Treatment drop-in in a contemporary cohort used to derive cardiovascular risk prediction equations.

BACKGROUND: No routinely recommended cardiovascular disease (CVD) risk prediction equations have adjusted for CVD preventive medications initiated during follow-up (treatment drop-in) in their derivation cohorts. This will lead to underestimation of risk when equations are applied in clinical practice if treatment drop-in is common. We aimed to quantify the treatment drop-in in a large contemporary national cohort to determine whether equations are likely to require adjustment. METHODS: Eight de-identified individual-level national health administrative datasets in Aotearoa New Zealand were linked to establish a cohort of almost all New Zealanders without CVD and aged 30-74 years in 2006. Individuals dispensing blood-pressure-lowering and/or lipid-lowering medications between 1 July 2006 and 31 December 2006 (baseline dispensing), and in each 6-month period during 12 years' follow-up to 31 December 2018 (follow-up dispensing), were identified. Person-years of treatment drop-in were determined. RESULTS: A total of 1 399 348 (80%) out of the 1 746 695 individuals in the cohort were not dispensed CVD medications at baseline. Blood-pressure-lowering and/or lipid-lowering treatment drop-in accounted for 14% of follow-up time in the group untreated at baseline and increased significantly with increasing predicted baseline 5-year CVD risk (12%, 31%, 34% and 37% in <5%, 5-9%, 10-14% and ≥15% risk groups, respectively) and with increasing age (8% in 30-44 year-olds to 30% in 60-74 year-olds). CONCLUSIONS: CVD preventive treatment drop-in accounted for approximately one-third of follow-up time among participants typically eligible for preventive treatment (≥5% 5-year predicted risk). Equations derived from cohorts with long-term follow-up that do not adjust for treatment drop-in effect will underestimate CVD risk in higher risk individuals and lead to undertreatment. Future CVD risk prediction studies need to address this potential flaw.

Short, Medium and Long-Term Cause-Specific Mortality Following First-Ever Heart Failure Hospitalisation in New Zealand.

BACKGROUND: Heart failure (HF) is associated with high mortality, but there are limited reports on the underlying cause of death. This study reports short-, medium- and long-term cause-specific mortality following first-ever HF hospitalisation in New Zealand. METHOD: First-ever HF hospitalisations were identified from hospital discharge coding between 2010 and 2013. Mortality outcomes were obtained via anonymised linkage to national datasets. Short (0-30 days), medium (31-364 days), and long-term (1-5 years) mortality rates were identified. Cause of death was identified from death certification coding and classified as cardiovascular and non-cardiovascular. Cox regression analysis was performed to adjust for confounding variables. RESULTS: A cohort of 34,264 individuals with first-ever HF hospitalisation were identified. Mean age was 75.8±13 years and 50.5% were male. A total of 21,637 (63.1%) died within 5 years of hospitalisation; 4,122 (12.0%) within the first 30 days, 6,358 (18.6%) between 31-364 days, and 11,157 (32.6%) between 1 and 5 years. Older age, male gender, Maori ethnicity, higher socioeconomic deprivation and increased comorbidity were independent factors associated with higher all-cause mortality. Cardiovascular causes accounted for 51% of total deaths. Cardiovascular mortality was 6.0%, 9.5%, and 16.7% at 30 days, 31-364 days, and 1-5 years, respectively. The most common causes of non-cardiovascular mortality were neoplasms, chronic respiratory diseases and infections, accounting for 14.6%, 11.0%, and 5.5% of total deaths respectively. Comorbidity was associated with higher non-cardiovascular mortality (hazard ratio [HR] 3.35; 95% confidence interval [CI] 3.16-3.55) but not cardiovascular mortality (HR 0.79; 95% CI 0.72-0.86). CONCLUSIONS: In New Zealand, mortality following first-ever HF hospitalisation is high. Non-cardiovascular death is common and there are ethnic inequities.

ANZACS-QI Heart Failure Registry: a new approach using age-stratified sampling of hospital discharges to guide quality improvement (ANZACS-QI 79).

Heart failure is a major healthcare problem in New Zealand. The Acute Decompensated Heart Failure (ADHF) Registry was introduced in 2015, and has identified the need for quality improvement strategies to improve care of patients hospitalised with heart failure. In this paper, we describe the implementation of the revised ANZACS-QI Heart Failure Registry, which has a primary aim to support evidence-based management of and quality improvement measures for patients who are hospitalised with heart failure in New Zealand. Taking the learnings from the initial experience with the ADHF Registry, the revised ANZACS-QI Heart Failure Registry i) utilises age-stratified sampling of hospital discharge coding to identify a representative heart failure cohort, ii) utilises existing ANZACS-QI infrastructure for data-linkage to reduce the burden of manual data entry, iii) receives governance from the Heart Failure Working Group, and iv) focusses on established quality improvement indicators for heart failure management.

Stroke Survivors' Interaction With Hand Rehabilitation Devices: Observational Study.

BACKGROUND: The hand is crucial for carrying out activities of daily living as well as social interaction. Functional use of the upper limb is affected in up to 55% to 75% of stroke survivors 3 to 6 months after stroke. Rehabilitation can help restore function, and several rehabilitation devices have been designed to improve hand function. However, access to these devices is compromised in people with more severe loss of function. OBJECTIVE: In this study, we aimed to observe stroke survivors with poor hand function interacting with a range of commonly used hand rehabilitation devices. METHODS: Participants were engaged in an 8-week rehabilitation intervention at a technology-enriched rehabilitation gym. The participants spent 50-60 minutes of the 2-hour session in the upper limb section at least twice a week. Each participant communicated their rehabilitation goals, and an Action Research Arm Test (ARAT) was used to measure and categorize hand function as poor (scores of 0-9), moderate (scores of 10-56), or good (score of 57). Participants were observed during their interactions with 3 hand-based rehabilitation devices that focused on hand rehabilitation: the GripAble, NeuroBall, and Semi-Circular Peg Board. Observations of device interactions were recorded for each session. RESULTS: A total of 29 participants were included in this study, of whom 10 (34%) had poor hand function, 17 (59%) had moderate hand function, and 2 (7%) had good hand function. There were no differences in the age and years after stroke among participants with poor hand function and those with moderate (P=.06 and P=.09, respectively) and good (P=.37 and P=.99, respectively) hand function. Regarding the ability of the 10 participants with poor hand function to interact with the 3 hand-based rehabilitation devices, 2 (20%) participants with an ARAT score greater than 0 were able to interact with the devices, whereas the other 8 (80%) who had an ARAT score of 0 could not. Their inability to interact with these devices was clinically examined, and the reason was determined to be a result of either the presence of (1) muscle tone or stiffness or (2) muscle weakness. CONCLUSIONS: Not all stroke survivors with impairments in their hands can make use of currently available rehabilitation technologies. Those with an ARAT score of 0 cannot actively interact with hand rehabilitation devices, as they cannot carry out the hand movement necessary for such interaction. The design of devices for hand rehabilitation should consider the accessibility needs of those with poor hand function.

Guideline versus clinician recommended duration of dual antiplatelet therapy following acute coronary syndrome (ANZACS-QI 78).

AIM: The recommended duration of dual anti-platelet therapy (DAPT) following acute coronary syndrome (ACS) for patients without atrial fibrillation varies from 1 month to 1 year depending on the balance of risks of ischaemia and major bleeding. Patients on DAPT with a high risk of gastrointestinal bleeding are also recommended to receive a proton pump inhibitor (PPI). Our aim was to audit current practice against the 2020 European Society of Cardiology (ESC) guideline recommendations. METHODS: One hundred consecutive ACS patients treated with percutaneous coronary intervention discharged from Middlemore Hospital and without atrial fibrillation in the first quarter of 2023 were studied. ANZACS-QI ischaemic (I) and bleeding (B) risk scores were calculated, with patients categorised in four groups based on ESC recommendations-low I/low B risk, low I/high B, high I/low B and high I/high B. Guideline and clinician recommended duration of DAPT and prescription of PPI were compared. RESULTS: All patients were planned for DAPT at discharge and 91% a PPI. Up to four out of five ACS patients could have been planned for shorter DAPT durations based on the ESC guideline recommendations. Over half of included patients (53%) had a high bleeding risk, yet 85% of these patients received 12 months of DAPT despite ESC recommendations of 1-3 months. CONCLUSIONS: There was a divergence between clinical practice and the recommendations of the 2020 ESC guidelines. We discuss these results in relation to the updated August 2023 ESC guidelines, which have reaffirmed a 12-month duration of DAPT as the default position.

Validation Study of Cardiovascular International Statistical Classification of Diseases and Related Health Problems, Tenth Edition, Australian Modification (ICD-10-AM) Codes in Administrative Healthcare Databases (ANZACS-QI 77).

BACKGROUND: Administrative healthcare databases can be utilised for research. The accuracy of the International Statistical Classification of Diseases and Related Health Problems, Tenth Edition, Australian Modification (ICD-10-AM) coding of cardiovascular conditions in New Zealand is not known and requires validation. METHOD: International Statistical Classification of Diseases and Related Health Problems, Tenth Edition, Australian Modification coded discharges for acute coronary syndrome (ACS), heart failure (HF) and atrial fibrillation (AF), in both primary and secondary diagnostic positions, were identified from four district health boards between 1 January 2019 and 31 June 2019. A sample was randomly selected for retrospective clinician review for evidence of the coded diagnosis according to contemporary diagnostic criteria. Positive predictive values (PPVs) for ICD-10-AM coding vs clinician review were calculated. This study is also known as All of New Zealand, Acute Coronary Syndrome-Quality Improvement (ANZACS-QI) 77. RESULTS: A total of 600 cases (200 for each diagnosis, 5.0% of total identified cases) were reviewed. The PPV of ACS was 93% (95% confidence interval [CI] 89%-96%), HF was 93% (95% CI 89%-96%) and AF was 96% (95% CI 92%-98%). There were no differences in PPV between district health boards. PPV for ACS were lower in Maori vs non-Maori (72% vs 96%; p=0.004), discharge from non-Cardiology vs Cardiology services (89% vs 96%; p=0.048) and ICD-10-AM coding for unstable angina vs myocardial infarction (81% vs 95%; p=0.011). PPV for HF were higher in the primary vs secondary diagnostic position (100% vs 89%; p=0.001). CONCLUSIONS: The PPVs of ICD-10-AM coding for ACS, HF, and AF were high in this validation study. ICD-10-AM coding can be used to identify these diagnoses in administrative databases for the purposes of healthcare evaluation and research.

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.

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.

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.

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.

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.

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.