Staff awareness and bundling reduce skin breaks and blood tests in neonatal intensive care.

AIM: Skin breaks (SBs) for procedures and blood sampling are common in neonatal intensive care units (NICU), contributing to pain, infection risk and anaemia. We aimed to document their prevalence, identify areas for improvement and, through staff awareness, reduce their frequency. METHODS: Quality improvement project via prospective audit at a tertiary-level NICU in Australia was conducted. All infants admitted to the NICU for >24 h during two audit periods were included in the study. A specifically designed bedside audit tool was used to prospectively document all SB and blood tests performed on infants during a 4-week audit period (audit 1). Results were reviewed to identify areas for improvement, and disseminated to staff at unit meetings, shift handover and email. Following education and awareness, the audit was repeated (audit 2), and data were compared. Frequency of SB and blood tests performed was measured. Data were tested for normality and analysed using parametric or non-parametric tests where appropriate. RESULTS: There were 52 NICU admissions during each audit period (104 total), with 34 (65%) and 31 (60%) having audit sheets completed, respectively. Median (interquartile range) gestational age and mean (standard deviation) birthweight were 29 (26.3-35) weeks and 1836 (1185) g for audit 1, 30 (28.5-31.5) weeks and 1523 (913) g for audit 2. The reduction in total blood tests (mean) was 36.3%, skin breaks per admitted baby day reduced by 60% and total blood volume sampled (mean) by 37.7%. CONCLUSIONS: A quality improvement project by prospective audit and staff education was associated with reductions in frequency of skin breaks and blood tests in the NICU.

Inhibition of Endothelial Notch Signaling Impairs Fatty Acid Transport and Leads to Metabolic and Vascular Remodeling of the Adult Heart.

BACKGROUND: Nutrients are transported through endothelial cells before being metabolized in muscle cells. However, little is known about the regulation of endothelial transport processes. Notch signaling is a critical regulator of metabolism and angiogenesis during development. Here, we studied how genetic and pharmacological manipulation of endothelial Notch signaling in adult mice affects endothelial fatty acid transport, cardiac angiogenesis, and heart function. METHODS: Endothelial-specific Notch inhibition was achieved by conditional genetic inactivation of Rbp-jκ in adult mice to analyze fatty acid metabolism and heart function. Wild-type mice were treated with neutralizing antibodies against the Notch ligand Delta-like 4. Fatty acid transport was studied in cultured endothelial cells and transgenic mice. RESULTS: Treatment of wild-type mice with Delta-like 4 neutralizing antibodies for 8 weeks impaired fractional shortening and ejection fraction in the majority of mice. Inhibition of Notch signaling specifically in the endothelium of adult mice by genetic ablation of Rbp-jκ caused heart hypertrophy and failure. Impaired heart function was preceded by alterations in fatty acid metabolism and an increase in cardiac blood vessel density. Endothelial Notch signaling controlled the expression of endothelial lipase, Angptl4, CD36, and Fabp4, which are all needed for fatty acid transport across the vessel wall. In endothelial-specific Rbp-jκ-mutant mice, lipase activity and transendothelial transport of long-chain fatty acids to muscle cells were impaired. In turn, lipids accumulated in the plasma and liver. The attenuated supply of cardiomyocytes with long-chain fatty acids was accompanied by higher glucose uptake, increased concentration of glycolysis intermediates, and mTOR-S6K signaling. Treatment with the mTOR inhibitor rapamycin or displacing glucose as cardiac substrate by feeding a ketogenic diet prolonged the survival of endothelial-specific Rbp-jκ-deficient mice. CONCLUSIONS: This study identifies Notch signaling as a novel regulator of fatty acid transport across the endothelium and as an essential repressor of angiogenesis in the adult heart. The data imply that the endothelium controls cardiomyocyte metabolism and function.

Identification of new risk factors for rolandic epilepsy: CNV at Xp22.31 and alterations at cholinergic synapses.

BACKGROUND: Rolandic epilepsy (RE) is the most common genetic childhood epilepsy, consisting of focal, nocturnal seizures and frequent neurodevelopmental impairments in speech, language, literacy and attention. A complex genetic aetiology is presumed in most, with monogenic mutations in GRIN2A accounting for >5% of cases. OBJECTIVE: To identify rare, causal CNV in patients with RE. METHODS: We used high-density SNP arrays to analyse the presence of rare CNVs in 186 patients with RE from the UK, the USA, Sardinia, Argentina and Kerala, India. RESULTS: We identified 84 patients with one or more rare CNVs, and, within this group, 14 (7.5%) with recurrent risk factor CNVs and 15 (8.0%) with likely pathogenic CNVs. Nine patients carried recurrent hotspot CNVs including at 16p13.11 and 1p36, with the most striking finding that four individuals (three from Sardinia) carried a duplication, and one a deletion, at Xp22.31. Five patients with RE carried a rare CNV that disrupted genes associated with other epilepsies (KCTD7, ARHGEF15, CACNA2D1, GRIN2A and ARHGEF4), and 17 cases carried CNVs that disrupted genes associated with other neurological conditions or that are involved in neuronal signalling/development. Network analysis of disrupted genes with high brain expression identified significant enrichment in pathways of the cholinergic synapse, guanine-exchange factor activation and the mammalian target of rapamycin. CONCLUSION: Our results provide a CNV profile of an ethnically diverse cohort of patients with RE, uncovering new areas of research focus, and emphasise the importance of studying non-western European populations in oligogenic disorders to uncover a full picture of risk variation.

A quality improvement initiative to reduce central line infection in neonates using checklists.

Central line associated blood stream infections (CLABSI) are the most common complication of central catheters in neonates. These infections increase length of hospital stay, hospital costs and impact on mortality and morbidities. We performed a quasi-experimental study, over 24 months, utilising a pre-post design to determine the impact checklists had on central line infections. We introduced checklists for insertion, daily maintenance and procedural access based on the existing clinical guideline. Infections and compliance were monitored and reported back to the unit each month. We utilised the interrupted time series analysis to evaluate the impact of introduction of the checklists. Over the 24 months, 318 infants were included with a total of 509 central lines inserted. In the post intervention phase, definite CLABSI rates declined by 41%, from 13.8 definite CLABSIs per 1000 central-line days to 7.8 definite CLABSIs per 1000 central-line days. There was significant change in the mean levels in the post intervention phase (coefficient crude -0.01015; 95% CI -0.01980-0.00051, p value 0.039). Checklist compliance for insertion was 70%, and daily maintenance compliance overall mean was 66%. CONCLUSION: Our quality improvement initiative using checklists, supported with education and feedback, significantly reduced CLABSI in our neonatal unit. What is Known: • Central line associated blood stream infection (CLABSI) continue to cause mortality and morbidity in the neonatal population. • Bundles of intervention use quality improvement methodology to reduce CLABSI and checklists can assist with the introduction of these. What is New: • Checklists assist with reducing central line infection. • To ensure the success of checklists, robust education, leadership and continuous feedback are vital.

Skin antisepsis for reducing central venous catheter-related infections.

BACKGROUND: The central venous catheter (CVC) is a device used for many functions, including monitoring haemodynamic indicators and administering intravenous medications, fluids, blood products and parenteral nutrition. However, as a foreign object, it is susceptible to colonisation by micro-organisms, which may lead to catheter-related blood stream infection (BSI) and in turn, increased mortality, morbidities and health care costs. OBJECTIVES: To assess the effects of skin antisepsis as part of CVC care for reducing catheter-related BSIs, catheter colonisation, and patient mortality and morbidities. SEARCH METHODS: In May 2016 we searched: The Cochrane Wounds Specialised Register; The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library); Ovid MEDLINE (including In-Process & Other Non-Indexed Citations and Epub Ahead of Print); Ovid EMBASE and EBSCO CINAHL Plus. We also searched clinical trial registries for ongoing and unpublished studies. There were no restrictions with respect to language, date of publication or study setting. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that assessed any type of skin antiseptic agent used either alone or in combination, compared with one or more other skin antiseptic agent(s), placebo or no skin antisepsis in patients with a CVC in place. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the studies for their eligibility, extracted data and assessed risk of bias. We expressed our results in terms of risk ratio (RR), absolute risk reduction (ARR) and number need to treat for an additional beneficial outcome (NNTB) for dichotomous data, and mean difference (MD) for continuous data, with 95% confidence intervals (CIs). MAIN RESULTS: Thirteen studies were eligible for inclusion, but only 12 studies contributed data, with a total of 3446 CVCs assessed. The total number of participants enrolled was unclear as some studies did not provide such information. The participants were mainly adults admitted to intensive care units, haematology oncology units or general wards. Most studies assessed skin antisepsis prior to insertion and regularly thereafter during the in-dwelling period of the CVC, ranging from every 24 h to every 72 h. The methodological quality of the included studies was mixed due to wide variation in their risk of bias. Most trials did not adequately blind the participants or personnel, and four of the 12 studies had a high risk of bias for incomplete outcome data.Three studies compared different antisepsis regimens with no antisepsis. There was no clear evidence of a difference in all outcomes examined, including catheter-related BSI, septicaemia, catheter colonisation and number of patients who required systemic antibiotics for any of the three comparisons involving three different antisepsis regimens (aqueous povidone-iodine, aqueous chlorhexidine and alcohol compared with no skin antisepsis). However, there were great uncertainties in all estimates due to underpowered analyses and the overall very low quality of evidence presented.There were multiple head-to-head comparisons between different skin antiseptic agents, with different combinations of active substance and base solutions. The most frequent comparison was chlorhexidine solution versus povidone-iodine solution (any base). There was very low quality evidence (downgraded for risk of bias and imprecision) that chlorhexidine may reduce catheter-related BSI compared with povidone-iodine (RR of 0.64, 95% CI 0.41 to 0.99; ARR 2.30%, 95% CI 0.06 to 3.70%). This evidence came from four studies involving 1436 catheters. None of the individual subgroup comparisons of aqueous chlorhexidine versus aqueous povidone-iodine, alcoholic chlorhexidine versus aqueous povidone-iodine and alcoholic chlorhexidine versus alcoholic povidone-iodine showed clear differences for catheter-related BSI or mortality (and were generally underpowered). Mortality was only reported in a single study.There was very low quality evidence that skin antisepsis with chlorhexidine may also reduce catheter colonisation relative to povidone-iodine (RR of 0.68, 95% CI 0.56 to 0.84; ARR 8%, 95% CI 3% to 12%; ; five studies, 1533 catheters, downgraded for risk of bias, indirectness and inconsistency).Evaluations of other skin antiseptic agents were generally in single, small studies, many of which did not report the primary outcome of catheter-related BSI. Trials also poorly reported other outcomes, such as skin infections and adverse events. AUTHORS' CONCLUSIONS: It is not clear whether cleaning the skin around CVC insertion sites with antiseptic reduces catheter related blood stream infection compared with no skin cleansing. Skin cleansing with chlorhexidine solution may reduce rates of CRBSI and catheter colonisation compared with cleaning with povidone iodine. These results are based on very low quality evidence, which means the true effects may be very different. Moreover these results may be influenced by the nature of the antiseptic solution (i.e. aqueous or alcohol-based). Further RCTs are needed to assess the effectiveness and safety of different skin antisepsis regimens in CVC care; these should measure and report critical clinical outcomes such as sepsis, catheter-related BSI and mortality.

Antimicrobial dressings for the prevention of catheter-related infections in newborn infants with central venous catheters.

BACKGROUND: Central venous catheters (CVCs) provide secured venous access in neonates. Antimicrobial dressings applied over the CVC sites have been proposed to reduce catheter-related blood stream infection (CRBSI) by decreasing colonisation. However, there may be concerns on the local and systemic adverse effects of these dressings in neonates. OBJECTIVES: We assessed the effectiveness and safety of antimicrobial (antiseptic or antibiotic) dressings in reducing CVC-related infections in newborn infants. Had there been relevant data, we would have evaluated the effects of antimicrobial dressings in different subgroups, including infants who received different types of CVCs, infants who required CVC for different durations, infants with CVCs with and without other antimicrobial modifications, and infants who received an antimicrobial dressing with and without a clearly defined co-intervention. SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review Group (CNRG). We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library 2015, Issue 9), MEDLINE (PubMed), EMBASE (EBCHOST), CINAHL and references cited in our short-listed articles using keywords and MeSH headings, up to September 2015. SELECTION CRITERIA: We included randomised controlled trials that compared an antimicrobial CVC dressing against no dressing or another dressing in newborn infants. DATA COLLECTION AND ANALYSIS: We extracted data using the standard methods of the CNRG. Two review authors independently assessed the eligibility and risk of bias of the retrieved records. We expressed our results using risk difference (RD) and risk ratio (RR) with 95% confidence intervals (CIs). MAIN RESULTS: Out of 173 articles screened, three studies were included. There were two comparisons: chlorhexidine dressing following alcohol cleansing versus polyurethane dressing following povidone-iodine cleansing (one study); and silver-alginate patch versus control (two studies). A total of 855 infants from level III neonatal intensive care units (NICUs) were evaluated, 705 of whom were from a single study. All studies were at high risk of bias for blinding of care personnel or unclear risk of bias for blinding of outcome assessors. There was moderate-quality evidence for all major outcomes.The single study comparing chlorhexidine dressing/alcohol cleansing against polyurethane dressing/povidone-iodine cleansing showed no significant difference in the risk of CRBSI (RR 1.18, 95% CI 0.53 to 2.65; RD 0.01, 95% CI -0.02 to 0.03; 655 infants, moderate-quality evidence) and sepsis without a source (RR 1.06, 95% CI 0.75 to 1.52; RD 0.01, 95% CI -0.04 to 0.06; 705 infants, moderate-quality evidence). There was a significant reduction in the risk of catheter colonisation favouring chlorhexidine dressing/alcohol cleansing group (RR 0.62, 95% CI 0.45 to 0.86; RD -0.09, 95% CI -0.15 to -0.03; number needed to treat for an additional beneficial outcome (NNTB) 11, 95% CI 7 to 33; 655 infants, moderate-quality evidence). However, infants in the chlorhexidine dressing/alcohol cleansing group were significantly more likely to develop contact dermatitis, with 19 infants in the chlorhexidine dressing/alcohol cleansing group having developed contact dermatitis compared to none in the polyurethane dressing/povidone-iodine cleansing group (RR 43.06, 95% CI 2.61 to 710.44; RD 0.06, 95% CI 0.03 to 0.08; number needed to treat for an additional harmful outcome (NNTH) 17, 95% CI 13 to 33; 705 infants, moderate-quality evidence). The roles of chlorhexidine dressing in the outcomes reported were unclear, as the two assigned groups received different co-interventions in the form of different skin cleansing agents prior to catheter insertion and during each dressing change.In the other comparison, silver-alginate patch versus control, the data for CRBSI were analysed separately in two subgroups as the two included studies reported the outcome using different denominators: one using infants and another using catheters. There were no significant differences between infants who received silver-alginate patch against infants who received standard line dressing in CRBSI, whether expressed as the number of infants (RR 0.50, 95% CI 0.14 to 1.78; RD -0.12, 95% CI -0.33 to 0.09; 1 study, 50 participants, moderate-quality evidence) or as the number of catheters (RR 0.72, 95% CI 0.27 to 1.89; RD -0.05, 95% CI -0.20 to 0.10; 1 study, 118 participants, moderate-quality evidence). There was also no significant difference between the two groups in mortality (RR 0.55, 95% CI 0.15 to 2.05; RD -0.04, 95% CI -0.13 to 0.05; two studies, 150 infants, I² = 0%, moderate-quality evidence). No adverse skin reaction was recorded in either group. AUTHORS' CONCLUSIONS: Based on moderate-quality evidence, chlorhexidine dressing/alcohol skin cleansing reduced catheter colonisation, but made no significant difference in major outcomes like sepsis and CRBSI compared to polyurethane dressing/povidone-iodine cleansing. Chlorhexidine dressing/alcohol cleansing posed a substantial risk of contact dermatitis in preterm infants, although it was unclear whether this was contributed mainly by the dressing material or the cleansing agent. While silver-alginate patch appeared safe, evidence is still insufficient for a recommendation in practice. Future research that evaluates antimicrobial dressing should ensure blinding of caregivers and outcome assessors and ensure that all participants receive the same co-interventions, such as the skin cleansing agent. Major outcomes like sepsis, CRBSI and mortality should be assessed in infants of different gestation and birth weight.

Risk factors for reading disability in families with rolandic epilepsy.

OBJECTIVE: The high prevalence and impact of neurodevelopmental comorbidities in childhood epilepsy are now well known, as are the increased risks and familial aggregation of reading disability (RD) and speech sound disorder (SSD) in rolandic epilepsy (RE). The risk factors for RD in the general population include male sex, SSD, and ADHD, but it is not known if these are the same in RE or whether there is a contributory role of seizure and treatment-related variables. METHODS: An observational study of 108 probands with RE (age range: 3.6-22 years) and their 159 siblings (age range: 1-29 years; 83 with EEG data) were singly ascertained in the US or UK through a proband affected by RE. We used a nested case-control design, multiple logistic regression, and generalized estimating equations to test the hypothesis of an association between RD and seizure variables or antiepileptic drug treatment in RE; we also assessed an association between EEG focal sharp waves and RD in siblings. RESULTS: Reading disability was reported in 42% of probands and 22% of siblings. Among probands, RD was strongly associated with a history of SSD (OR: 9.64, 95% CI: 2.45-37.21), ADHD symptoms (OR: 10.31, 95% CI: 2.15-49.44), and male sex (OR: 3.62, 95% CI: 1.11-11.75) but not with seizure or treatment variables. Among siblings, RD was independently associated only with SSD (OR: 4.30, 95% CI: 1.42-13.0) and not with the presence of interictal EEG focal sharp waves. SIGNIFICANCE: The principal risk factors for RD in RE are SSD, ADHD, and male sex, the same risk factors as for RD without epilepsy. Seizure or treatment variables do not appear to be important risk factors for RD in probands with RE, and there was no evidence to support interictal EEG focal sharp waves as a risk factor for RD in siblings. Future studies should focus on the precise neuropsychological characterization of RD in families with RE and on the effectiveness of standard oral-language and reading interventions.

Antibiotic lock for the prevention of catheter-related infection in neonates.

BACKGROUND: Use of a central venous catheter (CVC) in neonates is associated with an increase in nosocomial infection. Numerous strategies exist to prevent catheter-related bloodstream infection (CRBSI); however, CRBSI continues to be a major problem. Antibiotic locking catheters is a new and promising treatment that potentially prevents this severe condition. OBJECTIVES: To assess the effectiveness of antibiotic lock versus no antibiotic lock or alternative antibiotic lock in the prevention of catheter-related infections in newborn infants of any gestational age during their initial stay in the neonatal unit and to study any relevant adverse effects from antibiotic lock therapy. SEARCH METHODS: Methods followed those of the Cochrane Neonatal Review Group (CNRG). We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library 2014, Issue 5); MEDLINE (via PubMed); EMBASE (hosted by EBCHOST); CINAHL; abstracts from Pediatric Academic Societies, European Society for Paediatric Research and trials registries; and references cited in our short listed articles using keywords and MeSH headings, up to April 2015. SELECTION CRITERIA: We considered all trials utilising random or quasi-random participant allocation. Participants included all newborn infants of any postmenstrual age who required any type of CVC. We compared an antibiotic lock technique with no antibiotic lock or placebo, such as heparinised saline, for any duration of time. DATA COLLECTION AND ANALYSIS: We extracted data using the standard methods of the CNRG. Two review authors independently assessed the relevance and risk of bias of the retrieved records. We expressed our dichotomous results using risk ratio (RR) with their 95% confidence intervals (CIs). We assessed for heterogeneity using the I(2) statistic. MAIN RESULTS: We included three trials (271 infants) in this review. Two of the three included studies had an overall low risk of bias and the remaining study had high risk of selection and performance biases. The use of an antibiotic lock decreased the incidence of confirmed catheter-related infection (typical RR 0.15, 95% CI 0.06 to 0.40; 3 studies, 271 infants) (high-quality evidence). The typical absolute risk reduction (ARR) was 18.5% and the number needed to treat for an additional beneficial outcome (NNTB) was 5. The effect of use of an antibiotic lock on suspected catheter infection was imprecise (typical RR 0.65, 95% CI 0.22 to 1.92) (moderate quality evidence). Confirmed and suspect infection rates combined were lower in the antibiotic lock group (absolute rates, RR 0.25, 95% CI 0.12 to 0.49; rate per 1000 catheter days, RR 0.17, 95% CI 0.07 to 0.40). The ARR was 20.5% and the NNTB was 5. None of the studies report resistance to the antibiotic used during the lock treatment. There was no significant difference in the detectable serum levels of antibiotic. When the data from two studies were pooled, there were significantly fewer episodes of hypoglycaemia in the treatment arm (typical RR 0.51, 95% CI 0.28 to 0.92). There was no statistically significant difference for mortality due to sepsis between the control and intervention group. AUTHORS' CONCLUSIONS: Based on a small number of trials and neonates, antibiotic lock solution appeared to be effective in preventing CRBSI in the neonatal population. However, as each included study used a different antibiotics and antibiotic resistance could not be reliably assessed, the evidence to-date is insufficient to determine the effects of antibiotic lock on infections in neonates.

A survey of central venous catheter practices in Australian and New Zealand tertiary neonatal units.

BACKGROUND: Infection is the most common problem with central venous catheters (CVCs) in neonates. There are two published guidelines, including the Centers for Disease Control and Prevention (CDC), for the prevention of intravascular catheter-related infection that describes evidence-based practice to reduce nosocomial infection. OBJECTIVE: Our aims were to survey current medical and nursing management of central venous catheters in tertiary neonatal intensive care units in Australia and New Zealand and to compare with the CDC evidence-based practice guideline. METHODS: A cross sectional survey was performed across 27 Australian and New Zealand neonatal units in September 2012. Two web-based questionnaires were distributed, one to medical directors related to the insertion of CVCs while CVC "maintenance" surveys were sent to nurse unit managers. RESULTS: Seventy percent (19/27) medical management and 59% (16/27) on nursing management surveys were completed. In all neonatal intensive care units (NICUs) there were guidelines for CVC maintenance and for 18 out of 19 there were guidelines for insertion. In the seven units using femoral lines, three had a guideline on insertion and four for maintenance. CVC insertion was restricted to credentialed staff in 57.9% of neonatal units. Only 26.5% used full maximal sterile barriers for insertion. Skin disinfection practices widely varied. Dressing use and dressing change regimens were standardised; all using a semi-permeable dressing. Duration of cleaning time of the access point varied significantly; however, the majority used a chlorhexidine with alcohol solution (68.8%). Line and fluid changes varied from daily to 96 h. The majority used sterile gloves and a sterile dressing pack to access the CVC (68.8%). In the majority of NICUs stopcocks were used (62.5%) with a needle-less access point attached (87.5%). In less than 50% of NICUs education was provided on insertion and maintenance. CONCLUSION: There is diversity of current practices and some aspects vary from the CDC guideline. There is a need to review NICU current practices to align with evidence based guidelines. The introduction of a common guideline may reduce variations in practice.

Body composition and functional correlates of CF youth experiencing pulmonary exacerbation and recovery.

BACKGROUND: Youth with cystic fibrosis (CF) and pulmonary exacerbation (PEx) often experience weight loss, then rapid weight gain. Little is known about body composition and its relationship to functional outcomes during this critical period. METHODS: Twenty CF youth experiencing PEx were assessed on the day following admission and 7-17 days later at discharge for body mass index (BMI), fat mass index (FMI), lean mass index (LMI), skeletal muscle mass index (SMMI), and functional measures: percent predicted forced expiratory volume in 1 second (FEV1) (ppFEV1), maximal inspiratory and expiratory pressures (MIPs and MEPs), and handgrip strength (HGS). Changes from admission to discharge and correlations among body composition indices and functional measures at both times are reported. RESULTS: Upon admission, participant BMI percentile and ppFEV1 varied from 2 to 97 and 29 to 113, respectively. Thirteen had an LMI below the 25th percentile and nine had a percent body fat above the 75th percentile. BMI and FMI increased significantly (p = 0.03, 0.003) during hospitalization. LMI and SMMI did not change. FEV1 and MIPS increased (p = 0.0003, 0.007), independent of weight gain, during treatment. HGS did not improve. CONCLUSIONS: Many youth with CF, independent of BMI, frequently carried a small muscle mass and disproportionate fat at the time of PEx. During hospital treatment, weight gain largely represented fat deposition; muscle mass and strength did not improve. A need for trials of interventions designed to augment muscle mass and function, and limit fat mass accretion, at the time of PEx is suggested by these observations.

Endothelial Notch1 signaling in white adipose tissue promotes cancer cachexia.

Cachexia is a major cause of morbidity and mortality in individuals with cancer and is characterized by weight loss due to adipose and muscle tissue wasting. Hallmarks of white adipose tissue (WAT) remodeling, which often precedes weight loss, are impaired lipid storage, inflammation and eventually fibrosis. Tissue wasting occurs in response to tumor-secreted factors. Considering that the continuous endothelium in WAT is the first line of contact with circulating factors, we postulated whether the endothelium itself may orchestrate tissue remodeling. Here, we show using human and mouse cancer models that during precachexia, tumors overactivate Notch1 signaling in distant WAT endothelium. Sustained endothelial Notch1 signaling induces a WAT wasting phenotype in male mice through excessive retinoic acid production. Pharmacological blockade of retinoic acid signaling was sufficient to inhibit WAT wasting in a mouse cancer cachexia model. This demonstrates that cancer manipulates the endothelium at distant sites to mediate WAT wasting by altering angiocrine signals.

Pseudoachondroplasia and multiple epiphyseal dysplasia: a 7-year comprehensive analysis of the known disease genes identify novel and recurrent mutations and provides an accurate assessment of their relative contribution.

Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED) are relatively common skeletal dysplasias resulting in short-limbed dwarfism, joint pain, and stiffness. PSACH and the largest proportion of autosomal dominant MED (AD-MED) results from mutations in cartilage oligomeric matrix protein (COMP); however, AD-MED is genetically heterogenous and can also result from mutations in matrilin-3 (MATN3) and type IX collagen (COL9A1, COL9A2, and COL9A3). In contrast, autosomal recessive MED (rMED) appears to result exclusively from mutations in sulphate transporter solute carrier family 26 (SLC26A2). The diagnosis of PSACH and MED can be difficult for the nonexpert due to various complications and similarities with other related diseases and often mutation analysis is requested to either confirm or exclude the diagnosis. Since 2003, the European Skeletal Dysplasia Network (ESDN) has used an on-line review system to efficiently diagnose cases referred to the network prior to mutation analysis. In this study, we present the molecular findings in 130 patients referred to ESDN, which includes the identification of novel and recurrent mutations in over 100 patients. Furthermore, this study provides the first indication of the relative contribution of each gene and confirms that they account for the majority of PSACH and MED.

Ketone body oxidation increases cardiac endothelial cell proliferation.

Blood vessel formation is dependent on metabolic adaption in endothelial cells. Glucose and fatty acids are essential substrates for ATP and biomass production; however, the metabolism of other substrates remains poorly understood. Ketone bodies are important nutrients for cardiomyocytes during starvation or consumption of carbohydrate-restrictive diets. This raises the question whether cardiac endothelial cells would not only transport ketone bodies but also consume some of these to achieve their metabolic needs. Here, we report that cardiac endothelial cells are able to oxidize ketone bodies and that this enhances cell proliferation, migration, and vessel sprouting. Mechanistically, this requires succinyl-CoA:3-oxoacid-CoA transferase, a key enzyme of ketone body oxidation. Targeted metabolite profiling revealed that carbon from ketone bodies got incorporated into tricarboxylic acid cycle intermediates as well as other metabolites fueling biomass production. Elevation of ketone body levels by a high-fat, low-carbohydrate ketogenic diet transiently increased endothelial cell proliferation in mouse hearts. Notably, in a mouse model of heart hypertrophy, ketogenic diet prevented blood vessel rarefication. This suggests a potential beneficial role of dietary intervention in heart diseases.

Endothelial RBPJ Is Essential for the Education of Tumor-Associated Macrophages.

Epithelial ovarian cancer (EOC) is one of the most lethal gynecologic cancers worldwide. EOC cells educate tumor-associated macrophages (TAM) through CD44-mediated cholesterol depletion to generate an immunosuppressive tumor microenvironment (TME). In addition, tumor cells frequently activate Notch1 receptors on endothelial cells (EC) to facilitate metastasis. However, further work is required to establish whether the endothelium also influences the education of recruited monocytes. Here, we report that canonical Notch signaling through RBPJ in ECs is an important player in the education of TAMs and EOC progression. Deletion of Rbpj in the endothelium of adult mice reduced infiltration of monocyte-derived macrophages into the TME of EOC and prevented the acquisition of a typical TAM gene signature; this was associated with stronger cytotoxic activity of T cells and decreased tumor burden. Mechanistically, CXCL2 was identified as a novel Notch/RBPJ target gene that regulated the expression of CD44 on monocytes and subsequent cholesterol depletion of TAMs. Bioinformatic analysis of ovarian cancer patient data showed that increased CXCL2 expression is accompanied by higher expression of CD44 and TAM education. Together, these findings indicate that EOC cells induce the tumor endothelium to secrete CXCL2 to establish an immunosuppressive microenvironment. SIGNIFICANCE: Endothelial Notch signaling favors immunosuppression by increasing CXCL2 secretion to stimulate CD44 expression in macrophages, facilitating their education by tumor cells.

Tracheal suctioning without disconnection in intubated ventilated neonates.

BACKGROUND: Assisted mechanical ventilation is a necessity in the neonatal population for a variety of respiratory and surgical conditions. However, there are a number of potential hazards associated with this life saving intervention. New suctioning techniques have been introduced into clinical practice which aim to prevent or reduce these untoward effects. OBJECTIVES: To assess the effects of endotracheal suctioning without disconnection in intubated ventilated neonates. SEARCH METHODS: The review has drawn on the search strategy for the Cochrane Neonatal Review Group. A comprehensive search of Cochrane databases, MEDLINE and CINAHL, and the Society for Pediatric Research abstracts was undertaken by the review authors (July 2011). SELECTION CRITERIA: All trials that utilised random or quasi-random patient allocation and in which suctioning with or without disconnection from the ventilator was compared. DATA COLLECTION AND ANALYSIS: Standard methods of the Cochrane Neonatal Group were used. Each review author separately reviewed trials for eligibility and quality and extracted data; they then compared and resolved differences. Analysis was performed using the fixed-effect model and outcomes were reported using relative risk (RR) for categorical data and mean difference (MD) for outcomes measured on a continuous scale. MAIN RESULTS: Four trials (252 infants) were included in this review. The trials employed a cross-over design in which suctioning with or without disconnection was compared. Suctioning without disconnection resulted in a reduction in episodes of hypoxia (typical RR 0.48, CI 95% 0.31 to 0.74; 3 studies; 241 participants). There were also fewer infants who experienced episodes where the transcutaneous partial pressure of oxygen (TcPO(2)) decreased by > 10% (typical RR 0.39, 95% CI 0.19 to 0.82; 1 study; 11 participants). Suctioning without disconnection resulted in a smaller percentage change in heart rate (weighted mean difference (WMD) 6.77, 95% CI 4.01 to 9.52; 4 studies; 239 participants) and a reduction in the number of infants experiencing a decrease in heart rate by > 10% (typical RR 0.61, CI 0.40 to 0.93; 3 studies; 52 participants).The number of infants having bradycardic episodes was also reduced during closed suctioning (typical RR 0.38, CI 95% 0.15 to 0.92; 3 studies; 241 participants). AUTHORS' CONCLUSIONS: There is some evidence to suggest suctioning without disconnection from the ventilator improves the short term outcomes; however the evidence is not strong enough to recommend this practice as the only method of endotracheal suctioning. Future research utilising larger trials needs to address the implications of the different techniques on ventilator associated pneumonia, pulmonary morbidities and neurodevelopment. Infants less than 28 weeks also need to be included in the trials.

Type IX collagen gene mutations can result in multiple epiphyseal dysplasia that is associated with osteochondritis dissecans and a mild myopathy.

Multiple epiphyseal dysplasia (MED) is a clinically variable and genetically heterogeneous disease that is characterized by mild short stature and early onset osteoarthritis. Autosomal dominant forms are caused by mutations in the genes that encode type IX collagen, cartilage oligomeric matrix protein, and matrilin-3: COL9A1, COL9A2, COL9A3, COMP, and MATN3, respectively. Splicing mutations have been identified in all three genes encoding type IX collagen and are restricted to specific exons encoding an equivalent region of the COL3 domain in all three alpha(IX) chains. MED has been associated with mild myopathy in some families, in particular one family with a COL9A3 mutation and two families with C-terminal COMP mutations. In this study we have identified COL9A2 mutations in two families with MED that also have osteochondritis dissecans and mild myopathy. This study therefore extends the range of gene-mutations that can cause MED-related myopathy. (c) 2010 Wiley-Liss, Inc.

Generation of immune cell containing adipose organoids for in vitro analysis of immune metabolism.

Adipose tissue is an organized endocrine organ with important metabolic and immunological functions and immune cell-adipocyte crosstalk is known to drive various disease pathologies. Suitable 3D adipose tissue organoid models often lack resident immune cell populations and therefore require the addition of immune cells isolated from other organs. We have created the first 3D adipose tissue organoid model which could contain and maintain resident immune cell populations of the stromal vascular fraction (SVF) and proved to be effective in studying adipose tissue biology in a convenient manner. Macrophage and mast cell populations were successfully confirmed within our organoid model and were maintained in culture without the addition of growth factors. We demonstrated the suitability of our model for monitoring the lipidome during adipocyte differentiation in vitro and confirmed that this model reflects the physiological lipidome better than standard 2D cultures. In addition, we applied mass spectrometry-based lipidomics to track lipidomic changes in the lipidome upon dietary and immunomodulatory interventions. We conclude that this model represents a valuable tool for immune-metabolic research.

Endothelial Notch signaling controls insulin transport in muscle.

The role of the endothelium is not just limited to acting as an inert barrier for facilitating blood transport. Endothelial cells (ECs), through expression of a repertoire of angiocrine molecules, regulate metabolic demands in an organ-specific manner. Insulin flux across the endothelium to muscle cells is a rate-limiting process influencing insulin-mediated lowering of blood glucose. Here, we demonstrate that Notch signaling in ECs regulates insulin transport to muscle. Notch signaling activity was higher in ECs isolated from obese mice compared to non-obese. Sustained Notch signaling in ECs lowered insulin sensitivity and increased blood glucose levels. On the contrary, EC-specific inhibition of Notch signaling increased insulin sensitivity and improved glucose tolerance and glucose uptake in muscle in a high-fat diet-induced insulin resistance model. This was associated with increased transcription of Cav1, Cav2, and Cavin1, higher number of caveolae in ECs, and insulin uptake rates, as well as increased microvessel density. These data imply that Notch signaling in the endothelium actively controls insulin sensitivity and glucose homeostasis and may therefore represent a therapeutic target for diabetes.

A nonclonal outbreak of vancomycin-sensitive Enterococcus faecalis bacteremia in a neonatal intensive care unit.

OBJECTIVE: To describe an outbreak of bacteremia caused by vancomycin-sensitive Enterococcus faecalis (VSEfe). DESIGN: An investigation by retrospective case control and molecular typing by whole-genome sequencing (WGS). SETTING: A tertiary-care neonatal unit in Melbourne, Australia. METHODS: Risk factors for 30 consecutive neonates with VSEfe bacteremia from June 2011 to December 2014 were analyzed using a case control study. Controls were neonates matched for gestational age, birth weight, and year of birth. Isolates were typed using WGS, and multilocus sequence typing (MLST) was determined. RESULTS: Bacteremia for case patients occurred at a median time after delivery of 23.5 days (interquartile range, 14.9-35.8). Previous described risk factors for nosocomial bacteremia did not contribute to excess risk for VSEfe. WGS typing results designated 43% ST179 as well as 14 other sequence types, indicating a polyclonal outbreak. A multimodal intervention that included education, insertion checklists, guidelines on maintenance and access of central lines, adjustments to the late onset sepsis antibiotic treatment, and the introduction of diaper bags for disposal of soiled diapers after being handled inside the bed, led to termination of the outbreak. CONCLUSIONS: Typing using WGS identified this outbreak as predominately nonclonal and therefore not due to cross transmission. A multimodal approach was then sought to reduce the incidence of VSEfe bacteremia.