Impact of a dietitian-led very low calorie diet clinic on perioperative risk for patients with obesity awaiting elective, non-bariatric surgery: A retrospective cohort study.

BACKGROUND: Despite a lack of evidence that intentional weight loss reduces the risk of postoperative complications, adults with obesity are commonly asked to lose weight before elective surgery. We hypothesized that patients undertaking dietitian-led preoperative, very low calorie diet treatment could reduce perioperative surgery risks, as per validated risk scoring systems. The purpose of this study was to measure the impact of a dietitian-led preoperative very low calorie diet clinic on the American Society of Anesthesiologists physical status scores and National Surgical Quality Improvement Program Surgical Risk Calculator scores for patients with obesity awaiting non-bariatric elective surgery. METHODS: This retrospective cohort study included patients referred to the preoperative dietitian-led very low calorie diet clinic before elective surgical procedures over a 2-year-9-month period. The dietitian prescribed individualized, very low calorie diet-based treatment. Primary outcomes were changes in the American Society of Anesthesiologists and Surgical Risk Calculator scores from pretreatment until surgery. RESULTS: A total of 141 eligible participants (48 ± 13.4 years, 76% women, body mass index 41.7 ± 6.3 kg/m2) demonstrated clinically significant weight loss (mean 7.1 ± 6.1kg, 5.2% body weight, P < .001). Median treatment duration was 13 weeks (interquartile range 6.2-19.2 weeks). Five participants (3.5%) avoided surgery due to weight loss-related improvements in their condition. American Society of Anesthesiologists scores improved for 16% (n = 22/141) of participants. Overall, the median surgical risk calculator estimated risk of 'serious' and 'any' postoperative complication reduced from 4.8% to 3.9% (P < .001) and 6% to 5.1% (P < .001), respectively. Reduction in all Surgical Risk Calculator scores occurred, including surgical site infection, re-admission, and cardiac events (P < .05). CONCLUSION: The dietitian-led preoperative, very low calorie diet clinic improved American Society of Anesthesiologists and Surgical Risk Calculator scores for non-bariatric elective surgery patients with obesity. Randomized controlled trials comparing this approach with a control group are warranted.

Survey of Australian clinicians' antenatal care and management practices in pregnant women with a history of bariatric surgery.

Background: Pregnancy following bariatric surgery requires tailored care. The current Australian care provision and its alignment with consensus guidelines is unclear. Methods: Antenatal care clinicians were invited to complete a web-based survey assessing multidisciplinary referral, gestational diabetes mellitus (GDM) and micronutrient management practices. Results: Respondents (n = 100) cared for pregnant women with a history of bariatric surgery at least monthly (63%) with most (54%) not using a specific guideline to direct care. GDM screening methods included one-week of home blood glucose monitoring (43%) or the oral glucose tolerance test (42%). Pregnancy multivitamin supplementation changes (59%) with bariatric surgery type were common. Half (54%) screened for micronutrient deficiencies every trimester and conducted additional growth ultrasounds (50%). Conclusion: The care clinicians report providing may not align with current international consensus guidelines. Further studies with increased obstetric clinician response may aid increased understanding of current practices. The development of workplace management guidelines for pregnancy in women with a history of bariatric surgery may assist with providing consistent evidence-based care.

Multi-site evaluation of advanced practice hand therapy clinics for the management of patients with trigger digit.

STUDY DESIGN: Prospective cohort design. BACKGROUND: Patient time on Australian public hospital surgical outpatient department (SOPD) waitlists often exceeds clinical recommendations for chronic hand conditions. Diversion to allied health is an alternative option, however evidence regarding patient and organizational outcomes in hand therapy is lacking. PURPOSE OF THE STUDY: To evaluate clinical and organizational efficacy, patient outcomes and satisfaction of diversion of referrals for patients with trigger digit (TD) from SOPD waitlists to Advanced Practice Hand Therapy (APHT) at 3 Australian hospitals. METHODS: Data was collected from eligible patients with TD through chart reviews and telephone satisfaction surveys. Data included number of patients requiring SOPD review, repeat referral to SOPD in the 12 months following APHT discharge, patient-rated outcomes, satisfaction scores, wait times to SOPD review and conversion to surgery-rates. Mann Whitney-U, t-test, Pearson's chi-squared test and a Binary Logistic Regression analysis were performed. RESULTS: 104 patients completed APHT treatment. Seventy patients (67%) did not require return to the SOPD waitlist. Repeat referral to SOPD within 12 months of APHT discharge occurred for only 1 patient. Patients requiring SOPD review after APHT treatment were seen within target time frames and demonstrated 88% conversion to surgery-rates. Michigan Hand Outcome Questionnaire scores showed greater improvement in those not requiring SOPD review (P< .001~25.9 vs 4.2). Regression analysis identified a negative association between initial total Michigan Hand Outcome Questionnaire scores and unfavorable discharge outcomes (OR 0.96, P= .007). Most (81%-93%) patients indicated satisfaction with the APHT service. CONCLUSION: Diversion of referrals for TD from SOPD to APHT is an effective waitlist management strategy, with the propensity to reduce waiting times, improve patient flow, whilst resulting in favorable clinical and patient-rated outcomes and satisfaction.

Elective Surgery in Adult Patients with Excess Weight: Can Preoperative Dietary Interventions Improve Surgical Outcomes? A Systematic Review.

This systematic review summarises the literature regarding the impact of preoperative dietary interventions on non-bariatric surgery outcomes for patients with excess weight/obesity, a known risk factor for poor surgical outcomes. Four electronic databases were searched for non-bariatric surgery studies that evaluated the surgical outcomes of a preoperative diet that focused on weight/fat loss or improvement of liver steatosis. Meta-analysis was unfeasible due to the extreme heterogeneity of variables. Fourteen studies, including five randomised controlled trials, were selected. Laparoscopic cholecystectomy, hernia repair, and liver resection were most studied. Diet-induced weight loss ranged from 1.4 kg to 25 kg. Preoperative very low calorie diet (≤800 kcal) or low calorie diet (≤900 kcal) for one to three weeks resulted in: reduction in blood loss for two liver resection and one gastrectomy study (-27 to -411 mL, p < 0.05), and for laparoscopic cholecystectomy, reduction of six minutes in operating time (p < 0.05) and reduced difficulty of aspects of procedure (p < 0.05). There was no difference in length of stay (n = 7 studies). Preoperative ≤ 900 kcal diets for one to three weeks could improve surgical outcomes for laparoscopic cholecystectomy, liver resection, and gastrectomy. Multiple randomised controlled trials with common surgical outcomes are required to establish impact on other surgeries.

Investigating antenatal nutrition education preferences in South-East Queensland, including Maori and Pasifika women.

BACKGROUND: Little is reported about the nutrition-related needs and preferences of women seeking maternity services, particularly Maori and Pasifika (M&P) women who have higher chronic disease rates in Queensland. AIM: Nutrition-related knowledge, needs, behaviours and education preferences were compared between women of M&P ancestry and non-Maori and Pasifika women (NMP). METHOD: Women (≥18 years) admitted to the postnatal ward were surveyed. Anthropometry, dietary quality, nutrition education preferences, country of birth and ancestry were collected. Analysis included chi-squared and t-tests. FINDINGS: The survey was completed by 399 eligible women. Country of birth data suggested 4% of respondents were Pasifika and failed to separately identify New Zealand Maori, whereas 18% of respondents (n=73) reported M&P ancestry. Descriptors were similar between groups (28±5 years; 91% any breastfeeding; 18% gestational diabetes mellitus; p>0.05). However M&P women were less often university educated (M&P:6(9%); NMP:71(22%), p<0.01) and more likely had >2 children (M&P: 30(54%); NMP:70(30%), p<0.01). M&P women reported heavier weight at conception (M&P:79.0±20.2kg, 29.2±7.5kg/m2; NMP:71.3±18.9kg, 26.3±6.5kg/m2, p<0.01), and were more likely to report excess gestational weight gain (M&P:30(56%), NMP:96(36%), p<0.05). Most (>75%) women did not know their recommended weight gain. Many respondents reported inadequate intake of vegetables (95%), fruit (29%) and dairy (69%) during pregnancy. Two-fifths (38-41%) reported interest in perinatal nutrition education, with topics including healthy eating postpartum. DISCUSSION: Findings enable targeted service delivery according to women's preferences. CONCLUSION: Collecting ancestral and maternal data to facilitate the provision of appropriate nutrition education may be critical for achieving optimal maternal outcomes in Maori and Pasifika women.

Novel diversity-oriented synthesis-derived respiratory syncytial virus inhibitors identified via a high throughput replicon-based screen.

Respiratory syncytial virus (RSV) infections affect millions of children and adults every year. Despite the significant disease burden, there are currently no safe and effective vaccines or therapeutics. We employed a replicon-based high throughput screen combined with live-virus triaging assays to identify three novel diversity-oriented synthesis-derived scaffolds with activity against RSV. One of these small molecules is shown to target the RSV polymerase (L protein) to inhibit viral replication and transcription; the mechanisms of action of the other small molecules are currently unknown. The compounds described herein may provide attractive inhibitors for lead optimization campaigns.

High-throughput identification of genotype-specific cancer vulnerabilities in mixtures of barcoded tumor cell lines.

Hundreds of genetically characterized cell lines are available for the discovery of genotype-specific cancer vulnerabilities. However, screening large numbers of compounds against large numbers of cell lines is currently impractical, and such experiments are often difficult to control. Here we report a method called PRISM that allows pooled screening of mixtures of cancer cell lines by labeling each cell line with 24-nucleotide barcodes. PRISM revealed the expected patterns of cell killing seen in conventional (unpooled) assays. In a screen of 102 cell lines across 8,400 compounds, PRISM led to the identification of BRD-7880 as a potent and highly specific inhibitor of aurora kinases B and C. Cell line pools also efficiently formed tumors as xenografts, and PRISM recapitulated the expected pattern of erlotinib sensitivity in vivo.

Modulators of hepatic lipoprotein metabolism identified in a search for small-molecule inducers of tribbles pseudokinase 1 expression.

Recent genome wide association studies have linked tribbles pseudokinase 1 (TRIB1) to the risk of coronary artery disease (CAD). Based on the observations that increased expression of TRIB1 reduces secretion of VLDL and is associated with lower plasma levels of LDL cholesterol and triglycerides, higher plasma levels of HDL cholesterol and reduced risk for myocardial infarction, we carried out a high throughput phenotypic screen based on quantitative RT-PCR assay to identify compounds that induce TRIB1 expression in human HepG2 hepatoma cells. In a screen of a collection of diversity-oriented synthesis (DOS)-derived compounds, we identified a series of benzofuran-based compounds that upregulate TRIB1 expression and phenocopy the effects of TRIB1 cDNA overexpression, as they inhibit triglyceride synthesis and apoB secretion in cells. In addition, the compounds downregulate expression of MTTP and APOC3, key components of the lipoprotein assembly pathway. However, CRISPR-Cas9 induced chromosomal disruption of the TRIB1 locus in HepG2 cells, while confirming its regulatory role in lipoprotein metabolism, demonstrated that the effects of benzofurans persist in TRIB1-null cells indicating that TRIB1 is sufficient but not necessary to transmit the effects of the drug. Remarkably, active benzofurans, as well as natural products capable of TRIB1 upregulation, also modulate hepatic cell cholesterol metabolism by elevating the expression of LDLR transcript and LDL receptor protein, while reducing the levels of PCSK9 transcript and secreted PCSK9 protein and stimulating LDL uptake. The effects of benzofurans are not masked by cholesterol depletion and are independent of the SREBP-2 regulatory circuit, indicating that these compounds represent a novel class of chemically tractable small-molecule modulators that shift cellular lipoprotein metabolism in HepG2 cells from lipogenesis to scavenging.

Diversity-oriented synthesis-facilitated medicinal chemistry: toward the development of novel antimalarial agents.

Here, we describe medicinal chemistry that was accelerated by a diversity-oriented synthesis (DOS) pathway, and in vivo studies of our previously reported macrocyclic antimalarial agent that derived from the synthetic pathway. Structure-activity relationships that focused on both appendage and skeletal features yielded a nanomolar inhibitor of P. falciparum asexual blood-stage growth with improved solubility and microsomal stability and reduced hERG binding. The build/couple/pair (B/C/P) synthetic strategy, used in the preparation of the original screening library, facilitated medicinal chemistry optimization of the antimalarial lead.

Informing maternity service development by surveying new mothers about preferences for nutrition education during their pregnancy in an area of social disadvantage.

BACKGROUND: A demonstrated link exists between maternal diet and maternal and infant health outcomes during and after pregnancy. A dietetic maternity service (0.6FTE for 3500 births) was introduced in 2012 at our hospital in a socially-disadvantaged area. We needed to develop evidence-based, patient-oriented improvements to nutrition services within resource limitations. AIM: This cross-sectional study gathered knowledge, eating behaviours, and nutrition-related needs of our women ante- and postnatally to inform this process. METHODS: Women (≥ 18 years) admitted to the postnatal ward completed our survey. Data including dietary quality, nutritional knowledge and interest in nutrition education were collected. Analysis included descriptive, chi-squared and t-tests. FINDINGS: Three hundred and nine eligible women responded (28 ± 6 years, 27 ± 7 kg/m(2) pre-pregnancy body mass index, 12% gestational diabetes). Two-fifths (42%) self-reported gaining excess weight during pregnancy. One quarter reported knowing their gestational weight gain goals, yet only 1.6% was correct. Half reported interest in receiving nutrition education during pregnancy and post-delivery (45%, n=134; 43%, n=123, respectively). Women had poor diet quality (daily serves - fruit: 1.8 ± 1.0; vegetables: 2.0 ± 1.2; dairy: 1.9 ± 1.2), despite identifying healthy eating as a personal priority. Nutrition topics requested included healthy eating for development of baby pre- and post-delivery and maternal weight management. CONCLUSION: Women attending our hospital have dietary issues and levels of interest in nutrition similar to women in tertiary maternity centres. Service changes planned will explore formats that meet higher and lower education levels; group workshops may be supplemented by formats such as internet and DVD-delivered education to overcome access and literacy issues, respectively.

Phenotypic high-throughput screening elucidates target pathway in breast cancer stem cell-like cells.

Cancer stem cells (CSCs) are resistant to standard cancer treatments and are likely responsible for cancer recurrence, but few therapies target this subpopulation. Due to the difficulty in propagating CSCs outside of the tumor environment, previous work identified CSC-like cells by inducing human breast epithelial cells into an epithelial-to-mesenchymal transdifferentiated state (HMLE_sh_ECad). A phenotypic screen was conducted against HMLE_sh_ECad with 300 718 compounds from the Molecular Libraries Small Molecule Repository to identify selective inhibitors of CSC growth. The screen yielded 2244 hits that were evaluated for toxicity and selectivity toward an isogenic control cell line. An acyl hydrazone scaffold emerged as a potent and selective scaffold targeting HMLE_sh_ECad. Fifty-three analogues were acquired and tested; compounds ranged in potency from 790 nM to inactive against HMLE_sh_ECad. Of the analogues, ML239 was best-in-class with an IC(50)= 1.18 µM against HMLE_sh_ECad, demonstrated a >23-fold selectivity over the control line, and was toxic to another CSC-like line, HMLE_shTwist, and a breast carcinoma cell line, MDA-MB-231. Gene expression studies conducted with ML239-treated cells showed altered gene expression in the NF-κB pathway in the HMLE_sh_ECad line but not in the isogenic control line. Future studies will be directed toward the identification of ML239 target(s).

Screening for inhibitors of an essential chromatin remodeler in mouse embryonic stem cells by monitoring transcriptional regulation.

The SWI/SNF-like adenosine triphosphate (ATP)-dependent chromatin remodeling complex, esBAF, is both necessary and, in some contexts, sufficient to induce the pluripotent state. Furthermore, mutations in various BAF subunits are associated with cancer. Little is known regarding the precise mechanism(s) by which this complex exerts its activities. Thus, it is unclear which protein interactions would be important to disrupt to isolate a relevant readout of mechanism. To address this, we developed a gene expression-based assay to identify inhibitors of the native esBAF complex. Specifically, a quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) assay was developed in mouse embryonic stem (ES) cells to monitor expression of Bmi1, a developmentally important gene repressed by the esBAF complex. The assay was miniaturized to a 384-well format and used to screen a diverse collection of compounds, including novel products of diversity-oriented synthesis (DOS). Confirmed hits were validated using a knock-in ES cell reporter line in which luciferase is inserted into the Bmi1 locus. Several of the validated hits regulate a panel of target genes in a manner similar to the BAF chromatin-remodeling complex. Together these data indicate that expression-based screening using qRT-PCR is a successful approach to identify compounds targeting the regulation of key developmental genes in ES cells.

Purchase rates and energy content of nutritionally promoted and traditional fast foods purchased at lunchtime in Australia - a pilot study.

OBJECTIVE: Nutritionally promoted foods are now available at fast-food establishments. Little is known about their popularity, who is purchasing them, or their impact on dietary intake. Our study aimed to determine: how often nutritionally promoted fast foods were purchased; the demographic characteristics of people purchasing these foods; and if purchasing these foods resulted in reduced energy, and increased vegetable, content of lunches compared with those who purchased traditional fast foods. DESIGN: A survey collecting lunchtime fast-food purchases and demographic details was administered over two months. Nutritionally promoted products included the McDonalds' 'Heart Foundation Tick Approved' range and Subway's 'Six grams of fat or less' range. Energy and vegetable contents were estimated using information from fast-food companies' websites. Differences in demographics, energy and vegetable contents between individuals purchasing nutritionally promoted and traditional lunches were assessed using χ2 and t tests. SETTING: Queensland, Australia. SUBJECTS: Lunchtime diners aged over 16 years at Subway and McDonalds. RESULTS: Surveys were collected from 927 respondents (58 % male, median age 25 (range 16-84) years; 73 % response rate). Only 3 % (n 24/910) of respondents who ordered a main option had purchased a nutritionally promoted item. Purchasers of nutritionally promoted foods were ∼13 years older, predominantly female (79 %), and more often reported involvement in a health-related profession (29 % v. 11 %) than purchasers of traditional foods (P < 0·05). Purchasers of nutritionally promoted foods ordered 1·5 fewer megajoules and 0·6 more vegetable servings than purchasers of traditional foods (P < 0·05). CONCLUSIONS: Nutritionally promoted fast foods may reduce lunchtime energy content, however these foods were infrequently chosen.

Hormonal contraceptive practices in young Australian women (≤ 25 years) and their possible impact on menstrual frequency and iron requirements.

OBJECTIVES: To investigate the hormonal contraceptive practices of female university students aged ≤ 25 years, their menstrual bleeding frequency, and interest in contraceptive regimens that reduce menstrual frequency or duration. STUDY DESIGN: A 20-item questionnaire was distributed to female students at Griffith University, Gold Coast campus. This included questions relating to: demographics, menstrual bleeding frequency, current contraceptive practices, and interest in future oral contraceptive regimens that reduce menstrual bleeding frequency and duration. MAIN OUTCOME MEASURES: Determination of hormonal contraceptive practices and menstrual bleeding frequency undertaken by the sample population. RESULTS: Eight hundred and fifty one participants completed the questionnaire, ~ 2/3rds of respondents are currently using a hormonal contraceptive (66% of all respondents), with the oral contraceptive pill (OCP) being most common. Most women (73%) reported monthly menstruation, although 16% indicated that they sometimes missed their monthly period, with bleeding every two months. Of all OCP users, approximately 2/3rds have skipped their monthly period at some time, the most common reasons being for convenience (89%). Approximately 70% of respondents were interested in OCP regimens that reduced frequency or duration of menstruation. CONCLUSION: OCP use is popular amongst Australian university women, with many being interested in the concept of using the OCP to delay menstruation. Given this interest and the availability of hormonal contraceptives that reduce menstrual frequency and duration, assessing the impact of reduced menstrual blood loss on iron stores may be warranted.

Cell-based high-throughput screening assay system for monitoring G protein-coupled receptor activation using beta-galactosidase enzyme complementation technology.

A novel cell-based functional assay to directly monitor G protein-coupled receptor (GPCR) activation in a high-throughput format, based on a common GPCR regulation mechanism, the interaction between beta-arrestin and ligand-activated GPCR, is described. A protein-protein interaction technology, the InteraX trade mark system, uses a pair of inactive beta-galactosidase (beta-gal) deletion mutants as fusion partners to the protein targets of interest. To monitor GPCR activation, stable cell lines expressing both GPCR- and beta-arrestin-beta-gal fusion proteins are generated. Following ligand stimulation, beta-arrestin binds to the activated GPCR, and this interaction drives functional complementation of the beta-gal mutant fragments. GPCR activation is measured directly by quantitating restored beta-gal activity. The authors have validated this assay system with two functionally divergent GPCRs: the beta2-adrenergic amine receptor and the CXCR2 chemokine-binding receptor. Both receptors are activated or blocked with known agonists and antagonists in a dose-dependent manner. The beta2-adrenergic receptor cell line was screened with the LOPAC trade mark compound library to identify both agonists and antagonists, validating this system for high-throughput screening performance in a 96-well microplate format. Hit specificity was confirmed by quantitating the level of cAMP. This assay system has also been performed in a high-density (384-well) microplate format. This system provides a specific, sensitive, and robust methodology for studying and screening GPCR-mediated signaling pathways.