Search

In response to the opioid epidemic in the United States, the federal and state governments have initiated various public health responses to mitigate the problem. Among others, Drug-Induced Homicide Laws (DIHL) have been introduced to disrupt opioid supply by imposing unconventionally punitive sanctions against sales and distribution. The purpose of this study was to examine whether DIHL had an impact on opioid-related deaths, while controlling for other laws and socioeconomic indices. A dynamic panel model was used with cases from 92 counties across 10 states and the District of Columbia between 2013 and 2018. The findings suggest that DIHL implementation has curtailed the rate of opioid mortality. Supply-interruption approaches may have merits and should be further evaluated.

Laboratory diagnostics play an essential role in pandemic preparedness. In January 2020, the first US case of COVID-19 was confirmed in Washington State. At the same time, the Washington State Public Health Laboratory (WA PHL) was in the process of building upon and initiating innovative preparedness activities to strengthen laboratory testing capabilities, operations, and logistics. The response efforts of WA PHL, in conjunction with the Centers for Disease Control and Prevention, to the COVID-19 outbreak in Washington are described herein—from the initial detection of severe acute respiratory syndrome coronavirus 2 through the subsequent 2 months. Factors that contributed to an effective laboratory response are described, including preparing early to establish testing capacity, instituting dynamic workforce solutions, advancing information management systems, refining laboratory operations, and leveraging laboratory partnerships. We also report on the challenges faced, successful steps taken, and lessons learned by WA PHL to respond to COVID-19. The actions taken by WA PHL to mount an effective public health response may be useful for US laboratories as they continue to respond to the COVID-19 pandemic and may help inform current and future laboratory pandemic preparedness activities.

This study analyzed the association between the implementation of the Tennessee Fetal Assault Law (TFAL), which allowed prosecutors to incarcerate people who used substances during pregnancy, and out-of-state births among residents of Tennessee.The main data source is vital records on singleton births in hospitals to people aged 15-44 years during the period January 2010 to June 2016. We include data from 33 states and the District of Columbia where birth certificate data are comparable over this time period. The statistical significance of the difference in outcomes observed before and after TFAL implementation was tested using a difference-in-differences analysis between Tennessee and the comparison group.After TFAL implementation, the odds of having an out-of-state birth increased by 13% for residents of Tennessee (odds ratio, 1.13; 95% confidence interval, 1.09-1.16) relative to residents of the comparison states. When we adopted different thresholds for travel distances to the birth hospital, the odds of residents of Tennessee having an out-of-state birth more than 75 miles away increased by 17% (odds ratio, 1.17; 95% confidence interval, 1.13-1.21) after TFAL implementation.The results of this study suggest that the implementation of a policy allowing incarceration of people who use substances during pregnancy is associated with an increase in out-of-state births, potentially putting pregnant people and their infants at greater risk.

Though they have comparable prevalence of mental illness, American racial and ethnic minorities are less likely to receive mental health services than white Americans. Minorities are often part of racial and ethnic social networks, which may affect mental health service utilization in two ways. While these networks can encourage service utilization by working as a channel of knowledge spillover and social support, they can also discourage utilization by stigmatizing mental illness. This study examined the association of racial and ethnic social networks with mental health service utilization and depression diagnosis in the USA. Using the 2012 Behavioral Risk Factor Surveillance System (BRFSS) data, a multilevel mixed-effect generalized linear model was adopted, controlling for predisposing, need, and enabling factors of mental health service utilization. The association of racial and ethnic social networks with mental health service utilization and depression diagnosis was significant and negative among African Americans. Despite having a comparable number of bad mental health days, the association was insignificant among Hispanic, Asian, and non-Hispanic white respondents. An African American living in a county where all residents were African American was less likely to utilize mental health services by 84.3-86.8% and less likely to be diagnosed with depression by 76.0-84.8% than an African American living in a county where no residents were African American. These results suggest racial and ethnic social networks can discourage mental health service utilization and should be engaged in efforts to improve mental health, particularly among African American communities in the USA.

As health care costs and demands for health care services have been rising for decades in the United States, health care reforms have focused on increasing the performance of health care delivery. Competition has been considered as a mechanism to improve the quality of health care services and operational performance. Evidence on health care performance and market competition, however, has not sufficiently been reported to track its progress. The purpose of this study is twofold: First, we measure hospital performance over nine years, using the Malmquist Productivity Index. Second, we examine the impact of market competition on hospital efficiency in Pennsylvania, using a two-stage estimation procedure. The bootstrapped Malmquist productivity indices resulted in noticeable performance improvements. However, no steady performance trends were found during the course of nine years. In examining the impact of market competition, the bootstrapped panel Tobit analysis was applied after computing the efficiency scores with Data Envelopment Analysis. The results of the Tobit model found that hospitals run more efficiently in less competitive regions than in more competitive regions. The finding implies that hospitals underperforming in productivity growth should benchmark best practices of efficient hospitals to improve their productivity level. Another implication is that market competition would not be the best approach to effect the improvement of hospital efficiency in delivering health care services.

ObjectiveTo provide recommendations on how to most effectively implement advanced features of acute care patient portals, including: (1) patient-provider communication, (2) care plan information, (3) clinical data viewing, (4) patient education, (5) patient safety, (6) caregiver access, and (7) hospital amenities.RecommendationsWe summarize the experiences of 6 organizations that have implemented acute care portals, representing a variety of settings and technologies. We discuss the considerations for and challenges of incorporating various features into an acute care patient portal, and extract the lessons learned from each institution’s experience. We recommend that stakeholders in acute care patient portals should: (1) consider the benefits and challenges of generic and structured electronic care team messaging; (2) examine strategies to provide rich care plan information, such as daily schedule, problem list, care goals, discharge criteria, and post-hospitalization care plan; (3) offer increasingly comprehensive access to clinical data and medical record information; (4) develop alternative strategies for patient education that go beyond infobuttons; (5) focus on improving patient safety through explicit safety-oriented features; (6) consider strategies to engage patient caregivers through portals while remaining cognizant of potential Health Insurance Portability and Accountability Act (HIPAA) violations; (7) consider offering amenities to patients through acute care portals, such as information about navigating the hospital or electronic food ordering.

We investigate the unsaturated resin flow behavior in a dual scale porosity preform by observing the pressure distribution and the void content. The experimental data show that the pressure profile in the unsaturated flow is nonlinear with positive curvature whereas that in the saturated flow is linear as expected from the classical Darcy's law. To address this issue, the governing equation for mass conservation is modified by introducing a mass sink term. Eventually, it has been found that the discrepancy between the unsaturated and saturated permeability values comes from a misinterpretation of the pressure gradient at the flow front in the unsaturated permeability measurement method and the permeability for a given preform is a unique value regardless of measurement method or flow condition. Based on this investigation, the ratio of unsaturated permeability to saturated permeability is represented as a dimensionless number in terms of void content. © The Author(s) 2016.

Dopaminergic neurons of the substantia nigra pars compacta are defective in Parkinson's disease, but the specificity of this dysfunction is not understood. One hypothesis is that mitochondrial bioenergetic capacity is intrinsically lower in striatal dopaminergic presynaptic nerve varicosities, making them unusually susceptible to inhibition of electron transport by oxidative damage. To test this hypothesis, we separated isolated synaptosomes bearing dopamine transporters using immunomagnetic beads and compared their respiration with that of the residual nondopaminergic synaptosomes. As predicted, dopaminergic synaptosomes from striatum had lower respiratory rates. However, so did dopaminergic synaptosomes from cortex, indicating a lack of the predicted striatal specificity. We used fluorescent probes to analyze the bioenergetic competence of individual synaptosomes in the two fractions. The respiratory differences became nonsignificant when respiration rates were normalized to the number of respiration-competent synaptosomes, suggesting that differences reflected the quality of the different fractions. To circumvent damage induced by synaptosomal separation, we monitored membrane potentials in whole unseparated single synaptosomes using fluorescent imaging, and then identified the dopaminergic subpopulation using a fluorescent dopamine transporter substrate (ASP+[4-(4-diethylaminostyryl)-N-methylpyridinium iodide]). The capacity of dopaminergic and nondopaminergic synaptosomes to maintain plasma membrane and mitochondrial membrane potential under several stresses did not differ. In addition, this capacity did not decline in either subpopulation with age, a risk factor for Parkinson's disease. We conclude that the intrinsic bioenergetic capacities of dopaminergic and nondopaminergic presynaptic synaptosomes from mice do not differ.

Parkinson's disease (PD) involves both motor and non-motor disturbances. Non-motor features include alterations in sensory olfactory function which may constitute a viable biomarker for the disorder. It is not clear what causes olfactory dysfunction but it appears to coincide with the development of synucleopathy within the olfactory bulb (OB). Elevation in alpha-synuclein (a-syn) is indeed a risk factor for development of the sporadic disorder. The multifactorial nature of the idiopathic disease combined with variability in its presentation suggests that it is likely to be influenced by several factors and that in vivo models that explore the synergistic effect of alpha-synuclein elevation with other potential contributing factors are likely to be of importance in understanding the disease etiology. Using a dual transgenic (DTg) mouse model of dopaminergic alpha-synuclein overexpression coupled with doxycycline (Dox)-inducible glutathione (GSH) depletion in these same cells, we demonstrate an age-related loss in behavioral olfactory function coupled with a significant neurodegeneration of glomerular dopaminergic neurons. This is accompanied by increase in alpha-synuclein levels in non-dopaminergic cells in the granule cell layer (GCL). In addition, isolated olfactory bulb synaptosomes from dual transgenic lines with Dox consistently showed a slight but significant reduction in maximum mitochondrial respiration compared to controls. These results suggest that in the presence of increased oxidative stress, increased alpha-synuclein expression within dopaminergic OB neurons results in neurodegeneration in the glomerular layer (GL) and increased alpha-synuclein levels in the granular cell layer which coincide with olfactory dysfunction.

BACKGROUND Low power ultrasound delivered through an angioplasty-like guidewire may be effective for intracoronary thrombolysis. We evaluated the preclinical feasibility and safety of such wire. METHODS AND RESULTS In 15 anesthetized Yucatan minipigs, the ultrasonic wire was advanced percutaneously into all three coronaries. Each coronary was randomized to long activation (6 minutes), short activation (3 minutes), or control (3 minutes indwelling, no activation). The energy delivered was 0.14 +/- 0.01 W/cm of active length (20 kHz). No changes in heart rate, rhythm, or arterial pressure occurred during wire positioning or activation. Mean lumen diameter (MLD) by quantitative angiography was not significantly different pre- and postintervention (2.36 +/- 0.12 mm vs 2.36 +/- 0.11 mm for long activation, P = 0.96; 2.33 +/- 0.15 mm vs 2.34 +/- 0.14 mm for short activation, P = 0.54; 2.30 +/- 0.12 mm vs 2.33 +/- 0.12 mm for control, P = 0.21). There were no angiographic stenoses at 60 or 90 days follow-up. Compared with baseline, MLD at follow-up increased in all the three groups (2.40 +/- 0.13 mm vs 2.53 +/- 0.11 mm, P = 0.004 for long activation; 2.37 +/- 0.17 mm vs 2.52 +/- 0.14 mm, P = 0.023 for short activation; 2.20 +/- 0.12 mm vs 2.33 +/- 0.11 mm, P = 0.001 for the control group). By histology, there were no clinically significant pathologic changes in coronary morphology. CONCLUSION Use of a transverse cavitation therapeutic wire is feasible and well tolerated acutely in the normal porcine coronary. At 60 and 90 days, no angiographically apparent damage, no clinically significant pathologic changes, and no adverse events were seen. This technology may be safely used during percutaneous coronary intervention. Further studies are justified to evaluate its efficacy for intracoronary thrombus ablation.

Models to predict the split growth in notched AS4/3501-6 graphite/epoxy quasi-isotropic laminates under tension-dominated fatigue are presented. First, a power law model and an artificial neural network (ANN) model are developed to describe the split growth under constant-amplitude fatigue. They are then applied in conjunction with a linear damage growth model to predict the split growth under spectrum fatigue. The ANN model is found to work better than the power law model as a predictive tool for split growth.

The subcritical damage growth in notched AS4/3501-6 graphite/epoxy quasi-isotropic laminates under compression–compression and compression-dominated spectrum fatigue was investigated using the longitudinal split length as a damage measure. A linear split growth model was successfully used to predict the split growth in spectrum fatigue using the corresponding data under constant-amplitude fatigue. However, a linear degradation assumption was found to be inappropriate as it overpredicted lifetime under spectrum fatigue. The residual compressive strength did not show any sign of gradual reduction. The damage mode near the hole changed from longitudinal splitting to transverse extension of fiber failure and delamination as the fatigue stress increased. Thus, while the longitudinal split may serve as a measure of damage in high-cycle fatigue, the extent of transverse fiber failure is a better indication of residual compressive strength. It was shown that a compression-dominated fatigue loading spectrum could be shortened substantially by omitting the two lowest load levels at which no significant damage growth was seen under constant-amplitude fatigue.

Oxidative stress is frequently implicated in the pathology of neurodegenerative disease. The chief source of this stress is from mitochondrial respiration, via the passage of reducing equivalents through the respiratory chain resulting in a small but potentially pathological production of superoxide. The superoxide that is produced during normal respiration is primarily detoxified within the mitochondria by superoxide dismutase 2 (Sod2), a key protein for maintaining mitochondrial function. Mitochondria are distributed throughout the soma of neurons, as well as along neuronal processes and at the synaptic terminus. This distribution of potentially independent mitochondria throughout the neuron, at distinct subcellular locations, allows for the possibility of regional subcellular deficits in mitochondrial function. There has been increasing interest in the quantification and characterization of messages and proteins at the synapse, due to its importance in neurodegenerative disease, most notably Alzheimer’s disease. Here, we report the transcriptomic and proteomic changes that occur in synaptosomes from frontal cortices of Sod2 null mice. Constitutively null Sod2 mice were differentially dosed with the synthetic catalytic antioxidant EUK-189, which can extend the lifespan of these mice, as well as uncover or prevent neurodegeneration due to endogenous oxidative stress. This approach facilitated insight into quantification of trafficked messages and proteins to the synaptosome. We used two complementary methods to investigate the nature of the synaptosome under oxidative stress; either whole genome gene expression microarrays or mass spectrometry-based proteomics using isobaric tagging for relative and absolute quantitation (iTRAQ) of proteins. We have characterized the relative enrichments of gene ontologies at both gene and protein expression that occur due to mitochondrial oxidative stress in the synaptosome, which may lead to new avenues of investigation in understanding the regulation of the synaptic function in normal and diseased states. As a result of using these approaches, we report for the first time an activation of the mTOR pathway in synaptosomes isolated from Sod2 null mice, confirmed by an upregulation of the phosphorylation of 4E-BP1.

Presynaptic nerve terminals require high levels of ATP for the maintenance of synaptic function. Failure of synaptic mitochondria to generate adequate ATP has been implicated as a causative event preceding the loss of synaptic networks in neurodegenerative disease. Endogenous oxidative stress has often been postulated as an etiological basis for this pathology, but has been difficult to test in vivo. Inactivation of the superoxide dismutase gene (Sod2) encoding the chief defense enzyme against mitochondrial superoxide radicals results in neonatal lethality. However, intervention with an SOD mimetic extends the life span of this model and uncovers a neurodegenerative phenotype providing a unique model for the examination of in vivo oxidative stress. We present here studies on synaptic termini isolated from the frontal cortex of Sod2 null mice demonstrating impaired bioenergetic function as a result of mitochondrial oxidative stress. Cortical synaptosomes from Sod2 null mice demonstrate a severe decline in mitochondrial spare respiratory capacity in response to physiological demand induced by mitochondrial respiratory chain uncoupling with FCCP or by plasma membrane depolarization induced by 4-aminopyridine treatment. However, Sod2 null animals compensate for impaired oxidative metabolism in part by the Pasteur effect allowing for normal neurotransmitter release at the synapse, setting up a potentially detrimental energetic paradigm. The results of this study demonstrate that high-throughput respirometry is a facile method for analyzing specific regions of the brain in transgenic models and can uncover bioenergetic deficits in subcellular regions due to endogenous oxidative stress.

Respirometry using modified cell culture microplates offers an increase in throughput and a decrease in biological material required for each assay. Plate based respirometers are susceptible to a range of diffusion phenomena; as O(2) is consumed by the specimen, atmospheric O(2) leaks into the measurement volume. Oxygen also dissolves in and diffuses passively through the polystyrene commonly used as a microplate material. Consequently the walls of such respirometer chambers are not just permeable to O(2) but also store substantial amounts of gas. O(2) flux between the walls and the measurement volume biases the measured oxygen consumption rate depending on the actual [O(2)] gradient. We describe a compartment model-based correction algorithm to deconvolute the biological oxygen consumption rate from the measured [O(2)]. We optimize the algorithm to work with the Seahorse XF24 extracellular flux analyzer. The correction algorithm is biologically validated using mouse cortical synaptosomes and liver mitochondria attached to XF24 V7 cell culture microplates, and by comparison to classical Clark electrode oxygraph measurements. The algorithm increases the useful range of oxygen consumption rates, the temporal resolution, and durations of measurements. The algorithm is presented in a general format and is therefore applicable to other respirometer systems.

Objective Our objective was to determine whether autologous endothelial progenitor cells (EPCs) delivered into the pericardial space will migrate to and incorporate into ischemic myocardium in a porcine model. Background Use of EPCs to enhance neovascularization and preserve myocardial function in ischemic tissue is undergoing intense scrutiny as a potential therapy. Delivery into the pericardial sac may overcome some of the limitations of currently employed cell delivery techniques. Methods EPCs were immunopurified from peripheral blood of Yorkshire pigs by selecting for the CD31 surface antigen, and adherent cells were cultured for 3–5 days. After myocardial ischemia was induced in the left anterior descending (LAD) artery, either autologous DiI (1,1′-dioctadecyl-1-3,3,3′,3′-tetramethylindocarbocyanine perchlorate)-labeled EPCs ( n =10) or serum-free medium (SFM; n =8) was delivered into the pericardial space using a percutaneous transatrial approach. Animals were sacrificed on Day 7 or 21. Echocardiography was performed at baseline, during ischemia, and on Day 7 in six SFM group animals and six EPC group animals. Results On Day 7, EPCs were identified in the left ventricular (LV) anterior wall or anterior septum in all six EPC-treated animals (cell density of 626±122/mm 2 ). On Day 21, EPCs were identified in the LV anterior wall or anterior septum in three of four EPC-treated animals (cell density of 267±167/mm 2 ). These cells showed dual staining for DiI and Bandeiraea simplicifolia lectin I (a marker of both native and exogenous endothelial cells). At the Day 7 follow-up, echocardiography demonstrated that fractional shortening in the EPC-treated group was 30.6±3.4, compared with 22.6±2.8 in SFM controls ( P =.05). Conclusions EPCs can migrate from the pericardial space to incorporate exclusively into areas of ischemic myocardium and may have favorable effects on LV function.

Successful treatment of infants with gastrointestinal involvement in Langerhans cell histiocytosis (LCH) has been poor, with no specific chemotherapeutic regimen of clear benefit. An 8-month-old male, diagnosed with LCH by skin and gastrointestinal biopsies, was treated with several cycles of 2-chlorodeoxyadenosine, vinblastine and prednisone with only partial response. Ultimately, two cycles of 2-chlorodeoxyadenosine concomitant with high-dose cytarabine led to a durable complete response. Twenty-seven months since the last course of chemotherapy, the patient continues to thrive free of disease. Treatment with 2-chlorodeoxyadenosine and cytarabine should be considered for further study in patients with poor-prognosis LCH.

Graft-versus-host disease (GVHD) is a principal cause of morbidity and mortality following allogeneic hematopoietic cell transplant (HCT). Standard therapy for GVHD, high dose steroids, results in complete responses in only 35% of patients. Because tumor necrosis factor-α (TNFα) is an important effector of GVHD in animal models we treated 61 pts with new onset GVHD with methlyprednisolone 2 mg/kg/d plus etanercept, a TNFα inhibitor. All pts continued their GVHD prophylaxis agent, usually tacrolimus, at therapeutic dosing. Etanercept was given subcutaneously twice weekly for 8 wks at a dose of 0.4 mg/kg/dose (maximum dose 25 mg). The outcomes in these 61 pts were compared to those of 99 contemporaneous pts with GVHD whose initial therapy was steroids alone. Both groups of pts were similar with respect to age, transplant conditioning intensity, donor type and degree of HLA-match, and severity of GVHD at onset. Pts treated with etanercept plus steroids were significantly more likely to achieve a complete response 4 wks later than were pts treated with steroids alone [69% (95% CI: 57%, 81%) vs 33% (95% CI: 24%, 42%), p Pts treated with etanercept plus steroids were significantly more likely to be alive 100 days from the initiation of GVHD treatment than pts treated with steroids alone (82% vs 66%, p=0.04). The infection rates in the first 100d from initiation of GVHD treatment were not different between pts treated with etanercept plus steroids or treated with steroids alone for bacterial, invasive fungal or viral infections Blood samples obtained at onset of GVHD and four wks later were analyzed for plasma levels of TNF-receptor 1 (TNFR1) as a biomarker of GVHD activity. At the onset of GVHD the mean plasma TNFR1 levels were significantly elevated compared to levels at a similar timepoint from a control group of pts without GVHD; 4 wks later mean plasma TNFR1 levels were decreased significantly only in pts with CR. Although not a randomized phase III trial, these large differences between treatment groups strongly suggest that etanercept plus steroids as initial therapy for acute GVHD results in improved complete response rates compared to steroids alone. Figure Figure Complete Response Rates at Four Weeks According to Treatment Group Steroids alone Etanercept plus steroids p value Overall 33/99 (33%) 42/61 (69%)