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Using the converse of Noether’s first theorem, this chapter shows that the Bessel-Hagen-type transformations are uniquely selected in the case of electrodynamics, which powerfully dissolves the methodological ambiguity at hand. It then considers how this line of argument applies to a variety of other cases, including in particular the challenge of defining an energy-momentum tensor for the gravitational field in linearised gravity. Finally, the search for proper Noether energy-momentum tensors is put into context with recent claims that Noether’s theorem and its converse make statements on equivalence classes of symmetries and conservation laws. The aim is to identify clearly the limitations of this latter move, and to develop this position by contrast with recent philosophical discussions about how symmetries relate to the representational capacities of theories.
Invasive aquatic plants constantly threaten freshwaters and associated environs globally. Water resource managers frequently seek new control tactics to combat invasive macrophytes, especially when the availability of herbicides registered for submersed plant control is limited. The synthetic auxin herbicide, florpyrauxifen-benzyl, recently registered (2018) for aquatic site applications in the United States, has shown success in controlling several invasive aquatic weeds. Studies were conducted to evaluate native and invasive submersed plant response to florpyrauxifen-benzyl under growth chamber conditions to provide insight on the selectivity of varying herbicide concentrations in New Zealand. Florpyrauxifen-benzyl concentrations evaluated ranged from 0.01 to 107.86 µg ai L-1, encompassing the maximum use concentration (48 µg ai L-1) for submersed plant applications. Dose-response metrics indicated the New Zealand native species, Myriophyllum triphyllum, was highly sensitive to florpyrauxifen-benzyl following a 21-day static exposure, having a dry weight 50% effective concentration (EC50) value of 1.2 µg ai L-1. The invasive species Lagarosiphon major and Elodea canadensis were less sensitive, with dry weight EC50 values of 35.4 and >107.86 µg ai L-1, respectively. Egeria densa was most tolerant to the tested concentrations, as EC50 values were not achieved. Overall, results indicate florpyrauxifen-benzyl demonstrates potential for controlling L. major, with further large-scale screening required to confirm control among field site applications. Since the native species (M. triphyllum) was most sensitive to florpyrauxifen-benzyl compared to the invasive plant evaluated (I/N ratio indicated >31.3 times more sensitive), any targeted concentration used for invasive plant control for field applications would likely injure the native M. triphyllum plants. Future studies should investigate additional native and invasive species for management guidance, and consider how exposure times influence plant response using similar florpyrauxifen-benzyl concentrations tested in the present study.
Late Holocene relative sea-level reconstructions are commonly generated using proxies preserved in salt-marsh and mangrove sediment. These depositional environments provide abundant material for radiocarbon dating in the form of identifiable macrofossils (salt marshes) and bulk organic sediment (mangroves). We explore if single-step graphitization of these samples in preparation for radiocarbon dating can increase the number and temporal resolution of relative sea-level reconstructions without a corresponding increase in cost. Dating of salt-marsh macrofossils from the northeastern United States and bulk mangrove sediment from the Federated States of Micronesia indicates that single-step graphitization generates radiocarbon ages that are indistinguishable from replicates prepared using traditional graphitization, but with a modest increase in error (mean/maximum of 6.25/15 additional 14C yr for salt-marsh macrofossils). Low 12C currents measured on bulk mangrove sediment following single-step graphitization likely render them unreliable despite their apparent accuracy. Simulated chronologies for six salt-marsh cores indicate that having twice as many radiocarbon dates (since single-step graphitization costs ∼50% of traditional graphitization) results in narrower confidence intervals for sample age estimated by age-depth models when the additional error from the single-step method is less than ∼50 14C yr (∼30 14C yr if the chronology also utilizes historical age markers). Since these thresholds are greater than our empirical estimates of the additional error, we conclude that adopting single-step graphitization for radiocarbon measurements on plant macrofossils is likely to increase precision of age-depth models by more than 20/10% (without/with historical age markers). This improvement can be implemented without additional cost.
Consumers, public officials, and even managers of health care and insurance are unhappy about care quality, access, and costs. This book shows that is because efforts to do something about these problems often rely on hope or conjecture, not rigorous evidence of effectiveness. In this book, experts in the field separate the speculative from the proven with regard to how care is rendered, how patients can be in control, how providers should be paid, and how disparities can be reduced – and they also identify the issues for which evidence is currently missing. It provides an antidote to frustration and a clear-eyed guide for forward progress, helping health care and insurance innovators make better decisions on deciding whether to go ahead now based on current evidence, to seek and wait for additional evidence, or to move on to different ideas. It will be useful to practitioners in hospital systems, medical groups, and insurance organizations and can also be used in executive and MBA teaching.
Coronavirus disease 2019 (COVID-19) spread globally, including across Europe, resulting in different morbidity and mortality outcomes. The aim of this study was to explore the progression of the COVID-19 pandemic over 18 mo in relation to the effect of COVID-19 vaccination at a population level across 35 nations in Europe, while evaluating the data for cross-border epidemiological trends to identify any pertinent lessons that can be implemented in the future.
Epidemiological data were obtained from European Centre for Disease Prevention and Control and Our World in Data databases while Ministry of Health websites of each respective country and local newspapers were used for COVID-19-related vaccination strategies. Case, mortality, and vaccination incidence comparative analyses were made across neighboring countries.
Similar morbidity and mortality outcomes were evident across neighboring countries over 18 mo, with a bidirectional relationship evident between cumulative fully vaccinated population and case fatality rates.
Countries’ COVID-19 outcome is related on national mitigative measures, vaccination rollouts, and neighboring countries’ actions and COVID-19 situations. Mass population vaccination appeared to be effective in reducing COVID-19 case severity and mortality rates. Vaccination equity and pan-European commitment for cross-border governance appear to be the way forward to ensure populations’ return to “normality.”
People with serious mental illness (SMI) experience higher mortality partially attributable to higher long-term condition (LTC) prevalence. However, little is known about multiple LTCs (MLTCs) clustering in this population.
People from South London with SMI and two or more existing LTCs aged 18+ at diagnosis were included using linked primary and mental healthcare records, 2012–2020. Latent class analysis (LCA) determined MLTC classes and multinominal logistic regression examined associations between demographic/clinical characteristics and latent class membership.
The sample included 1924 patients (mean (s.d.) age 48.2 (17.3) years). Five latent classes were identified: ‘substance related’ (24.9%), ‘atopic’ (24.2%), ‘pure affective’ (30.4%), ‘cardiovascular’ (14.1%), and ‘complex multimorbidity’ (6.4%). Patients had on average 7–9 LTCs in each cluster. Males were at increased odds of MLTCs in all four clusters, compared to the ‘pure affective’. Compared to the largest cluster (‘pure affective’), the ‘substance related’ and the ‘atopic’ clusters were younger [odds ratios (OR) per year increase 0.99 (95% CI 0.98–1.00) and 0.96 (0.95–0.97) respectively], and the ‘cardiovascular’ and ‘complex multimorbidity’ clusters were older (ORs 1.09 (1.07–1.10) and 1.16 (1.14–1.18) respectively). The ‘substance related’ cluster was more likely to be White, the ‘cardiovascular’ cluster more likely to be Black (compared to White; OR 1.75, 95% CI 1.10–2.79), and both more likely to have schizophrenia, compared to other clusters.
The current study identified five latent class MLTC clusters among patients with SMI. An integrated care model for treating MLTCs in this population is recommended to improve multimorbidity care.
Deutetrabenazine is FDA-approved for the treatment of tardive dyskinesia (TD) in adults. In two 12-week pivotal trials (ARM-TD/AIM-TD), deutetrabenazine significantly improved Abnormal Involuntary Movement Scale (AIMS) scores and was well-tolerated. This post hoc analysis examined the efficacy and safety of long-term deutetrabenazine treatment in TD patients with comorbid psychiatric illness, including schizophrenia/schizoaffective disorder and mood disorders (bipolar/depression/other).
Patients who completed ARM-TD or AIM-TD enrolled in the 3-year, open-label extension (OLE) study. Deutetrabenazine was titrated based on dyskinesia control and tolerability. Change from baseline in total motor AIMS score, Patient Global Impression of Change (PGIC), Clinical Global Impression of Change (CGIC), and adverse events (AEs) were analyzed in subgroups by comorbid psychiatric illness.
A total of 337 patients in the OLE study were included in the analysis: 205 patients with schizophrenia/schizoaffective disorder (mean age, 55 years; 50% male; 6.4 years since diagnosis; 92% taking DRA) and 131 patients with mood disorders (mean age, 60 years; 35% male; 4.6 years since diagnosis; 50% taking DRA). At week 145, mean ± SE dose was 40.4 ± 1.1 mg/day for schizophrenia/schizoaffective disorder (n = 88) and 38.5 ± 1.2 mg/day for mood disorders (n = 72). Mean ± SE change from baseline in AIMS score at week 145 was −6.3 ± 0.49 and −7.1 ± 0.58, 56% and 72% achieved PGIC treatment success, and 66% and 82% achieved CGIC treatment success in schizophrenia/schizoaffective disorder and mood disorder patients, respectively. Overall AE incidence (exposure-adjusted incidence rates [incidence/patient-years]) was low: any, 1.02 and 1.71; serious, 0.10 and 0.12; leading to discontinuation, 0.07 and 0.05).
Long-term deutetrabenazine treatment provided clinically meaningful improvements in TD-related movements, with a favorable safety profile, regardless of underlying comorbid psychiatric illness.
Teva Pharmaceutical Industries Ltd., Petach Tikva, Israel
Tardive dyskinesia (TD) is an involuntary movement disorder that can result from exposure to dopamine-receptor antagonists (DRAs). Deutetrabenazine demonstrated significant improvements in Abnormal Involuntary Movement Scale (AIMS) scores in the 12-week pivotal trials (ARM-TD/AIM-TD). This post hoc analysis assessed the long-term efficacy and safety of deutetrabenazine by baseline DRA use.
Patients who completed ARM-TD or AIM-TD enrolled in the 3-year, open-label extension (OLE) study, with deutetrabenazine dose titrated based on dyskinesia control and tolerability. Change from baseline in total motor AIMS score, Patient Global Impression of Change (PGIC), Clinical Global Impression of Change (CGIC), and adverse event (AE) rates were analyzed in subgroups by baseline DRA use.
Of 337 patients in the OLE study, 254 were taking DRAs at baseline (mean age, 56 years; 48% male; 6.0 years since diagnosis) and 83 were not (mean age, 60 years; 31% male; 4.9 years since diagnosis). Mean ± SE dose at week 145 was 39.9 ± 1.0 mg/day in patients taking DRAs (n = 108) and 38.5 ± 1.5 mg/day in patients not taking DRAs (n = 53). At week 145, mean ± SE change from baseline in AIMS score was −6.1 ± 0.43 and −7.5 ± 0.71; 64% and 62% achieved PGIC treatment success; and 69% and 81% achieved CGIC treatment success, respectively. Overall AE incidence was low (exposure-adjusted incidence rates [incidence/patient-years]: any, 1.08 and 1.97; serious, 0.10 and 0.12; leading to discontinuation, 0.06 and 0.05).
This analysis suggests that deutetrabenazine for long-term treatment of TD is beneficial, with a favorable safety profile, regardless of concomitant DRA use.
Teva Pharmaceutical Industries Ltd., Petach Tikva, Israel
We honour a great man and a true giant. Lodewyk H.S. van Mierop (March 31, 1927 – October 17, 2021), known as Bob, was not only a Paediatric Cardiologist but also a dedicated Scientist. He made many significant and ground-breaking contributions to the fields of cardiac anatomy and embryology. He was devoted as a teacher, spending many hours with medical students, Residents, and Fellows, all of whom appreciated his regularly scheduled educational sessions. Those of us who were fortunate to know and spend time with him will always remember his great mind, his willingness to share his knowledge, and his ability to encourage spirited and fruitful discussions. His life was most productive, and he will long be remembered by many through his awesome and exemplary scientific contributions.
His legacy continues to influence the current and future generations of surgeons and all providers of paediatric and congenital cardiac care through the invaluable archive he established at University of Florida in Gainesville: The University of Florida van Mierop Heart Archive. Undoubtedly, with these extraordinary contributions to the fields of cardiac anatomy and embryology, which were way ahead of his time, Professor van Mierop was a true giant in Paediatric Cardiology. The invaluable archive he established at University of Florida in Gainesville, The University of Florida van Mierop Heart Archive, has been instrumental in teaching medical students, Residents, Medical Fellows, and Surgical Fellows. Only a handful of similar archives exist across the globe, and these archives are the true legacy of giants such as Dr. van Mierop. We have an important obligation to leave no stone unturned to continue to preserve these archives for the future generations of surgeons, physicians, all providers of paediatric and congenital cardiac care, and, most importantly, our patients.
OBJECTIVES/GOALS: a) Explore topics related to AMC CRP job titles, descriptions, and pre-requisites for hire b) Describe impact of COVID-19 on the AMC CRP workforce c) Discuss opportunities for improving diversity in the CRP workforce d) Discuss opportunities to enhance institutional staffing culture to retain CRP workforce METHODS/STUDY POPULATION: Qualitative data from a series of workshop breakout sessions and open-text survey materials focusing on AMC CRP recruitment, retention and diversity were analyzed to inform content and recommendations for clinical research job titles and descriptions, pre-requisites, diversity, and current needs. RESULTS/ANTICIPATED RESULTS: While certain institutions have established competency-based frameworks for job descriptions and career ladders, standardization remains generally lacking across CTSA hubs. Significant hiring needs have reached exponential proportions across hubs, unable to meet current and projected clinical research goals. Data confirmed an urgent need for closing gaps in clinical research workforce at AMCs, especially for improving diversity and equity of personnel. Improved collaboration with human resource departments, engagement with principal investigators, and overcoming both organizational and resource challenges were suggested strategies, as well as pipeline development via outreach to universities, community colleges, and high schools to raise awareness of the professional pathways for CRPs. DISCUSSION/SIGNIFICANCE: Based on input from 130 CRP leaders at 38 CTSA hubs and 4 IDeA sites evaluating data from 23 breakout transcripts and ~92 surveys from the Collaborative Conversations Unmeeting, new opportunities emerged during the analysis. The findings will be summarized in a 2022 Synergy manuscript including best practice benchmarking recommendations.
Response to lithium in patients with bipolar disorder is associated with clinical and transdiagnostic genetic factors. The predictive combination of these variables might help clinicians better predict which patients will respond to lithium treatment.
To use a combination of transdiagnostic genetic and clinical factors to predict lithium response in patients with bipolar disorder.
This study utilised genetic and clinical data (n = 1034) collected as part of the International Consortium on Lithium Genetics (ConLi+Gen) project. Polygenic risk scores (PRS) were computed for schizophrenia and major depressive disorder, and then combined with clinical variables using a cross-validated machine-learning regression approach. Unimodal, multimodal and genetically stratified models were trained and validated using ridge, elastic net and random forest regression on 692 patients with bipolar disorder from ten study sites using leave-site-out cross-validation. All models were then tested on an independent test set of 342 patients. The best performing models were then tested in a classification framework.
The best performing linear model explained 5.1% (P = 0.0001) of variance in lithium response and was composed of clinical variables, PRS variables and interaction terms between them. The best performing non-linear model used only clinical variables and explained 8.1% (P = 0.0001) of variance in lithium response. A priori genomic stratification improved non-linear model performance to 13.7% (P = 0.0001) and improved the binary classification of lithium response. This model stratified patients based on their meta-polygenic loadings for major depressive disorder and schizophrenia and was then trained using clinical data.
Using PRS to first stratify patients genetically and then train machine-learning models with clinical predictors led to large improvements in lithium response prediction. When used with other PRS and biological markers in the future this approach may help inform which patients are most likely to respond to lithium treatment.
Most psychiatric disorders are associated with several risk factors, but a few underlying psychopathological dimensions account for the common co-occurrence of disorders. If these underlying psychopathological dimensions mediate associations of the risk factors with psychiatric disorders, it would support a trans-diagnostic orientation to etiological research and treatment development.
An analysis was performed of the 2012–2013 National Epidemiologic Survey on Alcohol and Related Conditions III (NESARC-III), a US nationally representative sample of non-institutionalized civilian adults, focusing on respondents who were aged ⩾21 (n = 34 712). Structural equation modeling was used to identify the psychopathological dimensions underlying psychiatric disorders; to examine associations between risk factors, psychopathological dimensions and individual disorders; and to test whether associations of risk factors occurring earlier in life were mediated by risk factors occurring later in life.
A bifactor model of 13 axis I disorders provided a good fit (CFI = 0.987, TLI = 0.982, and RMSEA = 0.011) including an overall psychopathology factor as measured by all 13 disorders and 2 specific factors, one for externalizing disorders and one for fear-related disorders. A substantial proportion of the total effects of the risk factors occurring early in life were indirectly mediated through factors occurring later in life. All risk factors showed a significant total effect on the general psychopathology, externalizing and fear-related factors. Only 23 of 325 direct associations of risk factors with psychiatric disorders achieved statistical significance.
Most risk factors for psychiatric disorders are mediated through broad psychopathological dimensions. The central role of these dimensions supports trans-diagnostic etiological and intervention research.