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Williamson (2000) argues that the KK principle is inconsistent with knowledge of margin for error in cases of inexact perceptual observations. This paper argues, primarily by analogy to a different scenario, that Williamson's argument is fallacious. Margin for error principles describe the agent's knowledge as a result of an inexact perceptual event, not the agent's knowledge state in general. Therefore, epistemic agents can use their knowledge of margin for error at most once after a perceptual event, but not more. This insight blocks a crucial step in Williamson's original argument. Along the way, the value of standard epistemic logic for analyzing margin for error reasoning is challenged.
Reward processing has been proposed to underpin the atypical social feature of autism spectrum disorder (ASD). However, previous neuroimaging studies have yielded inconsistent results regarding the specificity of atypicalities for social reward processing in ASD.
Utilising a large sample, we aimed to assess reward processing in response to reward type (social, monetary) and reward phase (anticipation, delivery) in ASD.
Functional magnetic resonance imaging during social and monetary reward anticipation and delivery was performed in 212 individuals with ASD (7.6–30.6 years of age) and 181 typically developing participants (7.6–30.8 years of age).
Across social and monetary reward anticipation, whole-brain analyses showed hypoactivation of the right ventral striatum in participants with ASD compared with typically developing participants. Further, region of interest analysis across both reward types yielded ASD-related hypoactivation in both the left and right ventral striatum. Across delivery of social and monetary reward, hyperactivation of the ventral striatum in individuals with ASD did not survive correction for multiple comparisons. Dimensional analyses of autism and attention-deficit hyperactivity disorder (ADHD) scores were not significant. In categorical analyses, post hoc comparisons showed that ASD effects were most pronounced in participants with ASD without co-occurring ADHD.
Our results do not support current theories linking atypical social interaction in ASD to specific alterations in social reward processing. Instead, they point towards a generalised hypoactivity of ventral striatum in ASD during anticipation of both social and monetary rewards. We suggest this indicates attenuated reward seeking in ASD independent of social content and that elevated ADHD symptoms may attenuate altered reward seeking in ASD.
This essay walks us through the methodological questions provoked by the popularity of poetry in the antebellum period. It urges scholars to focus less on authorial innovation and critical reception and more on readers and reading, where we find an absolute saturation of poetic enthusiasm and the traces of a transatlantic and commonplace poetic language that has been obscured by the predominance of prose in scholarship on antebellum literature.
Among the many, many transitions in American literature that have been attributed to the US Civil War, one of the less often noted is that the war years coincided with a decisive shift away from authorial anonymity. This transition can be observed in the publication practices of the day’s leading magazines. Harper’s, which had been started in 1850, began naming authors in the index to its twentieth volume (1860), while the Atlantic Monthly, introduced in 1857, began publishing the names of its authors in the index to its tenth volume (1862). The first series of Putnam’s, which ran in the 1850s, did not identify authors in either its issues or its volume indices, but the second series, begun in 1868, did, a distinction that holds when comparing the Continental Monthly, which ran during the war (1862–64) and never identified authors, with the Galaxy, which debuted in 1866 and always did. Even the hoary North American Review got into the act, and started attributing its authors with the January issue of 1868, after more than fifty years of never doing so. There were, of course, exceptions to this trend; antebellum periodicals like Graham’s Magazine or the Broadway Journal sometimes identified the more famous authors who contributed to their pages, while reprint journals like Littell’s Living Age (1844–96) attributed only the original publication sources of its contents, never the individual authors, even at the end of the century. In general, though, postbellum readers of American magazines would be much more likely than their antebellum forebears to know the name of the person who had written whichever article they were reading.
The severe acute respiratory syndrome coronavirus disease-2 (SARS-CoV-2) pandemic of 2020-2021 created unprecedented challenges for clinicians in critical care transport (CCT). These CCT services had to rapidly adjust their clinical approaches to evolving patient demographics, a preponderance of respiratory failure, and transport utilization stratagem. Organizations had to develop and implement new protocols and guidelines in rapid succession, often without the education and training that would have been involved pre-coronavirus disease 2019 (COVID-19). These changes were complicated by the need to protect crew members as well as to optimize patient care. Clinical initiatives included developing an awake proning transport protocol and a protocol to transport intubated proned patients. One service developed a protocol for helmet ventilation to minimize aerosolization risks for patients on noninvasive positive pressure ventilation (NIPPV). While these clinical protocols were developed specifically for COVID-19, the growth in practice will enhance the care of patients with other causes of respiratory failure. Additionally, these processes will apply to future respiratory epidemics and pandemics.
The Colorado is a river in transition – a newly “closed” basin where demands have exhausted reliable supplies. Decades of often short-sighted management decisions have contributed to the crisis environment that currently surrounds the Colorado River. Over the past fifteen years, however, stakeholders and managers have enacted significant changes to the rules and regulations governing the Colorado, and additional reforms remain close to enactment. Unlike the deal-making that characterized negotiations in the twentieth century, recent efforts focus primarily on strategies to promote coordinated management, reduce consumption, and restore a more holistic watershed perspective to a river that was legally apportioned long ago among a highly complex amalgam of jurisdictions and water users. In many respects, the river management system is a successful example of adaptation to changing social and hydrological conditions. Yet, it remains an open question whether the pace and scale of reform is sufficient to deal with the basin’s future.
Hypotension is an adverse event that may be related to systemic exposure of milrinone; however, the true exposure–safety relationship is unknown.
Using the Pediatric Trials Network multicentre repository, we identified children ≤17 years treated with milrinone. Hypotension was defined according to age, using the Pediatric Advanced Life Support guidelines. Clinically significant hypotension was defined as hypotension with concomitant lactate >3 mg/dl. A prior population pharmacokinetic model was used to simulate milrinone exposures to evaluate exposure–safety relationships.
We included 399 children with a median (quarter 1, quarter 3) age of 1 year (0,5) who received 428 intravenous doses of milrinone (median infusion rate 0.31 mcg/kg/min [0.29,0.5]). Median maximum plasma milrinone concentration was 110.7 ng/ml (48.4,206.2). Median lowest systolic and diastolic blood pressures were 74 mmHg (60,85) and 35 mmHg (25,42), respectively. At least 1 episode of hypotension occurred in 178 (45%) subjects; clinically significant hypotension occurred in 10 (2%). The maximum simulated milrinone plasma concentrations were higher in subjects with clinically significant hypotension (251 ng/ml [129,329]) versus with hypotension alone (86 ng/ml [44, 173]) versus without hypotension (122 ng/ml [57, 208], p = 0.002); however, this relationship was not retained on multivariable analysis (odds ratio 1.01; 95% confidence interval 0.998, 1.01).
We successfully leveraged a population pharmacokinetic model and electronic health record data to evaluate the relationship between simulated plasma concentration of milrinone and systemic hypotension occurrence, respectively, supporting the broader applicability of our novel, efficient, and cost-effective study design for examining drug exposure–response and –safety relationships.
In view of the increasing complexity of both cardiovascular implantable electronic devices (CIEDs) and patients in the current era, practice guidelines, by necessity, have become increasingly specific. This document is an expert consensus statement that has been developed to update and further delineate indications and management of CIEDs in pediatric patients, defined as ≤21 years of age, and is intended to focus primarily on the indications for CIEDs in the setting of specific disease categories. The document also highlights variations between previously published adult and pediatric CIED recommendations and provides rationale for underlying important differences. The document addresses some of the deterrents to CIED access in low- and middle-income countries and strategies to circumvent them. The document sections were divided up and drafted by the writing committee members according to their expertise. The recommendations represent the consensus opinion of the entire writing committee, graded by class of recommendation and level of evidence. Several questions addressed in this document either do not lend themselves to clinical trials or are rare disease entities, and in these instances recommendations are based on consensus expert opinion. Furthermore, specific recommendations, even when supported by substantial data, do not replace the need for clinical judgment and patient-specific decision-making. The recommendations were opened for public comment to Pediatric and Congenital Electrophysiology Society (PACES) members and underwent external review by the scientific and clinical document committee of the Heart Rhythm Society (HRS), the science advisory and coordinating committee of the American Heart Association (AHA), the American College of Cardiology (ACC), and the Association for European Paediatric and Congenital Cardiology (AEPC). The document received endorsement by all the collaborators and the Asia Pacific Heart Rhythm Society (APHRS), the Indian Heart Rhythm Society (IHRS), and the Latin American Heart Rhythm Society (LAHRS). This document is expected to provide support for clinicians and patients to allow for appropriate CIED use, appropriate CIED management, and appropriate CIED follow-up in pediatric patients.
Targeted drug development efforts in patients with CHD are needed to standardise care, improve outcomes, and limit adverse events in the post-operative period. To identify major gaps in knowledge that can be addressed by drug development efforts and provide a rationale for current clinical practice, this review evaluates the evidence behind the most common medication classes used in the post-operative care of children with CHD undergoing cardiac surgery with cardiopulmonary bypass.
We systematically searched PubMed and EMBASE from 2000 to 2019 using a controlled vocabulary and keywords related to diuretics, vasoactives, sedatives, analgesics, pulmonary vasodilators, coagulation system medications, antiarrhythmics, steroids, and other endocrine drugs. We included studies of drugs given post-operatively to children with CHD undergoing repair or palliation with cardiopulmonary bypass.
We identified a total of 127 studies with 51,573 total children across medication classes. Most studies were retrospective cohorts at single centres. There is significant age- and disease-related variability in drug disposition, efficacy, and safety.
In this study, we discovered major gaps in knowledge for each medication class and identified areas for future research. Advances in data collection through electronic health records, novel trial methods, and collaboration can aid drug development efforts in standardising care, improving outcomes, and limiting adverse events in the post-operative period.
ABSTRACT IMPACT: Through its interdisciplinary, tailored approach, the FLOW program could change the way that we approach promoting healthy lifestyle changes in the primary care field. OBJECTIVES/GOALS: The goal of this project is to assess patient outcomes associated with the implementation of the Fitness, Lifestyle, and Optimal Wellness (FLOW) Program. The ultimate aim of this program is two-fold: increasing patient-reported wellness and improving objective health measurements. METHODS/STUDY POPULATION: The FLOW program consists of a multidisciplinary team of sports medicine physicians, nutritionists, fitness trainers, and clinical psychologists. Patients who choose to participate in the program undergo a comprehensive physician-guided assessment, including lifestyle and metabolic evaluation, biomarker profile, and body composition analysis. Based on the patient’s goals and results of evaluation, he/she is then connected with other members of the FLOW team to develop a comprehensive plan and offer resources for potential improvements in physical activity, nutrition, and/or behavior. The patient will undergo follow-up assessments and questionnaires at three and six months to track their objective measurements and reported progress. RESULTS/ANTICIPATED RESULTS: The anticipated results of the FLOW program are an overall improvement in patient health and wellbeing. More specifically, we anticipate seeing increased levels of exercise from initial reported levels, as well as better nutrition habits. We expect to see improvements in follow-up body composition assessments, with gains in fat-free mass and decreased body fat, in addition to patient-reported improvements in behavioral health as measured by PHQ-9, GAD-2, and the Perceived Stress Scale. We will also assess reported sleep health with the hopes to see improvement in follow-up assessments. DISCUSSION/SIGNIFICANCE OF FINDINGS: The FLOW program is designed to address health inequities that disproportionately affect the Deep South. Through this program, we propose a new role of the primary care team in promoting healthy lifestyle habits and disease prevention through exercise, nutrition, and behavioral health services.
Antidepressant medication and interpersonal psychotherapy (IPT) are both recommended interventions in depression treatment guidelines based on literature reviews and meta-analyses. However, ‘conventional’ meta-analyses comparing their efficacy are limited by their reliance on reported study-level information and a narrow focus on depression outcome measures assessed at treatment completion. Individual participant data (IPD) meta-analysis, considered the gold standard in evidence synthesis, can improve the quality of the analyses when compared with conventional meta-analysis.
We describe the protocol for a systematic review and IPD meta-analysis comparing the efficacy of antidepressants and IPT for adult acute-phase depression across a range of outcome measures, including depressive symptom severity as well as functioning and well-being, at both post-treatment and follow-up (PROSPERO: CRD42020219891).
We will conduct a systematic literature search in PubMed, PsycINFO, Embase and the Cochrane Library to identify randomised clinical trials comparing antidepressants and IPT in the acute-phase treatment of adults with depression. We will invite the authors of these studies to share the participant-level data of their trials. One-stage IPD meta-analyses will be conducted using mixed-effects models to assess treatment effects at post-treatment and follow-up for all outcome measures that are assessed in at least two studies.
This will be the first IPD meta-analysis examining antidepressants versus IPT efficacy. This study has the potential to enhance our knowledge of depression treatment by comparing the short- and long-term effects of two widely used interventions across a range of outcome measures using state-of-the-art statistical techniques.
There is minimal data regarding antegrade-only accessory pathways in young patients. Given evolving recommendations and treatments, retrospective analysis of the clinical and electrophysiologic properties of antegrade-only pathways in patients <21 years old was performed, with subsequent comparison of electrophysiology properties to age-matched controls with bidirectional pathways. Of 522 consecutive young patients with ventricular pre-excitation referred for electrophysiology study, 33 (6.3%) had antegrade-only accessory pathways. Indications included palpitations (47%), chest pain (25%), and syncope (22%). The shortest value for either the accessory pathway effective refractory period or the pre-excited R-R interval was taken for each patient, with the median of the antegrade-only group significantly greater than shortest values for the bidirectional group (310 [280–360] ms versus 270 [240–302] ms, p < 0.001). However, the prevalence of pathways with high-risk properties (effective refractory period or shortest pre-excited R-R interval <250 ms) was similar in both study patients and controls (13% versus 21%) (p = 0.55). Sixteen patients had a single antegrade-only accessory pathway and no inducible arrhythmia. Six patients had Mahaim fibres, all right anterolateral with inducible antidromic reciprocating tachycardia. However, 11 patients with antegrade-only accessory pathways and 3 with Mahaim fibres had inducible tachycardia due to a second substrate recognised at electrophysiology study. These included concealed accessory pathways (7), bidirectional accessory pathways (5), and atrioventricular node re-entry (2). Antegrade-only accessory pathways require comprehensive electrophysiology evaluation as confounding factors such as high-risk conduction properties or inducible Supraventricular Tachycardia (SVT) due to a second substrate of tachycardia are often present.
The integrity of democratic elections, both in the United States and abroad, is an important problem. In this Element, we present a data-driven approach that evaluates the performance of the administration of a democratic election, before, during, and after Election Day. We show that this data-driven method can help to improve confidence in the integrity of American elections.
Extracorporeal membrane oxygenation (ECMO) has accelerated rapidly for patients in severe cardiac or respiratory failure. As a result, ECMO networks are being developed across the world using a “hub and spoke” model. Current guidelines call for all patients transported on ECMO to be accompanied by a physician during transport. However, as ECMO centers and networks grow, the increasing number of transports will be limited by this mandate.
The aim of this study was to compare rates of adverse events occurring during transport of ECMO patients with and without an additional clinician, defined as a physician, nurse practitioner (NP), or physician assistant (PA).
This is a retrospective cohort study of all adults transported while cannulated on ECMO from 2011-2018 via ground and air between 21 hospitals in the northeastern United States, comparing transports with and without additional clinicians. The primary outcome was the rate of major adverse events, and the secondary outcome was minor adverse events.
Over the seven-year study period, 93 patients on ECMO were transported. Twenty-three transports (24.7%) were accompanied by a physician or other additional clinician. Major adverse events occurred in 21.5% of all transports. There was no difference in the total rate of major adverse events between accompanied and unaccompanied transports (P = .91). Multivariate analysis did not demonstrate any parameter as being predictive of major adverse events.
In a retrospective cohort study of transports of ECMO patients, there was no association between the overall rate of major adverse events in transport and the accompaniment of an additional clinician. No variables were associated with major adverse events in either cohort.
The study describes the implementation of a prehospital treatment algorithm that included intravenous (IV) bolus (IVB) nitroglycerin (NTG) followed by maintenance infusion for the treatment of acute pulmonary edema (APE) in a single, high-volume Emergency Medical Services (EMS) system.
This is a retrospective chart review of patients who received IVB NTG for APE in a large EMS system in Minnesota and Wisconsin (USA). Inclusion criteria for treatment included a diagnosis of APE, systolic blood pressure ≥120mmHg, and oxygen saturation (SpO2) ≤93% following 800mcg of sublingual NTG. Patients received a 400mcg IVB of NTG, repeated every two minutes as needed, and subsequent infusion at 80mcg/min for transport times ≥10 minutes.
Forty-four patients were treated with IVB NTG. The median total bolus dose was 400mcg. Twenty patients were treated with NTG infusion following IVB NTG. The median infusion rate was 80mcg/min. For all patients, the initial median blood pressure was 191/113mmHg. Five minutes following IVB NTG, it was 160/94mmHg, and on arrival to the emergency department (ED) it was 152/90mmHg. Five minutes after the initial dose of IVB NTG, median SpO2 increased to 92% from an initial reading of 88% and was 94% at hospital arrival. One episode of transient hypotension occurred during EMS transport.
Patients treated with IVB NTG for APE had reduction in blood pressure and improvement in SpO2 compared to their original presentation. Prehospital treatment of APE with IVB appears to be feasible and safe. A randomized trial is needed to confirm these findings.