[Influence of paternal age in schizophrenia].
Schizophrenia is an aetiologically heterogeneous syndrome, with a strong genetic component. Despite a reduced fertility in this disorder, its prevalence is maintained and could be explained by de novo genetic mutations. Advanced paternal age (APA) is a major source of new mutations in human beings and could thus be associated with an increased risk of developing schizophrenia in offspring. New mutations related to APA have been implicated as a cause of sporadic cases in several autosomal dominant diseases and also in neurodevelopmental diseases, autism, intellectual disabilities, and social functioning. The aim of the present study was to summarize the results of studies investigating the role of APA, and to discuss some interpretations. All relevant studies were identified through the National Library of Medicine (PubMed(®) database). Keywords used for research were "age" and "schizophrenia" linked to "paternal or father". We have identified and analysed eight cohort studies, five case-control studies, two meta-analyses, and one review concerning different father's mutations potentially transmitted, two studies comparing paternal age at conception between sporadic versus familial cases of schizophrenia. All studies selected have been published between 2000 and 2009. After controlling for several confounding factors including maternal age, the relative risk of schizophrenia increased from 1.84 to 4.62 in offspring of fathers with an older age of fatherhood. Mother's age showed no significant effects after adjusting for paternal age. There was a significant association between paternal age and risk of developing schizophrenia, there was a weaker association with psychosis. The results of these different studies are confirmed by two recent meta-analyses which found an increased risk of schizophrenia in offspring of fathers older than 35 years. Two main hypotheses could explain these results. The first one is based on the presence of new mutations in the spermatogonia, possibly because of accumulating replication errors in spermatogonial cell lines. This hypothesis is confirmed by Malaspina et al. (2002) [19], who found that patients without a family history of schizophrenia had significantly older fathers than probands with a positive family history of schizophrenia. However, this result has not been confirmed by other studies, and paternal age effect could be also explained by a mechanism called imprinting, which is a form of gene regulation. The second hypothesis is based on the fact that fathers with schizophrenia spectrum personality disorder, known to be genetically related to schizophrenia, could have an advanced age at conception. However, regarding this hypothesis, advanced maternal age at conception should be a risk factor for schizophrenia, and this is not the case. Thus, the first hypothesis seems more plausible than the second. APA has been identified as a risk factor for other psychiatric disorders such as autism, bipolar disorder, obsessive-compulsive disorder, and phobia, and thus seems to be a non-specific risk factor. Furthermore, its association with impaired neurocognitive outcomes during infancy and childhood in normal populations raises the question of the phenotype linked to APA. APA at conception appears to be a risk factor for schizophrenia. This risk factor probably interacts with genetic factors in a gene-environment interaction. To date, there is no validated cut-off at which the risk is significantly increased in offspring. In the future, studies could benefit from analyzing the phenotype related to APA.


Phylogenetic analysis of classical swine fever virus isolates from Peru.
Classical swine fever (CSF) is considered to be endemic in Peru with outbreaks reported to the World Organization for Animal Health as recently as 2008 and 2009. Nevertheless, little is known regarding the genetic subgroup(s) of CSF virus that are circulating in Peru or their relationship to recent CSF viruses that have been isolated from neighbouring South American countries or other parts of the world. In this study, we molecularly characterize CSF viruses that were isolated from domestic pigs from different regions of Peru from the middle of 2007 to early 2008. All virus isolates were found to belong to genetic subgroup 1.1, consistent with the subgroup of viruses that have been identified from other South American countries. Although the Peruvian isolates are most closely related to viruses from Colombia and Brazil, they form a monophyletic clade, which suggests they have a distinct evolutionary history.


Genome-wide identification and transcriptional profiling of small heat shock protein gene family under diverse abiotic stress conditions in Sorghum bicolor (L.).
The small heat shock proteins (sHsps/Hsp20s) are the molecular chaperones that maintain proper folding, trafficking and disaggregation of proteins under diverse abiotic stress conditions. In the present investigation, a genome-wide scan revealed the presence of a total of 47 sHsps in Sorghum bicolor (SbsHsps), distributed across 10 subfamilies, the major subfamily being P (plastid) group with 17 genes. Chromosomes 1 and 3 appear as the hot spot regions for SbsHsps, and majority of them were found acidic, hydrophilic, unstable and intron less. Interestingly, promoter analysis indicated that they are associated with both biotic and abiotic stresses, as well as plant development. Sorghum sHsps exhibited 15 paralogous and 20 orthologous duplications. Expression analysis of 15 genes selected from different subfamilies showed high transcript levels in roots and leaves implying that they are likely to participate in the developmental processes. SbsHsp genes were highly induced by diverse abiotic stresses inferring their critical role in mediating the environmental stress responses. Gene expression data revealed that SbsHsp-02 is a candidate gene expressed in all the tissues under varied stress conditions tested. Our results contribute to the understanding of the complexity of SbsHsp genes and help to analyse them further for functional validation.


Beyond knowing nature: Contact, emotion, compassion, meaning, and beauty are pathways to nature connection.
Feeling connected to nature has been shown to be beneficial to wellbeing and pro-environmental behaviour. General nature contact and knowledge based activities are often used in an attempt to engage people with nature. However the specific routes to nature connectedness have not been examined systematically. Two online surveys (total n = 321) of engagement with, and value of, nature activities structured around the nine values of the Biophila Hypothesis were conducted. Contact, emotion, meaning, and compassion, with the latter mediated by engagement with natural beauty, were predictors of connection with nature, yet knowledge based activities were not. In a third study (n = 72), a walking intervention with activities operationalising the identified predictors, was found to significantly increase connection to nature when compared to walking in nature alone or walking in and engaging with the built environment. The findings indicate that contact, emotion, meaning, compassion, and beauty are pathways for improving nature connectedness. The pathways also provide alternative values and frames to the traditional knowledge and identification routes often used by organisations when engaging the public with nature.


The risk of hypotension following co-prescription of macrolide antibiotics and calcium-channel blockers.
The macrolide antibiotics clarithromycin and erythromycin may potentiate calcium-channel blockers by inhibiting cytochrome P450 isoenzyme 3A4. However, this potential drug interaction is widely underappreciated and its clinical consequences have not been well characterized. We explored the risk of hypotension or shock requiring hospital admission following the simultaneous use of calcium-channel blockers and macrolide antibiotics. We conducted a population-based, nested, case-crossover study involving people aged 66 years and older who had been prescribed a calcium-channel blocker between Apr. 1, 1994, and Mar. 31, 2009. Of these patients, we included those who had been admitted to hospital for the treatment of hypotension or shock. For each antibiotic, we estimated the risk of hypotension or shock associated with the use of a calcium blocker using a pair-matched analytic approach to contrast each patient's exposure to each macrolide antibiotic (erythromycin, clarithromycin or azithromycin) in a seven-day risk interval immediately before admission to hospital and in a seven-day control interval one month earlier. Of the 7100 patients admitted to hospital because of hypotension while receiving a calcium-channel blocker, 176 had been prescribed a macrolide antibiotic during either the risk or control intervals. Erythromycin (the strongest inhibitor of cytochrome P450 3A4) was most strongly associated with hypotension (odds ratio [OR] 5.8, 95% confidence interval [CI] 2.3-15.0), followed by clarithromycin (OR 3.7, 95% CI 2.3-6.1). Azithromycin, which does not inhibit cytochrome P450 3A4, was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8). We found similar results in a stratified analysis of patients who received only dihydropyridine calcium-channel blockers. In older patients receiving a calcium-channel blocker, use of erythromycin or clarithromycin was associated with an increased risk of hypotension or shock requiring admission to hospital. Preferential use of azithromycin should be considered when a macrolide antibiotic is required for patients already receiving a calcium-channel blocker.


Checklists to reduce diagnostic errors.
Diagnostic errors are common and can often be traced to physicians' cognitive biases and failed heuristics (mental shortcuts). A great deal is known about how these faulty thinking processes lead to error, but little is known about how to prevent them. Faulty thinking plagues other high-risk, high-reliability professions, such as airline pilots and nuclear plant operators, but these professions have reduced errors by using checklists. Recently, checklists have gained acceptance in medical settings, such as operating rooms and intensive care units. This article extends the checklist concept to diagnosis and describes three types of checklists: (1) a general checklist that prompts physicians to optimize their cognitive approach, (2) a differential diagnosis checklist to help physicians avoid the most common cause of diagnostic error--failure to consider the correct diagnosis as a possibility, and (3) a checklist of common pitfalls and cognitive forcing functions to improve evaluation of selected diseases. These checklists were developed informally and have not been subjected to rigorous evaluation. The purpose of this article is to argue for the further investigation and revision of these initial attempts to apply checklists to the diagnostic process. The basic idea behind checklists is to provide an alternative to reliance on intuition and memory in clinical problem solving. This kind of solution is demanded by the complexity of diagnostic reasoning, which often involves sense-making under conditions of great uncertainty and limited time.


Fluctuations in species-level protein expression occur during element and nutrient cycling in the subsurface.
While microbial activities in environmental systems play a key role in the utilization and cycling of essential elements and compounds, microbial activity and growth frequently fluctuates in response to environmental stimuli and perturbations. To investigate these fluctuations within a saturated aquifer system, we monitored a carbon-stimulated in situ Geobacter population while iron reduction was occurring, using 16S rRNA abundances and high-resolution tandem mass spectrometry proteome measurements. Following carbon amendment, 16S rRNA analysis of temporally separated samples revealed the rapid enrichment of Geobacter-like environmental strains with strong similarity to G. bemidjiensis. Tandem mass spectrometry proteomics measurements suggest high carbon flux through Geobacter respiratory pathways, and the synthesis of anapleurotic four carbon compounds from acetyl-CoA via pyruvate ferredoxin oxidoreductase activity. Across a 40-day period where Fe(III) reduction was occurring, fluctuations in protein expression reflected changes in anabolic versus catabolic reactions, with increased levels of biosynthesis occurring soon after acetate arrival in the aquifer. In addition, localized shifts in nutrient limitation were inferred based on expression of nitrogenase enzymes and phosphate uptake proteins. These temporal data offer the first example of differing microbial protein expression associated with changing geochemical conditions in a subsurface environment.


Preparing for Operations in a Resource-Depleted and/or Extended Evacuation Environment.
The wars in Afghanistan and Iraq are the only conflicts to which many medics have ever been exposed. These mature theaters have robust medical systems that ensure rapid access to full-spectrum medical care for all combat-wounded and medically injured personnel. As current conflicts draw to a close, U.S. medics may be deployed to environments that will require the ability to stabilize casualties for longer than 1 hour. Historical mission analysis reveals the need to review skills that have not been emphasized during upgrade and predeployment training. This unit?s preparation for the extended care environment can be accomplished using a 4-point approach: (1) review of specific long-term skills training, (2) an extended care lab that reviews extended care skills and then lets the medic practice in a real-time scenario, (3) introduction to the HITMAN mnemonic tool, which helps identify and address patient needs, and (4) teleconsultation.


Anesthetic care for patients with anti-NMDA receptor encephalitis.
Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis, an autoimmune disorder resulting from antibodies directed against the NMDA (glutamate) receptor, is the second most frequent cause of immune-mediated encephalitis. To date, the information related to the anesthetic care of children with this disorder is limited to anecdotal reports. We reviewed the anesthetic care of six patients with anti-NMDA receptor encephalitis who underwent 21 procedures at our institution from 2014 through 2019. The study cohort included six patients, ranging in age from 2 to 18 years, who required anesthetic care during 21 procedures. Airway management included a laryngeal mask airway (n = 8), endotracheal intubation (n = 12), and native airway with spontaneous ventilation (n = 1). Intravenous (IV) induction with propofol was used in 17 procedures for five patients, including three that required rapid sequence intubation using rocuronium or succinylcholine. Inhalation induction with sevoflurane in nitrous oxide (N2O)/oxygen (O2) was chosen for two procedures in two patients. A combination of both induction techniques was used for two patients in two procedures. Maintenance anesthesia was accomplished with a volatile agent, predominantly sevoflurane, for 18 of the 21 procedures; propofol infusion for one procedure; and single dose of propofol was used for two short procedures. N2O was not used for maintenance anesthesia in any of the encounters. None of the patients exhibited adverse events, including hemodynamic instability, thermoregulatory problems, or respiratory events perioperatively. Postoperatively, there was no observed deterioration in clinical status attributed to anesthetic care. Multisystem involvement in anti-NMDA receptor encephalitis includes memory loss, behavior irregularity, psychosis, arrhythmias, blood pressure (BP) instability, and hypoventilation. In our study cohort, we noted no intraoperative issues and deterioration in clinical status following the use of volatile anesthetic agents, opioids, dexmedetomidine, and propofol for general anesthesia (GA) or sedation. As ketamine, xenon, and N2O mediate their anesthetic effects, primarily, through antagonism of NMDA receptors, theoretical concerns suggest that they should be avoided.


Unstirred water layers in intestine: rate determinant of fatty acid absorption from micellar solutions.
Bile acid and fatty acid uptake from micellar solutions by intestinal cells fails to reflect the incremental free energy changes expected for permeation that is rate limited by cell membranes. However, altering the size of the diffulsing particle or the thickness of tle unstirred water layer does change uptake. These observations show that the unstirred water layer is rate limiting for intestinal absorption of lipids from micellar solutions.


OligoPVP: Phenotype-driven analysis of individual genomic information to prioritize oligogenic disease variants.
An increasing number of disorders have been identified for which two or more distinct alleles in two or more genes are required to either cause the disease or to significantly modify its onset, severity or phenotype. It is difficult to discover such interactions using existing approaches. The purpose of our work is to develop and evaluate a system that can identify combinations of alleles underlying digenic and oligogenic diseases in individual whole exome or whole genome sequences. Information that links patient phenotypes to databases of gene-phenotype associations observed in clinical or non-human model organism research can provide useful information and improve variant prioritization for genetic diseases. Additional background knowledge about interactions between genes can be utilized to identify sets of variants in different genes in the same individual which may then contribute to the overall disease phenotype. We have developed OligoPVP, an algorithm that can be used to prioritize causative combinations of variants in digenic and oligogenic diseases, using whole exome or whole genome sequences together with patient phenotypes as input. We demonstrate that OligoPVP has significantly improved performance when compared to state of the art pathogenicity detection methods in the case of digenic diseases. Our results show that OligoPVP can efficiently prioritize sets of variants in digenic diseases using a phenotype-driven approach and identify etiologically important variants in whole genomes. OligoPVP naturally extends to oligogenic disease involving interactions between variants in two or more genes. It can be applied to the identification of multiple interacting candidate variants contributing to phenotype, where the action of modifier genes is suspected from pedigree analysis or failure of traditional causative variant identification.


The phosphoinositide phosphatase MTM-1 regulates apoptotic cell corpse clearance through CED-5-CED-12 in C. elegans.
Multicellular organisms use programmed cell death to eliminate unwanted or potentially harmful cells. Improper cell corpse removal can lead to autoimmune diseases. The development of interventional therapies that increase engulfment activity could represent an attractive approach to treat such diseases. Here, we describe mtm-1, the Caenorhabditis elegans homolog of human myotubularin 1, as a potential negative regulator of apoptotic cell corpse clearance. Loss of mtm-1 function leads to substantially reduced numbers of persistent cell corpses in engulfment mutants, which is a result of a restoration of engulfment function rather than of impaired or delayed programmed cell death. Epistatic analyses place mtm-1 upstream of the ternary GEF complex, which consists of ced-2, ced-5 and ced-12, and parallel to mig-2. Over-activation of engulfment results in the removal of viable cells that have been brought to the verge of death under limiting caspase activity. In addition, mtm-1 also promotes phagosome maturation in the hermaphrodite gonad, potentially through CED-1 receptor recycling. Finally, we show that the CED-12 PH domain can bind to PtdIns(3,5)P(2) (one target of MTM-1 phosphatase activity), suggesting that MTM-1 might regulate CED-12 recruitment to the plasma membrane.


The patient's experience of primary ciliary dyskinesia: a systematic review.
Primary ciliary dyskinesia (PCD) is a rare genetic disorder characterised by progressive sinopulmonary disease, with symptoms starting soon after birth. The aim of this study is to critically review, analyse, and synthesise the literature in order to understand the experiences of patients with primary ciliary dyskinesia (PCD) and the impact on health-related quality of life. MEDLINE, EBSCO, Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO and EMBASE were searched according to the inclusion criteria. A qualitative analysis of 14 studies was conducted. Fourteen studies were included in the review, five with qualitative methodologies. Studies originated from the UK, USA, Italy, Denmark and Belgium, one study included a survey distributed internationally. Significant relationships were found between age and worsening of respiratory symptoms, physical, and mental domains of health-related quality of life, with a greater decline compared with reference populations. Variations between the UK and Italy were found for health-related quality of life and its correlation with time since diagnosis. PCD was found to have a physical impact in all age groups: patients found it difficult to keep up with others, and found energy levels were easily depleted compared to family or peers. In terms of social impact, symptoms lead to embarrassment and a sense of isolation, with patients concealing symptoms and/or their diagnosis. In turn, isolation was also linked with the lack of public and medical knowledge. In relation to emotional impact, anxiety was reported in a number of qualitative studies; patients were anxious about getting sick or when thinking about their future health. The burden of treatment and factors influencing adherence were also discussed in depth. Health-related quality of life decreases with age in patients with PCD. For all age groups, PCD was found to greatly impact physical, emotional, social functioning, and treatment burden. More research is needed on the psychosocial impact of the illness, disease burden and its effect on quality of life.


The Contributing Risk of Tobacco Use for ARDS Development in Burn-Injured Adults With Inhalation Injury.
This study aims to determine the relationship between tobacco use, inhalation injury, and ARDS in burn-injured adults. This study was an observational cohort of 2,485 primary burn admissions to a referral burn center between January 1, 2008 and March 15, 2015. Subjects were evaluated by methods used to account for mediation and traditional approaches (multivariable logistic regression and propensity score analysis). Mediation analysis examined both the (1) indirect effect of tobacco use via inhalation injury as the mediator on ARDS development and (2) the direct effect of tobacco use alone on ARDS development. ARDS development occurred in 6.8% (n = 170) of the cohort. Inhalation injury occurred in 5.0% (n = 125) of the cohort, and ARDS developed in 48.8% (n = 83) of the subjects with inhalation injury. Tobacco use was 2-fold more common in subjects with ARDS. In the mediated model, the direct effect of tobacco use on ARDS, including interaction between tobacco use and inhalation injury, was not significant (odds ratio [OR] 1.63, 95% CI 0.91-2.92, P = .10). However, the indirect effect of tobacco use via inhalation injury as the mediator was significant (OR 1.61, 95% CI 1.25-2.07, P < .001), and the proportion of the total effect of tobacco use operating through the mediator was 55.6%. In the non-mediation models (multivariable logistic regression and propensity score analysis), which controlled for inhalation injury and other covariables, the OR for the association between tobacco use and ARDS was 1.84 (95% CI 1.22-2.81, P < .001) and 1.69 (95% CI 1.04-2.75, P = .03), respectively. In mediation analysis, inhalation injury was the overwhelming predictor for ARDS development, whereas tobacco use has its strongest effect indirectly through inhalation injury. Patients with at least moderate inhalation injury are at greatest risk for ARDS development despite baseline risk factors like tobacco use.


Brothers Leading Healthy Lives: Outcomes from the pilot testing of a culturally and contextually congruent HIV prevention intervention for black male college students.
We used a treatment group-only design to pilot test a newly developed intervention to increase condom use among higher risk heterosexually active African American/black male college students. A community-based participatory research partnership developed the intervention called Brothers Leading Healthy Lives. Following an initial screening of 245 men, 81 eligible men were contacted for participation. Of the 64 men who agreed to participate, 57 completed the intervention and 54 of those completed the 3-month follow-up assessment, for a 93% completion rate. Results show significant changes between the baseline and 3-month follow-up assessments in behavioral outcomes, including reductions in unprotected sex, increase in protection during last intercourse, and fewer condom use errors. Most potential mediators (knowledge, attitudes, intentions, and condom use self-efficacy) also changed significantly in the expected direction. These demonstrated changes provide good evidence that men exposed to this intervention will see changes that reduce their risk for HIV.


Investigation of road salts and biotic stressors on freshwater wetland communities.
The application of road deicing salts has led to the salinization of freshwater ecosystems in northern regions worldwide. Increased chloride concentrations in lakes, streams, ponds, and wetlands may negatively affect freshwater biota, potentially threatening ecosystem services. In an effort to reduce the effects of road salt, operators have increased the use of salt alternatives, yet we lack an understanding of how these deicers affect aquatic communities. We examined the direct and indirect effects of the most commonly used road salt (NaCl) and a proprietary salt mixture (NaCl, KCl, MgCl2), at three environmentally relevant concentrations (150, 470, and 780 mg Cl-/L) on freshwater wetland communities in combination with one of three biotic stressors (control, predator cues, and competitors). The communities contained periphyton, phytoplankton, zooplankton, and two tadpole species (American toads, Anaxyrus americanus; wood frogs, Lithobates sylvaticus). Overall, we found the two road salts did not interact with the natural stressors. Both salts decreased pH and reduced zooplankton abundance. The strong decrease in zooplankton abundance in the highest NaCl concentration caused a trophic cascade that resulted in increased phytoplankton abundance. The highest NaCl concentration also reduced toad activity. For the biotic stressors, predatory stress decreased whereas competitive stress increased the activity of both tadpole species. Wood frog survival, time to metamorphosis, and mass at metamorphosis all decreased under competitive stress whereas toad time to metamorphosis increased and mass at metamorphosis decreased. Road salts and biotic stressors can both affect freshwater communities, but their effects are not interactive.


Quantitative assessment of exposure-response relationships for the efficacy and tolerability of varenicline for smoking cessation.
Population exposure-response analyses involving approximately 2,000 cigarette smokers provided an integrated understanding of dose, exposure, patient characteristics, and response relating to the efficacy and tolerability of varenicline for smoking cessation. Full models with a linear function of area under the concentration-time curve at steady state AUC(0-24)(ss) and covariate effects on the baseline probability of response were constructed. Logistic regression results consistently showed that the end-of-treatment abstinence rate increased with increasing varenicline exposure, from 38% at 0.5 mg b.i.d. to 56% at 1 mg b.i.d. (vs. 22% for placebo). Baseline smoking status and age were predictive of smoking cessation, whereas race and gender showed little or no influence. Nausea was the most common adverse event, with an incidence that was gender-related and that increased with varenicline exposure; at a dosage of 1 mg b.i.d. the predicted probability of nausea relative to placebo was 24 vs. 7% in male subjects and 40 vs. 14% in female subjects. The incidence of nausea also showed a decreasing trend with time.


Electroweak Baryogenesis from Dark-Sector CP Violation.
We present a novel mechanism of electroweak baryogenesis where CP violation occurs in a dark sector, comprised of standard model gauge singlets, thereby evading the strong electric dipole moment constraints. In this framework, the background of the timelike component of a new gauge boson Z_{μ}^{'}, generated at electroweak temperatures, drives the electroweak sphaleron processes to create the required baryon asymmetry. We first discuss the crucial ingredients for this mechanism to work, and then show that all of them can be elegantly embedded in ultraviolet completions with a spontaneously broken gauged lepton number. The models under consideration have a rich phenomenology and can be experimentally probed in leptophilic Z^{'} searches, dark matter searches, heavy Majorana neutrino searches, as well as through hunting for new Higgs portal scalars in multilepton channels at colliders.


Accuracy of estimated phylogenetic trees from molecular data. II. Gene frequency data.
The accuracies and efficiencies of three different methods of making phylogenetic trees from gene frequency data were examined by using computer simulation. The methods examined are UPGMA, Farris' (1972) method, and Tateno et al.'s (1982) modified Farris method. In the computer simulation eight species (or populations) were assumed to evolve according to a given model tree, and the evolutionary changes of allele frequencies were followed by using the infinite-allele model. At the end of the simulated evolution five genetic distance measures (Nei's standard and minimum distances, Rogers' distance, Cavalli-Sforza's f theta, and the modified Cavalli-Sforza distance) were computed for all pairs of species, and the distance matrix obtained for each distance measure was used for reconstructing a phylogenetic tree. The phylogenetic tree obtained was then compared with the model tree. The results obtained indicate that in all tree-making methods examined the accuracies of both the topology and branch lengths of a reconstructed tree (rooted tree) are very low when the number of loci used is less than 20 but gradually increase with increasing number of loci. When the expected number of gene substitutions (M) for the shortest branch is 0.1 or more per locus and 30 or more loci are used, the topological error as measured by the distortion index (dT) is not great, but the probability of obtaining the correct topology (P) is less than 0.5 even with 60 loci. When M is as small as 0.004, P is substantially lower. In obtaining a good topology (small dT and high P) UPGMA and the modified Farris method generally show a better performance than the Farris method. The poor performance of the Farris method is observed even when Rogers' distance which obeys the triangle inequality is used. The main reason for this seems to be that the Farris method often gives overestimates of branch lengths. For estimating the expected branch lengths of the true tree UPGMA shows the best performance. For this purpose Nei's standard distance gives a better result than the others because of its linear relationship with the number of gene substitutions. Rogers' or Cavalli-Sforza's distance gives a phylogenetic tree in which the parts near the root are condensed and the other parts are elongated. It is recommended that more than 30 loci, including both polymorphic and monomorphic loci, be used for making phylogenetic trees. The conclusions from this study seem to apply also to data on nucleotide differences obtained by the restriction enzyme techniques.


A social marketing approach to implementing evidence-based practice in VHA QUERI: the TIDES depression collaborative care model.
Collaborative care models for depression in primary care are effective and cost-effective, but difficult to spread to new sites. Translating Initiatives for Depression into Effective Solutions (TIDES) is an initiative to promote evidence-based collaborative care in the U.S. Veterans Health Administration (VHA). Social marketing applies marketing techniques to promote positive behavior change. Described in this paper, TIDES used a social marketing approach to foster national spread of collaborative care models. The approach relied on a sequential model of behavior change and explicit attention to audience segmentation. Segments included VHA national leadership, Veterans Integrated Service Network (VISN) regional leadership, facility managers, frontline providers, and veterans. TIDES communications, materials and messages targeted each segment, guided by an overall marketing plan. Depression collaborative care based on the TIDES model was adopted by VHA as part of the new Primary Care Mental Health Initiative and associated policies. It is currently in use in more than 50 primary care practices across the United States, and continues to spread, suggesting success for its social marketing-based dissemination strategy. Development, execution and evaluation of the TIDES marketing effort shows that social marketing is a promising approach for promoting implementation of evidence-based interventions in integrated healthcare systems.


The feasibility of computer-assisted 3D navigation in multiple-level lateral lumbar interbody fusion in combination with posterior instrumentation for adult spinal deformity.
The lateral lumbar interbody fusion (LLIF) technique is used to treat many common spinal degenerative pathologies including kyphoscoliosis. The use of spinal navigation for LLIF has not been broadly adopted, especially in adult spinal deformity. The purpose of this study was to evaluate the feasibility as well as the intraoperative and navigation-related complications of computer-assisted 3D navigation (CaN) during multiple-level LLIF for spinal deformity. Retrospective analysis of clinical and operative characteristics was performed for all patients > 18 years of age who underwent multiple-level CaN LLIF combined with posterior instrumentation for adult spinal deformity at the University of Michigan between 2014 and 2020. Intraoperative CaN-related complications, LLIF approach-related postoperative complications, and medical postoperative complications were assessed. Fifty-nine patients were identified. The mean age was 66.3 years (range 42-83 years) and body mass index was 27.6 kg/m2 (range 18-43 kg/m2). The average coronal Cobb angle was 26.8° (range 3.6°-67.0°) and sagittal vertical axis was 6.3 cm (range -2.3 to 14.7 cm). The average number of LLIF and posterior instrumentation levels were 2.97 cages (range 2-5 cages) and 5.78 levels (range 3-14 levels), respectively. A total of 6 intraoperative complications related to the LLIF stage occurred in 5 patients. Three of these were CaN-related and occurred in 2 patients (3.4%), including 1 misplaced lateral interbody cage (0.6% of 175 total lateral cages placed) requiring intraoperative revision. No patient required a return to the operating room for a misplaced interbody cage. A total of 12 intraoperative complications related to the posterior stage occurred in 11 patients, with 5 being CaN-related and occurring in 4 patients (6.8%). Univariate and multivariate analyses revealed no statistically significant risk factors for intraoperative and CaN-related complications. Transient hip weakness and numbness were found to be in 20.3% and 22.0% of patients, respectively. At the 1-month follow-up, weakness was observed in 3.4% and numbness in 11.9% of patients. Use of CaN in multiple-level LLIF in the treatment of adult spinal deformity appears to be a safe and effective technique. The incidence of approach-related complications with CaN was 3.4% and cage placement accuracy was high.


A Study on the Clinical Outcome of Abiraterone Acetate in Castration Resistant Prostate Cancer Patients.
Background: Abiraterone acetate was approved by FDA and EMA in April and September 2011, respectively for treatment of patients with casteration resistant prostate cancer and those previously treated with docetaxel. It is a selective inhibitor of androgen biosynthesis which potentially and irreversibly blocks CYP17, a crucial enzyme in oestrogen and testosterone synthesis. Materials and Methods: This retrospective study was conducted to evaluate the safety and efficacy of abiraterone acetate in the treatment of castration resistant prostate cancer patients. Twenty-two male patients diagnosed with CRPC and experienced treatment failure with one or more lines of treatment (hormonal manipulation or chemotherapy) were selected and administered abiraterone acetate (1,000 mg daily) along with prednisone (5 mg twice daily). Results: Out of 22 patients, 32% had a good response in reduction of PSA values, while 22% had progression in disease and 45% had a stable disease. Potassium, Haemoglobin, and serum sreatinine levels were not affected by the drug. Due to severe GI intolerance, the drug had to be stopped for one patient. The results of this study showed that abiraterone acetate significantly lowered the PSA values and prolonged progression- free survival in metastatic castration resistant prostate cancer patients who had progressed after first-line or second-line treatment. The overall average median survival and the median duration of drug exposure for CRPC who received AA was found to be 11.1 months [range 3-18]. Since AA plus prednisolone are available as oral dosage forms, they can be given in outpatient setting. Conclusion: Abiraterone acetate is a drug of choice for CRPC and also for those who had previously received one or two chemotherapy regimens. Since it is a new therapeutic regimen, this study included small sample size, but there are a few studies indicating the therapeutic efficacy of AA among patients with castration-resistant prostate cancer.


Frameshift mutations at coding mononucleotide repeats of the hRAD50 gene in gastrointestinal carcinomas with microsatellite instability.
Microsatellite instability (MSI) and frameshift mutations in genes containing nucleotide repeats have been reported in a subset of colorectal and gastric carcinomas. This study describes the analysis of MSI-positive colorectal (39 cases) and gastric carcinomas (36 cases) for the presence of frameshift mutations of the six genes known to be involved in DNA repair and containing mononucleotide repeats in their coding region. Our mutational study of the 75 MSI-positive tumors revealed frequent mutations in hRAD50 (23 cases, 31%), BLM (16 cases, 21%), and hMSH6 (16 cases, 21%); rare mutations in BRCA1 (1 case, 1%) and ATM (3 cases, 4%); and no mutation in NBS1. In contrast, no frameshift mutation was found in 60 MSI-negative colorectal and gastric carcinomas. The mutation of hRAD50, a gene that is involved in the response to cellular DNA damage and forms a complex with hMRE11 and NBS1, has not been reported previously. Our results suggest that frameshift mutations of hRAD50, BLM, and hMSH6 are selected and play a role in the tumorigenesis of colorectal and gastric carcinomas with MSI. The MSI targeting of the hRAD50 and BLM genes represents an additional link between MSI and DNA repair because alteration of these genes could accelerate defective DNA repair.


Iliotibial band syndrome in runners: a systematic review.
The popularity of running is still growing and, as participation increases, the incidence of running-related injuries will also rise. Iliotibial band syndrome (ITBS) is the most common injury of the lateral side of the knee in runners, with an incidence estimated to be between 5% and 14%. In order to facilitate the evidence-based management of ITBS in runners, more needs to be learned about the aetiology, diagnosis and treatment of this injury. This article provides a systematic review of the literature on the aetiology, diagnosis and treatment of ITBS in runners. The Cochrane Library, MEDLINE, EMBASE, CINAHL, Web of Science, and reference lists were searched for relevant articles. Systematic reviews, clinical trials or observational studies involving adult runners (>18 years) that focused on the aetiology, diagnosis and/or treatment of ITBS were included and articles not written in English, French, German or Dutch were excluded. Two reviewers independently screened search results, assessed methodological quality and extracted data. The sum of all positive ratings divided by the maximum score was the percentage quality score (QS). Only studies with a QS higher than 60% were included in the analysis. The following data were extracted: study design; number and characteristics of participants; diagnostic criteria for ITBS; exposure/treatment characteristics; analyses/outcome variables of the study; and setting and theoretical perspective on ITBS. The studies of the aetiology of ITBS in runners provide limited or conflicting evidence and it is not clear whether hip abductor weakness has a major role in ITBS. The kinetics and kinematics of the hip, knee and/or ankle/foot appear to be considerably different in runners with ITBS to those without. The biomechanical studies involved small samples, and data seem to have been influenced by sex, height and weight of participants. Although most studies monitored the management of ITBS using clinical tests, these tests have not been validated for this patient group. While the articles were inconsistent regarding the treatment of ITBS, hip/knee coordination and running style appear to be key factors in the treatment of ITBS. Runners might also benefit from mobilization, exercises to strengthen the hip, and advice about running shoes and running surface. The methodological quality of research into the management of ITBS in runners is poor and the results are highly conflicting. Therefore, the study designs should be improved to prevent selection bias and to increase the generalizability of findings.


Plant functional trait change across a warming tundra biome.
The tundra is warming more rapidly than any other biome on Earth, and the potential ramifications are far-reaching because of global feedback effects between vegetation and climate. A better understanding of how environmental factors shape plant structure and function is crucial for predicting the consequences of environmental change for ecosystem functioning. Here we explore the biome-wide relationships between temperature, moisture and seven key plant functional traits both across space and over three decades of warming at 117 tundra locations. Spatial temperature-trait relationships were generally strong but soil moisture had a marked influence on the strength and direction of these relationships, highlighting the potentially important influence of changes in water availability on future trait shifts in tundra plant communities. Community height increased with warming across all sites over the past three decades, but other traits lagged far behind predicted rates of change. Our findings highlight the challenge of using space-for-time substitution to predict the functional consequences of future warming and suggest that functions that are tied closely to plant height will experience the most rapid change. They also reveal the strength with which environmental factors shape biotic communities at the coldest extremes of the planet and will help to improve projections of functional changes in tundra ecosystems with climate warming.


Cohort profile: the Right to Care Clinical HIV Cohort, South Africa.
The research objectives of the Right to Care Clinical HIV Cohort analyses are to: (1) monitor treatment outcomes (including death, loss to follow-up, viral suppression and CD4 count gain among others) for patients on antiretroviral therapy (ART); (2) evaluate the impact of changes in the national treatment guidelines around when to initiate ART on HIV treatment outcomes; (3) evaluate the impact of changes in the national treatment guidelines around what ART regimens to initiate on drug switches; (4) evaluate the cost and cost-effectiveness of HIV treatment delivery models; (5) evaluate the need for and outcomes on second-line and third-line ART; (6) evaluate the impact of comorbidity with non-communicable diseases on HIV treatment outcomes and (7) evaluate the impact of the switch to initiating all patients onto ART regardless of CD4 count. The Right to Care Clinical HIV Cohort is an open cohort of data from 10 clinics in two provinces within South Africa. All clinics include data from 2004 onwards. The cohort currently has data on over 115 000 patients initiated on HIV treatment and patients are followed up every 3-6 months for clinical and laboratory monitoring. Cohort data includes information on demographics, clinical visit, laboratory data, medication history and clinical diagnoses. The data have been used to identify rates and predictors of first-line failure, to identify predictors of mortality for patients on second-line (eg, low CD4 counts) and to show that adolescents and young adults are at increased risk of unsuppressed viral loads compared with adults. Future analyses will inform national models of HIV care and treatment to improve HIV care policy in South Africa.


Epidermal growth factor receptor blockers for the treatment of ovarian cancer.
This is the protocol for a review and there is no abstract. The objectives are as follows: To compare the effectiveness and harmful effects of interventions, which target the epidermal growth factor receptor, in the treatment of ovarian cancer.


Management Strategies to Improve Outcomes of Patients With Inflammatory Bowel Diseases.
Strategies for management of inflammatory bowel diseases are shifting from simple control of symptoms toward full control of these diseases (clinical and endoscopic remission), with the final aim of blocking their progression and preventing bowel damage and disability. New goals have been proposed for treatment, such as treat to target and tight control based on therapeutic monitoring and early intervention. For patients who achieve clinical remission, there is often interest in discontinuation of therapy due to safety or economic concerns. We review the evidence supporting these emerging paradigms, the reasons that early effective treatment can alter progression of inflammatory bowel diseases, the importance of examining objective signs of inflammation, and the safety of reducing treatment dosage. We also discuss recent findings regarding personalization of care, including factors that predict patient outcomes and response to therapies, as well as preventative strategies.


REAPR: a universal tool for genome assembly evaluation.
Methods to reliably assess the accuracy of genome sequence data are lacking. Currently completeness is only described qualitatively and mis-assemblies are overlooked. Here we present REAPR, a tool that precisely identifies errors in genome assemblies without the need for a reference sequence. We have validated REAPR on complete genomes or de novo assemblies from bacteria, malaria and Caenorhabditis elegans, and demonstrate that 86% and 82% of the human and mouse reference genomes are error-free, respectively. When applied to an ongoing genome project, REAPR provides corrected assembly statistics allowing the quantitative comparison of multiple assemblies. REAPR is available at http://www.sanger.ac.uk/resources/software/reapr/.


Non-invasive Fecal Steroid Measurements for Monitoring the Reproductive Status of a Critically Endangered Yangtze Finless Porpoises (Neophocaena asiaeorientalis asiaeorientalis).
Yangtze finless porpoise (Neophocaena asiaeorientalis asiaeorientalis) is a critically endangered freshwater cetacean dwelling in the Yangtze River and its adjoining lakes. Affected mainly by the various anthropogenic activities in this region, its population decreased dramatically in the past two decades. To protect this animal from extinction, captive breeding program is an important way to provide basic knowledge for wild population conservation. Non-invasive fecal steroid radioimmunoassay technique was validated in three captive Yangtze finless porpoises for the first time in this study. The seasonality of one captive male and the reproductive status of two females were investigated by longitudinal monitoring their fecal reproductive steroid hormone metabolites. Pregnancy could be diagnosed by an abrupt increase in fecal progesterone metabolites. In late pregnancy (4 months before birth), a significant decrease of fecal progesterone metabolites was observed, which might be referenced for the expectation of parturition date. Seven estrous cycles were recognized in one breeding season of a non-pregnant female judged by the variation of fecal progesterone metabolite levels. The fecal progesterone metabolite level was proved a reliable and precise indicator for estrus and pregnancy diagnosis.


Extending professional education to health workers at grass root level: an experience from all India institute of medical sciences, new delhi.
In India, the opportunities for professional education of the grass root level health workers are grossly inadequate. Capacity building of all categories of health workers is needed for enhancing health outcomes. To plan and implement a professional development training program for all categories of allied health workers and to assess its outcomes in terms of knowledge and skills. We planned and organized a 'one week'(15 h) training program for 10 categories of allied health workers (1260) working in our hospital. The program included nine generic skills/topics: the prestige of AIIMS, sterilization & infection control, universal precaution, biomedical waste management, public health, life style & healthy nutrition, fire safety, communication skills and office procedure besides subject specific skills. Trainers were drawn from 12 departments. Training methodology included interactive lectures, narratives, demonstrations, videos, PPT slides, and informal discussions with participants. The effectiveness of the program was judged on the basis of participants' feedback, feedback from the supervisors, and our own observations post training. Feedback from the participants and their supervisors after training was encouraging. The participants described training as a "life time experience". The supervisors reported improvement in confidence, communication skills, and awareness of workers. The success of the program was due to the use of interactive methods, involvement of multidisciplinary team, and commitment from leadership. We recommend that professional education should be linked with career advancement. Academic institutions can play a key role in taking such initiatives.


The DEMS-DOSS study: validating a delirium monitoring tool in hospitalised older adults.
to evaluate the sensitivity, specificity and test-retest reliability of the Delirium Early Monitoring System-Delirium Observation Screening Scale (DEMS-DOSS). prospective diagnostic accuracy study of a convenience sample of admitted older adults with DEMS-DOSS and reference standard assessments. 60-bed aged care precinct at a metropolitan hospital in Sydney, Australia. 156 patients (aged ≥65 years old) were recruited to participate between April 2018 and March 2020. One hundred participants were included in the analysis. Participants were scored on the DEMS-DOSS. Trained senior aged care nurses conducted a standardised clinical interview based on the Diagnostic and Statistical Manual of Mental Disorder (DSM)-IV delirium criteria, within two hours of DEMS-DOSS completion. The senior aged care nurse undertaking the DSM-IV interview was blinded to the results of the DEMS-DOSS. Participants' mean age was 84 (SD ±7.3) years and 39% (n = 39) had a documented diagnosis of dementia. Delirium was detected in 38% (n = 38) according to the reference standard. The DEMS-DOSS had a sensitivity of 76.3% and a specificity of 75.8% for delirium. The area under the receiver operating characteristics curve for delirium was 0.76. The test-retest reliability of the DEMS-DOSS was found to be high (r = 0.915). DEMS-DOSS is a sensitive and specific tool to assist with monitoring new onset and established delirium in hospitalised older adults. Further studies are required to evaluate the impact of the monitoring tool on health outcomes.


Fungal natural products in research and development.
To date approximately 100 000 fungal species are known although far more than one million are expected. The variety of species and the diversity of their habitats, some of them less exploited, allow the conclusion that fungi continue to be a rich source of new metabolites. Besides the conventional fungal isolates, an increasing interest in endophytic and in marine-derived fungi has been noticed. In addition new screening strategies based on innovative chemical, biological, and genetic approaches have led to novel fungal metabolites in recent years. The present review focuses on new fungal natural products published from 2009 to 2013 highlighting the originality of the structures and their biological potential. Furthermore synthetic products based on fungal metabolites as well as new developments in the uses or the biological activity of known compounds or new derivatives are discussed.


Theranostic magnetic nanoparticles.
Early detection and treatment of disease is the most important component of a favorable prognosis. Biomedical researchers have thus invested tremendous effort in improving imaging techniques and treatment methods. Over the past decade, concepts and tools derived from nanotechnology have been applied to overcome the problems of conventional techniques for advanced diagnosis and therapy. In particular, advances in nanoparticle technology have created new paradigms for theranostics, which is defined as the combination of therapeutic and diagnostic agents within a single platform. In this Account, we examine the potential advantages and opportunities afforded by magnetic nanoparticles as platform materials for theranostics. We begin with a brief overview of relevant magnetic parameters, such as saturation magnetization, coercivity, and magnetocrystalline anisotropy. Understanding the interplay of these parameters is critical for optimizing magnetic characteristics needed for effective imaging and therapeutics, which include magnetic resonance imaging (MRI) relaxivity, heat emission, and attractive forces. We then discuss approaches to constructing an MRI nanoparticle contrast agent with high sensitivity. We further introduce a new design concept for a fault-free contrast agent, which is a T1 and T2 dual mode hybrid. Important capabilities of magnetic nanoparticles are the external controllability of magnetic heat generation and magnetic attractive forces for the transportation and movement of biological objects. We show that these functions can be utilized not only for therapeutic hyperthermia of cancer but also for controlled release of cancer drugs through the application of an external magnetic field. Additionally, the use of magnetic nanoparticles to drive mechanical forces is demonstrated to be useful for molecular-level cell signaling and for controlling the ultimate fate of the cell. Finally, we show that targeted imaging and therapy are made possible by attaching a variety of imaging and therapeutic components. These added components include therapeutic genes (small interfering RNA, or siRNA), cancer-specific ligands, and optical reporting dyes. The wide range of accessible features of magnetic nanoparticles underscores their potential as the most promising platform material available for theranostics.


Nerve injuries associated with pediatric supracondylar humeral fractures: a meta-analysis.
Supracondylar fractures of the humerus are the most common type of elbow fracture in children. Of all complications associated with supracondylar fractures, nerve injury ranks highest, although reports of the incidence of specific neurapraxia vary. This meta-analysis aims primarily to determine the risk of traumatic neurapraxia in extension-type supracondylar fractures as compared with that of flexion-type fractures; secondarily it aims to use subgroup analysis to assess the risk of iatrogenic neurapraxia induced by pin fixation. A literature search identified studies that reported the incidence of nerve injury presenting with displaced supracondylar fractures of the humerus in children. Meta-analysis was subsequently performed to evaluate the risk of traumatic neurapraxia associated with supracondylar fractures. Subgroup analysis of included articles was additionally performed to assess the risk of iatrogenic neurapraxia associated with lateral-only or medial/lateral pin fixation. Data from 5148 patients with 5154 fractures were pooled for meta-analysis. Among these patients, traumatic neurapraxia occurred at a weighted event rate of 11.3%. Anterior interosseous nerve injury predominated in extension-type fractures, representing 34.1% of associated neurapraxias; meanwhile, ulnar neuropathy occurred most frequently in flexion-type injuries, representing 91.3% of associated neurapraxias. Nerve injury induced by lateral-only pinning occurred at a weighted event rate of 3.4%, while the introduction of a medial pin elicited neurapraxia at a weighted event rate of 4.1%. Lateral pinning carried increased risk of median neuropathy, whereas the use of a medial pin significantly increased the risk of ulnar nerve injury. Of nerve injury associated with extension-type fractures, anterior interosseous neurapraxia ranks highest, whereas of flexion-type neuropathy, ulnar nerve injury predominates. We confirm that medial pinning carries the greater overall risk of nerve injury as compared with lateral-only pinning and that the ulnar nerve is at risk of injury in medially pinned patients. We additionally suggest that lateral pinning carries neurapraxic risk with respect to the median nerve. Level IV; Meta-analysis.


Kurtosis-Based CRTRL Algorithms for Fully Connected Recurrent Neural Networks.
In this paper, kurtosis-based complex-valued real-time recurrent learning (KCRTRL) and kurtosis-based augmented CRTRL (KACRTRL) algorithms are proposed for training fully connected recurrent neural networks (FCRNNs) in the complex domain. These algorithms are designed by minimizing the cost functions based on the kurtosis of a complex-valued error signal. The KCRTRL algorithm exploits the circularity properties of the complex-valued signals, and this algorithm not only provides a faster convergence rate but also results in a lower steady-state error. However, the KCRTRL algorithm is suboptimal in the processing of noncircular (NC) complex-valued signals. On the other hand, the KACRTRL algorithm contains a complete second-order information due to the augmented statistics, thus considerably improves the performance of the FCRNN in the processing of NC complex-valued signals. Simulation results on the one-step-ahead prediction problems show that the proposed KCRTRL algorithm significantly enhances the performance for only circular complex-valued signals, whereas the proposed KACRTRL algorithm provides more superior performance than existing algorithms for NC complex-valued signals in terms of the convergence rate and the steady-state error.


Allostatic Self-efficacy: A Metacognitive Theory of Dyshomeostasis-Induced Fatigue and Depression.
This paper outlines a hierarchical Bayesian framework for interoception, homeostatic/allostatic control, and meta-cognition that connects fatigue and depression to the experience of chronic dyshomeostasis. Specifically, viewing interoception as the inversion of a generative model of viscerosensory inputs allows for a formal definition of dyshomeostasis (as chronically enhanced surprise about bodily signals, or, equivalently, low evidence for the brain's model of bodily states) and allostasis (as a change in prior beliefs or predictions which define setpoints for homeostatic reflex arcs). Critically, we propose that the performance of interoceptive-allostatic circuitry is monitored by a metacognitive layer that updates beliefs about the brain's capacity to successfully regulate bodily states (allostatic self-efficacy). In this framework, fatigue and depression can be understood as sequential responses to the interoceptive experience of dyshomeostasis and the ensuing metacognitive diagnosis of low allostatic self-efficacy. While fatigue might represent an early response with adaptive value (cf. sickness behavior), the experience of chronic dyshomeostasis may trigger a generalized belief of low self-efficacy and lack of control (cf. learned helplessness), resulting in depression. This perspective implies alternative pathophysiological mechanisms that are reflected by differential abnormalities in the effective connectivity of circuits for interoception and allostasis. We discuss suitably extended models of effective connectivity that could distinguish these connectivity patterns in individual patients and may help inform differential diagnosis of fatigue and depression in the future.


DNA Barcoding of Metazoan Zooplankton Copepods from South Korea.
Copepods, small aquatic crustaceans, are the most abundant metazoan zooplankton and outnumber every other group of multicellular animals on earth. In spite of ecological and biological importance in aquatic environment, their morphological plasticity, originated from their various lifestyles and their incomparable capacity to adapt to a variety of environments, has made the identification of species challenging, even for expert taxonomists. Molecular approaches to species identification have allowed rapid detection, discrimination, and identification of cryptic or sibling species based on DNA sequence data. We examined sequence variation of a partial mitochondrial cytochrome C oxidase I gene (COI) from 133 copepod individuals collected from the Korean Peninsula, in order to identify and discriminate 94 copepod species covering six copepod orders of Calanoida, Cyclopoida, Harpacticoida, Monstrilloida, Poecilostomatoida and Siphonostomatoida. The results showed that there exists a clear gap with ca. 20 fold difference between the averages of within-specific sequence divergence (2.42%) and that of between-specific sequence divergence (42.79%) in COI, suggesting the plausible utility of this gene in delimitating copepod species. The results showed, with the COI barcoding data among 94 copepod species, that a copepod species could be distinguished from the others very clearly, only with four exceptions as followings: Mesocyclops dissimilis-Mesocyclops pehpeiensis (0.26% K2P distance in percent) and Oithona davisae-Oithona similis (1.1%) in Cyclopoida, Ostrincola japonica-Pseudomyicola spinosus (1.5%) in Poecilostomatoida, and Hatschekia japonica-Caligus quadratus (5.2%) in Siphonostomatoida. Thus, it strongly indicated that COI may be a useful tool in identifying various copepod species and make an initial progress toward the construction of a comprehensive DNA barcode database for copepods inhabiting the Korean Peninsula.


Fibroblast-secreted hepatocyte growth factor mediates epidermal growth factor receptor tyrosine kinase inhibitor resistance in triple-negative breast cancers through paracrine activation of Met.
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have shown clinical efficacy in lung, colon, and pancreatic cancers. In lung cancer, resistance to EGFR TKIs correlates with amplification of the hepatocyte growth factor (HGF) receptor tyrosine kinase Met. Breast cancers do not respond to EGFR TKIs, even though EGFR is overexpressed. This intrinsic resistance to EGFR TKIs in breast cancer does not correlate with Met amplification. In several tissue monoculture models of human breast cancer, Met, although expressed, is not phosphorylated, suggesting a requirement for a paracrine-produced ligand. In fact, HGF, the ligand for Met, is not expressed in epithelial cells but is secreted by fibroblasts in the tumor stroma. We have identified a number of breast cancer cell lines that are sensitive to EGFR TKIs. This sensitivity is in conflict with the observed clinical resistance to EGFR TKIs in breast cancers. Here we demonstrate that fibroblast secretion of HGF activates Met and leads to EGFR/Met crosstalk and resistance to EGFR TKIs in triple-negative breast cancer (TNBC). The SUM102 and SUM149 TNBC cell lines were used in this study. Recombinant HGF as well as conditioned media from fibroblasts expressing HGF were used as sources for Met activation. Furthermore, we co-cultured HGF-secreting fibroblasts with Met-expressing cancer cells to mimic the paracrine HGF/Met pathway, which is active in the tumor microenvironment. Cell growth, survival, and transformation were measured by cell counting, clonogenic and MTS assays, and soft agar colony formation, respectively. Student's t test was used for all statistical analysis. Here we demonstrate that treatment of breast cancer cells sensitive to EGFR TKIs with recombinant HGF confers a resistance to EGFR TKIs. Interestingly, knocking down EGFR abrogated HGF-mediated cell survival, suggesting a crosstalk between EGFR and Met. HGF is secreted as a single-chain pro-form, which has to be proteolytically cleaved in order to activate Met. To determine whether the proteases required to activate pro-HGF were present in the breast cancer cells, we utilized a fibroblast cell line expressing pro-HGF (RMF-HGF). Addition of pro-HGF-secreting conditioned fibroblast media to TNBC cells as well as co-culturing of TNBC cells with RMF-HGF fibroblasts resulted in robust phosphorylation of Met and stimulated proliferation in the presence of an EGFR TKI. Taken together, these data suggest a role for Met in clinical resistance to EGFR TKIs in breast cancer through EGFR/Met crosstalk mediated by tumor-stromal interactions.


Biomedical and psychosocial factors associated with disability after peripheral nerve injury.
The purpose of this study was to evaluate the biomedical and psychosocial factors associated with disability at a minimum of six months following upper-extremity nerve injury. This cross-sectional study included patients who were assessed between six months and fifteen years following an upper-extremity nerve injury. Assessment measures included patient self-report questionnaires (the Disabilities of the Arm, Shoulder and Hand Questionnaire [DASH]; pain questionnaires; and general health and mental health questionnaires). DASH scores were compared by using unpaired t tests (sex, Workers' Compensation/litigation, affected limb, marital status, education, and geographic location), analysis of variance (nerve injured, work status, and income), or correlations (age and time since injury). Multivariable linear regression analysis was used to evaluate the predictors of the DASH scores. The sample included 158 patients with a mean age (and standard deviation) of 41 ± 16 years. The median time from injury was fourteen months (range, six to 167 months). The DASH scores were significantly higher for patients receiving Workers' Compensation or involved in litigation (p = 0.02), had a brachial plexus injury (p = 0.001), or were unemployed (p < 0.001). There was a significant positive correlation between the DASH scores and pain intensity (r = 0.51, p < 0.001). In the multivariable regression analysis of the predictors of the DASH scores, the following predictors explained 52.7% of the variance in the final model: pain intensity (Beta = 0.230, p = 0.006), brachial plexus injury (Beta = -0.220, p = 0.000), time since injury (Beta = -0.198, p = 0.002), pain catastrophizing score (Beta = 0.192, p = 0.025), age (Beta = 0.187, p = 0.002), work status (Beta = 0.179, p = 0.008), cold sensitivity (Beta = 0.171, p = 0.015), depression score (Beta = 0.133, p = 0.066), Workers' Compensation/litigation (Beta = 0.116, p = 0.049), and female sex (Beta = -0.104, p = 0.090). Patients with a peripheral nerve injury report substantial disability, pain, and cold sensitivity. Disability as measured with the DASH was predicted by brachial plexus injury, older age, pain intensity, work status, time since injury, cold sensitivity, and pain catastrophizing.


Trial registration in Latin America and the Caribbean's: study of randomized trials published in 2010.
To determine the prevalence of trial registration in randomized controlled trials (RCTs) published in 2010 (PUBMED/LILACS) from Latin America and the Caribbean's (LAC) and to compare methodological characteristics between registered and nonregistered RCTs. A search for detecting RCTs in which at least the first/contact author had a LAC's affiliation was made. We determined if RCTs were registered in the International Clinical Trial Registry Platform (ICTRP). Data were independently extracted by two authors. The risk of bias (RoB) was assessed in all registered RCTs (n=89) and in a sample of nonregistered RCTs (n=237). The search identified 1,695 references; 526 RCTs from 19 countries were included. 16.9% (89/526) of RCTs were registered in the ICTRP; however, only 21 (4.0%) were prospectively registered. A significant difference was found in the overall assessment of the RoB between registered and nonregistered RCTs. Overall, registered RCTs were multinational, had larger sample size and longer follow-up, and reported more frequently information on funding, conflict of interests, and ethic issues. No significant differences were found when analyzing prospectively registered RCTs. This study shows that trial registration rates are still low in LAC and the quality of reporting needs to be improved.


Summary of the recommendations on sexual dysfunctions in men.
Sexual health is an integral part of overall health. Sexual dysfunction can have a major impact on quality of life and psychosocial and emotional well-being. To provide evidence-based, expert-opinion consensus guidelines for clinical management of sexual dysfunction in men. An international consultation collaborating with major urologic and sexual medicine societies convened in Paris, July 2009. More than 190 multidisciplinary experts from 33 countries were assembled into 25 consultation committees. Committee members established scope and objectives for each chapter. Following an exhaustive review of available data and publications, committees developed evidence-based guidelines in each area. Main Outcome Measures. New algorithms and guidelines for assessment and treatment of sexual dysfunctions were developed based on work of previous consultations and evidence from scientific literature published from 2003 to 2009. The Oxford system of evidence-based review was systematically applied. Expert opinion was based on systematic grading of medical literature, and cultural and ethical considerations. Algorithms, recommendations, and guidelines for sexual dysfunction in men are presented. These guidelines were developed in an evidence-based, patient-centered, multidisciplinary manner. It was felt that all sexual dysfunctions should be evaluated and managed following a uniform strategy, thus the International Consultation of Sexual Medicine (ICSM-5) developed a stepwise diagnostic and treatment algorithm for sexual dysfunction. The main goal of ICSM-5 is to unmask the underlying etiology and/or indicate appropriate treatment options according to men's and women's individual needs (patient-centered medicine) using the best available data from population-based research (evidence-based medicine). Specific evaluation, treatment guidelines, and algorithms were developed for every sexual dysfunction in men, including erectile dysfunction; disorders of libido, orgasm, and ejaculation; Peyronie's disease; and priapism. Sexual dysfunction in men represents a group of common medical conditions that need to be managed from a multidisciplinary perspective.


NAADP receptors.
Nicotinic acid adenine dinucleotide phosphate (NAADP) is a recently described Ca2+ mobilizing messenger. First described in the sea urchin egg, it has been shown to mobilize Ca2+ from intracellular stores. It is a remarkably potent molecule, and recent reports show that its cellular levels change in response to a variety of agonists confirming its role as a Ca2+ mobilizing messenger. In many cases NAADP interacts with other Ca2+ mobilizing messengers such as inositol 1,4,5 trisphosphate (IP3 and cyclic adenosine diphosphate ribose (cADPR) in shaping cytosolic Ca2+ signals. What is not clear is the molecular nature of the NAADP-sensitive Ca2+ release mechanism and its sub-cellular localization. In this review we focus on the recent progress made in sea urchin eggs, which indicates that NAADP activates a novel Ca2+ release channel distinct from the relatively well-characterized IP3 and ryanodine receptors. Furthermore, in the sea urchin egg, the NAADP-sensitive store appears to be separate from the endoplasmic reticulum (ER) and is most likely an acidic store. These findings have also been reinforced by similar findings by some in mammalian cells. Finally, we discuss ongoing strategies to characterise NAADP-binding proteins which will greatly enhance our understanding of NAADP-mediated Ca2+ signalling, and lead to the development of more selective tools to probe the role of this messenger.


Beyond neurovascular coupling, role of astrocytes in the regulation of vascular tone.
The brain possesses two intricate mechanisms that fulfill its continuous metabolic needs: cerebral autoregulation, which ensures constant cerebral blood flow over a wide range of arterial pressures and functional hyperemia, which ensures rapid delivery of oxygen and glucose to active neurons. Over the past decade, a number of important studies have identified astrocytes as key intermediaries in neurovascular coupling (NVC), the mechanism by which active neurons signal blood vessels to change their diameter. Activity-dependent increases in astrocytic Ca(2+) activity are thought to contribute to the release of vasoactive substances that facilitate arteriole vasodilation. A number of vasoactive signals have been identified and their role on vessel caliber assessed both in vitro and in vivo. In this review, we discuss mechanisms implicating astrocytes in NVC-mediated vascular responses, limitations encountered as a result of the challenges in maintaining all the constituents of the neurovascular unit intact and deliberate current controversial findings disputing a main role for astrocytes in NVC. Finally, we briefly discuss the potential role of pericytes and microglia in NVC-mediated processes.


Pharmacokinetics of EF5 [2-(2-nitro-1-H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl) acetamide] in human patients: implications for hypoxia measurements in vivo by 2-nitroimidazoles.
Pharmacokinetic studies were performed on the first 28 patients enrolled in a phase I trial to determine the ability of EF5 [2-(2-nitro-1-H-imidazolI-yl)-N-(2,2,3,3,3-pentafluoropropyl) acetamide] to detect hypoxia in human tumors in the absence of patient toxicity. EF5 was made in purified form and formulated for intravenous injection by the National Cancer Institute. After obtaining consent from the patients, EF5 was administered and blood samples were drawn at various times over approximately 48 h. For most patients it was possible to collect total urine at approximately 8-h intervals. EF5 in plasma and urine was analyzed by high-performance liquid chromatography. EF5's plasma concentration followed a simple exponential decay following infusion. The plasma half-life was 11.7 +/- 2.6 h (+/- SD) and was not affected by drug dose (9 to 28 mg/kg), fractional urine recovery, patient weight or gender. Absolute plasma values suggested even biodistribution of the drug throughout the soft tissue with a volume of distribution equal to 0.56 l/ kg. Despite the relatively high lipid partition coefficient (logP = 0.6), EF5 was excreted primarily (up to 70%) via kidney clearance. No drug metabolites (e.g. retaining the 2-nitroimidazole chromophore) were detected in either plasma or urine. No toxicity was found at drug doses adequate to detect tumor hypoxia. Currently held paradigms of 2-nitroimidazole metabolism (e.g. clearance rate and toxicity as affected by octanol/ water partition coefficient) are discussed. The results reported herein suggest that EF5 is biologically stable with predictable pharmacokinetics. EF5's consistent half-life and clearance properties will allow quantitative analysis of EF5 binding relative to tissue oxygen levels.


Collecting and applying data on social determinants of health in health care settings.
Despite strong evidence linking patients' social circumstances to their health, little guidance exists for health care practitioners and institutions on addressing social needs in clinical settings. Current approaches to social determinants generally focus on population-level and policy interventions; these overlook individual and clinical innovations within health care that can address patients' social circumstances. This article proposes a framework for how social determinants interventions in the health care system can be construed across 3 tiers-patient, institution, and broader population-and describes ways to collect data and target interventions at these levels.


Butylphenyl dGTP: a selective and potent inhibitor of mammalian DNA polymerase alpha.
BuPdGTP , the 2'-deoxyribonucleoside 5'-triphosphate of the DNA polymerase alpha (pol alpha)-specific inhibitor, N2-(p-n- butylphenyl )guanine, was examined with respect to its mechanism and its capacity to inhibit the mammalian DNA polymerases, pol alpha, pol beta, and pol gamma. BuP dGTP was specifically inhibitory for pol alpha, with no discernible activity on pol beta and pol gamma. The potency of BuP dGTP is unprecedented, with an apparent Ki less than 10 nanomolar. The unusual potency of the BuP dGTP is derived primarily from the 5' alpha and beta phosphoryl moieties, whose binding to enzyme complements that of the base-linked butylphenyl substituent. BuP dGTP is competitive with dGTP and apparently not subject to polymerization. Experiments employing BuP dGTP in the presence of a non-complementary template suggest that the core polymerase or an associated coprotein contains dNTP binding sites which recognize specific nucleic acid bases. The partial sensitivity of selected, non-mammalian DNA polymerases suggests that modification of the N2 substituent of dGTP will be a useful route to the design of novel, polymerase-specific affinity-probes.


Maximizing the population benefit from thrombolysis in acute ischemic stroke: a modeling study of in-hospital delays.
To maximize the benefits of thrombolysis, it is necessary not only to treat more patients, but to deliver treatment as early as possible. The aims of our study were to prospectively evaluate the clinical benefit from reducing delays in the emergency stroke pathway at our district hospital and examine outcomes from scenarios that include extension of the alteplase license. We developed a discrete-event simulation from prospective data for patients with stroke arriving at our large district hospital. We modeled current practice and assessed the impact on stroke outcomes of measures to reduce in-hospital delays to alteplase treatment and of extensions to the European license for alteplase from 3 to 4.5 hours and to people aged >80 years. Extension of the time window to 4.5 hours increases the thrombolysis rate by 4%, yielding an additional 2 patients per year with minimal or no disability at 3 months. Time window extension is most effective when combined with a system of prealerts, achieving a thrombolysis rate of 15% and an additional 8 patients per year with minimal or no disability, increasing to 13 patients per year with extension of the license to patients >80 years. If implemented alone, extension of the time window for alteplase has only a modest additional population disability benefit, but this benefit can be increased 5-fold if time window extension is combined with substantial reductions to in-hospital delays.


Generating synthesized computed tomography (CT) from cone-beam computed tomography (CBCT) using CycleGAN for adaptive radiation therapy.
Throughout the course of delivering a radiation therapy treatment, which may take several weeks, a patient's anatomy may change drastically, and adaptive radiation therapy (ART) may be needed. Cone-beam computed tomography (CBCT), which is often available during the treatment process, can be used for both patient positioning and ART re-planning. However, due to the prominent amount of noise, artifacts, and inaccurate Hounsfield unit (HU) values, the dose calculation based on CBCT images could be inaccurate for treatment planning. One way to solve this problem is to convert CBCT images to more accurate synthesized CT (sCT) images. In this work, we have developed a cycle-consistent generative adversarial network framework (CycleGAN) to synthesize CT images from CBCT images. This model is capable of image-to-image translation using unpaired CT and CBCT images in an unsupervised learning setting. The sCT images generated from CBCT through this CycleGAN model are visually and quantitatively similar to real CT images with decreased mean absolute error (MAE) from 69.29 HU to 29.85 HU for head-and-neck (H&N) cancer patients. The dose distributions calculated on the sCT by CycleGAN demonstrated a higher accuracy than those on CBCT in a 3D gamma index analysis with increased gamma index pass rate from 86.92% to 96.26% under 1 mm/1% criteria, when using the deformed planning CT image (dpCT) as the reference. We also compared the CycleGAN model with other unsupervised learning methods, including deep convolutional generative adversarial networks (DCGAN) and progressive growing of GANs (PGGAN), and demonstrated that CycleGAN outperformed the other two models. A phantom study has been conducted to compare sCT with dpCT, and the increase of structural similarity index from 0.91 to 0.93 shows that CycleGAN performed better than DIR in terms of preserving anatomical accuracy.


Sex, race, and the development of acute lung injury.
Prior studies suggest that mortality differs by sex and race in patients who develop acute lung injury (ALI). Whether differences in presentation account for these disparities remains unclear. We sought to determine whether sexual and racial differences exist in the rate of ALI development and ALI-related mortality after accounting for differences in clinical presentations. This was a multicenter, observational cohort study of 5,201 patients at risk for ALI. Multivariable logistic regression with adjustment for center-level effects was used to adjust for potential covariates. The incidence of ALI development was 5.9%; in-hospital mortality was 5.0% for the entire cohort, and 24.4% for those patients who developed ALI. Men were more likely to develop ALI compared to women (6.9% vs 4.7%, P , .001) and had a nonsignificant increase in mortality when ALI developed (27.6% vs 18.5%, P 5 .08). However, after adjustment for baseline imbalances between sexes these differences were no longer significant. Black patients, compared to white patients, presented more frequently with pneumonia, sepsis, or shock and had higher severity of illness. Black patients were less likely to develop ALI than whites (4.5% vs. 6.5%, P 5 .014), and this association remained statistically significant after adjusting for differences in presentation (OR, 0.66; 95 % CI, 0.45-0.96). Sex and race differences exist in the clinical presentation of patients at risk of developing ALI. After accounting for differences in presentation, there was no sex difference in ALI development and outcome. Black patients were less likely to develop ALI despite increased severity of illness on presentation.


Prediction of an extremely long exciton lifetime in a Janus-MoSTe monolayer.
The electron-hole separation efficiency is a key factor that determines the performance of two-dimensional (2D) transition metal dichalcogenides (TMDs) and devices. Therefore, searching for novel 2D TMD materials with a long timescale of carrier lifetime has become one of the most important topics. Here, based on time-domain density functional theory (TD-DFT), we propose a brand new TMD material, namely Janus-MoSTe, which exhibits a strong built-in electric field. Our results show that in the Janus-MoSTe monolayer, the exciton consisting of an electron and hole has a relatively wide spatial extension and low binding energy. In addition, a slow electron-hole recombination process is observed, with a timescale on the order of 1.31 ns, which is even comparable to those of van der Waals (vdW) heterostructures. Further analysis reveals that the extremely long timescale for electron-hole recombination could be ascribed to the strong Coulomb screening effect as well as the small overlap of wavefunctions between electrons and holes. Our findings establish the built-in electric field as an effective factor to control the electron-hole recombination dynamics in TMD monolayers and facilitate their future applications in light detection and harvesting.


Sympathetic cross-innervation of SHR and genetic controls suggests a trophic influence on vascular muscle membranes.
We have attempted to differentiate neural from humoral environmental factors as the cause of altered arterial muscle membrane properties in spontaneously hypertensive rats (SHR). This laboratory has previously reported that alterations in membrane electrical properties appear to be responsible for increased NE sensitivity in caudal arteries from SHR. In this study, caudal arteries were transplanted into innervated or denervated anterior eye chambers of the same (KNR in KNR, SHR in SHR) or the opposite (KNR in SHR, SHR in KNR) strain. Seven weeks later, we measured membrane potential (Em) and norepinephrine (NE) contractile sensitivity (EC50) in both transplanted and host caudal arteries. Caudal arteries from 2-week-old donor animals transplanted into hosts reinnervated and developed Em and NE EC50 values characteristic of the host strain, interconverting between SHR and KNR characteristics in cross-transplantations. In other experiments, the superior cervical ganglion ipsilateral to the transplanted eye chamber was removed 1 day before transplantation to eliminate the influence of sympathetic nerves. Em values were the same in transplants denied sympathetic innervation whether the arteries were transplanted into the same or opposite strains. Although denervation increased NE sensitivity of KNR caudal arteries, sensitivity of arteries from the SHR strain was unchanged. Therefore, without sympathetic reinnervation, there was no interconversion of Em or NE EC50 characteristics between SHR and KNR by cross-transplantation. These results suggest that neural factors control the development of membrane properties of vascular muscle. It appears that the sympathetic nervous system of the SHR has altered trophic influences that contribute importantly to altered membrane properties in hypertension.


Changes in the viral distribution pattern after the appearance of the novel influenza A H1N1 (pH1N1) virus in influenza-like illness patients in Peru.
We describe the temporal variation in viral agents detected in influenza like illness (ILI) patients before and after the appearance of the ongoing pandemic influenza A (H1N1) (pH1N1) in Peru between 4-January and 13-July 2009. At the health centers, one oropharyngeal swab was obtained for viral isolation. From epidemiological week (EW) 1 to 18, at the US Naval Medical Research Center Detachment (NMRCD) in Lima, the specimens were inoculated into four cell lines for virus isolation. In addition, from EW 19 to 28, the specimens were also analyzed by real time-polymerase-chain-reaction (rRT-PCR). We enrolled 2,872 patients: 1,422 cases before the appearance of the pH1N1 virus, and 1,450 during the pandemic. Non-pH1N1 influenza A virus was the predominant viral strain circulating in Peru through (EW) 18, representing 57.8% of the confirmed cases; however, this predominance shifted to pH1N1 (51.5%) from EW 19-28. During this study period, most of pH1N1 cases were diagnosed in the capital city (Lima) followed by other cities including Cusco and Trujillo. In contrast, novel influenza cases were essentially absent in the tropical rain forest (jungle) cities during our study period. The city of Iquitos (Jungle) had the highest number of influenza B cases and only one pH1N1 case. The viral distribution in Peru changed upon the introduction of the pH1N1 virus compared to previous months. Although influenza A viruses continue to be the predominant viral pathogen, the pH1N1 virus predominated over the other influenza A viruses.


Evidence-based well-baby care. Part 2: Education and advice section of the next generation of the Rourke Baby Record.
Well baby and child care in the primary care setting has not always been based on evidence that has been shown to be effective in preventing and detecting disease and injury. To help physicians and nurses provide care that is more effective than a routine complete examination, the Rourke Baby Record has been revised to include evidence-based recommendations for preventive care for infants and young children. The revision incorporates the approach and recommendations of the Canadian Task Force on the Periodic Health Examination. The updated record is now called the Rourke Baby Record: Evidence-Based Infant/Child Health Maintenance Guide (Rourke Baby Record: EB). Part 2 of this two-part article discusses the maneuvers included in the education and advice section of the record. These maneuvers are discussed under the subheadings safety, behaviour, family coping, high-risk children, and other. Using the Rourke Baby Record: EB and incorporating it into their office record systems as a working guide will help increase the effectiveness of the primary preventive care physicians provide to infants and young children.


Dual-mobility cups for revision due to instability are associated with a low rate of re-revisions due to dislocation: 228 patients from the Swedish Hip Arthroplasty Register.
Revision total hip arthroplasty (THA) due to recurrent dislocations is associated with a high risk of persistent instability. We hypothesized that the use of dual-mobility cups would reduce the risk of re-revision due to dislocation after revision THA. 228 THA cup revisions (in 228 patients) performed due to recurrent dislocations and employing a specific dual-mobility cup (Avantage) were identified in the Swedish Hip Arthroplasty Register. Kaplan-Meier survival analysis was performed with re-revision due to dislocation as the primary endpoint and re-revision for any reason as the secondary endpoint. Cox regression models were fitted in order to calculate the influence of various covariates on the risk of re-revision. 58 patients (25%) had been revised at least once prior to the index cup revision. The surgical approach at the index cup revision was lateral in 99 cases (44%) and posterior in 124 cases (56%). Median follow-up was 2 (0-6) years after the index cup revision, and by then 18 patients (8%) had been re-revised for any reason. Of these, 4 patients (2%) had been re-revised due to dislocation. Survival after 2 years with the endpoint revision of any component due to dislocation was 99% (95% CI: 97-100), and it was 93% (CI: 90-97) with the endpoint revision of any component for any reason. Risk factors for subsequent re-revision for any reason were age between 50-59 years at the time of the index cup revision (risk ratio (RR) = 5 when compared with age > 75, CI: 1-23) and previous revision surgery to the relevant joint (RR = 1.7 per previous revision, CI: 1-3). The risk of re-revision due to dislocation after insertion of dual-mobility cups during revision THA performed for recurrent dislocations appears to be low in the short term. Since most dislocations occur early after revision THA, we believe that this device adequately addresses the problem of recurrent instability. Younger age and prior hip revision surgery are risk factors for further revision surgery. However, problems such as potentially increased liner wear and subsequent aseptic loosening may be associated with the use of such devices in the long term.


The Mayo Clinic experience with Morel-Lavallée lesions: establishment of a practice management guideline.
Although uncommon, Morel-Lavallée lesions (also called closed degloving injuries) are associated with considerable morbidity in trauma patients. There is lack of consensus regarding proper management of these lesions. Management options include nonoperative therapies, along with percutaneous and operative techniques. We sought to define the factors associated with failure of percutaneous aspiration to better identify patients requiring immediate operative management. We retrospectively searched our prospectively collected database for patient records containing the terms Morel-Lavallée, closed degloving injury, or posttraumatic seroma from February 2, 2004, through December 23, 2011. Treatment methods included compression wraps or observation (nonoperative management), percutaneous aspiration, or operative management with incision/drainage or formal debridement of skin and soft tissues that resulted in wound vacuum-assisted closure placement and/or split-thickness skin graft (operative management). The treatment groups were compared using univariate analysis and χ testing. We identified 79 patients with 87 Morel-Lavallée lesions in the setting of trauma. Most were caused by motor vehicle collisions (25%). No difference was observed between the treatment groups in sex, body mass index, anticoagulation treatment, diabetes mellitus, smoking history, or alcohol use. The percutaneous aspiration group had higher rates of recurrence (56% vs. 19% and 15% in nonoperative and operative groups, respectively). The percentage of patients who had aspiration of more than 50 mL of fluid was higher for lesions that recurred than for lesions that resolved (83% vs. 33%, p = 0.02). Aspiration of more than 50 mL of fluid from Morel-Lavallée lesions was much more common among lesions that recurred (83%) than among those that resolved (33%). We therefore recommend that aspiration of more than 50 mL of fluid from a Morel-Lavallée lesion prompts operative intervention. We have now adopted this as a practice management guideline. Therapeutic/care management study, level III.


Neuropharmacological modulation of cognitive deficits after brain damage.
This review discusses recent studies that have implications for potential neuropharmacological interventions which target cognitive deficits resulting from traumatic brain injury or stroke. An important new study concerning the activity of N-methyl-D-aspartate (NMDA) receptors after brain injury reveals that previous influential hypotheses about an increase in glutamate triggering neuronal death may need to be revised. Furthermore, the study suggests that cognitive function may be best preserved by stimulation of NMDA receptors with agonists rather than by the use of antagonists, as previously believed. Investigations of animal models of stroke and traumatic brain injury have further demonstrated the possibility of intervening in the acute and sub-acute stages to protect specific brain systems, such as preservation of the cholinergic system (via cholinesterase inhibitors) and hippocampal neurons (via a D2 agonist). Clinical trials in humans indicate it is also possible to target these neurotransmitter systems to enhance cognitive performance in patients with chronic deficits. In particular, recent studies demonstrated that it is possible to ameliorate the effects of two common cognitive syndromes, visual neglect and aphasia. Cognitive deficits are an extremely common consequence of either traumatic brain injury or stroke. Recent studies demonstrate the potential for using neuropharmacological intervention after acquired brain injury to prevent or ameliorate the effects of cognitive impairments. These treatments, however, are still in their preliminary stages and further research is required to identify the most effective compounds.


Competition between Heterodera glycines and Meloidogyne incognita or Pratylenchus penetrans: Independent Infection Rate Measurements.
Competition on soybean between Heterodera glycines (race 3) and Meloidogyne incognita or H. glycines and Pratylenchus penetrans were investigated in greenhouse experiments. Each pair of nematode species was mixed in 3-ml suspensions at ratios of 1,000:0, 750:250, 500:500, 250:750, and 0:1,000 second-stage juveniles or mixed stages for P. penetrans. Nematodes from a whole root system were counted and infection rates standardized per 1,000 nematodes (per replication) prior to testing the null hypothesis through a lack-of-fit F-test. Although the effect of increasing H. glycines proportions on the infection rate of M. incognita was generally adverse, the rate deviated significantly from a trend of linear decline at the 75% H. glycines level in one of two experiments. All lack-of-fit F-tests for the H. glycines and P. penetrans mix were significant, indicating that infection rates for both nematodes varied considerably across inocula. The infection rate of H. glycines decreased with increasing P. penetrans proportions. The rate of P. penetrans infection increased with increasing H. glycines proportions up to the 50% level, but declined at the 75% level. Competition had no effect on nematode development. The general adverse relationships between M. incognita and H. glycines and those between P. penetrans and H. glycines showed a linear trend. The relationship between H. glycines and P. penetrans indicates that the former may be competitive when present at higher proportions than the latter. In this study we have evaluated nematode competition under controlled conditions and provide results that can form a basis for understanding the physical and physiological trends of multiple nematode interactions. Methods critical to data analyses also are outlined.