Resilience interventions in higher education: surveying the research landscape

Learning Objectives Describe scoping review purpose, objectives, and methods Describe key findings on range and nature of resilience programming for college students Explore current resilience programming and research among session participants’ home institutions Identify next steps for resilience research and evidence-based programmin

Lymph node macrophages restrict murine cytomegalovirus dissemination

Cytomegaloviruses (CMVs) establish chronic infections that spread from a primary entry site to secondary vascular sites, such as the spleen, and then to tertiary shedding sites, such as the salivary glands. Human CMV (HCMV) is difficult to analyze, because its spread precedes clinical presentation. Murine CMV (MCMV) offers a tractable model. It is hypothesized to spread from peripheral sites via vascular endothelial cells and associated monocytes. However, viral luciferase imaging showed footpad-inoculated MCMV first reaching the popliteal lymph nodes (PLN). PLN colonization was rapid and further spread was slow, implying that LN infection can be a significant bottleneck. Most acutely infected PLN cells were CD169(+) subcapsular sinus macrophages (SSM). Replication-deficient MCMV also reached them, indicating direct infection. Many SSM expressed viral reporter genes, but few expressed lytic genes. SSM expressed CD11c, and MCMV with a cre-sensitive fluorochrome switch showed switched infected cells in PLN of CD11c-cre mice but yielded little switched virus. SSM depletion with liposomal clodronate or via a CD169-diphtheria toxin receptor transgene shifted infection to ER-TR7(+) stromal cells, increased virus production, and accelerated its spread to the spleen. Therefore, MCMV disseminated via LN, and SSM slowed this spread by shielding permissive fibroblasts and poorly supporting viral lytic replication

Local replication of simian immunodeficiency virus in the breast milk compartment of chronically-infected, lactating rhesus monkeys

Breast milk transmission remains a major mode of infant HIV acquisition, yet anatomic and immunologic forces shaping virus quasispecies in milk are not well characterized. In this study, phylogenic analysis of envelope sequences of milk SIV variants revealed groups of nearly identical viruses, indicating local virus production. However, comparison of the patterns and rates of CTL escape of blood and milk virus demonstrated only subtle differences between the compartments. These findings suggest that a substantial fraction of milk viruses are produced by locally-infected cells, but are shaped by cellular immune pressures similar to that in the blood

Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney.

Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation

The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals

To dissect the genetic architecture of blood pressure and assess effects on target-organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure loci, of which 17 were novel and 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target-organ damage in multiple tissues, with minor effects in the kidney. Our findings expand current knowledge of blood pressure pathways and highlight tissues beyond the classic renal system in blood pressure regulation

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Therapeutic targeting of cathepsin C::from pathophysiology to treatment

Cathepsin C (CatC) is a highly conserved tetrameric lysosomal cysteine dipeptidyl aminopeptidase. The best characterized physiological function of CatC is the activation of pro-inflammatory granule-associated serine proteases. These proteases are synthesized as inactive zymogens containing an N-terminal pro-dipeptide, which maintains the zymogen in its inactive conformation and prevents premature activation, which is potentially toxic to the cell. The activation of serine protease zymogens occurs through cleavage of the N-terminal dipeptide by CatC during cell maturation in the bone marrow. In vivo data suggest that pharmacological inhibition of pro-inflammatory serine proteases would suppress or attenuate deleterious effects of inflammatory/auto-immune disorders mediated by these proteases. The pathological deficiency in CatC is associated with Papillon-Lefèvre syndrome. The patients however do not present marked immunodeficiency despite the absence of active serine proteases in immune defense cells. Hence, the transitory pharmacological blockade of CatC activity in the precursor cells of the bone marrow may represent an attractive therapeutic strategy to regulate activity of serine proteases in inflammatory and immunologic conditions. A variety of CatC inhibitors have been developed both by pharmaceutical companies and academic investigators, some of which are currently being employed and evaluated in preclinical/clinical trials

Beyond the patient: understanding and addressing third-party disability in family members of people with Parkinson’s disease

Thesis (Ph.D.)--University of Washington, 2018Purpose: Family members of people with communication disorders associated with Parkinson’s disease (PD) experience third-party disability. It is unknown whether these experiences are addressed in the rehabilitation process for communication disorders. The purpose of this study was to explore family member involvement in treatment from the perspectives of family members and speech-language pathologists (SLPs) to understand how third-party disability is addressed. Methods: A mixed-methods design was used to capture the perspectives from two stakeholder groups, family members of people with PD and SLPs who provided services to people with PD. The first phase of this study used qualitative interviews with nine family members. After a preliminary analysis of the family member data, a survey was developed and administered to SLPs in the United States as the second phase. A total of 110 completed surveys were used for analysis. Qualitative data were analyzed for emergent patterns, and quantitative data were analyzed using descriptive measures. Data were then integrated and analyzed together. Results: Three topic areas emerged from the data. First, family member involvement in treatment was typically for the purpose of supporting communication for the person with PD. However, family members and SLPs held divergent views such that family members reported little to no involvement, whereas many SLPs reported involving most family members in treatment. Second, there was a range in perspectives of family members and SLPs with regard to meeting family member needs in treatment. Several family members reported that their need to understand the person with PD was met, as improvements were seen in his/her communication abilities. However, other needs such as managing the challenging communication interactions between them and the person with PD were not met. Many SLPs reported supporting family members by counseling them and referring them to additional supportive services, but few had goals specifically addressing family member needs. Although family members did not differentiate between the type of communication disorder in the person with PD, fewer SLPs reported involving family members of people with PD who had cognitive-communication disorders than those with dysarthria. Third, there were multiple factors influencing SLPs’ ability to involve family members in treatment. SLPs’ views about including family members and their perceptions about family members’ and clients’ beliefs and preferences suggested that these factors may not have a negative influence on their practice. However, SLPs held mixed opinions about the work environment to support their practice. Many SLPs reported that their work setting supported their time to involve family members, but insurance reimbursement also limited their ability to do. The final key finding from this study suggested that SLPs perceived many resources to be helpful in preparing them to involve family members in treatment. Almost all (if not all) SLPs reported that the clinical experiences they gained over time and learning from colleagues were helpful resources. Attendance at continuing education events and reading publications that were both peer-reviewed and non-peer reviewed were also helpful. However, SLPs’ had ambivalent ideas about the strength and usefulness of the evidence base. Most SLPs felt that there was strong evidence demonstrating the role of family members in treatment, but only about half believed that the evidence guided their practice specifically on meeting family members’ needs. Finally, with regard to the clinical training and education that they received from their graduate education, fewer SLPs felt that these resources were helpful in preparing them to include family members in treatment. Conclusions: Prior literature demonstrates that family members experience third-party disability associated with communication disorders that are present in people with PD. Family members in this study discussed needing various supports from treatment, but not all of their needs were met. SLPs appeared to express positive opinions about involving family members in treatment, but there may be barriers related to the work environment and the current evidence base to support them in their practice. The challenging experiences that family members face as a result of communication disorders in the person with PD and the barriers affecting SLPs’ practice suggest that there should be a shift of the healthcare system to adopt family-centered care so that outcomes from the rehabilitation process can be enhanced

Trends and predictors of quality of care in VA nursing homes related to serious mental illness

Objective: Within Veterans Affairs (VA) nursing homes (NHs), quality issues have a tremendous impact on the population with serious mental illness (SMI), who are more likely than their non-SMI Veteran counterparts to use NH services. We examined recent trends in quality indicators (QIs) measuring poor performance of VA NHs and whether the facility-level QIs vary with SMI concentration within the facility. Methods: From VA administrative records including Minimum Data Set assessments, we identified all residents in the 135 VA NHs between fiscal years 2005 (FY05) through FY07. We used a zero-inflated Poisson regression to assess trends in and facility-level predictors of 3 process-related QIs: depression without antidepressant therapy; bladder/bowel incontinence without a toileting plan; and physical restraint use. Facility-level predictors included collocated special care units, rurality, staffing, physical plant characteristics, SMI prevalence, and SMI admission volume. Results: During FY05–FY07, restraint use declined from 1.2% to 1.1% and incontinence without a toileting plan from 25.8% to 22.1%, but untreated depression increased from 5.1% to 5.5%. Despite overall gains in quality, higher SMI prevalence was associated with higher odds of physical restraint use and lack of toileting plan. Higher SMI prevalence was also associated with higher frequency of untreated depression. Other characteristics such as complex building structure were predictive of variation in quality, but the relationships were not consistent across QI types. Conclusion: VA NHs had significant improvements in these examined QIs during the study period. Nonetheless, overall poorer quality was observed at sites with higher SMI concentrations