This Forum article synthesizes the current evidence on the links between predator-prey interactions, protected areas and spatial variations in Lyme disease risk in Fennoscandia. I suggest key research directions to better understand the role of protected areas in promoting the persistence of diverse predator guilds. Conserving predators could help reducing host populations and Lyme disease risk in northern Europe. There is an urgent need to find possible win-win solutions for biodiversity conservation and human health in ecosystems facing rapid global environmental change. Borrelia burgdorferi sensu lato (s.l.) species complex, carried and transmitted by several species of Ixodes ticks, the most common in Europe being Ixodes ricinus , which take a single blood meal from a wide range of hosts before molting to the next stage , or reproducing and dying   is the most common tick-borne disease in temperate forested regions of North America and Eurasia, with increased number of reported cases worldwide  Increasing incidence of LD cases have been reported in Finland  host population trends in the study area; (2) how trophic interactions could affect these main host species; finally (3) how PAs may impact predator abundance, host species and thus tick abundance and LD risk.Sorex araneus) and small rodents (Microtus and Myodes voles and Apodemus mice) are the most important hosts of larval I. ricinus in Fennoscandia , see Ecke et al. Insectivores  and lagomorphs (Lepus timidus and L. Europaeus) are important feeding hosts for adult Ixodes ticks  are known to be key hosts for nymphal ticks in Europe  are still present, offering a unique opportunity to study intra-guild relationships between these species, their potential impact on mesocarnivore abundance  reducing the most important host species abundance or changing the host community composition and (2) inducing fear-mediated changes in habitat use of the main host species, which could decrease LD transmission risks  is a common prey of the lynx  influence the trophic pathways identified above and impact LD risk at various scales  and combining empirical, experimental and modeling approaches at local and global scales. Existing nation-wide datasets of LD incidence and wildlife community composition can be used in several northern European countries to assess the environmental drivers of LD incidence. Comparative designs inside and outside PAs, where host abundance, predator community structure, tick density and infection prevalence in ticks and hosts are sampled, would help determine how multi-level trophic cascades influence LD risk in boreal ecosystems.In conclusion, it is time for research to strive to understand the top-down processes regulating LD transmission in Fennoscandia. Such research could improve public attitude toward predators and provide powerful motivation for society to preserve complex ecological networks in boreal ecosystems currently facing the combined effects of land cover change and climate change.


We developed SNPnexus to meet this need by assessing the potential significance of known and novel SNPs on the major transcriptome, proteome, regulatory and structural variation models. Since its previous release in 2012, we have made significant improvements to the annotation categories and updated the query and data viewing systems. The most notable changes include broader functional annotation of noncoding variants and expanding annotations to the most recent human genome assembly GRCh38/hg38. SNPnexus has now integrated rich resources from ENCODE and Roadmap Epigenomics Consortium to map and annotate the noncoding variants onto different classes of regulatory regions and noncoding RNAs as well as providing their predicted functional impact from eight popular non-coding variant scoring algorithms and computational methods. A novel functionality offered now is the support for neo-epitope predictions from leading tools to facilitate its use in immunotherapeutic applications. These updates to SNPnexus are in preparation for its future expansion towards a fully comprehensive computational workflow for disease-associated variant prioritization from sequencing data, placing its users at the forefront of translational research. SNPnexus is freely available at  SNPnexus is a popular analytical tool that was designed to meet this need  and neo-epitope prediction for the immunotherapeutic application (for hg38). These will be added to other assemblies as soon as the primary datasets are made available from their respective sources. A complete list of the annotation categories is provided in http://www.roadmapepigenomics.org/) and the FANTOM project  , Roadmap project  have beeThe vast majority of germline and somatic variations occur in the noncoding part of the genome, only a small fraction of which are believed to be functional. From the tens of thousands of noncoding variations detectable in each genome, distinguishing the potential functional variants from non-functional ones is a challenge. Going beyond SIFT and PolyPhen predictions for deleterious effect of coding variants on protein functions, SNPnexus users can now obtain the predicted functional impact of noncoding variants from eight popular noncoding variant scoring algorithms, namely CADD , DeepSEAhttp://hapmap.ncbi.nlm.nih.gov/), the new release also provides minor allele frequency (MAF) data generated from the 1000 Genomes (1KG) Project . 1KG data covers 26 different populations around the globe grouped together in 5 super populations: AFR (African), AMR (Ad Mixed American), EAS (East Asian), EUR (European) and SAS (South Asian). Since the release of Phase 3 data in 2013 with information on over 84 million genetic variants (MAF > 1%), the 1KG project has overshadowed the utility of HapMap data and established itself as a research standard for population genetics. SNPnexus also provides MAF data generated as part of the Exome Aggregation Consortium (ExAC)  . ExAC coWith ever-increasing number of association studies identifying new relationships among genetic variation and phenotypes, SNPnexus has added another resource ClinVar  along wihttps://doi.org/10.1101/174243) and NetTepi  molecule is considered as the essential factor for determining the viability of a peptide as neo-epitope. For user-specified human leukocyte antigen (HLA) allele type corresponding to MHC-I protein, SNPnexus employs NetMHCpan and MHCflurry to report the predicted peptide-MHC (pMHC) binding affinity of each n-mer mutated and wild-type peptide pair in nanoMolar (nM) unit. SNPnexus also reports prediction scores from NetTepi, which integrates pMHC binding affinity with pMHC stability and T-cell propensity in its calculations. By reporting scores from multiple immunogenicity prediction methods, SNPnexus enables users to make a better-informed decision on subsequent wet-lab investigations.It has now become well established that somatic variation within a tumour gives rise to neo-epitopes  that may make strong candidates for personalized cancer immunotherapy vaccines . Assumin NetTepi . For eacSNPnexus utilizes primary annotation datasets from different sources to instantly calculate and report variant-centric functional annotations. Currently, we maintain three separate databases for GRCh38/hg38, GRCh37/hg19 and NCBI36/hg18 assemblies. The primary datasets for annotation categories present in the previous release remain unchanged. Most of the primary datasets for hg38 assembly are downloaded from either UCSC genome annotation database or Ensembl 90 data dumps. Among others, the 1KG Project datasets are downloaded from the International Genome Sample Resource (IGSR) FTP site. ExAC, COSMIC and miRBase data are downloaded from their respective FTP sites. The most recent ClinVar data are extracted from the NCBI ClinVar FTP site. Most of the non-coding variant scoring tools except DeepSEA provide pre-computed genome-wide scores, which are downloaded. No such pre-computed scores are available for DeepSEA, for which the respective standalone tool is installed in SNPnexus server and executed for each submission. Similarly, the standalone versions of the three neo-epitope prediction tools are installed and executed from the SNPnexus server. The complete list of data sources for SNPnexus annotation categories is provided in About section with an overview of the available annotation categories. The User Guide compiles the sources of primary annotation data, followed by exhaustive descriptions of query format and output data types. An Example section is available, with practical demonstrations of how to use SNPnexus.The query interface has been redesigned with dedicated navigation tabs for different sequence assemblies. It allows users to analyse variants mapped on different assemblies with greater ease. The results are presented with easier navigation facility and in an interactive tabular format with filtering, pagination and sorting options, and are available for download in multiple formats. Where appropriate, results are also summarized in graphical format using the open source visualization library Google Charts. The website contains an SNPnexus and other similar resources work on the principle of aggregating/calculating variant annotation information from disparate sources, which would be otherwise laborious for researchers to explore individually. As such, users need to apply their own discretion when interpreting findings reported in SNPnexus, notably those from the prediction algorithms  with varying efficiency. Users should consult the individual resources and related peer-reviewed publications to check the reliability of the results generated by these algorithms.http://wannovar.wglab.org), the freely accessible web version of ANNOVAR, doesn’t provide all the functionalities provided by its command line version. With the provision of predicted functional impact of noncoding variants and putative neo-antigen detection, SNPnexus also surpasses the functionalities offered by the Ensembl VEP Web (http://www.ensembl.org/vep).To the best of our knowledge, no single tool, or combinations thereof, available in the public domain provides the range of functionalities offered by SNPnexus. A few command-line-based tools such as ANNOVAR , EnsemblThe enhancements made in the current release of SNPnexus ensure that it remains a cutting-edge tool and continues to contribute toward maximizing the knowledge extracted from sequence variation data. Looking forward, the analytical focus of SNPnexus will expand toward multi-sample cohort study. This will allow users to build genetic variation profiles within and between samples, highlighting the shared variants and significantly mutated genes contributing to the phenotype studied. Based on the fully annotated variant results in one individual and/or across multiple samples, SNPnexus could then derive a prioritized list of putative disease-associated variants and genes for further investigation of clinical utility. At the same time, the addition of neoepitope prediction feature has propelled SNPnexus to the forefront of personalized medicine with the potential to intersect genomics and immunology. We are planning further useful expansions, for example, mining a candidate neoepitope in known antigen databases and assessing the expression pattern of the corresponding mutated gene, to grow SNPnexus’ application in personalized immunotherapy.Supplementary DataClick here for additional data file.


Recent genomic studies identified a putative rdh gene in an uncultured deltaproteobacterial genome that was not accompanied by an rdhB gene, but contained transmembrane helixes in N-terminus. Therefore, rather than having a separate membrane anchor protein, this putative RDase is likely a hybrid of RdhA and RdhB, and directly connected to the membrane with transmembrane helixes. However, functionality of the hybrid putative RDase remains unknown. Further analysis showed that the hybrid putative rdh genes are present in the genomes of pure cultures and uncultured members of Bacteriodetes and Deltaproteobacteria, but also in the genomes of the candidate divisions. The encoded hybrid putative RDases have cytoplasmic or exoplasmic C-terminus localization, and cluster phylogenetically separately from the existing RDase groups. With increasing availability of (meta)genomes, more diverse and likely novel rdh genes are expected, but questions regarding their functionality and ecological roles remain open.Attempts for bioremediation of toxic organohalogens resulted in the identification of organohalide-respiring bacteria harbouring reductive dehalogenases (RDases) enzymes. RDases consist of the catalytic subunit (RdhA, encoded by  Recent genomic analysis revealed putative reductive dehalogenase genes from extreme subsurface environments that unlike known reductive dehalogenases have membrane integral domains. With the advent of the Industrial Revolution, human impacts on the environment increased dramatically. Hazardous halogenated organic compounds, organohalogens, were widely distributed in the natural environment through careless use and indiscriminate disposal, and caused major public concerns due to possible effects on human and environmental health Häggblom . In atteet al. rdh) have a conserved operon structure that consists of rdhA, coding for the catalytic subunit (RdhA); rdhB, coding for a small putative membrane anchor (RdhB) that (presumably) locates the A subunit to the outside of the cytoplasmic membrane; and a variable set of accessory genes (e.g. rdhCTKZED)  in the N-terminus. Whereas the known respiratory RDases do not have membrane-integral domains, most RdhBs have three TMHs . Although the existence of rdh genes lacking the TAT motif and rdhB were reported in the genomes of strain NaphS2 and D. sandiegensis  by reoxidation of respiratory cofactors for membrane-bound RDases, and catabolic reductive dehalogenation for cytoplasmic RDases  RDases? Detoxification of organohalogens and thereby securing a hospitable environments for themselves and the nearby organisms? Providing carbon sources for themselves (catabolic RDase) or others (respiratory RDase)?et al. rdh genes  RDases be involved in the production of halogenated bioactive compounds as was shown for biosynthesis of marine bacterial pyrroles mediated by a reductive debrominase that utilizes a redox thiol mechanism (El Gamal Genomics and allied technologies have greatly increased the diversity of putative ce Table , Antarct


Hepatic arterioportal fistulae are frequent vascular complications due to neoplasm, trauma and iatrogenic injury. On the other hand, fistulae between the hepatic arteries and hepatic veins (arteriohepatic venous fistula) are rare. We report the case of a 45-year-old male who suffered from a blunt abdominal trauma with abdominal distension. Initial cross-sectional imaging revealed laceration of the right lobe of liver with an arteriovenous fistula and hemoperitoneum. The diagnosis of arteriohepatic venous fistulae was confirmed on digital subtraction angiography (DSA) and treated angiographically with superselective coil embolization. Post-embolization angiogram showed complete occlusion of arteriovenous fistulae. We emphasis on the management part of the fistulae and endovascular treatment. We emphasis on the management part of the fistulae and endovascular treatment.Hepatic arterioportal fistulae are frequent vascular complications due to neoplasm, trauma and iatrogenic injury. On the other hand, fistulae between the hepatic arteries and hepatic veins (arteriohepatic venous fistula) are rare. We report the case of a 45-year-old male who suffered from a blunt abdominal trauma with abdominal distension. Initial cross-sectional imaging revealed laceration of the right lobe of liver with an arteriovenous fistula and hemoperitoneum. The diagnosis of arteriohepatic venous fistulae was confirmed on digital substraction angiography (DSA) and treated angiographically with superselective coil embolization. Post-embolization angiogram showed complete occlusion of arteriovenous fistulae. Hung et alA 45-year-old male with history of blunt abdominal trauma was brought to casualty with abdominal distension and drop in haemoglobin levels. Initial ultrasound imaging revealed free fluid in the abdomen. Exploratory laprotomy was done that show hemoperitoneum, and liver laceration in the right lobe. Perihepatic packing was done to achieve hemostasis.CT imaging done on day two revealed replaced right hepatic artery arising from superior mesenteric artery (SMA) with hepatic laceration involving segment VI and VII. Arterial phase CT images showed a prominent segmental branch of the right hepatic artery with a fistulous track communicating with the right hepatic vein –2. Two dFrom a transfemoral approach, the superior mesenteric artery was catheterized with 6F catheter (Chuang-William Cook Europe APS). Selective angiogram showed two prominent hepatic artery segmental branches leading to the lacerated liver parenchyma with early filling of the right hepatic vein suggesting post-traumatic arteriovenous fistulae . The rep2 congenital anomaly,3 trauma and iatrogenic injuries like needle biopsy and percutaneous drainage.4The most common cause of liver injury is blunt abdominal trauma. The incidence of hepatic vascular injuries after blunt trauma is much lower than that after penetrating injury. Traumatic intrahepatic arteriovenous fistulae are rarely encountered which generally involve arterial to portal venous connection  and rarely result in arterial to hepatic vein connection. The leading cause of arteriovenous fistulae are neoplasm,4 in his series of patients after needle biopsy and percutaneous biliary drainage demonstrated arterioportal fistula in eight patients and arteriohepatic venous fistula in one patient on angiography. Fistulae of systemic venous system can lead to cardiovascular compromise with high output cardiac failure.5 Infrequent cause of arteriohepatic venous fistulas may be attributed to the larger distance between artery and hepatic vein. Post-traumatic arterioportal shunts are more frequent as these vessel systems are in close proximity at the portal tract. Dessousky et al6 in his series of patients with intrahepatic vascular shunts proposed a strategy for early identification, classification and management of shunts.Okuda et al7 Congestive cardiac failure, portal hypertension, portosystemic encephalopathy, cholangitis and atypical cirrhosis have been reported as possible serious complications related to this condition. Thus, a correct diagnosis is important and diagnostic imaging has a fundamental role in the evaluation of shunts and determination of the appropriate management.8 Two types of shunts were identified- arteriovenous (72%) and venovenous (28%). Arteriovenous shunts can be further classified into arterioportal and arteriohepatic shunts, whereas venovenous shunts can be further classified into portovenous, portoportal and venovenous shunts.6Intrahepatic vascular shunts (IHVSs) are abnormal communications between intrahepatic vasculature involving the arterial, portal or hepatic venous systems. The etiology of these shunts is controversial and may be either acquired, as those associated with cirrhosis or hepatocellular carcinoma, those that occur after traumatic injuries to the liver or interventional transhepatic procedures , or they may appear in the form of congenital and idiopathic vascular malformations, as in Rendu–Osler–Weber syndrome (hereditary hemorrhagic telangiectasia).6 proposed a practical strategy with therapeutic implication based on both imaging and clinical findings and categorized patients into three groups as follows: Group I included asymptomatic patients with small non-neoplastic shunts (3–6 mm) and with shunt ratio < 30%. They were followed by Doppler and clinical examination at 3 to 6 months interval. If the shunt did not change or regressed, and no signs or symptoms developed, then conservative management was applied according to the type of shunt.Dessousky et alGroup II included patients with symptomatic shunts, large (15–23 mm) or aneurysmal shunt (28–45 mm), those with shunt ratio >30% or neoplastic shunt. These shunts are usually managed by interventional technique.Group III included patents with diffuse shunts or with shunt ratio >60%, and were planned directly for surgery.In our case, as the patient was symptomatic and as the size of the fistulae were >15 mm, management with embolization was considered.9 Early angiographic embolization decreases the incidence of blood transfusion and number of liver-related operations.8 Transcatheter arterial embolization has proved to be effective in treatment of arterioportal shunts, and its associated complications are rare.103D post-processing of CT angiography with multiplanar reformation (MPR), maximal intensity projection (MIP) and volume rendering technique (VRT) is especially helpful in detection of vascular injuries. In this case, CT promptly showed the hypertrophic segmental branches leading to the fistulae. Interventional techniques, especially angiographic embolization, are well-known as useful adjunct in non-operative management of blunt liver trauma.Arteriovenous shunts are rare complication of blunt trauma. Arteriohepatic shunts are rarer than arterioportal shunts. Multiphasic MDCT can be very helpful in proper planning before an interventional procedure. Angiographic embolization can decrease the incidence of transfusion and surgical procedures. Intrahepatic vascular shunts can be managed by interventional technique, and surgery depending on clinical presentation and shunt ratio.Arteriohepatic venous shunts can occur rarely when compared with arterioportal shunts in abdominal trauma.Management of arteriohepatic venous shunts is similar to arterioportal shunts by interventional technique like micro coil embolization depending on the shunt ratio and clinical presentation.Written informed consent was obtained from the patient(s) for publication of this case report, including accompanying images.


Social relationships are a well-established correlate of late-life well-being. Extensive research finds social support is associated with fewer depressive symptoms, yet few studies distinguish fine-grained types of support from spouse, children, other family and friends, nor whether these linkages differ by gender and marital status. Studies exploring coarse associations between support and well-being may conceal gender and marital status differences. We use data from two waves of the Health and Retirement Study  to study fine-grained linkages between diverse types of relationship strain and support and depressive symptoms (CESD) among adults aged 51+. The results show that the association between support/strain and depressive symptoms varies based on the source of support. For instance, among married/partnered older adults, spousal support is negatively associated with depressive symptoms whereas friend strain is positively associated with depressive symptoms. Among widowed respondents, friend support is negatively associated with depressive symptoms. These marital status patterns differed by gender however, such that the impact of friend strain on depressive symptoms was especially large for divorced men. Our results suggest that no single form of social support (or strain) is uniformly protective (or distressing), so services and interventions to enhance late-life mental health should more fully consider older adults’ social location, including gender and marital status. For current cohorts of older adults, who have lower rates of marriage and childbearing than their predecessors, it is critically important to understand both the levels and impacts of alternative sources of support from other kin and friends.


Cardiac resynchronization therapy (CRT) is an effective treatment for patients with heart failure (HF) and conduction abnormalities. Conceptually, CRT works by improving myocardial contraction synchrony and performance with a parallel left ventricular (LV) reverse remodeling and subsequent improvement in morbidity and mortality -3. CurreCRT mechanically ameliorates the activation delay between opposing contracting walls of LV by an extra lead implanted into LV free wall. Echocardiography can provide the additional necessary improvement in selection of patients by identifying more precisely the asymmetry in contraction and activation delay between the opposing contracting walls of LV. Over the years, a number of echocardiographic techniques have been introduced to identify this asymmetry more commonly known as mechanical dyssynchrony . DespiteRecent studies applied some new echocardiographic techniques focusing on the physiology of a how a CRT works which have shown promising results in small-scale studies , 3. One This editorial focusses on the sub-study performed on the Echocardiography guided cardiac resynchronization therapy (EchoCRT) trial data by Tayal et al. . In EchoThis study highlights the limitation of time-to-peak dyssynchrony methods, bringing forward the discussion on the role of dyssynchrony in patients treated with CRT and its physiology. Future trials applying these newer echocardiographic techniques in selection of patients with wide QRS (> 130ms) for CRT in multicenter randomized settings can provide more convincing evidence. Specifically focusing on groups where the guidelines are still ambiguous, such as LBBB patients with intermediate QRS duration (130-149 ms) and non-LBBB morphology (> 130ms) would be of benefit by reducing unnecessary implants.


Dually eligible individuals  often have worse health and greater functional limitations than patients eligible for Medicare only. For dually eligible patients receiving inpatient rehabilitation services following a major illness or injury, improvement in function may be lower than for Medicare-only patients. To our knowledge, this is the first study to examine the relationship of dual eligibility on improvement in mobility for inpatient rehabilitation facility (IRF) patients by 13 primary diagnosis groups . Data was collected on the IRF-Patient Assessment Instrument at admission and discharge for all IRF patients discharged during 2017 . A generalized linear model was run for each primary diagnosis group to examine the effect of dual eligibility on change in mobility during an IRF stay, adjusting for sociodemographic factors, clinical factors, and comorbidities. The proportion of patients who were dually eligible varied among primary diagnosis groups . Compared to patients who were non-dually eligible, dually eligible patients had lower improvement in mobility across all 13 diagnostic groups. The strongest effect of dual eligibility on lower improvement in mobility was among patients with hip and/or knee replacements  and patients with non-traumatic spinal cord dysfunction . This research indicates that dually eligible patients may have worse functional mobility outcomes than non-dually eligible patients for some IRF primary diagnosis groups, and these patients may need additional support after discharge.


Eucalyptus nitens breeding population focused on improvement for solid wood production. A high-density SNP chip (EUChip60K) was used to genotype 691 individuals in the breeding population, which represented two seed orchards with different selection histories. Phenotypic records for growth and form traits at age six, and for wood quality traits at age seven were available to build genomic prediction models using GBLUP, which were compared to the traditional pedigree-based alternative using BLUP. GBLUP demonstrated that breeding value accuracy would be improved and substantial increases in genetic gains towards solid wood production would be achieved. Cross-validation within and across two different seed orchards indicated that genomic predictions would likely benefit in terms of higher predictive accuracy from increasing the size of the training data sets through higher relatedness and better utilization of LDGenomic selection is expected to enhance the genetic improvement of forest tree species by providing more accurate estimates of breeding values through marker-based relationship matrices compared with pedigree-based methodologies. When adequately robust genomic prediction models are available, an additional increase in genetic gains can be made possible with the shortening of the breeding cycle through elimination of the progeny testing phase and early selection of parental candidates. The potential of genomic selection was investigated in an advanced  Eucalyptus nitens (Deane & Maiden), is the most important commercial eucalypt species in New Zealand, with an advanced breeding programme moving towards its fourth generation  breeding population, therefore, some inaccuracy in breeding values is expected due to unknown paternal contribution and plausible pedigree errors. Precisely recorded pedigrees and known ancestors of the breeding population individuals are prerequisites for accurate genetic evaluation and consequently, efficient breeding programme management and boosted genetic gain in forest tree species.Shining gum, Genomic selection was proposed as a tool to predict individual breeding values on the basis of information from high-density genetic marker panels through multiple regression models  was estimated in terms of status number as following Ɵ is group co-ancestry of individuals  individuals per family used for genomic prediction analysis for which genomic information and phenotypic trait records were available. The Waiouru seed orchard was represented by 431 genotyped individuals with effective population size of 133.2, while the Tinkers seed orchard was represented by 236 genotyped individuals with effective population size of 64.7. The effective population size . The marker data were filtered for genTrain score > 0.5, GenCall > 0.15, minor allele frequency > 0.01, SNP call rate > 0.6 and pairwise LD in terms of a composite estimate (r2 < 0.9), with 12,236 SNPs selected to train genomic prediction models. The missing data were imputed through expectation-maximisation algorithm implemented in “rrBLUP” package   following A is the average numerator relationship matrix  is set nested within replication following e following X and Z1, Z2 and Z3 are incidence matrices assigning fixed and random effects to measurements in vector y  from breeding cycles and selections based only on genetic markers. It was estimated as follows:The full efficiency of genomic selection was investigated by comparing genetic gains per generation using pedigree-based estimated breeding values (BLUP) with genetic gains using genomic marker-based estimated breeding values (GBLUP). Both of these individual based estimated genetic gains included the availability of phenotypic records for all traits. The mean value of BLUP and GBLUP breeding values of the 20% of selected individuals was the measurement for the estimated genetic gain.Pedigree-based analysis showed low to moderate within seed orchard heritabilities in both seed orchards Table . PedigreAcross seed orchard heritability estimates were generally higher using marker-based breeding values than pedigree-based with only a few exceptions Table . RecondiMarker-based breeding values had consistently higher accuracies than pedigree-based breeding values. Generally, accuracies of breeding values were higher for both seed orchards when using marker-based rather than pedigree-based estimated breeding values. However, there were some inconsistencies, with the Tinkers seed orchard showing lower genomic breeding value accuracies for radial wood shrinkage, DBH and height than for the same traits using pedigree-based models, reflecting the pattern in heritability.The cross-validation analysis showed no, or very low, predictive accuracy for breeding values for one seed orchard when based on a model trained in an alternative seed orchard, using pedigree-based or marker-based models Table . Within Generally estimated absolute genetic gains per generation were as expected higher when using GBLUP breeding values rather than BLUP breeding values Table . The estThe benefits of using information from genomic markers in the genetic evaluation were apparent in the current study, where both within seed orchard and across seed orchard estimations supported the use of GBLUP over BLUP predictions. The reduced number of SNPs after filtering still provided sufficient genomic information to perform efficient marker-based predictions, which improved breeding value accuracies when compared with pedigree-based evaluations. A gain in accuracy of breeding values would likely be even more substantial when increasing the size of training population by additional genotyping. Grattapaglia and Resende  estimateForest tree breeding programmes are generally in the very early stages compared to animal and crop breeding programmes with faster generation turnover  plays a significant role in forestry tree breeding (Li et al. Estimated absolute genetic gains based on GBLUP breeding values per generation indicate that genomic selection would significantly improve the efficiency of selection for solid wood properties. The major benefit of genomic selection in accelerating the rate of genetic improvement would be derived from the ability to shorten the generation interval through the very early selection at the seedling stage (Resende et al. E. nitens breeding population. A question remains as to how well prediction models perform after several breeding cycles (Resende et al. E. nitens breeding population is required to find the best possible methodology, including additional data infusions of wider breeding population that will reflect better the future selection population than in the current study. We expect further data infusions to result in considerably higher predictive accuracy of genomic breeding values compared to pedigree-based methods. Increasing the training population size as well as applying different statistical methods that can account efficiently for the accuracy due to LD may give further confidence in implementing GEBVs in the breeding programme (Habier et al. The potential to make faster selections by skipping progeny testing should be pursued in this E. nitens was possible by implementing genomic marker-based prediction compared to pedigree-based prediction. The greatest improvement in genetic parameters was obtained for tangential air-dry wood shrinkage and growth strain, which are the key traits in selection for solid wood production in eucalypts. Wood shrinkage traits had moderate heritabilities, which mainly increased further with genomic prediction.This study showed that a significant improvement in breeding value accuracy and genetic gains for selection of wood properties in Results from cross-validation analysis implied that further infusions of additional seed-orchard material into the training data would be useful to increase the efficiency of genomics in the selection, regarding breeding value accuracy and predictive accuracy. Further analysis, including more progeny trial sites to investigate the transferability of these models across generations and environments is recommended.Data available from Dryad: 10.5061/dryad.pf58510.


OBJECTIVES/SPECIFIC AIMS: To develop a robust spatial normalization pipeline for brains of individuals with focal cortical lesions. METHODS/STUDY POPULATION: Individuals with chronic focal cortical lesions from stroke. RESULTS/ANTICIPATED RESULTS: We have developed a robust spatial normalization pipeline for brains of individuals with focal cortical lesions, and demonstrate how the pipeline overcomes obfuscated neuroanatomy to yield both consistent and excellent results. DISCUSSION/SIGNIFICANCE OF IMPACT: Our robust normalization pipeline will enable group analyses of individuals with cortical lesions with greater spatial precision. This greater spatial precision will improve answers to questions about functional localization in the brain, and ultimately allow translation of findings from neuroimaging studies in individuals with cortical lesions to the clinic.


The two branches of the autonomic nervous system (ANS) have been individually linked to age-related changes in cognitive functioning: The parasympathetic nervous system (PNS) is thought to support healthy cognitive aging, whereas the sympathetic nervous system (SNS) has been linked to heightened cognitive decline. Despite these separate findings and despite the integrative nature of the ANS, little work has examined the two branches simultaneously to better understand their interactive effects on age-related cognitive changes. We examined cognitive change in two waves of the MIDUS cognitive project and indexed PNS and SNS activity from heart rate variability and epinephrine levels (respectively) from the MIDUS biomarker project . Our findings indicate that higher PNS levels attenuate cognitive decline, but only among individuals with low SNS levels; at higher SNS levels, the beneficial effects of the PNS are blocked. Further, lower PNS levels can be somewhat compensated for by increased SNS levels. This pattern was most robust among individuals transitioning to mid-life . These results suggest that interventions targeting the ANS as a modifiable factor in cognitive aging should consider both ANS branch’s effects simultaneously, particularly in the early stages of midlife.


Cancer cell dormancy is an important source of treatment failure. We studied the molecular characteristics and functional behaviour of dormant colorectal cancer cells finding them to be a differentiated yet plastic population. Organoid drug screening identified itraconazole perturbs dormancy through non-canonical hedgehog signalling effects on the WNT pathway. Functional heterogeneity can be defined as differences in both the identity and phenotype of cancer cells and has been shown to poorly correlate with mutational background.3 Studies seeking to understand functional heterogeneity have tended to focus on understanding the nature of highly clonogenic so-called cancer stem cell populations. Efforts to explore cell cycle-defined functional heterogeneity have been limited despite the well-established connection between cell cycle progression and clonogenic status.Heterogeneity exists at multiple levels in colorectal cancer (CRC) and over the last decade, major progress has been made cataloguing and quantifying inter-tumoral genetic differences.4 The study of tumour dormancy is technically difficult as there are only a small number of suitable experimental assays that can be used to identify dormant cells. The most common technique used to identify and isolate dormant cells is through label-retention. Label-retaining assays involve initially marking all cells of interest with a visible label. Following labelling, proliferative cells will gradually dilute out the marker with subsequent divisions whereas dormant cells will retain a visible label (label-retaining cells).Adjuvant CRC therapy relies on s-phase cytotoxics, which target exclusively dividing cells. Therefore, it is of vital clinical importance to effectively identify and target dormant CRC cell populations as potential drivers of disease recurrence. Prevalent prolonged intermission between primary disease treatment and representation with metastases in CRC patients indicates that reactivation of chemotherapy-resistant quiescent cancer cells may indeed be key in disease relapse. Having previously defined the nature of quiescent cells in the normal murine intestinal epithelium we sought to apply insights from normal stem cell biology to aid the identification of dormant CRC cells.5 Cells were grown in spheroid culture to permit the simultaneous culture of both clonogenic and differentiated cells thereby mirroring primary CRC cellular heterogeneity. In other cancers dormant cells have commonly been found to possess cancer stem cell features, however we unexpectedly found dormant CRC cells to reside in a differentiated state. Furthermore, upon re-culture in a permissive environment, we found dormant cells readily re-entered the cell cycle and acquired a cancer stem cell identity. These surprising results are consistent with a recent report from Toshiro Sato’s group who lineage-traced LGR5+ (leucine-rich repeat-containing G-protein coupled receptor 5) cancer stem cells and KRT20+ (keratin 20) differentiated cells in murine CRC xenografts.6 In agreement with our findings, Sato and colleagues observed that following elimination of LGR5+ cancer stem cells, KRT20+ cells de-differentiated and acquired cancer stem cell features. This plasticity of cancer cell identity and functionality demonstrated by ourselves and the Sato group resembles the previously described reversion of partially differentiated intestinal progenitors to a stem cell state upon perturbation of homeostasis.7To define the molecular landscape of CRC cell dormancy we applied a label-retaining approach, to a panel of cell lines representing the molecular diversity found in CRC, in combination with transcriptomic profiling.We hypothesised that perturbing dormancy would render the tumour, as a whole, more sensitive to conventional chemotherapy. Therefore, to identify compounds that could alter the dormant state of label-retaining cells we carried out a functional murine organoid drug screen. The most striking phenotype identified from our drug screen was found with the anti-fungal itraconazole. Itraconazole generated profound organoid collapse, almost complete loss of dormant cells  followed by global senescence. We validated our murine organoid findings in human CRC cell lines, human primary and metastatic patient-derived organoids, and performed transcriptomic analysis to examine the mechanism of the itraconazole derived phenotype.8 Itraconazole has previously been shown to inhibit canonical hedgehog signalling by binding smoothened (SMO).9 Unexpectedly, we found hedgehog pathway inhibition was inconsistently associated with itraconazole responsiveness. Conversely, WNT pathway inhibition was uniformly correlated with the itraconazole response and phenotype. We hypothesised that suppressor of fused (SUFU) may link an apparent hedgehog pathway inhibitor with WNT inhibition. Indeed, siRNA knockdown of SUFU rescued the itraconazole phenotype and WNT signalling thereby confirming the novel effect of itraconazole on the key regulatory pathway of CRC development (in vivo pre-clinical validation studies indicating that itraconazole causes irreversible tumour growth arrest, WNT pathway inhibition and synergistic activity with classical s-phase cytotoxics.Canonical hedgehog signalling in CRC is predominantly paracrine with pathway activation found in the stromal microenvironment alone.elopment . Finally10 Our findings and that of Lange and colleagues are highly compatible with the exception that Regan et al. propose that the non-canonical hedgehog derived effect is Patched-1 dependent. However, our data show this to be SMO and SUFU mediated. Interestingly, we found that another classical smoothened inhibitor, cyclopamine failed to reproduce the findings found with itraconazole. This suggests that SMO inhibitors may induce distinctive structural changes which may differentially alter the subsequent interaction between SMO and SUFU and potentially explain the difference between Lange’s findings and ours.Autocrine non-canonical hedgehog effects on WNT signalling and differentiation status in CRC has been recently described by Martin Lange’s group.High CRC and also renders dormant cells temporarily vulnerable to cytotoxic therapy prior to entering permanent senescence paving the way for future clinical studies.Cumulatively, our study provides evidence that a safe FDA-approved compound generates profound growth retardation in WNT


Recent Zika virus (ZIKV) epidemics necessitate the urgent development of effective drugs and vaccines, which can be accelerated by an enhanced understanding of ZIKV biology. One of the ZIKV structural proteins, precursor membrane (prM), plays an important role in the assembly of mature virions through cleavage of prM into M protein. Recent studies have suggested that prM protein might be implicated in the neurovirulence of ZIKV. Most vaccines targeting ZIKV include prM as the immunogen. Here, we review progress in our understanding of ZIKV prM protein and its application in ZIKV vaccine development. Zika virus (ZIKV) was first isolated in 1947 from a rhesus monkey taken from the Zika Forest in Uganda . Prior tZika virus outbreaks from 2015 onward have been of major public health concern due to their associated clinical complications, such as Guillain-Barre syndrome in adults and neonatal microcephaly, suggesting mother to child transmission of the virus . Owing tZika virus is mainly transmitted to humans through mosquito-borne vectors , though trans-Golgi network before release of mature virions  and dengue virus. ZIKV has an approximately 11 kb positive-stranded RNA genome, with untranslated regions flanking the 5′ and 3′ ends of its open reading frame. The genome is translated into structural proteins  and non-structural (NS) proteins  [reviewed in ]. The NS virions . The prMiviruses . A conseiviruses . Therefoiviruses . This shTable 1). These genomic variations might have been driven by ZIKV adopting an urban-based transmission cycle targeting humans as hosts rather than the original sylvatic mode of transmission that normally involves Aedes mosquitoes and non-human primates    . These sroteins) .pr peptide of prM protein might not be present in the final vaccine formulation.The ZIKV vaccines currently under development are mainly based on purified inactivated viruses, plasmid DNA, or mRNA platforms . ImportaA vaccine produced by immunizing mice with VLPs that incorporates full-length ZIKV structural proteins (C-prM-E) can also endow full protection against ZIKV and induces production of more ZIKV-neutralizing antibodies than DNA vaccines . A chimeSuccessful immunization and neutralizing antibody production in C57BL/6 mice has been demonstrated for an RNA nanoparticle vaccine based on prM-E . This vaModified mRNA vaccines based on ZIKV prM-E proteins have also been developed . These mZika virus has become a major public health concern, with outbreaks of the disease spreading across the globe and resulting in congenital birth defects in some instances. Evolutionary and purifying selection pressures might have facilitated modifications of the ZIKV genome that enhance its replication efficiency and reduce host immune efficiency as it adapted to new hosts in urban environments. This has led to virus strains being categorized as either pre-epidemic or epidemic, with the latter being associated with recent infection outbreaks. Thus far, the S139N amino acid substitution of prM protein has been linked to increased neurovirulence, suggesting that alterations of ZIKV prM protein may enhance viral virulence. Further studies on other observed amino acid substitutions in all viral proteins should be carried out to establish their roles in viral replication efficiency.Various platforms have been employed to generate vaccines against ZIKV infections, including purified inactivated virus, plasmid DNA, and mRNA nanoparticles. Despite these platforms having been adapted from studies of other flaviviruses, the resulting vaccines have exhibited experimental success when a combination of both prM and E proteins are utilized. In contrast, sole use of ZIKV prM protein in vaccines against ZIKV has not yet proven as effective as prM-E combinations.It remains unclear if future epidemics will have the same clinical implications as the most recent epidemic or which viral protein modifications are more likely to result in another epidemic. Furthermore, whether the ZIKV vaccines currently under development can be effective against future epidemics is uncertain. These basic questions should guide research efforts for the prevention, control and therapeutic strategies of ZIKV. Additional focused studies on the molecular and structural biology of ZIKV prM may accelerate our ability to tackle this emerging public health concern.PN wrote the manuscript. W-CS contributed to the framework and the editing of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Oxidative stress has a role in the initiation and progression of breastcancer .OxidatiBy damaging DNA, activating oncogenes, and producing genomic instability,reactive oxygen species can initiate carcinogenesis . ReactivBreast cancer tumors with enhanced proliferative capacity produce high levelsof reactive oxygen species during their chronic cycles of ischemia, reperfusion, andangiogenesis, resulting in growth signaling . Cancer Many chemotherapeutic drugs and radiation treatments eliminate tumors throughthe induction of reactive oxygen species in cancer cells . HoweverEndogenous antioxidants, including non-enzyme and enzyme antioxidant defensesystems  act to prevent or limit tissue damage by scavenging free radicals incells . SuperoxExogenous antioxidants from dietary intake such as vitamin A, vitamin E, andVitamin C, may also have a role in the alleviation of oxidative stress, which couldreduce risk of breast cancer or slow progression of the disease . HoweverResults from observational epidemiologic studies conducted over the pastseveral decades demonstrate that physical activity and weight control are importantdeterminants of breast cancer risk and progression . OxidatiIn order to inform future studies of antioxidant chemo-preventive agents thatmay reduce risk of breast cancer initiation or progression, the complexities of howredox imbalance contributes to cancer and other chronic diseases should beconsidered. This includes the observation that although high levels of reactiveoxygen species disrupt cellular processes, lower levels of reactive oxygen speciescan act as cell signaling messengers by reversibly oxidizing protein thiol groupsand modifying protein structure . Thus, t


A 76-year-old male with a small bowel neuroendocrine tumor with hepatic metastases presented with new onset lower extremity swelling, bloating, and weight gain which ultimately lead to cardiac magnetic resonance (CMR) to evaluate for cardiac involvement of disease. CMR showed right and left ventricular myocardial metastases along with findings suggestive of carcinoid heart disease. The patient had severe tricuspid valve regurgitation necessitating surgical valve repair. The patient underwent bioprosthetic tricuspid valve replacement and debulking of the metastases with surgical pathology confirming neuroendocrine tumor metastases. Follow-up clinical evaluations at 3, 6, and 9 months postoperatively showed improvement in cardiac function and stable hepatic tumor burden. This case demonstrates the utility of CMR to diagnose myocardial metastases and carcinoid heart disease complicated by severe tricuspid regurgitation, which guided surgical management. Neuroendocrine tumors (NETs) are a diverse group of tumors arising from neuroendocrine cells, and they can cause primary tumors in many different organs including the lungs, small intestine, rectum, pancreas, and other organs . Within NETs of the midgut  commonly release vasoactive substances including 5-hydroxytryptamine (serotonin), histamine, tachykinins, and prostaglandins . When thIn rare cases, NETs can metastasize to the heart , 11. CarA 76-year-old male with stage IV, small bowel NET metastatic to the liver had been followed by our institution for 4 years with stable hepatic metastatic disease on octreotide long-acting release (LAR) therapy. Originally, the tumor Ki-67 index was 5% and 24-hour urine 5-hydroxyindole acetic acid (5-HIAA) was 105 mg. The patient presented with mild progression of disease on abdominal magnetic resonance imaging (MRI)  after apCMR  showed aThe patient underwent bioprosthetic tricuspid valve replacement and biopsy and debulking of the myocardial tumors. The myocardial tumors were histologically confirmed as NET metastases. The patient recovered well from surgery, and follow-up clinical visits demonstrated significant improvement in his carcinoid heart disease. As of the latest visit, the patient has excellent cardiac function with resolution of tricuspid regurgitation. His 9-month postoperative follow-up CT scan showed relatively stable disease, and his urine 5-HIAA was improving. The patient is continuing on octreotide LAR 30 mg.We present a unique case of carcinoid heart disease and myocardial metastases both contributing to this patient's severe symptomatic tricuspid regurgitation. The tricuspid valve thickening is a specific finding of carcinoid heart disease, and well-defined lesions with arterial perfusion in the RV and LV walls are specific for metastases. Previous authors have suggested that vasoactive mediators associated with myocardial metastases may accelerate the onset of carcinoid heart disease, which could explain the case described here , 16.Carcinoid heart disease manifests via the accumulation of carcinoid plaque composed of smooth muscle, myofibroblasts, and elastic tissue . Plaque Echocardiography serves as first line screening for cardiac involvement in patients with carcinoid syndrome. Common echocardiographic features of carcinoid heart disease include morphologic changes to the tricuspid valve causing a thick retracted appearance with decreased mobility and enlargement of the right atrium and ventricle related to valvular insufficiency . SurgicaCMR offers more specific evaluation of cardiac lesions to help differentiate benign lesions from metastases compared to echocardiography evaluation which is based on lesion intrinsic signal and perfusion characteristics . While eThis case demonstrates the importance of CMR to evaluate for carcinoid heart disease and cardiac metastases. The results of the CMR exam in our case lead to characterization of myocardial metastases and allowed for planning of metastasis resection during the tricuspid valve bioprosthetic surgery. The case also serves as a reminder for providers that while echocardiography may offer first line screening for cardiac involvement when carcinoid heart disease is suspected, CMR may be useful when myocardial metastases are suspected for potential surgical planning.


Seven enterprises that have had recent Cleaner Production (CP) audits in Beijing were interviewed to identify whether these enterprises implemented the audit recommendations. If enterprises did implement the recommendations, their reasons and the results were analyzed. Finally, some suggestions on how to promote enterprise-wide CP were given.


Utilizing two-photon fluorescence lifetime imaging microscopy and the phasor analysis method, we have observed AD-related variations of endogenous fluorescence of reduced nicotinamide adenine dinucleotide (NADH) in vivo. We collected NADH FLIM images from the cerebral cortices of both APPswe:PS1dE9 mice to model amyloid Disruptions and alterations to cerebral energy metabolism play a vital role in the onset and progression of many neurodegenerative disorders and cerebral pathologies. In order to precisely understand the complex alterations underlying Alzheimer’s disease (AD) progression,  Current estimates indicate that AD accounts for 60% to 80% of dementia cases,–in vitro conditions, oxygen levels can be adjusted and metabolic substrates can be added such that the sample’s NADH can reversibly be adjusted between its fully oxidized and fully reduced states, therefore providing calibration for the minimal and maximal detectable NADH fluorescence signal. Confounds arising from toxicity prevent calibration and absolute quantitation in living organisms; however, evaluating relative changes of in vivo NADH fluorescence intensity still provides a useful indication of pathology-induced variations of mitochondrial function and intracellular oxygen requirements.in vivo measurement techniques’ utility was greatly extended by coupling NADH fluorescence with 2-photon microscopy (2PM),,,,–in vivo FLIM measurements can resolve disruptions to the TCA cycle, electron transport chain, and oxidative phosphorylation.–For several decades, measurements of reduced nicotinamide adenine dinucleotide (NADH) have been utilized as a nondestructive tool to characterize mitochondrial respiratory chain activities. NADH is an electron carrier molecule residing in almost all eukaryotic cells both in cytosol and mitochondria, and it performs vital roles in both anaerobic glycolysis and aerobic oxidative metabolism.In this report, we apply two-photon fluorescence lifetime imaging microscopy (2P-FLIM) of endogenous cortical NADH for minimally invasive characterization of AD-induced variations in cerebral metabolism in a mouse model of AD. We utilized phasor analysis to show that amyloid 2,Our imaging experiments were performed under a protocol approved by the Institutional Animal Care and Use Committee at Massachusetts General Hospital. For our studies, we utilized female transgenic APPswe:PS1dE9 mice . By integrating the photon count matrices along the time axis, intensity images were generated and used for preprocessing. First, to isolate parenchymal NADH fluorescence, features such as blood vessels were masked out manually, as well as constituents displaying endogenous fluorescence such as lipofuscin granules. The boundaries for ,The coordinates, 3We sought to evaluate AD-related alterations to mitochondrial function by measuring NADH in the living cortex of AD mouse models. Similar to flavin adenine dinucleotide (FAD), NADH is endogenous and ubiquitous within most eukaryotic cells, and it participates in multiple steps of glucose breakdown and ATP synthesis. Monitoring the fluorescence of these electron carriers uniquely enables nondisruptive assessment of energy metabolism within living biological tissue.,in vivo and in vitro. Conversely, lipofuscin phasor clusters were broad and dispersed over a range of short lifetimes. For both endogenous fluorophores, phasor clusters corresponding to measurements taken from regions near After masking, phasor computations were performed on all measurements and grouped using our custom software. ,To evaluate the spatial extent of metabolic variations around in vitro observations of impaired respiration and mitochondrial toxicity induced by intracellular Although further validation is required, the present, phasor-based observations of endogenous NADH fluorescence from living cortices of AD mouse models strongly indicate a pronounced influence of ,,Conversely, our observations of plaque-induced variations in lipofuscin fluorescence lifetime were unanticipated and raise intriguing questions regarding the nature and mechanisms of plaque-related toxicity. Often regarded as an aging-related pigment, lipofuscin granules are chemically and morphologically hetereogeneous masses primarily comprised of oxidatively modified protein and lipid residues that resist degradation by lysosomes. Lipofuscin is considered “biological garbage” that progressively accumulates within several tissues with age, but the rate of accumulation can be accelerated in the presence of higher oxygen or reduced by administration of antioxidants.in vivo measurements of endogenous fluorescence are useful for characterizing distinct variations in mitochondrial metabolism and lipofuscin accumulation in the presence of Our study shows that phasor-based


Background: According to the notion of maturational dualism, the link between mind and body weakens with age and this weakening has important consequences for emotional experiences. Specifically, it is hypothesized that age-related decline in interoceptive awareness and physiological reactivity reduce the ability to use bodily states to guide judgments about emotions. If this hypothesis is valid, then age may moderate the association between explicit measures  and implicit measures  of affective reactivity. Purpose: To investigate whether age moderates the association between explicit and implicit measures of negative affective reactivity. Methods: A sample of 275 participants (age range=20-78) viewed 25 pictures validated to induce negative emotions. Participants filled in the PANAS assessing explicit affect and the IPANAT assessing implicit affect before and after viewing the pictures. Emotional reactivity was operationalized as residualized gain scores derived from regressions of baseline affect on affect following picture viewing. Results: Age moderated the association between implicit negative affective reactivity and explicit negative affective reactivity (B=60). Discussion: The results showed a reduced association between explicit and implicit negative affective reactivity with age. This finding is consistent with the notion of maturational dualism and may indicate that older adults use affective processes that are not represented consciously  less than young adults when judging their emotional state.


Breast cancer may affect young women who have not yet completed childbearing.Assisted reproductive technology (ART) provides alternatives for fertilitypreservation such as oocyte, embryo or ovarian tissue cryopreservation. Wereviewed the published literature on fertility-preserving management in breastcancer, aiming at finding evidence to answer the following questions: (1) Whatare the fertility sparing options available?; (2) How do these women respond toIVF? and (3) Can pregnancy influence breast cancer recurrence? There is apaucity of publications describing clinical experience and outcome data whichlimits accessibility to fertility preservation in this setting. Presently,oocyte or embryo cryopreservation are the main options for fertilitypreservation. IVF success rates are comparable to the ones of non-oncologicalpopulations according to the woman's age but current published studies lack dataon definitive success rates following embryo banking for cancer patients. Theperception that IVF and pregnancy may worsen cancer prognosis remains, despitethe lack of scientific evidence to support this notion. Published studies showreassuring results for pregnancies occurring >2 years after breast cancerdiagnosis. The best published evidence suggests pregnancy after breast cancerdoes not increase the risk of disease recurrence, thus pregnancy should not beforbidden once treatment is completed. Decision making for women diagnosed withcancer requires up-to-date knowledge of the efficacy and safety of availableoptions. Providing consultation with a reproductive specialist and appropriateinformation on fertility preservation for these women should be an essentialaspect of their supportive care. Cancer still represents an enormous global health burden, and published data revealedabout 14.1 million new cases and 8.2 million deaths in 2012 worldwide  estimates that there will be 252,710 cases of invasive breast cancerdiagnosed in US women and 40,610 deaths. Data also shows that breast cancer isresponsible for 30% of new cancer cases, and 1 in 8 women will develop breast cancerduring their lifetime ,but only a small part of the patients (10%) used fertility preservation  is achieved by subcutaneousinjection of gonadotropins for 8 to 14 days, along with pituitary blockagewith GnRH analogues. Follicular growth is monitored by transvaginalultrasound and final oocyte maturation can be triggered by hCG or GnRH-a.However, due to the concerns pertaining to the effects of supraphysiologicalhormonal concentrations, several different protocols have been studied in anattempt to minimize possible worsening in oncological prognosis  and embryoor oocyte cryopreservation is the most effective option for fertilitypreservation in breast cancer. Ovarian stimulation significantly increasesestradiol levels, which raises concerns regarding safety of such a procedure aswell as the possible role of malignancy and BRCA mutation in reducing ovarianresponse to stimulation , as wellas comparable live-birth-rates   in comparison to the electivecryopreservation group  considers that evidence on anydifference in prognosis between pregnant and nonpregnant women with breastcancer is lacking, and it does not recommend pregnancy termination regardless oftumor status (Overall, the literature is reassuring and does not show a worse outcome for womenwith previously diagnosed and treated breast cancer who seek to become pregnantafterwards. Some data even suggest a better survival outcome. Those findingsshould bring comfort to physicians and to women with a previous breast cancerdiagnosis.In summary, the best available published evidence so far suggests that pregnancyafter breast cancer does not increase a woman's risk of disease recurrence.Pregnancy should not be forbidden after breast cancer treatment solely becauseof concerns on cancer recurrence and death, since current available data israther reassuring. If pregnancy is an option, these women must receive carefullycoordinated multidisciplinary approach. More large randomized prospective trialsare nedded to develop appropriate protocols in this setting.Hundreds of thousands of women in their reproductive years are diagnosed with cancereach year. Advances in breast cancer treatment result in increased numbers of femalepatients who survive cancer raising the demand for effective and individualizedfertility preservation options. Unfortunately fertility counseling remains asecondary issue for many breast cancer specialists. The perception that IVF andpregnancy may worsen cancer prognosis remains, despite the lack of scientificevidence to support this notion. Currently there are limited clinical options forfertility preservation, and the paucity of publications describing clinicalexperience and outcome data has limited accessibility to these options. Decisionmaking for patients diagnosed with cancer requires up-to-date knowledge of theefficacy and safety of available techniques. Providing consultation with areproductive specialist and appropriate information on fertility preservation forwomen with breast cancer should be an essential aspect of their supportive care.


Current research must utilize nationally-representative samples of older adults and their family caregivers to accurately reflect the growing diversity of the United States. This study aims to use a stress process model to examine potential racial differences in caregiving in a population-based sample of 844 White and 389 Black family caregivers in the United States. We conducted 3 x 2 x 2 (relationship type x race x dementia care status) factorial ANOVAs to examine potential differences in caregiving stressors, appraisals, resources, and mental and physical health outcomes among primary family caregivers. Results indicated significant racial differences in caregiving on several stress process measures. Although Black caregivers reported more caregiving stressors, compared to White caregivers, they tended to report more positive appraisals of caregiving and more caregiving resources. Dementia caregivers tended to report greater caregiving stressors and worse measures of appraisal compared to non-dementia caregivers. There was a significant two-way interaction among relationship type and dementia care status for the caregiving stressor, hours of care. A stress process model can allow researchers to investigate various factors associated with racial differences in caregiving.


South African adolescents experience high levels of trauma, including various types of childhood maltreatment. Different types of maltreatment often co-occur. Previous research suggests that childhood maltreatment provokes a latent liability to internalising and externalising dimensions of psychopathology. Our objective was to examine the effects of childhood maltreatment on internalising and externalising disorders in trauma-exposed adolescents and to assess the mediating effect of post-traumatic stress disorder (PTSD) on these associations.A cross-sectional study was conducted with 262 trauma exposed adolescents (aged 12–18 years) in South Africa. Childhood maltreatment and PTSD severity were assessed using the Childhood Trauma Questionnaire and the Child PTSD Checklist, respectively. Psychiatric disorders were diagnosed utilising the Kiddie Schedule for Affective Disorders and Schizophrenia – Present and Lifetime version – and were grouped into internalising and externalising disorders. Hierarchal logistic regression was used to assess the association between childhood maltreatment types and internalising and externalising disorders, controlling for statistically significant socio-demographic characteristics, with PTSD severity added to the final model as a potential mediator.B = 0.07, p = 0.011), although this effect was mediated by PTSD severity . In contrast, physical abuse  and gender  were associated with externalising disorders, but the addition of PTSD severity did not significantly alter these associations.Sexual abuse was significantly associated with internalising disorders (The association between sexual abuse and internalising disorders was fully mediated by PTSD symptom severity. Gender and physical abuse severity, but not PTSD severity, was associated with the presence of externalising disorders. Adolescents displaying internalising or externalising psychopathology need to be assessed for exposure to childhood physical and sexual abuse and PTSD comorbidity.


Aspergillus spp. spores found ubiquitously in the ambient environment is uncommon in immunocompetent patients. Previous reports of invasive upper airway aspergillosis in immunocompetent patients have generally demonstrated the efficacy of treatment regimens utilizing antifungal agents in combination with periodic endoscopic debridement, with symptoms typically resolving within months of initiating therapy.The development of respiratory infections secondary to Aspergillus fumigatus was isolated on tissue culture. Several months of oral voriconazole monotherapy failed to resolve her symptoms and she underwent mechanical debridement for symptom control. Following transient improvement, her symptoms subsequently returned and failed to fully resolve in spite of increased voriconazole dosing and multiple additional tissue debridements over the course of many years.A 43-year-old previously healthy female presented with worsening respiratory symptoms after failing to respond to long-term antibiotic treatment of bacterial sinusitis. Biopsy of her nasopharynx and trachea revealed extensive fungal infiltration and Invasive upper airway aspergillosis is exceedingly uncommon in immunocompetent patients. In the rare instances that such infections do occur, combinatorial voriconazole and endoscopic debridement is typically an efficacious treatment approach. However, some patients may continue to experience refractory symptoms. In such cases, continued aggressive treatment may potentially slow disease progression even if complete disease resolution cannot be achieved. Invasivpatients –7.Immunocompetent patients suffering from invasive upper airway aspergillosis can be particularly challenging to diagnose given that many initially present with indolent sinus symptoms easily mistaken for bacterial sinusitis , 8. WithA 43-year-old female with no significant past medical history presented with a chief complaint of worsening respiratory symptoms that included purulent nasal secretions, dysphagia, mild dysphonia and dyspnea with chronic cough. The symptoms had begun approximately 2 years previously and had failed to completely resolve in spite of multiple rounds of empiric antibiotic therapy for a presumed bacterial upper respiratory infection. She denied previous tobacco use and had no pertinent family history. Her physical exam was notable for erythematous nasal mucosa and a small anterior septal perforation. Blood work demonstrated a white blood cell count (WBC) of 11,400/uL (neutrophils 93.8%) and an erythrocyte sedimentation rate (ESR) of 11 mm/h. Electrolytes were all within normal limits and a random glucose was 96 mg/dL. Head and chest computed tomography (CT) showed air-fluid levels in the bilateral maxillary sinuses and irregular thickening along the left lateral and posterior tracheal wall just above the level of the medial clavicles but was negative for lung parenchymal changes.Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa but showed no fungal growth. As such, the patient was treated with intravenous vancomycin and cefepime in addition to steroids and nebulized treatments. Her breathing significantly improved during the course of her hospitalization and she was subsequently discharged with plans to continue outpatient intravenous antibiotics for an additional 2 months.Given these imaging findings in the setting of worsening dyspnea, the patient underwent a laryngoscopic examination, which revealed subglottic crusting with diffuse purulent secretions, anterolateral cricoid inflammation, and vocal cord inflammation. Her nasal cavity also demonstrated thick purulent secretions in the middle meatus bilaterally extending to the nasopharynx. Biopsies of the trachea, subglottis, and nasal septum demonstrated purulent, atypical squamous epithelium and necrotic tissue with bacterial colonies. Cultures from these sites were positive for methicillin-resistant Aspergillus fumigatus. Given a new diagnosis of invasive pseudomembranous aspergillosis, the patient was started on oral voriconazole  with close outpatient follow-up.Several months later, the patient returned for follow-up and was found to have similar upper airway symptoms despite completing her antibiotic regimen. She again underwent endoscopic examination that revealed multiple regions of white, friable pseudomembranous patches spanning her mid-trachea, subglottis, and nasopharynx Fig. . BiopsieAspergillus fumigatus. A formal immunological workup during this time was non-revealing with normal immunoglobulin levels, CD4+ T cell counts, absolute neutrophil counts, and complement levels. HIV testing was negative. Given her poor response to antifungal monotherapy, she was initiated on topical amphotericin B (100 mcg/ml) and budesonide (10 mcg/ml) nasopharyngeal rinses twice daily for symptomatic flares in addition to an increased dose of oral voriconazole .Over the following year, despite continuous antifungal treatment, the patient continued to experience tenacious, mucoid secretions, worsening dysphonia, nighttime pharyngitis, and frequent low-grade fevers. She required two separate inpatient admissions due to symptom escalation requiring endoscopic debridement of her trachea, pharynx, and nasal passages. Repeat tissue biopsies during this time period continued to demonstrate necrotic exudates in the presence of fungal hyphae with cultures continuing to grow pan-sensitive The patient continued on this regimen for 2 months and was found to have marked improvement on repeat endoscopic examination, at this point 18 months after her initial diagnosis of invasive aspergillosis. Her larynx and subglottis had near normal appearance; her nasal cavities were dry bilaterally; her nasopharynx demonstrated mild scarring but otherwise demonstrated significantly less mucopurulence than on previous exams. However, in spite of this transient improvement, the patient again began developing upper airway symptoms over the following year, correlating with increased purulence in the nasal cavities along with the reformation of pseudomembranous, brown-mucoid layering in the nasopharynx seen on endoscopic exam. Increases in her voriconazole dosing to as high as 300 mg, twice daily were attempted but did not result in significant improvement and were further complicated by vision changes attributed to supratherapeutic voriconazole trough drug levels. Additionally, while the frequency of mechanical debridement had previously averaged once every four to 6 months, the patient began requiring nearly monthly endoscopic suctioning of her nasal passage and pharynx for symptom control.Approximately 6 years after her initial diagnosis of invasive aspergillosis the patient continued to experience chronic symptoms including dysphagia, persistent dysphonia, and purulent secretions. Erosive changes to her posterior nasopharynx resulted in velopharyngeal insufficiency. Of note, serial chest x-rays during the course of her treatment never demonstrated abnormal parenchymal findings suggesting long-standing upper airway disease without progression to lower airway involvement. In the setting of persistently positive fungal hyphae seen on upper airway tissue biopsy, she was continued on oral antifungal therapy in combination with oral rinses and periodic mechanical debridement for symptomatic relief.Invasive aspergillosis of the respiratory tract is a rare but serious airway disease typically seen in immunocompromised patients. However, it is becoming increasingly clear that these infections can also occur in patients lacking the classic risk factors normally associated with underlying immunodeficiency. In the preceding case report, we presented the clinical course of an immunocompetent patient with clinical, microbiological, and histopathologic evidence of invasive pseudomembranous upper airway and tracheal aspergillosis persisting for many years in spite of longstanding treatment efforts. In our reading of the literature, this appears to be one of the most chronic cases of respiratory aspergillosis reported in an immunocompetent patient.aspergillus-related respiratory infections typically should have a formal immunological evaluation to rule-out primary and secondary causes of immunodeficiency. While different screening studies can be performed, enumeration of T cells and neutrophil counts are particularly important given their essential role in clearing fungal infections [Patients found to have invasive fections . Given tfections , more adfections .aspergillus-related respiratory infections develop in immunocompetent patients is poorly understood and difficult to study given the infrequency with which such cases occur and are reported. Interestingly, many of the comorbidities previously reported in immunocompetent patients diagnosed with invasive upper airway and tracheobronchial disease were notably absent in the case of our patient. D’Anza et al. [The mechanism by which a et al.  identifia et al.  identifiaspergillus invasion in the absence of any other overt systemic predisposing risk factors. This is also potentially hinted at by the anatomical distribution of fungal disease seen in this case which appears to have mirrored the involvement of pre-existing invasive bacterial infection both histologically and on culture from the patient’s trachea and nasopharynx during her initial course. We also note that concurrent infection of the upper airway and tracheobronchial tree appears to be a particularly rare anatomic distribution for invasive respiratory aspergillosis, with infection of these sites typically occurring in isolation of one another or in combination with lung parenchymal involvement when the disease becomes particularly widespread and aggressive [Given the absence of these previously described comorbidities, the question as to what initially predisposed our patient to her longstanding infection still remains. It does seem noteworthy that prior to presenting to our care, the patient was treated for mixed MRSA/pseudomonal bacterial sinusitis for approximately 2 years before developing evidence of aspergillosis on biopsy and culture data. Several case reports seem to suggest that chronic invasive aspergillosis may develop as a secondary infection following initial respiratory infections in immunocompetent patients. While these cases seem to be associated more often with viral etiologies such as influenza or even dengue , 12, it gressive , 13.Aside from the challenges in identifying the source of our patient’s infection, understanding her poor response to combinatorial systemic antifungal therapy and mechanical debridement has proven equally challenging. In accordance with current treatment guidelines for invasive aspergillosis, oral voriconazole was started and continued for the duration of her disease course –16. HoweWhen used in combination, voriconazole and endoscopic debridement of infected tissue typically results in excellent outcomes in immunocompetent patients. Looking specifically at cases of upper airway aspergillosis, the patients described by D’Anza et al.  all requBased on this previous work, the expectation at the outset of our patient’s treatment was that this combinatorial approach would be efficacious, particularly given her benign past medical history. However, it is notable that after years of active invasive infection, the patient had no radiographic involvement of the lung parenchyma on serial imaging, suggesting that while unable to completely resolve her disease, her treatment appears to have at least slowed her disease progression. The use of topical amphotericin B and steroid rinses, while more conventionally used for treatment of allergic fungal rhinosinusitis , 18 rathAlthough invasive upper airway aspergillosis is exceedingly uncommon in immunocompetent patients, such patients with chronic sinusitis and respiratory symptoms should be evaluated for the possibility of secondary invasive fungal infections, particularly those who fail to improve with appropriate antibiotic therapy. Although combinatorial voriconazole and endoscopic debridement is typically an efficacious treatment approach, some patients may continue to experience refractory symptoms, in which case continued aggressive treatment may potentially slow disease progression even if complete disease resolution cannot be achieved. Ultimately, this case highlights the possibility of refractory invasive aspergillosis in an immunocompetent patient and demonstrates the importance of further investigation into the pathogenesis of invasive fungal disease in the absence of overt systemic immunosuppression.


Traditional approaches aimed at delaying or preventing age-dependent diseases view each disease as a distinct entity, resulting from separate pathophysiological chains of events. However, it is becoming increasing clear that even in adult animals there remains significant plasticity in terms of ageing trajectories and lifespan, suggesting that targeting ageing processes directly may be a promising alternative strategy. However, to date effects of even the most efficacious pharmacological interventions are smaller than those of ageing mutations, even when targeting the same ageing pathways. Interestingly, it has been shown that simultaneously targeting multiple ageing pathways can result in lifespan benefits that are synergistic (more than additive). We have recently shown that dramatic lifespan and healthspan extension can also be archived by leveraging interactions between drugs targeting distinct subsets of the gene-regulatory network controlling ageing of C. elegans. These interventions were highly efficacious, even when animals were treated only as adults.


OBJECTIVES/SPECIFIC AIMS: To describe how Michigan Institute for Clinical & Health Research (MICHR) has engaged communities in its leadership and governance structure. This presentation will describe these practices, how they are being evaluated, and future plans for institute-wide engagement of communities in translational research. METHODS/STUDY POPULATION: Engaged partners from various communities across Michigan in various ways within MICHR’s Community Engagement Program. RESULTS/ANTICIPATED RESULTS: MICHR has utilized participatory practices in the development of the CAB to strengthen existing relationships and build new ones with potential partners. DISCUSSION/SIGNIFICANCE OF IMPACT: MICHR-wide Community Advisory Board (CAB) will ensure community voices are heard and utilized in leadership and strategic decisions for CTSA activities.


Cardiac lipomas are rare benign primary cardiac tumours primarily composed of mature adipocytes. They are usually well defined, encapsulated masses, but rarely demonstrate malignant characteristics by infiltrating the myocardium. This causes diagnostic uncertainty as it becomes a priority to rule out primary malignant cardiac tumours such as sarcoma which often carry a poor prognosis.A 61 year old female presenting with chest pain was found to have an infiltrating right atrial hypertrophic mass. Mutli-disciplinary team (MDT) discussions along with the presence of symptoms and likelihood of malignancy led to the recommendations for surgery.Intraoperatively this involved the right pulmonary veins and superior vena cava (SVC). The mass was resected with good margins and reconstruction of the right atrium, pulmonary veins and SVC was done using porcine pericardial patch. The patient made a good postoperative recovery and was discharged home in sinus rhythm with no significant valvular lesions. This was further confirmed at 6 month follow up. Final histology was that of infiltrating lipoma.In this rare case of infiltrating cardiac lipoma in a relatively young patient, the diagnostic uncertainty despite multimodal imaging meant surgery was indicated due to the high suspicion of cancer. Even in benign cases, fatty infiltration can lead to conduction defects and embolisation. Technical difficulties in sectioning these specimens is caused by intra-tumour variability and current recommendations are for excision biopsy, for best characterisation.The management of these patients requires an MDT with Cardiac surgery being a safe approach providing definitive management. Primary cardiac neoplasms are rare with post-mortem incidence estimates ranging from 0.001% to 0.03% . CardiacFurthermore, myocardial infiltration can result in conduction defects causing rhythm disturbances .A 61 year old female with a background of asthma, hypertension and previous smoking, presented with chest pain and was found to have an infiltrating right atrial hypertrophic mass suspicious for sarcoma on transthoracic echocardiography and cardiac MRI.Coronary angiogram showed no flow-limiting lesions and cardiac echocardiogram showed restrictive changes with epicardial thickening in the right atrium and around the superior vena cava (SVC). Cardiac computed tomography (CT)Fig.  and magnFollowing multi-disciplinary team (MDT), patient and family discussions, the patient consented to surgery.Intraoperatively, there was a fatty infiltrating mass involving the right atrium, right superior pulmonary vein and SVC. The patient was placed onto cardiopulmonary bypass using bicaval cannulation with the SVC cannulated as distal as possible. The mass was resected with good margins. Right atrium, pulmonary veins and proximal SVC were reconstructed using porcine pericardium.Tissue was sent for histology, Sections showed lipomatous tumour entrapping myocardial cells, composed of lobules of mature adipocytes and very thin fibro-vascular septa. No significant cytological atypia was observed. On molecular genetic testing, MDM2 gene amplification was negative by interphase FISH ruling out a malignant liposarcoma. A diagnosis of infiltrating lipoma involving the right atrium was established.The patient made a good postoperative recovery and was discharged in sinus rhythm with no significant valvular lesions. This was confirmed at six months review.Infiltrating cardiac lipoma provides a diagnostic challenge. It cannot be distinguished from primary malignant cardiac lesions such as liposarcoma based on clinical presentation or non- invasive diagnostic modalities. Cardiac liposarcomas are aggressive malignant mesenchymal neoplasms which carry poor prognosis and hence represent important differentials to be ruled out . Intra-cIn a literature review, we found seven cases of infiltrating cardiac lipoma. Three of these cases describe lipomas originating on the epicardial aspect infiltrating into the underlying ventricular myocardium one of which reported multiple infiltrating lipomas –13. The Due to the rarity of cardiac lipomas, there have been no large cohort studies or randomised trials to produce guidelines on treatment. Prompt surgical management can however lead to complete cure resulting in excellent long-term prognosis. Even if benign, infiltrating cardiac lipomas can manifest in fatal clinical sequelae such as arrythmias and heart failure. The management of infiltrating lipomas provides for diagnostic challenges and hence requires an MDT approach and comprehensive patient counselling. We have demonstrated cardiac surgery in this setting is safe and provides good medium to long-term results.


Mice that overexpress mutant human tau in forebrain neurons develop many features of Alzheimer’s disease (AD), including behavioral impairments and neurodegeneration by 5 months of age. While an appropriate model to study AD-like pathology, the transgene’s high neurotoxicity makes it difficult to investigate how aging impacts AD onset and progression. The removal of endogenous mouse tau decreases the transgene’s neurotoxicity in young mice, which has allowed us to age mice to 20 months of age and investigate behavior at a more AD-relevant stage of life. Interestingly, the tau transgenic mice show increased discrimination between familiar and unfamiliar objects than non-transgenic littermates (p = 0.02) suggesting tau transgenic mice have better memory. The transgenic mice also displayed increased physical activity in the Open Field Test than non-transgenic littermates . Their improved behavioral performance occurred despite significant forebrain atrophy . Interestingly, the non-transgenic control mice lacking endogenous mouse tau developed insulin resistance and obesity, and had significantly smaller cerebellum than transgenic mice . These data suggest that insulin resistance and obesity contribute more profoundly to poor behavioral performance than forebrain neurodegeneration. Moreover our study suggests that the cerebellum, recognized primarily for its role in coordination and motor function, may be an important mediator of late life cognitive function, especially in the presence of insulin resistance and obesity.


Although functional mobility limitations are associated with increased healthcare needs in later life, little research explores how older adults with varying functional mobility trajectories experience healthcare quality. To this end, we explore the effects of functional mobility trajectories on differences in healthcare treatment satisfaction, perceived disability discrimination in healthcare settings, and perceived everyday disability discrimination. We analyzed 9 waves of the Health and Retirement Study . First, we estimate age-specific group-based trajectories of functional mobility across age using finite mixture models. Second, we use multinomial logistic regression to identify sociodemographic factors that place individuals at elevated risk of membership in each group. Third, we explore how membership in one disability trajectory group over another affects healthcare satisfaction, perceptions of everyday discrimination in the context of healthcare treatment settings, and perceived discrimination in everyday life. Regression models include clustered standard errors to account for heteroscedasticity across repeated observations of individuals over time. We identify six group-based trajectories of functional mobility limitation among aging Americans. Black, female, and less-educated Americans are at higher risk of membership in disadvantaged trajectories, characterized by more rapidly increasing counts of functional mobility limitations, than their counterparts. Disadvantaged functional limitation trajectories are associated with lower levels of healthcare satisfaction, higher levels of perceived physical disability discrimination in healthcare treatment settings, and higher levels of perceived physical discrimination in other contexts of everyday life. The present study advances our knowledge of how older adults experience healthcare settings and discrimination across functional mobility status trajectories.


Biases against older adults and people with disabilities can lead to discriminatory behaviors. One way to better understand attitudes towards these populations is through the examination of implicit (unconscious) factors. This paper utilizes The Implicit Association Test, a computer-based categorization task designed to assess implicit or unconscious attitudes, to assess the impact of an intergenerational service-learning course created to support the human animal bond between vulnerable pet owners and their companion animals. This study, using the Wilcoxon signed-rank test, assessed the impact of college students’ interactions with older pet owners on these students’ implicit attitudes. Pre- and post-assessment of participating students found statistically significant decreased biases towards older people and people with disabilities after completing the course (p=.032). Results from this study suggest that participating in an intergenerational service-learning course centered around the human animal bond can positively affect implicit attitudes towards older adults or people with disabilities.


STimulator of INterferon Gene (STING), canonically known for initiating a type I IFN production and innate immune response to cytosolic DNA, is required for host defense against neurotropic RNA viruses. We evaluated the role of STING in host defense to control WNV infection and pathology in a murine model of infection. When challenged with WNV, STING knock out (-/-) mice displayed increased morbidity and mortality compared to wild type (WT) mice. Virologic analysis and assessment of STING activation revealed that STING signaling was not required for control of WNV in the spleen nor was WNV sufficient to mediate canonical STING activation in vitro. However, STING-/- mice exhibited a clear trend of increased viral load and virus dissemination in the CNS. We found that STING-/- mice exhibited increased and prolonged neurological signs compared to WT mice. Pathological examination revealed increased lesions, mononuclear cellular infiltration and neuronal death in the CNS of STING-/- mice, with sustained pathology after viral clearance. We found that STING was required in bone marrow derived macrophages for early control of WNV replication and innate immune activation. In vivo, STING-/- mice developed an aberrant T cell response in both the spleen and brain during WNV infection that linked with increased and sustained CNS pathology compared to WT mice. Our findings demonstrate that STING plays a critical role in immune programming for the control of neurotropic WNV infection and CNS disease.West Nile Virus (WNV), an emerging and re-emerging RNA virus, is the leading source of arboviral encephalitic morbidity and mortality in the United States. WNV infections are acutely controlled by innate immunity in peripheral tissues outside of the central nervous system (CNS) but WNV can evade the actions of interferon (IFN) to facilitate CNS invasion, causing encephalitis, encephalomyelitis, and death. Recent studies indicate that  Stimulator of Interferon Genes (STING) in conferring host defense during WNV infection in a murine model. Our studies revealed that STING is essential for restricting pathology in the CNS during WNV infection. Further, STING is required for effective programming of the innate and adaptive immune response to WNV. In the absence of STING, aberrant immune development leads to ineffective viral clearance and immunopathology in the CNS. These studies uncover a critical and previously unidentified role for STING in the restriction of WNV that may have broader implications for a role in conferring host defense against RNA viruses.In recent years, outbreaks of emerging and re-emerging neuroinvasive West Nile virus (WNV) infection have brought about a critical need to understand host factors that restrict neuropathology and disease. WNV infection in humans typically is either asymptomatic or results in a mild febrile illness, but in some cases virus spreads to the central nervous (CNS) causing a more severe form of neuropathological disease. Previous studies established that both innate and adaptive immune responses are essential for controlling WNV disease and restricting the virus from the CNS. In this study, we examined the role of  Flavivirus infections, including West Nile virus (WNV), are ongoing or emerging threats to global health  BME and [40ng/mL] murine MCSF (mMCSF). Cells were cultured for 7 days in non-TC coated plates, then scraped, washed with PBS and seeded at 1E6 cells/well in 12-well TC coated plates with cDMEM+BME+mMCSF. Cells were infected or transfected the next day.in vivo work, while WNV-TX ic (infectious clone) stocks were utilized for cell culture (in vitro) studies. Working stocks were propagated in Vero-E6  and titered by standard plaque assay on VeroWHO and BHK21  cells as previously described . Images acquired using [Allen Brain Institute Brain Explorer 2]. Available from: [http://mouse.brain-map.org/static/brainexplorer].STING localization in the brain is centralized to the hind/mid-brain, hippocampus, primary motor-cortex and olfactory bulb in the brain. Square: midbrain/thalamus region. Oval: hindbrain (cerebellum and brain-stem). Image is from the Allen Institute for Brain Science. [Allen Mouse Brain Atlas]. Available from: [(TIF)Click here for additional data file.


Summary: Today’s American elders are increasingly being seen as an asset to society through civic engagement. A new challenge facing America now and in the years ahead is how to tap such asset. Formal organizations should play a leading role in institutionalizing American elders’ civic engagement. Due to a structural lag between social changes and organizational practices, however, many organizations are not ready to engage the large number of American elders. To address this issue, formal organizations first need to know which factors affect American elders’ civic engagement and then are able to come up with effective solutions. Although some studies have investigated the contributing factors of American elders’ civic engagement, there are very few systematic syntheses of these factors from various different studies. To fill this gap, the authors conducted a mixed methods systematic literature review using meta-summary. Through electronic search of five databases and hand search of bibliographies, 22 articles were used in final analysis based on eligibility criteria, including 19 quantitative studies, two qualitative studies and one mixed methods study. Findings: The review identified six themes and 28 factors related to American elders’ civic engagement. These themes encompassed socio-demographic factors (eight factors), health status (four factors), program characteristics (four factors), engagement opportunities (three factors), engagement outcomes (five factors) and social capital (four factors). Applications: Formal organizations are advised to develop relevant competencies to capture the influences of identified factors. Social workers are also required to develop multilevel competencies to better engage American elders with the organizational settings.