A Web-Based, Population-Based Cirrhosis Identification and Management System for Improving Cirrhosis Care: Qualitative Formative Evaluation.

BACKGROUND: Cirrhosis, or scarring of the liver, is a debilitating condition that affects millions of US adults. Early identification, linkage to care, and retention of care are critical for preventing severe complications and death from cirrhosis. OBJECTIVE: The purpose of this study is to conduct a preimplementation formative evaluation to identify factors that could impact implementation of the Population-Based Cirrhosis Identification and Management System (P-CIMS) in clinics serving patients with cirrhosis. P-CIMS is a web-based informatics tool designed to facilitate patient outreach and cirrhosis care management. METHODS: Semistructured interviews were conducted between January and May 2016 with frontline providers in liver disease and primary care clinics at 3 Veterans Health Administration medical centers. A total of 10 providers were interviewed, including 8 physicians and midlevel providers from liver-related specialty clinics and 2 primary care providers who managed patients with cirrhosis. The Consolidated Framework for Implementation Research guided the development of the interview guides. Inductive consensus coding and content analysis were used to analyze transcribed interviews and abstracted coded passages, elucidated themes, and insights. RESULTS: The following themes and subthemes emerged from the analyses: outer setting: needs and resources for patients with cirrhosis; inner setting: readiness for implementation (subthemes: lack of resources, lack of leadership support), and implementation climate (subtheme: competing priorities); characteristics of individuals: role within clinic; knowledge and beliefs about P-CIMS (subtheme: perceived and realized benefits; useful features; suggestions for improvement); and perceptions of current practices in managing cirrhosis cases (subthemes: preimplementation process for identifying and linking patients to cirrhosis care; structural and social barriers to follow-up). Overall, P-CIMS was viewed as a powerful tool for improving linkage and retention, but its integration in the clinical workflow required leadership support, time, and staffing. Providers also cited the need for more intuitive interface elements to enhance usability. CONCLUSIONS: P-CIMS shows promise as a powerful tool for identifying, linking, and retaining care in patients living with cirrhosis. The current evaluation identified several improvements and advantages of P-CIMS over current care processes and provides lessons for others implementing similar population-based identification and management tools in populations with chronic disease.

Myostatin inhibition prevents skeletal muscle pathophysiology in Huntington's disease mice.

Huntington's disease (HD) is an inherited neurodegenerative disorder of which skeletal muscle atrophy is a common feature, and multiple lines of evidence support a muscle-based pathophysiology in HD mouse models. Inhibition of myostatin signaling increases muscle mass, and therapeutic approaches based on this are in clinical development. We have used a soluble ActRIIB decoy receptor (ACVR2B/Fc) to test the effects of myostatin/activin A inhibition in the R6/2 mouse model of HD. Weekly administration from 5 to 11 weeks of age prevented body weight loss, skeletal muscle atrophy, muscle weakness, contractile abnormalities, the loss of functional motor units in EDL muscles and delayed end-stage disease. Inhibition of myostatin/activin A signaling activated transcriptional profiles to increase muscle mass in wild type and R6/2 mice but did little to modulate the extensive Huntington's disease-associated transcriptional dysregulation, consistent with treatment having little impact on HTT aggregation levels. Modalities that inhibit myostatin signaling are currently in clinical trials for a variety of indications, the outcomes of which will present the opportunity to assess the potential benefits of targeting this pathway in HD patients.

Improving the Electronic Capture of Advance Care Directives in a Healthcare Delivery System.

OBJECTIVES: To determine the effectiveness of a multifaceted quality improvement intervention in outpatient clinics at an integrated healthcare delivery system on capture rate of advance directives (ADs) in the electronic medical record (EMR). DESIGN: Interrupted time series analysis with control groups between January 2010 and June 2015. SETTING: Oncology, nephrology, and primary care outpatient clinics in an integrated healthcare delivery system. PARTICIPANTS: All individuals aged 65 and older with at least one office visit in any outpatient clinic in the care delivery system (n = 77,350 with 502,446 office visits). INTERVENTION: A series of quality improvement interventions to improve rates of advance care planning discussions and capture of those discussions in the EMR between 2010 and 2014. MEASUREMENTS: Capture rate of ADs in the EMR. RESULTS: Visits in the intervention primary care clinic were twice as likely to mention ADs in the EMR (53.4%) than visits in nonintervention primary care clinics (26.5%). Visits in the intervention oncology clinic were more than eight times as likely to mention ADs in the EMR (49.3% vs 6.0%), and visits in the intervention nephrology clinic were 2.5 times as likely to mention ADs (15.4% vs 6.0%) than visits in other specialty clinics. CONCLUSIONS: A series of quality improvement interventions to increase discussions about advance care planning and capture of advance care directives in the EMR significantly increased the rate of capture in primary care and specialty care outpatient settings.

Frequency of nuclear mutant huntingtin inclusion formation in neurons and glia is cell-type-specific.

Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disorder that is caused by a CAG expansion in the Huntingtin (HTT) gene, leading to HTT inclusion formation in the brain. The mutant huntingtin protein (mHTT) is ubiquitously expressed and therefore nuclear inclusions could be present in all brain cells. The effects of nuclear inclusion formation have been mainly studied in neurons, while the effect on glia has been comparatively disregarded. Astrocytes, microglia, and oligodendrocytes are glial cells that are essential for normal brain function and are implicated in several neurological diseases. Here we examined the number of nuclear mHTT inclusions in both neurons and various types of glia in the two brain areas that are the most affected in HD, frontal cortex, and striatum. We compared nuclear mHTT inclusion body formation in three HD mouse models that express either full-length HTT or an N-terminal exon1 fragment of mHTT, and we observed nuclear inclusions in neurons, astrocytes, oligodendrocytes, and microglia. When studying the frequency of cells with nuclear inclusions in mice, we found that half of the population of neurons contained nuclear inclusions at the disease end stage, whereas the proportion of GFAP-positive astrocytes and oligodendrocytes having a nuclear inclusion was much lower, while microglia hardly showed any nuclear inclusions. Nuclear inclusions were also present in neurons and all studied glial cell types in human patient material. This is the first report to compare nuclear mHTT inclusions in glia and neurons in different HD mouse models and HD patient brains. GLIA 2016;65:50-61.

Collaborative Care for Depression in Chronic Hepatitis C Clinics.

OBJECTIVE: Depression is highly prevalent yet underdiagnosed and undertreated among patients with chronic hepatitis C virus (HCV) infection. Collaborative care models have improved depression outcomes in primary care settings, and this study aimed to provide more information on testing such methods in specialty HCV care. METHODS: Hepatitis C Translating Initiatives for Depression Into Effective Solutions (HEPTIDES) was a randomized controlled trial that tested a collaborative depression care model in HCV clinics at four Veterans Affairs facilities. The HEPTIDES intervention consisted of an offsite depression care team (depression care manager, pharmacist, and psychiatrist) that delivered collaborative care. Participant interview data were collected at baseline and at six months. The outcome was depression severity measured with the Hopkins Symptom Checklist (SCL-20) and reported as treatment response (≥50% decrease in SCL-20 item score), remission (mean SCL-20 item score <.5), and depression-free days (DFDs). RESULTS: Baseline screening identified 263 HCV-infected patients with depression. In unadjusted analyses, intervention participants' reports trended toward more treatment response (19% versus 13%) and remission (12% versus 6%), but total number of DFDs (50.9) was similar to that of usual care participants (50.7). These trends did not reach statistical significance for the overall sample in the adjusted analyses: response (odds ratio [OR]=2.02, 95% confidence interval [CI]=.98-4.20), remission (OR=2.63, CI=1.00-6.94), and DFDs (ß=7.6 days, CI=-.99 to 16.2). However, the intervention was effective in improving all three outcomes for patients who did not meet criteria for remission at baseline (SCL-20 score >.5, N=245). CONCLUSIONS: Depression collaborative care resulted in modest improvements in HCV patient depression outcomes. Future research should investigate intervention modifications to improve outcomes in specialty HCV clinics.

Correction: SIRT1 Activity Is Linked to Its Brain Region-Specific Phosphorylation and Is Impaired in Huntington's Disease Mice.

[This corrects the article DOI: 10.1371/journal.pone.0145425.].

SIRT1 Activity Is Linked to Its Brain Region-Specific Phosphorylation and Is Impaired in Huntington's Disease Mice.

Huntington's disease (HD) is a neurodegenerative disorder for which there are no disease-modifying treatments. SIRT1 is a NAD+-dependent protein deacetylase that is implicated in maintaining neuronal health during development, differentiation and ageing. Previous studies suggested that the modulation of SIRT1 activity is neuroprotective in HD mouse models, however, the mechanisms controlling SIRT1 activity are unknown. We have identified a striatum-specific phosphorylation-dependent regulatory mechanism of SIRT1 induction under normal physiological conditions, which is impaired in HD. We demonstrate that SIRT1 activity is down-regulated in the brains of two complementary HD mouse models, which correlated with altered SIRT1 phosphorylation levels. This SIRT1 impairment could not be rescued by the ablation of DBC1, a negative regulator of SIRT1, but was linked to changes in the sub-cellular distribution of AMPK-α1, a positive regulator of SIRT1 function. This work provides insights into the regulation of SIRT1 activity with the potential for the development of novel therapeutic strategies.

Qualitative analysis of patient-centered decision attributes associated with initiating hepatitis C treatment.

BACKGROUND: In this era of a constantly changing landscape of antiviral treatment options for chronic viral hepatitis C (CHC), shared clinical decision-making addresses the need to engage patients in complex treatment decisions. However, little is known about the decision attributes that CHC patients consider when making treatment decisions. We identify key patient-centered decision attributes, and explore relationships among these attributes, to help inform the development of a future CHC shared decision-making aid. METHODS: Semi-structured qualitative interviews with CHC patients at four Veterans Health Administration (VHA) hospitals, in three comparison groups: contemplating CHC treatment at the time of data collection (Group 1), recently declined CHC treatment (Group 2), or recently started CHC treatment (Group 3). Participant descriptions of decision attributes were analyzed for the entire sample as well as by patient group and by gender. RESULTS: Twenty-nine Veteran patients participated (21 males, eight females): 12 were contemplating treatment, nine had recently declined treatment, and eight had recently started treatment. Patients on average described eight (range 5-13) decision attributes. The attributes most frequently reported overall were: physical side effects (83%); treatment efficacy (79%), new treatment drugs in development (55%); psychological side effects (55%); and condition of the liver (52%), with some variation based on group and gender. Personal life circumstance attributes (such as availability of family support and the burden of financial responsibilities) influencing treatment decisions were also noted by all participants. Multiple decision attributes were interrelated in highly complex ways. CONCLUSIONS: Participants considered numerous attributes in their CHC treatment decisions. A better understanding of these attributes that influence patient decision-making is crucial in order to inform patient-centered clinical approaches to care (such as shared decision-making augmented with relevant decision-making aids) that respond to patients' needs, preferences, and circumstances.

Characterisation of immune cell function in fragment and full-length Huntington's disease mouse models.

Inflammation is a growing area of research in neurodegeneration. In Huntington's disease (HD), a fatal inherited neurodegenerative disease caused by a CAG-repeat expansion in the gene encoding huntingtin, patients have increased plasma levels of inflammatory cytokines and circulating monocytes that are hyper-responsive to immune stimuli. Several mouse models of HD also show elevated plasma levels of inflammatory cytokines. To further determine the degree to which these models recapitulate observations in HD patients, we evaluated various myeloid cell populations from different HD mouse models to determine whether they are similarly hyper-responsive, as well as measuring other aspects of myeloid cell function. Myeloid cells from each of the three mouse models studied, R6/2, HdhQ150 knock-in and YAC128, showed increased cytokine production when stimulated. However, bone marrow CD11b(+) cells did not show the same hyper-responsive phenotype as spleen and blood cells. Furthermore, macrophages isolated from R6/2 mice show increased levels of phagocytosis, similar to findings in HD patients. Taken together, these results show significant promise for these mouse models to be used to study targeting innate immune pathways identified in human cells, thereby helping to understand the role the peripheral immune system plays in HD progression.

Workplace model for physical therapists and occupational therapists.

PURPOSE: The purpose of this paper is to test a model linking physical therapy (PT) and occupational therapy (OT) practitioners' perceptions of resonant leadership, structural empowerment and psychological empowerment to their experiences of spirit at work (SAW), job satisfaction and organizational commitment within the Canadian workplace. DESIGN/METHODOLOGY/APPROACH: The authors tested the model using LISREL 8.80 and survey data from 101 OTs and 169 PTs, randomly selected by the Alberta professional licensing associations. Content analysis of responses to the open-ended comments section provided additional depth and insight. FINDINGS: Analysis of results culminated in minor modifications to the original theoretical model, creating separate PT and OT models. Both models revealed a good fit with the observed data. Several SAW concepts accounted for moderate to large amounts of variance in both PT and OT models, indicating that SAW is a comprehensive workplace outcome. RESEARCH LIMITATIONS/IMPLICATIONS: Theory was derived from business and nursing research literature due to limited rehabilitation research literature. Discussion of OT results must consider the small sample size. This study is initial exploratory research. PRACTICAL IMPLICATIONS: Each discipline-specific model provides professionals, health care leaders and policy makers with a rich body of information upon which to base beneficial workplace decisions. SAW will guide leaders in the holistic development and enrichment of the work environment. ORIGINALITY/VALUE: This research contributes to the substantive knowledge of the OT and PT disciplines, particularly in the areas of leadership, workplace structural organization and indicators of healthy work environments such as SAW, empowerment, job satisfaction and organizational commitment.

Dysfunction of the CNS-heart axis in mouse models of Huntington's disease.

Cardiac remodelling and contractile dysfunction occur during both acute and chronic disease processes including the accumulation of insoluble aggregates of misfolded amyloid proteins that are typical features of Alzheimer's, Parkinson's and Huntington's disease (HD). While HD has been described mainly as a neurological disease, multiple epidemiological studies have shown that HD patients exhibit a high incidence of cardiovascular events leading to heart failure, and that this is the second highest cause of death. Given that huntingtin is ubiquitously expressed, cardiomyocytes may be at risk of an HD-related dysfunction. In mice, the forced expression of an expanded polyQ repeat under the control of a cardiac specific promoter led to severe heart failure followed by reduced lifespan. However the mechanism leading to cardiac dysfunction in the clinical and pre-clinical HD settings remains unknown. To unravel this mechanism, we employed the R6/2 transgenic and HdhQ150 knock-in mouse models of HD. We found that pre-symptomatic animals developed connexin-43 relocation and a significant deregulation of hypertrophic markers and Bdnf transcripts. In the symptomatic animals, pronounced functional changes were visualised by cardiac MRI revealing a contractile dysfunction, which might be a part of dilatated cardiomyopathy (DCM). This was accompanied by the re-expression of foetal genes, apoptotic cardiomyocyte loss and a moderate degree of interstitial fibrosis. To our surprise, we could identify neither mutant HTT aggregates in cardiac tissue nor a HD-specific transcriptional dysregulation, even at the end stage of disease. We postulate that the HD-related cardiomyopathy is caused by altered central autonomic pathways although the pathogenic effects of mutant HTT acting intrinsically in the heart may also be a contributing factor.

Dynamic recruitment of active proteasomes into polyglutamine initiated inclusion bodies.

Neurodegenerative disorders such as Huntington's disease are hallmarked by neuronal intracellular inclusion body formation. Whether proteasomes are irreversibly recruited into inclusion bodies in these protein misfolding disorders is a controversial subject. In addition, it has been proposed that the proteasomes may become clogged by the aggregated protein fragments, leading to impairment of the ubiquitin-proteasome system. Here, we show by fluorescence pulse-chase experiments in living cells that proteasomes are dynamically and reversibly recruited into inclusion bodies. As these recruited proteasomes remain catalytically active and accessible to substrates, our results challenge the concept of proteasome sequestration and impairment in Huntington's disease, and support the reported absence of proteasome impairment in mouse models of Huntington's disease.

Transforming Ward Rounds Through Rounding-in-Flow.

BACKGROUND: Traditional "batched" bedside clinical care rounds, where rounds for all patients precede clinical tasks, may delay clinical care and reduce resident work efficiency. INNOVATION: Using Lean concepts, we developed a novel "Rounding-in-Flow" approach, with the patient care team completing all tasks for a single patient before initiating any tasks for the next patient. Outcome measures included timely patient discharge and intern work hours. METHODS: We performed a retrospective cohort study with historic and contemporaneous control groups, with time series adjustment for underlying temporal trends at a single medical center. Primary outcomes were timely patient discharge orders and resident duty hours. Participants were 17 376 consecutive hospital inpatients between January 1, 2011, and June 30, 2012, and medical ward rounding teams of interns, residents, and attending hospitalists. RESULTS: Timely discharge orders, defined as written by 9:00 am, improved from 8.6% to 26.6% (OR, 1.55; 95% CI 1.17-2.06; P  =  .003). Time of actual patient discharge was unchanged. Resident duty hour violations, defined as less than 10 hours between clinical duties, decreased from 2.96 to 0.98 per intern per rotation (difference, 1.98; 95% CI 1.09-2.87; P < .001). Average daily intern work hours decreased from 12.3 to 11.9 hours (difference, 0.4 hours; 95% CI 0.16-0.69; P  =  .002). CONCLUSIONS: Compared with batched rounding, Lean Rounding-in-Flow using "1-piece flow" principles was associated with more discharge orders written before 9:00 am and fewer violations in the 10-hour break rule, with minimal changes to intern total work hours and actual patient discharge time.

HDAC4 reduction: a novel therapeutic strategy to target cytoplasmic huntingtin and ameliorate neurodegeneration.

Histone deacetylase (HDAC) 4 is a transcriptional repressor that contains a glutamine-rich domain. We hypothesised that it may be involved in the molecular pathogenesis of Huntington's disease (HD), a protein-folding neurodegenerative disorder caused by an aggregation-prone polyglutamine expansion in the huntingtin protein. We found that HDAC4 associates with huntingtin in a polyglutamine-length-dependent manner and co-localises with cytoplasmic inclusions. We show that HDAC4 reduction delayed cytoplasmic aggregate formation, restored Bdnf transcript levels, and rescued neuronal and cortico-striatal synaptic function in HD mouse models. This was accompanied by an improvement in motor coordination, neurological phenotypes, and increased lifespan. Surprisingly, HDAC4 reduction had no effect on global transcriptional dysfunction and did not modulate nuclear huntingtin aggregation. Our results define a crucial role for the cytoplasmic aggregation process in the molecular pathology of HD. HDAC4 reduction presents a novel strategy for targeting huntingtin aggregation, which may be amenable to small-molecule therapeutics.

Aberrant splicing of HTT generates the pathogenic exon 1 protein in Huntington disease.

Huntington disease (HD) is a devastating, late-onset, inherited neurodegenerative disorder that manifests with personality changes, movement disorders, and cognitive decline. It is caused by a CAG repeat expansion in exon 1 of the HTT gene that translates to a polyglutamine tract in the huntingtin protein (HTT). The formation of HTT fragments has been implicated as an essential step in the molecular pathogenesis of HD and several proteases that cleave HTT have been identified. However, the importance of smaller N-terminal fragments has been highlighted by their presence in HD postmortem brains and by the fact that nuclear inclusions are only detected by antibodies to the N terminus of HTT. Despite an intense research effort, the precise length of these fragments and the mechanism by which they are generated remains unknown. Here we show that CAG repeat length-dependent aberrant splicing of exon 1 HTT results in a short polyadenylated mRNA that is translated into an exon 1 HTT protein. Given that mutant exon 1 HTT proteins have consistently been shown to be highly pathogenic in HD mouse models, the aberrant splicing of HTT mRNA provides a mechanistic basis for the molecular pathogenesis of HD. RNA-targeted therapeutic strategies designed to lower the levels of HTT are under development. Many of these approaches would not prevent the production of exon 1 HTT and should be reviewed in light of our findings.

Resonant leadership, workplace empowerment, and "spirit at work": impact on RN job satisfaction and organizational commitment.

Canadian researchers have developed the Spirit At Work (SAW) tool for identifying the experiences of individuals who are passionate about and energized by their work. This article describes (a) what registered nurses perceive as contributing to their personal SAW; and (b) the relationships among resonant leadership, structural empowerment concepts, psychological empowerment concepts, SAW concepts, job satisfaction, organizational commitment, and the demographic variables of experience, education, and rank in the RN workplace. The theoretical model was tested using LISREL 8.80 and survey data from 147 randomly selected RNs. Engaging work was found to account for 63% of the explained variance in the model's endogenous variables. Spiritual connection had a causal effect on organizational commitment, while resonant leadership and individual empowerment had significant causal influence on SAW, job satisfaction, and organizational commitment. These results strengthen those of previous studies reporting workplace structures/processes/contributions leading to superior care environments. Future studies will clarify the role of SAW in the workplace.

Oral administration of the pimelic diphenylamide HDAC inhibitor HDACi 4b is unsuitable for chronic inhibition of HDAC activity in the CNS in vivo.

Histone deacetylase (HDAC) inhibitors have received considerable attention as potential therapeutics for a variety of cancers and neurological disorders. Recent publications on a class of pimelic diphenylamide HDAC inhibitors have highlighted their promise in the treatment of the neurodegenerative diseases Friedreich's ataxia and Huntington's disease, based on efficacy in cell and mouse models. These studies' authors have proposed that the unique action of these compounds compared to hydroxamic acid-based HDAC inhibitors results from their unusual slow-on/slow-off kinetics of binding, preferentially to HDAC3, resulting in a distinctive pharmacological profile and reduced toxicity. Here, we evaluate the HDAC subtype selectivity, cellular activity, absorption, distribution, metabolism and excretion (ADME) properties, as well as the central pharmacodynamic profile of one such compound, HDACi 4b, previously described to show efficacy in vivo in the R6/2 mouse model of Huntington's disease. Based on our data reported here, we conclude that while the in vitro selectivity and binding mode are largely in agreement with previous reports, the physicochemical properties, metabolic and p-glycoprotein (Pgp) substrate liability of HDACi 4b render this compound suboptimal to investigate central Class I HDAC inhibition in vivo in mouse per oral administration. A drug administration regimen using HDACi 4b dissolved in drinking water was used in the previous proof of concept study, casting doubt on the validation of CNS HDAC3 inhibition as a target for the treatment of Huntington's disease. We highlight physicochemical stability and metabolic issues with 4b that are likely intrinsic liabilities of the benzamide chemotype in general.

Rhodium-catalyzed [2 + 2] cycloaddition of ynamides with nitroalkenes.

In the presence of a diene-ligated rhodium complex, ynamides and nitroalkenes undergo catalytic [2 + 2] cycloadditions to provide cyclobutenamides. The presence of sodium tetraphenylborate was found to be crucial for the reactions to proceed efficiently.

Palladium-catalyzed hydroacyloxylation of ynamides.

In the presence of substoichiometric Pd(OAc)(2), carboxylic acids undergo highly regio- and stereoselective additions to ynamides to provide α-acyloxyenamides.