The neuroimmune guidance cue netrin-1 promotes atherosclerosis by inhibiting the emigration of macrophages from plaques.

Atherosclerotic plaque formation is fueled by the persistence of lipid-laden macrophages in the artery wall. The mechanisms by which these cells become trapped, thereby establishing chronic inflammation, remain unknown. Here we found that netrin-1, a neuroimmune guidance cue, was secreted by macrophages in human and mouse atheroma, where it inactivated the migration of macrophages toward chemokines linked to their egress from plaques. Acting via its receptor, UNC5b, netrin-1 inhibited the migration of macrophages directed by the chemokines CCL2 and CCL19, activation of the actin-remodeling GTPase Rac1 and actin polymerization. Targeted deletion of netrin-1 in macrophages resulted in much less atherosclerosis in mice deficient in the receptor for low-density lipoprotein and promoted the emigration of macrophages from plaques. Thus, netrin-1 promoted atherosclerosis by retaining macrophages in the artery wall. Our results establish a causative role for negative regulators of leukocyte migration in chronic inflammation.

Comparison between genetic and pharmaceutical disruption of Ldlr expression for the development of atherosclerosis.

Antisense oligonucleotides (ASOs) against Ldl receptor (Ldlr-ASO) represent a promising strategy to promote hypercholesterolemic atherosclerosis in animal models without the need for complex breeding strategies. Here, we sought to characterize and contrast atherosclerosis in mice given Ldlr-ASO with those bearing genetic Ldlr deficiency. To promote atherosclerosis, male and female C57Bl6/J mice were either given weekly injections of Ldlr-ASO (5 mg/kg once per week) or genetically deficient in Ldlr (Ldlr-/-). Mice consumed either standard rodent chow or a diet high in saturated fat and sucrose with 0.15% added cholesterol for 16 weeks. While both models of Ldlr deficiency promoted hypercholesterolemia, Ldlr-/- mice exhibited nearly 2-fold higher cholesterol levels than Ldlr-ASO mice, reflected by increased VLDL and LDL levels. Consistent with this, the en face atherosclerotic lesion area was 3-fold and 3.6-fold greater in male and female mice with genetic Ldlr deficiency, respectively, as compared with the modest atherosclerosis observed following Ldlr-ASO treatment. Aortic sinus lesion sizes, fibrosis, smooth muscle actin, and necrotic core areas were also larger in Ldlr-/- mice, suggesting a more advanced phenotype. Despite a more modest effect on hypercholesterolemia, Ldlr-ASO induced greater hepatic inflammatory gene expression, macrophage accumulation, and histological lobular inflammation than was observed in Ldlr-/- mice. We conclude Ldlr-ASO is a promising tool for the generation of complex rodent models with which to study atherosclerosis but does not promote comparable levels of hypercholesterolemia or atherosclerosis as Ldlr-/- mice and increases hepatic inflammation. Thus, genetic Ldlr deficiency may be a superior model, depending on the proposed use.

Niacin Increases Atherogenic Proteins in High-Density Lipoprotein of Statin-Treated Subjects.

OBJECTIVE: Niacin therapy fails to reduce cardiovascular events in statin-treated subjects even though it increases plasma HDL-C (HDL [high-density lipoprotein] cholesterol) and decreases LDL-C (LDL [low-density lipoprotein] cholesterol) and triglyceride levels. To investigate potential mechanisms for this lack of cardioprotection, we quantified the HDL proteome of subjects in 2 niacin clinical trials: the CPC study (Carotid Plaque Composition) and the HDL Proteomics substudy of the AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides). APPROACH AND RESULTS: Using targeted proteomics, we quantified levels of 31 HDL proteins from 124 CPC subjects and 120 AIM-HIGH subjects. The samples were obtained at baseline and after 1 year of statin monotherapy or niacin-statin combination therapy. Compared with statin monotherapy, niacin-statin combination therapy did not reduce HDL-associated apolipoproteins APOC1, APOC2, APOC3, and APOC4, despite significantly lowering triglycerides. In contrast, niacin markedly elevated HDL-associated PLTP (phospholipid transfer protein), CLU (clusterin), and HP/HPR (haptoglobin/haptoglobinrelated proteins; P≤0.0001 for each) in both the CPC and AIM-HIGH cohorts. CONCLUSIONS: The addition of niacin to statin therapy resulted in elevated levels of multiple HDL proteins linked to increased atherosclerotic risk, which might have compromised the cardioprotective effects associated with higher HDL-C levels and lower levels of LDL-C and triglycerides. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00715273; NCT00880178; NCT00120289.

Sexually Dimorphic Relationships Among Saa3 (Serum Amyloid A3), Inflammation, and Cholesterol Metabolism Modulate Atherosclerosis in Mice.

[Figure: see text].

Chronic hindbrain administration of oxytocin elicits weight loss in male diet-induced obese mice.

Previous studies indicate that oxytocin (OT) administration reduces body weight in high-fat diet (HFD)-induced obese (DIO) rodents through both reductions in food intake and increases in energy expenditure. We recently demonstrated that chronic hindbrain [fourth ventricular (4V)] infusions of OT evoke weight loss in DIO rats. Based on these findings, we hypothesized that chronic 4V OT would elicit weight loss in DIO mice. We assessed the effects of 4V infusions of OT (16 nmol/day) or vehicle over 28 days on body weight, food intake, and body composition. OT reduced body weight by approximately 4.5% ± 1.4% in DIO mice relative to OT pretreatment body weight (P < 0.05). These effects were associated with reduced adiposity and adipocyte size [inguinal white adipose tissue (IWAT)] (P < 0.05) and attributed, in part, to reduced energy intake (P < 0.05) at a dose that did not increase kaolin intake (P = NS). OT tended to increase uncoupling protein-1 expression in IWAT (0.05 < P < 0.1) suggesting that OT stimulates browning of WAT. To assess OT-elicited changes in brown adipose tissue (BAT) thermogenesis, we examined the effects of 4V OT on interscapular BAT temperature (TIBAT). 4V OT (1 µg) elevated TIBAT at 0.75 (P = 0.08), 1, and 1.25 h (P < 0.05) postinjection; a higher dose (5 µg) elevated TIBAT at 0.75-, 1-, 1.25-, 1.5-, 1.75- (P < 0.05), and 2-h (0.05 < P < 0.1) postinjection. Together, these findings support the hypothesis that chronic hindbrain OT treatment evokes sustained weight loss in DIO mice by reducing energy intake and increasing BAT thermogenesis at a dose that is not associated with evidence of visceral illness.

Hematopoietic Cell-Expressed Endothelial Nitric Oxide Protects the Liver From Insulin Resistance.

OBJECTIVE: Mice genetically deficient in endothelial nitric oxide synthase (Nos3-/-) have fasting hyperinsulinemia and hepatic insulin resistance, indicating the importance of Nos3 (nitric oxide synthase) in maintaining metabolic homeostasis. Although the current paradigm holds that these metabolic effects are derived specifically from the expression of Nos3 in the endothelium, it has been established that bone marrow-derived cells also express Nos3. The aim of this study was to investigate whether bone marrow-derived cell Nos3 is important in maintaining metabolic homeostasis. Approach and Results: To test the hypothesis that bone marrow-derived cell Nos3 contributes to metabolic homeostasis, we generated chimeric male mice deficient or competent for Nos3 expression in circulating blood cells. These mice were placed on a low-fat diet for 5 weeks, a time period which is known to induce hepatic insulin resistance in global Nos3-deficient mice but not in wild-type C57Bl/6 mice. Surprisingly, we found that the absence of Nos3 in the bone marrow-derived component is associated with hepatic insulin resistance and that restoration of Nos3 in the bone marrow-derived component in global Nos3-deficient mice is sufficient to restore hepatic insulin sensitivity. Furthermore, we found that overexpression of Nos3 in bone marrow-derived component in wild-type mice attenuates the development of hepatic insulin resistance during high-fat feeding. Finally, compared with wild-type macrophages, the loss of macrophage Nos3 is associated with increased inflammatory responses to lipopolysaccharides and reduced anti-inflammatory responses to IL-4, a macrophage phenotype associated with the development of hepatic and systemic insulin resistance. CONCLUSIONS: These results would suggest that the metabolic and hepatic consequences of high-fat feeding are mediated by loss of Nos3/nitric oxide actions in bone marrow-derived cells, not in endothelial cells.

A scoping review of new implementations of interprofessional bedside rounding models to improve teamwork, care, and outcomes in hospitals.

Poor communication within healthcare teams occurs commonly, contributing to inefficiency, medical errors, conflict, and other adverse outcomes. Interprofessional bedside rounds (IBR) are a promising model that brings two or more health professions together with patients and families as part of a consistent, team-based routine to share information and collaboratively arrive at a daily plan of care. The purpose of this systematic scoping review was to investigate the breadth and quality of IBR literature to identify and describe gaps and opportunities for future research. We followed an adapted Arksey and O'Malley Framework and PRISMA scoping review guidelines. PubMed, CINAHL, PsycINFO, and Embase were systematically searched for key IBR words and concepts through June 2020. Seventy-nine articles met inclusion criteria and underwent data abstraction. Study quality was assessed using the Mixed Methods Assessment Tool. Publications in this field have increased since 2014, and the majority of studies reported positive impacts of IBR implementation across an array of team, patient, and care quality/delivery outcomes. Despite the preponderance of positive findings, great heterogeneity, and a reliance on quantitative non-randomized study designs remain in the extant research. A growing number of interventions to improve safety, quality, and care experiences in hospital settings focus on redesigning daily inpatient rounds. Limited information on IBR characteristics and implementation strategies coupled with widespread variation in terminology, study quality, and design create challenges in assessing the effectiveness of models of rounds and optimal implementation strategies. This scoping review highlights the need for additional studies of rounding models, implementation strategies, and outcomes that facilitate comparative research.

Unlocking the Secrets of Mitochondria in the Cardiovascular System: Path to a Cure in Heart Failure­A Report from the 2018 National Heart, Lung, and Blood Institute Workshop

Mitochondria have emerged as a central factor in the pathogenesis and progression of heart failure, and other cardiovascular diseases, as well, but no therapies are available to treat mitochondrial dysfunction. The National Heart, Lung, and Blood Institute convened a group of leading experts in heart failure, cardiovascular diseases, and mitochondria research in August 2018. These experts reviewed the current state of science and identified key gaps and opportunities in basic, translational, and clinical research focusing on the potential of mitochondria-based therapeutic strategies in heart failure. The workshop provided short- and long-term recommendations for moving the field toward clinical strategies for the prevention and treatment of heart failure and cardiovascular diseases by using mitochondria-based approaches.

Lp(a) (Lipoprotein(a)) Levels Predict Progression of Carotid Atherosclerosis in Subjects With Atherosclerotic Cardiovascular Disease on Intensive Lipid Therapy: An Analysis of the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes) Carotid Magnetic Resonance Imaging Substudy-Brief Report.

OBJECTIVE: To assess whether Lp(a) (lipoprotein(a)) levels and other lipid levels were predictive of progression of atherosclerosis burden as assessed by carotid magnetic resonance imaging in subjects who have been treated with LDL-C (low-density lipoprotein cholesterol)-lowering therapy and participated in the AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes). APPROACH AND RESULTS: AIM-HIGH was a randomized, double-blind study of subjects with established vascular disease, elevated triglycerides, and low HDL-C (high-density lipoprotein cholesterol). One hundred fifty-two AIM-HIGH subjects underwent both baseline and 2-year follow-up carotid artery magnetic resonance imaging. Plaque burden was measured by the percent wall volume (%WV) of the carotid artery. Associations between annualized change in %WV with baseline and on-study (1 year) lipid variables were evaluated using multivariate linear regression and the Bonferroni correction to account for multiple comparisons. Average %WV at baseline was 41.6±6.8% and annualized change in %WV over 2 years ranged from -3.2% to 3.7% per year (mean: 0.2±1.1% per year; P=0.032). Increases in %WV were significantly associated with higher baseline Lp(a) (ß=0.34 per 1-SD increase of Lp(a); 95% confidence interval, 0.15-0.52; P<0.001) after adjusting for clinical risk factors and other lipid levels. On-study Lp(a) had a similar positive association with %WV progression (ß=0.33; 95% confidence interval, 0.15-0.52; P<0.001). CONCLUSIONS: Despite intensive lipid therapy, aimed at aggressively lowering LDL-C to <70 mg/dL, carotid atherosclerosis continued to progress as assessed by carotid magnetic resonance imaging and that elevated Lp(a) levels were independent predictors of increases in atherosclerosis burden.

Purposeful interprofessional team intervention improves relational coordination among advanced heart failure care teams.

Effective delivery of healthcare is highly interdependent within and between interprofessional (IP) care teams and the patients they serve. This is particularly true for complex health conditions such as advanced heart failure (AHF). Our Academic Practice Partnership received funding to carry out IP workforce development with inpatient AHF care teams. Our objectives were to (a) identify challenges in team functioning that affected communication and relationships among the AHF care teams, (b) collaboratively identify a focal work process in need of improvement, and (c) test whether facilitated the implementation of team training and work process changes would lead to improvements in team communication, relationships, and process outcomes. The health-care team identified implementation of structured IP bedside rounds (SIBR) as the preferred approach to improving collaborative care. Utilizing a cross-sectional pre/post design, changes in team communication and relationships before and after a team intervention that included TeamSTEPPS training and SIBR implementation, were assessed using a validated Relational Coordination (RC) survey. The study population included AHF care team members (n ~ 100) representing seven workgroups (e.g., nurses, pharmacists) from two inpatient cardiology units at a 450-bed academic medical center in the Pacific Northwest during 2015-2016. Improvements in RC scores were demonstrated across all seven RC dimensions from baseline (Year 1) to follow-up (Year 2). Percent change on each of the seven dimensions ranged from 3.57% to 9.85%. Changes were statistically significant for improvements between baseline and follow-up on all but one of the seven RC dimensions (shared knowledge). The IP team intervention was associated with improvements in RC from baseline to follow-up. Additional research is needed to assess patient perspectives and outcomes of the IP team intervention. Findings of this study are consistent with the growing body of RC and SIBR research and provide a useful model of an IP team-based intervention in clinical practice.

Chronic oral rapamycin decreases adiposity, hepatic triglycerides and insulin resistance in male mice fed a diet high in sucrose and saturated fat.

NEW FINDINGS: What is the central question of this study? Whether chronic oral rapamycin promotes beneficial effects on glucose/lipid metabolism and energy balance when administered to mice with an obesogenic diet rich in saturated fat and sucrose has not been explored. What is the main finding and its importance? Chronic oral rapamycin reduces body weight and fat gain, improves insulin sensitivity and reduces hepatic steatosis when administered to mice with a high-fat, high-sucrose diet. In addition, we make the new observation that there appear to be tissue-specific effects of rapamycin. Although rapamycin appears to impart its effects mainly on visceral adipose tissue, its effects on insulin sensitivity are mediated by subcutaneous adipose tissue. ABSTRACT: Excess adiposity is commonly associated with insulin resistance, which can increase the risk of cardiovascular disease. However, the exact molecular mechanisms by which obesity results in insulin resistance are yet to be understood clearly. The intracellular nutrient-sensing protein, mechanistic target of rapamycin (mTOR), is a crucial signalling component in the development of obesity-associated insulin resistance. Given that increased tissue activation of mTOR complex-1 (mTORC1) occurs in obesity, diabetes and ageing, we hypothesized that pharmacological inhibition of mTORC1 would improve metabolic dysregulation in diet-induced obesity. We administered continuous rapamycin, a specific mTORC1 inhibitor, orally to C57BL/6J mice concurrently with a high-fat, high-sucrose (HFHS) diet for 20 weeks. The control group received placebo microcapsules. Rapamycin-treated mice showed significantly reduced weight gain and adiposity (33.6 ± 4.9 versus 40.4 ± 3.0% body fat, P < 0.001, n = 8 mice per group), despite increased or equivalent food intake compared with the placebo group. The rapamycin-fed mice also demonstrated reduced plasma glucose (252 ± 57 versus 297 ± 67 mg dl-1 , P < 0.001) and improved insulin sensitivity during insulin and glucose tolerance testing. Rapamycin-treated mice also had lower plasma triglycerides (48 ± 13 versus 67 ± 11 mg/dL, P < 0.01) and hepatic triglyceride content (89 ± 15 versus 110 ± 19 mg/g liver, P < 0.05) compared with the placebo group. A moderately low dose of rapamycin decreased adiposity and improved the metabolic profile in a model of diet-induced obesity. These data suggest that low-grade chronic mTORC1 inhibition might be a potential strategy for anti-obesity therapies.

Adipocyte-Specific Deficiency of NADPH Oxidase 4 Delays the Onset of Insulin Resistance and Attenuates Adipose Tissue Inflammation in Obesity.

OBJECTIVE: Obesity is associated with insulin resistance and adipose tissue inflammation. Reactive oxygen species (ROS) increase in adipose tissue during the development of obesity. We previously showed that in response to excess nutrients like glucose and palmitate, adipocytes generated ROS via NADPH oxidase (NOX) 4, the major adipocyte isoform, instead of using mitochondrial oxidation. However, the role of NOX4-derived ROS in the development of whole body insulin resistance, adipocyte inflammation, and recruitment of macrophages to adipose tissue during the development of obesity is unknown. APPROACH AND RESULTS: In this study, control C57BL/6 mice and mice in which NOX4 has been deleted specifically in adipocytes were fed a high-fat, high-sucrose diet. During the development of obesity in control mice, adipocyte NOX4 and pentose phosphate pathway activity were transiently increased. Primary adipocytes differentiated from mice with adipocytes deficient in NOX4 showed resistance against high glucose or palmitate-induced adipocyte inflammation. Mice with adipocytes deficient in NOX4 showed a delayed onset of insulin resistance during the development of obesity, with an initial reduction in adipose tissue inflammation that normalized with prolonged high-fat, high-sucrose feeding. CONCLUSIONS: These findings imply that NOX4-derived ROS may play a role in the onset of insulin resistance and adipose tissue inflammation. As such, therapeutics targeting NOX4-mediated ROS production could be effective in preventing obesity-associated conditions, such as insulin resistance.

Orthodontic treatment for prominent upper front teeth (Class II malocclusion) in children and adolescents.

BACKGROUND: Prominent upper front teeth are a common problem affecting about a quarter of 12-year-old children in the UK. The condition develops when permanent teeth erupt. These teeth are more likely to be injured and their appearance can cause significant distress. Children are often referred to an orthodontist for treatment with dental braces to reduce the prominence of their teeth. If a child is referred at a young age, the orthodontist is faced with the dilemma of whether to treat the patient early or to wait and provide treatment in adolescence. OBJECTIVES: To assess the effects of orthodontic treatment for prominent upper front teeth initiated when children are seven to 11 years old ('early treatment' in two phases) compared to in adolescence at around 12 to 16 years old ('late treatment' in one phase); to assess the effects of late treatment compared to no treatment; and to assess the effects of different types of orthodontic braces. SEARCH METHODS: Cochrane Oral Health's Information Specialist searched the following databases: Cochrane Oral Health's Trials Register (to 27 September 2017), the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, 2017, Issue 8), MEDLINE Ovid (1946 to 27 September 2017), and Embase Ovid (1980 to 27 September 2017). The US National Institutes of Health Ongoing Trials Registry (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform were searched for ongoing trials. No restrictions were placed on the language or date of publication when searching the electronic databases. SELECTION CRITERIA: Randomised controlled trials of orthodontic treatments to correct prominent upper front teeth (Class II malocclusion) in children and adolescents. We included trials that compared early treatment in children (two-phase) with any type of orthodontic braces (removable, fixed, functional) or head-braces versus late treatment in adolescents (one-phase) with any type of orthodontic braces or head-braces, and trials that compared any type of orthodontic braces or head-braces versus no treatment or another type of orthodontic brace or appliance (where treatment started at a similar age in the intervention groups).We excluded trials involving participants with a cleft lip or palate, or other craniofacial deformity/syndrome, and trials that recruited patients who had previously received surgical treatment for their Class II malocclusion. DATA COLLECTION AND ANALYSIS: Review authors screened the search results, extracted data and assessed risk of bias independently. We used odds ratios (ORs) and 95% confidence intervals (CIs) for dichotomous outcomes, and mean differences (MDs) and 95% CIs for continuous outcomes. We used the fixed-effect model for meta-analyses including two or three studies and the random-effects model for more than three studies. MAIN RESULTS: We included 27 RCTs based on data from 1251 participants.Three trials compared early treatment with a functional appliance versus late treatment for overjet, ANB and incisal trauma. After phase one of early treatment (i.e. before the other group had received any intervention), there was a reduction in overjet and ANB reduction favouring treatment with a functional appliance; however, when both groups had completed treatment, there was no difference between groups in final overjet (MD 0.21, 95% CI -0.10 to 0.51, P = 0.18; 343 participants) (low-quality evidence) or ANB (MD -0.02, 95% CI -0.47 to 0.43; 347 participants) (moderate-quality evidence). Early treatment with functional appliances reduced the incidence of incisal trauma compared to late treatment (OR 0.56, 95% CI 0.33 to 0.95; 332 participants) (moderate-quality evidence). The difference in the incidence of incisal trauma was clinically important with 30% (51/171) of participants reporting new trauma in the late treatment group compared to only 19% (31/161) of participants who had received early treatment.Two trials compared early treatment using headgear versus late treatment. After phase one of early treatment, headgear had reduced overjet and ANB; however, when both groups had completed treatment, there was no evidence of a difference between groups in overjet (MD -0.22, 95% CI -0.56 to 0.12; 238 participants) (low-quality evidence) or ANB (MD -0.27, 95% CI -0.80 to 0.26; 231 participants) (low-quality evidence). Early (two-phase) treatment with headgear reduced the incidence of incisal trauma (OR 0.45, 95% CI 0.25 to 0.80; 237 participants) (low-quality evidence), with almost half the incidence of new incisal trauma (24/117) compared to the late treatment group (44/120).Seven trials compared late treatment with functional appliances versus no treatment. There was a reduction in final overjet with both fixed functional appliances (MD -5.46 mm, 95% CI -6.63 to -4.28; 2 trials, 61 participants) and removable functional appliances (MD -4.62, 95% CI -5.33 to -3.92; 3 trials, 122 participants) (low-quality evidence). There was no evidence of a difference in final ANB between fixed functional appliances and no treatment (MD -0.53°, 95% CI -1.27 to -0.22; 3 trials, 89 participants) (low-quality evidence), but removable functional appliances seemed to reduce ANB compared to no treatment (MD -2.37°, 95% CI -3.01 to -1.74; 2 trials, 99 participants) (low-quality evidence).Six trials compared orthodontic treatment for adolescents with Twin Block versus other appliances and found no difference in overjet (0.08 mm, 95% CI -0.60 to 0.76; 4 trials, 259 participants) (low-quality evidence). The reduction in ANB favoured treatment with a Twin Block (-0.56°, 95% CI -0.96 to -0.16; 6 trials, 320 participants) (low-quality evidence).Three trials compared orthodontic treatment for adolescents with removable functional appliances versus fixed functional appliances and found a reduction in overjet in favour of fixed appliances (0.74, 95% CI 0.15 to 1.33; two trials, 154 participants) (low-quality evidence), and a reduction in ANB in favour of removable appliances (-1.04°, 95% CI -1.60 to -0.49; 3 trials, 185 participants) (low-quality evidence). AUTHORS' CONCLUSIONS: Evidence of low to moderate quality suggests that providing early orthodontic treatment for children with prominent upper front teeth is more effective for reducing the incidence of incisal trauma than providing one course of orthodontic treatment in adolescence. There appear to be no other advantages of providing early treatment when compared to late treatment. Low-quality evidence suggests that, compared to no treatment, late treatment in adolescence with functional appliances, is effective for reducing the prominence of upper front teeth.

Orthodontic treatment for deep bite and retroclined upper front teeth in children.

BACKGROUND: A Class II division 2 malocclusion is characterised by upper front teeth that are retroclined (tilted toward the roof of the mouth) and an increased overbite (deep overbite), which can cause oral problems and may affect appearance.This problem can be corrected by the use of special dental braces (functional appliances) that move the upper front teeth forward and change the growth of the upper or lower jaws, or both. Most types of functional appliances are removable and this treatment approach does not usually require extraction of any permanent teeth. Additional treatment with fixed braces may be necessary to ensure the best result.An alternative approach is to provide space for the correction of the front teeth by moving the molar teeth backwards. This is done by applying a force to the teeth from the back of the head using a head brace (headgear) and transmitting this force to part of a fixed or removable dental brace that is attached to the back teeth. The treatment may be carried out with or without extraction of permanent teeth.If headgear use is not feasible, the back teeth may be held in place by bands connected to a fixed bar placed across the roof of the mouth or in contact with the front of the roof of the mouth. This treatment usually requires two permanent teeth to be taken out from the middle of the upper arch (one on each side). OBJECTIVES: To establish whether orthodontic treatment that does not involve extraction of permanent teeth produces a result that is any different from no orthodontic treatment or orthodontic treatment involving extraction of permanent teeth, in children with a Class II division 2 malocclusion. SEARCH METHODS: Cochrane Oral Health's Information Specialist searched the following electronic databases: Cochrane Oral Health's Trials Register (to 13 November 2017), the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, 2017, Issue 10), MEDLINE Ovid (1946 to 13 November 2017), and Embase Ovid (1980 to 13 November 2017). To identify any unpublished or ongoing trials, the US National Institutes of Health Ongoing Trials Register (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform (apps.who.int/trialsearch) were searched. We also contacted international researchers who were likely to be involved in any Class II division 2 clinical trials. SELECTION CRITERIA: Randomised controlled trials (RCTs) and controlled clinical trials (CCTs) of orthodontic treatments to correct deep bite and retroclined upper front teeth in children. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the search results to find eligible studies, and would have extracted data and assessed the risk of bias from any included trials. We had planned to use random-effects meta-analysis; to express effect estimates as mean differences for continuous outcomes and risk ratios for dichotomous outcomes, with 95% confidence intervals; and to investigate any clinical or methodological heterogeneity. MAIN RESULTS: We did not identify any RCTs or CCTs that assessed the treatment of Class II division 2 malocclusion in children. AUTHORS' CONCLUSIONS: There is no evidence from clinical trials to recommend or discourage any type of orthodontic treatment to correct Class II division 2 malocclusion in children. This situation seems unlikely to change as trials to evaluate the best management of Class II division 2 malocclusion are challenging to design and conduct due to low prevalence, difficulties with recruitment and ethical issues with randomisation.

Deficiency of Invariant Natural Killer T Cells Does Not Protect Against Obesity but Exacerbates Atherosclerosis in Ldlr-/- Mice.

Obesity is a chronic inflammatory state characterized by altered levels of adipose tissue immune cell populations. Natural killer T (NKT) cells are CD1d restricted lymphocyte subsets that recognize lipid antigens whose level decreases in obese adipose tissue. However, studies in mice with deficiency or increased levels of NKT cells have yielded contradictory results, so the exact role of these cells in obesity and adipose tissue inflammation is not yet established. We previously showed that Ldlr-/- mice with excess invariant NKT (iNKT) cells demonstrate significant weight gain, adiposity, metabolic abnormalities, and atherosclerosis. The current study evaluates the effects of NKT cell deficiency on obesity, associated metabolic changes, and atherosclerosis in Jα18-/-Ldlr-/- (lacking iNKT cells) and Cd1d-/-Ldlr-/- (lacking invariant and type II NKT cells) mice, and control mice were fed an obesogenic diet (high fat, sucrose, cholesterol) for 16 weeks. Contrary to expectations, Ja18-/-Ldlr-/- mice gained significantly more weight than Ldlr-/- or Cd1d-/-Ldlr-/- mice, developed hypertriglyceridemia, and had worsened adipose tissue inflammation. All the mice developed insulin resistance and hepatic triglyceride accumulation. Ja18-/-Ldlr-/- mice also had increased atherosclerotic lesion area. Our findings suggest that iNKT cells exacerbates the metabolic, inflammatory, and atherosclerotic features of diet-induced obesity. Further work is required to unravel the paradox of an apparently similar effect of iNKT cell surplus and depletion on obesity.

An interprofessional collaborative practice approach to transform heart failure care: An overview.

Interprofessional collaborative practice (IPCP) approaches to health care are increasingly recognized as necessary to achieve the Triple Aim-improved health of the population, improved patient care experience, and improved affordability of care. This paper introduces and provides an overview of an interprofessional intervention to improve a healthcare team, healthcare system, and patient outcomes for hospitalized patients with heart failure. In this paper, we describe the overall project resulting from a workforce training grant and the proposed series of future papers resulting from the interprofessional intervention. Collectively, these papers will describe the results of a unique IPCP approach on team, system, and patient outcomes as well as describe and compare organizational and leadership traits that affect collaborative practice. Our hope is that the intervention approaches, evaluation results, and lessons learned described in these papers will help further the efforts to spread IPCP approaches to transforming health care.

Diaporthe soft tissue infection in a heart transplant patient.

Infections caused by Diaporthe species are very uncommon. We describe a heart transplant recipient 14 years post transplant who developed a soft tissue fungal infection due to a Diaporthe species that responded well to surgical excision and posaconazole therapy. The Aspergillus galactomannan index was markedly elevated, and returned to normal following treatment. Solid organ transplant patients remain at risk of infection long after transplantation and should be counseled about risk avoidance.

Orthodontic treatment for deep bite and retroclined upper front teeth in children.

BACKGROUND: A Class II division 2 malocclusion is characterised by upper front teeth that are retroclined (tilted toward the roof of the mouth) and an increased overbite (deep overbite), which can cause oral problems and may affect appearance.This problem can be corrected by the use of special dental braces (functional appliances) that move the upper front teeth forward and change the growth of the upper or lower jaws, or both. Most types of functional appliances braces are removeable and this treatment approach does not usually require extraction of any permanent teeth. Additional treatment with fixed braces may be necessary to ensure the best result.An alternative approach is to provide space for the correction of the front teeth by moving the molar teeth backwards. This is done by applying a force to the teeth from the back of the head using a head brace (headgear) and transmitting this force to part of a fixed or removable dental brace that is attached to the back teeth. The treatment may be carried out with or without extraction of permanent teeth.If headgear use is not feasible, the back teeth may be held in place by bands connected to a fixed bar placed across the roof of the mouth or in contact with the front of the roof of the mouth. This treatment usually requires two permanent teeth to be taken out (one on each side). OBJECTIVES: To establish whether orthodontic treatment that does not involve extraction of permanent teeth produces a result that is any different from no orthodontic treatment or orthodontic treatment involving extraction of permanent teeth, in children with a Class II division 2 malocclusion. SEARCH METHODS: Cochrane Oral Health's Information Specialist searched the following electronic databases: Cochrane Oral Health's Trials Register (to 10 January 2017), the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, 2016, Issue 11), MEDLINE Ovid (1946 to 10 January 2017), and Embase Ovid (1980 to 10 January 2017). To identify any unpublished or ongoing trials, the US National Institutes of Health Ongoing Trials Register (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform (apps.who.int/trialsearch) were searched. We also contacted international researchers who were likely to be involved in any Class II division 2 clinical trials. SELECTION CRITERIA: Randomised controlled trials (RCTs) and controlled clinical trials (CCTs) of orthodontic treatments to correct deep bite and retroclined upper front teeth in children. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the search results to find eligible studies, and would have extracted data and assessed the risk of bias from any included trials. We had planned to use random-effects meta-analysis; to express effect estimates as mean differences for continuous outcomes and risk ratios for dichotomous outcomes, with 95% confidence intervals; and to investigate any clinical or methodological heterogeneity. MAIN RESULTS: We did not identify any RCTs or CCTs that assessed the treatment of Class II division 2 malocclusion in children. AUTHORS' CONCLUSIONS: It is not possible to provide any evidence-based guidance to recommend or discourage any type of orthodontic treatment to correct Class II division 2 malocclusion in children. Trials should be conducted to evaluate the best management of Class II division 2 malocclusion.

Genetic associations with valvular calcification and aortic stenosis.

BACKGROUND: Limited information is available regarding genetic contributions to valvular calcification, which is an important precursor of clinical valve disease. METHODS: We determined genomewide associations with the presence of aortic-valve calcification (among 6942 participants) and mitral annular calcification (among 3795 participants), as detected by computed tomographic (CT) scanning; the study population for this analysis included persons of white European ancestry from three cohorts participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (discovery population). Findings were replicated in independent cohorts of persons with either CT-detected valvular calcification or clinical aortic stenosis. RESULTS: One SNP in the lipoprotein(a) (LPA) locus (rs10455872) reached genomewide significance for the presence of aortic-valve calcification (odds ratio per allele, 2.05; P=9.0×10(-10)), a finding that was replicated in additional white European, African-American, and Hispanic-American cohorts (P<0.05 for all comparisons). Genetically determined Lp(a) levels, as predicted by LPA genotype, were also associated with aortic-valve calcification, supporting a causal role for Lp(a). In prospective analyses, LPA genotype was associated with incident aortic stenosis (hazard ratio per allele, 1.68; 95% confidence interval [CI], 1.32 to 2.15) and aortic-valve replacement (hazard ratio, 1.54; 95% CI, 1.05 to 2.27) in a large Swedish cohort; the association with incident aortic stenosis was also replicated in an independent Danish cohort. Two SNPs (rs17659543 and rs13415097) near the proinflammatory gene IL1F9 achieved genomewide significance for mitral annular calcification (P=1.5×10(-8) and P=1.8×10(-8), respectively), but the findings were not replicated consistently. CONCLUSIONS: Genetic variation in the LPA locus, mediated by Lp(a) levels, is associated with aortic-valve calcification across multiple ethnic groups and with incident clinical aortic stenosis. (Funded by the National Heart, Lung, and Blood Institute and others.).