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Increased healthcare resource utilization in higher disease activity levels in initiators of TNF inhibitors among US rheumatoid arthritis patients

Wed, 05/17/2017 - 8:28am

OBJECTIVE: Determine healthcare resource utilization (HCRU) in biologic-naive initiators of TNF inhibitors (TNFis) associated with their disease activity from a national cohort of rheumatoid arthritis (RA) patients. METHODS: RA patients were identified at their first TNFi initiation (index date) in the Corrona registry. Patients with age of RA onset <18, comorbid psoriasis/psoriatic arthritis, fibromyalgia, or osteoarthritis were excluded. Patients were categorized into disease activity (DA) strata by the lowest level of DA (and sustaining low levels for at least two visits) using the Clinical Disease Activity Index (CDAI) across all visits in Corrona while on a TNFi during 1 year after initiation. Rates of all-cause and RA-related hospitalizations, rheumatologist visits, and joint surgeries while on TNFi therapy were reported and compared across DA levels along with the incidence rate ratio (IRR) adjusted for age, gender, and RA duration using Poisson mixed models. RESULTS: Of 1931 RA patients: 15% achieved sustained remission, 22% remission, 14% sustained low DA, 23% low DA and 27% moderate/high DA (M/HDA). Those in M/HDA had statistically higher rates of hospitalizations (37.3 per 100 patient years (py), 95% CI: 31.6-43.7 and joint surgeries (20.8 per 100 py, 95% CI: 16.6-25.8) compared to the sustained remission cohort, resulting in respective IRRs of 2.3 (p < 0.001) and 1.7 (p = 0.046). CONCLUSION: Many biologic naive RA patients initiating TNFi failed to achieve sustained remission during a 1 year period while remaining on TNFi therapy. Patients in higher DA levels had higher HCRU rates vs. patients in sustained remission, suggesting that achieving treat-to-target goals would reduce health care expenses.

RANK-Independent Osteoclast Formation and Bone Erosion in Inflammatory Arthritis

Wed, 05/17/2017 - 8:28am

OBJECTIVE: Proinflammatory molecules promote osteoclast-mediated bone erosion by up-regulating local RANKL production. However, recent evidence suggests that combinations of cytokines, such as tumor necrosis factor (TNF) plus interleukin-6 (IL-6), induce RANKL-independent osteoclastogenesis. The purpose of this study was to better understand TNF/IL-6-induced osteoclast formation and to determine whether RANK is absolutely required for osteoclastogenesis and bone erosion in murine inflammatory arthritis.

METHODS: Myeloid precursors from wild-type (WT) mice or mice with either germline or conditional deletion of Rank, Nfatc1, Dap12, or Fcrg were treated with either RANKL or TNF plus IL-6. Osteoprotegerin, anti-IL-6 receptor (anti-IL-6R), and hydroxyurea were used to block RANKL, the IL-6R, and cell proliferation, respectively. Clinical scoring, histologic assessment, micro-computed tomography, and quantitative polymerase chain reaction (qPCR) were used to evaluate K/BxN serum-transfer arthritis in WT and RANK-deleted mice. Loss of Rank was verified by qPCR and by osteoclast cultures.

RESULTS: TNF/IL-6 generated osteoclasts in vitro that resorbed mineralized tissue through a pathway dependent on IL-6R, NFATc1, DNAX-activation protein 12, and cell proliferation, but independent of RANKL or RANK. Bone erosion and osteoclast formation were reduced, but not absent, in arthritic mice with inducible deficiency of RANK. TNF/IL-6, but not RANKL, induced osteoclast formation in bone marrow and synovial cultures from animals deficient in Rank. Multiple IL-6 family members (IL-6, leukemia inhibitory factor, oncostatin M) were up-regulated in the synovium of arthritic mice.

CONCLUSION: The persistence of bone erosion and synovial osteoclasts in Rank-deficient mice, and the ability of TNF/IL-6 to induce osteoclastogenesis, suggest that more than one cytokine pathway exists to generate these bone-resorbing cells in inflamed joints.

Comparative effectiveness of abatacept versus tocilizumab in rheumatoid arthritis patients with prior TNFi exposure in the US Corrona registry

Wed, 05/17/2017 - 8:28am


We compared the effectiveness of abatacept (ABA) vs tocilizumab (TCA) in tumor necrosis factor inhibitor (TNFi) experienced patients. METHODS:

We identified rheumatoid arthritis (RA) patients from a large observational US cohort (1 January 2010-31 May 2014) who had discontinued at least one TNFi and initiated ABA or TCZ in moderate or high disease activity based on the Clinical Disease Activity Index (CDAI) and had no prior exposure to the comparator drug. Using propensity score matching (1:1) stratified by prior TNF use (1 TNFi vs ≥2 TNFis), effectiveness at 6 months after initiation was evaluated. Mean change in CDAI over 6 months following initiation was the primary outcome, with secondary outcomes of achievement of low disease activity/remission (CDAI ≤ 10) and mean change in modified Health Assessment Questionnaire (mHAQ) score. RESULTS:

The 264 pairs of propensity score-matched ABA and TCZ initiators were well matched with no substantial differences in the baseline characteristics, defined as standardized differences >0.1 in the stratification. Both treatment groups had similar mean change in CDAI at 6 months (-11.3 in ABA vs -9.9 in TCZ; mean difference -1.27, 95% CI -3.65, 1.11). Similar proportions of both treatment groups achieved low disease activity/remission (adjusted odds ratio for ABA vs TCZ 0.99, 95% CI 0.69, 1.43). Mean change in mHAQ was -0.12 in ABA initiators vs -0.11 in TCZ initiations (mean difference -0.01, 95% CI -0.09, 0.06). CONCLUSIONS:

Patients receiving either ABA or TCZ had substantial improvement in clinical disease activity. In this propensity score-matched sample, similar outcomes were observed for both treatment cohorts.

Reducing Suicide Risk: Challenges and Opportunities in the Emergency Department

Wed, 05/17/2017 - 8:28am

Emergency departments (ED) are prime locations for identifying individuals at high risk of suicide and for making life-saving interventions. In an ideal scenario, all ED patients at risk of suicide could be identified and connected with effective, feasible interventions, and this would occur in a supportive system not overburdened by screening or assessment requirements. In this review, we focus on challenges to achieving this ideal--along with potential solutions--at the level of patients, providers, the ED environment, and the larger health care system. .

Roux-en-Y Gastric Bypass Surgery Regulates Mitochondrial Dynamics Proteins in Primary Human Myotubes Derived from Severely Obese Humans

Tue, 05/16/2017 - 4:45pm

Mitochondrial dynamics including mitochondrial fission (e.g., Dynamin-related protein 1 (Drp1) and Fission 1 (Fis1)) and fusion (e.g., Mitofusin 2 (MFN 2)) regulates mitochondrial homeostasis. Defects in mitochondrial dynamics are suggested to contribute to skeletal muscle mitochondrial dysfunction and insulin resistance associated with severe obesity. Roux-en-Y gastric bypass (RYGB) surgery markedly improves metabolic health as indicated by enhanced substrate oxidation and insulin action in skeletal muscle. However, the underlying cellular mechanisms responsible for these are unclear and could possibly be due to the improvement of mitochondrial dynamics.

PURPOSE: The purpose of this study was to determine whether RYGB surgery improves mitochondria dynamics proteins in primary human myotubes from severely obese humans.

METHODS: Primary skeletal muscle cells were isolated from muscle biopsies obtained from six lean subjects (BMI = 23.4 ± 0.6 kg/m2) and six RYGB patients prior to, 1-month and 7-months after surgery (BMI = 50.2 ± 2.0, 43.2 ± 2.8 and 35.7 ± 2.2 kg/m2, respectively) and were differentiated to myotubes. On day 7 of differentiation, myotubes were harvested for further assessing the expressions of mitochondria dynamics proteins.

RESULTS: Before surgery, Drp1Ser616 phosphorylation and Fis1 expression were significantly higher in myotubes derived from severely obese patients when compared to lean controls (41% and 26%, respectively, P < 0.05). While there were no improvements at 1-month post-surgery, Drp1Ser616 phosphorylation and Fis1 expression were significantly decreased in myotubes from severely obese humans at 7-months post-surgery (Pre vs. 7-months post: 0.046 ± 0.004 vs. 0.035 ± 0.003; 0.023 ± 0.008 vs. 0.014 ± 0.003 AU; respectively, P < 0.05), and not statistically different from lean controls. However, MFN2 expression did not change post-surgery in comparison to pre-surgery.

CONCLUSION: These data suggest that RYGB surgery reduces obesity-induced rise in mitochondrial fission, but not fusion in primary human myotubes derived from severely obese humans.

Direct-to-Patient PRO Collection to Support Quality Improvement in TJR

Tue, 05/16/2017 - 4:45pm

Introduction: Patient-reported outcomes (PROs) are widely used in orthopedic clinical research to evaluate quality of care. However, it is difficult to capture complete post-operative PRO data through surgeon office visits. The UK and Sweden collect post-TJR PRO measures directly from patients in their homes. We compared two US post-operative PRO collection processes- PROs in clinic at scheduled office visits and direct-to-patient collection, to evaluate timing and completeness of both approaches.

Methods: At a large TJR center that has collected PROs at office visits routinely for years, post-TJR patients complete a PRO survey on a computer at follow-up clinic visits. In contrast, the national FORCE-TJR cohort manages post-operative PRO surveys across dozens of offices by sending PROs to patients directly via web-based questionnaires or scannable paper forms. We calculated post-operative PRO response rates and timing from these two approaches and compared patient physical outcomes between them.

Results: In the clinic, 892 patients had TJR surgery during the study period. Of these, 392 (44%) completed post-operative surveys; 115 (29%) between 5 months and 7 months after surgery, and 85 (22%) after 7 months. Direct to patient PRO surveys were centrally distributed in month 5 after surgery. Of 11,702 TJR patients, 8283 (71%) completed the PRO survey within 5 to 9 months post-op. Of these, 90% were returned between 5 and 7 months. SF36 PCS scores were comparable between these two approaches.

Discussion: While PRO collection at the office visit can support individual patient care decisions, patients return to the surgeon office at varied time points after TJR based on their recovery progress and convenience. Direct to patient PRO collection with appropriate retention processes can lead to uniform data timing and optimal completeness. Quality monitoring programs will benefit from consistent data across providers and should consider these factors in designing PRO procedures.

Using mHealth App to Support TKR Decision Making for Knee Arthritis Patients

Tue, 05/16/2017 - 4:45pm

Introduction: Mobile health (mHealth) technology can be used to integrate into medical decision making for patients with advanced knee arthritis. We explored patient preferences on content and design of a mobile health app to facilitate daily symptom capture and summary feedback reporting, in order to inform treatment decisions, including use of total knee replacement surgery (TKR).

Methods: We developed an Android-based smart phone app for knee arthritis patients to assess arthritis symptoms and individual readiness for TKR surgery. Patient focus groups were conducted to gather requirements for mHealth app development and to refine the design and content of the app. Clinician (physical therapist, surgeon) interviews were conducted to understand clinician expectations from the summary trend report generated by the app.

Results: Sixteen patients attended focus groups with an average age of 67 and 63% female, and three clinicians participated in clinician interviews. The preliminary findings revealed that the patients preferred easy tap user interfaces to multi-tap or slider methods, and vertical question layout to horizontal orientation. Patients liked to be engaged by progress feedback reports and educational tips. Both patients and clinicians found a trended outcome summary report helpful which provides more precise details on whether and how the symptoms are changing over time.

Discussion: User input can inform the design and implementation of mHealth technology to deliver tailored knowledge to patients through a user-defined, patient-centered smart phone app. The tool will support future knee arthritis patient decisions regarding the need for, and timing of TKR surgery.

Enhancement of the Abscopal Effect in Radiotherapy by In-situ Delivered CD40 Antibody: Pancreatic Adenocarcinoma Model

Tue, 05/16/2017 - 4:45pm

Metastasis is the cause of death in most cancers. It has been observed by Mole and others that radiotherapy at one site may lead to regression of metastatic cancer at other sites, which were not irradiated, this phenomenon is called ‘abscopal’ effect. Unfortunately, this regression is not predictable.

Few studies observed some enhancement by systemic application of immunoadjuvants, which also has limited application because of generalized adverse effect. The purpose of this study is to evaluate the enhancing and abscopal effect of radiotherapy by in-situ delivered anti-CD40 in the treatment of pancreatic cancer.

A syngeneic mouse model of pancreatic adenocarcinoma was generated in C57/BL6 background mouse using Panc02 cell lines in both flanks. The palpable sized tumors of left flanks were treated as four different randomized cohorts: control with no treatment, direct treatment with 5 Gy of radiation, intra tumor treatment with CD40 antibody, and in combination. Tumor growth was measured on both sides.

Result shows that in-situ application of CD40 antibody significantly enhances the effect of radiotherapy. Reduction of tumor volume was observed in both sides. The treated tumors (left) show average of 75% reduction of tumor volume by combination treatment compare to 32% reduction by radiation alone. On the untreated side (right), it was 86% reduction with combination treatment compare to 20% reduction with the radiation alone which may be reminiscent of an abscopal effect. This result shows potential for translational studies to significantly extend the use of radiotherapy for the treatment of both localized and metastatic cancers.

Effect of Exercise Training on Microvascular Function in African American and Caucasian Women

Tue, 05/16/2017 - 4:45pm

African Americans (AA), especially women, exhibit long-standing disparities in cardiovascular disease (CVD) and obesity. The prevalence of endothelial dysfunction, directly linked to hypertension, is considerably greater in AA than Caucasians (C). Vascular smooth muscle function (mediating endothelium-independent vasodilation) is also related to CVD risk factors but is underappreciated because most literature in C suggest endothelium-independent vasodilatory response is resistance to change with disease (hypertension) or exercise training. Furthermore, the regulation of local skeletal muscle blood flow (an important site of peripheral resistance) has not been sufficiently assessed. Microdialysis is the only method that allows monitoring of microvascular blood flow while affecting the local tissue with pharmacological agents in the absence of systemic, or organ level, effects in humans. Microvascular blood flow was assessed by microdialysis in vivo in skeletal muscle before and after 12 weeks of aerobic exercise training in young, obese AA and C women. Our preliminary data suggested that microvascular endothelial function, assessed by percent change in blood flow from basal (Δ Blood Flow) in response to acetylcholine perfusion was improved in both obese AA (n=5) and obese C (n=4) women. Microvascular endothelium-independent blood flow, assessed by percent change in blood flow from baseline (Δ Blood Flow) upon addition of sodium nitroprusside to the perfusate, was improved in AA (n=3) but not in C (n=9) women.

Exercise training may improve endothelium-dependent vascular function in both AA and C, but improve endothelium-independent vascular function only in AA. Results of this study have potential to inform preventive interventions including lifestyle and pharmacological approaches designed to reduce disparities in hypertension and end-organ damage.

Pre-exposure Immunoprophylaxis by Genetically Encoded DMAb anti-OspA Human Monoclonal Antibody to Prevent Lyme Disease

Tue, 05/16/2017 - 4:45pm

Tick transmission of Borrelia spirochetes to humans results in significant morbidity from Lyme disease. Animal studies have demonstrated that transmission of Borrelia from tick vector to the mammalian host can be blocked by antibodies against outer surface protein A (OspA). We have recently developed borreliacidal human IgG1 monoclonal antibodies (HuMabs) directed against OspA. HuMab 319-44 was borreliacidal against B. burgdorferi (IC50Borreliatransmission after a single dose of 2 mg/kg administered on the day of tick challenge. Since passively administered IgG1 antibodies do not have a sufficient half-life to provide protection for the 6-7 month peak risk period, we investigated a novel approach of vector-mediated gene transfer of HuMabs that could potentially provide protection against Lyme disease during the seasonal risk period.

A modified HuMab, 319-44 mod, expressed by a synthetic DNA plasmid (DMAb) was optimized and characterized in in vitro OspA binding and bactericidal assays. To assess in vivo protection, mice were administered a single DMAb injection into the quadriceps followed by electroporation. The mice were then challenged by B. burgdorferi-infected nymphs. Tissue samples were monitored by dark-field microscopy for spirochete growth. Serum samples were analyzed by ELISA to determine antibody concentrations.

The modified 319-44 DMAb maintained in vitro biological activity comparable to the un-modified wild type antibody, and formulation-based delivery of DMAb resulted in long-term expression. This led to effective pre-exposure prophylaxis preventing transmission of spirochetes in 80% of mice in the murine model of tick-transmitted Lyme disease. These studies represent the first demonstration of employing DNA transfer as a rapid, novel delivery system for biologically relevant functional full-length HuMAbs in an in vivo animal model and provide support for such an approach for pre-exposure immunoprophylaxis to prevent Lyme disease.

Accuracy and Coverage of Using the Assigned International Classification of Diseases, 9th and 10th Revision, Clinical Modification Codes for Detecting Bleeding Events in Electronic Health Record

Tue, 05/16/2017 - 4:45pm

Background: Hemorrhages are common events that confer significant risk for in-hospital and post-discharge morbidity and mortality among cardiovascular disease (CVD) patients treated with anticoagulation. International Classification of Diseases, 9th and 10th Revision, Clinical Modification (ICD-9-CM, ICD-10-CM) codes have been widely used in CVD research and managements.

Objective: To determine the accuracy and coverage of assigned ICD-CM codes for reporting bleeding events.

Methods: From the University of Massachusetts Medical School electronic health record (EHR) database we identified 21k patients on anticoagulation with high bleeding risks based on their ICD-9-CM or ICD-10-CM codes. Through manual chart review, we selected one unstructured note (i.e., physical exam findings, historical narratives) from each patient and identified 299 notes with and 102 free from bleeds using convenience sampling. We extracted bleeding events, labeled them as “current” or “historical”, and determined their severity (major/minor, clinically relevant/irrelevant) based on International Society on Thrombosis and Haemostasis (ISTH) criteria. Using the chart extractions as gold standard, we calculated the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of ICD-9-CM and ICD10-CM for detecting bleeding.

Results: In Administrative claims data, ICD-9-CM had a sensitivity of 35.3%, 96.1% specificity, 96.7% PPV, and 31.2% NPV for detecting bleeding, whereas ICD-10-CM codes had a sensitivity of 55.0%, 96.3% specificity, 97. 9% PPV, and 40.6% NPV. Both ICD-CM codes exhibited better sensitivity for detecting current bleeds (41.1%, 73.4%) and major bleeds (50.0%, 62.9%) as compared with historical (32.4%, 43.8%) and minor ones (31.6%, 56.8%).

Conclusions: Half of all bleeding events among patients with CVD were not reflected in administrative claims data. Although the code’s precision is acceptable, the low sensitivity suggests bleeding events may be under-reported by claims data. Our findings have important clinical implications and suggest that novel methods are needed to enhance bleeding identification to improve clinical decision making.

Implementation of SAMHSA-funded Offender Re-Entry Programs Addressing Substance Use and Co-occurring Disorders among Justice Involved Latino Adults

Tue, 05/16/2017 - 4:45pm

Objectives: Racial and ethnic minorities have high rates of incarceration and persons entering the criminal justice system have disproportionate rates of mental health and substance use disorders Justice involved individuals do not receive adequate treatment resulting in greater risk of recidivism and relapse. This study examines the facilitators and barriers to implementing a SAMHSA-funded Offender Re-Entry Program (ORP) to better understand the factors that influence successful implementation of integrated bilingual/bicultural treatment, recovery, and re-entry services for recently incarcerated adult Latino individuals with substance use and co-occurring behavioral health disorders.

Methods: Structured interviews were conducted with leadership, direct staff, and non-direct staff involved in the development and implementation of the Rumbo a Casa ORP at Casa Esperanza, Inc. Using the Consolidated Framework for Implementation Research (CFIR), we investigated the domains and constructs that were critical to successful implementation. Interviews were analyzed using NVivo 11 software.

Results: Qualitative analyses show that across all domains, inner setting, particularly the implementation climate of an organization, is reported most often as influencing (positively or negatively) the implementation of the program. Findings show that the current process structure and the characteristics of individuals are greatly impacting program implementation as reported by direct staff. These findings demonstrate that the process of implementation which includes planning, engaging, executing, reflecting and evaluating constructs is essential for the successful implementation an offender-reentry program. Dedicated leadership is necessary to enhance implementation of fundamental program activities using a Plan-Do-Study-Act (PDSA) quality improvement cycle.

Conclusion: An established implementation research framework can identify key issues critical to the implementation and evaluation processes. This study provides a deepened understanding of components critical to the successful implementation of an ORP and adds to the limited implementation research knowledge on evidence-based care approaches for justice involved Latino adults.

Optimizing Microfluidic Design for Cell Separation

Tue, 05/16/2017 - 4:45pm

To evaluate the performance of various designs of crossflow filtration microfluidic devices, blood flow was modeled using computational fluid dynamics software (COMSOL Multiphysics). Velocity profiles were generated and used to analyze four critical design parameters: pillar size, pillar shape, gap size, and wall length. These parameters were optimized to yield greatest flow from an unfiltered main channel into two filtered side channels of the device, thereby maximizing filtration capacity.

Devices containing pillars of 10 µm diameter yielded a significantly greater filtration capacity than devices with pillars of 20 µm diameter. Flow patterns from the main channel to the side channels were not significantly affected when circular, octagonal, and hexagonal pillars were compared; however, use of triangular and square pillars caused a reduction in side channel flow rates. Side channel velocities consistently improved as gap sizes were increased from 3.0 µm to 8.0 µm; however, 3.5 µm gaps were included in the final design for the purpose of separating red and white blood cells. Backflow prevention walls were placed at bends in the device and were systematically lengthened until all backflow was eliminated.

Following optimization of the microfluidic device, two prototypes were prepared: a polydimethylsiloxane (PDMS) device with glass backing and a silicon device with PDMS backing. The filtration capacity of these devices were tested using polystyrene microspheres with sizes corresponding to those of red and white blood cells. In both prototypes, between 73 and 75% of small microspheres were consistently filtered into the side channels. Silicon-PDMS devices demonstrated better retention of large microspheres in the main channel and less microsphere agglomeration than did PDMS-glass devices. The benefits of silicon-PDMS devices, however, came at the cost of a difficult fabrication process.

Polymeric Nanoparticles for Targeted Combination Treatment of Temozolomide Resistant Glioblastoma Multiforme (GBM)

Tue, 05/16/2017 - 4:45pm

Glioblastoma Multiforme (GBM) is an aggressive cancer that originates from astrocytes and spreads to spinal cord and other parts of the brain. Increase in replication of glial cells leads to advantageous mutations in the tumor. According to the cancer statistics from 2015 about 15,320 deaths were reported due to GBM. Five-year survival is less than 5% making GBM a dreadful form of cancer. Current treatment involves complex invasive surgery, followed by chemotherapy and radiation. The goal of this study is to develop a combination therapy to treat GBM using Poly (lactic-co-glycolic acid) (PLGA) nanoparticles encapsulated with two drugs namely gefitinib and GSK461364, each with a unique target. Gefitinib is a Tyrosine Kinase inhibitor, which competes for ATP-binding site of EGFR-TK. GSK461364 is a Polo-like Kinase (PLK-1) inhibitor that blocks the G2/M transition in tumor cell cycle. These distinct hydrophobic drugs are tested on U-87 MG (human malignant glioma) cell line. PLGA is attached to Polyethylene glycol (PEG), which is conjugated to transferrin receptor binding peptide. These transferrin peptides bind to transferrin receptors (TfR) or CD71 and enable the entry of PLGA-PEG nanoparticles across the Blood Brain Barrier (BBB). Results of characterization, TEM, SEM images, in vitro drug release profiles, stability, cytotoxicity assay, flow cytometry data of uptake of the nanoparticles will be presented.

Transcriptional Regulation of Cardiac Remodeling in a Porcine Model with Validation in Human Subjects

Tue, 05/16/2017 - 4:45pm

Introduction: The majority of new atrial fibrillation (AF) cases occur in elderly patients with cardiac remodeling (CR) in the setting of structural heart disease and heart failure (HF). We leveraged a unique animal model to identify cardiac microRNAs (miRNAs) and gene regulatory mechanisms that drive this process.

Methods: We prospectively quantified atrial expression of 48 miRNAs by high-throughput qRT-PCR in 15 pigs with right-atrial pacing-induced heart disease (5 pigs with AF/severe HF, 5 pigs with AF/mild HF, and 5 control pigs) as well as in 21 patients (11 with AF and CR and 10 controls) undergoing cardiac surgery. CR and HF were defined through a metric of left atrial volume index, BNP and ejection fraction. MiRNA levels were normalized to global mean and expression compared across pig subtypes and between the two human groups.

Results: In the porcine model, miR-208b was upregulated at week 1 (ΔCT= -3.9, pT = -5.5, pT = -1.5, pT = -1.5, p<0.05) after induction of AF compared to sinus rhythm animals. The increase persisted at week 3 compared to week 1 (ΔCT = -1.5, p<0.05). Similarly, humans with AF and HF had higher tissue expression of miR-208b compared to controls (ΔCT = -1.5, p<0.05).

Conclusions: Dysregulation of miR-208b is confirmed in our porcine model and is validated in humans. Prior studies have identified miR-208b in both myosin isoform switching and conduction disease. We theorize that dysregulation of miR-208b may play a critical role in atrial structural remodeling and vulnerability to AF.

Pediatric Critical Care Transfusion and Anemia Expertise Initiative

Tue, 05/16/2017 - 4:45pm

Introduction/Hypothesis: Despite evidence that a lower hemoglobin threshold is safe in hemodynamically stable children, studies have shown that transfusion thresholds in practice are higher, exposing these children to the morbidity and mortality associated with RBC transfusion. Therefore, there is increased need for evidence-based blood management strategies for clinicians caring for critically ill children.

Methods: The Pediatric Critical Care Transfusion and Anemia Expertise Initiative has brought together a group of 49 international experts in pediatric transfusion/critical care in collaboration with the Pediatric Critical Care Blood Research Network (BloodNet), and the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI), to conduct a consensus conference series on pediatric critical care blood management. The methodology is modeled after that used in the Pediatric Acute Lung Injury and Consensus Conference and will create consensus statements via a structured process outlining existing data in RBC transfusion. Novel features include engagement with implementation science experts to enable consensus uptake.

Results: Two of the three expert meetings have been successfully conducted. Ten topics were identified and include recommendations on indications for RBC transfusion in critically ill children 1) based on hemoglobin triggers in the general population, 2) based on physiological triggers in the general population, 3) traumatic brain injury, 4) congenital heart disease, 5) hematologic/oncologic disease, 6) respiratory failure, 7) shock, 8) bleeding, 9) extracorporeal support, and 10) alternative processing. The systematic review was performed. The short text recommendations were generated, discussed at the second meeting and will undergo voting using the RAND UCLA Appropriateness Method to achieve consensus.

Conclusions: The TAXI consensus series is the first consensus series to convene international and multidisciplinary experts to create consensus statements on transfusion practices to improve outcomes and safety for critically ill children at risk for, or who require, RBC transfusions.

Home Interventions for Older Adults with Asthma

Tue, 05/16/2017 - 4:45pm

Older asthmatic adults are more likely to experience respiratory failure than younger adults and children with asthma. Older adults spend up to 90% of their time in the home where many allergens are found. While there is sufficient evidence that home interventions improve the health of asthmatic children, there is insufficient evidence for the effectiveness of home interventions with adults. Our research evaluates the hypothesis that multi-trigger, multifaceted home interventions improve respiratory health and reduce home asthma triggers for older adults.

Methods: We evaluated the effectiveness of conducting interventions in the homes of 86 diverse, low-income older adults (age 62 or above) diagnosed with asthma, residing in public and private subsidized housing. The two largest populations include Hispanics (45%) and Asians (20%). Data was collected on respiratory health outcomes before and after the home intervention (questionnaires on symptoms, quality of life, medication use, doctor/ER/hospital visits, and exhaled nitric oxide (eNO) a measure of lung inflammation). Asthma trigger activities (ATAs) and exposures were also evaluated before and after the home intervention (questionnaire, home survey, measurement of nitrogen dioxide (NO2), dust samples for rodent and cockroach allergens, biomarker for cigarette smoke exposure (urinary cotinine).

Interventions included education on asthma and environmental triggers; environmental remediation including mattress/pillow covers, provision of vacuum with HEPA filters, green cleaning supplies and changes in home as needed (commercial cleaning, integrated pest management, gas stove replacement, mold remediation).

Results: Significant health improvements were found in the following areas: number of doctor visits due to asthma, quality of life indicators including symptom and activity levels, and asthma control test.

Inhibition of Insulin Amyloid Formation by Small Organofluorine Molecules

Tue, 05/16/2017 - 4:45pm

Many human diseases, including Alzheimer’s disease (AD) and diabetes mellitus type II (DM) have been connected to protein misfolding and the formation of highly ordered fibrillar protein aggregates called amyloids. DM is characterized by an overproduction of insulin to the point of insulin resistance in the body. The protein deposits in the AD-affected brain is related to the aggregation of tau protein and amyloid β (Aβ) peptide. Amyloid fibrils and their oligomeric precursors are known to be cytotoxic inducing neurological cell death. Recent clinical studies have suggested a link between Alzheimer’s disease and DM based on the fact that DM patients have double the risk of developing Alzheimer’s disease. It is believed that the increased risk of heart disease and stroke linked to DM causes further damage to blood vessels that eventually target the brain. Due to the continued rise of both diseases among aging adults, there is considerable interest in eluciditating the similarities and differences in the mechanism of amyloid formation of insulin and Aβ and understanding how the oligomeric state of the two peptides affect each other’s aggregation and role. Our group has already designed and experimentally tested a broad variety of small molecules, including organofluorines that effectively inhibit the self-assembly of Aβ. As an extension of these earlier studies the same group of organofluorine molecules are being tested for their inhibitory activity in the formation of insulin fibrils. The aggregation of insulin with/without these potential inhibitors at 37°C and pH=7.4 are followed by a kinetic Thioflavin T (ThT) fluorescence assay and visualized by Atomic Force Microscopy (AFM). The small molecule-insulin interactions are also investigated by electrospray mass spectrometry (HR-ESI-MS).

The Effects of Yoga on Adults with Type II Diabetes: A Systematic Review and Meta-analysis

Tue, 05/16/2017 - 4:45pm

Objective: The purpose of this meta-analysis was to examine the effects of yoga for glycemic control among adults with type II diabetes (T2DM).

Methods: Comprehensive electronic databases searches located 2,559 unique studies with relevant key terms. Studies were included if they a) evaluated a yoga intervention to promote T2DM management, b) used an objective measure to assess glycemic control at post-intervention, and c) had follow-up length or post-test of at least 8 weeks from baseline. Studies were excluded if yoga was not the primary intervention focus (e.g., if yoga was part of a mindfulness-based intervention). Independent raters coded participant, design and methodological characteristics and intervention content. Weighted mean effect sizes and 95% confidence intervals (CI) were calculated.

Results: Total 23 studies with 2,473 participants (M age = 53 years; 43% women) met eligibility criteria. Most studies (18) were conducted in India; 2 were conducted in England, 1 in Cuba, 1 in Indonesia, and 1 in Iran. Compared with controls, yoga participants were successful in improving their HbA1c (d+ = 0.37, 95% CI = 0.18, 0.55; k = 14), fasting blood glucose (d+ = 0.57, 95% CI = 0.38, 0.76; k = 19), postprandial blood glucose (d+ = 0.29, 95% CI = 0.17, 0.41; k = 11). Yoga was also associated with significant improvements in lipid profile, blood pressure, body mass index and waist/hip ratio. Overall, studies satisfied an average of 41% of the methodological quality (MQ) criteria; however, MQ score was not associated with any outcome (ps >.05).

Conclusion: Yoga improved glycemic outcomes and other risk factors for complications in adults with T2DM relative to a control condition. Additional studies with longer follow-ups are needed to determine the long-term efficacy of yoga for adults with T2DM.

Companion Diagnostics for Breast Cancer Chemotherapeutics

Tue, 05/16/2017 - 4:45pm

Chemotherapy plays a major role in breast cancer treatment. However, not every chemotherapeutics is appropriate for each cancer due to the person’s individual cancer characteristics and whether the patient has developed chemoresistance to a particular drug. In this research, the InVitro-Q is used to detect subtle differences in tumor cell proliferation post-treatment with four-breast cancer chemotherapeutics used: paclitaxel, docetaxel, nocodazole, and cytochalasin B. Our multi-well cell-based sensor that can monitor real-time biological changes in living cells, such as mass redistribution, and viscoelasticity. This system provides unique kinetic information regarding the phenotypic change in the cells post treatment. Each drug induces apoptosis by targeting a different mechanism of action. Each drug was assayed for 48h with MCF-7 or SK-Br-3 breast cancer cells, and data collected. Post analysis we created quantitative projection regarding the efficacy of each drug on the specific cancer type.