Citations

ABSTRACT Background Implementation of checklists has been shown to be effective in improving patient safety. This study aims to evaluate the effectiveness of implementation of a checklist for daily care processes into clinical practice of pediatric intensive care units (PICUs) with limited resources. Methods Prospective before–after study in eight PICUs from China, Congo, Croatia, Fiji, and India after implementation of a daily checklist into the ICU rounds. Results Seven hundred and thirty-five patients from eight centers were enrolled between 2015 and 2017. Baseline stage had 292 patients and post-implementation 443. The ICU length of stay post-implementation decreased significantly [9.4 (4–15.5) vs. 7.3 (3.4–13.4) days, p = 0.01], with a nominal improvement in the hospital length of stay [15.4 (8.4–25) vs. 12.6 (7.5–24.4) days, p = 0.055]. The hospital mortality and ICU mortality between baseline group and post-implementation group did not show a significant difference, 14.4% vs. 11.3%; p = 0.22 for each. There was a variable impact of checklist implementation on adherence to various processes of care recommendations. A decreased exposure in days was noticed for; mechanical ventilation from 42.6% to 33.8%, p < 0.01; central line from 31.3% to 25.3%, p < 0.01; and urinary catheter from 30.6% to 24.4%, p < 0.01. Although there was an increased utilization of antimicrobials (89.9–93.2%, p < 0.01). Conclusions Checklists for the treatment of acute illness and injury in the PICU setting marginally impacted the outcome and processes of care. The intervention led to increasing adherence with guidelines in multiple ICU processes and led to decreased length of stay.

Abstract Introduction Insomnia is a novel and modifiable risk factor for incident cardiovascular disease (CVD). However, identification of early markers of subclinical CVD in diagnosed insomnia is understudied. Our aim for this ongoing study is to contrast markers of cardiovascular structure and function between people with insomnia and good-sleeping controls. Methods Persons with insomnia (met ICSD-III criteria) and good sleeping controls (<8 Insomnia Severity Index, mean 8-night SOL and WASO<31min) were recruited from the community. Twenty-two adults (21-39y; 55% women) with no history of CVD, diabetes, inflammatory conditions, significant hypertension, or current sleep-disordered breathing (WatchPat200, Itamar Medical) were enrolled and underwent fasting cardiovascular testing. Testing included: Central augmented aortic pressure (AP) and carotid-femoral pulse wave velocity (cfPWV) for vascular stiffness; brachial artery flow mediated dilation (FMD) to assess endothelial function; and 2D echocardiography to assess ejection fraction (EF%), left ventricular global longitudinal strain (LVGLS), left atrial volume index (LAVI), mitral valve E/e’ ratio (E/e’), and lateral e’. ANCOVA models, adjusting for age, comparing persons with insomnia (n=6) to good sleeping controls (n=16) on each cardiovascular measure were conducted. Results AP (range:-5,10mmHg), cfPWV (range: 4.8-7.6m/s), EF% (range:55.0-72.0%), LVGLS (range:-26,-19%) LAVI (range:14.1-26.7mL/m2), E/e’ (range:3.2-7.8), and lateral e’ (range:0.09-0.22cm/sec) were all within normal ranges according to age and sex normative standards. Mean FMD was 8.8% (SD=4.3, range:4.3-19.8%). Age adjusted ANCOVA models indicated that the insomnia group had significantly worse cardiovascular function than good sleeping controls on cfPWV (M=6.8±0.3 vs. M=5.7±0.2; p=0.004), EF% (M=60.0±1.7 vs. M=65.2±1.0; p=0.017), LVGLS (M=-21.6±0.6 vs. M=-24.3±0.4; p=0.001), and lateral e’ (M=0.12±0.01 vs. M=0.18±0.01; p=0.003). No group differences were found for AP, FMD, LAVI, and E/e’. Conclusion Among relatively healthy young adults, people with insomnia had greater arterial stiffness and worse left ventricular systolic and diastolic functioning. Support American Academy of Sleep Medicine Foundation Focused Projects Award for Junior Investigators 179-FP-18

Background Adolescent idiopathic scoliosis (AIS) is a genetically heterogeneous disease characterised by three-dimensional deformity of the spine in the absence of a congenital spinal anomaly or neurological musculoskeletal disorder. The clinical variability and incomplete penetrance of some genes linked with AIS indicate that this disease constitutes an oligogenic trait. Objective We aimed to explore the oligogenic nature of this disease and identify novel AIS genes. Methods We analysed rare damaging variants within AIS-associated genes by using exome sequencing in 40 AIS trios and 183 sporadic patients. Results Multiple variants within AIS-associated genes were identified in eight AIS trios, and five individuals harboured rare damaging variants in the FLNB gene. The patients showed more frequent oligogenicity than the controls. In the gene-based burden test, the top signal resided in FLNB . In functional studies, we found that the AIS-associated FLNB variants altered the protein’s conformation and subcellular localisation and its interaction with other proteins (TTC26 and OFD1) involved in AIS. The most compelling evidence of an oligogenic basis was that the number of rare damaging variants was recognised as an independent prognostic factor for curve progression in Cox regression analysis. Conclusion Our data indicate that AIS is an oligogenic disease and identify FLNB as a susceptibility gene for AIS.

Abstract Background Hypothyroidism is known to be associated with adverse clinical outcomes in heart failure. The association between hypothyroidism and cardiac resynchronization therapy outcomes in patients with severe heart failure is not clear. Methods The study included 1,316 patients who received cardiac resynchronization therapy between 2002 and 2015. Baseline demographics and cardiac resynchronization therapy outcomes, including left ventricular ejection fraction, New York Heart Association class, appropriate implantable cardioverter-defibrillator therapy, and all-cause mortality, were collected from the electronic health record. Results Of the study cohort, 349 patients (26.5%) were classified as the hypothyroidism group. The median duration of follow-up was 3.6 years (interquartile range, 1.7-6.2). Hypothyroidism was associated with a greater all-cause mortality than euthyroidism (hazard ratio, 1.19; 95% CI, 1.01-1.38; P=0.04). In this group, the risk of appropriate implantable cardioverter-defibrillator therapy significantly increased in association with increased baseline thyroid-stimulating hormone level (hazard ratio, 1.27 per 5 mIU/L increase, 95% CI, 1.00-1.53, P=0.04). Conclusions Cardiac resynchronization therapy improves cardiac function in hypothyroid patients. Hypothyroidism has adverse effects on cardiac resynchronization therapy outcomes with reduced survival and increased implantable cardioverter-defibrillator therapies for ventricular arrhythmic events.

Restless legs syndrome (RLS) is a common sleep‐related movement disorder characterised by an uncomfortable urge to move the legs that occurs during periods of inactivity. Although there have been many case reports on antipsychotic‐induced RLS, ziprasidone has never been reported as a cause of RLS. We present a case of a female patient with schizophrenia who presented with symptoms of RLS following the administration of high doses of ziprasidone added to quetiapine and valproate. The patient’s symptoms of RLS occurred following the administration and titration of ziprasidone to 160 mg, and were relieved upon reducing the dose to 120 mg/day. Other potential causative medications and differential diagnoses that could have caused similar symptoms were excluded. Clinicians should be aware of the potential for ziprasidone‐induced RLS. Dopamine and serotonin interaction could be the mechanism underlying ziprasidone‐induced RLS.

AbstractBackgroundThe 2018 Lipids in Parenteral Nutrition summit involved a panel of experts in clinical nutrition, lipid metabolism, and pharmacology, to assess the current state of knowledge and develop expert consensus statements regarding the use of intravenous lipid emulsions in various patient populations and clinical settings. The main purpose of the consensus statements is to assist healthcare professionals by providing practical guidance on common clinical questions related to the provision of lipid emulsions as part of parenteral nutrition (PN).MethodsThe summit was designed to allow interactive discussion and consensus development. The resulting consensus statements represent the collective opinion of the members of the expert panel, which was informed and supported by scientific evidence and clinical experience.ResultsThe current article summarizes the key discussion topics from the summit and provides a set of consensus statements designed to complement existing evidence‐based guidelines. Lipid emulsions are a major component of PN, serving as a condensed source of energy and essential fatty acids. In addition, lipids modulate a variety of biologic functions, including inflammatory and immune responses, coagulation, and cell signaling. A growing body of evidence suggests that lipid emulsions containing ω‐3 fatty acids from fish oil confer important clinical benefits via suppression of inflammatory mediators and activation of pathways involved in the resolution of inflammation.ConclusionsThis article provides a set of expert consensus statements to complement formal PN guideline recommendations.

Two lysine acyltransferases govern histone H3 propionylation at lysine 23 in normal and pathological conditions.

Abstract Background: In early stage, ERα-positive breast cancer, the concurrent use of endocrine therapy and chemotherapy has not been shown to be superior to sequential use. We hypothesized that genetic biomarkers can aid in selecting patients who would benefit from chemo-endocrine therapy. Our previous genome-wide association study (GWAS) and functional studies revealed that a single nucleotide polymorphism (SNP) in ZNF423, rs9940645, determines tamoxifen response. Specifically, 4-hydroxytamoxifen (4-OH-TAM) increases the gene expression of ZNF423, a transcription factor for BRCA1, in cells that are carry the rs9940645 variant, but not the wildtype, genotype. In this study, we set out to identify additional genes regulated by ZNF423, which, upon identifying a relationship between ZNF423 and cell cycle genes, led us to investigate taxane response in a SNP- and tamoxifen-dependent fashion. Method: Gene correlation analysis using The Cancer Genome Atlas (TCGA) breast cancer dataset was used to identify genes with expression correlated with that of ZNF423. Quantitative reverse transcription PCR, chromatin immunoprecipitation, and luciferase reporter assays were used to validate the gene associations. To test ZNF423 rs9940645-specific phenotypes, we used ZR75-1 cells, which are homozygous for the variant SNP, and ZR75-1 cells that were generated to be homozygous wild type (WT) using CRISPR-Cas9 technology, in addition to Hs578T breast cells with ERα overexpression (WT) and HCC1500 cells (variant). Cell cycle was assessed by propidium iodide staining. Cytotoxicity was assessed using a colorimetric assay. Results: Mitosis-related genes VRK1 and PBK, which encode histone H3 kinases, were experimentally validated to be regulated by ZNF423. Specifically, ZNF423 knockdown resulted in decreased VRK1 and PBK expression and activity. Additionally, ZNF423 knockdown resulted in enhanced docetaxel-induced G2/M arrest and cytotoxicity which could be rescued by VRK1 or PBK overexpression. Lastly, breast cancer cells carrying the rs9940645 variant SNP genotype had increased G2-M arrest and decreased cell viability when treated with docetaxel in combination with estradiol and 4-OH-TAM. Conclusion: We identified ZNF423regulated genes involved in the G2/M phase of the cell cycle. We found that 4-OH-TAM sensitized ERα-positive breast cancer cells to docetaxel treatment in a ZNF423 SNP-dependent manner. Our findings suggest that patients with rs9940645 variant genotype may benefit from concurrent tamoxifen endocrine therapy and docetaxel chemotherapy. This would impact a substantial proportion of patients given the minor allele frequency of 0.47 for this SNP. Citation Format: Gen Wang, Sisi QIN, Jacqueline Zayas, James N. Ingle, Mohan Liu, Richard Weinshilboum, Kunwei Shen, Liewei Wang. 4-Hydroxytamoxifen enhances sensitivity of estrogen receptor α-positive breast cancer to docetaxel in an estrogen and ZNF423 SNP-dependent fashion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2940.