Functional Activity of Enantiomeric Oximes and Diastereomeric Amines and Cyano Substituents at C9 in 3-Hydroxy-N-phenethyl-5-phenylmorphans.

The synthesis of stereochemically pure oximes, amines, saturated and unsaturated cyanomethyl compounds, and methylaminomethyl compounds at the C9 position in 3-hydroxy-N-phenethyl-5-phenylmorphans provided µ-opioid receptor (MOR) agonists with varied efficacy and potency. One of the most interesting compounds, (2-((1S,5R,9R)-5-(3-hydroxyphenyl)-2-phenethyl-2-azabicyclo[3.3.1]nonan-9-yl)acetonitrile), was found to be a potent partial MOR agonist (EC50 = 2.5 nM, %Emax = 89.6%), as determined in the forskolin-induced cAMP accumulation assay. Others ranged in potency and efficacy at the MOR, from nanomolar potency with a C9 cyanomethyl compound (EC50 = 0.85 nM) to its totally inactive diastereomer, and three compounds exhibited weak MOR antagonist activity (the primary amine 3, the secondary amine 8, and the cyanomethyl compound 41). Many of the compounds were fully efficacious; their efficacy and potency were affected by both the stereochemistry of the molecule and the specific C9 substituent. Most of the MOR agonists were selective in their receptor interactions, and only a few had δ-opioid receptor (DOR) or κ-opioid receptor (KOR) agonist activity. Only one compound, a C9-methylaminomethyl-substituted phenylmorphan, was moderately potent and fully efficacious as a KOR agonist (KOR EC50 = 18 nM (% Emax = 103%)).

Comparison of electrographic changes, clinical features and outcomes in different variants of Takotsubo syndrome.

BACKGROUND: Dysfunction of the left ventricular (LV) apex (apical variant) is the most common form in Takotsubo syndrome (TS). Several less common non-apical variants have been described - mid-ventricular, basal and focal. We hypothesised that the clinical presentation, and electrocardiographic (ECG) findings may vary between apical and non-apical TS. METHODS: We prospectively identified 194 consecutive patients with TS presenting to Middlemore Hospital, Auckland and obtained clinical, echocardiography, coronary angiography, and long-term follow-up data. ECGs at admission and Day 1 were compared. RESULTS: Of 194 patients with TS, 168 (86.6%) had apical TS, and 26 (13.4%) non-apical TS (11 mid-ventricular TS, 5 basal TS, 10 focal TS). Apical TS patients had more significant LV systolic impairment (p = 0.001) and longer length of stay (p = 0.001). The extent of T-wave inversion (TWI) was similar for both groups on admission (p = 0.88). By Day 1 the extent of TWI was greater in apical TS group (median number of leads 5 vs. 1, p = 0.02). The change in QTc interval between admission and Day 1 was greater in apical TS group (29.7 ms vs. 2.77 ms, p < 0.001). Composite in-hospital complication rate was similar for both groups (13.7% vs. 15.4%, p = 0.77). CONCLUSIONS: Compared with non-apical variants, apical TS patients develop more extensive TWI and greater QT prolongation on ECG, and more significant LV systolic impairment, but in-hospital complications were similar. Clinicians should be aware that there is a sub-group of TS patients who have non-apical regional wall motion abnormalities and who don't develop ECG changes typical of the more common apical variant.

Recurrent Takotsubo Syndrome: How Frequent, and How Does It Present?

BACKGROUND: Recurrent Takotsubo syndrome (TS) is not uncommon but experience with TS recurrence is inherently limited by the infrequency of the condition itself and incomplete long-term follow-up. There is limited published data on the clinical features and outcomes of patients with recurrent TS. We aimed to describe the clinical characteristics and outcomes of patients with recurrent TS in a large Auckland cohort. METHOD: The clinical profile, in-hospital, and long-term outcomes were prospectively assessed in consecutive patients with recurrent TS presenting to Auckland's three major hospitals between January 2006 and January 2023. RESULTS: During the study period, 472 TS patients were identified. Of the 467 patients discharged alive after the index event, 45 (9.6%) patients (mean age 62.3±11.0 years), all women, experienced recurrent TS. Median time interval from index event to the first recurrence was 3.14 years (range 27 days to 13.8 years). In 27 (60%) of the 45 patients, the subsequent events involved a stressor (physical triggers, n=8; emotional triggers, n=19). The stressor type differed between the index and recurrent event in 18 (40%) of the 45 patients. Thirteen (28.9%) had a different echocardiographic variant of TS at first recurrence. All patients with recurrent TS were discharged alive. Four patients died late after discharge from the first recurrence, all but one from a non-cardiac cause. CONCLUSIONS: One in 10 patients with TS experience recurrent events. These may occur many years later, and both the stressor type and the echocardiographic variant may be different at the recurrent event.

Cardiogenic Shock Prior to Percutaneous Coronary Intervention in ST-Elevation Myocardial Infarction: Outcomes and Predictors of Mortality (ANZACS-QI 73).

BACKGROUND & AIMS: Cardiogenic shock (CS) is a serious complication of acute myocardial infarction (MI) and is associated with significant mortality. We describe a contemporary, real-world cohort of patients with ST-elevation MI (STEMI) and CS, including 30-day mortality and clinically relevant predictors of mortality. METHODS: All patients presenting with STEMI who were treated with percutaneous coronary intervention (PCI) in New Zealand (2016 to 2020) were identified from the Aotearoa New Zealand All Cardiology Services Quality Improvement (ANZACS-QI) registry and stratified based on their Killip class on arrival to the cardiac catheterisation laboratory. Primary outcome was 30-day all-cause mortality. Multivariable analysis was used to identify predictors of mortality prior to PCI and to develop a mortality scoring system. RESULTS: In total, 6,649 patients were identified, including 192 (2.9%) Killip IV (CS) patients. Thirty-day mortality was 47.5% in patients with CS, 14.6% in those with heart failure without shock, and 3% in those without heart failure. Independent predictors of 30-day mortality for patients with CS were: estimated glomerular filtration rate <60 mL/min/1.73m2 (relative risk [RR] 1.89, 95% confidence interval [CI] 1.39-2.58), cardiac arrest (RR 1.54, 95% CI 1.15-2.06), diabetes (RR 1.31, 95% CI 1.01-1.70), female sex (RR 1.32, 95% CI 1.01-1.72), femoral arterial access (RR 1.42, 95% CI 1.06-1.90) and left main stem culprit (RR 2.16, 95% CI 1.65-2.84). A multivariable Shock score was developed which predicts 30-day mortality with good global discrimination (area under the curve 0.79, 95% CI 0.73-0.85). CONCLUSION: In this national cohort, the 30-day mortality for STEMI patients presenting with CS treated with PCI remains high, at nearly 50%. The ANZACS-QI Shock score is a promising tool for mortality risk stratification prior to PCI but requires further validation.

New Alpha9 nAChR Ligands Based on a 5-(Quinuclidin-3-ylmethyl)-1,2,4-oxadiazole Scaffold.

Several lines of evidence have indicated that nicotinic acetylcholine receptors (nAChR) that contain α9 subunits, probably in combination with α10 subunits, may be valuable targets for the management of pain associated with inflammatory diseases through a cholinergic anti-inflammatory system (CAS), which has also been associated with α7 nAChR. Both α7- and α9-containing neuronal nAChR can be pharmacologically distinguished from the high-affinity nicotinic receptors of the brain by their sensitivity to α-bungarotoxin, but in other ways, they have quite distinct pharmacological profiles. The early association of α7 with CAS led to the development of numerous new ligands, variously characterized as α7 agonists, partial agonists, or silent agonists that desensitized α7 receptors without activation. Subsequent reinvestigation of one such family of α7 ligands based on an N,N-diethyl-N'-phenylpiperazine scaffold led to the identification of potent agonists and antagonists for α9. In this paper, we characterize the α9/α10 activity of a series of compounds based on a 5-(quinuclidin-3-ylmethyl)-1,2,4-oxadiazole (QMO) scaffold and identify two new potent ligands of α9, QMO-28, an agonist, and QMO-17, an antagonist. We separated the stereoisomers of these compounds to identify the most potent agonist and discovered that only the 3R isomer of QMO-17 was an α9 antagonist, permitting an in silico model of α9 antagonism to be developed. The α9 activity of these compounds was confirmed to be potentially useful for CAS management of inflammatory pain in cell-based assays of cytokine release.

Design, Synthesis, and Structure-Activity Relationship Studies of Novel GPR88 Agonists (4-Substituted-phenyl)acetamides Based on the Reversed Amide Scaffold.

The development of synthetic agonists for the orphan receptor GPR88 has recently attracted significant interest, given the promise of GPR88 as a novel drug target for psychiatric and neurodegenerative disorders. Examination of structure-activity relationships of two known agonist scaffolds 2-PCCA and 2-AMPP, as well as the recently resolved cryo-EM structure of 2-PCCA-bound GPR88, led to the design of a new scaffold based on the "reversed amide" strategy of 2-AMPP. A series of novel (4-substituted-phenyl)acetamides were synthesized and assessed in cAMP accumulation assays as GPR88 agonists, which led to the discovery of several compounds with better or comparable potencies to 2-AMPP. Computational docking studies suggest that these novel GPR88 agonists bind to the same allosteric site of GPR88 that 2-PCCA occupies. Collectively, our findings provide structural insight and SAR requirement at the allosteric site of GPR88 and a new scaffold for further development of GPR88 allosteric agonists.

Sex differences in outcomes after acute coronary syndrome vary with age: a New Zealand national study.

AIMS: This study investigated age-specific sex differences in short- and long-term clinical outcomes following hospitalization for a first-time acute coronary syndrome (ACS) in New Zealand (NZ). METHODS AND RESULTS: Using linked national health datasets, people admitted to hospital for a first-time ACS between January 2010 and December 2016 were included. Analyses were stratified by sex and 10-year age groups. Logistic and Cox regression were used to assess in-hospital death and from discharge the primary outcome of time to first cardiovascular (CV) readmission or death and other secondary outcomes at 30 days and 2 years. Among 63 245 people (mean age 69 years, 40% women), women were older than men at the time of the ACS admission (mean age 73 vs. 66 years), with a higher comorbidity burden. Overall compared with men, women experienced higher rates of unadjusted in-hospital death (10% vs. 7%), 30-day (16% vs. 12%) and 2-year (44% vs. 34%) death, or CV readmission (all P < 0.001). Age group-specific analyses showed sex differences in outcomes varied with age, with younger women (<65 years) at higher risk than men and older women (≥85 years) at lower risk than men: unadjusted hazard ratio of 2-year death or CV readmission for women aged 18-44 years = 1.51 [95% confidence interval (CI) 1.21-1.84] and aged ≥85 years = 0.88 (95% CI 0.83-0.93). The increased risk for younger women was no longer significant after multivariable adjustment whereas the increased risk for older men remained. CONCLUSION: Men and women admitted with first-time ACS have differing age and comorbidity profiles, resulting in contrasting age-specific sex differences in the risk of adverse outcomes between the youngest and oldest age groups.

Development and validation of cardiovascular risk prediction equations in 76 000 people with known cardiovascular disease.

AIMS: Multiple health administrative databases can be individually linked in Aotearoa New Zealand, using encrypted identifiers. These databases were used to develop cardiovascular risk prediction equations for patients with known cardiovascular disease (CVD). METHODS AND RESULTS: Administrative health databases were linked to identify all people aged 18-84 years with known CVD, living in Auckland and Northland, Aotearoa New Zealand, on 1 January 2014. The cohort was followed until study outcome, death, or 5 years. The study outcome was death or hospitalization due to ischaemic heart disease, stroke, heart failure, or peripheral vascular disease. Sex-specific 5-year CVD risk prediction equations were developed using multivariable Fine and Gray models. A total of 43 862 men {median age: 67 years [interquartile range (IQR): 59-75]} and 32 724 women [median age: 70 years (IQR: 60-77)] had 14 252 and 9551 cardiovascular events, respectively. Equations were well calibrated with good discrimination. Increasing age and deprivation, recent cardiovascular hospitalization, Mori ethnicity, smoking history, heart failure, diabetes, chronic renal disease, atrial fibrillation, use of blood pressure lowering and anti-thrombotic drugs, haemoglobin A1c, total cholesterol/HDL cholesterol, and creatinine were statistically significant independent predictors of the study outcome. Fourteen per cent of men and 23% of women had predicted 5-year cardiovascular risk <15%, while 28 and 24% had ≥40% risk. CONCLUSION: Robust cardiovascular risk prediction equations were developed from linked routine health databases, a currently underutilized resource worldwide. The marked heterogeneity demonstrated in predicted risk suggests that preventive therapy in people with known CVD would be better informed by risk stratification beyond a one-size-fits-all high-risk categorization.

Using regionwide New Zealand health databases, methods of predicting hospitalization risk in patients with existing heart disease were developed. Using only data from health databases, it was possible to predict the risk accurately.Among patients with existing heart disease, the predicted risk varied markedly which could help improve preventive strategies.

Widening ethnic inequities in heart failure incidence in New Zealand.

OBJECTIVE: Ethnic inequities in heart failure (HF) have been documented in several countries. This study describes New Zealand (NZ) trends in incident HF hospitalisation by ethnicity between 2006 and 2018. METHODS: Incident HF hospitalisations in ≥20-year-old subjects were identified through International Classification of Diseases, 10th Revision-coded national hospitalisation records. Incidence was calculated for different ethnic, sex and age groups and were age standardised. Trends were estimated with joinpoint regression. RESULTS: Of 116 113 incident HF hospitalisations, 12.8% were Maori, 5.7% Pacific people, 3.0% Asians and 78.6% Europeans/others. 64% of Maori and Pacific patients were aged <70 years, compared with 37% of Asian and 19% of European/others. In 2018, incidence rate ratios compared with European/others were 6.0 (95% CI 4.9 to 7.3), 7.5 (95% CI 6.0 to 9.4) and 0.5 (95% CI 0.3 to 0.8) for Maori, Pacific people and Asians aged 20-49 years; 3.7 (95% CI 3.4 to 4.0), 3.6 (95% CI 3.2 to 4.1) and 0.5 (95% CI 0.4 to 0.6) for Maori, Pacific people and Asians aged 50-69 years; and 1.5 (95% CI 1.4 to 1.6), 1.5 (95% CI 1.3 to 1.7) and 0.5 (95% CI 0.5 to 0.6) for Maori, Pacific people and Asians aged ≥70 years. Between 2006 and 2018, ethnicity-specific rates diverged in ≥70-year-old subjects due to a decline in European/others (annual percentage change (APC) -2.0%, 95% CI -2.5% to -1.6%) and Asians (APC -3.3%, 95% CI -4.4% to -2.1%), but rates remained unchanged for Maori and Pacific people. In contrast, regardless of ethnicity, rates either increased or remained unchanged in <70-year-old subjects. CONCLUSION: Ethnic inequities in incident HF hospitalisation have widened in NZ over the past 13 years. Urgent action is required to address the predisposing factors that lead to development of HF in Maori and Pacific people.

Potent MOR Agonists from 2'-Hydroxy-5,9-dimethyl-N-phenethyl Substituted-6,7-benzomorphans and from C8-Hydroxy, Methylene and Methyl Derivatives of N-Phenethylnormetazocine.

(-)-5,9-Dimethyl-6,7-benzomorphan (normetazocine) derivatives with a para-OH or ortho-F substituent in the aromatic ring of the N-phenethyl moiety were synthesized and found to have subnanomolar potency at MOR, and both were fully efficacious in vitro. These new compounds, (1R,5R,9R)-6,11-dimethyl-3-(2-fluorophenethyl)-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-ol and (1R,5R,9R)-6,11-dimethyl-3-(4-hydroxyphenethyl)-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-ol, were more potent than the unsubstituted compound N-phenethylnormetazocine and about 30 or 40 times more potent than morphine, respectively. A variety of substituents in the ortho, meta, or para position in the aromatic ring of the N-phenethyl moiety were synthesized, 25 of these compounds, and found to have varying effects on potency and efficacy as determined by the forskolin-induced cAMP accumulation assay. The N-phenethyl moiety was also modified by increasing chain length to form a N-phenylpropyl side chain with and without a para-nitro moiety, and by an N-cinnamyl side chain. Also, an indole ethylamine normetazocine was synthesized to replace the N-phenethylamine side chain in normetazocine. The phenylpropylamine, propenylamine (cinnamyl) and the para-nitropropylamine had little or no MOR potency. The indole-ethylamine on the normetazocine nucleus, however, had moderate potency (MOR EC50 = 12 nM), and was fully efficacious (%Emax = 102%) in the cAMP assay. Retention of the N-phenethyl moiety and the addition of alkyl and alkenyl moieties on C8 in (-)-N-phenethylnormetazocine gave a C8-methylene derivative that had subnanomolar potency at MOR and a C8-methyl analog that had nanomolar potency. Five C8-substituted compounds were synthesized.

Investigation and treatment after non-ST segment elevation acute coronary syndrome for patients presenting to rural or urban hospitals in Aotearoa New Zealand: ANZACS-QI 75.

AIMS: Compare the care patients with non-ST segment elevation acute coronary syndrome (NSTEACS) received in Aotearoa New Zealand depending on the rural-urban category of the hospital they are first admitted to. METHODS: Patients with NSTEACS investigated with invasive coronary angiogram between 1 January 2014 and 31 December 2019 were included. There were three hospital categories (routine access to percutaneous coronary intervention [urban interventional], other urban [urban non-interventional] and rural) and three ethnicity categories (Maori, Pacific and non-Maori/non-Pacific). Clinical performance measures included: angiography ≤3 days, assessment of left ventricular ejection fraction (LVEF) and prescription of secondary prevention medication. RESULTS: Of 26,779 patients, 66.2% presented to urban-interventional, 25.6% to urban non-interventional and 8.2% to rural hospitals. A smaller percentage of patients presenting to urban interventional than urban non-interventional and rural hospitals were Maori (8.1%, 17.0% and 13.0%). Patients presenting to urban interventional hospitals were more likely to receive timely angiography than urban non-interventional or rural hospitals (78.5%, 60.8% and 63.1%). They were also more likely to have a LVEF assessment (78.5%, 65.4% and 66.3%). In contrast, the use of secondary prevention medications at discharge was similar between hospital categories. Maori and Pacific patients presenting to urban interventional hospitals were less likely than non-Maori/non-Pacific to receive timely angiography but more likely to have LVEF assessed. However, LVEF assessment and timely angiography in urban non-interventional and rural hospitals were lower than in urban interventional hospitals for both Maori and non-Maori/non-Pacific. CONCLUSIONS: Patients presenting to urban hospitals without routine interventional access and rural hospitals were less likely to receive LVEF assessment or timely angiography. This disproportionately impacts Maori, who are more likely to live in these hospital catchments.

Anchor Group Bottlebrush Polymers as Oil Additive Friction Modifiers.

Surface-tethered polymers have been shown to be an efficient lubrication strategy for boundary and mixed lubrication by providing a solvated film between solid surfaces. We have assessed the performance of various graft copolymers as friction modifier additives in oil and revealed important structure-property relationships for this application. The polymers consisted of an oil-soluble, grafted poly(lauryl acrylate) segment and a polar, linear poly(4-acryloylmorpholine) anchor group. Reversible addition-fragmentation chain transfer polymerization was used to access various architectures with control of the grafting density and position of the anchor group. Macrotribological studies displayed promising results with ≈50% reduction in friction coefficient at low polymer treatment rates. QCM-D experiments, neutron reflectometry, small-angle neutron scattering, and atomic force microscopy were used to gather detailed information on these polymers' surface adsorption characteristics, film structure, and solution behavior.

Incidence, risk factors and outcomes of checkpoint inhibitor-induced liver injury: A 10-year real-world retrospective cohort study.

Background & Aims: Checkpoint inhibitors (CPI) account for increasing numbers of drug-induced liver injury (DILI) cases. We aimed to determine the incidence rate and risk factors associated with checkpoint inhibitor-induced liver injury (ChILI). Methods: Prescription event monitoring was performed on all melanoma and renal cancer patients who received CPI at a tertiary centre between 2011 and 2021. ChILI cases were identified using the definitions, grading, and causality assessment methods validated for DILI. We assessed risk factors associated with ChILI in CPI-naive patients using multivariable logistic regression model. Consecutive patients with suspected ChILI from two other tertiary centres were adjudicated and combined for case characterisation and outcomes of ChILI. Results: Out of 432 patients who received CPI over 10 years, ChILI occurred in 38 (8.8%) with an overall incidence rate of 11.5 per 1,000 person-months (95% CI 8.2-15.8). Probability of ChILI was highest in combination therapy (32%) and no new events occurred beyond 135 days of treatment. Risk factor analysis showed that combination therapy, female sex, higher baseline alanine transferase level and lower baseline alkaline phosphatase level were independently associated with higher risk of ChILI. In total, 99 patients were adjudicated to have ChILI from three centres. Although Common Terminology Criteria for Adverse Events classified 20 patients (20.2%) to have 'life-threatening' grade 4 hepatitis, ChILI severity was graded as mild in 45 (45.5%) and moderate in the remaining 54 (54.5%) cases. Conclusions: The real-world risk of ChILI is higher than previously reported. Among patients receiving dual CPI, this risk falls markedly after 4.5 months. As Common Terminology Criteria for Adverse Events overestimates its clinical severity, case-definition, evaluation and management of ChILI should be revised to harmonise care. Impact and implications: Using prescription event monitoring over a 10-year period, the incidence rate of checkpoint inhibitor induced liver injury (ChILI) based on established case definitions for drug-induced liver injury (DILI) is 11.5 per 1,000 person-months. Formal causality assessment identified an alternative cause in 19% of patients with suspected ChILI highlighting the importance of systematic evaluation by clinicians to minimise unnecessary immunosuppression. Intensity of monitoring in patients receiving combination therapy regime after 4.5 months of therapy can be reduced as the risk of new onset ChILI beyond this point is minimal. Current Common Terminology Criteria for Adverse Events (CTCAE) grading overestimates clinical severity of ChILI and hence contributes to avoidable hospitalisation.

Paired risk scores to predict ischaemic and bleeding risk twenty-eight days to one year after an acute coronary syndrome.

OBJECTIVE: The recommended duration of dual anti-platelet therapy (DAPT) following acute coronary syndrome (ACS) varies from 1 month to 1 year depending on the balance of risks of ischaemia and major bleeding. We designed paired ischaemic and major bleeding risk scores to inform this decision. METHODS: New Zealand (NZ) patients with ACS investigated with coronary angiography are recorded in the All NZ ACS Quality Improvement registry and linked to national health datasets. Patients were aged 18-84 years (2012-2020), event free at 28 days postdischarge and without atrial fibrillation. Two 28-day to 1-year postdischarge multivariable risk prediction scores were developed: (1) cardiovascular mortality/rehospitalisation with myocardial infarction or ischaemic stroke (ischaemic score) and (2) bleeding mortality/rehospitalisation with bleeding (bleeding score). FINDINGS: In 27 755 patients, there were 1200 (4.3%) ischaemic and 548 (2.0%) major bleeding events. Both scores were well calibrated with moderate discrimination performance (Harrell's c-statistic 0.75 (95% CI, 0.74 to 0.77) and 0.69 (95% CI, 0.67 to 0 .71), respectively). Applying these scores to the 2020 European Society of Cardiology ACS antithrombotic treatment algorithm, the 31% of the cohort at elevated (>2%) bleeding and ischaemic risk would be considered for an abbreviated DAPT duration. For those at low bleeding risk, but elevated ischaemic risk (37% of the cohort), prolonged DAPT may be appropriate, and for those with low bleeding and ischaemic risk (29% of the cohort) short duration DAPT may be justified. CONCLUSION: We present a pair of ischaemic and bleeding risk scores specifically to assist clinicians and their patients in deciding on DAPT duration beyond the first month post-ACS.

Discovery of a Potent Highly Biased MOR Partial Agonist among Diastereomeric C9-Hydroxyalkyl-5-phenylmorphans.

All possible diastereomeric C9-hydroxymethyl-, hydroxyethyl-, and hydroxypropyl-substituted 5-phenylmorphans were synthesized to explore the three-dimensional space around the C9 substituent in our search for potent MOR partial agonists. These compounds were designed to lessen the lipophilicity observed with their C9-alkenyl substituted relatives. Many of the 12 diastereomers that were obtained were found to have nanomolar or subnanomolar potency in the forskolin-induced cAMP accumulation assay. Almost all these potent compounds were fully efficacious, and three of those chosen for in vivo evaluation, 15, 21, and 36, were all extremely G-protein biased; none of the three compounds recruited beta-arrestin2. Only one of the 12 diastereomers, 21 (3-((1S,5R,9R)-9-(2-hydroxyethyl)-2-phenethyl-2-azabicyclo[3.3.1]nonan-5-yl)phenol), was a MOR partial agonist with good, but not full, efficacy (Emax = 85%) and subnanomolar potency (EC50 = 0.91 nM) in the cAMP assay. It did not have any KOR agonist activity. This compound was unlike morphine in that it had a limited ventilatory effect in vivo. The activity of 21 could be related to one or more of three well-known theories that attempt to predict a dissociation of the desired analgesia from the undesirable opioid-like side-effects associated with clinically used opioids. In accordance with the theories, 21 was a potent MOR partial agonist, it was highly G-protein biased and did not attract beta-arrestin2, and it was found to have both MOR and DOR agonist activity. All the other diastereomers that were synthesized were either much less potent than 21 or had either too little or too much efficacy for our purposes. It was also noted that a C9-methoxymethyl compound with 1R,5S,9R stereochemistry (41) was more potent than the comparable C9-hydroxymethyl compound 11 (EC50 = 0.65 nM for 41 vs. 2.05 nM for 11). Both 41 and 11 were fully efficacious.

Invasive Management and Outcomes in Acute Coronary Syndromes and Chronic Kidney Disease (ANZACS-QI 70).

AIMS: Guidelines recommend management with an invasive coronary angiogram in acute coronary syndromes (ACS), but most studies excluded patients with advanced chronic kidney disease (CKD). Our aims were to describe, in a comprehensive ACS cohort, the incidence of CKD, coronary angiography utilisation and outcomes, according to CKD stage. METHODS: National datasets were used to identify hospitalised ACS patients (2013 to 2018) in the Northern region of New Zealand. CKD stage was obtained from a linked laboratory dataset. Outcomes included all-cause and cause-specific mortality, and non-fatal myocardial infarction, heart failure and stroke. RESULTS: Thirty-eight percent (38%) of the 23,432 ACS patients had CKD stage 3 or higher: 2,403 (10%) had stages 4/5 CKD. Overall 61% received coronary angiography. Compared with normal renal function the adjusted rate of coronary angiography was lower in CKD stage 3b (RR 0.75, 95% confidence intervals [CIs] 0.69, 0.82) and stages 4/5 without dialysis (RR 0.41, 95% CIs 0.36, 0.46), but similar for those on dialysis (RR 0.89, 95% CIs 0.77, 1.02). All-cause mortality (mean follow-up 3.2 years) increased with CKD stage from 8% (normal kidney function) to 69% (stages 4/5 CKD without dialysis). Compared with coronary angiography, the adjusted all-cause and CVD mortality risks were higher in those without coronary angiography, except for those on dialysis, where these risks converged. CONCLUSIONS: Invasive management fell below an eGFR of 45 mL/min (≤ stage 3b), and nearly half of all deaths occurred in these patients. Clinical trials are needed to assess the role of invasive management in ACS and advanced CKD.

Outcomes and access to angiography following non-ST-segment elevation acute coronary syndromes in patients who present to rural or urban hospitals: ANZACS-QI 72.

AIM: This study's aim was to identify differences in invasive angiography performed and health outcomes for patients with non-ST-segment elevation acute coronary syndrome (NSTEACS) presenting to either i) a rural hospital, or an urban hospital ii) with or iii) without routine access to percutaneous intervention (PCI) in New Zealand. METHODS: Patients with NSTEACS between 1 January 2014 and 31 December 2017 were included. Logistic regression was used to model each of the outcome measures: angiography performed within 1 year; 30-day, 1-year and 2-year all-cause mortality; and readmission within 1 year of presentation with either heart failure, a major adverse cardiac event or major bleeding. RESULTS: There were 42,923 patients included. Compared to urban hospitals with access to PCI, the odds of a patient receiving an angiogram were reduced for rural and urban hospitals without routine access to PCI (odds ratio [OR] 0.82 and 0.75) respectively. There was a small increase in the odds of dying at 2 years (OR 1.16), but not 30 days or 1 year for patients presenting to a rural hospital. CONCLUSION: Patients who present to hospitals without PCI are less likely to receive angiography. Reassuringly there is no difference in mortality, except at 2 years, for patients that present to rural hospitals.

External Validation of a Clinical Score to Differentiate Takotsubo Syndrome From Non-ST-Elevation Myocardial Infarction in Women.

BACKGROUND AND AIMS: Clinical presentation of Takotsubo Syndrome (TS) mimics acute coronary syndrome (ACS). A score to differentiate TS from ACS would be helpful to facilitate appropriate investigation and management. We have previously developed a clinical score (NSTE-Takotsubo Score) to distinguish women with non-ST-segment elevation myocardial infarction (NSTEMI) from TS with non-ST-segment elevation (NSTE-TS). This study sought to assess the diagnostic validity of this score in an external validation cohort. METHODS: The external cohort consisted of women with NSTE-TS (n=110) and NSTEMI (n=113) from two major tertiary hospitals in New Zealand. The five variables in the arithmetic score (range -6 to +5) and their relative weights are: T-wave inversion (TWI) in ≥6 leads (3 points), recent stress (2 points), diabetes mellitus (DM) (-1 point), prior cardiovascular disease (CVD) (-2 points) and presence of ST depression (-3 points). Two clinicians blinded to the diagnoses calculated the score using clinical and electrocardiogram (ECG) data on day 1 post-admission. RESULTS: The NSTE-Takotsubo Score discriminated well between NSTE-TS and NSTEMI. The sensitivity and specificity of a score ≥1 to distinguish NSTE-TS from NSTEMI were 78% and 85%, respectively. The area under the receiver operator curve was 0.78 (95% CI 0.72 to 0.84). CONCLUSION: In an external validation cohort, the NSTE-Takotsubo Score was easy to apply and useful to identify women likely to have NSTE-TS on day 1 post-admission.

A Risk Model to Predict Statin Non-Adherence Following an Acute Coronary Syndrome.

BACKGROUND: Patients at risk of statin non-adherence are often not identified during hospital admission with an acute coronary syndrome (ACS). METHODS: In 19,942 patients hospitalised for ACS, statin dispensing was determined from the national pharmaceutical dispensing database. A risk score for non-adherence was developed from a multivariable Poisson regression model of associations between risk factors and the statin Medication Possession Ratio (MPR) <0.8 6-18 months after hospital discharge. RESULTS: Statin MPR was <0.8 in 4,736 (24%) patients. MPR <0.8 was more likely in patients with a history of cardiovascular disease (CVD) (RR 3.79, CI 95% 3.42-4.20) and those without known CVD (RR 2.25, 95% CI 2.04-2.48) who were not taking a statin on ACS admission, compared to patients with low density lipoprotein (LDL) cholesterol <2 mmol/L who were on a statin. For patients taking a statin on admission, higher LDL was associated with MPR <0.8 (≥3 versus <2 mmol/L, RR 1.96, 95%CI 1.72-2.24). Other independent risk factors for MPR <0.8 were age <45 years, female, disadvantaged ethnic groups, and no coronary revascularisation during the ACS admission. The risk score, which included nine variables, had a C-statistic of 0.67. MPR was <0.8 in 12% of 5,348 patients with a score ≤5 (lowest quartile) and 45% of 5,858 patients with a score ≥11 (highest quartile). CONCLUSION: A risk score generated from routinely collected data predicts statin non-adherence in patients hospitalised with ACS. This may be used to target inpatient and outpatient interventions to improve medication adherence.