Warfarin remains the preferred anticoagulant for many patients with CHD. The complexity of management led our centre to shift from a nurse-physician-managed model with many providers to a pharmacist-managed model with a centralized anticoagulation team. We aim to describe the patient cohort managed by our Anticoagulation Program and evaluate the impact of implementation of this consistent, pharmacist-managed model on time in therapeutic range, an evidence-based marker for clinical outcomes.

A single-centre retrospective cohort study was conducted to evaluate the impact of the transition to a pharmacist-managed model to improve anticoagulation management at a tertiary pediatric heart centre. The percent time in therapeutic range for a cohort managed by both models was compared using a paired t-test. Patient characteristics and time in therapeutic range of the program were also described.

After implementing the pharmacist-managed model, the time in therapeutic range for a cohort of 58 patients increased from 65.7 to 80.2% (p < .001), and our Anticoagulation Program consistently maintained this improvement from 2013 to 2022. The cohort of patients managed by the Anticoagulation Program in 2022 included 119 patients with a median age of 24 years (range 19 months–69 years) with the most common indication for warfarin being mechanical valve replacement (n = 81, 68%).

Through a practice change incorporating a collaborative, centralized, pharmacist-managed model, this cohort of CHD patients on warfarin had a fifteen percent increase in time in therapeutic range, which was sustained for nine years.

Coronary artery dilation associated with bicuspid/unicuspid aortic valves is described in adults with limited data in children. We aimed to describe the clinical course of children with bicuspid/unicuspid aortic valves and coronary dilation including coronary Z-score changes over time, association of coronary changes with aortic valve anatomy/function, and complications.

Institutional databases were searched for children ≤18 years with both bicuspid/unicuspid aortic valves and coronary dilation (1/2006-6/2021). Kawasaki disease and isolated supra-/subvalvar aortic stenosis were excluded. Statistics were descriptive with associations measured by Fisher’s exact test and overlapping 83.7% confidence intervals.

Of 17 children, bicuspid/unicuspid aortic valve was diagnosed at birth in 14 (82%). Median age at coronary dilation diagnosis was 6.4 years (range: 0-17.0). Aortic stenosis was present in 14 (82%) [2 (14%) moderate, 8 (57%) severe]; 10 (59%) had aortic regurgitation; 8 (47%) had aortic dilation. The right coronary was dilated in 15 (88%), left main in 6 (35%), and left anterior descending in 1 (6%) with no relationship between leaflet fusion pattern or severity of aortic regurgitation/stenosis on coronary Z-score. Follow-up evaluations were available for 11 (mean 9.3 years, range 1.1–14.8) with coronary Z-scores increasing in 9/11 (82%). Aspirin was used in 10 (59%). There were no deaths or coronary artery thrombosis.

In children with bicuspid/unicuspid aortic valves and coronary dilation, the right coronary artery was most frequently involved. Coronary dilation was observed in early childhood and frequently progressed. Antiplatelet medication use was inconsistent, but no child died nor developed thrombosis.

Children with heart disease may require inpatient care for many reasons, but ultimately have a final reason for hospitalisation prior to discharge. Factors influencing length of stay in paediatric cardiac acute care units have been described but the last reason for hospitalisation has not been studied. Our aim was to describe Final Hospital Need as a novel measure, determine Final Hospital Need in our patients, and describe factors associated with this Need.

Single-centre survey design. Discharging providers selected a Final Hospital Need from the following categories: cardiovascular, respiratory, feeding/fluid, haematology/ID, pain/sedation, systems issues, and other/wound issues. Univariable and multivariable analyses were performed separately for outcomes “cardiovascular” and “feeding/fluid.”

Survey response rate was 99% (624 encounters). The most frequent Final Hospital Needs were cardiovascular (36%), feeding/fluid (24%) and systems issues (13%). Probability of Final Hospital Need “cardiovascular” decreased as length of stay increased. Multivariate analysis showed Final Hospital Need “cardiovascular” was negatively associated with aortic arch repair, Norwood procedure, and Final ICU Need “respiratory” and “other.” Final Hospital Need "feeding/fluid” was negatively associated with left-sided valve procedure, but positively associated with final ICU need “respiratory,” and tube feeding at discharge.

Final Hospital Need is a novel measure that can be predicted by clinical factors including age, Final ICU Need, and type of surgery. Final Hospital Need may be utilised to track changes in clinical care over time and as a target for improvement work.

Major depressive disorder (MDD) was previously associated with negative affective biases. Evidence from larger population-based studies, however, is lacking, including whether biases normalise with remission. We investigated associations between affective bias measures and depressive symptom severity across a large community-based sample, followed by examining differences between remitted individuals and controls.

Participants from Generation Scotland (N = 1109) completed the: (i) Bristol Emotion Recognition Task (BERT), (ii) Face Affective Go/No-go (FAGN), and (iii) Cambridge Gambling Task (CGT). Individuals were classified as MDD-current (n = 43), MDD-remitted (n = 282), or controls (n = 784). Analyses included using affective bias summary measures (primary analyses), followed by detailed emotion/condition analyses of BERT and FAGN (secondary analyses).

For summary measures, the only significant finding was an association between greater symptoms and lower risk adjustment for CGT across the sample (individuals with greater symptoms were less likely to bet more, despite increasingly favourable conditions). This was no longer significant when controlling for non-affective cognition. No differences were found for remitted-MDD v. controls. Detailed analysis of BERT and FAGN indicated subtle negative biases across multiple measures of affective cognition with increasing symptom severity, that were independent of non-effective cognition [e.g. greater tendency to rate faces as angry (BERT), and lower accuracy for happy/neutral conditions (FAGN)]. Results for remitted-MDD were inconsistent.

This suggests the presence of subtle negative affective biases at the level of emotion/condition in association with depressive symptoms across the sample, over and above those accounted for by non-affective cognition, with no evidence for affective biases in remitted individuals.

Smartphones have the potential for capturing subtle changes in cognition that characterize preclinical Alzheimer’s disease (AD) in older adults. The Ambulatory Research in Cognition (ARC) smartphone application is based on principles from ecological momentary assessment (EMA) and administers brief tests of associative memory, processing speed, and working memory up to 4 times per day over 7 consecutive days. ARC was designed to be administered unsupervised using participants’ personal devices in their everyday environments.

We evaluated the reliability and validity of ARC in a sample of 268 cognitively normal older adults (ages 65–97 years) and 22 individuals with very mild dementia (ages 61–88 years). Participants completed at least one 7-day cycle of ARC testing and conventional cognitive assessments; most also completed cerebrospinal fluid, amyloid and tau positron emission tomography, and structural magnetic resonance imaging studies.

First, ARC tasks were reliable as between-person reliability across the 7-day cycle and test-retest reliabilities at 6-month and 1-year follow-ups all exceeded 0.85. Second, ARC demonstrated construct validity as evidenced by correlations with conventional cognitive measures (r = 0.53 between composite scores). Third, ARC measures correlated with AD biomarker burden at baseline to a similar degree as conventional cognitive measures. Finally, the intensive 7-day cycle indicated that ARC was feasible (86.50% approached chose to enroll), well tolerated (80.42% adherence, 4.83% dropout), and was rated favorably by older adult participants.

Overall, the results suggest that ARC is reliable and valid and represents a feasible tool for assessing cognitive changes associated with the earliest stages of AD.

Copy number variants (CNVs) have been associated with the risk of schizophrenia, autism and intellectual disability. However, little is known about their spectrum of psychopathology in adulthood.

We investigated the psychiatric phenotypes of adult CNV carriers and compared probands, who were ascertained through clinical genetics services, with carriers who were not. One hundred twenty-four adult participants (age 18–76), each bearing one of 15 rare CNVs, were recruited through a variety of sources including clinical genetics services, charities for carriers of genetic variants, and online advertising. A battery of psychiatric assessments was used to determine psychopathology.

The frequencies of psychopathology were consistently higher for the CNV group compared to general population rates. We found particularly high rates of neurodevelopmental disorders (NDDs) (48%), mood disorders (42%), anxiety disorders (47%) and personality disorders (73%) as well as high rates of psychiatric multimorbidity (median number of diagnoses: 2 in non-probands, 3 in probands). NDDs [odds ratio (OR) = 4.67, 95% confidence interval (CI) 1.32–16.51; p = 0.017) and psychotic disorders (OR = 6.8, 95% CI 1.3–36.3; p = 0.025) occurred significantly more frequently in probands (N = 45; NDD: 39[87%]; psychosis: 8[18%]) than non-probands (N = 79; NDD: 20 [25%]; psychosis: 3[4%]). Participants also had somatic diagnoses pertaining to all organ systems, particularly conotruncal cardiac malformations (in individuals with 22q11.2 deletion syndrome specifically), musculoskeletal, immunological, and endocrine diseases.

Adult CNV carriers had a markedly increased rate of anxiety and personality disorders not previously reported and high rates of psychiatric multimorbidity. Our findings support in-depth psychiatric and medical assessments of carriers of CNVs and the establishment of multidisciplinary clinical services.

Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools.

To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics.

Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts.

Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO.

AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.

A novel paediatric disease, multi-system inflammatory syndrome in children, has emerged during the 2019 coronavirus disease pandemic.

To describe the short-term evolution of cardiac complications and associated risk factors in patients with multi-system inflammatory syndrome in children.

Retrospective single-centre study of confirmed multi-system inflammatory syndrome in children treated from 29 March, 2020 to 1 September, 2020. Cardiac complications during the acute phase were defined as decreased systolic function, coronary artery abnormalities, pericardial effusion, or mitral and/or tricuspid valve regurgitation. Patients with or without cardiac complications were compared with chi-square, Fisher’s exact, and Wilcoxon rank sum.

Thirty-nine children with median (interquartile range) age 7.8 (3.6–12.7) years were included. Nineteen (49%) patients developed cardiac complications including systolic dysfunction (33%), valvular regurgitation (31%), coronary artery abnormalities (18%), and pericardial effusion (5%). At the time of the most recent follow-up, at a median (interquartile range) of 49 (26–61) days, cardiac complications resolved in 16/19 (84%) patients. Two patients had persistent mild systolic dysfunction and one patient had persistent coronary artery abnormality. Children with cardiac complications were more likely to have higher N-terminal B-type natriuretic peptide (p = 0.01), higher white blood cell count (p = 0.01), higher neutrophil count (p = 0.02), severe lymphopenia (p = 0.05), use of milrinone (p = 0.03), and intensive care requirement (p = 0.04).

Patients with multi-system inflammatory syndrome in children had a high rate of cardiac complications in the acute phase, with associated inflammatory markers. Although cardiac complications resolved in 84% of patients, further long-term studies are needed to assess if the cardiac abnormalities (transient or persistent) are associated with major cardiac events.

Coronavirus disease 2019 (COVID-19) vaccination effectiveness in healthcare personnel (HCP) has been established. However, questions remain regarding its performance in high-risk healthcare occupations and work locations. We describe the effect of a COVID-19 HCP vaccination campaign on SARS-CoV-2 infection by timing of vaccination, job type, and work location.

We conducted a retrospective review of COVID-19 vaccination acceptance, incidence of postvaccination COVID-19, hospitalization, and mortality among 16,156 faculty, students, and staff at a large academic medical center. Data were collected 8 weeks prior to the start of phase 1a vaccination of frontline employees and ended 11 weeks after campaign onset.

The COVID-19 incidence rate among HCP at our institution decreased from 3.2% during the 8 weeks prior to the start of vaccinations to 0.38% by 4 weeks after campaign initiation. COVID-19 risk was reduced among individuals who received a single vaccination (hazard ratio [HR], 0.52; 95% confidence interval [CI], 0.40–0.68; P < .0001) and was further reduced with 2 doses of vaccine (HR, 0.17; 95% CI, 0.09–0.32; P < .0001). By 2 weeks after the second dose, the observed case positivity rate was 0.04%. Among phase 1a HCP, we observed a lower risk of COVID-19 among physicians and a trend toward higher risk for respiratory therapists independent of vaccination status. Rates of infection were similar in a subgroup of nurses when examined by work location.

Our findings show the real-world effectiveness of COVID-19 vaccination in HCP. Despite these encouraging results, unvaccinated HCP remain at an elevated risk of infection, highlighting the need for targeted outreach to combat vaccine hesitancy.

Olanzapine effectively treats schizophrenia and bipolar I disorder (BD-I); however, its use is hindered by significant weight gain. A combination of olanzapine and samidorphan (OLZ/SAM) is in development to provide the efficacy of olanzapine while mitigating olanzapine-associated weight gain through opioid-receptor blockade. Here, we summarize OLZ/SAM clinical data.

The OLZ/SAM development program consists of 18 phase 1–3 clinical studies evaluating antipsychotic and weight mitigation efficacy of OLZ/SAM, along with pharmacokinetics, safety, and tolerability. Safety evaluation also included metabolic laboratory assessments.

OLZ/SAM significantly improved psychotic symptoms (measured by Positive and Negative Syndrome Scale); improvements were similar to that observed with olanzapine vs placebo. OLZ/SAM resulted in significantly less weight gain than olanzapine. Additionally, 2 long-term phase 3 extension studies confirmed the durability of antipsychotic effect, as well as stabilization of weight and metabolic parameters in those continuing treatment. Supporting the potential use of OLZ/SAM in BD-I, OLZ/SAM or olanzapine resulted in bioequivalent olanzapine plasma concentrations, and OLZ/SAM did not affect lithium or valproate pharmacokinetics. OLZ/SAM treatment had no clinically relevant effects on ECG parameters (including QTc interval). OLZ/SAM and olanzapine safety were similar, except for reduced weight gain with OLZ/SAM; no additional safety risks were identified.

Data across 18 OLZ/SAM studies in >1600 subjects support an antipsychotic efficacy and safety profile for OLZ/SAM that is similar to olanzapine, with significantly less weight gain than olanzapine. OLZ/SAM is a potential new treatment for schizophrenia and BD-I patients needing efficacious long-term treatment with reduced risk of weight gain.

Alkermes, Inc.

To describe a pilot project infection prevention and control (IPC) assessment conducted in skilled nursing facilities (SNFs) in New York State (NYS) during a pivotal 2-week period when the region became the nation’s epicenter for coronavirus disease 2019 (COVID-19).

A telephone and video assessment of IPC measures in SNFs at high risk or experiencing COVID-19 activity.

SNFs in 14 New York counties, including New York City.

A 3-component remote IPC assessment: (1) screening tool; (2) telephone IPC checklist; and (3) COVID-19 video IPC assessment (ie, “COVIDeo”).

In total, 92 SNFs completed the IPC screening tool and checklist: 52 (57%) were conducted as part COVID-19 investigations, and 40 (43%) were proactive prevention-based assessments. Among the 40 proactive assessments, 14 (35%) identified suspected or confirmed COVID-19 cases. COVIDeo was performed in 26 (28%) of 92 assessments and provided observations that other tools would have missed: personal protective equipment (PPE) that was not easily accessible, redundant, or improperly donned, doffed, or stored and specific challenges implementing IPC in specialty populations. The IPC assessments took ∼1 hour each and reached an estimated 4 times as many SNFs as on-site visits in a similar time frame.

Remote IPC assessments by telephone and video were timely and feasible methods of assessing the extent to which IPC interventions had been implemented in a vulnerable setting and to disseminate real-time recommendations. Remote assessments are now being implemented across New York State and in various healthcare facility types. Similar methods have been adapted nationally by the Centers for Disease Control and Prevention.

To determine the Final ICU Need in the 24 hours prior to ICU discharge for children with cardiac disease by utilising a single-centre survey.

A cross-sectional survey was utilised to determine Final ICU Need, which was categorised as “Cardiovascular”, “Respiratory”, “Feeding”, “Sedation”, “Systems Issue”, or “Other” for each encounter. Survey responses were obtained from attending physicians who discharged children (≤18 years of age with ICU length of stay >24 hours) from the Cardiac ICU between April 2016 and July 2018.

Survey response rate was 99% (n = 1073), with 667 encounters eligible for analysis. “Cardiovascular” (61%) and “Respiratory” (26%) were the most frequently chosen Final ICU Needs. From a multivariable mixed effects logistic regression model fitted to “Cardiovascular” and “Respiratory”, operations with significantly reduced odds of having “Cardiovascular” Final ICU Need included Glenn palliation (p = 0.003), total anomalous pulmonary venous connection repair (p = 0.024), truncus arteriosus repair (p = 0.044), and vascular ring repair (p < 0.001). Short lengths of stay (<7.9 days) had significantly higher odds of “Cardiovascular” Final ICU Need (p < 0.001). “Cardiovascular” and “Respiratory” Final ICU Needs were also associated with provider and ICU discharge season.

Final ICU Need is a novel metric to identify variations in Cardiac ICU utilisation and clinical trajectories. Final ICU Need was significantly influenced by benchmark operation, length of stay, provider, and season. Future applications of Final ICU Need include targeting quality and research initiatives, calibrating provider and family expectations, and identifying provider-level variability in care processes and mental models.

Studies suggest that alcohol consumption and alcohol use disorders have distinct genetic backgrounds.

We examined whether polygenic risk scores (PRS) for consumption and problem subscales of the Alcohol Use Disorders Identification Test (AUDIT-C, AUDIT-P) in the UK Biobank (UKB; N = 121 630) correlate with alcohol outcomes in four independent samples: an ascertained cohort, the Collaborative Study on the Genetics of Alcoholism (COGA; N = 6850), and population-based cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC; N = 5911), Generation Scotland (GS; N = 17 461), and an independent subset of UKB (N = 245 947). Regression models and survival analyses tested whether the PRS were associated with the alcohol-related outcomes.

In COGA, AUDIT-P PRS was associated with alcohol dependence, AUD symptom count, maximum drinks (R2 = 0.47–0.68%, p = 2.0 × 10−8–1.0 × 10−10), and increased likelihood of onset of alcohol dependence (hazard ratio = 1.15, p = 4.7 × 10−8); AUDIT-C PRS was not an independent predictor of any phenotype. In ALSPAC, the AUDIT-C PRS was associated with alcohol dependence (R2 = 0.96%, p = 4.8 × 10−6). In GS, AUDIT-C PRS was a better predictor of weekly alcohol use (R2 = 0.27%, p = 5.5 × 10−11), while AUDIT-P PRS was more associated with problem drinking (R2 = 0.40%, p = 9.0 × 10−7). Lastly, AUDIT-P PRS was associated with ICD-based alcohol-related disorders in the UKB subset (R2 = 0.18%, p < 2.0 × 10−16).

AUDIT-P PRS was associated with a range of alcohol-related phenotypes across population-based and ascertained cohorts, while AUDIT-C PRS showed less utility in the ascertained cohort. We show that AUDIT-P is genetically correlated with both use and misuse and demonstrate the influence of ascertainment schemes on PRS analyses.

Apolipoprotein E (APOE) E4 is the main genetic risk factor for Alzheimer’s disease (AD). Due to the consistent association, there is interest as to whether E4 influences the risk of other neurodegenerative diseases. Further, there is a constant search for other genetic biomarkers contributing to these phenotypes, such as microtubule-associated protein tau (MAPT) haplotypes. Here, participants from the Ontario Neurodegenerative Disease Research Initiative were genotyped to investigate whether the APOE E4 allele or MAPT H1 haplotype are associated with five neurodegenerative diseases: (1) AD and mild cognitive impairment (MCI), (2) amyotrophic lateral sclerosis, (3) frontotemporal dementia (FTD), (4) Parkinson’s disease, and (5) vascular cognitive impairment.

Genotypes were defined for their respective APOE allele and MAPT haplotype calls for each participant, and logistic regression analyses were performed to identify the associations with the presentations of neurodegenerative diseases.

Our work confirmed the association of the E4 allele with a dose-dependent increased presentation of AD, and an association between the E4 allele alone and MCI; however, the other four diseases were not associated with E4. Further, the APOE E2 allele was associated with decreased presentation of both AD and MCI. No associations were identified between MAPT haplotype and the neurodegenerative disease cohorts; but following subtyping of the FTD cohort, the H1 haplotype was significantly associated with progressive supranuclear palsy.

This is the first study to concurrently analyze the association of APOE isoforms and MAPT haplotypes with five neurodegenerative diseases using consistent enrollment criteria and broad phenotypic analysis.