Testing of the therapeutic efficacy and safety of AMPA receptor RNA aptamers in an ALS mouse model.

In motor neurons of sporadic amyotrophic lateral sclerosis (ALS) patients, the RNA editing at the glutamine/arginine site of the GluA2 subunit of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors is defective or incomplete. As a result, AMPA receptors containing the abnormally expressed, unedited isoform of GluA2 are highly Ca2+-permeable, and are responsible for mediating abnormal Ca2+ influx, thereby triggering motor neuron degeneration and cell death. Thus, blocking the AMPA receptor-mediated, abnormal Ca2+ influx is a potential therapeutic strategy for treatment of sporadic ALS. Here, we report a study of the efficacy and safety of two RNA aptamers targeting AMPA receptors on the ALS phenotype of AR2 mice. A 12-wk continuous, intracerebroventricular infusion of aptamers to AR2 mice reduced the progression of motor dysfunction, normalized TDP-43 mislocalization, and prevented death of motor neurons. Our results demonstrate that the use of AMPA receptor aptamers as a novel class of AMPA receptor antagonists is a promising strategy for developing an ALS treatment approach.

Enhancing transient protein expression in HEK-293 cells by briefly exposing the culture to DMSO.

BACKGROUND: Transient expression of proteins in mammalian cells is a key technique for many functional and structural studies of human and higher eukaryotic genes as well as for the production of recombinant protein therapeutics. Maximizing the expression efficiency to achieve a higher expression yield is desirable and may be even critical when, for instance, an expressed protein must be characterized at the single-cell level. NEW METHODS: Our goal was to develop a simple method by which protein expression yield in human embryonic kidney (HEK)-293 cells could be enhanced with a brief treatment of dimethyl sulfoxide (DMSO) solution. RESULTS: By expressing green fluorescent protein (GFP) as a reporter protein using the calcium phosphate transfection method and imaging a large population of cells, we found that a 5-min exposure of 10 % DMSO to HEK-293 cells, 4 h after transfection of the protein of interest, leads to ∼1.6-fold increase in the expression yield without causing any appreciable cytotoxicity. By expressing an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and separately a kainate receptor in HEK-293 cells and measuring glutamate-induced whole-cell current response, we also found that such a brief DMSO treatment did not affect channel activity. CONCLUSION: This method is simple, efficient and inexpensive to use for enhancing transient transfection yield in HEK-293 cells.

A kainate receptor-selective RNA aptamer.

Kainate and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are two major, closely related receptor subtypes in the glutamate ion channel family. Excessive activities of these receptors have been implicated in a number of central nervous system diseases. Designing potent and selective antagonists of these receptors, especially of kainate receptors, is useful for developing potential treatment strategies for these neurological diseases. Here, we report on two RNA aptamers designed to individually inhibit kainate and AMPA receptors. To improve the biostability of these aptamers, we also chemically modified these aptamers by substituting their 2'-OH group with 2'-fluorine. These 2'-fluoro aptamers, FB9s-b and FB9s-r, were markedly resistant to RNase-catalyzed degradation, with a half-life of ∼5 days in rat cerebrospinal fluid or serum-containing medium. Furthermore, FB9s-r blocked AMPA receptor activity. Aptamer FB9s-b selectively inhibited GluK1 and GluK2 kainate receptor subunits, and also GluK1/GluK5 and GluK2/GluK5 heteromeric kainate receptors with equal potency. This inhibitory profile makes FB9s-b a powerful template for developing tool molecules and drug candidates for treatment of neurological diseases involving excessive activities of the GluK1 and GluK2 subunits.

Fostering Interprofessional Education Through a Multidisciplinary, Community-Based Pandemic Mass Vaccination Exercise.

We expanded health care services to economically disadvantaged individuals in an interprofessional, student-driven vaccination effort that also served as a pandemic planning drill. Health care professional students from colleges in and around Rockford, Illinois participated in implementing a mass vaccination event from 2011 to 2014 that targeted the underserved population. There was a 459% increase in total vaccinations administered to at-risk patients from year 1 to year 4. This interprofessional health care student-driven effort expanded medical service to disadvantaged individuals.

Pre-ESRD Care and Mortality in Incident ESRD Patients With Multiple Myeloma.

OBJECTIVES: The relationship between mortality and pre-ESRD (end-stage renal disease) nephrology care in incident ESRD patients with multiple myeloma (MM) as the primary cause of renal failure has not been examined. MATERIALS AND METHODS: Among 439,206 incident US hemodialysis patients with MM as the primary cause of ESRD (June 1, 2005 to May 31, 2009) identified using the US Renal Data System, adjusted odds ratios (OR) for reported pre-ESRD nephrology care for ESRD due to MM (n=4561) versus other causes (n=434,645) were calculated. The association of pre-ESRD nephrology care with subsequent mortality in MM-ESRD patients was examined. RESULTS: MM-ESRD patients were less likely to have any predialysis nephrology care in the year before initiation of dialysis (34.8% vs. 58.5%; OR=0.38; 95% confidence interval [CI], 0.34-0.43) compared with patients with ESRD due to other causes. MM-ESRD patients compared with others were more likely to have catheters on first dialysis (91.8% vs. 75.6%; OR=4.15; 95% CI, 3.54-4.86). Incident MM-ESRD patients receiving predialysis care for ≥6 months had significantly lower 1-year mortality (hazard ratio 0.89; 95% CI, 0.82-0.97 and 0.88; 95% CI, 0.80-0.96, respectively), relative to those without this care. A catheter for dialysis access was associated with a 1.6-fold increase in 1-year mortality in incident MM-ESRD (hazard ratio 1.55; 95% CI, 1.32-1.83). CONCLUSIONS: MM-ESRD patients were less likely to have predialysis nephrology care and more likely to use catheters on first dialysis. However, predialysis care is independently associated with lower mortality in MM-ESRD patients. Predialysis care should be prioritized in MM patients approaching ESRD.

WISP3 mutation associated with pseudorheumatoid dysplasia.

Progressive pseudorheumatoid dysplasia (PPD) is a skeletal dysplasia characterized by predominant involvement of articular cartilage with progressive joint stiffness. Here we report genetic characterization of a consanguineous family segregating an uncharacterized from of skeletal dysplasia. Whole-exome sequencing of four affected siblings and their parents identified a loss-of-function homozygous mutation in the WISP3 gene, leading to diagnosis of PPD in the affected individuals. The identified variant (Chr6: 112382301; WISP3:c.156C>A p.Cys52*) is rare and predicted to cause premature termination of the WISP3 protein.

A Peer-to-Peer Mentoring Program for In-Center Hemodialysis: A Patient-Centered Quality Improvement Program.

A patient-centered quality improvement program implemented in one Virginia hemodialysis facility sought to determine if peer-to-peer (P2P) programs can assist patients on in-center hemodialysis with self-management and improve outcomes. Using a single-arm, repeatedmeasurement, quasi-experimental design, 46 patients participated in a four-month P2P intervention. Outcomes include knowledge, self-management behaviors, and psychosocial health indicators: self-efficacy, perceived social support, hemodialysis social support, and healthrelated quality of life (HRQoL). Physiological health indicators included missed and shortened treatments, arteriovenous fistula placement, interdialytic weight gain, serum phosphorus, and hospitalizations. Mentees demonstrated increased knowledge, self-efficacy, perceived social support, hemodialysis social support, and HRQoL. Missed treatments decreased. Mentors experienced increases in knowledge, self-management, and social support. A P2P mentoring program for in-center hemodialysis can benefit both mentees and mentors.

Right TraC™ Post-Hospitalization Care Transitions Program to Reduce Readmissions for Hemodialysis Patients.

BACKGROUND: Hemodialysis (HD) patients have high hospitalization rates. This nonrandomized trial tested the effect of a bundle of renal-specific "Right TraC™" strategies on 30-day all-cause readmission rates and, secondarily, 90-day readmissions and overall admissions among HD patients. METHODS: Twenty-six Fresenius clinics in West Virginia, Ohio, and Kentucky participated in the interventions. Eighteen matched clinics served as controls; intervention clinics also served as their own controls. We deployed the intervention in 3 incremental phases focused on patient information exchange, post-hospital follow-up, and telephonic case management. Thirty-day hospital readmissions per patient year (ppy) were calculated by dividing the total number of readmissions within 30 days of index admission by the total number of patient-years in baseline (2012) and remeasurement (2014) periods. We also compared readmission rates from 2010 to 2015. We used repeated measures Poisson regression to compare outcomes between groups and time periods. RESULTS: From 2012 to 2014, 30-day all-cause readmissions ppy declined for Right TraC clinics (from 0.88 to 0.66 [p < 0.001]; for controls, from 0.73 to 0.61 [p = 0.16]). Difference in change between groups was nonsignificant (p = 0.26). Overall admissions ppy declined: for Right TraC clinics from 2.51 to 1.97 (p < 0.001); for controls from 2.14 to1.92 (p = 0.21); difference in change between groups was significant (p = 0.01). For 2010, 2011, and 2012, Right TraC clinic 30-day readmissions ppy were unchanged: 0.89, 1.00, 0.88 (p = 0.61 and p = 0.49); they declined to 0.66 (p < 0.001) in 2014 (intervention year); rose to 0.70 (p = 0.06) in 2015 (interventions discontinued). CONCLUSION: We conclude that Right TraC interventions may have been helpful in reducing hospital readmission rates.

Association of AHSG with alopecia and mental retardation (APMR) syndrome.

Alopecia with mental retardation syndrome (APMR) is a very rare autosomal recessive condition that is associated with total or partial absence of hair from the scalp and other parts of the body as well as variable intellectual disability. Here we present whole-exome sequencing results of a large consanguineous family segregating APMR syndrome with seven affected family members. Our study revealed a novel predicted pathogenic, homozygous missense mutation in the AHSG (OMIM 138680) gene (AHSG: NM_001622:exon7:c.950G>A:p.Arg317His). The variant is predicted to affect a region of the protein required for protein processing and disrupts a phosphorylation motif. In addition, the altered protein migrates with an aberrant size relative to healthy individuals. Consistent with the phenotype, AHSG maps within APMR linkage region 1 (APMR 1) as reported before, and falls within runs of homozygosity (ROH). Previous families with APMR syndrome have been studied through linkage analyses and the linkage resolution did not allow pointing out to a single gene candidate. Our study is the first report to identify a homozygous missense mutation for APMR syndrome through whole-exome sequencing.

Integrating Preventive Cardiovascular Healthcare Into Home Health: A Pilot Study.

The viability of measuring and integrating preventive cardiovascular care into home healthcare was investigated through a pilot study fielded during 2013 and 2014. The study tested the feasibility of using a data registry to measure preventive cardiovascular care delivered in home healthcare, examined opportunities for quality improvement, and looked at the association between exposure to evidence-based tools and improvement in aspirin use and blood pressure screening and control among a convenience sample of 20 agencies. Based on promising results, the home healthcare cardiovascular quality initiative continues in alignment with Million Hearts® and offers tools that clinicians can use to understand the risks for heart attack and stroke within their agency's population of patients and respond with best practices.

Making a Dent in Undiagnosed and Untreated Depression among Older West Virginians.

IMPORTANCE: Depression, a serious and debilitating disease, remains under-diagnosed and inadequately treated among older adults. OBJECTIVE: To describe the prevalence of depression among older West Virginians and report the extent to which primary care providers screen Medicare beneficiaries for depression. METHODOLOGY: Descriptive analysis using 2014 Behavioral Risk Factor Surveillance System to estimate depression prevalence; Medicare Part B claims, 2012 - 2014, to measure depression screening. FINDINGS: In 2014, depression affected 10.1%, 95% CI [8.6%, 11.6%] of older West Virginians. While screening increased, less than 4% of Medicare beneficiaries seen in primary care that year were screened. CONCLUSION: We have a significant opportunity to improve diagnosis, treatment and quality of life for older West Virginians with depression, and Medicare reimbursement for screening is available to primary care providers. Although many older depressed patients can be treated in the primary care setting, integration of behavioral health and primary care has distinct benefits.

Correlates of change in health care worker seasonal influenza vaccination rates among dialysis facilities.

We conducted a campaign to increase seasonal influenza vaccination of dialysis health care workers (HCWs) in the District of Columbia, Maryland, Virginia, and West Virginia. Between the 2010-2011 and 2011-2012 influenza seasons we examined the correlates of change. HCW vaccination rates improved significantly (P < .01) from a mean ± standard deviation of 64.5 ± 27.4 to 72.7 ± 23.1. Evidence-based practices were in wide use and although we did not find an association between these and improvement, we did find that lower-performing facilities tended to improve more (P < .01) and there was a positive relationship between patient influenza vaccination rates and improvement in HCW rates (P < .01), with the mean ± standard deviation patient rate of 88.3 ± 7.9 exceeding the HCW rate during the 2011-2012 season (P < .01).

Exploratory analysis of the relationship between home health agency engagement in a national campaign and reduction in acute care hospitalization in US home care patients.

RATIONALE, AIMS AND OBJECTIVES: To determine whether US home health agencies that intensively engaged with the 2010 Home Health Quality Improvement National Campaign were more likely to reduce acute care hospitalization (ACH) rates than less engaged agencies. METHOD: We included all Medicare-certified agencies that accessed Campaign resources in the first month of the Campaign and also responded to an online survey of resource utilization at month two. We used the survey data and item response theory to estimate a latent construct we called engagement with the campaign. ACH rates were calculated from the Centers for Medicare & Medicaid Services Outcome and Assessment Information Set for pre- and post-intervention periods (March-November 2009 and 2010, respectively). RESULTS: Staff from 1077 agencies accessed resources in the first month of the Campaign. Of these, 382 provided information about resource use and had 10 or more monthly discharges throughout the measurement periods. Dividing these agencies into quartiles based on engagement score, we found an association between engagement and reduction in ACH rates, P=0.049 (χ(2) for trend). Exploratory path analysis revealed the effect of engagement score on reduction in ACH rate to be partially mediated through reduction in average length of service rates. CONCLUSION: We found evidence that early intensity of engagement with the Campaign, as measured through use of activities and resources, was positively associated with improvement. To continue the investigation of this relationship, future work in this and other campaigns should focus on further development of engagement measures.

High one year mortality in adults with sickle cell disease and end-stage renal disease.

Adequate pre-dialysis care reduces mortality among end-stage renal disease (ESRD) patients. We tested the hypothesis that individuals with ESRD due to sickle cell disease (SCD-ESRD) receiving pre-ESRD care have lower mortality compared to individuals without pre-ESRD care. We examined the association between mortality and pre-ESRD care in incident SCD-ESRD patients who started haemodialysis between 1 June, 2005 and 31 May, 2009 using data provided by the Centers for Medicare and Medicaid Services (CMS). SCD-ESRD was reported for 410 (0·1%) of 442 017 patients. One year after starting dialysis, 108 (26·3%) patients with incident ESRD attributed to SCD died; the hazard ratio (HR) for mortality among patients with SCD-ESRD compared to those without SCD as the primary cause of renal failure was 2·80 (95% confidence interval [CI] 2·31-3·38). Patients with SCD-ESRD receiving pre-dialysis nephrology care had a lower death rate than those with SCD-ESRD who did not receive pre-dialysis nephrology care (HR = 0·67, 95% CI 0·45-0·99). The one-year mortality rate following an ESRD diagnosis was almost three times higher in individuals with SCD when compared to those without SCD but with ESRD and could be attenuated by pre-dialysis nephrology care.

Prevalence of arteriovenous fistulas in incident hemodialysis patients: correlation with patient factors that may be associated with maturation failure.

BACKGROUND: Lok et al previously reported a risk equation for arteriovenous fistula (AVF) maturation failure. It is unclear whether this model or a more comprehensive model correlates with incident AVF use in the US hemodialysis population. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: 195,756 adult patients initiating outpatient hemodialysis therapy in the United States between July 1, 2005, and December 31, 2009, with 6 months or more prior nephrology care. PREDICTOR: Patient characteristics (age, peripheral vascular disease, coronary artery disease, and race) populating the AVF maturation failure risk equation and other demographic and clinical variables from the Centers for Medicare & Medicaid Services (CMS) Medical Evidence Report (CMS 2728). OUTCOMES & MEASUREMENTS: AVF use at first outpatient dialysis treatment as recorded on the CMS 2728. RESULTS: Using the risk categories defined by Lok et al, AVF use varied from 19.0% (very high risk) to 25.6% (low risk). In a model using only these risk categories, logistic regression showed lower ORs for moderate-, 0.90 (95% CI, 0.88-0.93); high-, 0.80 (95% CI, 0.78-0.83); and very high-risk patients, 0.68 (95% CI, 0.63-0.73) compared with low risk. In the expanded model, odds were lower for women, blacks, Hispanics, age older than 85 years, diabetes, peripheral vascular disease, congestive heart failure, other cardiac disease, and underweight. Odds were higher for hypertension, overweight, obesity, 12 months or more nephrologist care, most insurance types, and each successive year after 2005. Despite associations, the C statistic for the expanded model was 0.64. LIMITATIONS: This analysis is limited by lack of access creation history before dialysis therapy initiation and minimal external validation of CMS 2728 data. CONCLUSIONS: Clinical risk factors identified by Lok and expanded in this analysis have limited ability to predict incident AVF use. Even patients judged at highest risk can have successful AVF construction and initiate dialysis therapy through a functioning AVF.

Achieving the goal: results from the Fistula First Breakthrough Initiative.

PURPOSE OF REVIEW: This review summarizes the background and implementation of the Fistula First Breakthrough Initiative (FFBI), published information about changes in vascular access practice since its inception, and several issues raised by the program. RECENT FINDINGS: The FFBI is a surveillance system using the End-Stage Renal Disease (ESRD) Networks to spread improvement ideas. Concomitant with implementation of the program, prevalent arteriovenous fistula use has increased an average of 3.3% annually since 2003, an incremental improvement of 1.3% over the preexisting trend. At the same time, long-term central venous catheter (CVC) use declined among the prevalent population. Increasingly, individual facilities are achieving the FFBI goal of 66% prevalent arteriovenous fistula use; however, results vary across geographic regions and are not explained by patient demographic and clinical characteristics alone. SUMMARY: ESRD Network interventions as a function of the FFBI are associated with increasing arteriovenous fistula use and likely contributed to improvement, but improvement cannot be unequivocally attributed to the Networks due to lack of rigorous research design. Questions and opportunities remain. It is not yet clear how to identify patients who may not be appropriate candidates for an arteriovenous fistula. The ultimate impact of the FFBI on patient mortality is yet to be determined. The FFBI must continue to identify variations in use and the contributing causes, and implement strategies to address these causes if the FFBI goal is to be fully achieved.

Achieving the goal of the Fistula First breakthrough initiative for prevalent maintenance hemodialysis patients.

BACKGROUND: The Centers for Medicare & Medicaid Services (CMS) established a national goal of 66% arteriovenous fistula (AVF) use in prevalent hemodialysis (HD) patients for the current Fistula First Breakthrough Initiative. The feasibility of achieving the goal has been debated. We examined contemporary patterns of AVF use in prevalent patients to assess the potential for attaining the goal by dialysis facilities and their associated End-Stage Renal Disease Networks in the United States. STUDY DESIGN: Observational study. SETTING & PARTICIPANTS: US dialysis facilities with a mean HD patient census of 10 or more during the 40-month study period, January 2007-April 2010. OUTCOMES & MEASUREMENTS: Mean changes in facility-level AVF use and percentage of facilities achieving the 66% prevalent AVF goal within the United States and each network. RESULTS: Mean prevalent AVF use within dialysis facilities increased from 45.3% to 55.5% (P < 0.001) in the United States, but varied substantially across regions. The percentage of facilities achieving the 66% AVF use goal increased from 6.4% to 19.0% (P < 0.001). During the 40 months, 35.9% of facilities achieved the CMS goal for at least 1 month. On average, these facilities sustained mean use ≥66% for 12.9 ± 11.7 (SD) months. Case-mix and other facility characteristics explained 20% of the variation in proportion of facility patients using an AVF in the last measured month, leaving substantial unexplained variability. LIMITATIONS: This analysis is limited by the absence of facility case-mix data over time, and the national scope of the initiative precludes use of a comparison group. CONCLUSIONS: Achieving the CMS goal of 66% prevalent AVF use is feasible for individual dialysis facilities. There is a need to decrease regional variation before the CMS goal can be fully realized for US HD facilities.

Improving influenza vaccination in dialysis facilities.

The End-Stage Renal Disease Network 5 sought to improve the influenza vaccination rate for the period September 1, 2008, to January 31, 2009, through an awareness campaign, coupled with primary data collection in the form of a tracking tool prepopulated with patient names. The latter served as a reminder to staff to determine the immunization status of patients and offer the influenza vaccination, as appropriate. Targets for the intervention were all facilities and their prevalent hemodialysis and peritoneal dialysis patients, with the exclusion of military treatment centers, Veterans Health Administration hospitals, and prisons. The majority of eligible network facilities (86.9%) participated in the project to achieve an overall adult influenza vaccination rate of 82.6% (95% confidence interval = 82.1%, 83.2%), greatly exceeding the project goal of 64.5% and representing substantial progress toward the 2010 goal of 90%. The initiative is reported here using the Standards for Quality Improvement Reporting Excellence (SQUIRE).

A statewide collaborative initiative to improve the quality of care for patients with acute myocardial infarction and heart failure.

BACKGROUND: To enhance quality improvement, we created a unique statewide collaboration among 3 organizations: the Virginia Health Quality Center (Virginia's Medicare Quality Improvement Organization), the American College of Cardiology, and the American Heart Association. The goal was to improve discharge measures for acute myocardial infarction and heart failure. METHODS AND RESULTS: In 2004, 29 hospitals participated in the collaborative initiative. Using Medicare data submitted from 2004 through the second quarter of 2006, we analyzed adherence to individual discharge measures and all-or-none appropriate care measures for acute myocardial infarction, heart failure, and both. To control for differences in hospital characteristics, we were able to match 21 of the participating hospitals with 21 similar nonparticipating hospitals. In this paired analysis, the total appropriate care measure increased from 61% to 77% in participating hospitals compared with an increase from 51% to 60% in nonparticipating hospitals (P<0.0001). A generalized linear mixed model examining the full data set at the patient level failed to show a clear advantage among participating hospitals. Participating hospitals had higher baseline rates for most quality measures, suggesting a possible effect of a prior collaborative. Further analysis of only hospitals that participated in a prior collaborative showed that participants in the current collaborative initiative had higher rates of improvement for 7 of 10 quality measures and appropriate care measures for heart failure, acute myocardial infarction, or both (all P<0.05). CONCLUSIONS: We report a unique collaboration of a Medicare Quality Improvement Organization and 2 national organizations to address quality of care for acute myocardial infarction and heart failure. A composite measure of quality (the total appropriate care measure) improved more in the participating hospitals during the timeframe of the intervention, although the greater improvement in this and other measures in the participating hospitals appeared to be dependent on participation in a prior collaborative initiative.