Assessing the Sympatholytic Effects of SGLT2 Inhibitors in Anuric Haemodialysis Patients Using Microneurography: Study Protocol for a Mechanistic Proof-of-Concept Trial.

INTRODUCTION: Sodium-glucose co-transporter 2 inhibitors (SGLT2is) have been shown to provide effective cardiorenal protection, reducing mortality in conditions such as heart failure and chronic kidney disease. While several mechanisms have been identified, recent research has shed light on the drug's ability to attenuate sympathetic nervous system (SNS) activity. Controversy exists on whether this is due to the extra-renal effects of the drug, or simply due to its renoprotective effects. However, recent trials have highlighted the persistent efficacy of SGLT2i despite declining renal function. Therefore, investigating the ability of SGLT2i to attenuate the SNS independently of the kidney could lead to more insight into its mechanism of action. So far, there has been limited research done on investigating the extra-renal effects of SGLT2i in human subjects on dialysis where the glycosuric renal effects of SGLT2i are negligible. This current study therefore aims to investigate the effects of SGLT2i on the SNS in anuric haemodialysis patients. METHODS: We developed a protocol for a mechanistic study to investigate the extra-renal effects of SGLT2i on the SNS. The study will be an investigator-led, open-label, prospective study involving 20 adult (aged ≥18 years) haemodialysis patients with a residual urine output of ≤250 mL/day. Participants will be administered empagliflozin 25 mg/day for 6 weeks. Baseline SNS activity will be measured before and after administration by microneurography to assess central SNS outflow. Secondary outcomes such as changes from baseline in SNS stressor response, heart rate variability, and endothelial function will also be examined. We hypothesize that the use of empagliflozin will result in reduced sympathetic drive in anuric haemodialysis patients. DISCUSSION: This will be the first study evaluating the effects of SGLT2i on the SNS in haemodialysis subjects. This study aims to enhance our understanding of the potential role of SGLT2i-induced SNS reduction in the setting of markedly reduced renal function. The study has received ethics approval from the Royal Perth Hospital Human Research Ethics Committee (RGS0000003840) (Australian New Zealand Clinical Trials Registry [ANZCTR] ID: ACTRN12623001237673).

Demographic and clinical characteristics of patients who recommence clozapine following therapy interruptions.

OBJECTIVE: The proportion of patients who recommence clozapine after cessation, the time taken to resume clozapine post-cessation, and distinguishing demographic and clinical characteristics of this group have been poorly researched. We evaluated these in the current study. METHOD: We retrospectively extracted selected demographic and clinical variables and clozapine treatment interruption and recommencement data up to December 2018 of a cohort of 458 patients who first commenced clozapine between 2006 and 2016. The study was conducted at three Australian health services. RESULTS: Of the 310 (69%) patients who had at least one interruption of clozapine treatment, 170 (54.8%) did not resume clozapine, and 140 (45.2%) recommenced it after the first interruption. More than half of those who recommenced did so within a month and 80% by 12 months. Cox regression analysis revealed that age was significantly associated with recommencement, with a 2% decrease in the likelihood of restarting after an interruption for each year later that clozapine was initially commenced (HR = 0.98 95%CI: 0.97, 0.997, p = 0.02). Those who ceased clozapine due to adverse effects were less likely to restart than those who ceased due to noncompliance (HR = 0.63 95%CI: 0.41, 0.97, p = 0.03). More time on clozapine prior to interruption increased the likelihood of restarting it, with each additional month on clozapine increasing this likelihood by 1% (HR = 1.01 95%CI: 1.01, 1.02, p < 0.001). CONCLUSION: If the distinguishing demographic and clinical characteristics of the group identified in this study are corroborated through further research, this could further validate the need to identify treatment resistance and commence clozapine early in people with schizophrenia and provide appropriate interventions to those more at risk of permanent discontinuation of clozapine.

Multivariable Analysis of Patients With Severe Persistent Postprocedural Hypotension After Carotid Artery Stenting.

Purpose: To assess the incidence and predictors of severe, persistent postprocedural hypotension (PPH) after carotid artery stenting (CAS). Materials and Methods: A total of 146 patients (mean age 72.8 years; 104 men) who underwent 160 CAS procedures using a standardized protocol at 3 vascular centers were retrospectively analyzed. The primary endpoint was postprocedural hypotension, defined as a reduction in systolic blood pressure (SBP) >40 mm Hg from baseline or an SBP of <90 mm Hg sustained for >1 hour after CAS. Potential prognostic factors for postprocedural hypotension were identified and subjected to logistic regression analyses; outcomes are presented as the odds ratios (ORs) with 95% confidence intervals (CIs). Results: PPH developed in 36 (24.7%) patients after 37 (23.1%) CAS procedures. These patients had significantly longer intensive care unit and hospital stays than those who did not develop hypotension (p<0.001). PPH was associated with severe lesion calcification (OR 6.28, 95% CI 1.81 to 21.98, p=0.004) and contrast volume (OR 1.02, 95% CI 1.01 to 1.02, p<0.001). A 4-fold increase in the risk of PPH (OR 4.22, 95% CI 1.38 to 13.33, p=0.012) was found between the embolic protection device most associated with PPH (Angioguard) and the device least associated with PPH (Emboshield NAV6). A similar trend was also observed for the Precise vs Xact stents (OR 6, 95% CI 2.08 to 17.6, p=0.001). Bootstrapped multivariable modeling identified the Precise stent and contrast volume as significant predictors of persistent postprocedural hypotension. Further investigation of the contrast volume revealed associations with sex, severe calcification, arch type, previous coronary artery bypass surgery, and primary stenting, suggesting that the contrast volume reflects the complexity of the procedure. Conclusion: The complexity of the procedure and type of stent may play a role in the development of postprocedural hypotension after CAS.

Patient-Controlled Analgesia and Length of Hospital Stay in Orthognathic Surgery: A Randomized Controlled Trial.

PURPOSE: The objective of this prospective, randomized controlled pilot study of patients undergoing orthognathic surgery was to compare the hospital length of stay (LOS) in patients using intravenous patient-controlled analgesia (PCA) versus patients receiving scheduled and as-needed oral analgesia. PATIENTS AND METHODS: A total of 40 patients (19 male and 21 female patients) aged 16 to 56 years (mean, 20.73 years; standard deviation, 6.87 years) were recruited prospectively and randomized to PCA and non-PCA groups of equal size. Recording of the patient-reported pain score using a visual analog scale was commenced at 8:00 am on day 1 after surgery until discharge. The pain score from routine nursing observations during the postoperative period was recorded until the patient was discharged from the hospital. RESULTS: Randomization resulted in approximately equal proportions of male patients (45% vs 50%) and median ages (18.5 years vs 20 years) for the PCA group versus the non-PCA group; however, the PCA group was noted to have a higher proportion of double-jaw surgery (65% vs 40%). The median LOS was 2 days for both the PCA and non-PCA groups (P = .06). No statistically significant difference in pain scores was found between the 2 groups either at rest (P = .27) or on movement (P = .13). CONCLUSIONS: No evidence was found to indicate the superiority of either the PCA or non-PCA regimen with respect to LOS and pain scores; however, this is not evidence of equivalence of the 2 pain management approaches.

Factorial Effects of Evolocumab and Atorvastatin on Lipoprotein Metabolism.

BACKGROUND: Monoclonal antibodies against proprotein convertase subtilisin kexin type 9 (PCSK9), such as evolocumab, lower plasma low-density lipoprotein (LDL)-cholesterol concentrations. Evolocumab is under investigation for its effects on cardiovascular outcomes in statin-treated, high-risk patients. The mechanism of action of PCSK9 monoclonal antibodies on lipoprotein metabolism remains to be fully evaluated. Stable isotope tracer kinetics can effectively elucidate the mode of action of new lipid-regulating pharmacotherapies. METHODS: We conducted a 2-by-2 factorial trial of the effects of atorvastatin (80 mg daily) and subcutaneous evolocumab (420 mg every 2 weeks) for 8 weeks on the plasma kinetics of very-low-density lipoprotein (VLDL)-apolipoprotein B-100 (apoB), intermediate-density lipoprotein-apoB, and LDL-apoB in 81 healthy, normolipidemic, nonobese men. The kinetics of apoB in these lipoproteins was studied using a stable isotope infusion of D3-leucine, gas chromatography/mass spectrometry, and multicompartmental modeling. RESULTS: Atorvastatin and evolocumab independently accelerated the fractional catabolism of VLDL-apoB (P<0.001 and P.032, respectively), intermediate-density lipoprotein-apoB (P=0.021 and P=.002, respectively), and LDL-apoB (P<0.001, both interventions). Evolocumab but not atorvastatin decreased the production rate of intermediate-density lipoprotein-apoB (P=0.043) and LDL-apoB (P<0.001), which contributed to the reduction in the plasma pool sizes of these lipoprotein particles. The reduction in LDL-apoB and LDL-cholesterol concentrations was significantly greater with combination versus either monotherapy (P<0.001). Whereas evolocumab but not atorvastatin lowered the concentration of free PCSK9, atorvastatin lowered the lathosterol/campesterol ratio (a measure of cholesterol synthesis/absorption) and apoC-III concentration. Both interventions decreased plasma apoE, but neither significantly altered lipoprotein lipase and cholesteryl ester protein mass or measures of insulin resistance. CONCLUSIONS: In healthy, normolipidemic subjects, evolocumab decreased the concentration of atherogenic lipoproteins, particularly LDL, by accelerating their catabolism. Reductions in intermediate-density lipoprotein and LDL production also contributed to the decrease in LDL particle concentration with evolocumab by a mechanism distinct from that of atorvastatin. These kinetic findings provide a metabolic basis for understanding the potential benefits of PCSK9 monoclonal antibodies incremental to statins in on-going clinical end point trials. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02189837.

Anemia in hospitalized patients: an overlooked risk in medical care.

BACKGROUND: This study investigated the association between nadir anemia and mortality and length of stay (LOS) in a general population of hospitalized patients. STUDY DESIGN AND METHODS: A retrospective cohort study of tertiary hospital admissions in Western Australia between July 2010 and June 2015. Outcome measures were in-hospital mortality and LOS. RESULTS: Of 80,765 inpatients, 45,675 (56.55%) had anemia during admission. Mild and moderate/severe anemia were independently associated with increased in-hospital mortality (odds ratio [OR] 1.5, 95% confidence interval [CI] 1.36-1.86, p = 0.001; OR 2.77, 95% CI 2.32-3.30, p < 0.001, respectively). Anemia was also associated with increased LOS, demonstrating a larger effect in emergency (mild anemia-incident rate ratio [IRR] 1.52, 95% CI 1.48-1.56, p < 0.001; moderate/severe anemia-IRR 2.18, 95% CI 2.11-2.26, p < 0.001) compared to elective admissions (mild anemia-IRR 1.30, 95% CI 1.21-1.41, p < 0.001; moderate/severe anemia-IRR 1.69, 95% CI 1.55-1.83, p < 0.001). LOS was longer in patients who developed anemia during admission compared to those who had anemia on admission (IRR 1.13, 95% CI 1.10-1.17, p < 0.001). Red cell transfusion was independently associated with 2.23 times higher odds of in-hospital mortality (95% CI 1.89-2.64, p < 0.001) and 1.31 times longer LOS (95% CI 1.25-1.37, p < 0.001). CONCLUSION: More than one-third of patients not anemic on admission developed anemia during admission. Even mild anemia is independently associated with increased mortality and LOS; however, transfusion to treat anemia is an independent and additive risk factor.

First-in-man experience of self-expanding nitinol stents combined with drug-coated balloon in the treatment of femoropopliteal occlusive disease.

Purpose The present study aimed to determine the safety and efficacy of a drug-coated balloon inflated within a thin-strut self-expanding bare-metal stent in patients with severe and complex femoropopliteal occlusive disease. Methods This prospective study used the Pulsar-self-expanding stent and Passeo-18 Lux drug-coated balloon in patients with severe and complex femoropopliteal occlusive disease. The primary endpoint was the 12-month primary patency, and the secondary endpoints included 24-month primary patency, assisted primary patency, secondary patency, and clinically associated target lesion revascularisation. Results The study included 44 patients (51 limbs). The mean age of the patients was 67.6 ± 10.2 years, with 73% men. Chronic limb severity was classified as Rutherford Category III in 41% of the patients, stage IV in 31%, and stage V in 27%. Lesions were predominantly Trans-Atlantic Inter-Society Consensus (TASC 2007) D (51%) and C (45%), with 32 (63%) chronic total occlusions. Procedural success was obtained in all cases. The mean lesion length was 200 ± 74.55 mm (95% CI = 167.09-208.01) with a mean number of stents per limb used of 1.57 ± 0.70 (95% CI = 1.37-1.76). Distal embolisation occurred in two patients. The primary patency rates at the 12- and 24-month follow-up were 94% (95% CI = 82.9-98.1) and 88% (95% CI = 75.7-94.5), respectively. The assisted primary was 94% (95% CI = 82.9-98.1) and secondary patency was 96% (95% CI = 85.2-99.0) at 24-month follow-up. The cumulative stent fracture rate at the 24-month follow-up was 10%. Freedom from clinically driven target lesion revascularisation was 94% (95% CI = 83-98%) at 12-month follow-up and 88% (95% CI = 76-94%) at 24-month follow-up, with two patients requiring a bypass graft. Conclusion Our novel approach involving the combination of a thin-strut bare-metal stent and a drug-coated balloon may be safe and effective, with sustainable and promising clinical outcomes up to 24 months after treatment.

Dental patch testing in patients with undifferentiated oral lichen planus.

BACKGROUND/OBJECTIVES: Distinguishing between oral lichen planus (LP) and lichenoid reactions to dental restorations can be impossible on clinical and histopathological grounds. Epicutaneous patch testing is an investigation that may guide patients and physicians in making timely and costly decisions to replace or cover existing dental restorations. This study aimed to assess the role of epicutaneous patch testing with a battery of dental allergens in patients with undifferentiated oral LP. METHODS: A retrospective review of the medical records of patients with biopsy-proven oral LP referred by an oral medicine specialist and who presented for dental epicutaneous patch testing at a dermatology clinic in Perth, Western Australia between 2009 and 2016 was performed. RESULTS: In total, 68 patients were included, of whom 54 (79%) had positive patch tests. Gold 26 (48%), mercury 24 (44%), nickel 22 (41%), copper 19 (35%), potassium dichromate 14 (26%) and methylhydroquinone 13 (24%) were the most common allergens for which patients tested positive. Hypothyroidism and non-steroidal anti-inflammatory drugs were associated with negative patch tests (P = 0.01 and 0.04, respectively). Smoking history, other medications and comorbidities, the location of the dental restorations and unilateral or bilateral disease were not significantly associated with the patch test results. Restorations were removed in 23 patients: 21 of these (91%) had positive epicutaneous patch tests. Of the 20 patients followed up, 19 (95%) experienced some improvement, among whom 11 (58%) had complete remission. CONCLUSION: Epicutaneous patch testing disclosed a high proportion of relevant positives. This guided the clinical decision to change dental restorations, with high rate of clinical improvement.

Improved outcomes and reduced costs associated with a health-system-wide patient blood management program: a retrospective observational study in four major adult tertiary-care hospitals.

BACKGROUND: Patient blood management (PBM) programs are associated with improved patient outcomes, reduced transfusions and costs. In 2008, the Western Australia Department of Health initiated a comprehensive health-system-wide PBM program. This study assesses program outcomes. STUDY DESIGN AND METHODS: This was a retrospective study of 605,046 patients admitted to four major adult tertiary-care hospitals between July 2008 and June 2014. Outcome measures were red blood cell (RBC), fresh-frozen plasma (FFP), and platelet units transfused; single-unit RBC transfusions; pretransfusion hemoglobin levels; elective surgery patients anemic at admission; product and activity-based costs of transfusion; in-hospital mortality; length of stay; 28-day all-cause emergency readmissions; and hospital-acquired complications. RESULTS: Comparing final year with baseline, units of RBCs, FFP, and platelets transfused per admission decreased 41% (p < 0.001), representing a saving of AU$18,507,092 (US$18,078,258) and between AU$80 million and AU$100 million (US$78 million and US$97 million) estimated activity-based savings. Mean pretransfusion hemoglobin levels decreased 7.9 g/dL to 7.3 g/dL (p < 0.001), and anemic elective surgery admissions decreased 20.8% to 14.4% (p = 0.001). Single-unit RBC transfusions increased from 33.3% to 63.7% (p < 0.001). There were risk-adjusted reductions in hospital mortality (odds ratio [OR], 0.72; 95% confidence interval [CI], 0.67-0.77; p < 0.001), length of stay (incidence rate ratio, 0.85; 95% CI, 0.84-0.87; p < 0.001), hospital-acquired infections (OR, 0.79; 95% CI, 0.73-0.86; p < 0.001), and acute myocardial infarction-stroke (OR, 0.69; 95% CI, 0.58-0.82; p < 0.001). All-cause emergency readmissions increased (OR, 1.06; 95% CI, 1.02-1.10; p = 0.001). CONCLUSION: Implementation of a unique, jurisdiction-wide PBM program was associated with improved patient outcomes, reduced blood product utilization, and product-related cost savings.

Resistin and NGAL are associated with inflammatory response, endothelial activation and clinical outcomes in sepsis.

OBJECTIVE AND DESIGN: Resistin and neutrophil gelatinase-associated lipocalin (NGAL) are upregulated in circulating leucocytes in sepsis, but the significance of this is uncertain. We evaluated associations between Resistin and NGAL with endothelial cell activation and clinical outcomes in a prospective observational study in the Emergency Department (ED). METHODS: Serum levels of Resistin, NGAL, inflammatory cytokines (IL-6, IL-10) and soluble endothelial adhesion molecules (VCAM-1, ICAM-1) were measured at defined time points up to 24 h. Patterns and relationships between markers were investigated using linear mixed regression models. Predictive values for clinical outcomes for markers at enrollment were assessed by logistic regression and receiver operator characteristic (ROC) curves. RESULTS: 186 participants (89 septic-shock, 69 sepsis, 28 uncomplicated infection) were compared with 29 healthy controls. Median Resistin and NGAL were higher in uncomplicated infection compared to controls, and in septic shock compared to non-shock sepsis. Resistin and NGAL correlated with IL-6 and IL-10, with VCAM-1 and ICAM-1, and with organ failure. Resistin and NGAL were associated with septic shock but had limited predictive utility for mortality. CONCLUSION: Resistin and NGAL correlate with expression of endothelial cell adhesion molecules in sepsis. Further evaluation of the role of Resistin and NGAL in sepsis pathogenesis is warranted.

Effects of prenatal n-3 fatty acid supplementation on offspring resolvins at birth and 12 years of age: a double-blind, randomised controlled clinical trial.

Resolution of inflammation is an active process involving specialised pro-resolving mediators (SPM) generated from the n-3 fatty acids EPA and DHA. n-3 Fatty acid supplementation during pregnancy may provide an intervention strategy to modify these novel SPM. This study aimed to assess the effect of n-3 fatty acid supplementation in pregnancy on offspring SPM at birth and 12 years of age (12 years). In all, ninety-eight atopic pregnant women were randomised to 3·7 g daily n-3 fatty acids or a control (olive oil), from 20 weeks gestation until delivery. Blood was collected from the offspring at birth and at 12 years. Plasma SPM consisting of 18-hydroxyeicosapentaenoic acid (18-HEPE), E-series resolvins, 17-hydroxydocosahexaenoic acid (17-HDHA), D-series resolvins, 14-hydroxydocosahexaenoic acid (14-HDHA), 10 S,17S-dihydroxydocosahexaenoic acid, maresins and protectin 1, were measured by liquid chromatography-tandem MS. We identified the resolvins RvE1, RvE2, RvE3, RvD1, 17R-RvD1 and RvD2 for the first time in human cord blood. n-3 Fatty acids increased cord blood 18-HEPE (P<0·001) derived from EPA relative to the control group. DHA-derived 17-HDHA at birth was significantly increased in the n-3 fatty acid group relative to the controls (P=0·001), but other SPM were not different between the groups. n-3 Fatty acid supplementation during pregnancy was associated with an increase in SPM precursors in the offspring at birth but the effects were not sustained at 12 years. The presence of these SPM, particularly at birth, may have functions relevant in the newborn that remain to be established, which may be useful for future investigations.

Viremic HIV Controllers Exhibit High Plasmacytoid Dendritic Cell-Reactive Opsonophagocytic IgG Antibody Responses against HIV-1 p24 Associated with Greater Antibody Isotype Diversification.

Identifying the mechanisms of natural control of HIV-1 infection could lead to novel approaches to prevent or cure HIV infection. Several studies have associated natural control of HIV-1 infection with IgG Abs against HIV-1 Gag proteins (e.g., p24) and/or production of IgG2 Abs against HIV-1 proteins. These Abs likely exert their effect by activating antiviral effector cell responses rather than virus neutralization. We hypothesized that an opsonophagocytic IgG Ab response against HIV-1 p24 that activates plasmacytoid dendritic cells (pDCs) through FcγRIIa would be associated with control of HIV and that this would be enhanced by Ab isotype diversification. Using the Gen2.2 pDC cell line, we demonstrated that pDC-reactive opsonophagocytic IgG Ab responses against HIV-1 p24 were higher in HIV controllers (HIV RNA < 2000 copies/ml) than noncontrollers (HIV RNA > 10,000 copies/ml), particularly in controllers with low but detectable viremia (HIV RNA 75-2000 copies/ml). Opsonophagocytic Ab responses correlated with plasma levels of IgG1 and IgG2 anti-HIV-1 p24 and, notably, correlated inversely with plasma HIV RNA levels in viremic HIV patients. Phagocytosis of these Abs was mediated via FcγRIIa. Isotype diversification (toward IgG2) was greatest in HIV controllers, and depletion of IgG2 from Ig preparations indicated that IgG2 Abs to HIV-1 p24 do not enhance phagocytosis, suggesting that they enhance other aspects of Ab function, such as Ag opsonization. Our findings emulate those for pDC-reactive opsonophagocytic Ab responses against coxsackie, picorna, and influenza viruses and demonstrate a previously undefined immune correlate of HIV-1 control that may be relevant to HIV vaccine development.

A Cluster Randomised Controlled Trial of a Brief Child Health Nurse Intervention to Reduce Infant Secondhand Smoke Exposure.

Background Exposure to secondhand smoke (SHS) is a significant contributor to ill health in children. A study was undertaken to determine the effectiveness of two brief multi-strategic child health nurse delivered interventions in: decreasing the prevalence of infants exposed to SHS; decreasing the prevalence of smoking amongst parent/carers of infants and increasing the prevalence of household smoking bans. Methods This study was a 3 arm, cluster randomised controlled trial. Clusters were 39 community based well child health clinics in one local area health service. Clinics were stratified according to annual number of client appointments and then randomly assigned in a 1:1:1 ratio, (Intervention 1: Intervention 2: Control), with 13 clinics in each cluster. Parents/carers of infants in the intervention groups received a brief multi-strategic intervention from child health nurses during clinic consultations. Treatment condition 1 included computer delivered risk assessment and feedback and nurse brief advice. Treatment condition 2 included all elements of Treatment condition 1 with the addition of biochemical feedback of infant SHS exposure. Results When compared to the Control group at 12 months, no significant differences in the prevalence of infant exposure to SHS were detected from baseline to follow-up for Treatment condition 1 (OR 1.16, 95 % CI 0.73-1.85, p = 0.53) or Treatment condition 2 (OR 1.30, 95 % CI 0.88-1.92, p = 0.19) Similarly, no significant differences were detected in the proportion of parent/carers who reported that they were smokers (T1:OR 0.95, 95 % CI 0.78-1.15, p = 0.58 and T2:OR 0.97, 95 % CI 0.80-1.18, p = 0.77), or in the proportion of households reported to have a complete smoking ban (T1:OR 1.21, 95 % CI 0.89-1.64, p = 0.23 and T2:OR 1.06, 95 % CI 0.79-1.43, p = 0.68). Conclusions Further research is required to identify effective interventions that can be consistently provided by child health nurses if the potential of such settings to contribute to reductions in child SHS exposure is to be realised.

Serum 25-hydroxyvitamin D concentrations and cardiometabolic risk factors in adolescents and young adults.

Evidence associating serum 25-hydroxyvitamin D (25(OH)D) concentrations and cardiometabolic risk factors is inconsistent and studies have largely been conducted in adult populations. We examined the prospective associations between serum 25(OH)D concentrations and cardiometabolic risk factors from adolescence to young adulthood in the West Australian Pregnancy Cohort (Raine) Study. Serum 25(OH)D concentrations, BMI, homoeostasis model assessment for insulin resistance (HOMA-IR), TAG, HDL-cholesterol and systolic blood pressure (SBP) were measured at the 17-year (n 1015) and 20-year (n 1117) follow-ups. Hierarchical linear mixed models with maximum likelihood estimation were used to investigate associations between serum 25(OH)D concentrations and cardiometabolic risk factors, accounting for potential confounders. In males and females, respectively, mean serum 25(OH)D concentrations were 73·6 (sd 28·2) and 75·4 (sd 25·9) nmol/l at 17 years and 70·0 (sd 24·2) and 74·3 (sd 26·2) nmol/l at 20 years. Deseasonalised serum 25(OH)D3 concentrations were inversely associated with BMI (coefficient -0·01; 95 % CI -0·03, -0·003; P=0·014). No change over time was detected in the association for males; for females, the inverse association was stronger at 20 years compared with 17 years. Serum 25(OH)D concentrations were inversely associated with log-HOMA-IR (coefficient -0·002; 95 % CI -0·003, -0·001; P<0·001) and positively associated with log-TAG in females (coefficient 0·002; 95 % CI 0·0008, 0·004; P=0·003). These associations did not vary over time. There were no significant associations between serum 25(OH)D concentrations and HDL-cholesterol or SBP. Clinical trials in those with insufficient vitamin D status may be warranted to determine any beneficial effect of vitamin D supplementation on insulin resistance, while monitoring for any deleterious effect on TAG.

Increased hospital costs associated with red blood cell transfusion.

BACKGROUND: Red blood cell (RBC) transfusion is independently associated in a dose-dependent manner with increased intensive care unit stay, total hospital length of stay, and hospital-acquired complications. Since little is known of the cost of these transfusion-associated adverse outcomes our aim was to determine the total hospital cost associated with RBC transfusion and to assess any dose-dependent relationship. STUDY DESIGN AND METHODS: A retrospective cohort study of all multiday acute care inpatients discharged from a five hospital health service in Western Australia between July 2011 and June 2012 was conducted. Main outcome measures were incidence of RBC transfusion and mean inpatient hospital costs. RESULTS: Of 89,996 multiday, acute care inpatient discharges, 4805 (5.3%) were transfused at least 1 unit of RBCs. After potential confounders were adjusted for, the mean inpatient cost was 1.83 times higher in the transfused group compared with the nontransfused group (95% confidence interval, 1.78-1.89; p < 0.001). The estimated total hospital-associated cost of RBC transfusion in this study was AUD $77 million (US $72 million), representing 7.8% of total hospital expenditure on acute care inpatients. There was a significant dose-dependent association between the number of RBC units transfused and increased costs after adjusting for confounders. CONCLUSION: RBC transfusions were independently associated with significantly higher hospital costs. The financial implication to hospital budgets will assist in prioritizing areas to reduce the rate of RBC transfusions and in implementing patient blood management programs.

Use of the Dietary Guideline Index to assess cardiometabolic risk in adolescents.

The long-term adherence to the dietary guidelines has not been evaluated against emergence of cardiometabolic risks in adolescents with increasing rates of obesity. The present study aimed to (1) determine the level of adherence to the guidelines using the Australian Dietary Guideline Index for Children and Adolescents (DGI-CA) in adolescents of age 14 and 17 years and to (2) examine the relationship between their assessed diet quality and concurrently measured cardiometabolic risk factors over time. Data were analysed from the Western Australian Pregnancy Cohort (Raine) Study. The DGI-CA was determined from a FFQ. Anthropometry and fasting biochemical measures were taken using standard procedures. Hierarchical linear mixed models examined associations between cardiometabolic risk factors and DGI-CA, adjusting for socio-economic status, physical activity, BMI, and sex, and examining for interactions. The mean DGI-CA scores were 47·1 (SD 10·2) at 14 years (n 1419) and 47·7 (SD 11·0) at 17 years (n 843), and were not different between sex. There was a significant inverse association between DGI-CA and insulin, homeostasis model assessment score and heart rate. The DGI-CA was positively associated with BMI (P= 0·029) but negatively with waist:hip ratio (P= 0·026). It was not associated with lipids or blood pressure, with the exception of a negative association with TAG (P= 0·011). The degree of adherence in the Raine Study adolescents was suboptimal but similar to the Australian Children's Nutrition and Physical Activity Survey. The present study shows that, at any particular time, better diet quality was associated with better insulin sensitivity and TAG levels and decreased abdominal fatness.

Systematic detection of familial hypercholesterolaemia in primary health care: a community based prospective study of three methods.

BACKGROUND: Familial hypercholesterolaemia (FH), a co-dominantly inherited disease of cholesterol that markedly increases risk of premature coronary artery disease (CAD), is significantly under-diagnosed. Primary health care is increasingly seen as a setting in which to increase the detection rate of index cases. We report a prospective study of three methods of case detection using pre-existing primary health care services in one community. METHODS: Three methods of case detection were tested: pathology laboratory database search, workplace health checks and general practice database search. People identified at risk by each of the three screening methods were offered detailed assessment for FH using the Dutch Lipid Clinic Network Criteria score (DLCNCS). RESULTS: 1316 participants underwent detailed assessment for FH. The proportion of at risk people identified for further assessment was in decreasing order: GP (659 of 2494, 26.4%), workplace assessment (60 of 268, 22.4%) and pathology database (597 of 4517, 13.2%) p<0.001. Eight-six (6.5%) were identified as clinical FH (DLCNCS>5) of which 59 had genetic testing and 11 of 59, 18.6%, were confirmed to have a mutation causing FH. Pathology database detected the greatest number of clinical FH (51 of 86, 59.3%) and mutation positive participants (8 of 11, 72.7%). CONCLUSION: Screening within primary health care was successful in detecting participants with FH. An integrated case detection model combining screening of pathology and GP databases is proposed.

Gender and the active smoking and high-sensitivity C-reactive protein relation in late adolescence.

C-reactive protein (CRP), smoking, and oral contraceptive (OC) use are associated with CVD risk in adults. This study examines the effect of smoking on high-sensitivity CRP (hs-CRP) levels, and the interactive effects of sex and OC use on this relationship in an adolescent cohort. A total of 1,050 adolescents (mean age 17 ± 0.25 years) from the Western Australian Pregnancy Cohort (Raine) Study had anthropometric, lifestyle, and metabolic measures recorded. The association between smoking status and log-transformed hs-CRP was analyzed using multivariable Tobit linear regression models, with adjustment for adiposity, lifestyle, and early-life confounders. A three-level variable (girls not using OCs, girls using OCs, and boys) was employed to assess the interactive effects of sex, OC use, and smoking. Smoking associated with higher hs-CRP levels in girls not using OCs (b = 0.571; P = 0.001), but not in girls using OCs (b = -0.117; P = 0.598) or in boys (b = 0.183; P = 0.2). OC use in nonsmoking girls was the strongest factor associated with higher hs-CRP levels (b = 1.189; P < 0.001). This study has demonstrated a more robust effect of smoking on hs-CRP levels in girls not using OCs compared with boys. The findings may explain why CVD risk conferred by smoking is higher in women than in men.

Importance of cardiometabolic risk factors in the association between nonalcoholic fatty liver disease and arterial stiffness in adolescents.

UNLABELLED: Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide and is regarded as the hepatic manifestation of the metabolic syndrome. In adults, NAFLD is a determinant of arterial stiffness and cardiovascular risk, independent of the metabolic syndrome. Our aim was to ascertain if NAFLD is associated with arterial stiffness, independent of cardiometabolic factors in a population-based cohort of adolescents. The 17-year-olds (n = 964) from an Australian birth cohort had measures of anthropometry, blood pressure, fasting insulin, glucose, lipids, and NAFLD by ultrasound. Two-step cluster analysis identified youth at high metabolic risk. Measures of arterial stiffness (pulse wave velocity [PWV] and augmentation index corrected for heart rate [AI@75]) were obtained using applanation tonometry. The overall prevalence of NAFLD was 13.3%. The "high risk" metabolic cluster at age 17 years included 16% males and 19% females. Compared to "low risk," the "high risk" cluster participants had greater waist circumference, triglycerides, insulin, systolic blood pressure, and lower high-density lipoprotein (HDL) cholesterol (all P < 0.0001). Those who had NAFLD but were not in the "high risk" metabolic cluster did not have increased PWV or AI@75. However, males and females who had NAFLD in the presence of the metabolic cluster had greater PWV (b = 0.20, 95% confidence interval [CI] 0.01 to 0.38, P = 0.037). Males who had NAFLD in the presence of the metabolic cluster had greater AI@75 (b = 6.3, 95% CI 1.9 to 10.7, P = 0.005). CONCLUSION: NAFLD is only associated with increased arterial stiffness in the presence of the "high risk" metabolic cluster. This suggests that arterial stiffness related to the presence of NAFLD is predicated on the presence of an adverse metabolic profile in adolescents.

Vitamin D status and predictors of serum 25-hydroxyvitamin D concentrations in Western Australian adolescents.

Despite the importance of skeletal growth during adolescence, there is limited research reporting vitamin D status and its predictors in adolescents. Using prospective data from the Western Australian Pregnancy Cohort (Raine) Study, we investigated vitamin D status and predictors of serum 25-hydroxyvitamin D (25(OH)D) concentrations in adolescents. Serum 25(OH)D concentrations were measured in the same participants at 14 and 17 years (n 1045 at both time points). The percentage of adolescents with serum 25(OH)D concentrations < 50, 50-74·9 and ≥ 75 nmol/l was reported year-round and by month of blood collection. We examined the predictors of serum 25(OH)D concentrations, including sex, race, month of blood collection, physical activity, BMI, family income, and Ca and vitamin D intakes (n 919 at 14 years; n 570 at 17 years), using a general linear mixed model. At 14 years, 31 % of adolescents had serum 25(OH)D concentrations between 50 and 74·9 nmol/l and a further 4 % had concentrations < 50 nmol/l. At 17 years, 40 % of adolescents had serum 25(OH)D concentrations between 50 and 74·9 nmol/l and 12 % had concentrations < 50 nmol/l. Caucasian ethnicity, being sampled at the end of summer, exercising more, having a lower BMI, a higher Ca intake and a higher family income were significantly associated with higher serum 25(OH)D concentrations. The proportion of adolescents with serum 25(OH)D concentrations < 50 nmol/l was low in this Western Australian cohort. There is a need for international consensus on defining adequate vitamin D status in order to determine whether strategies to increase vitamin D status in adolescents are warranted.