexoyglucose (18FDG) uptake as a measure of neonatal acute lung injury. Inasmuch as intrapulmonary sequestration of neutrophils is a hallmark of acute lung injury, quantification of neutrophil activity using 18FDG may offer a novel, in vivo technique to examine the progression and resolution of this disease. Ten newborn piglets were studied: six received bronchoalveolar lavage followed by 4 h of high pressure ventilation of create acute lung injury. Four healthy piglets served as controls. 18FDG (0.8 mCi/kg; 29.6 MBq) was given i.v. and PET (ECAT 953/31, Siemens) was performed for 90 min. During PET, all animals were sedated, paralyzed, and ventilated to maintain normal blood gases. The time course of radioactivity in lung regions and in plasma was used to calculate the rate constant for the metabolic trapping of 18FDG in tissue according to the method of C. S. Patlak. Median 18FDG influx constants were significantly higher in injured piglets (0.0187 min-1) than in control piglets (0.0052 min-1) (p < 0.01). Moreover, consistent with the 18FDG uptake data, injured piglets had moderate to severe injury on lung histology whereas control piglets had only slight and focal histologic changes. We conclude that PET of 18FDG uptake is an accurate, readily repeatable in vivo measure of neonatal acute lung injury.


Hybridizable ribonucleic acid of rat brain.
1. Cerebral RNA of adult and newborn rats was labelled in vivo by intracervical injection of [5-(3)H]uridine or [(32)P]phosphate. Hepatic RNA of similar animals was labelled by intraperitoneal administration of [6-(14)C]orotic acid. Nuclear and cytoplasmic fractions were isolated and purified by procedures involving extraction with phenol and repeated precipitation with ethanol. 2. The fraction of pulse-labelled RNA from cerebral nuclei that hybridized to homologous DNA exhibited a wide range of turnover values and was heterogeneous in sucrose density gradients. 3. Base composition of the hybridizable RNA was similar to that of the total pulse-labelled material; both were DNA-like. 4. Pulse-labelled cerebral nuclear RNA hybridized to a greater extent than cytoplasmic RNA for at least a week after administration of labelled precursor. This finding suggested that cerebral nuclei contained a hybridizable component that was not transferred to cytoplasm. 5. The rates of decay of the hybridizable fractions of cerebral nuclei and cytoplasm were faster in the newborn animal than in the adult. Presumably a larger proportion of labile messenger RNA molecules was present in the immature brain. 6. Cerebral nuclear and cytoplasmic RNA fractions from newborn or adult rats, labelled either in vivo for periods varying from 4min. to 7 days or in vitro by exposure to [(3)H]-dimethyl sulphate, uniformly hybridized more effectively than the corresponding hepatic preparation. These data suggested that a larger proportion of RNA synthesis was oriented towards messenger RNA formation in brain than in liver.


Evidence for a mass community effect of insecticide-treated bednets on the incidence of malaria on the Kenyan coast.
The use of insecticide-treated bednets (ITBNs) has been shown to be effective in reducing mortality and morbidity from malaria. However, there is mixed evidence as to whether or not community-wide use of ITBNs engenders a 'mass effect', such that those not sleeping under bednets are offered protection from widespread ITBN use in the area in which they live. We have analysed data collected in Kilifi, Kenya, from a cohort of children followed from birth to investigate how the degree of net usage in the locality of a child affects the risk of developing malaria. This effect was explored using a Cox proportional hazards model. For those not using ITBNs, we found that an increasing level of ITBN usage within the area surrounding each child was associated with a decreasing risk of developing malaria, thus providing evidence in support of a mass community effect. The size and significance of this effect were found to decrease as non-overlapping areas of increasing distance away from a child's home were considered. The effect was significant for areas at distances of up to 1.5 km away from each child.


Decrease in GABA synthesis rate in rat cortex following GABA-transaminase inhibition correlates with the decrease in GAD(67) protein.
gamma-Aminobutyric acid (GABA) synthesis in the brain is mediated by two major isoforms of glutamic acid decarboxylase, GAD(65) and GAD(67). The contribution of these isoforms to GABA synthesis flux (V(GAD)) is not known quantitatively. In the present study we compared V(GAD) in cortex of control and vigabatrin-treated rats under alpha-chloralose/70% nitrous oxide anesthesia, with total GAD activity and GAD isoform composition (GAD(65) and GAD(67)) measured by enzymatic assay and quantitative immunoblotting. V(GAD) was determined by re-analysis of 13C NMR data obtained ex vivo and in vivo during infusions of [1-13C]glucose using an extension of a model of glutamate-glutamine cycling that included a discrete GABAergic neuronal compartment with relevant interconnecting fluxes. V(GAD) was significantly lower in vigabatrin-treated rats (0.030-0.05 micromol/min per g, P<0.003) compared to the non-treated control group (0.10-0.15 micromol/min per g). The 67-70% decrease in V(GAD) was associated with a 13% decrease in total GAD activity (P=0.01) and a selective 44+/-15% decrease in GAD(67) protein (from 0.63+/-0.10 to 0.35+/-0.08 microg protein/mg tissue, P<0.05); GAD(65) protein was unchanged. The reduction in GAD(67) protein could account for a maximum of approximately 65% of the decrease in V(GAD) in vigabatrin-treated animals suggesting that inhibition of GAD(65) must have also occurred in these experiments, although product inhibition of GAD(67) by increased GABA could play a role. GAD(67) could account for 56-85% of cortical GABA synthesis flux under basal conditions and the entire flux after vigabatrin treatment.


First clinical trial of tomographic neurofeedback in attention-deficit/hyperactivity disorder: evaluation of voluntary cortical control.
Tomographic neurofeedback (tNF) training was evaluated as a treatment for attention-deficit/hyperactivity disorder (ADHD). To investigate the specificity of the treatment, outcomes were related to learning during tNF. Thirteen children with ADHD trained over 36 lessons to regulate their brain activity in the anterior cingulate cortex (ACC) using both theta-beta frequency and slow cortical potential (SCP) protocols. Thirty-channel electroencephalogram (EEG) was used to calculate low-resolution electromagnetic tNF and to assess the course of the training. Pre- and post-assessments included questionnaires, tests of attention, EEG recordings, and cognitive event-related potentials. Despite behavioural improvement and EEG artefact reduction, only partial learning was found for ACC parameters. Successful regulation was observed only for a simple feedback variant of SCP training, but with ACC-specific effects. Over training, resting EEG analysis indicated individual frequency normalisation rather than unidirectional changes across subjects. These results indicate that clinical improvement after ACC-tNF training can parallel artefact reduction without substantial learning of improved cortical control. However, individual normalisation of resting EEG activity and partial SCP control proved possible in this specific brain region affected in ADHD using tNF. Further studies are needed to clarify which critical aspects mediate region-specific learning in neurofeedback. This study is the first to systematically investigate tNF in children suffering from a psychiatric disorder.


Attitudes regarding organ donation from non-heart-beating donors.
To determine the attitudes toward organ donation from non-heart-beating cadaver donors in a sample of the general public and health care workers. A moderator-administered questionnaire was completed by members of the general public, recruited randomly from a professional consumer research group's database, and health care workers recruited from the same database, family practice clinics, and local hospitals. Two primary scenarios were tested: (1) patient in coma, not going to survive intensive care unit (ICU), and (2) patient lapsing in and out of consciousness, lifetime institutional care. Sixty members of the general public and 68 health care workers completed the questionnaire. The majority of both groups were aware life support could be withdrawn in Scenario 1, however, significantly fewer were aware life support could also be withdrawn in Scenario 2 (83% general public vs 34% general public, P <.001 and 94% health care workers vs 78% health care workers, P =.012). Uncertainty in prognosis was cited as the primary concern. The issue of organ donation was directly linked with withdrawal of life support. The majority of both groups believed that organ donation would be permissible if further life support were deemed to be not in the patient's best interest because of poor short-term prognosis (94% health care workers and 98% general public for Scenario 1 and 87% health care workers and 81% general public for Scenario 2). The greatest difficulty arose in defining futility of care. Expected quality of life, patient's and family's values, opinions, and religious beliefs were felt to be most important in determining decisions regarding futility and withdrawal of life support. Physician beliefs and values were felt to influence decisions more than they should. Both the general public and health care workers support the use of non-heart-beating cadaver donors once a decision has been made to withdraw life support. However, both groups raised concerns regarding how the decision to withdraw life support is made.


Analysis of bovine mammary gland EST and functional annotation of the Bos taurus gene index.
Functional genomic studies of the mammary gland require an appropriate collection of cDNA sequences to assess gene expression patterns from the different developmental and operational states of underlying cell types. To better capture the range of gene expression, a normalized cDNA library was constructed from pooled bovine mammary tissues, and 23,202 expressed sequence tags (EST) were produced and deposited into GenBank. Assembly of these EST with sequences in the Bos taurus Gene Index (BtGI) helped to form 5751 of the current 23,883 tentative consensus (TC) sequences. The majority (87%) of these 5751 assemblies contained only one to three mammary-derived EST. In contrast, 18% of the mammary EST assembled with TC sequences corresponding to 12 genes. These results suggest library normalization was only partially effective, because the reduction in EST for genes abundantly transcribed during lactation could be attributed to pooling. For better assessment of novel content in the mammary library and to add to existing annotation of all bovine sequence elements, gene ontology assignments, and comparative sequence analyses against human genome sequence, human and rodent gene indices, and an index of orthologous alignments of genes across eukaryotes (TOGA) were performed, and results were added to existing BtGI annotation. Over 35,000 of the bovine elements significantly matched human genome sequence, and the positions of some alignments (3%) were unique relative to those using human expressed sequences. Because 3445 TC sequences had no significant match with any data set, mammary-derived cDNA clones representing 23 of these elements were analyzed further for expression and novelty. Only one clone met criteria suggesting the corresponding gene was a divergent ortholog or expressed sequence unique to cattle. These results demonstrate that bovine sequence expression data serve as a resource for characterizing mammalian transcriptomes and identifying those genes potentially unique to ruminants.


Osseous impingement occurs early in flexion in cam-type femoroacetabular impingement: a 4D CT model.
The aim of this study was to examine the real time in vivo kinematics of the hip in patients with cam-type femoroacetabular impingement (FAI). A total of 50 patients (83 hips) underwent 4D dynamic CT scanning of the hip, producing real time osseous models of the pelvis and femur being moved through flexion, adduction, and internal rotation. The location and size of the cam deformity and its relationship to the angle of flexion of the hip and pelvic tilt, and the position of impingement were recorded. In these patients with cam-type FAI, there was significant correlation between the alpha angle and flexion to the point of impingement (mean 41.36°; 14.32° to 57.95°) (R = -0.5815 and p = < 0.001). Patients with a large cam deformity (alpha angle > 78°) had significantly less flexion to the point of impingement (mean 36.30°; 14.32° to 55.18°) than patients with a small cam deformity (alpha angle 60° to 78°) (mean 45.34°; 27.25° to 57.95°) (p = < 0.001). This study has shown that cam-type impingement can occur early in flexion (40°), particularly in patients with large anterior deformities. These patients risk chondrolabral damage during routine activities such as walking, and going up stairs. These findings offer important insights into the cause of the symptoms, the mechanisms of screening and the forms of treatment available for these patients. Cite this article: Bone Joint J 2017;99-B(4 Supple B):41-8.


Cognitive dysfunction following adjuvant chemotherapy for breast cancer: two case studies.
To describe the cognitive dysfunction experienced by two women after they received adjuvant chemotherapy for breast cancer and to discuss the potential role of changes in reproductive status and depression in the development of cognitive dysfunction. Journal articles, research data, and clinical experience. Following chemotherapy, 17%-50% of women with breast cancer experience cognitive dysfunction that may include decrements in memory, attention, and psychomotor efficiency. One mechanism that may contribute to cognitive dysfunction involves changes in reproductive status resulting from chemotherapy. Additionally, the presence of depression may confound the experience of cognitive dysfunction. A comprehensive description of cognitive dysfunction and improved understanding of the interrelationships among cognitive dysfunction, reproductive hormone levels, and depression in women with breast cancer receiving adjuvant chemotherapy may hasten the development of interventions for the management of cognitive dysfunction. Nurses should teach women with breast cancer and their families about the potential for cognitive dysfunction after chemotherapy so the problem can be recognized and interventions can be implemented to help women compensate for the dysfunction.


Surgical site infection after gastrointestinal surgery in children: an international, multicentre, prospective cohort study.
Surgical site infection (SSI) is one of the most common healthcare-associated infections (HAIs). However, there is a lack of data available about SSI in children worldwide, especially from low-income and middle-income countries. This study aimed to estimate the incidence of SSI in children and associations between SSI and morbidity across human development settings. A multicentre, international, prospective, validated cohort study of children aged under 16 years undergoing clean-contaminated, contaminated or dirty gastrointestinal surgery. Any hospital in the world providing paediatric surgery was eligible to contribute data between January and July 2016. The primary outcome was the incidence of SSI by 30 days. Relationships between explanatory variables and SSI were examined using multilevel logistic regression. Countries were stratified into high development, middle development and low development groups using the United Nations Human Development Index (HDI). Of 1159 children across 181 hospitals in 51 countries, 523 (45·1%) children were from high HDI, 397 (34·2%) from middle HDI and 239 (20·6%) from low HDI countries. The 30-day SSI rate was 6.3% (33/523) in high HDI, 12·8% (51/397) in middle HDI and 24·7% (59/239) in low HDI countries. SSI was associated with higher incidence of 30-day mortality, intervention, organ-space infection and other HAIs, with the highest rates seen in low HDI countries. Median length of stay in patients who had an SSI was longer (7.0 days), compared with 3.0 days in patients who did not have an SSI. Use of laparoscopy was associated with significantly lower SSI rates, even after accounting for HDI. The odds of SSI in children is nearly four times greater in low HDI compared with high HDI countries. Policies to reduce SSI should be prioritised as part of the wider global agenda.


TypeTE: a tool to genotype mobile element insertions from whole genome resequencing data.
Alu retrotransposons account for more than 10% of the human genome, and insertions of these elements create structural variants segregating in human populations. Such polymorphic Alus are powerful markers to understand population structure, and they represent variants that can greatly impact genome function, including gene expression. Accurate genotyping of Alus and other mobile elements has been challenging. Indeed, we found that Alu genotypes previously called for the 1000 Genomes Project are sometimes erroneous, which poses significant problems for phasing these insertions with other variants that comprise the haplotype. To ameliorate this issue, we introduce a new pipeline - TypeTE - which genotypes Alu insertions from whole-genome sequencing data. Starting from a list of polymorphic Alus, TypeTE identifies the hallmarks (poly-A tail and target site duplication) and orientation of Alu insertions using local re-assembly to reconstruct presence and absence alleles. Genotype likelihoods are then computed after re-mapping sequencing reads to the reconstructed alleles. Using a high-quality set of PCR-based genotyping of >200 loci, we show that TypeTE improves genotype accuracy from 83% to 92% in the 1000 Genomes dataset. TypeTE can be readily adapted to other retrotransposon families and brings a valuable toolbox addition for population genomics.


Pilot cluster-randomised trial of adjunctive motivational interviewing to reduce crack cocaine use in clients on methadone maintenance.
This pilot trial explored the effectiveness of an adjunctive single session of motivational interviewing (MI) to reduce crack cocaine use in a methadone maintenance treatment population. Twenty-nine participants were cluster randomised by clinician to MI or a crack information control condition as part of treatment as usual. The intervention had a modest impact on one crack cocaine measure but was not statistically significant in this small sample. A large and statistically significant reduction in heroin use amongst those in the MI condition was observed. This pilot study demonstrated that it was feasible to incorporate a psychosocial intervention within a busy outpatient methadone maintenance programme and the findings support the value of undertaking a larger trial.


Release of mycobacterial antigens.
Mycobacterium tuberculosis has evolved from a Mycobacterium canettii-like progenitor pool into one of the most successful and widespread human pathogens. The pathogenicity of M. tuberculosis is linked to its ability to secrete/export/release selected mycobacterial proteins, and it is also established that active release of mycobacterial antigens is a prerequisite for strong immune recognition. Recent research has enabled mycobacterial secretion systems and vesicle-based release of mycobacterial antigens to be elucidated, which together with host-related specificities constitute key variables that determine the outcome of infection. Here, we discuss recently discovered, novel aspects on the nature and the regulation of antigen release of the tuberculosis agent with particular emphasis on the biological characterization of mycobacteria-specific ESX/type VII secretion systems and their secreted proteins, belonging to the Esx, PE, and PPE categories. The importance of specific mycobacterial antigen release is probably best exemplified by the striking differences observed between the cellular events during infection with the ESX-1-deficient, attenuated Mycobacterium bovis BCG compared to the virulent M. tuberculosis, which are clearly important for design of more specific diagnostics and more efficient vaccines.


Imaging characteristics of intraocular foreign bodies: a comparative study of plain film X-ray, computed tomography, ultrasound, and magnetic resonance imaging.
To determine the imaging features of common intraocular foreign bodies (IOFBs) and the ability to differentiate types of IOFBs. Four-mm IOFBs were inserted via through pars plana approach into cadaveric lamb eyes. Six metallic (aluminum, brass, copper, silver, steel, and lead) and seven nonmetallic (plastic [CF6 spectacle plastic and polyvinyl chloride pipe], glass [bottle glass and windshield glass], wood [dry and wet poplar], and stone [slate]) IOFBs were imaged using plain film x-ray, computed tomography scan, ultrasound, and magnetic resonance imaging (T1, T2, and gradient echo sequences). Plain film x-ray had limited ability to differentiate most IOFBs. Computed tomography findings can be divided into low attenuation objects (wood), moderate attenuation (CF6 spectacle plastic), high attenuation without surrounding artifact (polyvinyl chloride, slate, bottle glass, windshield glass, and aluminum), high attenuation with shadow artifact and minimal edge streak artifact (steel, brass, copper), and high attenuation with significant shadow artifact and prominent streak artifact (silver and lead). Density (in Hounsfield units) aided in differentiating the types of IOFBs. Gradient echo sequences on magnetic resonance imaging also held utility. Ultrasound images had considerable overlap in appearances. Imaging techniques can significantly aid in determining the IOFBs type, with computed tomography serving as the best initial modality. X-ray holds limited utility while ultrasound and magnetic resonance imaging are best reserved as adjunctive tests.


Informal coercion in acute inpatient setting--knowledge and attitudes held by mental health professionals.
This pilot study aimed at investigating how mental health professionals on acute psychiatric wards recognize different levels of formal and informal coercions and treatment pressures as well as their attitude towards these interventions. An explorative cross-sectional survey among mental health professionals (N=39) was conducted using a questionnaire that consisted of 15 vignettes describing typical clinical situations on five different stages of the continuum of coercion. Low levels of coercion are recognized adequately while higher levels are grossly underestimated. The degree of coercion inherent to interventions comprising persuasion and leverage was underestimated by professionals with a positive attitude and overestimated by those with a negative attitude towards the respective interventions. No associations of the ability to recognize different levels of coercion with ward or staff related variables were found. Higher knowledge on ambiguous variations of coercive interventions seems to foster more balanced reflections about their ethical implications. Advanced understanding of influencing factors of professionals׳ attitudes towards coercion could lead to improved training of professionals in utilizing interventions to enhance treatment adherence in an informed and ethical way.


Human Genetics of Obesity and Type 2 Diabetes Mellitus: Past, Present, and Future.
Type 2 diabetes mellitus (T2D) and obesity already represent 2 of the most prominent risk factors for cardiovascular disease, and are destined to increase in importance given the global changes in lifestyle. Ten years have passed since the first round of genome-wide association studies for T2D and obesity. During this decade, we have witnessed remarkable developments in human genetics. We have graduated from the despair of candidate gene-based studies that generated few consistently replicated genotype-phenotype associations, to the excitement of an exponential harvest of loci robustly associated with medical outcomes through ever larger genome-wide association study meta-analyses. As well as discovering hundreds of loci, genome-wide association studies have provided transformative insights into the genetic architecture of T2D and other complex traits, highlighting the extent of polygenicity and the tiny effect sizes of many common risk alleles. Genome-wide association studies have also provided a critical starting point for discovering new biology relevant to these traits. Expectations are high that these discoveries will foster development of more effective strategies for intervention, through optimization of precision medicine approaches. In this article, we review current knowledge and provide suggestions for the next steps in genetic research for T2D and obesity. We focus on four areas relevant to precision medicine: genetic architecture, pharmacogenetics and other gene-environment interactions, mechanistic inference, and drug development. As we describe, the genetic architecture of complex traits has major implications for the prospects of precision medicine, rendering some anticipated approaches decidedly unrealistic. We highlight obstacles to the translation of human genetic findings into mechanism inference but are optimistic that, as these are overcome, there is untapped potential for novel drugs and more effective strategies for treating and preventing T2D and obesity.


Optimization of the Light Sword Lens for Presbyopia Correction.
We propose and evaluate the modifications of a light sword lens (LSL) to obtain better performance for distance vision while maintaining good operation for near and intermediate vision. The modifications consisted of assigning angular or circular windows for distance vision while rescaling the LSL profile in the remaining area of the element. The objective performance of the redesigned LSLs was verified numerically by the Strehl ratio and experimentally using correlation coefficients and Michelson contrast. Subjective assessments were provided by monocular visual acuity (VA) and contrast sensitivity (CS) through-focus curves for six patients with paralyzed accommodation. The tested object vergence range was [-4.0, 0.0] diopters (D). All experiments were conducted in a custom-made monocular visual simulator. Computational simulations and objective experiments confirmed the better performance of the modified LSL for the imaging of distant objects. The proposed angular and radial modulations resulted in flat VA and CS through-focus curves, indicating more uniform quality of vision with clearly improved distance vision. The VA provided by the modified LSL profiles showed a maximal improvement of 1.5 lines of acuity with respect to the VA provided by the conventional LSL at distance vision. Optimized LSLs provide better imaging of distant objects while maintaining a large depth of focus. This results in comparable and acceptable quality for distance, intermediate, and near vision. Therefore, the modified LSLs appear to be promising presbyopia correctors. The new design of LSL reveals an improved performance for all ranges of vision and becomes a promissory element for a real presbyopia correction in clinical applications.


In-hospital death and hospital-acquired complications among patients undergoing partial cystectomy for bladder cancer in the United States.
Partial cystectomy (PC) is a therapeutic option for select patients with bladder cancer, but its associated perioperative risks and costs are unknown. We estimated annual rates of PC in a nationally representative sample of hospitals, and analyzed whether hospital volume affects postoperative outcomes and costs in patients undergoing PC. From the Nationwide Inpatient Sample, we selected a weighted cohort of patients with bladder cancer who underwent PC between 2002 and 2008. Differences in length of stay, charges, and clinical outcomes were calculated based on operative volume, and univariate and multivariate regression models were fitted to predict in-hospital mortality (IHM) and hospital-acquired conditions. A total of 10,780 patients with bladder cancer who underwent PC were identified with an annual rate between 1457 and 1628 cases. IHM rates were 1.8%, constituting 195 patients (between 9 and 46 annually). A total of 417 patients (3.9%) experienced a "never event" complication, which Medicare no longer reimburses. The mean annual hospital volume of patients who died was 1.7 cases/y compared with 2.4 cases/y among those without fatal complications. No cases of IHM were identified among hospitals performing at least 5 partial cystectomies/y. In a multivariate regression model increased hospital volume was independently associated with decreased mortality (odds ratio = 0.70, 95% confidence interval; 0.60-0.80). Approximately 1 in 25 patients undergoing PC experience a hospital-acquired complication, and nearly 1 in 50 die as a result of the operation. For each additional case a hospital performs annually, the risk of IHM decreases by 30%.