Directly Observed Care: Crossing the Chasm of Quality Measurement.

After more than two decades of national attention to quality improvement in US healthcare, significant gaps in quality remain. A fundamental problem is that current approaches to measure quality are indirect and therefore imprecise, focusing on clinical documentation of care rather than the actual delivery of care. The National Academy of Medicine (NAM) has identified six domains of quality that are essential to address to improve quality: patient-centeredness, equity, timeliness, efficiency, effectiveness, and safety. In this perspective, we describe how directly observed care-a recorded audit of clinical care delivery-may address problems with current quality measurement, providing a more holistic assessment of healthcare delivery. We further show how directly observed care has the potential to improve each NAM domain of quality.

Entropy Related to K-Banhatti Indices via Valency Based on the Presence of C6H6 in Various Molecules.

Entropy is a measure of a system's molecular disorder or unpredictability since work is produced by organized molecular motion. Shannon's entropy metric is applied to represent a random graph's variability. Entropy is a thermodynamic function in physics that, based on the variety of possible configurations for molecules to take, describes the randomness and disorder of molecules in a given system or process. Numerous issues in the fields of mathematics, biology, chemical graph theory, organic and inorganic chemistry, and other disciplines are resolved using distance-based entropy. These applications cover quantifying molecules' chemical and electrical structures, signal processing, structural investigations on crystals, and molecular ensembles. In this paper, we look at K-Banhatti entropies using K-Banhatti indices for C6H6 embedded in different chemical networks. Our goal is to investigate the valency-based molecular invariants and K-Banhatti entropies for three chemical networks: the circumnaphthalene (CNBn), the honeycomb (HBn), and the pyrene (PYn). In order to reach conclusions, we apply the method of atom-bond partitioning based on valences, which is an application of spectral graph theory. We obtain the precise values of the first K-Banhatti entropy, the second K-Banhatti entropy, the first hyper K-Banhatti entropy, and the second hyper K-Banhatti entropy for the three chemical networks in the main results and conclusion.

Loss of Acta2 in cardiac fibroblasts does not prevent the myofibroblast differentiation or affect the cardiac repair after myocardial infarction.

In response to myocardial infarction (MI), quiescent cardiac fibroblasts differentiate into myofibroblasts mediating tissue repair. One of the most widely accepted markers of myofibroblast differentiation is the expression of Acta2 which encodes smooth muscle alpha-actin (SMαA) that is assembled into stress fibers. However, the requirement of Acta2/SMαA in the myofibroblast differentiation of cardiac fibroblasts and its role in post-MI cardiac repair remained unknown. To answer these questions, we generated a tamoxifen-inducible cardiac fibroblast-specific Acta2 knockout mouse line. Surprisingly, mice that lacked Acta2 in cardiac fibroblasts had a normal post-MI survival rate. Moreover, Acta2 deletion did not affect the function or histology of infarcted hearts. No difference was detected in the proliferation, migration, or contractility between WT and Acta2-null cardiac myofibroblasts. Acta2-null cardiac myofibroblasts had a normal total filamentous actin level and total actin level. Acta2 deletion caused a significant compensatory increase in the transcription level of non-Acta2 actin isoforms, especially Actg2 and Acta1. Moreover, in myofibroblasts, the transcription levels of cytoplasmic actin isoforms were significantly higher than those of muscle actin isoforms. In addition, we found that myocardin-related transcription factor-A is critical for myofibroblast differentiation but is not required for the compensatory effects of non-Acta2 isoforms. In conclusion, the Acta2 deletion does not prevent the myofibroblast differentiation of cardiac fibroblasts or affect the post-MI cardiac repair, and the increased expression and stress fiber formation of non-SMαA actin isoforms and the functional redundancy between actin isoforms are able to compensate for the loss of Acta2 in cardiac myofibroblasts.

Developing Treatment Guidelines During a Pandemic Health Crisis: Lessons Learned From COVID-19.

The development of the National Institutes of Health (NIH) COVID-19 Treatment Guidelines began in March 2020 in response to a request from the White House Coronavirus Task Force. Within 4 days of the request, the NIH COVID-19 Treatment Guidelines Panel was established and the first meeting took place (virtually-as did subsequent meetings). The Panel comprises 57 individuals representing 6 governmental agencies, 11 professional societies, and 33 medical centers, plus 2 community members, who have worked together to create and frequently update the guidelines on the basis of evidence from the most recent clinical studies available. The initial version of the guidelines was completed within 2 weeks and posted online on 21 April 2020. Initially, sparse evidence was available to guide COVID-19 treatment recommendations. However, treatment data rapidly accrued based on results from clinical studies that used various study designs and evaluated different therapeutic agents and approaches. Data have continued to evolve at a rapid pace, leading to 24 revisions and updates of the guidelines in the first year. This process has provided important lessons for responding to an unprecedented public health emergency: Providers and stakeholders are eager to access credible, current treatment guidelines; governmental agencies, professional societies, and health care leaders can work together effectively and expeditiously; panelists from various disciplines, including biostatistics, are important for quickly developing well-informed recommendations; well-powered randomized clinical trials continue to provide the most compelling evidence to guide treatment recommendations; treatment recommendations need to be developed in a confidential setting free from external pressures; development of a user-friendly, web-based format for communicating with health care providers requires substantial administrative support; and frequent updates are necessary as clinical evidence rapidly emerges.

Label-free lipidome study of paraventricular thalamic nucleus (PVT) of rat brain with post-traumatic stress injury by Raman imaging.

Post-traumatic stress disorder (PTSD) is a widespread psychiatric injury that develops serious life-threatening symptoms like substance abuse, severe depression, cognitive impairments, and persistent anxiety. However, the mechanisms of post-traumatic stress injury in brain are poorly understood due to the lack of practical methods to reveal biochemical alterations in various brain regions affected by this type of injury. Here, we introduce a novel method that provides quantitative results from Raman maps in the paraventricular nucleus of the thalamus (PVT) region. By means of this approach, we have shown a lipidome comparison in PVT regions of control and PTSD rat brains. Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry was also employed for validation of the Raman results. Lipid alterations can reveal invaluable information regarding the PTSD mechanisms in affected regions of brain. We have showed that the concentration of cholesterol, cholesteryl palmitate, phosphatidylinositol, phosphatidylserine, phosphatidylethanolamine, sphingomyelin, ganglioside, glyceryl tripalmitate and sulfatide changes in the PVT region of PTSD compared to control rats. A higher concentration of cholesterol suggests a higher level of corticosterone in the brain. Moreover, concentration changes of phospholipids and sphingolipids suggest the alteration of phospholipase A2 (PLA2) which is associated with inflammatory processes in the brain. Our results have broadened the understanding of biomolecular mechanisms for PTSD in the PVT region of the brain. This is the first report regarding the application of Raman spectroscopy for PTSD studies. This method has a wide spectrum of applications and can be applied to various other brain related disorders or other regions of the brain.

Identifying neural signatures of tobacco retail outlet exposure: Preliminary validation of a "community neuroscience" paradigm.

An extensive epidemiological literature indicates that increased exposure to tobacco retail outlets (TROs) places never smokers at greater risk for smoking uptake and current smokers at greater risk for increased consumption and smoking relapse. Yet research into the mechanisms underlying this effect has been limited. This preliminary study represents the first effort to examine the neurobiological consequences of exposure to personally relevant TROs among both smokers (n = 17) and nonsmokers (n = 17). Individuals carried a global positioning system (GPS) tracker for 2 weeks. Traces were used to identify TROs and control outlets that fell inside and outside their ideographically defined activity space. Participants underwent functional MRI (fMRI) scanning during which they were presented with images of these storefronts, along with similar store images from a different county and rated their familiarity with these stores. The main effect of activity space was additive with a Smoking status × Store type interaction, resulting in smokers exhibiting greater neural activation to TROs falling inside activity space within the parahippocampus, precuneus, medial prefrontal cortex, and dorsal anterior insula. A similar pattern was observed for familiarity ratings. Together, these preliminary findings suggest that the otherwise distinct neural systems involved in self-orientation/self-relevance and smoking motivation may act in concert and underlie TRO influence on smoking behavior. This study also offers a novel methodological framework for evaluating the influence of community features on neural activity that can be readily adapted to study other health behaviors.

IGF-1 treatment during in vitro maturation improves developmental potential of ovine oocytes through the regulation of PI3K/Akt and apoptosis signaling.

This study aimed to assess the effect of the insulin-like grow factor 1 (IGF-1) treatment during in vitro maturation on the gene expression and developmental ability of ovine oocytes. Ovine cumulus-oocyte complexes (COC) were matured in vitro without (control) or with the supplementation of IGF-1 (100 ng/ml) and then subjected to in vitro fertilization and culture. The rate of oocyte maturation and embryo development was recorded and expression of the selected genes (involved in the PI3K/Akt and apoptosis signaling) was assessed in the matured oocytes. The IGF-1 treatment significantly (p < .05) improved the oocyte maturation rate (%) as compared to the control (81.5 ± 2.40 vs. 73.6 ± 0.94). Similarly, as compared to the control, the IGF-1 treatment significantly (p < .05) improved the rate (%) of cleavage (54.7 ± 1.58 vs. 67.2 ± 3.65) and the formation of 4-8 cell embryos (30.7 ± 2.89 vs. 44.1 ± 4.01) and morula (20.7 ± 2.08 vs. 32.8 ± 2.78). The IGF-1 treatment significantly (p < .05) upregulated the expression of IGF1R, PI3KR1, AKT1 and BCL2 and downregulated the expression of GSK3ß, FOXO3 and CASP9 in the matured oocytes. In conclusion, the IGF-1 treatment significantly improved the developmental competence of ovine oocytes through the regulation of the PI3K/Akt and apoptosis signaling.

Interleukin-7 improves in vitro maturation of ovine cumulus-oocyte complexes in a dose dependent manner.

Interleukin-7 (IL-7) mediated signals are linked to development, proliferation, survival and differentiation of cells. Recent evidences indicate its role in oocyte maturation process as well. Nevertheless, the underlying mechanisms of IL-7 involvement in oocyte maturation are not well characterized. In addition, currently no information is available on the effect of exogenous IL-7 on oocyte maturation in ovine or any other species. In this study, the effect of IL-7 supplementation during in vitro maturation (IVM) on the maturation rate, production of reactive oxygen species (ROS) and gene expression of ovine cumulus-oocyte complexes (COC) was assessed. IL-7 (0.5, 1, 2, 5 and 10 ng/ml) was supplemented in IVM medium at the beginning (0 h) and maturation rate of COC was assessed at the completion of IVM (24 h). The maturation rate (%) was found significantly (P = 0.000) greater with the 1 ng/ml of IL-7 supplementation (69.5) than control (60.0). In contrast, the maturation rate was reduced significantly (P = 0.000) with the 2 (47.1), 5 (39.2) and 10 ng/ml (39.1) of IL-7 as compared to the control. The level of intracellular ROS in the matured COC was found considerably higher with the 5 ng/ml of IL-7 followed by 1 ng/ml of IL-7 and control. It was evident that in the presence of superoxide dismutase-inhibitor, 1 ng/ml of IL-7 did not stimulate oocyte maturation. In contrast, oocyte maturation was improved with 5 ng/ml of IL-7 supplementation in the presence of NADPH-oxidase-inhibitor. IL-7 supplementation influenced gene expression in COC in a dose and time dependant manner. The expression of genes related to ROS production and apoptosis were upregulated and the genes associated with antioxidant mechanisms were downregulated noticeably with the supplementation of 5 ng/ml of IL-7. In conclusion, IL-7 at low concentration was beneficial for oocyte maturation, which was likely mediated through the favourable level of intracellular ROS and antioxidant mechanisms. In contrast, the detrimental effects of greater IL-7 concentrations on oocyte maturation were possibly arbitrated through the ROS-mediated oxidative stress, compromised antioxidant mechanism and stimulated apoptotic signalling.

Future considerations for clinical dermatology in the setting of 21st century American policy reform: Corporatization and the rise of private equity in dermatology.

Within the past 2 decades, for-profit financial groups have become increasingly involved in health care. Outlier dermatology practices with high volumes of well-reimbursed procedures are attractive to consolidation backed by private equity. With fewer choices for independent or group private practice, junior dermatologists are increasingly seeking employment without ownership in private equity-backed corporate groups whose primary fiscal responsibility lies with their investors. Medicare's response to corporatization and consolidation has already changed the practice of dermatopathology. Dermatologists should be aware of this history, given the ability of corporations and private equity groups to shape the present and future of our field.

Overuse of Repeat Upper Endoscopy in the Veterans Health Administration: A Retrospective Analysis.

OBJECTIVES: Americans undergo ∼7 million esophagogastroduodenoscopies (EGDs) annually, and one-third of Medicare beneficiaries undergo a repeat EGD within 3 years. As many as 43% of these repeat EGDs are inappropriate. We aimed to determine the rate of repeat inappropriate EGD within the Veterans Health Administration (VHA), and identify factors associated with repeat EGD. METHODS: We conducted retrospective analyses of Veterans undergoing an index EGD at 159 VHA facilities between 1 January 2003 and 30 June 2007. We excluded Veterans without regular use of VHA for health care or 5 years of follow-up. Appropriateness of repeat EGDs was classified based on diagnostic and procedure codes into three categories: Likely Appropriate, Possible Overuse, and Probable Overuse. The proportion of repeat EGDs in each category was tabulated. Multilevel logistic regression was performed to estimate the impact of patient-level and site-level factors on the odds of repeat EGD. RESULTS: Of the 235,855 included Veterans, 85,690 (36.3%) underwent a repeat EGD within 5 years. Of the repeat EGDs, 42,412 (49.5%) were Likely Appropriate, 35,503 (41.4%) represented Possible Overuse, and 7,756 (9.1%) represented Probable Overuse. Patients with more frequent encounters with primary care providers and access to facilities performing EGD and with greater complexity of services were more likely to receive repeat EGD, regardless of whether the repeat EGD was appropriate or overuse. Women were slightly more likely to undergo repeat EGD in Probable Overuse situations. CONCLUSIONS: Overuse of repeat EGD is common in VHA despite the absence of financial incentives that promote overuse. Efforts are needed to better understand the motivations for overuse and barriers to appropriate use, and to promote appropriate use of repeat EGD.

Multiple Sources of Prescription Payment and Risky Opioid Therapy Among Veterans.

BACKGROUND: Opioid overdose and other related harms are a major source of morbidity and mortality among US Veterans, in part due to high-risk opioid prescribing. OBJECTIVES: We sought to determine whether having multiple sources of payment for opioids-as a marker for out-of-system access-is associated with risky opioid therapy among veterans. RESEARCH DESIGN: Cross-sectional study examining the association between multiple sources of payment and risky opioid therapy among all individuals with Veterans Health Administration (VHA) payment for opioid analgesic prescriptions in Kentucky during fiscal year 2014-2015. MEASURES: Source of payment categories: (1) VHA only source of payment (sole source); (2) sources of payment were VHA and at least 1 cash payment [VHA+cash payment(s)] whether or not there was a third source of payment; and (3) at least one other noncash source: Medicare, Medicaid, or private insurance [VHA+noncash source(s)]. Our outcomes were 2 risky opioid therapies: combination opioid/benzodiazepine therapy and high-dose opioid therapy, defined as morphine equivalent daily dose ≥90 mg. RESULTS: Of the 14,795 individuals in the analytic sample, there were 81.9% in the sole source category, 6.6% in the VHA+cash payment(s) category, and 11.5% in the VHA+noncash source(s) category. In logistic regression, controlling for age and sex, persons with multiple payment sources had significantly higher odds of each risky opioid therapy, with those in the VHA+cash having significantly higher odds than those in the VHA+noncash source(s) group. CONCLUSIONS: Prescribers should examine the prescription monitoring program as multiple payment sources increase the odds of risky opioid therapy.

HR-LC-MS based analysis of two antibacterial metabolites from a marine sponge symbiont Streptomyces pharmamarensis ICN40.

On the effort to screen antibiotics against Methicillin resistant Staphylococcus aureus (MRSA), an actinomycete strain which can produce bactericidal compound was isolated from a marine sponge of Kanyakumari Coast, India. Two anti-MRSA compounds (PVI401 and PVI402) were isolated from the fermentation plates of Streptomyces pharmamarensis ICN40. TLC bioautography analysis yielded two active spots with Rf value of 0.75 (PVI401) and 0.8 (PVI402) from the crude extract. Both the compounds were characterized by HR-LC-MS analysis. LC-MS based de-replication analysis found out the compound PVI401 with an exact mass of 376.09435 Da and PVI402 with an exact mass of 273.26795 Da were found to be unidentified. Antibacterial spectrum showed significant minimal inhibitory concentration as 0.5 µg/ml of PVI401 and 2 µg/ml of PVI402 against MRSA. The whole organism zebrafish safety evaluation exhibited the compound PVI402 is safe upto 1 mg/ml 40 µg/ml of PVI401 exhibited thrombosis in cardiac chamber and this compound exhibited 44 µg/ml of LC50 against HepG2 hepatic carcinoma cell line. Both the compounds may be identified further for its structural novelty and clinical studies.

In vivo safety evaluation of antibacterial silver chloride nanoparticles from Streptomyces exfoliatus ICN25 in zebrafish embryos.

Silver chloride nanoparticles were synthesized from the cell-free culture supernatant of Streptomyces strain using green synthesis approach with good yield. The nanoparticles were characterized by UV-Vis, IR, SEM, AFM and XRD techniques. These nanoparticles exhibited broad spectrum of antibacterial activity towards Methicillin-resistant Staphylococcus aureus, Methicillin sensitive S. aureus, Escherichia coli, Pseudomonas aeruginosa and Klebsiella pneumonia at ≤ 2 µg/ml minimal inhibitory concentrations. In vivo bioassay in nanoparticles treated zebrafish embryos exhibited 16 µg/ml dose as maximal cardiac safety concentration and further increases in concentration revealed adverse effects such as pericardial bulging, mouth protrudation, hemorrhage and yolk sac elongation. The less toxicity of nanoparticles treated embryos in terms of cardiac assessment and lethality analysis was observed. The dose below 5 µg/ml is concluded as an in vitro and in vivo therapeutic dose. The properties of this biosynthesized nanoparticle suggest a path towards developing antibiotic nanoparticles that are likely to avoid development of multidrug resistance.

Perceptions of community-based field workers on the effect of a longitudinal biomedical research project on their sustainable livelihoods.

BACKGROUND: Researchers involved in biomedical community-based projects rarely seek the perspectives of community fieldworkers, who are the 'foot soldiers' in such projects. Understanding the effect of biomedical research on community-based field workers could identify benefits and shortfalls that may be crucial to the success of community-based studies. The present study explored the perceptions of community-based field workers on the effect of the Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development Project" (MAL-ED) South Africa on their tangible and intangible capital which together comprise sustainable livelihoods. METHODS: The study was conducted in Dzimauli community in Limpopo Province of South Africa between January-February 2016. The sustainable livelihoods framework was used to query community-based field workers' perspectives of both tangible assets such as income and physical assets and intangible assets such as social capital, confidence, and skills. Data were collected through twenty one individual in-depth interviews and one focus group discussion. Data were analysed using the Thematic Content Analysis approach supported by ATLAS.ti, version 7.5.10 software. RESULTS: All the field workers indicated that they benefitted from the MAL-ED South Africa project. The benefits included intangible assets such as acquisition of knowledge and skills, stronger social capital and personal development. Additionally, all indicated that MAL-ED South Africa provided them with the tangible assets of increased income and physical assets. Observations obtained from the focus group discussion and the community-based leaders concurred with the findings from the in-depth interviews. Additionally, some field workers expressed the desire for training in public relations, communication, problem solving and confidence building. CONCLUSIONS: The MAL-ED South Africa, biomedical research project, had positive effects on tangible and intangible assets that compose the sustainable livelihoods of community-based fieldworkers. However, the field workers expressed the need to acquire social skills to enable them carry out their duties more efficiently.

Effectiveness of the Mohs and Close Technique in Increasing the Efficiency of a Mohs Micrographic Surgery.

Editor's note: JDD welcomes Letters to the Editor that discuss controversy surrounding a recently published article. Letters being considered for publication may be sent to the authors of the original article, who may be given the opportunity to reply. Letters will be published at the discretion of the Editors.

Temporal expression of cumulus cell marker genes during in vitro maturation and oocyte developmental competence.

PURPOSE: Cumulus cells (CC) play important roles in oocyte development and cumulus expressed genes can be used as markers for oocyte quality. This study aimed to investigate temporal changes in the expression of cumulus marker genes during oocyte maturation as possible biomarkers of embryo developmental competence in ovine. METHODS: Gene expression was assessed in the CC of the BCB+ (developmentally competent) and BCB- (developmentally poor) oocytes at 0, 12, and 24 h of in vitro maturation (IVM). Further, the association between the temporal cumulus gene expression and in vitro oocyte and embryo development was assessed. RESULTS: The maturation and blastocyst formation rates were found significantly greater for the BCB+ than the BCB- oocytes. At the 0 h of IVM, a significant upregulation in the expression of PTGS2, STAR, SDC2, LHR, FGF2, BCL2, IL7RA, HSPA1A, and IFNT was observed in the CC of the poor (BCB-) as compared to the competent (BCB+) oocytes. In contrast, it was observed that as maturation progressed, the cumulus expression of most of the favorable genes was reduced and was found significantly downregulated at the completion of IVM in the poor as compared to the competent oocytes. CONCLUSIONS: The study revealed noticeable differences in the cumulus gene expression profile at different stages of IVM between ovine oocytes of differential developmental ability. The results indicated that the loss of cumulus gene expression along the maturation period in the poor oocytes was related to their intrinsic poor quality in the ovarian follicle.

Toward an autonomous brain machine interface: integrating sensorimotor reward modulation and reinforcement learning.

For decades, neurophysiologists have worked on elucidating the function of the cortical sensorimotor control system from the standpoint of kinematics or dynamics. Recently, computational neuroscientists have developed models that can emulate changes seen in the primary motor cortex during learning. However, these simulations rely on the existence of a reward-like signal in the primary sensorimotor cortex. Reward modulation of the primary sensorimotor cortex has yet to be characterized at the level of neural units. Here we demonstrate that single units/multiunits and local field potentials in the primary motor (M1) cortex of nonhuman primates (Macaca radiata) are modulated by reward expectation during reaching movements and that this modulation is present even while subjects passively view cursor motions that are predictive of either reward or nonreward. After establishing this reward modulation, we set out to determine whether we could correctly classify rewarding versus nonrewarding trials, on a moment-to-moment basis. This reward information could then be used in collaboration with reinforcement learning principles toward an autonomous brain-machine interface. The autonomous brain-machine interface would use M1 for both decoding movement intention and extraction of reward expectation information as evaluative feedback, which would then update the decoding algorithm as necessary. In the work presented here, we show that this, in theory, is possible.

Age-dependent alterations to paraventricular nucleus insulin-like growth factor 1 receptor as a possible link between sympathoexcitation and inflammation.

Modifications to neural circuits of the paraventricular hypothalamic nucleus (PVN) have been implicated in sympathoexcitation and systemic cardiovascular dysfunction. However, to date, the role of insulin-like growth factor 1 receptor (IGF-1R) expression on PVN pathophysiology is unknown. Using confocal immunofluorescence quantification and electrophysiological recordings from acute PVN slices, we investigated the mechanism through which age-dependent IGF-1R depletion contributes to the progression of inflammation and sympathoexcitation in the PVN of spontaneously hypertensive rats (SHR). Four and twenty weeks old SHR and Wistar Kyoto (WKY) rats were used for this study. Our data showed that angiotensin I/II and pro-inflammatory high mobility box group protein 1 (HMGB1) exhibited increased expression in the PVN of SHR versus WKY at 4 weeks (p < 0.01), and were even more highly expressed with age in SHR (p < 0.001). This correlated with a significant decrease in IGF-1R expression, with age, in the PVN of SHR when compared with WKY (p < 0.001) and were accompanied by related changes in astrocytes and microglia. In subsequent analyses, we found an age-dependent change in the expression of proteins associated with IGF-1R signaling pathways involved in inflammatory responses and synaptic function in the PVN. MAPK/ErK was more highly expressed in the PVN of SHR by the fourth week (p < 0.001; vs. WKY), while expression of neuronal nitric oxide synthase (p < 0.001) and calcium-calmodulin-dependent kinase II alpha (CamKIIα; p < 0.001) were significantly decreased by the 4th and 20th week, respectively. Age-dependent changes in MAPK/ErK expression in the PVN correlated with an increase in the expression of vesicular glutamate transporter (p < 0.001 vs. WKY), while decreased levels of CamKIIα was associated with a decreased expression of tyrosine hydroxylase (p < 0.001) by the 20th week. In addition, reduced labeling for ϒ-aminobutyric acid in the PVN of SHR (p < 0.001) correlated with a decrease in neuronal nitric oxide synthase labeling (p < 0.001) when compared with the WKY by the 20th week. Electrophysiological recordings from neurons in acute slice preparations of the PVN of 4 weeks old SHR revealed spontaneous post-synaptic currents of higher frequency when compared with neurons from WKY PNV slices of the same age (p < 0.001; n = 14 cells). This also correlated with an increase in PSD-95 in the PVN of SHR when compared with the WKY (p < 0.001). Overall, we found an age-dependent reduction of IGF-1R, and related altered expression of associated downstream signaling molecules that may represent a link between the concurrent progression of synaptic dysfunction and inflammation in the PVN of SHR.

Developing and Testing an Electronic Measure of Screening Colonoscopy Overuse in a Large Integrated Healthcare System.

BACKGROUND: Most existing performance measures focus on underuse of care, but there is growing interest in identifying and reducing overuse. OBJECTIVE: We aimed to develop a valid and reliable electronic performance measure of overuse of screening colonoscopy in the Veterans Affairs Health Care System (VA), and to quantify overuse in VA. DESIGN: This was a cross-sectional study with multiple cross-sections. SUBJECTS: U.S. Veterans who underwent screening colonoscopy between 2011 and 2013. MAIN MEASURES: Overuse of screening colonoscopy, using a validated electronic measure developed by an expert workgroup. KEY RESULTS: Compared to results obtained from manual record review, the electronic measure was highly specific (97 %) for overuse, but not sensitive (20 %). After exclusion of diagnostic and high-risk screening or surveillance procedures, the validated electronic measure identified 88,754 average-risk screening colonoscopies performed in VA during 2013. Of these, 20,530 (23 %) met the definition for probable (17 %) or possible (6 %) overuse. Substantial variation in colonoscopy overuse was noted between Veterans Integrated Care Networks (VISNs) and between facilities, with a nearly twofold difference between the maximum and minimum rates of overuse at the VISN level and a nearly eightfold difference at the facility level. Overuse at the VISN and facility level was relatively stable over time. CONCLUSIONS: Overuse of screening colonoscopy can be measured reliably and with high specificity using electronic data, and is common in a large integrated healthcare system. Overuse measures, such as those we have specified through a consensus workgroup process, could be combined with underuse measures to improve the appropriateness of colorectal cancer screening.

Angiotensin II-induced hypertensive renal inflammation is mediated through HMGB1-TLR4 signaling in rat tubulo-epithelial cells.

BACKGROUND AND PURPOSE: Angiotensin II is a vaso-constrictive peptide that regulates blood pressure homeostasis. Even though the inflammatory effects of AngII in renal pathophysiology have been studied, there still exists a paucity of data with regard to the mechanism of action of AngII-mediated kidney injury. The objective of this study was to elucidate the mechanistic role of HMGB1-TLR4 signaling in AngII-induced inflammation in the kidney. EXPERIMENTAL APPROACH: Rat tubular epithelial cells (NRK52E) were treated with AngII over a preset time-course. In another set of experiments, HMGB1 was neutralized and TLR4 was knocked down using small interfering RNA targeting TLR4. Cell extracts were subjected to RT-PCR, immunoblotting, flow cytometry, and ELISA. KEY RESULTS: AngII-induced inflammation in NRK52E cells increased gene and protein expression of TLR4, HMGB1 and key proinflammatory cytokines (TNFα and IL1ß). Pretreatment with Losartan (an AT1 receptor blocker) attenuated the AngII-induced expression of TLR4 and inflammatory cytokines. TLR4 silencing was used to elucidate the specific role played by TLR4 in AngII-induced inflammation. TLR4siRNA treatment in these cells significantly decreased the AngII-induced inflammatory effect. Consistent observations were made when the Ang II treated cells were pretreated with anti-HMGB1. Downstream activation of NFκB and rate of generation of ROS was also decreased on gene silencing of TLR4 and exposure to anti-HMGB1. CONCLUSIONS AND IMPLICATIONS: These results indicate a key role for HMGB1-TLR4 signaling in AngII-mediated inflammation in the renal epithelial cells. Our data also reveal that AngII-induced effects could be alleviated by HMGB1-TLR4 inhibition, suggesting this pathway as a potential therapeutic target for hypertensive renal dysfunctions.