Malglycemia in the critical care setting. Part III: Temporal patterns, relative potencies, and hospital mortality.

INTRODUCTION: The relationship between critical care mortality and combined impact of malglycemia remains undefined. METHODS: We assessed the risk-adjusted relationship (n = 4790) between hospital mortality with malglycemia, defined as hypergycemia (hours Glycemic Ratio ≥ 1.1, where GR is quotient of mean ICU blood glucose (BG) and estimated average BG), absolute hypoglycemia (hours BG < 70 mg/dL) and relative hypoglycemia (excursions GR < 0.7 in those with HbA1c ≥ 8%). RESULTS: Each malglycemia was independently associated with mortality - hyperglycemia (OR 1.0020/h, 95%CI 1.0009-1.0031, p = 0.0004), absolute hypoglycemia (OR 1.0616/h, 95%CI 1.0190-1.1061, p = 0.0043), and relative hypoglycemia (OR 1.2813/excursion, 95%CI 1.0704-1.5338, p = 0.0069). Absolute (7.4%) and relative hypoglycemia (6.7%) exposure dominated the first 24 h, decreasing thereafter. While hyperglycemia had lower risk association with mortality, it was persistently present across the length-of-stay (68-76% incidence daily), making it the dominant form of malglycemia. Relative contributions in the first five days from hyperglycemia, absolute hypoglycemia and relative hypoglycemia were 60%, 21% and 19% respectively. CONCLUSIONS: Absolute and relative hypoglycemia occurred largely in the first 24 h. Relative to all hypoglycemia, the associated mortality from the seemingly less potent but consistently more prevalent hyperglycemia steadily accumulated with increasing length-of-stay. This has important implications for interpretation of study results.

The impact of management option on out-of-pocket costs and perceived financial burden among men with localised prostate cancer in Australia within 6 months of diagnosis.

Objective This study aimed to quantify the out-of-pocket (OOP) costs and perceived financial burden among Australian men with localised prostate cancer in the first 6 months after diagnosis, by primary management option. Methods This cost-analysis quantified OOP costs using administrative claims data and self-reported survey data. Financial burden was assessed using the COmprehensive Score for financial Toxicity-Functional Assessment of Chronic Illness Therapy (COST-FACIT) tool. Participants were recruited into a randomised control trial from public or private treatment centres in Victoria and Queensland. Generalised linear models were used to predict OOP costs and COST-FACIT scores. Results Median total OOP costs within 6 months of diagnosis for 256 Australian patients with localised prostate cancer was A$1172 (A$343-2548). Up to 50% of the sample reported A$0 costs for most medical services. Compared with those managed with active surveillance, men having active treatment had 6.4 (95% CI: 3.2-12.7) times greater total OOP costs. Management option, higher Gleason score at diagnosis and having multiple comorbidities were significant predictors of higher OOP costs. Overall high scores on the COST-FACIT indicated low levels of financial burden for the entire sample. Conclusion Largely attributable to being managed with active surveillance, Australian men diagnosed with localised prostate cancer reported relatively low OOP costs and financial burden in the first 6 months post-diagnosis. Together with clinical outcomes, clinicians can use this up to date evidence on costs and perceived financial burdens to assist localised prostate cancer patients and their families make informed decisions about their preferred management option.

Comparative Effectiveness of Supine Avoidance versus Continuous Positive Airway Pressure for Treating Supine-isolated Sleep Apnea: A Clinical Trial.

Rationale: About 20-35% of patients with obstructive sleep apnea (OSA) have supine-isolated OSA, for which supine sleep avoidance could be an effective therapy. However, traditional supine discomfort-based methods show poor tolerance and compliance to treatment and so cannot be recommended. Supine alarm devices show promise, but evidence to support favorable adherence to treatment and effectiveness at reducing excessive daytime sleepiness compared with continuous positive airway pressure (CPAP) remains limited. Objectives: To establish if alarm-based supine-avoidance treatment in patients with supine-isolated OSA is noninferior to CPAP in reducing daytime sleepiness. Methods: After baseline questionnaire administration and in-home supine-time and polysomnography assessments, patients with supine-isolated OSA and Epworth Sleepiness Scale scores ⩾8 were randomized to ⩾6 weeks of supine-avoidance or CPAP treatment, followed by crossover to the remaining treatment with repeat assessments. Noninferiority was assessed from change in Epworth Sleepiness Scale with supine avoidance compared with CPAP using a prespecified noninferiority margin of 1.5. Average nightly treatment use over all nights and treatment efficacy and effectiveness at reducing respiratory disturbances were also compared between treatments. Results: The reduction in sleepiness score with supine avoidance (mean [95% confidence interval], -1.9 [-2.8 to -1.0]) was noninferior to that with CPAP (-2.4 [-3.3 to -1.4]) (supine avoidance-CPAP difference, -0.4 [-1.3 to 0.6]), and the lower confidence limit did not cross the noninferiority margin of 1.5 (P = 0.021). Average treatment use was higher with supine avoidance compared with CPAP (mean ± standard deviation, 5.7 ± 2.4 vs. 3.9 ± 2.7 h/night; P < 0.001). Conclusions: In patients with supine-isolated OSA, vibrotactile supine alarm device therapy is noninferior to CPAP for reducing sleepiness and shows superior treatment adherence. Clinical trial registered with www.anzctr.org.au (ACTRN 12613001242718).

Malglycemia in the critical care setting. Part II: Relative and absolute hypoglycemia.

INTRODUCTION: The relationship between critical care mortality and hypoglycemia, both relative (>30% below average preadmission glycemia) and absolute (blood glucose (BG) <70 mg/dL (<10 mmol/L)) requires further definition. METHODS: We assessed the risk-adjusted relationship between hospital mortality with relative hypoglycemia using the Glycemic Ratio (GR), and with absolute hypoglycemia using BG in a retrospective cohort investigation (n = 4790). RESULTS: Relative hypoglycemia excursions below GR 0.7 with a of 24-h non-exposure period between excursions in those with HbA1c ≥ 8% were independently associated with mortality (n = 373, OR 2.49, 95% CI 1.54-4.04, p = 0.0002) but not those with HbA1c < 8% (n = 4417, OR 0.98 95% CI 0.89-1.08, p = 0.70). Hours below GR 0.7 (1.0037, 0.9995-1.0080, 0.0846) or minimum GR (0.0896, 0.0030-2.6600, 0.1632) were not independently associated with outcome. Absolute hypoglycemia occurred across the HbA1c spectrum in a U-shaped pattern. There was no difference in mortality associated with exposure to BG < 70 mg/dL for HbA1c ≥ 6.5% vs <6.5% (29.7% vs 24.3%, p = 0.77). Hours below 70 mg/dL demonstrated strongest association with outcome, while minimum BG, and excursions below 70 mg/dL were also independently associated. CONCLUSIONS: Relative hypoglycemia represented by excursions below GR 0.7 in those with HbA1c ≥ 8% occurred commonly and was independently associated with mortality. Absolute hypoglycemia had similar association with mortality regardless of HbA1c.

Study protocol for ELders AT Ease (ELATE): a cluster randomised controlled trial of cognitive behaviour therapy to reduce depressive symptoms in aged care residents.

BACKGROUND: This protocol describes a study of the effectiveness of cognitive behaviour therapy (CBT) for reducing depressive symptoms in older adults living in residential aged care (RAC) facilities in Australia. Depressive symptoms are highly prevalent in this population, yet the benefits of CBT for reducing such symptoms in RAC facilities have not been widely investigated. Elders at Ease (ELATE) is a 16-session CBT intervention designed for implementation in RAC facilities. The intervention includes cognitive, behavioural and reminiscence strategies and is delivered by mental health trainees (MHTs) in collaboration with RAC facility staff and residents' family. METHODS AND ANALYSIS: ELATE will be evaluated using a cluster randomised trial comparing outcomes for residents who participate in the intervention with those living in usual care control facilities. The participants are RAC residents aged 65 years or above, with depressive symptoms (Patient Health Questionnaire-2 ≥ 3) and normal cognition or mild cognitive impairment (Standardised Mini Mental Status Examination ≥ 21). They are assessed at four time points: baseline prior to randomisation (T1), mid-treatment (T2; 2.5 months post randomisation), post-treatment (T3; 5 months post-randomisation) and 3-month follow-up (T4; 8 months post randomisation). The primary outcome is change in depressive symptoms between T1 and T3. Secondary outcomes are depressive symptoms at T4, anxiety, suicide ideation, sleep problems, quality of life, staff and family knowledge of late-life depression, stress levels and efficacy in caring for residents, and MHT levels of geropsychology competencies. Residents receiving the intervention are hypothesised to report a greater decrease in depressive symptoms between T1 and T3 compared to residents receiving usual care. The primary analysis is a regression, clustered over site to account for correlated readings, and independent variables are condition and depressive symptoms at T1. A cost-utility analysis is also undertaken. DISCUSSION: ELATE is a comprehensive CBT intervention for reducing depressive symptoms in RAC residents. It is designed to be implemented in collaboration with facility staff and residents' families, individually tailored to residents with normal cognition to mild cognitive impairment and delivered by trainee therapists. ELATE offers a model that may be widely applicable across the RAC sector. TRIAL REGISTRATION: Trial registered with the Australian and New Zealand Clinical Trial Registry (ANZCTR) Number ACTRN12619001037190, prospectively registered on 22 July 2019.

Impacts of high sensitivity troponin T reporting on care and outcomes in clinical practice: Interactions between low troponin concentrations and participant sex within two randomized clinical trials.

BACKGROUND: The impacts of high sensitivity cardiac troponin (hs-cTn) reporting on downstream interventions amongst suspected acute coronary syndrome (ACS) in the emergency department (ED), especially amongst those with newly identified hs-cTn elevations and in consideration of well-established sex-related disparities, has not been critically evaluated to date. This investigation explores the impact of hs-cTnT reporting on care and outcomes, particularly by participant sex. METHODS: Two similarly ED-based randomized controlled trials conducted between July 2011 to March 2013 (n = 1988) and August 2015 to April 2019 (n = 3378) were comparatively evaluated. Clinical outcomes were adjudicated to the Fourth Universal Definition of MI. Changes in practice were assessed at 30 days, and death or MI were explored to 12 months. RESULTS: The HS-Troponin study demonstrated no difference in death or MI with unmasking amongst those with hs-cTnT <30 ng/L, whereas the RAPID TnT study demonstrated a significantly higher rate. In RAPID TnT, there was significant increase in death or MI associated with unmasking for females with hs-cTnT <30 ng/L (masked: 11[1.5%], unmasked: 25[3.4%],HR: 2.27,95%C.I.:1.87-2.77,P < 0.001). Less cardiac stress testing with unmasking amongst those <30 ng/L was observed in males in both studies, which was significant in RAPID TnT (masked: 92[12.0%], unmasked: 55[7.0%], P = 0.008). In RAPID TnT, significantly higher rates of angiography in males were observed with unmasking, with no such changes amongst females <30 ng/L (masked: 28[3.7%], unmasked: 51[6.5%],P = 0.01). CONCLUSION: Compared with males, there were no evident impacts on downstream practices for females with unmasking in RAPID TnT, likely representing missed opportunities to reduce late death or MI.

Does virtual reality technology reduce pain and anxiety during outpatient hysteroscopy? A randomised controlled trial.

OBJECTIVE: To evaluate the effectiveness of virtual reality technology in reducing pain and anxiety during outpatient hysteroscopy. DESIGN: A prospective randomised controlled trial. SETTING: A London University Teaching Hospital. POPULATION: Women aged 18-70 years undergoing outpatient hysteroscopy procedures. METHODS: An unblinded randomised controlled trial was performed between March and October 2022 comparing standard outpatient hysteroscopy care with standard care with the addition of a virtual reality headset playing a virtual reality immersive scenario as a distraction technique. MAIN OUTCOME MEASURES: Pain and anxiety numeric rating scores (NRS) from 0 to 11. RESULTS: Eighty-three participants were randomly allocated to the control (n = 42) and virtual reality groups (n = 41). The virtual reality group experienced significantly less anxiety during the procedure than the control group (mean NRS 3.29 versus 4.73, mean difference 1.50; 95% confidence interval [CI] 0.12-2.88; P = 0.03). There was no difference in reported average pain (mean NRS 3.73. versus 4.24, mean difference 0.51; 95% CI -1.76 to 0.64; p = 0.41) or maximum pain scores (mean NRS 5.32 versus 5.07, mean difference 0.25; 95% CI -1.05 to 1.55; P = 0.71). CONCLUSIONS: The use of virtual reality technology as an adjunct to standard care can reduce patient-reported anxiety but not pain during outpatient hysteroscopy procedures. Continued improvements in the technology and the development of increasingly immersive environments may continue to increase the potential to improve the patient experience in this setting.

Malglycemia in the critical care setting. Part I: Defining hyperglycemia in the critical care setting using the glycemic ratio.

INTRODUCTION: Stress-induced hyperglycemia (SIH) is conventionally represented by Blood Glucose (BG) although recent evidence indicates the Glycemic Ratio (GR, quotient of mean BG and estimated preadmission BG) is a superior prognostic marker. We assessed the association between in-hospital mortality and SIH, using BG and GR in an adult medical-surgical ICU. METHODS: We included patients with hemoglobin A1c (HbA1c) and minimum four BGs in a retrospective cohort investigation (n = 4790). RESULTS: A critical SIH threshold of GR 1.1 was identified. Mortality increased with increasing exposure to GR ≥ 1.1 (r2 = 0.94, p = 0.0007). Duration of exposure to BG ≥ 180 mg/dL demonstrated a less robust association with mortality (r2 = 0.75, p = 0.059). In risk-adjusted analyses, hours GR ≥ 1.1 (OR 1.0014, 95%CI (1.0003-1.0026), p = 0.0161) and hours BG ≥ 180 mg/dL (OR 1.0080, 95%CI (1.0034-1.0126), p = 0.0006) were associated with mortality. In the cohort with no exposure to hypoglycemia however, only hours GR ≥ 1.1 was associated with mortality (OR 1.0027, 95%CI (1.0012-1.0043), p = 0.0007), not BG ≥ 180 mg/dL (OR 1.0031, 95%CI (0.9949-1.0114), p = 0.50) and this relationship remained intact for those who never experienced BG outside the 70-180 mg/dL range (n = 2494). CONCLUSIONS: Clinically significant SIH commenced above GR 1.1. Mortality was associated with hours of exposure to GR ≥ 1.1 which was a superior marker of SIH compared to BG.

Role of the endocannabinoid system in fragile X syndrome: potential mechanisms for benefit from cannabidiol treatment.

Multiple lines of evidence suggest a central role for the endocannabinoid system (ECS) in the neuronal development and cognitive function and in the pathogenesis of fragile X syndrome (FXS). This review describes the ECS, its role in the central nervous system, how it is dysregulated in FXS, and the potential role of cannabidiol as a treatment for FXS. FXS is caused by deficiency or absence of the fragile X messenger ribonucleoprotein 1 (FMR1) protein, FMRP, typically due to the presence of >200 cytosine, guanine, guanine sequence repeats leading to methylation of the FMR1 gene promoter. The absence of FMRP, following FMR1 gene-silencing, disrupts ECS signaling, which has been implicated in FXS pathogenesis. The ECS facilitates synaptic homeostasis and plasticity through the cannabinoid receptor 1, CB1, on presynaptic terminals, resulting in feedback inhibition of neuronal signaling. ECS-mediated feedback inhibition and synaptic plasticity are thought to be disrupted in FXS, leading to overstimulation, desensitization, and internalization of presynaptic CB1 receptors. Cannabidiol may help restore synaptic homeostasis by acting as a negative allosteric modulator of CB1, thereby attenuating the receptor overstimulation, desensitization, and internalization. Moreover, cannabidiol affects DNA methylation, serotonin 5HT1A signal transduction, gamma-aminobutyric acid receptor signaling, and dopamine D2 and D3 receptor signaling, which may contribute to beneficial effects in patients with FXS. Consistent with these proposed mechanisms of action of cannabidiol in FXS, in the CONNECT-FX trial the transdermal cannabidiol gel, ZYN002, was associated with improvements in measures of social avoidance, irritability, and social interaction, particularly in patients who are most affected, showing ≥90% methylation of the FMR1 gene.

Uterine-preserving treatments or hysterectomy reintervention after myomectomy or uterine artery embolisation: A retrospective cohort study of long-term outcomes.

OBJECTIVE: To assess comparative rates of further uterine-preserving procedures (UPP) or hysterectomy reintervention, after myomectomy or uterine artery embolisation (UAE). DESIGN: Population-based, retrospective cohort study. SETTING: England. POPULATION: Women who underwent myomectomy or UAE between 2010 and 2015 under the NHS. METHODS: Data was abstracted from NHS Health Episode Statistics datasets. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using Cox proportional-hazards regression. MAIN OUTCOMES MEASURES: 30-day readmission, UPP and hysterectomy reintervention rates. RESULTS: 9443 and 6224 women underwent elective myomectomy or UAE, respectively. After 118 136 total person-years of follow-up, the rate of hysterectomy was 8.34 and 20.98 per 1000 patient years for myomectomy or UAE, respectively. There was a 2.4-fold increased risk of undergoing hysterectomy after UAE when compared with myomectomy in adjusted models (HR 2.38 [95% CI 2.10-2.66]) [adjusted for age, ethnicity, multiple deprivation index, geographical region and comorbidities]. The HR for undergoing a UPP reintervention was 1.44 (95% CI 1.29-1.60) in favour of myomectomy. The rate of hysterectomy was increased 22% following UAE compared with laparoscopic myomectomy (0.97-1.52). Age may influence reintervention rates, and there was variation in hysterectomy risk when stratified by geographical region. CONCLUSIONS: After a median of 7 years of follow-up, there is a 2.4-fold increased rate of hysterectomy and 44% increased risk of UPPs as reintervention after UAE, relative to myomectomy. These findings will aid pre-procedure counselling for women with fibroids. Future work should investigate the effect of other outcome modifiers, such as fertility intentions and fibroid anatomical characteristics.

A randomized, controlled trial of ZYN002 cannabidiol transdermal gel in children and adolescents with fragile X syndrome (CONNECT-FX).

BACKGROUND: Fragile X syndrome (FXS) is associated with dysregulated endocannabinoid signaling and may therefore respond to cannabidiol therapy. DESIGN: CONNECT-FX was a double-blind, randomized phase 3 trial assessing efficacy and safety of ZYN002, transdermal cannabidiol gel, for the treatment of behavioral symptoms in children and adolescents with FXS. METHODS: Patients were randomized to 12 weeks of ZYN002 (250 mg or 500 mg daily [weight-based]) or placebo, as add-on to standard of care. The primary endpoint assessed change in social avoidance (SA) measured by the Aberrant Behavior Checklist-Community Edition FXS (ABC-CFXS) SA subscale in a full cohort of patients with a FXS full mutation, regardless of the FMR1 methylation status. Ad hoc analyses assessed efficacy in patients with ≥ 90% and 100% methylation of the promoter region of the FMR1 gene, in whom FMR1 gene silencing is most likely. RESULTS: A total of 212 patients, mean age 9.7 years, 75% males, were enrolled. A total of 169 (79.7%) patients presented with ≥ 90% methylation of the FMR1 promoter and full mutation of FMR1. Although statistical significance for the primary endpoint was not achieved in the full cohort, significant improvement was demonstrated in patients with ≥ 90% methylation of FMR1 (nominal P = 0.020). This group also achieved statistically significant improvements in Caregiver Global Impression-Change in SA and isolation, irritable and disruptive behaviors, and social interactions (nominal P-values: P = 0.038, P = 0.028, and P = 0.002). Similar results were seen in patients with 100% methylation of FMR1. ZYN002 was safe and well tolerated. All treatment-emergent adverse events (TEAEs) were mild or moderate. The most common treatment-related TEAE was application site pain (ZYN002: 6.4%; placebo: 1.0%). CONCLUSIONS: In CONNECT-FX, ZYN002 was well tolerated in patients with FXS and demonstrated evidence of efficacy with a favorable benefit risk relationship in patients with ≥ 90% methylation of the FMR1 gene, in whom gene silencing is most likely, and the impact of FXS is typically most severe. TRIAL REGISTRATION: The CONNECT-FX trial is registered on Clinicaltrials.gov (NCT03614663).

The Glycemic Ratio Is Strongly and Independently Associated With Mortality in the Critically Ill.

BACKGROUND: Interventional studies investigating blood glucose (BG) management in intensive care units (ICU) have been inconclusive. New insights are needed. We assessed the ability of a new metric, the Glycemic Ratio (GR), to determine the relationship of ICU glucose control relative to preadmission glycemia and mortality. METHODS: Retrospective cohort investigation (n = 4790) in an adult medical-surgical ICU included patients with minimum four BGs, hemoglobin (Hgb), and hemoglobin A1c (HbA1c). The GR is the quotient of mean ICU BGs (mBG) and estimated preadmission BG, derived from HbA1c. RESULTS: Mortality displayed a J-shaped curve with GR (nadir GR 0.9), independent of background glycemia, consistent for HbA1c <6.5% vs >6.5%, and Hgb >10 g/dL vs <10 g/dL and medical versus surgical. An optimal range of GR 0.80 to 0.99 was associated with decreased mortality compared with GR above and below this range. The mBG displayed a linear relationship with mortality at lower HbA1c but diminished for HbA1c >6.5%, and dependent on preadmission glycemia. In adjusted analysis, GR remained associated with mortality (odds ratio = 2.61, 95% confidence interval = 1.48-4.62, P = .0012), but mBG did not (1.004, 1.000-1.009, .059). A single value on admission was not independently associated with mortality. CONCLUSIONS: The GR provided new insight into malglycemia that was not apparent using mBG, or an admission value. Mortality was associated with acute change from preadmission glycemia (GR). Further assessment of the impact of GR deviations from the nadir in mortality at GR 0.80 to 0.99, as both relative hypo- and hyperglycemia, and as duration of exposure and intensity, may further define the multifaceted nature of malglycemia.

Pregnancy Outcomes After Transcervical Radiofrequency Ablation of Uterine Fibroids with the Sonata System.

Objective: To describe pregnancy outcomes in women who conceived after undergoing transcervical fibroid ablation (TFA) as treatment for symptomatic uterine fibroids. Materials and Methods: TFA was used to treat symptomatic uterine fibroids with radiofrequency energy, both under clinical trial protocol and commercial usage in hospitals in Europe, the United Kingdom, Mexico, and the United States. All women who reported pregnancies to their physicians after undergoing TFA with the Sonata® System and provided consent for use of their data were included. Results: There have been 36 pregnancies representing 20 deliveries among 28 women who were treated with TFA. Five women conceived more than once postablation, and four conceived as a result of assisted reproductive technology (ART). Outcomes include 8 vaginal deliveries, 12 Cesarean sections, 3 therapeutic abortions, and 8 first trimester spontaneous abortions (four occurring in a patient with a history of recurrent pregnancy loss and an immunologic disorder). Five women are currently pregnant, two of whom previously delivered after TFA. There were no 5-minute Apgar scores <7, and all neonates weighed >2500 g. All deliveries occurred at ≥37 weeks except for one delivery at 35 6/7 weeks. There were no uterine ruptures or abnormal placentation and no reports of postpartum hemorrhage or stillbirths. Ablated fibroids included transmural, submucous, and intramural myomata up to 7 cm in diameter. Conclusions: Normal pregnancy outcomes at term have occurred after TFA with the Sonata System, including in women with recurrent abortion and in those undergoing ART. There were no instances of low Apgar scores, low birthweight, stillbirth, postpartum hemorrhage, or uterine rupture (FAST-EU, NCT01226290; SONATA, NCT02228174; SAGE, NCT03 118037). (J GYNECOL SURG 38:207).

Uncertainty and the unmet informational needs of patients with cancer of unknown primary (CUP): a cross-sectional multi-site study.

OBJECTIVE: This study aimed to determine the healthcare experiences, quality of life, and psychosocial needs of patients with cancer of unknown primary (CUP) early after diagnosis; comparing their experiences to patients with advanced cancer of a known primary (non-CUP control patients) and published general population reference data where available. METHODS: This study was a cross-sectional, multi-site study comparing CUP patients (n = 139) compared to non-CUP controls (n = 45). Demographic, clinical information and patient-reported outcome questionnaire data were collected at baseline. RESULTS: Differences in healthcare experienced were found between CUP and non-CUP controls with CUP patients reporting higher scores for unmet medical communication/information needs compared with non-CUP control patients (p = 0.013) as well as greater uncertainty in illness (p = 0.042). Whilst no differences were found between CUP and non-CUP controls on the EORTC and PROMIS measures, of those that 'received written information about your cancer…' and asked '…how useful was it?' fewer CUP patients reported finding the information useful 40% vs 61%, and more were likely to not have received written information at all 59% vs 32%; (p = 0.002). Additionally, of those that found information about their cancer online, fewer patients with CUP reported finding it useful 32% vs 48% control patients (p = 0.005). CONCLUSIONS: CUP patients have unmet medical communication/information needs and greater uncertainty in illness but do not differ in health-related quality of life domains compared to patients with advanced cancer of a known primary.

COlchicine to Prevent PeriprocEdural Myocardial Injury in Percutaneous Coronary Intervention (COPE-PCI): Coronary Microvascular Physiology Pilot Substudy.

Aim: In this randomized pilot trial, we aimed to assess the anti-inflammatory effect of preprocedural colchicine on coronary microvascular physiology measurements before and after PCI. Methods: Patients undergoing PCI for stable angina (SA) or non-ST-elevation myocardial infarction (NSTEMI) were randomized to oral colchicine or placebo, 6- to 24-hours before the procedure. Strict prespecified inclusion/exclusion criteria were set to ensure all patients were given the study medication, had a PCI, and had pre- and post-PCI culprit vessel invasive coronary physiology measurements. Fractional flow reserve (FFR), Index of Microvascular Resistance (IMR), Coronary Flow Reserve (CFR), and Resistive Reserve Ratio (RRR) were measured immediately before and after PCI. CMVD was defined as any one of post-PCI IMR >32 or CFR <2 or RRR <2. High-sensitive-(hs)-troponin-I, hsCRP, and leucocyte count were measured before and 24 hours after PCI. Results: A total of 50 patients were randomized and met the strict prespecified inclusion/exclusion criteria: 24-colchicine and 26-placebo. Pre-PCI coronary physiology measurements, hs-troponin-I, and hsCRP were similar between groups. Although numerically lower in patients given colchicine, the proportion of patients who developed CMVD was not significantly different between groups (colchicine: 10 (42%) vs placebo: 16 (62%), p=0.16). Colchicine patients had higher post-PCI CFR and RRR vs placebo (respectively: 3.25 vs 2.00, p=0.03 & 4.25 vs 2.75, p < 0.01). Neutrophil count was lower after PCI in the colchicine arm (p=0.02), and hsCRP post-PCI remained low in both treatment arms (1.0 mg/L vs 1.7 mg/L, p=0.97). Patients randomized to colchicine had significantly less PCI-related absolute hs-troponin-I change (46 ng/L vs 152 ng/L, p=0.01). Conclusion: In this pilot randomized substudy, colchicine given 6 to 24 hours before PCI did not statistically impact the post-PCI CMVD definition used in this study, yet it did improve post-PCI RRR and CFR measurements, with less procedure-related troponin release and less inflammation.

Colchicine and Quality of Life in Patients With Acute Coronary Syndromes: Results From the COPS Randomized Trial.

BACKGROUND: Recent data suggest that colchicine may reduce cardiovascular events among patients presenting with acute coronary syndromes. This sub-study of the Australian COPS trial aimed to assess whether colchicine affects health status outcomes. METHODS: Health status was assessed at baseline and 12-months using the EuroQol-5 Dimension 5-level (EQ-5D-5L) score and the full 19-question Seattle Angina Questionnaire (SAQ). Data were available for 786 patients (388 randomized to colchicine, 398 to placebo). RESULTS: Baseline characteristics were well matched between groups; mean age was 60.1 (SD 14.8) years, and 20 % were female. Baseline health status scores were impaired, and most parameters demonstrated significant improvement from baseline to 12-months (EQ-5D-5L Visual Analogue Score [VAS] 69.3 to 77.7; SAQ angina frequency score 83.0 to 95.3, both p < 0.001). No significant differences in adjusted mean score change among any of the EQ-5D-5L or SAQ dimensions were observed between treatment groups in either intention-to-treat or per-protocol analysis. There were borderline interactions in EQ-5D-5L scores for those with previous MI vs not, and in SAQ scores for those with obesity vs not. In categorical analysis using observed data, patients treated with colchicine were more likely to have clinically significant improvement in physical limitation score over the period (36 % improved vs. 28 %, p < 0.05). Baseline health status scores were not associated with the primary endpoint at 12 months. CONCLUSIONS: Treatment with colchicine did not appear to affect change in measures of health status following acute coronary syndromes, but it did lead to a greater likelihood of improvement in physical limitation scores. TRIAL REGISTRATION: ACTRN, ACTRN12615000861550. Registered 18/08/2015, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=368973.

Quantitative assessment of pregnancy outcome following recurrent miscarriage clinic care: a prospective cohort study.

OBJECTIVES: To measure pregnancy outcome following attendance at a recurrent miscarriage service and identify factors that influence outcome. DESIGN: Prospective, observational electronic cohort study. SETTING: Participants attending a specialist recurrent miscarriage clinic, with a history of two or more pregnancy losses. 857 new patients attended over a 30-month period and were invited to participate. Participant data were recorded on a bespoke study database, 'Tommy's Net'. PARTICIPANTS: 777 women consented to participate (90.7% of new patients). 639 (82%) women continued within the cohort, and 138 were lost to follow-up. Mean age of active participants was 34 years for women and 37 years for partners, with a mean of 3.5 (1-19) previous pregnancy losses. Rates of obesity (maternal: 23.8%, paternal: 22.4%), smoking (maternal:7.4%, paternal: 19.4%) and alcohol consumption (maternal: 50%, paternal: 79.2%) were high and 55% of participants were not taking folic acid. OUTCOME MEASURES: Biannual collection of pregnancy outcomes, either through prompted self-reporting, or existing hospital systems. RESULTS: 639 (82%) women were followed up. 404 (83.4%) reported conception and 106 (16.6%) reported no pregnancy, at least 6 months following registration. Of those that conceived, 72.8% (294/404) had a viable pregnancy. Maternal smoking and body mass index (BMI) over 30 were significantly higher in those who did not conceive (p=0.001) CONCLUSIONS: Tommy's Net provides a secure electronic repository on data for couples with recurrent pregnancy loss and associated outcomes. The study identified that subfertility, as well as repeated miscarriage, maternal BMI and smoking status, contributed to failure to achieve live birth. Study findings may enable comparison of clinic outcomes and inform the development of a personalised holistic care package.

Cost effectiveness of a 1-hour high-sensitivity troponin-T protocol: An analysis of the RAPID-TnT trial.

BACKGROUND: To understand the economic impact of an accelerated 0/1-hour high-sensitivity troponin-T (hs-cTnT) protocol. OBJECTIVE: To conduct a patient-level economic analysis of the RAPID-TnT randomised trial in patients presenting with suspected acute coronary syndrome (ACS). METHODS: An economic evaluation was conducted with 3265 patients randomised to either the 0/1-hour hs-cTnT protocol (n = 1634) or the conventional 0/3-hour standard-of-care protocol (n = 1631) with costs reported in Australian dollars. The primary clinical outcome was all-cause mortality or new/recurrent myocardial infarction. RESULTS: Over 12-months, mean per patient costs were numerically higher in the 0/1-hour arm compared to the conventional 0/3-hour arm (by $472.49/patient, 95% confidence interval [95 %CI]: $-1,380.15 to $2,325.13, P = 0.617) with no statistically significant difference in primary outcome (0/1-hour: 62/1634 [3.8%], 0/3-hour: 82/1631 [5.0%], HR: 1.32 [95 %CI: 0.95-1.83], P = 0.100). The mean emergency department (ED) length of stay (LOS) was significantly lower in the 0/1-hour arm (by 0.62 h/patient, 95 %CI: 0.85 to 0.39, P < 0.001), but the subsequent 12-month unplanned inpatient costs was numerically higher (by $891.22/patient, 95 %CI: $-96.07 to 1,878.50, P = 0.077). Restricting the analysis to patients with hs-cTnT concentrations ≤ 29 ng/L, mean per patient cost remained numerically higher in the 0/1-hour arm (by $152.44/patient, 95 %CI:$-1,793.11 to $2,097.99, P = 0.988), whilst the reduction in ED LOS was more pronounced (by 0.70 h/patient, 95 %CI: 0.45-0.95, P < 0.001). CONCLUSIONS: There were no differences in resource utilization between the 0/1-hour hs-cTnT protocol versus the conventional 0/3-hour protocol for the assessment of suspected ACS, despite improved initial ED efficiency. Further refinements in strategies to improve clinical outcomes and subsequent management efficiency are needed.

COlchicine to Prevent PeriprocEdural Myocardial Injury in Percutaneous Coronary Intervention (COPE-PCI): A Descriptive Cytokine Pilot Sub-Study.

BACKGROUND: High levels of inflammation pre- and post-percutaneous coronary intervention (PCI) are associated with worse outcomes. Recent trials have suggested a benefit from treating inflammation with colchicine in coronary artery disease. In this randomised pilot COPE-PCI sub-study, we aimed to determine if administration of colchicine pre-PCI, would attenuate the inflammatory effect of PCI. METHODS: PCI patients were randomised to colchicine or placebo, 6 to 24-hours pre-procedure. Study blood samples were taken immediately pre-PCI, and 24-hours post-procedure. Samples were tested for a broad array of inflammatory biomarkers including high-sensitive(hs)-CRP, leucocyte counts, and hs-troponin-. Periprocedural Myocardial Injury (PM-Injury) was defined as per the ESC Third Universal Definitions of Myocardial Infarction. RESULTS: Thirty-six were randomised to colchicine and 39 to placebo. Treatment groups were similar for baseline variables. The median time from drug administration to pre-PCI blood sampling was 18-hours. Overall inflammation was low across the patient population, pre- & post-PCI hsCRP was <1.4 mg/L. Colchicine patients had numerically lower levels of pre-PCI cytokines: IL-1ß (p = 0.01), IL-6 (p = 0.02), IL-10 (p = 0.01), IFNγ (p = 0.01), TNFα (p = 0.02) and WBC-count (p = 0.04). Post-PCI (38-hours post-drug) measures of inflammation were similar between treatment arms. Absolute troponin change (post-PCI - pre-PCI levels) was less in colchicine patients (p = 0.02). CONCLUSION: The reduction in PCI-related myocardial injury that resulted from colchicine given on median 18 h pre-PCI, was associated with numerically lower levels of inflammation pre-PCI but no difference one day post-PCI in the colchicine vs placebo groups. CLINICAL TRIAL REGISTRATION: The trial was publicly registered at www.anzctr.org.au, Trial ID: ACTRN12615000485538.