Cardiovascular Risk Markers in Adults With Adrenal Incidentaloma and Mild Autonomous Cortisol Secretion.

CONTEXT: Many adrenal adenomas exhibit mild autonomous cortisol secretion (MACS). Although MACS is associated with increased cardiovascular mortality, the underlying mechanisms are not fully defined. OBJECTIVE: To investigate mechanisms that may link MACS and cardiovascular mortality in adults with adrenal adenoma. DESIGN: Cross-sectional study. PATIENTS: Twenty adults with adrenal adenoma and MACS and 20 controls with nonfunctioning adrenal adenoma. METHODS: Reactive hyperemia index (RHI) was measured by peripheral artery tonometry and 24-hour ambulatory blood pressure monitoring (24h AMBP) was performed. Indices of insulin secretion and sensitivity were estimated by measuring glucose and insulin fasting and following a mixed meal. MAIN OUTCOME MEASURE: The primary outcome was the difference in RHI between participants with MACS vs nonfunctioning adrenal adenoma. RESULTS: The average cortisol after 1-mg dexamethasone and urinary free cortisol were higher in patients with MACS. There was no significant difference in fasting RHI (2.0 [interquartile range (IQR) 1.6-2.4] vs 2.0 [IQR 1.7-2.2, P = .72), but postprandial RHI was higher in patients with MACS (2.2 [1.8-2.7] vs 1.8 [1.5-2.2], P = .04). 24-hour ambulatory blood pressure monitoring and Matsuda index were not significantly different in the groups. Fasting glucose and glucose area under the curve after the mixed meal were higher and insulinogenic index was lower in participants with MACS. CONCLUSION: Adults with adrenal adenoma and MACS do not have fasting endothelial dysfunction and postprandial endothelial function may be better. These patients have fasting and postprandial hyperglycemia with lower insulin secretion, which may underlie the association between MACS and increased cardiovascular mortality.

The Performance of Freestyle Libre Pro Flash Continuous Glucose Monitoring in Hospitalized Patients Treated with an Intravenous Insulin Infusion for Acute Prednisolone-Induced Hyperglycemia.

Few studies have evaluated the performance of flash glucose monitoring in hospitalized patients requiring intravenous insulin therapy. In this prospective study, an intravenous insulin infusion was adjusted hourly using flash glucose monitoring in hospitalized adults with prednisolone-associated hyperglycemia. The difference in paired point of care (POC) and flash glucose measurements and risk of severe hyper- or hypoglycemia (assessed by Clarke error grid analysis) were assessed. Glucose concentration measured by flash glucose monitoring was lower than POC glucose (mean difference 1.5 mmol/L [27 mg/dL], p < 0.001); however, mean POC glucose was within the target range (9.1 ± 4.1 mmol/L [164 ± 72 mg/dL]) and 97.8% of glucose measurements were within Zone A and B on error grid analysis. Flash glucose monitoring could be used in combination with POC glucose monitoring to minimize the frequency of finger prick blood glucose levels in hospitalized patients prescribed an intravenous insulin infusion.

Tiered escalation response systems in practice: A post hoc analysis examining the workload implications.

Objective: Many rapid response systems now have multiple tiers of escalation in addition to the traditional single tier of a medical emergency team. Given that the benefit to patient outcomes of this change is unclear, we sought to investigate the workload implications of a multitiered system, including the impact of trigger modification. Design: The study design incorporated a post hoc analysis using a matched case-control dataset. Setting: The study setting was an acute, adult tertiary referral hospital. Participants: Cases that had an adverse event (cardiac arrest or unanticipated intensive care unit admission) or a rapid response team (RRT) call participated in the study. Controls were matched by age, gender, ward and time of year, and no adverse event or RRT call. Participants were admitted between May 2014 and April 2015. Main outcome measures: The main outcome measure were the number of reviews, triggers, and modifications across three tiers of escalation; a nurse review, a multidisciplinary review (MDT-admitting medical team review), and an RRT call. Results: There were 321 cases and 321 controls. Overall, there were 1948 nurse triggers, of which 1431 (73.5%) were in cases and 517 (26.5%) in controls, 798 MDT triggers (660 [82.7%] in cases and 138 [17.3%] in controls), and 379 RRT triggers (351 [92.6%] in cases and 28 [7.4%] in controls). Per patient per 24 h, there were 3.03 nurse, 1.24 MDT, and 0.59 RRT triggers. Accounting for modifications, this reduced to 2.17, 0.88, and 0.42, respectively. The proportion of triggers that were modified, so as not to trigger a review, was similar across all the tiers, being 28.6% of nurse, 29.6% of MDT, and 28.2% of RRT triggers. Per patient per 24 h, there were 0.61 nurse reviews, 0.52 MDT reviews, and 0.08 RRT reviews. Conclusions: Lower-tier triggers were more prevalent, and modifications were common. Modifications significantly mitigated the escalation workload across all tiers of a multitiered system.

Vaccination, information and parental confidence in the digital age in England.

Background: Immunisation programmes have led to substantial reductions in vaccine-preventable infectious diseases globally. A variety of factors have been shown to impact parental confidence and uptake of childhood vaccines, from concerns about vaccine safety to a lack of perceived need. Determinants of vaccine decision making include information, risk perceptions, and modifying factors such as attitude, identity, norms, habit and barriers. With the rise of the internet and social media, there has been a vast increase in information available about vaccines, not all scientifically-based and well-informed. Methods: 285 locations in England were randomly selected to survey a nationally representative sample of the English population. 1735 primary care givers of children aged between 2 months and <5 years old from England were randomly selected and surveyed via face-to-face interviews between January and March 2019. Results: A much higher percentage of parents surveyed trust health care workers, the NHS, pharmacists and government for advice about immunisation, in comparison to media, the internet and social media. Most parents use official sources to obtain information on vaccines including parents who use the internet. The small proportion of parents who reported having seen negative information about vaccines were more likely to find it on the internet. Parents who felt they did not have enough information were more likely to have delayed or refused a vaccine for their child. Interpretation: This study showed that for parents of young children in England, vaccination continues to be the social norm but this can rapidly change and clear, consistent messaging from trusted sources continues to be important. Although a proportion do seek vaccine information on the internet, the majority use official sources. Representative attitudinal surveys continue to be key in identifying any emerging threats to parental vaccine confidence.

A novel likely pathogenic CLCN5 variant in Dent's disease.

BACKGROUND: The majority of cases of Dent's disease are caused by pathogenic variants in the CLCN5 gene, which encodes a voltage-gated chloride ion channel (ClC-5), resulting in proximal tubular dysfunction. We present three members of the same family and one unrelated paediatric patient with the same insertion-deletion CLCN5 variant. The identification of these patients and positive familial segregation led to the re-classification of this variant from one of unknown significance to one of likely pathogenicity. CASE PRESENTATION: A 41 year old male presented with end stage kidney failure, proteinuria and haematuria. Whole genome sequencing identified an insertion-deletion variant in CLCN5, resulting in a missense change (c.1744_1745delinsAA p.(Ala582Lys)). His brother and nephew, who both exhibited renal impairment, haematuria, proteinuria, glycosuria and nephrocalcinosis, were found to have the same variant. In addition, genetic testing of an unrelated paediatric patient who presented with proteinuria and hypercalciuria, demonstrated the same variant. CONCLUSIONS: The identification of this novel variant in four individuals with features of Dent's disease, has led to the re-classification of the variant to one of likely pathogenicity. As a result, our patients and any future patients with the same variant can be offered a likely diagnosis, without the need for kidney biopsy, and their family members can be offered genetic screening.

A primary care delivered, technology supported lifestyle program for Type 2 Diabetes Management: An evaluation of changes in metabolic health, feasibility, and acceptability - A pilot interventional study protocol.

Background: Type 2 Diabetes (T2D) is associated with significant health complications and socioeconomic costs. Previous research conducted through an outpatient research facility demonstrated use of a low carbohydrate (LC) diet and exercise plan delivered in the format of an education book combined with use of real-time continuous glucose monitoring (RT-CGM) is an effective self-management intervention to improve weight and blood glucose management in patients with T2D. Primary health care remains the central access point for patient management of T2D, but General Practitioners (GPs) lack access to effective evidenced-based, self-management programs that can be prescribed to improve patient outcomes. Methods: A single-arm, within-participant pilot intervention study will be conducted to evaluate the changes in metabolic health, acceptability and feasibility of a prescriptive LC diet and lifestyle program combined with RT-CGM (LC-RTC) delivered via GP practices. Forty adults with T2D will be recruited from GP practices and prescribed the LC-RTC intervention for 12 weeks. Outcomes will be assessed at baseline and 12-weeks post intervention. Changes in metabolic health will be assessed by changes in glycosylated hemoglobin (primary outcome), body weight, blood pressure, blood lipids, and medication usage. Post-intervention, participants will complete questionnaires and participate in focus groups to explore their experience of the LC-RTC program including acceptance, perceived benefits/barriers, limitations, financial feasibility, intervention drop-out rates, participant and GP engagement with the program (clinic attendance and contacts made to clinic for program support) and RT-CGM use and wear time acceptance. GPs and clinical staff involved will participate focus groups to evaluate the perceived value and feasibility of the LC-RTC program. Discussion: This trial will provide a powered evaluation of the changes in metabolic health, acceptability, and feasibility of the LC-RTC program for patients with T2D delivered via GP practices. Trial registration: ANZCTR: 12622000635763 (Website Link to full registration: ANZCTR - Registration). Registered 29th April 2022. Overall trial status: Commenced; Recruitment Status: Commenced 1st May 2022, with 40 participants recruited as of 2nd May 2023 using a rolling recruitment approach.

Weight loss with subcutaneous semaglutide versus other glucagon-like peptide 1 receptor agonists in type 2 diabetes: a systematic review.

Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) reduce elevated blood glucose levels and induce weight loss. Multiple GLP-1 RAs and one combined GLP-1/glucose-dependent insulinotropic polypeptide agonist are currently available. This review was conducted with the aim of summarising direct comparisons between subcutaneous semaglutide and other GLP-1 RAs in individuals with type 2 diabetes (T2D), particularly with respect to efficacy for inducing weight loss and improving other markers of metabolic health. This systematic review of PubMed and Embase from inception to early 2022 was registered on PROSPERO and was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Meta-Analysis of Observational Studies in Epidemiology guidelines. Of the 740 records identified in the search, five studies fulfilled the inclusion criteria. Comparators included liraglutide, exenatide, dulaglutide and tirzepatide. In the identified studies, multiple dosing regimens were utilised for semaglutide. Randomised trials support the superior efficacy of semaglutide over other GLP-1 RAs with respect to weight loss in T2D, but tirzepatide is more effective than semaglutide.

Clinical determinants of insulin requirements during treatment of prednisolone-induced hyperglycaemia.

AIMS: The optimal treatment of prednisolone-associated hyperglycaemia is unclear, but guidelines recommend using a body weight-based daily insulin dose. This study evaluated how clinical variables were associated with insulin requirements in hospitalised patients with prednisolone-associated hyperglycaemia. METHODS: In this prospective study, fifty adult inpatients who were taking prednisolone ≥20 mg/day and experienced hyperglycaemia were prescribed a 24-h intravenous insulin infusion. The daily insulin dose required to attain a mean glucose of 8 mmol/L was calculated. The associations between daily insulin dose and clinical variables were assessed. RESULTS: The participants age was 69 ± 10 years, daily prednisolone dose was 34 ± 10 mg, HbA1c was 7.7 ± 2.0 % (61 ± 10 mmol/mol), 77 % had known type 2 diabetes and 30 % were female. In univariate analysis, weight was associated with daily insulin dose (r2 = 0.11, p = 0.024). A multivariate model comprising sex, HbA1c, a prior diagnosis of diabetes, diabetes treatment and weight explained nearly-two thirds of the variability in daily insulin dose (r2 = 0.65, p < 0.001). CONCLUSIONS: In patients with prednisolone-associated hyperglycaemia, calculating insulin doses based on sex, HbA1c, diabetes status and regular diabetes treatment and weight may improve glycaemic control compared to weight-based dosing.

Intermittent fasting increases growth differentiation factor 15 in females with overweight or obesity but not associated with food intake.

Growth differentiation factor 15 (GDF15) increases with acute fast in animals, and high GDF15 reduces food intake in rodents. We explored whether GDF15 was altered following intermittent fasting (IF) versus caloric restriction (CR), and associations with energy intake. Females with obesity received all foods at 70% (IF70 and CR70) or 100% of energy requirements for 8 weeks. IF ate 2-9% less than provided on refeeding days, resulting in greater weight losses. GDF15 was increased 5% more in IF70 versus CR70, but not associated with energy intake. This rise in GDF15 is unlikely to explain restriction of energy intake during IF.

Time-restricted eating alters the 24-hour profile of adipose tissue transcriptome in men with obesity.

OBJECTIVE: Time-restricted eating (TRE) restores circadian rhythms in mice, but the evidence to support this in humans is limited. The objective of this study was to investigate the effects of TRE on 24-hour profiles of plasma metabolites, glucoregulatory hormones, and the subcutaneous adipose tissue (SAT) transcriptome in humans. METHODS: Men (n = 15, age = 63 [4] years, BMI 30.5 [2.4] kg/m2 ) were recruited. A 35-hour metabolic ward stay was conducted at baseline and after 8 weeks of 10-hour TRE. Assessment included 24-hour profiles of plasma glucose, nonesterified fatty acid (NEFA), triglyceride, glucoregulatory hormones, and the SAT transcriptome. Dim light melatonin onset and cortisol area under the curve were calculated. RESULTS: TRE did not alter dim light melatonin onset but reduced morning cortisol area under the curve. TRE altered 24-hour profiles of insulin, NEFA, triglyceride, and glucose-dependent insulinotropic peptide and increased transcripts of circadian locomotor output cycles protein kaput (CLOCK) and nuclear receptor subfamily 1 group D member 2 (NR1D2) and decreased period circadian regulator 1 (PER1) and nuclear receptor subfamily 1 group D member 1 (NR1D1) at 12:00 am. The rhythmicity of 450 genes was altered by TRE, which enriched in transcripts for transcription corepressor activity, DNA-binding transcription factor binding, regulation of chromatin organization, and small GTPase binding pathways. Weighted gene coexpression network analysis revealed eigengenes that were correlated with BMI, insulin, and NEFA. CONCLUSIONS: TRE restored 24-hour profiles in hormones, metabolites, and genes controlling transcriptional regulation in SAT, which could underpin its metabolic health benefit.

Perioperative micronutrients, macroscopic benefits?

'Micronutrients' are vitamins and minerals vital for healthy metabolic function, wound healing and disease and infection prevention. Micronutrients may play a role in significantly improving postoperative recovery and indices of patient comfort; however, minimal research exists for surgical patients. Furthermore, current guidelines on perioperative nutrition have a macronutrient focus which may fail to guide detection and treatment of the subclinical micronutrient deficiency in a patient who is not obviously malnourished. Limited research into supplementation of some micronutrient deficiencies shows favourable results; however, given the financial implications of wound care, the prevalence of micronutrient deficiency and possible benefits from attention to micronutrition for postoperative recovery, further research into this area is urgently warranted. Interventions to guide optimal future clinical practice are suggested.

Modular structures and the delivery of inpatient care in hospitals: a Network Science perspective on healthcare function and dysfunction.

BACKGROUND: Reinforced by the COVID-19 pandemic, the capacity of health systems to cope with increasing healthcare demands has been an abiding concern of both governments and the public. Health systems are made up from non-identical human and physical components interacting in diverse ways in varying locations. It is challenging to represent the function and dysfunction of such systems in a scientific manner. We describe a Network Science approach to that dilemma. General hospitals with large emergency caseloads are the resource intensive components of health systems. We propose that the care-delivery services in such entities are modular, and that their structure and function can be usefully analysed by contemporary Network Science. We explore that possibility in a study of Australian hospitals during 2019 and 2020. METHODS: We accessed monthly snapshots of whole of hospital administrative patient level data in two general hospitals during 2019 and 2020. We represented the organisations inpatient services as network graphs and explored their graph structural characteristics using the Louvain algorithm and other methods. We related graph topological features to aspects of observable function and dysfunction in the delivery of care. RESULTS: We constructed a series of whole of institution bipartite hospital graphs with clinical unit and labelled wards as nodes, and patients treated by units in particular wards as edges. Examples of the graphs are provided. Algorithmic identification of community structures confirmed the modular structure of the graphs. Their functional implications were readily identified by domain experts. Topological graph features could be related to functional and dysfunctional issues such as COVID-19 related service changes and levels of hospital congestion. DISCUSSION AND CONCLUSIONS: Contemporary Network Science is one of the fastest growing areas of current scientific and technical advance. Network Science confirms the modular nature of healthcare service structures. It holds considerable promise for understanding function and dysfunction in healthcare systems, and for reconceptualising issues such as hospital capacity in new and interesting ways.

A Health Care Professional Delivered Low Carbohydrate Diet Program Reduces Body Weight, Haemoglobin A1c, Diabetes Medication Use and Cardiovascular Risk Markers-A Single-Arm Intervention Analysis.

This study examined the effectiveness of a health care professional delivered low-carbohydrate diet program (Diversa Health Program) aiming to improve obesity/type-2-diabetes management for people living in Australia. 511 adults (Age:57.1 ± 13.7 [SD] yrs) who participated between January 2017−August 2021 for ≥30 days with pre-post data collected for ≥1 key outcome variable (body weight and HbA1c) were included in the analysis. Average participation duration was 218 ± 207 days with 5.4 ± 3.9 reported consultation visits. Body weight reduced from 92.3 ± 23.0 to 86.3 ± 21.1 kg (n = 506, p < 0.001). Weight loss was 0.9 ± 2.8 kg (1.3%), 4.5 ± 4.3 kg (5.7%) and 7.9 ± 7.2 kg (7.5%), respectively, for those with a classification of normal weight (n = 67), overweight (n = 122) and obese (n = 307) at commencement. HbA1c reduced from 6.0 ± 1.2 to 5.6 ± 0.7% (n = 212, p < 0.001). For members with a commencing HbA1c of <5.7% (n = 110), 5.7−6.4% (n = 55), and ≥6.5% (n = 48), HbA1c reduced −0.1 ± 0.2%, −0.3 ± 0.3%, and −1.4 ± 1.3%, respectively. For members with a commencing HbA1c ≥6.5%, 90% experienced a HbA1c reduction and 54% achieved a final HbA1c < 6.5%. With inclusion and exclusion of metformin, respectively, 124 and 82 diabetes medications were prescribed to 63 and 42 members that reduced to 82 and 35 medications prescribed to 51 and 26 members at final visit. A health care professional delivered low-carbohydrate diet program can facilitate weight loss and improve glycaemic control with greatest improvements and clinical relevance in individuals with worse baseline parameters.

The impact of standardised goals of care documentation on the use of cardiopulmonary resuscitation, mechanical ventilation, and intensive care unit admissions in older patients: a retrospective observational analysis.

Background In South Australian hospitals, 'Do Not Resuscitate' orders have been replaced by '7-Step Pathway Acute Resuscitation Plans', a standardised form and approach that encourages shared decision-making while providing staff with clarity about goals of care. This initiative has led to increased rates of documentation about treatment preferences, including 'Not-For-Cardiopulmonary Resuscitation'. Aim To quantify any effect of the 7-Step Pathway form versus previous 'Do Not Resuscitate' orders on cardiopulmonary resuscitation, mechanical ventilation, and/or intensive care unit admission during hospitalisation. Methods We completed a retrospective, observational study in two Australian tertiary hospitals using interrupted time-series analysis. We examined the number of medical inpatients aged 70 years and over who received one or more Intensive Treatments-cardiopulmonary resuscitation, mechanical ventilation, or intensive care unit admission-in the 2 years before and 2 years after the introduction of the form. Results There were 2759 Intensive Treatments across 66 051 inpatient admissions; 1304/32 489 (4.0%) pre-intervention and 1455/33 562 post-intervention (4.3%). Sub-group analysis of those who died in hospital showed 400/1669 (24%) received Intensive Treatments pre-intervention and 382/1624 post-intervention (24%). Interrupted time-series analysis suggested that the intervention did not significantly alter Intensive Treatments over time at Hospital 1 and was associated with a significant slowing of the already decreasing use of Intensive Treatments at Hospital 2. Among patients who died in hospital, there was minimal change at either site. Conclusions There was no reduction in Intensive Treatments in older medical inpatients following the introduction of standardised goals of care documentation.

Time-restricted eating improves glycemic control and dampens energy-consuming pathways in human adipose tissue.

OBJECTIVE: We sought to examine the effects of 8 wk of time-restricted eating (TRE) on glucose metabolism and the adipose tissue transcriptome during a metabolic ward stay in men with obesity. METHODS: In a single-arm, pre-post trial, 15 men (ages 63 ± 4 y, body mass index = 30.5 ± 2.4 kg/m2, waist circumference = 113 ± 4 cm) with obesity but no history of diabetes were enrolled and underwent 2 wk of baseline monitoring before they were instructed to eat their regular diets within a contiguous 10-h time frame each day for 8 wk. Metabolic testing was performed at baseline and week 8 during a 35-h metabolic ward stay, during which all food intake was strictly timed and controlled. Identical meal-tolerance tests were performed at breakfast and dinner. Blood glucose, glucoregulatory hormones, and subjective appetite score were measured. Subcutaneous adipose tissue biopsies were performed and the transcriptome was assessed. RESULTS: The primary outcome, plasma glucose area under the curve, was altered by TRE, being unchanged at breakfast but increased at dinner. However, TRE reduced fasting glucose, glycated hemoglobin, body weight, and body fat, and increased glucose-dependent insulinotropic peptide area under the curve at dinner. In subcutaneous adipose tissue, 117 genes were up-regulated and 202 genes down-regulated by TRE. Pathway analysis revealed down-regulation of genes involved in proteasome function and mitochondrial regulation. CONCLUSIONS: TRE had a net effect of reducing glycemia and dampening energy-consuming pathways in adipose tissue.

Designing the ultimate general medicine model.

The ideal model of care in general medicine remains elusive, perhaps because of interhospital heterogeneity in patient population and resource allocation to both general medicine and the medical subspecialties. We explain why successful interventions at one site are not easily applied in another and recommend a nationally coordinated examination of the best general medicine departments' methods of clinical practice improvement.

B-cell depletion abrogates immune mediated cytopenia and rejection of cord blood transplantation in Hurler syndrome.

Umbilical cord blood is the preferred donor cell source for children with Inherited Metabolic disorders undergoing Hematopoietic Cell Transplant (HCT), and its use has been associated with improved "engrafted survival" and higher donor chimerism compared to other cell sources. However, as in other pediatric cord blood transplants for non-malignant disease, immune-mediated cytopenia and primary graft failure limit its use, and the latter remains the commonest cause of death following cord blood transplant for non-malignant disease. We have previously shown an association between immune-mediated cytopenia and graft failure in inherited metabolic diseases suggesting that both immune-mediated cytopenia and graft failure could be mediated by antibodies from the residual recipient B cells. Since rituximab is effective in depletion of B cells and management of refractory immune-mediated cytopenia following HCT, we have added rituximab to the conditioning regimen. We studied 57 patients in 2 centers who received myeloablative conditioning for cord blood transplant in Hurler syndrome, and report a significant improvement in event-free survival with reduced incidence of graft failure and without any evidence of immune-mediated cytopenia in those patients that had received rituximab.

Sampling implications of variation in daily activity of the sheep tick, Ixodes ricinus at a coastal grassland site in the U.K.

The sheep tick, Ixodes ricinus L. (Acari: Ixodidae), is an important vector of many pathogens of medical and veterinary significance. Determining vector abundance is a requisite of assessing potential vector-borne disease risk. Estimation of tick abundance is often conducted by blanket drag sampling a site, conducted at one time point during the day. The time of day chosen for sampling can vary, is not widely standardized and is often unreported by the investigator. This study investigated whether the time of day chosen for sampling had an effect on tick collection at an open grassland coastal site in North Devon, U.K., during May 2019 to July 2019. Tick abundance for both adults and nymphs in the evening period was more than twice that found in the mid-day sampling period. Overall abundance differed with site aspect, ground temperature and relative humidity. This study shows that for this open grassland recreational site, the time of day chosen for sampling has important implications for tick collection and the assessment of the relative risk of human exposure to ticks and tick-borne infections.

Quantifying movement of multiple threatened species to inform adaptive management of environmental flows.

There is a growing need for water managers to refine and optimise environmental flow strategies (e-flows) to balance water requirements for humans and nature. With increasing demands for freshwater and consequent declines in biodiversity, managers are faced with the problem of how to adaptively manage e-flows for multiple stakeholders and species whose flow requirements may overlap or vary. This study assessed the effectiveness of a regulated e-flow release strategy from a dam, aimed at providing movement opportunities and facilitating reproductive processes for multiple threatened species. Movements of 24 Mary River cod (Maccullochella mariensis), 20 Australian lungfish (Neoceratodus forsteri) and 13 Mary River turtle (Elusor macrurus) were quantified using acoustic telemetry over a three-year period. The influence of regulated e-flow releases, season, river depth, water temperature and rainfall on animal movements was assessed using Generalised linear mixed models (GLMMs). Models showed that hydraulic connectivity provided by both natural flows and regulated e-flow releases facilitated movement of all three species between pool habitats, throughout the year. Mary River turtles made extensive use of regulated e-flow releases when moving between habitats, whereas Mary River cod and Australian lungfish required additional natural rises in river height above the regulated e-flows to trigger movements. Significant movement activity was also recorded for cod and turtles during the dry season (winter and spring), broadly coinciding with breeding periods for these species. The effectiveness of, and potential improvements to, current e-flow strategies to sustain key life-history requirements of these species is discussed. Findings suggest a revised e-flow strategy with relatively minor increases in the magnitude of e-flow releases throughout winter and spring, would be effective in providing movement opportunities and supporting reproductive success for all three species. This study demonstrates that by quantifying movement behaviour in an e-flow context, ecological risk assessment frameworks can then be used to assess and provide for critical life-history requirements of multiple species within the context of a highly regulated system under increasing water use demands.

Colchicine inhibits ROS generation in response to glycoprotein VI stimulation.

Colchicine inhibits coronary and cerebrovascular events in patients with coronary artery disease (CAD), and although known to have anti-inflammatory properties, its mechanisms of action are incompletely understood. In this study, we investigated the effects of colchicine on platelet activation with a particular focus on its effects on activation via the collagen glycoprotein (GP)VI receptor, P2Y12 receptor, and procoagulant platelet formation. Therapeutic concentrations of colchicine in vitro (equivalent to plasma levels) significantly decreased platelet aggregation in whole blood and in platelet rich plasma in response to collagen (multiplate aggregometry) and reduced reactive oxygen species (ROS) generation (H2DCF-DA, flow cytometry) in response to GPVI stimulation with collagen related peptide-XL (CRP-XL, GPVI specific agonist). Other platelet activation pathways including P-selectin expression, GPIIb/IIIa conformational change and procoagulant platelet formation (GSAO+/CD62P+) (flow cytometry) were inhibited with higher concentrations of colchicine known to inhibit microtubule depolymerization. Pathway specific mechanisms of action of colchicine on platelets, including modulation of the GPVI receptor pathway at low concentrations, may contribute to its protective role in CAD.