Neuroinflammatory disease disrupts the blood-CNS barrier via crosstalk between proinflammatory and endothelial-to-mesenchymal-transition signaling.

Breakdown of the blood-central nervous system barrier (BCNSB) is a hallmark of many neuroinflammatory disorders, such as multiple sclerosis (MS). Using a mouse model of MS, experimental autoimmune encephalomyelitis (EAE), we show that endothelial-to-mesenchymal transition (EndoMT) occurs in the CNS before the onset of clinical symptoms and plays a major role in the breakdown of BCNSB function. EndoMT can be induced by an IL-1ß-stimulated signaling pathway in which activation of the small GTPase ADP ribosylation factor 6 (ARF6) leads to crosstalk with the activin receptor-like kinase (ALK)-SMAD1/5 pathway. Inhibiting the activation of ARF6 both prevents and reverses EndoMT, stabilizes BCNSB function, reduces demyelination, and attenuates symptoms even after the establishment of severe EAE, without immunocompromising the host. Pan-inhibition of ALKs also reduces disease severity in the EAE model. Therefore, multiple components of the IL-1ß-ARF6-ALK-SMAD1/5 pathway could be targeted for the treatment of a variety of neuroinflammatory disorders.

Overground gait kinematics and muscle activation patterns in the Yucatan mini pig.

Objective.The objectives of this study were to assess gait biomechanics and the effect of overground walking speed on gait parameters, kinematics, and electromyographic (EMG) activity in the hindlimb muscles of Yucatan minipigs (YMPs).Approach.Nine neurologically-intact, adult YMPs were trained to walk overground in a straight line. Whole-body kinematics and EMG activity of hindlimb muscles were recorded and analyzed at six different speed ranges (0.4-0.59, 0.6-0.79, 0.8-0.99, 1.0-1.19, 1.2-1.39, and 1.4-1.6 m s-1). A MATLAB program was developed to detect strides and gait events automatically from motion-captured data. The kinematics and EMG activity were analyzed for each stride based on the detected events.Main results.Significant decreases in stride duration, stance and swing times and an increase in stride length were observed with increasing speed. A transition in gait pattern occurred at the 1.0 m s-1walking speed. Significant increases in the range of motion of the knee and ankle joints were observed at higher speeds. Also, the points of minimum and maximum joint angles occurred earlier in the gait cycle as the walking speed increased. The onset of EMG activity in the biceps femoris muscle occurred significantly earlier in the gait cycle with increasing speed.Significance.YMPs are becoming frequently used as large animal models for preclinical testing and translation of novel interventions to humans. A comprehensive characterization of overground walking in neurologically-intact YMPs is provided in this study. These normative measures set the basis against which the effects of future interventions on locomotor capacity in YMPs can be compared.

Injectable drug delivery systems of doxorubicin revisited: In vitro-in vivo relationships using human clinical data.

A growing number of nanomedicines entered the clinical trials and improved our understanding of the in vivo responses expected in humans. The in vitro drug release represents an important critical quality attribute involved in pharmacokinetics. Establishing in vitro-in vivo relationships for nanomedicines requires a careful analysis of the clinical data with respect to the unique differences between drugs and nanomedicines. Also, the biorelevant assay must reflect the release mechanism of the carrier. Four drug delivery systems of doxorubicin were evaluated for their in vitro release behavior under biorelevant conditions using the dispersion releaser. The pharmacokinetics observed during the first-in-men clinical trials were analyzed using a custom-made physiologically-based nanocarrier biopharmaceutics model. The drug product Lipodox® and the clinical candidate NanoCore-7.4 were evaluated to validate the model. Afterward, the in vivo performances of the preclinical candidates NanoCore-6.4 and doxorubicin-loaded nano-cellular vesicle technology systems (an extracellular vesicle preparation) were predicted. In vitro and in vivo release were in good correlation as indicated by the coefficients of determination of 0.98648 (NanoCore-7.4) and 0.94107 (Lipodox®). The predictions required an estimation of the carrier half-life in blood circulation leading to considerable uncertainty. Still, the simulations narrow down the possible scenarios in the clinical evaluation of nanomedicines and provide a valuable addition to animal studies.

Intravitreal AAV2.COMP-Ang1 Attenuates Deep Capillary Plexus Expansion in the Aged Diabetic Mouse Retina.

Purpose: We determine whether intravitreal angiopoietin-1 combined with the short coiled-coil domain of cartilage oligomeric matrix protein by adeno-associated viral serotype 2 (AAV2.COMP-Ang1) delivery following the onset of vascular damage could rescue or repair damaged vascular beds and attenuate neuronal atrophy and dysfunction in the retinas of aged diabetic mice. Methods: AAV2.COMP-Ang1 was bilaterally injected into the vitreous of 6-month-old male Ins2Akita mice. Age-matched controls consisted of uninjected C57BL/6J and Ins2Akita males, and of Ins2Akita males injected with PBS or AAV2.REPORTER (AcGFP or LacZ). Retinal thickness and visual acuity were measured in vivo at baseline and at the 10.5-month endpoint. Ex vivo vascular parameters were measured from retinal flat mounts, and Western blot was used to detect protein expression. Results: All three Ins2Akita control groups showed significantly increased deep vascular density at 10.5 months compared to uninjected C57BL/6J retinas (as measured by vessel area, length, lacunarity, and number of junctions). In contrast, deep microvascular density of Ins2Akita retinas treated with AAV2.COMP-Ang1 was more similar to uninjected C57BL/6J retinas for all parameters. However, no significant improvement in retinal thinning or diabetic retinopathy-associated visual loss was found in treated diabetic retinas. Conclusions: Deep retinal microvasculature of diabetic Ins2Akita eyes shows late stage changes consistent with disorganized vascular proliferation. We show that intravitreally injected AAV2.COMP-Ang1 blocks this increase in deep microvascularity, even when administered subsequent to development of the first detectable vascular defects. However, improving vascular normalization did not attenuate neuroretinal degeneration or loss of visual acuity. Therefore, additional interventions are required to address neurodegenerative changes that are already underway.

Impact of problem-based charting on the utilization and accuracy of the electronic problem list.

Objective: Problem-based charting (PBC) is a method for clinician documentation in commercially available electronic medical record systems that integrates note writing and problem list management. We report the effect of PBC on problem list utilization and accuracy at an academic intensive care unit (ICU). Materials and Methods: An interrupted time series design was used to assess the effect of PBC on problem list utilization, which is defined as the number of new problems added to the problem list by clinicians per patient encounter, and of problem list accuracy, which was determined by calculating the recall and precision of the problem list in capturing 5 common ICU diagnoses. Results: In total, 3650 and 4344 patient records were identified before and after PBC implementation at Stanford Hospital. An increase of 2.18 problems (>50% increase) in the mean number of new problems added to the problem list per patient encounter can be attributed to the initiation of PBC. There was a significant increase in recall attributed to the initiation of PBC for sepsis (ß = 0.45, P < .001) and acute renal failure (ß = 0.2, P = .007), but not for acute respiratory failure, pneumonia, or venous thromboembolism. Discussion: The problem list is an underutilized component of the electronic medical record that can be a source of clinician-structured data representing the patient's clinical condition in real time. PBC is a readily available tool that can integrate problem list management into physician workflow. Conclusion: PBC improved problem list utilization and accuracy at an academic ICU.

Use of a Hands Free, Instantaneous, Closed-Loop Communication Device Improves Perception of Communication and Workflow Integration in an Academic Teaching Hospital: A Pilot Study.

Efficient and effective communication between providers is critical to quality patient care within a hospital system. Hands free communication devices (HFCD) allow instantaneous, closed-loop communication between physicians and other members of a multidisciplinary team, providing a communication advantage over traditional pager systems. HFCD have been shown to decrease emergency room interruptions, improve nursing communication, improve speed of information flow, and eliminate health care waste. We evaluated the integration of an HFCD with an existing alphanumeric paging system on an acute inpatient medicine service. We conducted a prospective, observational, survey-based study over twenty-four weeks in an academic tertiary care center with attending physicians and residents. Our intervention involved the implementation of an HFCD alongside the existing paging system. Fifty-six pre and post surveys evaluated the perception of improvement in communication and the integration of the HFCD into existing workflow. We saw significant improvements in the ability of an HFCD to help physicians communicate thoughts clearly, communicate thoughts effectively, reach team members, reach ancillary staff, and stay informed about patients. Physicians also reported better workflow integration during admissions, rounds, discharge, and teaching sessions. Qualitative data from post surveys demonstrated that the greatest strengths of the HFCD included the ability to reach colleagues and staff quickly, provide instant access to individuals of the care team, and improve overall communication. Integration of an instantaneous, hands free, closed loop communication system alongside the existing pager system can provide improvements in the perceptions of communication and workflow integration in an academic medicine service. Future studies are needed to correlate these subjective findings with objective measures of quality and safety.

A high value care curriculum for interns: a description of curricular design, implementation and housestaff feedback.

PURPOSE: Most residency programmes do not have a formal high value care curriculum. Our goal was to design and implement a multidisciplinary high value care curriculum specifically targeted at interns. DESIGN: Our curriculum was designed with multidisciplinary input from attendings, fellows and residents at Stanford. Curricular topics were inspired by the American Board of Internal Medicine's Choosing Wisely campaign, Alliance for Academic Internal Medicine, American College of Physicians and Society of Hospital Medicine. Our topics were as follows: introduction to value-based care; telemetry utilisation; lab ordering; optimal approach to thrombophilia work-ups and fresh frozen plasma use; optimal approach to palliative care referrals; antibiotic stewardship; and optimal approach to imaging for low back pain. Our curriculum was implemented at the Stanford Internal Medicine residency programme over the course of two academic years (2014 and 2015), during which 100 interns participated in our high value care curriculum. After each high value care session, interns were offered the opportunity to complete surveys regarding feedback on the curriculum, self-reported improvements in knowledge, skills and attitudinal module objectives, and quiz-based knowledge assessments. RESULTS: The overall survey response rate was 67.1%. Overall, the material was rated as highly useful on a 5-point Likert scale (mean 4.4, SD 0.6). On average, interns reported a significant improvement in their self-rated knowledge, skills and attitudes after the six seminars (mean improvement 1.6 points, SD 0.4 (95% CI 1.5 to 1.7), p<0.001). CONCLUSIONS: We successfully implemented a novel high value care curriculum that specifically targets intern physicians.

Targeted Intraceptor Nanoparticle for Neovascular Macular Degeneration: Preclinical Dose Optimization and Toxicology Assessment.

Neovascular age-related macular degeneration (AMD) is treated with anti-VEGF intravitreal injections, which can cause geographic atrophy, infection, and retinal fibrosis. To minimize these toxicities, we developed a nanoparticle delivery system for recombinant Flt23k intraceptor plasmid (RGD.Flt23k.NP) to suppress VEGF intracellularly within choroidal neovascular (CNV) lesions in a laser-induced CNV mouse model through intravenous administration. In the current study, we examined the efficacy and safety of RGD.Flt23k.NP in mice. The effect of various doses was determined using fluorescein angiography and optical coherence tomography to evaluate CNV leakage and volume. Efficacy was determined by the rate of inhibition of CNV volume at 2 weeks post-treatment. RGD.Flt23k.NP had peak efficacy at a dose range of 30-60 µg pFlt23k/mouse. Using the lower dose (30 µg pFlt23k/mouse), RGD.Flt23k.NP safety was determined both in single-dose groups and in repeat-dose (three times) groups by measuring body weight, organ weight, hemoglobin levels, complement C3 levels, and histological changes in vital organs. Neither toxicity nor inflammation from RGD.Flt23k.NP was detected. No side effect was detected on visual function. Thus, systemic RGD.Flt23k.NP may be an alternative to standard intravitreal anti-VEGF therapy for the treatment of neovascular AMD.

Why providers transfuse blood products outside recommended guidelines in spite of integrated electronic best practice alerts.

BACKGROUND: Best practice alerts (BPAs) provide clinical decision support (CDS) at the point of care to reduce unnecessary blood product transfusions, yet substantial transfusions continue outside of recommended guidelines. OBJECTIVE: To understand why providers order blood transfusions outside of recommended guidelines despite interruptive alerts. DESIGN: Retrospective review. SETTING: Tertiary care hospital. PARTICIPANTS: Inpatient healthcare providers. INTERVENTION: Provider-BPA interaction data were collected from January 2011 to August 2012 from the hospital electronic medical record. MEASUREMENTS: Provider (free-text) responses to blood transfusion BPA prompts were independently reviewed and categorized by 2 licensed physicians, with agreement assessed by χ(2) analysis and kappa scoring. RESULTS: Rationale for overriding blood transfusion BPAs was highly diverse, acute bleeding being the most common (>34%), followed by protocolized behaviors on specialty services (up to 26%), to "symptomatic" anemia (11%-12%). Many providers transfused in anticipation of surgical or procedural intervention (10%-15%) or imminent hospital discharge (2%-5%). Resident physicians represented the majority (55%) of providers interacting with BPAs. CONCLUSION: Providers interacting with BPAs (primarily residents and midlevel providers) often do not have the negotiating power to change ordering behavior. Protocolized behaviors, unlikely to be influenced by BPAs, are among the most commonly cited reasons for transfusing outside of guidelines. Symptomatic anemia is a common, albeit subjective, indication cited for blood transfusion. With a wide swath of individually uncommon rationales for transfusion behavior, secondary use of electronic medical record databases and integrated CDS tools are important to efficiently analyze common practice behaviors.

Cost and turn-around time display decreases inpatient ordering of reference laboratory tests: a time series.

OBJECTIVE: Reference tests, also known as send-out tests, are commonly ordered laboratory tests with variable costs and turn-around times. We aim to examine the effects of displaying reference laboratory costs and turn-around times during computerised physician order entry (CPOE) on inpatient physician ordering behaviour. DESIGN: We conducted a prospective observational study at a tertiary care hospital involving inpatient attending physicians and residents. Physician ordering behaviour was prospectively observed between September 2010 and December 2012. An intervention was implemented to display cost and turn-around time for reference tests within our CPOE. We examined changes in the mean number of monthly physician orders per inpatient day at risk, the mean cost per order, and the average turn-around time per order. RESULTS: After our intervention, the mean number of monthly physician orders per inpatient day at risk decreased by 26% (51 vs 38, p<0.0001) with a decrease in mean cost per order (US$146.50 vs US$134.20, p=0.0004). There were no significant differences in mean turn-around time per order (5.6 vs 5.7 days, p=0.057). A stratified analysis of both cost and turn-around time showed significant decreases in physician ordering. The intervention projected a mean annual savings of US$330 439. Reference test cost and turn-around time variables were poorly correlated (r=0.2). These findings occurred in the setting of non-significant change to physician ordering in a control cohort of non-reference laboratory tests. CONCLUSIONS: Display of reference laboratory cost and turn-around time data during real-time ordering may result in significant decreases in ordering of reference laboratory tests with subsequent cost savings.

Burnout in premedical undergraduate students.

BACKGROUND: There has been growing recognition that medical students, interns, residents and practicing physicians across many specialties are prone to burnout, with recent studies linking high rates of burnout to adverse mental health issues. Little is known about the trajectory and origins of burnout or whether its roots may be traced to earlier in medical training, specifically, during undergraduate studies. Here, the authors surveyed undergraduates at UC San Diego (UCSD) to assess the relationship of burnout to premedical status while controlling for depression severity. METHODS: Undergraduate students at UCSD were invited to participate in a web-based survey, consisting of demographic questions; the Maslach Burnout Inventory Student Survey (MBI-SS), which gauged the three dimensions of burnout; and the nine-item Patient Health Questionnaire (PHQ-9), to assess depression severity. RESULTS: A total of 618 premedical students and 1,441 non-premedical students completed the questionnaire. Premedical students had greater depression severity and emotional exhaustion than non-premedical students, but they also exhibited a greater sense of personal efficacy. The burnout differences were persistent even after adjusting for depression. Also, premedical women and Hispanic students had especially high levels of burnout, although differences between groups became nonsignificant after accounting for depression. CONCLUSIONS: Despite the limitations of using a burnout questionnaire not specifically normed for undergraduates, the unique ethnic characteristics of the sample, and the uncertain response rate, the findings highlight the importance of recognizing the unique strains and mental health disturbances that may be more common among premedical students than non-premedical students. Results also underscore the close relationship between depression and burnout, and point the way for subsequent longitudinal, multi-institutional studies that could help identify opportunities for prevention and intervention.

Depression in Asian-American and Caucasian undergraduate students.

BACKGROUND: Depression is a serious and often under-diagnosed and undertreated mental health problem in college students which may have fatal consequences. Little is known about ethnic differences in prevalence of depression in US college campuses. This study compares depression severity in Asian-American and Caucasian undergraduate students at the University of California San Diego (UCSD). METHODS: Participants completed the nine item Patient Health Questionnaire and key demographic information via an anonymous online questionnaire. RESULTS: Compared to Caucasians, Asian-Americans exhibited significantly elevated levels of depression. Furthermore, Korean-American students were significantly more depressed than Chinese-American, other minority Asian-American, and Caucasian students. In general, females were significantly more depressed than males. Results were upheld when level of acculturation was considered. LIMITATIONS: The demographic breakdown of the student population at UCSD is not representative to that of the nation. CONCLUSIONS: These findings suggest that outreach to female and Asian-American undergraduate students is important and attention to Korean-American undergraduates may be especially worthwhile.

Depression in premedical undergraduates:a cross-sectional survey.

BACKGROUND: Medical students and residents are known to have high rates of depression, a common stress-related challenge that impairs quality of life and job satisfaction and predisposes those affected to general medical illness. Our primary hypothesis was that premedical students would exhibit greater depressive symptoms than nonpremedical students. A secondary aim was to explore the interactions of premedical student status with gender and ethnicity in the context of depression. METHOD: In this cross-sectional study 647 premedical and 1,495 nonpremedical undergraduates at the University of California, San Diego, were surveyed to examine whether seeds of depression can be identified even before formal medical training. Participants completed a series of demographic questions along with the 9-item Patient Health Questionnaire to gauge depression intensity. The survey was made available online for a period of 3 months from March 2009-June 2009. RESULTS: Premedical students were more likely to meet screening criteria suggestive of the presence of major depressive disorder and to exhibit more severe depression than nonpremedical students. Female premedical students exhibited greater depression than female nonpremedical students and males in general. Hispanic premedical students, in particular, had a greater prevalence of depression and greater intensity of depressive symptoms than other premedical students and Hispanic nonpremedical students. No differences were found in current, past, or family history between premedical and nonpremedical students. CONCLUSIONS: These findings underscore the importance of understanding the unique strains and mental health consequences of a premedical curriculum, especially for women and certain minority ethnic populations. A meaningful next step would be a larger study, conducted by several representative university campuses, to confirm these findings; a follow-up of these cohorts could track longitudinal progress. More research must be done to determine the etiology of these findings with the ultimate intention of identifying opportunities for prevention and early intervention, which may provide significant public health payoffs in the long run.

Rotational path of insertion for removable partial dentures with an anterior saddle.

The provision of removable partial dentures remains a viable treatment modality for many partially dentate patients. Replacing missing anterior teeth with a removable partial denture using a rotational path of insertion provides improved retention and appearance. The use of a rotational path of insertion also provides additional retention for a removable partial denture restoring combined anterior and posterior bounded saddles. Two case reports demonstrate the use of the rotational path of insertion for partial denture design.

Clinical evaluation of Dyract AP restorative in permanent molars: 2-year results.

PURPOSE: To evaluate the clinical behavior of a compomer restorative system, Dyract AP, placed in combination with Non-Rinse Conditioner and Prime&Bond NT in permanent posterior teeth. MATERIALS AND METHODS: Fifty Class II and 41 Class I restorations were placed in 39 patients in a dental teaching hospital. The restorations were evaluated directly at baseline and after 6, 12 and 24 months using the modified USPHS-Ryge criteria. Clinical photographs, polyvinylsiloxane impressions and bitewing radiographs of each restoration were taken for indirect assessment. RESULTS: After 2 years, all 76 restorations were evaluated in situ. Color matching ability and surface characteristics were excellent. A gradual deterioration in marginal discoloration and marginal integrity was noted. The percentages of Alfa scores for each criterion at the 24-month evaluation were: color match 96%, marginal discoloration 50%, marginal integrity 26%, anatomic form 97% and surface texture 95%. Five of the restorations (6%) had experienced partial fracture or recurrent caries. After 6, 12 and 24 months, the net mean occlusal wear values were 18.5 microm, 35.7 microm and 55.9 microm, respectively. There was no statistically significant difference between Class I and II restorations for each criterion (Fisher's exact test, P > 0.05).