Extra virgin olive oil improves HDL lipid fraction but not HDL-mediated cholesterol efflux capacity: a double-blind, randomised, controlled, cross-over study (OLIVAUS).

Olive oil (OO) polyphenols have been shown to improve HDL anti-atherogenic function, thus demonstrating beneficial effects against cardiovascular risk factors. The aim of the present study was to investigate the effect of extra virgin high polyphenol olive oil (HPOO) v. low polyphenol olive oil (LPOO) on the capacity of HDL to promote cholesterol efflux in healthy adults. In a double-blind, randomised cross-over trial, fifty participants (aged 38·5 (sd 13·9) years, 66 % females) were supplemented with a daily dose (60 ml) of HPOO (320 mg/kg polyphenols) or LPOO (86 mg/kg polyphenols) for 3 weeks. Following a 2-week washout period, participants crossed over to the alternate treatment. Serum HDL-cholesterol efflux capacity, circulating lipids (i.e. total cholesterol, TAG, HDL, LDL) and anthropometrics were measured at baseline and follow-up. No significant between-group differences were observed. Furthermore, no significant changes in HDL-cholesterol efflux were found within either the LPOO and HPOO treatment arms; mean changes were 0·54 % (95 % CI (0·29, 1·37)) and 0·10 % (95 % CI (0·74, 0·94)), respectively. Serum HDL increased significantly after LPOO and HPOO intake by 0·13 mmol/l (95 % CI (0·04, 0·22)) and 0·10 mmol/l (95 % CI (0·02, 0·19)), respectively. A small but significant increase in LDL of 0·14 mmol/l (95 % CI (0·001, 0·28)) was observed following the HPOO intervention. Our results suggest that additional research is warranted to further understand the effect of OO with different phenolic content on mechanisms of cholesterol efflux via different pathways in multi-ethnic populations with diverse diets.

Altered gastrointestinal tract structure and microbiome following cerebral malaria infection.

Cerebral malaria (CM) is the most severe form of malaria with the highest mortality rate and can result in life-long neurological deficits and ongoing comorbidities. Factors contributing to severity of infection and development of CM are not fully elucidated. Recent studies have indicated a key role of the gut microbiome in a range of health conditions that affect the brain, but limited microbiome research has been conducted in the context of malaria. To address this knowledge gap, the impact of CM on the gut microbiome was investigated in mice. C57BL/6J mice were infected with Plasmodium berghei ANKA (PbA) parasites and compared to non-infected controls. Microbial DNA from faecal pellets collected daily for 6-days post-infection were extracted, and microbiome comparisons conducted using 16S rRNA profiling. We identified significant differences in the composition of bacterial communities between the infected and the non-infected groups, including a higher abundance of the genera Akkermansia, Alistipes and Alloprevotella in PbA-infected mice. Furthermore, intestinal samples were collected post-cull for morphological analysis. We determined that the caecal weight was significantly lower, and the small intestine was significantly longer in PbA-infected mice than in the non-infected controls. We concluded that changes in microbial community composition were primarily driven by the infection protocol and, to a lesser extent, by the time of infection. Our findings pave the way for a new area of research and novel intervention strategies to modulate the severity of cerebral malaria disease.

Mapping the core concepts of physiology across Australian university curricula.

Core concepts in physiology, designed by physiology educators to promote improved learning and teaching, have existed for over a decade. This study aimed to investigate the extent to which a set of 15 core concepts of physiology (developed by Michael and McFarland, U.S.-based educators) are reflected in the learning outcomes (LOs) of units (subjects) comprising physiology curricula in Australian universities. From publicly accessible online information, we identified 17 Australian universities that offered a physiology major for undergraduate degree students and downloaded 788 LOs from the 166 units that comprised the majors. Each LO was blindly mapped against the 15 core concepts by 8 physiology educators from 3 Australian universities. Additionally, text-matching software was employed to match keywords and phrases (identified as descriptors of the 15 core concepts) against the LOs. The frequency of individual words and two-word phrases for each core concept was calculated and ranked. There was variability in rating LOs for the same university among academic mappers; nevertheless, many of the 15 core concepts did not appear to be adequately covered in the LOs. Two core concepts most matched manually were in the top three most mapped by the software. These were, from most common, structure/function and interdependence. Our findings suggest a lack of alignment of LOs with the core concepts across Australian physiology curricula. This highlights the need for Australia-wide agreement on a set of core concepts in physiology as the first step in collaboratively improving assessment and learning and teaching practice in physiology.NEW & NOTEWORTHY This is the first time an existing set of core concepts for physiology, developed by Michael and McFarland (U.S.-based educators), have been mapped against unit (subject) learning outcomes across physiology curricula in Australian universities to gauge uptake and the need for agreement on a set of core concepts in the Australian higher education context.

The anti-inflammatory effects of a Mediterranean diet: a review.

PURPOSE OF REVIEW: Chronic noncommunicable diseases remain the leading cause of morbidity and mortality worldwide and the majority are preventable with a healthy diet and lifestyle, but controversy remains as to the best approach. Greater adherence to a traditional Mediterranean diet has consistently been associated with lower morbidity and mortality from cardiovascular disease, diabetes and many cancers, and lower all-cause mortality. Despite the well known benefits on chronic disease risk there remains some scepticism as to the effects of this dietary pattern across populations outside the Mediterranean and the mechanisms of action of this traditional plant-based dietary pattern.This narrative review aims to summarize the latest evidence on the health protective effects of a traditional Mediterranean diet on chronic noncommunicable diseases, specifically focussing on the anti-inflammatory effects of this highly published dietary pattern. RECENT FINDINGS: Recent high-quality evidence now supports a Mediterranean diet in secondary prevention of cardiovascular disease with impacts on atherosclerosis progression, likely through reduction of systemic inflammation and irrespective of changes in cholesterol or weight. The Mediterranean diet has a low Dietary Inflammatory Index illustrating its anti-inflammatory potential. This dietary pattern beneficially modulates the gut microbiota and immune system, including emerging evidence for efficacy against severe acute respiratory syndrome coronavirus 2 (coronavirus disease 2019). Emerging evidence shows clinicians are not routinely recommending a Mediterranean diet despite well known evidence due to barriers such as lack of training, patient materials and concerns about potential patient adherence. SUMMARY: The physiological mechanisms of action of this healthy diet pattern are becoming better understood to be multisystem and involving the gut. Larger controlled trials investigating mechanistic effects in broader non-Mediterranean populations are warranted. Although reflected in therapeutic guidelines for chronic disease management worldwide there are individual, clinical practice and health system barriers to its implementation that need a multisectoral approach to address.

Extra virgin olive oil high in polyphenols improves antioxidant status in adults: a double-blind, randomized, controlled, cross-over study (OLIVAUS).

PURPOSE: Olive oil polyphenols have been associated with cardiovascular health benefits. This study examined the antioxidant and anti-inflammatory effect of extra-virgin high polyphenol olive oil (HPOO) vs. low polyphenol olive oil (LPOO) in healthy Australian adults. METHODS: In a double-blind cross-over trial, 50 participants (aged 38.5 ± 13.9 years, 66% females) were randomized to consume 60 mL/day of HPOO (320 mg/kg polyphenols) or LPOO (86 mg/kg polyphenols) for three weeks. Following a 2-week wash-out period, participants crossed-over to the alternate treatment. Plasma oxidized low-density lipoprotein (ox-LDL), total antioxidant capacity (TAC), high-sensitivity C-reactive protein (hs-CRP) and anthropometrics were measured at baseline and follow-up. RESULTS: Fourty-three participants completed the study. Although there were no significant differences between treatments in the total sample, plasma ox-LDL decreased by 6.5 mU/mL (95%CI - 12.4 to - 0.5) and TAC increased by 0.03 mM (95% CI 0.006-0.05) only in the HPOO arm. Stratified analyses were also performed by cardiovascular disease risk status defined by abdominal obesity (WC > 94 cm in males, > 80 cm in females) or inflammation (hs-CRP > 1 mg/L). In the subgroup with abdominal obesity, ox-LDL decreased by 13.5 mU/mL (95% CI - 23.5 to - 3.6) and TAC increased by 0.04 mM (95% CI 0.006-0.07) only after HPOO consumption. In the subgroup with inflammation, hs-CRP decreased by 1.9 mg/L (95% CI - 3.7 to -0.1) only in the HPOO arm. CONCLUSIONS: Although there were no significant differences between treatments, the changes observed after HPOO consumption demonstrate the antioxidant and anti-inflammatory effect of this oil, which is more pronounced in adults with high cardiometabolic risk (Clinical Trial Registration: ACTRN12618000706279).

Factors Associated With Half- and Full-Marathon Race-Related Injuries: A 3-Year Review.

OBJECTIVE: To better evaluate the relationships between training, demographics, and injury, this study sought to define race-related injury risk factors for half- and full-marathon runners. DESIGN: This 3-year, observational cross-sectional study included adults who participated in a half or full marathon. Prerace and 2-week postrace surveys collected data on demographics, training factors, and injuries. SETTING: This study took place during a nationally recognized marathon affiliated with a local hospital. PARTICIPANTS: Runners were recruited during the Expo in the days before the race. Postrace surveys were returned by 1043 half marathoners and 624 full marathoners (response rate, 83%). INTERVENTIONS: This was an observational study; independent variables included demographic data and race year. MAIN OUTCOME MEASURE: The primary outcome was race-related injury that occurred during the race or within 2 weeks after the race. RESULTS: Race-related injuries were reported by 24% of half marathoners and 30% of full marathoners. For half and full marathoners, respectively, significant factors for injuries were previous injury, lower peak weekly training mileage, and lower weekly mileage before race training. Factors significant for only half-marathon injuries were younger age, female sex, shorter distance of longest training run, and no formal training program. Factors significant for only full-marathon injuries were higher body mass index, fewer days running per week, and fewer years of running experience. CONCLUSIONS: Previous running injuries, undertraining, and inexperience increased race-related injury risk; women had higher risk than men. Decreased risk of injury was associated with training loads of greater than 23 miles/week for half marathoners and 40 miles/week for full marathoners.

E-portfolios and Entrustable Professional Activities to support competency-based education in dietetics.

The concept of Entrustable Professional Activities, recently pioneered in medical education, has emerged to support the implementation of competency-based education. Although competency-based frameworks are widely used in healthcare professional education to develop outcomes-based curricula, assessment of student competency in professional placement settings remains challenging. The novel concept of Entrustable Professional Activities together with established methods of competency assessment, namely e-portfolios and self-assessment, was implemented in the "[La Trobe University Dietetic program in 2015-2016. This study aimed to appraise the e-portfolio and evaluate the use of Entrustable Professional Activities to assess competence. A mixed-methods evaluation, using qualitative and quantitative surveys with follow-up structured consultations, was conducted with final year dietetics students and their supervisors. Dietetics students were comfortable with Entrustable Professional Activities and competency-based assessment, whereas supervisors preferred Entrustable Professional Activity based assessment. All stakeholders valued student self-assessment and the ongoing use of structured e-portfolios to develop and document competency. The use of structured e-portfolios, student self-assessment, and the emerging concept of Entrustable Professional Activities are useful tools to support dietetics student education in professional placement settings.

ERp57 is protective against mutant SOD1-induced cellular pathology in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder and mutations in superoxide dismutase 1 (SOD1) account for 20% of familial ALS cases. The aetiology of ALS remains unclear, but protein misfolding, endoplasmic reticulum (ER) stress and neuronal apoptosis are implicated. We previously established that protein disulphide isomerase (PDIA1) is protective against ER stress and apoptosis in neuronal cells expressing mutant SOD1, and recently mutations in PDIA1 and related PDI family member endoplasmic reticulum protein 57 (ERp57/PDIA3), were associated with ALS. Here, we examined whether ERp57 is also protective against mutant SOD1 or whether distinct specificity exists amongst individual PDI family members. Neuronal cells co-expressing SOD1 and ERp57 were examined for inclusion formation, ER stress, ubiquitin proteasome system (UPS) dysfunction and apoptosis. Over-expression of ERp57 inhibited inclusion formation, ER stress, UPS dysfunction and apoptosis, whereas silencing of ERp57 expression enhanced mutant SOD1 inclusion formation, ER stress and toxicity, indicating a protective role for ERp57 against SOD1 misfolding. ERp57 also inhibited the formation of mutant SOD1 inclusions and apoptosis in primary cortical neurons, thus confirming results obtained from cell lines. ERp57 partially co-localized with TAR DNA-binding protein-43 (TDP-43)-positive inclusions in spinal cords from sporadic ALS patients, thus linking ERp57 to protein misfolding in human sporadic disease. Our results therefore imply that ERp57 has a protective role against pathological events induced by mutant SOD1 and they link ERp57 to the misfolding of TDP-43. This study therefore has implications for the design of novel therapeutics based on the activities of the PDI family of proteins.

The effect of high-polyphenol extra virgin olive oil on cardiovascular risk factors: A systematic review and meta-analysis.

The polyphenol fraction of extra-virgin olive oil may be partly responsible for its cardioprotective effects. The aim of this systematic review and meta-analysis was to evaluate the effect of high versus low polyphenol olive oil on cardiovascular disease (CVD) risk factors in clinical trials. In accordance with PRISMA guidelines, CINAHL, PubMed, Embase and Cochrane databases were systematically searched for relevant studies. Randomized controlled trials that investigated markers of CVD risk (e.g. outcomes related to cholesterol, inflammation, oxidative stress) were included. Risk of bias was assessed using the Jadad scale. A meta-analysis was conducted using clinical trial data with available CVD risk outcomes. Twenty-six studies were included. Compared to low polyphenol olive oil, high polyphenol olive oil significantly improved measures of malondialdehyde (MD: -0.07µmol/L [95%CI: -0.12, -0.02µmol/L]; I2: 88%; p = 0.004), oxidized LDL (SMD: -0.44 [95%CI: -0.78, -0.10µmol/L]; I2: 41%; P = 0.01), total cholesterol (MD 4.5 mg/dL [95%CI: -6.54, -2.39 mg/dL]; p<0.0001) and HDL cholesterol (MD 2.37 mg/dL [95%CI: 0.41, 5.04 mg/dL]; p = 0.02). Subgroup analyses and individual studies reported additional improvements in inflammatory markers and blood pressure. Most studies were rated as having low-to-moderate risk of bias. High polyphenol oils confer some CVD-risk reduction benefits; however, further studies with longer duration and in non-Mediterranean populations are required.

The AUStralian MEDiterranean Diet Heart Trial (AUSMED Heart Trial): A randomized clinical trial in secondary prevention of coronary heart disease in a multiethnic Australian population: Study protocol.

The Mediterranean diet was first characterized as a heart-protective diet in the 1960s. The significant cardioprotective effects of the Mediterranean diet in comparison to the standard-care low-fat diet have been established in the primary prevention of cardiovascular disease (CVD); however, there is insufficient evidence in secondary prevention research to influence the current standard of care. Opportunity exists to assess the Mediterranean diet as a therapeutic target for secondary CVD prevention within Australia's ethnoculturally diverse communities. The AUSMED Heart Trial is a multisite randomized controlled trial that will evaluate the efficacy of the Mediterranean diet for secondary prevention of CVD in the Australian health care setting. This trial aims to evaluate the effect of a 6-month Mediterranean diet intervention (delivered by dietitians) versus a "standard-care" low-fat diet in reducing the composite incidence of cardiovascular events at 12 months and at trial end in participants with documented evidence of a previous acute myocardial infarction at trial entry. The quality of the diet at baseline and follow-up will be assessed using comprehensive dietary questionnaires and diaries as well as relevant dietary biomarkers (such as urinary polyphenols and erythrocyte fatty acids). Cardiovascular risk markers, including novel measures of immune and inflammatory status, endothelial function, vascular compliance, platelet activity, and body composition, will be collected to explore possible mechanisms for treatment effect. Cost-effectiveness will also be estimated to support policy translation. We plan to recruit 1,032 participants (516 per arm) from cardiology clinics in major Australian hospitals in Melbourne, Adelaide, and Brisbane.

Adeno-Associated Virus Gene Therapy: Translational Progress and Future Prospects in the Treatment of Heart Failure.

Despite advances in treatment over the past decade, heart failure remains a significant public health burden and a leading cause of death in the developed world. Gene therapy provides a promising approach for preventing and reversing cardiac abnormalities, however, clinical application has shown limited success to date. A substantial effort is being invested into the development of recombinant adeno-associated viruses (AAVs) for cardiac gene therapy as AAV gene therapy offers a high safety profile and provides sustained and efficient transgene expression following a once-off administration. Due to the physiological, anatomical and genetic similarities between large animals and humans, preclinical studies using large animal models for AAV gene therapy are crucial stepping stones between the laboratory and the clinic. Many molecular targets selected to treat heart failure using AAV gene therapy have been chosen because of their potential to regulate and restore cardiac contractility. Other genes targeted with AAV are involved with regulating angiogenesis, beta-adrenergic sensitivity, inflammation, physiological signalling and metabolism. While significant progress continues to be made in the field of AAV cardiac gene therapy, challenges remain in overcoming host neutralising antibodies, improving AAV vector cardiac-transduction efficiency and selectivity, and optimising the dose, route and method of delivery.

Simulation: An Effective Method of Teaching Cosmetic Botulinum Toxin Injection Technique.

BACKGROUND: Learning to inject botulinum toxin for cosmetic purposes is difficult for beginners, given the nature of the procedure and patient population. Simulation training is an effective modality for medical professionals to acquire skills in an environment that provides low stress and ample opportunity for questions and correction of mistakes. OBJECTIVES: Compare posttraining comfort, knowledge, and practical botulinum toxin injection scores among trainees who underwent simulation vs video training only. METHODS: A total of 20 nurse practitioners, physician assistants, and resident physicians underwent cosmetic botulinum toxin injection training either through lecture and video, or lecture and hands-on simulation training. Comfort, knowledge, and practical test scores were recorded and compared between the groups. RESULTS: There was no evidence of a statistically significant difference in comfort or knowledge scores between simulation and video groups. The median (range) practical score was significantly higher in the simulation group compared to the video group (59.0 [31-60] vs 44.5 [27-57]; P < 0.01). CONCLUSIONS: Despite feeling similarly comfortable and having similar written knowledge test scores, the trainees who underwent simulation training had significantly higher hands-on practical test scores compared to trainees who underwent video training only for cosmetic botulinum toxin injections.

Prevalence of BCL-2/J(H) Translocation in Healthy African Americans.

The translocation t(14;18)(q32;q21) (BCL-2/J(H)) is present in over 80 % of all follicular lymphomas and is detectable in peripheral blood lymphocytes (PBL) of healthy individuals. The prevalence of this translocation has not been studied in African Americans (AAs). Given the higher incidence of follicular lymphomas in whites compared to AAs in the United States (USA), we hypothesized that the translocation prevalence in the blood of AAs would be lower. DNA was isolated from PBL from blood samples collected from participants from FL. Polymerase chain reaction was performed on the BCL-2/J(H) major (MBC) and minor breakpoint cluster (mBC) regions. Eight of the 77 (10.4 %) blood samples from AA participants were positive for MBC (95 % CI, 4.6-19.5 %), and three (3.9 %) were positive for mBC (95 % CI, 0.81-10.97 %) of BCL-2/J(H), with a total of 11 (14.3 %) participants with positive samples (95 % CI, 7.35-24.13 %). In 167 white patient samples, 22 (13.2 %; 95 % CI, 8.44-19.26 %) were positive for MBC, and five (3.0 %; 95 % CI, 0.98-6.85 %) were positive for mBC, with a total of 25 (15 %) participants with positive samples (CI, 9.93-21.30 %). The prevalence of t(14;18)(q32;q21) is not significantly different among AAs and whites from the USA. The lower prevalence of follicular lymphomas in AAs compared with whites is likely a result of differences in secondary molecular alterations involved in follicular lymphoma development. This study is the first report of prevalence of t(14;18) in an AA cohort.

Effect of an endoscopic quality improvement program on adenoma detection rates: a multicenter cluster-randomized controlled trial in a clinical practice setting (EQUIP-3).

BACKGROUND: Colonoscopy is protective against colorectal cancer, but its quality and protective benefits can vary. Adenoma detection rate (ADR) is associated with quality and the degree of protection against colorectal cancer and death. In a previous, single academic center, randomized, controlled trial, we demonstrated that an endoscopic quality improvement program increased ADR (EQUIP-1) and that those increases were durable (EQUIP-2). We hypothesized that EQUIP training would increase ADR in a multicenter clinical practice setting. METHODS: Nine large clinical practice sites were recruited. After a baseline period (phase I), 5 sites were randomized to receive supplemental in-person EQUIP training with active feedback. After follow-up (phase II), the changes in ADRs at these sites were compared with the changes at 4 control sites that did not receive training or feedback until after study completion. RESULTS: Twenty-two thousand three hundred sixteen colonoscopies were included. There was a statistically significant increase in ADR at the training sites (odds ratio [OR], 1.28; P = .004) with a raw ADR of 31% in phase I and 42% in phase II after the intervention. However, raw ADRs also increased at the control sites (from 36% to 39%). As a result, there was limited evidence of a training effect (OR, 1.03; 95% confidence interval [CI], 0.84-1.25; P = .78). CONCLUSIONS: ADRs increased at the sites participating in the endoscopic quality improvement program. However it is not clear to what extent the training program is responsible for the changes, because raw ADRs also increased at the control sites but to a lesser extent. (Clinical Trials Registration number: NCT02325635.).

Intra-operative predictors of postoperative Takotsubo syndrome in liver transplant recipients-An exploratory case-control study.

INTRODUCTION: Takotsubo syndrome (TTS), also known as Takotsubo cardiomyopathy or stress-induced cardiomyopathy, has been described following a variety of surgeries and disease states. The relationship between intra-operative anesthesia management and the development of this syndrome has never been fully elucidated. OBJECTIVES: The primary objective of this study was to determine the relationship of multiple intra-operative factors on the pathogenesis of TTS. METHODS: A single-center retrospective review of all liver transplants performed at Mayo Clinic Florida from January 2005 to December 2014. Patients developing left ventricular dilation and a concomitant decrease in ejection fraction, a negative cardiac catheterization, or stress test within 30 days of transplantation were identified. Cases were matched 2:1 to controls with respect to MELD, age, sex, and indication for transplantation. Our evaluation included liver graft characteristics, intra-operative medications, and intra-operative hemodynamic measurements. RESULTS: We identified 24 cases of TTS from a pool of 1752 transplants, for an incidence of 1.4%. No statistically significant differences in intra-operative measures between the two groups were identified (all P ≥ .08). CONCLUSION: Our exploratory, single-center retrospective review evaluating 46 intra-operative characteristics found no association with the development of TTS.

Associations between meal patterns, binge eating, and weight for Latinas.

Establishing a regular pattern of eating is a core element of treatment for binge eating, yet no research to date has examined meal patterns of Latina women. OBJECTIVE: Compare eating patterns of Latinas who binge eat and those who do not, and examine associations between meal patterns and binge episodes, associated distress and concerns, and body mass index (BMI). METHOD: One-hundred fifty-five Latinas [65 Binge Eating Disorder (BED), 22 Bulimia Nervosa (BN), 68 with no eating disorder] were assessed with the Eating Disorder Examination. RESULTS: There were no significant differences in eating patterns between groups. Breakfast was the least and dinner the most consumed meal. For the BED group: greater frequency of lunch consumption was associated with higher BMI while more frequent evening snacking was associated with lower BMI and with less weight importance; more frequent breakfast consumption, mid-morning snack consumption and total meals were associated with greater distress regarding binge eating. For the BN group, evening snack frequency was associated with less dietary restriction and more weight and shape concern; total snack frequency was associated with more weight concern. Regular meal eaters reported more episodes of binge eating than those who did not eat meals regularly. DISCUSSION: Associations with meal patterns differed by eating disorder diagnosis. Study findings mostly are not consistent with results from prior research on primarily White women. CBT treatments may need to be tailored to address the association between binge eating and regular meal consumption for Latinas. Culturally, appropriate modifications that address traditional eating patterns should be considered. © 2016 Wiley Periodicals, Inc. (Int J Eat Disord 2017; 50:32-39).

Impact of an Endoscopic Quality Improvement Program Focused on Adenoma Detection on Sessile Serrated Adenoma/Polyp Detection.

BACKGROUND: Sessile serrated adenomas/polyps (SSA/P) are an under-recognized disease with a unique malignant pathway. Improved endoscopic recognition and pathological interpretation is needed. AIMS: To determine whether an educational intervention that improved adenoma detection rate (ADR) could improve SSA/P detection rate after reclassification of previously termed "hyperplastic" polyps. METHODS: We reanalyzed data from a prospective randomized trial of an educational intervention aimed at increasing ADR. All hyperplastic polyps ≥6 mm reported in a previously published study were rereviewed and reclassified using standardized criteria for serrated lesions. Detection rates of sessile serrated adenomas/polyps and other clinically relevant serrated polyps were calculated in the baseline and post-training phases of the original study. RESULTS: Of 263 available for rereview, 33 (12.5%) were reclassified as SSA/P (N = 32) or traditional serrated adenoma (TSA) (N = 1). Reclassification was more common in the right colon (18 vs. 8%, p = 0.02). Baseline SSA/P detection rate was 0.7% in the untrained group and 1.3% in the trained group. Post-training, the SSA/P detection rate increased to 2.1 and 1.5%, respectively. The clinically relevant serrated polyp detection rate at baseline was 14.2% in the untrained group and 11.3% in the trained group. After the educational intervention, the clinically relevant serrated polyp detection rates increased to 16.5 and 14.8% in the untrained and trained groups, respectively. The estimated odds of an endoscopist detecting either a SSA/P or other clinically relevant serrated polyp during colonoscopy increased by only 3% with the educational intervention (OR 1.03, 95% CI 0.61-1.74, p = 0.91). CONCLUSIONS: Pathological re-interpretation of larger serrated polyps resulted in the reclassification of 12.5% of lesions. Quality improvement methods focused on adenoma detection did not impact SSA/P detection, and thus specific methods for serrated polyp detection are needed.

Sympathetic nervous response to ischemia-reperfusion injury in humans is altered with remote ischemic preconditioning.

Sympathetic neural activation may be detrimentally involved in tissue injury caused by ischemia-reperfusion (IR). We examined the effects of experimental IR in the forearm on sympathetic nerve response, finger reactive hyperemia, and oxidative stress, and the protection afforded by applying remote ischemic preconditioning (RIPC). Ischemia was induced in the forearm for 20 min in healthy volunteers. RIPC was induced by applying two cycles, 5 min each, of ischemia and reperfusion to the upper leg immediately before IR. We examined muscle sympathetic nerve activity (MSNA) in the contralateral leg using microneurography, finger reactive hyperemia [ischemic reactive hyperemia index (RHI)], erythrocyte production of reduced gluthathione (GSH), and plasma nitric oxide (NO) concentration. In controls (no RIPC; n = 15), IR increased MSNA in the early and late phase of ischemia (70% at 5 min; 101% at 15 min). In subjects who underwent RIPC (n = 15), the increase in MSNA was delayed to the late phase of ischemia and increased only by 40%. GSH increased during ischemia in the control group (P = 0.05), but not in those who underwent RIPC. Nitrate and nitrite concentration, taken as an index of NO availability, decreased during the reperfusion period in control individuals (P < 0.05), while no change was observed in those who underwent RIPC. Experimental IR did not affect RHI in the control condition, but a significant vasodilatory response occurred in the RIPC group (P < 0.05). RIPC attenuated ischemia-induced sympathetic activation, prevented the production of an erythrocyte marker of oxidative stress and the reduction of NO availability, and ameliorated RHI.

Cerebellar c9RAN proteins associate with clinical and neuropathological characteristics of C9ORF72 repeat expansion carriers.

Clinical and neuropathological characteristics associated with G4C2 repeat expansions in chromosome 9 open reading frame 72 (C9ORF72), the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, are highly variable. To gain insight on the molecular basis for the heterogeneity among C9ORF72 mutation carriers, we evaluated associations between features of disease and levels of two abundantly expressed "c9RAN proteins" produced by repeat-associated non-ATG (RAN) translation of the expanded repeat. For these studies, we took a departure from traditional immunohistochemical approaches and instead employed immunoassays to quantitatively measure poly(GP) and poly(GA) levels in cerebellum, frontal cortex, motor cortex, and/or hippocampus from 55 C9ORF72 mutation carriers [12 patients with ALS, 24 with frontotemporal lobar degeneration (FTLD) and 19 with FTLD with motor neuron disease (FTLD-MND)]. We additionally investigated associations between levels of poly(GP) or poly(GA) and cognitive impairment in 15 C9ORF72 ALS patients for whom neuropsychological data were available. Among the neuroanatomical regions investigated, poly(GP) levels were highest in the cerebellum. In this same region, associations between poly(GP) and both neuropathological and clinical features were detected. Specifically, cerebellar poly(GP) levels were significantly lower in patients with ALS compared to patients with FTLD or FTLD-MND. Furthermore, cerebellar poly(GP) associated with cognitive score in our cohort of 15 patients. In the cerebellum, poly(GA) levels similarly trended lower in the ALS subgroup compared to FTLD or FTLD-MND subgroups, but no association between cerebellar poly(GA) and cognitive score was detected. Both cerebellar poly(GP) and poly(GA) associated with C9ORF72 variant 3 mRNA expression, but not variant 1 expression, repeat size, disease onset, or survival after onset. Overall, these data indicate that cerebellar abnormalities, as evidenced by poly(GP) accumulation, associate with neuropathological and clinical phenotypes, in particular cognitive impairment, of C9ORF72 mutation carriers.

Therapeutic silencing of miR-652 restores heart function and attenuates adverse remodeling in a setting of established pathological hypertrophy.

Expression of microRNA-652 (miR-652) increases in the diseased heart, decreases in a setting of cardioprotection, and is inversely correlated with heart function. The aim of this study was to assess the therapeutic potential of inhibiting miR-652 in a mouse model with established pathological hypertrophy and cardiac dysfunction due to pressure overload. Mice were subjected to a sham operation or transverse aortic constriction (TAC) for 4 wk to induce hypertrophy and cardiac dysfunction, followed by administration of a locked nucleic acid (LNA)-antimiR-652 (miR-652 inhibitor) or LNA control. Cardiac function was assessed before and 8 wk post-treatment. Expression of miR-652 increased in hearts subjected to TAC compared to sham surgery (2.9-fold), and this was suppressed by ∼95% in LNA-antimiR-652-treated TAC mice. Inhibition of miR-652 improved cardiac function in TAC mice (fractional shortening:29±1% at 4 wk post-TAC compared to 35±1% post-treatment) and attenuated cardiac hypertrophy. Improvement in heart function was associated with reduced cardiac fibrosis, less apoptosis and B-type natriuretic peptide gene expression, and preserved angiogenesis. Mechanistically, we identified Jagged1 (a Notch1 ligand) as a novel direct target of miR-652. In summary, these studies provide the first evidence that silencing of miR-652 protects the heart against pathological remodeling and improves heart function.