Ten years of success: Lessons learned from the Hood Canal Regional Pollution Identification and Correction (HCRPIC) Program

The Hood Canal watershed is home to shellfish resources that have great cultural, economic, recreational, and subsistence value to local tribes and residents, in addition to a striking natural setting that provides a strong sense of place, recreational opportunities, and other human wellbeing benefits. Hood Canal is also served primarily by on-site sewage systems (OSS), many near water bodies, which can fail as they age and contribute bacterial pollution to local waters. A regional approach to Pollution Identification and Correction (PIC) and water quality programs has been essential for protecting public health, ancestral shellfish practices, and other socio-ecological benefits by reducing bacterial and nutrient pollution sources. For the past 10 years, the Hood Canal Coordinating Council (HCCC) has partnered with its member jurisdictions and local partners to develop and implement the Hood Canal Regional Pollution Identification and Correction (HCRPIC) Program. The goals of the HCRPIC Program are to restore and protect public health, shellfish growing areas, water quality, and habitat in Hood Canal by correcting fecal pollution sources. The collaborative and inclusive nature of the HCRPIC Program provides a unique opportunity to combine and share the strengths, resources, and experience of each partners’ PIC and water quality programs. Coordinated efforts between these strategic partnerships has led to efficient and effective regional water quality efforts, including problem solving and information sharing between agencies and neighboring jurisdictions, development of policies and procedures, resource allocation, and data-guided prioritization of pollution investigations and corrections. Over time, the HCRPIC Program has evolved into an effective tool for achieving meaningful regional water quality successes, including shellfish growing area classification upgrades, sustainable funding for ongoing PIC work, expanded water quality monitoring, and numerous OSS repairs and corrections. HCCC continues to pursue opportunities to implement the HCRPIC Program to protect Hood Canal’s water quality

Dynamic nuclear structure emerges from chromatin crosslinks and motors

The cell nucleus houses the chromosomes, which are linked to a soft shell of lamin filaments. Experiments indicate that correlated chromosome dynamics and nuclear shape fluctuations arise from motor activity. To identify the physical mechanisms, we develop a model of an active, crosslinked Rouse chain bound to a polymeric shell. System-sized correlated motions occur but require both motor activity {\it and} crosslinks. Contractile motors, in particular, enhance chromosome dynamics by driving anomalous density fluctuations. Nuclear shape fluctuations depend on motor strength, crosslinking, and chromosome-lamina binding. Therefore, complex chromatin dynamics and nuclear shape emerge from a minimal, active chromosome-lamina system.Comment: 18 pages, 21 figure

Generalized Lévy walks and the role of chemokines in migration of effector CD8+ T cells.

Chemokines have a central role in regulating processes essential to the immune function of T cells, such as their migration within lymphoid tissues and targeting of pathogens in sites of inflammation. Here we track T cells using multi-photon microscopy to demonstrate that the chemokine CXCL10 enhances the ability of CD8+ T cells to control the pathogen Toxoplasma gondii in the brains of chronically infected mice. This chemokine boosts T-cell function in two different ways: it maintains the effector T-cell population in the brain and speeds up the average migration speed without changing the nature of the walk statistics. Notably, these statistics are not Brownian; rather, CD8+ T-cell motility in the brain is well described by a generalized Lévy walk. According to our model, this unexpected feature enables T cells to find rare targets with more than an order of magnitude more efficiency than Brownian random walkers. Thus, CD8+ T-cell behaviour is similar to Lévy strategies reported in organisms ranging from mussels to marine predators and monkeys, and CXCL10 aids T cells in shortening the average time taken to find rare targets

Differential expression of exosomal microRNAs in prefrontal cortices of schizophrenia and bipolar disorder patients

Exosomes are cellular secretory vesicles containing microRNAs (miRNAs). Once secreted, exosomes are able to attach to recipient cells and release miRNAs potentially modulating the function of the recipient cell. We hypothesized that exosomal miRNA expression in brains of patients diagnosed with schizophrenia (SZ) and bipolar disorder (BD) might differ from controls, reflecting either disease-specific or common aberrations in SZ and BD patients. The sources of the analyzed samples included McLean 66 Cohort Collection (Harvard Brain Tissue Resource Center), BrainNet Europe II (BNE, a consortium of 18 brain banks across Europe) and Boston Medical Center (BMC). Exosomal miRNAs from frozen postmortem prefrontal cortices with well-preserved RNA were isolated and submitted to profiling by Luminex FLEXMAP 3D microfluidic device. Multiple statistical analyses of microarray data suggested that certain exosomal miRNAs were differentially expressed in SZ and BD subjects in comparison to controls. RT-PCR validation confirmed that two miRNAs, miR-497 in SZ samples and miR-29c in BD samples, have significantly increased expression when compared to control samples. These results warrant future studies to evaluate the potential of exosome-derived miRNAs to serve as biomarkers of SZ and BD

Use of high cost care among Veterans with comorbid mental illness and Alzheimer's Disease and related dementias

Introduction/Objective Alzheimer's Disease and Other Related Dementias (AD/ADRD) leads to frequent emergency department (ED) and inpatient use. Mental health symptoms among persons with AD/ADRD increases cognitive and functional disabilities and could contribute to these high rates of intensive health care use. The objective of this paper is to assess the relationship of mental illness on 12-month patterns in hospitalization and ED use among Veterans aged 65 and over with a new AD/ADRD diagnosis. Methods We used an existing dataset of administrative electronic health record data of Veterans with AD/ADRD from the US Veterans Health Administration linked with Medicare claims data from 2011-2015. We use multivariable logistic regression to examine the association between no pre-existing mental illness, pre-existing mental illness (e.g., major depressive disorder, generalized anxiety disorder, or post-traumatic stress disorder), and pre-existing severe mental illness-or SMI-(e.g., bipolar disorder, major depressive disorder with psychosis, or schizophrenia) and 12- month ED and hospitalization use and readmissions among Veterans who had an initial hospitalization visit. We estimated predicted probabilities, differential effect, and associated 95% confidence intervals. Results In our sample, 1.4% had SMI and 11% had non-SMI mental illness. The unadjusted percentage with inpatient and ED use was higher among Veterans with SMI (34% and 26%, respectively) and Veterans with non-SMI mental illness (20%, 16%) compared with Veterans without pre-existing mental illness (12%, 9%). Compared to individuals with no pre-existing mental illness, having a pre-existing mental illness (1.27 percentage points, 95% CI: 0.76, 1.78) and a pre-existing SMI (7.17 percentage points, 95% CI: 5.66, 8.69) were both associated with an increased likelihood of ED use. The same pattern was observed for any inpatient use (mental illness 2.18, 95% CI: 1.59, 2.77; SMI 9.91, 95% CI: 8.21, 11.61). Only preexisting SMI was associated higher hospitalization readmission. Discussion Pre-existing mental illness increases use of high cost, intensive health care and this association is higher of more severe mental health conditions. We also show that pre-existing mental illness exerts a unique influence, above and beyond other comorbidities, such as diabetes, on ED and inpatient visits. More needs to be done to increase recognition of the unique risks of this combination of health conditions and encourage strategies to address them. Developing, testing, and implementing comprehensive strategies that address the intersection of ADRD and mental illness is promising approach that requires more focused attention

Self-Reported Pain in Male and Female Iraq/Afghanistan-Era Veterans: Associations with Psychiatric Symptoms and Functioning

Objective. To examine pain symptoms and co-occurring psychiatric and functional indices in male and female Iraq/Afghanistan-era veterans. Design. Self-reported data collection and interviews of Iraq/Afghanistan-era veterans who participated in a multisite study of postdeployment mental health. Setting. Veterans were enrolled at one of four participating VA sites. Subjects. Two thousand five hundred eighty-seven male and 662 female Iraq/Afghanistan-era veterans. Methods. Nonparametric Wilcoxon rank tests examined differences in pain scores between male and female veterans. Chi-square tests assessed differences between male and female veterans in the proportion of respondents endorsing moderate to high levels of pain vs no pain. Multilevel regression analyses evaluated the effect of pain on a variety of psychiatric and functional measures. Results. Compared with males, female veterans reported significantly higher mean levels of headache (P \u3c 0.0001), muscle soreness (P \u3c 0.008), and total pain (P \u3c 0.0001), and were more likely to report the highest levels of headache (P \u3c 0.0001) and muscle soreness (P \u3c 0.0039). The presence of pain symptoms in Iraq/Afghanistan-era veterans was positively associated with psychiatric comorbidity and negatively associated with psychosocial functioning. There were no observed gender differences in psychiatric and functional indices when levels of pain were equated. Conclusions. Although female Iraq/Afghanistan-era veterans reported higher levels of pain than male veterans overall, male and female veterans experienced similar levels of psychiatric and functional problems at equivalent levels of reported pain. These findings suggest that pain-associated psychological and functional impacts are comparable and consequential for both male and female veterans

Family caregiver use and value of support services in the VA Program of comprehensive assistance for family caregivers

Context: The US Congress in 2010 established the Program of Comprehensive Assistance for Family Caregivers (PCAFC) in the Department of Veterans Affairs’ (VA) healthcare system, expanding services for family caregivers of eligible veterans with injuries sustained or aggravated in the line of duty on or after 11 September 2001. The program includes a Caregiver Support Coordinator, stipends for caregivers, education/training, and additional services. Objective: The primary goal of this study was to examine the types of services that family caregivers of veterans use and value, how services are used and any limitations family caregivers’ experienced. Given that few interventions assess caregiver satisfaction with services, there is a gap in the existing literature addressing these outcomes. Methods: We assessed how caregivers use and value services with a national, web-based survey (N=1,407 caregivers) and semi-structured phone interviews (N=50 caregivers). Findings: Caregivers rated all services as helpful and especially valued financial support to be with the veteran, training in skills for symptom management, and assistance with navigating the healthcare system. A majority reported more confidence in caregiving, knowing about resources for caregiving and feeling better prepared to support the veteran’s progress and healthcare engagement. However, only a minority reported awareness of the full range of PCAFC services. Limitations: There was a low response rate to the survey, which may have implications for generalisability to the whole population of caregivers accessing PCAFC. Additionally, we rely on self-report rather than objective measures of service use and outcomes. Implications: This is the first in-depth examination of experiences of caregivers of using the innovative PCAFC model of support. It acknowledges the important role of caregivers in health and long-term (social) care delivery and can be used to inform development of strategies outside the VA healthcare system to recognise caregivers. Findings suggest that a system-wide program to effectively include caregivers as part of the care team should include mechanisms to help connect caregivers with an array of resources, options from which to find those which best fit their personal needs and preferences

Modulators of Cytoskeletal Reorganization in CA1 Hippocampal Neurons Show Increased Expression in Patients at Mid-Stage Alzheimer's Disease

During the progression of Alzheimer's disease (AD), hippocampal neurons undergo cytoskeletal reorganization, resulting in degenerative as well as regenerative changes. As neurofibrillary tangles form and dystrophic neurites appear, sprouting neuronal processes with growth cones emerge. Actin and tubulin are indispensable for normal neurite development and regenerative responses to injury and neurodegenerative stimuli. We have previously shown that actin capping protein beta2 subunit, Capzb2, binds tubulin and, in the presence of tau, affects microtubule polymerization necessary for neurite outgrowth and normal growth cone morphology. Accordingly, Capzb2 silencing in hippocampal neurons resulted in short, dystrophic neurites, seen in neurodegenerative diseases including AD. Here we demonstrate the statistically significant increase in the Capzb2 expression in the postmortem hippocampi in persons at mid-stage, Braak and Braak stage (BB) III-IV, non-familial AD in comparison to controls. The dynamics of Capzb2 expression in progressive AD stages cannot be attributed to reactive astrocytosis. Moreover, the increased expression of Capzb2 mRNA in CA1 pyramidal neurons in AD BB III-IV is accompanied by an increased mRNA expression of brain derived neurotrophic factor (BDNF) receptor tyrosine kinase B (TrkB), mediator of synaptic plasticity in hippocampal neurons. Thus, the up-regulation of Capzb2 and TrkB may reflect cytoskeletal reorganization and/or regenerative response occurring in hippocampal CA1 neurons at a specific stage of AD progression

Filament Depolymerization Can Explain Chromosome Pulling during Bacterial Mitosis

Chromosome segregation is fundamental to all cells, but the force-generating mechanisms underlying chromosome translocation in bacteria remain mysterious. Caulobacter crescentus utilizes a depolymerization-driven process in which a ParA protein structure elongates from the new cell pole, binds to a ParB-decorated chromosome, and then retracts via disassembly, pulling the chromosome across the cell. This poses the question of how a depolymerizing structure can robustly pull the chromosome that disassembles it. We perform Brownian dynamics simulations with a simple, physically consistent model of the ParABS system. The simulations suggest that the mechanism of translocation is “self-diffusiophoretic”: by disassembling ParA, ParB generates a ParA concentration gradient so that the ParA concentration is higher in front of the chromosome than behind it. Since the chromosome is attracted to ParA via ParB, it moves up the ParA gradient and across the cell. We find that translocation is most robust when ParB binds side-on to ParA filaments. In this case, robust translocation occurs over a wide parameter range and is controlled by a single dimensionless quantity: the product of the rate of ParA disassembly and a characteristic relaxation time of the chromosome. This time scale measures the time it takes for the chromosome to recover its average shape after it is has been pulled. Our results suggest explanations for observed phenomena such as segregation failure, filament-length-dependent translocation velocity, and chromosomal compaction