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Patients with Fontan failure are high-risk candidates for heart transplantation and other advanced therapies. Understanding the outcomes following initial heart failure consultation can help define appropriate timing of referral for advanced heart failure care.
This is a survey study of heart failure providers seeing any Fontan patient for initial heart failure care. Part 1 of the survey captured data on clinical characteristics at the time of heart failure consultation, and Part 2, completed 30 days later, captured outcomes (death, transplant evaluation outcome, and other interventions). Patients were classified as “too late” (death or declined for transplant due to being too sick) and/or “care escalation” (ventricular assist device implanted, inotrope initiated, and/or listed for transplant), within 30 days. “Late referral” was defined as those referred too late and/or had care escalation.
Between 7/2020 and 7/2022, 77 Fontan patients (52% inpatient) had an initial heart failure consultation. Ten per cent were referred too late (6 were too sick for heart transplantation with one subsequent death, and two others died without heart transplantation evaluation, within 30 days), and 36% had care escalation (21 listed ± 5 ventricular assist device implanted ± 6 inotrope initiated). Overall, 42% were late referrals. Heart failure consultation < 1 year after Fontan surgery was strongly associated with late referral (OR 6.2, 95% CI 1.8–21.5, p=0.004).
Over 40% of Fontan patients seen for an initial heart failure consultation were late referrals, with 10% dying or being declined for transplant within a month of consultation. Earlier referral, particularly for those with heart failure soon after Fontan surgery, should be encouraged.
Three factors converge to underscore the heightened importance of evaluating the potential health/well-being effects of friendships in older adulthood. First, policymakers, scientists, and the public alike are recognizing the importance of social relationships for health/well-being and creating national policies to promote social connection. Second, many populations are rapidly aging throughout the world. Third, we currently face what some call a ‘friendship recession’. Although, growing research documents associations between friendship with better health and well-being, friendship can also have a ‘dark side’ and can potentially promote negative outcomes. To better capture friendship’s potential heterogeneous effects, we took an outcome-wide analytic approach.
We analysed data from 12,998 participants in the Health and Retirement Study (HRS) – a prospective and nationally representative cohort of U.S. adults aged >50, and, evaluated if increases in friendship strength (between t0; 2006/2008 and t1; 2010/2012) were associated with better health/well-being across 35 outcomes (in t2; 2014/2016). To assess friendship strength, we leveraged all available friendship items in HRS and created a composite ‘friendship score’ that assessed the following three domains: (1) friendship network size, (2) friendship network contact frequency and (3) friendship network quality.
Stronger friendships were associated with better outcomes on some indicators of physical health (e.g. reduced risk of mortality), health behaviours (e.g. increased physical activity) and nearly all psychosocial indicators (e.g. higher positive affect and mastery, as well as lower negative affect and risk of depression). Friendship was also associated with increased likelihood of smoking and heavy drinking (although the latter association with heavy drinking did not reach conventional levels of statistical significance).
Our findings indicate that stronger friendships can have a dual impact on health and well-being. While stronger friendships appear to mainly promote a range of health and well-being outcomes, stronger friendships might also promote negative outcomes. Additional research is needed, and any future friendship interventions and policies that aim to enhance outcomes should focus on how to amplify positive outcomes while mitigating harmful ones.
Of 731 restricted antimicrobial prescriptions subject to antimicrobial stewardship program (ASP) prospective audit and feedback (PAF) over a 3-year period, 598 PAF recommendations (82%) were fully accepted. Physician auditors had an increased odds of PAF recommendation acceptance, reinforcing the complementary role of the ASP physician in the multidisciplinary ASP team.
Excessive and persistent fear of clusters of holes, also known as trypophobia, has been suggested to reflect cortical hyperexcitability and may be associated with mental health risks. No study, however, has yet examined these associations in representative epidemiological samples.
To examine the prevalence of trypophobia in a population-representative youth sample, its association with mental health and functioning, and its interaction with external stress.
A total of 2065 young people were consecutively recruited from a household-based epidemiological youth mental health study in Hong Kong. Trypophobia, symptoms of anxiety, depression and stress, and exposure to personal stressors were assessed. Logistic regression was used to assess the relationships between trypophobia and mental health. Potential additive and interaction effects of trypophobia and high stress exposure on mental health were also tested.
The prevalence of trypophobia was 17.6%. Trypophobia was significantly associated with severe symptoms of anxiety (odds ratio (OR) = 1.83, 95% CI = 1.32–2.53), depression (OR = 1.78, 95% CI = 1.24–2.56) and stress (OR = 1.68, 95% CI = 1.11–2.53), even when accounting for sociodemographic factors, personal and family psychiatric history, resilience and stress exposure. Dose–response relationships were observed, and trypophobia significantly potentiated the effects of stress exposure on symptom outcomes, particularly for depressive symptoms. Those with trypophobia also showed significantly poorer functioning across domains and poorer health-related quality of life.
Screening for trypophobia in young people may facilitate early risk detection and intervention, particularly among those with recent stress exposure. Nevertheless, the generally small effect sizes suggest that other factors have more prominent roles in determining recent mental health outcomes in population-based samples; these should be explored in future work.
Clinical trials provide the “gold standard” evidence for advancing the practice of medicine, even as they evolve to integrate real-world data sources. Modern clinical trials are increasingly incorporating real-world data sources – data not intended for research and often collected in free-living contexts. We refer to trials that incorporate real-world data sources as real-world trials. Such trials may have the potential to enhance the generalizability of findings, facilitate pragmatic study designs, and evaluate real-world effectiveness. However, key differences in the design, conduct, and implementation of real-world vs traditional trials have ramifications in data management that can threaten their desired rigor.
Three examples of real-world trials that leverage different types of data sources – wearables, medical devices, and electronic health records are described. Key insights applicable to all three trials in their relationship to Data and Safety Monitoring Boards (DSMBs) are derived.
Insight and recommendations are given on four topic areas: A. Charge of the DSMB; B. Composition of the DSMB; C. Pre-launch Activities; and D. Post-launch Activities. We recommend stronger and additional focus on data integrity.
Clinical trials can benefit from incorporating real-world data sources, potentially increasing the generalizability of findings and overall trial scale and efficiency. The data, however, present a level of informatic complexity that relies heavily on a robust data science infrastructure. The nature of monitoring the data and safety must evolve to adapt to new trial scenarios to protect the rigor of clinical trials.
Despite replicated cross-sectional evidence of aberrant levels of peripheral inflammatory markers in individuals with major depressive disorder (MDD), there is limited literature on associations between inflammatory tone and response to sequential pharmacotherapies.
To assess associations between plasma levels of pro-inflammatory markers and treatment response to escitalopram and adjunctive aripiprazole in adults with MDD.
In a 16-week open-label clinical trial, 211 participants with MDD were treated with escitalopram 10– 20 mg daily for 8 weeks. Responders continued on escitalopram while non-responders received adjunctive aripiprazole 2–10 mg daily for 8 weeks. Plasma levels of pro-inflammatory markers – C-reactive protein, Interleukin (IL)-1β, IL-6, IL-17, Interferon gamma (IFN)-Γ, Tumour Necrosis Factor (TNF)-α, and Chemokine C–C motif ligand-2 (CCL-2) - measured at baseline, and after 2, 8 and 16 weeks were included in logistic regression analyses to assess associations between inflammatory markers and treatment response.
Pre-treatment levels of IFN-Γ and CCL-2 were significantly higher in escitalopram non-responders compared to responders. Pre-treatment IFN-Γ and CCL-2 levels were significantly associated with a lower of odds of response to escitalopram at 8 weeks. Increases in CCL-2 levels from weeks 8 to 16 in escitalopram non-responders were significantly associated with higher odds of non-response to adjunctive aripiprazole at week 16.
Pre-treatment levels of IFN-Γ and CCL-2 were predictive of response to escitalopram. Increasing levels of these pro-inflammatory markers may predict non-response to adjunctive aripiprazole. These findings require validation in independent clinical populations.
Hospital-based biobanks are being increasingly considered as a resource for translating polygenic risk scores (PRS) into clinical practice. However, since these biobanks originate from patient populations, there is a possibility of bias in polygenic risk estimation due to overrepresentation of patients with higher frequency of healthcare interactions.
PRS for schizophrenia, bipolar disorder, and depression were calculated using summary statistics from the largest available genomic studies for a sample of 24 153 European ancestry participants in the Mass General Brigham (MGB) Biobank. To correct for selection bias, we fitted logistic regression models with inverse probability (IP) weights, which were estimated using 1839 sociodemographic, clinical, and healthcare utilization features extracted from electronic health records of 1 546 440 non-Hispanic White patients eligible to participate in the Biobank study at their first visit to the MGB-affiliated hospitals.
Case prevalence of bipolar disorder among participants in the top decile of bipolar disorder PRS was 10.0% (95% CI 8.8–11.2%) in the unweighted analysis but only 6.2% (5.0–7.5%) when selection bias was accounted for using IP weights. Similarly, case prevalence of depression among those in the top decile of depression PRS was reduced from 33.5% (31.7–35.4%) to 28.9% (25.8–31.9%) after IP weighting.
Non-random selection of participants into volunteer biobanks may induce clinically relevant selection bias that could impact implementation of PRS in research and clinical settings. As efforts to integrate PRS in medical practice expand, recognition and mitigation of these biases should be considered and may need to be optimized in a context-specific manner.
This paper used data from the Apathy in Dementia Methylphenidate Trial 2 (NCT02346201) to conduct a planned cost consequence analysis to investigate whether treatment of apathy with methylphenidate is economically attractive.
A total of 167 patients with clinically significant apathy randomized to either methylphenidate or placebo were included. The Resource Utilization in Dementia Lite instrument assessed resource utilization for the past 30 days and the EuroQol five dimension five level questionnaire assessed health utility at baseline, 3 months, and 6 months. Resources were converted to costs using standard sources and reported in 2021 USD. A repeated measures analysis of variance compared change in costs and utility over time between the treatment and placebo groups. A binary logistic regression was used to assess cost predictors.
Costs were not significantly different between groups whether the cost of methylphenidate was excluded (F(2,330) = 0.626, ηp2 = 0.004, p = 0.535) or included (F(2,330) = 0.629, ηp2 = 0.004, p = 0.534). Utility improved with methylphenidate treatment as there was a group by time interaction (F(2,330) = 7.525, ηp2 = 0.044, p < 0.001).
Results from this study indicated that there was no evidence for a difference in resource utilization costs between methylphenidate and placebo treatment. However, utility improved significantly over the 6-month follow-up period. These results can aid in decision-making to improve quality of life in patients with Alzheimer’s disease while considering the burden on the healthcare system.
The present study examines whether self-reported trust in humans and self-reported trust in [(different) products with built-in] artificial intelligence (AI) are associated with one another and with brain structure. We sampled 90 healthy participants who provided self-reported trust in humans and AI and underwent brain structural magnetic resonance imaging assessment. We found that trust in humans, as measured by the trust facet of the personality inventory NEO-PI-R, and trust in AI products, as measured by items assessing attitudes toward AI and by a composite score based on items assessing trust toward products with in-built AI, were not significantly correlated. We also used a concomitant dimensional neuroimaging approach employing a data-driven source-based morphometry (SBM) analysis of gray-matter-density to investigate neurostructural associations with each trust domain. We found that trust in humans was negatively (and significantly) correlated with an SBM component encompassing striato-thalamic and prefrontal regions. We did not observe significant brain structural association with trust in AI. The present findings provide evidence that trust in humans and trust in AI seem to be dissociable constructs. While the personal disposition to trust in humans might be “hardwired” to the brain’s neurostructural architecture (at least from an individual differences perspective), a corresponding significant link for the disposition to trust AI was not observed. These findings represent an initial step toward elucidating how different forms of trust might be processed on the behavioral and brain level.
Colliding collisionless shocks appear in a great variety of astrophysical phenomena and are thought to be possible sources of particle acceleration in the Universe. We have previously investigated particle acceleration induced by single super-critical shocks (whose magnetosonic Mach number is higher than the critical value of 2.7) (Yao et al., Nat. Phys., vol. 17, issue 10, 2021, pp. 1177–1182; Yao et al., Matter Radiat. Extrem., vol. 7, issue 1, 2022, 014402), as well as the collision of two sub-critical shocks (Fazzini et al., Astron. Astrophys., vol. 665, 2022, A87). Here, we propose to make measurements of accelerated particles from interpenetrating super-critical shocks to observe the ‘phase-locking effect’ (Fazzini et al., Astron. Astrophys., vol. 665, 2022, A87) from such an event. This effect is predicted to significantly boost the energy spectrum of the energized ions compared with a single super-critical collisionless shock. We thus anticipate that the results obtained in the proposed experiment could have a significant impact on our understanding of one type of primary source (acceleration of thermal ions as opposed to secondary acceleration mechanisms of already energetic ions) of ion energization of particles in the Universe.
In adults with Clostridioides difficile infection (CDI), higher stool concentrations of toxins A and B are associated with severe baseline disease, CDI-attributable severe outcomes, and recurrence. We evaluated whether toxin concentration predicts these presentations in children with CDI.
We conducted a prospective cohort study of inpatients aged 2–17 years with CDI who received treatment. Patients were followed for 40 days after diagnosis for severe outcomes (intensive care unit admission, colectomy, or death, categorized as CDI primarily attributable, CDI contributed, or CDI not contributing) and recurrence. Baseline stool toxin A and B concentrations were measured using ultrasensitive single-molecule array assay, and 12 plasma cytokines were measured when blood was available.
We enrolled 187 pediatric patients (median age, 9.6 years). Patients with severe baseline disease by IDSA-SHEA criteria (n = 34) had nonsignificantly higher median stool toxin A+B concentration than those without severe disease (n = 122; 3,217.2 vs 473.3 pg/mL; P = .08). Median toxin A+B concentration was nonsignificantly higher in children with a primarily attributed severe outcome (n = 4) versus no severe outcome (n = 148; 19,472.6 vs 429.1 pg/mL; P = .301). Recurrence occurred in 17 (9.4%) of 180 patients. Baseline toxin A+B concentration was significantly higher in patients with versus without recurrence: 4,398.8 versus 280.8 pg/mL (P = .024). Plasma granulocyte colony-stimulating factor concentration was significantly higher in CDI patients versus non-CDI diarrhea controls: 165.5 versus 28.5 pg/mL (P < .001).
Higher baseline stool toxin concentrations are present in children with CDI recurrence. Toxin quantification should be included in CDI treatment trials to evaluate its use in severity assessment and outcome prediction.
This systematic literature review aimed to provide an overview of the characteristics and methods used in studies applying the disability-adjusted life years (DALY) concept for infectious diseases within European Union (EU)/European Economic Area (EEA)/European Free Trade Association (EFTA) countries and the United Kingdom. Electronic databases and grey literature were searched for articles reporting the assessment of DALY and its components. We considered studies in which researchers performed DALY calculations using primary epidemiological data input sources. We screened 3053 studies of which 2948 were excluded and 105 studies met our inclusion criteria. Of these studies, 22 were multi-country and 83 were single-country studies, of which 46 were from the Netherlands. Food- and water-borne diseases were the most frequently studied infectious diseases. Between 2015 and 2022, the number of burden of infectious disease studies was 1.6 times higher compared to that published between 2000 and 2014. Almost all studies (97%) estimated DALYs based on the incidence- and pathogen-based approach and without social weighting functions; however, there was less methodological consensus with regards to the disability weights and life tables that were applied. The number of burden of infectious disease studies undertaken across Europe has increased over time. Development and use of guidelines will promote performing burden of infectious disease studies and facilitate comparability of the results.
This study addresses orbit design and optimisation for the situation of satellite interception in which the target spacecraft is capable of manoeuvring using continuous magnitude restricted thrust. For the purpose of designing a long-range continuous thrust interception orbit, the orbit motion equations of two satellites with J2 perturbation are constructed. This problem is assumed to be a typical pursuit-evasion problem in differential game theory; using boundary constraint conditions and a performance index function that includes time and fuel consumption, the saddle point solution corresponding to the bilateral optimal is derived, and then this pursuit-evasion problem is transformed into a two-point boundary value problem. A hybrid optimisation method using a genetic algorithm (GA) and sequential quadratic programming (SQP) is derived to obtain the optimal control strategy. The proposed model and algorithm are proved to be feasible for the given simulation cases.
Understanding how sustainable preference change can be achieved is of both scientific and practical importance. Recent work shows that merely responding or not responding to objects during go/no-go training can influence preferences for these objects right after the training, when people choose with a time limit. Here we examined whether and how such immediate preference change in fast choices can affect choices without time limit one week later. In two preregistered experiments, participants responded to go food items and withheld responses toward no-go food items during a go/no-go training. Immediately after the training, they made consumption choices for half of the items (with a time limit in Experiment 1; without time limit in Experiment 2). One week later, participants chose again (without time limit in both experiments). Half of the choices had been presented immediately after the training (repeated choices), while the other half had not (new choices). Participants preferred go over no-go items both immediately after the training and one week later. Furthermore, the effect was observed for both repeated and new choices after one week, revealing a direct effect of mere (non)responses on preferences one week later. Exploratory analyses revealed that the effect after one week is related to the memory of stimulus-response contingencies immediately after the training, and this memory is impaired by making choices. These findings show mere action versus inaction can directly induce preference change that lasts for at least one week, and memory of stimulus-response contingencies may play a crucial role in this effect.
Hand-collecting credit line drawdowns that firms classify as long-term debt, we first document how long-term drawdowns rise with high investment needs or weak external capital market conditions. Nearly all drawdown proceeds finance long-term investment, including M&A activity. Unrated and lower-rated firms rely more on long-term drawdowns than high or very poorly rated firms. We further find that credit lines have tighter covenants than terms loans. Drawdowns are repaid fairly quickly and often refinanced with other long-term debt. Our findings support the monitored liquidity insurance theory of credit lines and highlight that long-term drawdowns act as a valuable bridge financing mechanism.
Dietary fibre modulates gastrointestinal (GI) health and function, providing laxation, shifting microbiota, and altering bile acid (BA) metabolism. Fruit juice production removes the polyphenol- and fibre-rich pomace fraction. The effects of orange and apple pomaces on GI outcomes were investigated in healthy, free-living adults. Healthy adults were enrolled in two double-blinded, crossover trials, being randomised by baseline bowel movement (BM) frequency. In the first trial, subjects (n 91) received orange juice (OJ, 0 g fibre/d) or OJ + orange pomace (OJ + P, 10 g fibre/d) for 4 weeks, separated by a 3-week washout. Similarly, in the second trial, subjects (n 90) received apple juice (AJ, 0 g fibre/d) or AJ + apple pomace (AJ + P, 10 g fibre/d). Bowel habit diaries, GI tolerance surveys and 3-d diet records were collected throughout. Fresh faecal samples were collected from a participant subset for microbiota and BA analyses in each study. Neither pomace interventions influenced BM frequency. At Week 4, OJ + P tended to increase (P = 0·066) GI symptom occurrence compared with OJ, while AJ + P tended (P = 0·089) to increase flatulence compared with AJ. Faecalibacterium (P = 0·038) and Negativibacillus (P = 0·043) were differentially abundant between pre- and post-interventions in the apple trial but were no longer significant after false discovery rate (FDR) correction. Baseline fibre intake was independently associated with several microbial genera in both trials. Orange or apple pomace supplementation was insufficient to elicit changes in bowel habits, microbiota diversity or BA of free-living adults with healthy baseline BM. Future studies should consider baseline BM frequency and habitual fibre intake.
This study assesses governments' long-term non-pharmaceutical interventions upon the coronavirus disease 2019 (COVID-19) pandemic in East Asia. It advances the literature towards a better understanding of when and which control measures are effective. We (1) provide time-varying case fatality ratios and focus on the elderly's mortality and case fatality ratios, (2) measure the correlations between daily new cases (daily new deaths) and each index based on multiple domestic pandemic waves and (3) examine the lead–lag relationship between daily new cases (daily new deaths) and each index via the cross-correlation functions on the pre-whitened series. Our results show that the interventions reduce COVID-19 infections for some periods before the period of the Omicron variant. Moreover, there is no COVID-19 policy lag in Taiwan between daily new confirmed cases and each index. As of March 2022, the case fatality ratios of the elderly group in Japan, Hong Kong and South Korea are 4.69%, 4.72% and 1.48%, respectively, while the case fatality ratio of the elderly group in Taiwan is 25.01%. A government's COVID-19 vaccination distribution and prioritisation policies are pivotal for the elderly group to reduce the number of deaths. Immunising this specific group as best as possible should undoubtedly be a top priority.
The great demographic pressure brings tremendous volume of beef demand. The key to solve this problem is the growth and development of Chinese cattle. In order to find molecular markers conducive to the growth and development of Chinese cattle, sequencing was used to determine the position of copy number variations (CNVs), bioinformatics analysis was used to predict the function of ZNF146 gene, real-time fluorescent quantitative polymerase chain reaction (qPCR) was used for CNV genotyping and one-way analysis of variance was used for association analysis. The results showed that there exists CNV in Chr 18: 47225201-47229600 (5.0.1 version) of ZNF146 gene through the early sequencing results in the laboratory and predicted ZNF146 gene was expressed in liver, skeletal muscle and breast cells, and was amplified or overexpressed in pancreatic cancer, which promoted the development of tumour through bioinformatics. Therefore, it is predicted that ZNF146 gene affects the proliferation of muscle cells, and then affects the growth and development of cattle. Furthermore, CNV genotyping of ZNF146 gene was three types (deletion type, normal type and duplication type) by Real-time fluorescent quantitative PCR (qPCR). The association analysis results showed that ZNF146-CNV was significantly correlated with rump length of Qinchuan cattle, hucklebone width of Jiaxian red cattle and heart girth of Yunling cattle. From the above results, ZNF146-CNV had a significant effect on growth traits, which provided an important candidate molecular marker for growth and development of Chinese cattle.
Bragg scattering of nonlinear surface waves over a wavy bottom is studied using two-dimensional fully nonlinear numerical wave tanks (NWTs). In particular, we consider cases of high nonlinearity which lead to complex wave generation and transformations, hence possible multiple Bragg resonances. The performance of the NWTs is well verified by benchmarking experiments. Classic Bragg resonances associated with second-order triad interactions among two surface (linear incident and reflected waves) and one bottom wave components (class I), and third-order quartet interactions among three surface (linear incident and reflected waves, and second-order reflected/transmitted waves) and one bottom wave components (class III) are observed. In addition, class I Bragg resonance occurring for the second-order (rather than linear) transmitted waves, and Bragg resonance arising from quintet interactions among three surface and two bottom wave components, are newly captured. The latter is denoted class IV Bragg resonance which magnifies bottom nonlinearity. It is also found that wave reflection and transmission at class III Bragg resonance have a quadratic rather than a linear relation with the bottom slope if the bottom size increases to a certain level. The surface wave and bottom nonlinearities are found to play opposite roles in shifting the Bragg resonance conditions. Finally, the results indicate that Bragg resonances are responsible for the phenomena of beating and parasitic beating, leading to a significantly large local free surface motion in front of the depth transition.