Adaptive, Group Sequential Designs that Balance the Benefits and Risks of Wider Inclusion Criteria

We propose a new class of adaptive randomized trial designs aimed at gaining the advantages of wider generalizability and faster recruitment, while mitigating the risks of including a population for which there is greater a priori uncertainty. Our designs use adaptive enrichment, i.e., they have preplanned decision rules for modifying enrollment criteria based on data accrued at interim analyses. For example, enrollment can be restricted if the participants from predefined subpopulations are not benefiting from the new treatment. To the best of our knowledge, our designs are the first adaptive enrichment designs to have all of the following features: the multiple testing procedure fully leverages the correlation among statistics for different populations; the familywise Type I error rate is strongly controlled; for outcomes that are binary, normally distributed, or Poisson distributed, the decision rule and multiple testing procedure are functions of the data only through minimal sufficient statistics. The advantage of relying solely on minimal sufficient statistics is that not doing so can lead to losses in power. Our designs incorporate standard group sequential boundaries for each population of interest; this may be helpful in communicating our designs, since many clinical investigators are familiar with such boundaries, which can be summarized succinctly in a single table or graph. We demonstrate these adaptive designs in the context of a Phase III trial of a new treatment for stroke, and provide user-friendly, free software implementing these designs

Predictors of Shared Decision Making and Level of Agreement between Consumers and Providers in Psychiatric Care

The purpose of this study was to quantitatively examine elements of shared decision making (SDM), and to establish empirical evidence for factors correlated with SDM and the level of agreement between consumer and provider in psychiatric care. Transcripts containing 128 audio-recorded medication check-up visits with eight providers at three community mental health centers were rated using the Shared Decision Making scale, adapted from Braddock’s Informed Decision Making Scale (Braddock et al., 1997; 1999; 2008). Multilevel regression analyses revealed that greater consumer activity in the session and greater decision complexity significantly predicted the SDM score. The best predictor of agreement between consumer and provider was “exploration of consumer preference,” with a four-fold increase in full agreement when consumer preferences were discussed more completely. Enhancing active consumer participation, particularly by incorporating consumer preferences in the decision making process appears to be an important factor in SDM

Heart Failure in Humans Reduces Contractile Force in Myocardium from Both Ventricles

This study measured how heart failure affects the contractile properties of the human myocardium from the left and right ventricles. The data showed that maximum force and maximum power were reduced by approximately 30% in multicellular preparations from both ventricles, possibly because of ventricular remodeling (e.g., cellular disarray and/or excess fibrosis). Heart failure increased the calcium (Ca2+) sensitivity of contraction in both ventricles, but the effect was bigger in right ventricular samples. The changes in Ca2+ sensitivity were associated with ventricle-specific changes in the phosphorylation of troponin I, which indicated that adrenergic stimulation might induce different effects in the left and right ventricles

The detectability of dark matter annihilation with Fermi using the anisotropy energy spectrum of the gamma-ray background

The energy-dependence of the anisotropy (the anisotropy energy spectrum) of the large-scale diffuse gamma-ray background can reveal the presence of multiple source populations. Annihilating dark matter in the substructure of the Milky Way halo could give rise to a modulation in the anisotropy energy spectrum of the diffuse gamma-ray emission measured by Fermi, enabling the detection of a dark matter signal. We determine the detectability of a dark-matter-induced modulation for scenarios in which unresolved blazars are the primary contributor to the measured emission above ~1 GeV and find that in some scenarios pair-annihilation cross sections of order the value expected for thermal relic dark matter can produce a detectable feature. We anticipate that the sensitivity of this technique to specific dark matter models could be improved by tailored likelihood analysis methods.Comment: 9 pages, 7 figures; figures updated, other minor revisions, published in Ap

Measuring Shared Decision Making in Psychiatric Care

The official published article is available online at http://doi.org/10.1176/appi.ps.201100496.OBJECTIVE: Shared decision making is widely recognized to facilitate effective health care; tools are needed to measure the level of shared decision making in psychiatric practice. METHODS: A coding scheme assessing shared decision making in medical settings (1) was adapted, including creation of a manual. Trained raters analyzed 170 audio recordings of psychiatric medication check-up visits. RESULTS: Inter-rater reliability among three raters for a subset of 20 recordings ranged from 67% to 100% agreement for the presence of each of nine elements of shared decision making and 100% for the overall agreement between provider and consumer. Just over half of the decisions met minimum criteria for shared decision making. Shared decision making was not related to length of visit after controlling for complexity of decision. CONCLUSIONS: The shared decision making rating scale appears to reliably assess shared decision making in psychiatric practice and could be helpful for future research, training, and implementation efforts

Defining a recovery-oriented cascade of care for opioid use disorder: A community-driven, statewide cross-sectional assessment

Background In light of the accelerating and rapidly evolving overdose crisis in the United States (US), new strategies are needed to address the epidemic and to efficiently engage and retain individuals in care for opioid use disorder (OUD). Moreover, there is an increasing need for novel approaches to using health data to identify gaps in the cascade of care for persons with OUD. Methods and findings Between June 2018 and May 2019, we engaged a diverse stakeholder group (including directors of statewide health and social service agencies) to develop a statewide, patient-centered cascade of care for OUD for Rhode Island, a small state in New England, a region highly impacted by the opioid crisis. Through an iterative process, we modified the cascade of care defined by Williams et al. for use in Rhode Island using key national survey data and statewide health claims datasets to create a cross-sectional summary of 5 stages in the cascade. Approximately 47,000 Rhode Islanders (5.2%) were estimated to be at risk for OUD (stage 0) in 2016. At the same time, 26,000 Rhode Islanders had a medical claim related to an OUD diagnosis, accounting for 55% of the population at risk (stage 1); 27% of the stage 0 population, 12,700 people, showed evidence of initiation of medication for OUD (MOUD, stage 2), and 18%, or 8,300 people, had evidence of retention on MOUD (stage 3). Imputation from a national survey estimated that 4,200 Rhode Islanders were in recovery from OUD as of 2016, representing 9% of the total population at risk. Limitations included use of self-report data to arrive at estimates of the number of individuals at risk for OUD and using a national estimate to identify the number of individuals in recovery due to a lack of available state data sources. Conclusions Our findings indicate that cross-sectional summaries of the cascade of care for OUD can be used as a health policy tool to identify gaps in care, inform data-driven policy decisions, set benchmarks for quality, and improve health outcomes for persons with OUD. There exists a significant opportunity to increase engagement prior to the initiation of OUD treatment (i.e., identification of OUD symptoms via routine screening or acute presentation) and improve retention and remission from OUD symptoms through improved community-supported processes of recovery. To do this more precisely, states should work to systematically collect data to populate their own cascade of care as a health policy tool to enhance system-level interventions and maximize engagement in care

Reference Values for the Marx Activity Rating Scale in a Young Athletic Population: History of Knee Ligament Injury Is Associated With Higher Scores

Activity-related patient-reported outcome measures are an important component of assessment after knee ligament injury in young and physically active patients; however, normative data for most activity scales are limited

Engineering tyrosine-based electron flow pathways in proteins: The case of aplysia myoglobin

Tyrosine residues can act as redox cofactors that provide an electron transfer ("hole-hopping") route that enhances the rate of ferryl heme iron reduction by externally added reductants, for example, ascorbate. Aplysia fasciata myoglobin, having no naturally occurring tyrosines but 15 phenylalanines that can be selectively mutated to tyrosine residues, provides an ideal protein with which to study such through-protein electron transfer pathways and ways to manipulate them. Two surface exposed phenylalanines that are close to the heme have been mutated to tyrosines (F42Y, F98Y). In both of these, the rate of ferryl heme reduction increased by up to 3 orders of magnitude. This result cannot be explained in terms of distance or redox potential change between donor and acceptor but indicates that tyrosines, by virtue of their ability to form radicals, act as redox cofactors in a new pathway. The mechanism is discussed in terms of the Marcus theory and the specific protonation/deprotonation states of the oxoferryl iron and tyrosine. Tyrosine radicals have been observed and quantified by EPR spectroscopy in both mutants, consistent with the proposed mechanism. The location of each radical is unambiguous and allows us to validate theoretical methods that assign radical location on the basis of EPR hyperfine structure. Mutation to tyrosine decreases the lipid peroxidase activity of this myoglobin in the presence of low concentrations of reductant, and the possibility of decreasing the intrinsic toxicity of hemoglobin by introduction of these pathways is discussed. © 2012 American Chemical Society

Cultural pathway to osteopathic medical school: The Native American pre-admissions workshop

Background: Native Americans (NAs) experience significant health disparities compared to the general US population. Medical education has a key role to play in addressing these inequities; however, it is currently falling short. Providers lack sufficient knowledge of NA heritage, cultures, perspectives, and social determinants of health. Under-representation begins in the medical education pathway, with only 0.3% of residents and merely 0.15% of faculty serving the 2.9% of identifying NAs. Because NA health professionals are more likely to serve the NA community, training more NAs has the potential to address current workforce challenges in Indian Country. However, there is a void in literature specific to the recruitment, training, and development of NA providers in the US workforce. This likely contributes to the limited success of US medical schools to train NA physicians. Therefore, our primary objective is to increase awareness of osteopathic medicine, including introduction of osteopathic practice and philosophy, among NAs interested in pursuing a career in medicine. Our secondary objective is to provide prospective NA applicants exposure to the knowledge, skills, behaviors, and attitudes necessary for successful matriculation to osteopathic medical school.Methods: Due to COVID-19, the NAPA Workshops (Spring 2021 and Fall 2021) were held virtually via the telecommunications platform Zoom. This allowed nationwide participation for learning about the partnership between OSU-COM and the Cherokee Nation, Osteopathic Manipulative Medicine, clinical skills, admissions acumen, current student perspectives, and how the principles of Osteopathic Medicine parallel traditional NA beliefs and practices. For example, the osteopathic tenets address the body as a unit, with the person representing a combination of body, mind, and spirit. These same principles embody wellness and healing beliefs for many NAs.Results: When surveyed at the time of the inaugural NAPA Workshop, 56% of participants reported plans to apply to medical school within the next year, 33% within the next two to three years, 7% were unsure of their timeline, and 4% had already applied. In total, after the 2021 Spring and 2021 Fall NAPA Workshops, a total of forty-one students (twenty-seven in Spring, fourteen in Fall) had attended, nine students (one in 2020-2021 cycle, eight in 2021-2022 cycle) had completed applications, and two students (zero in 2020-2021 cycle, two in 2021-2022 cycle) had been admitted to the OSUCOM.Conclusion: Building on Oklahoma State University College of Osteopathic Medicine’s (OSUCOM) existing pathway programs focused on underrepresented groups, including Native Explorers, Native OKStars, Operation Orange, and the Minority Association of Pre-Medical Students (MAPS) Conference, the Native American Students of Osteopathic Medicine (NASOM) organization created the Native American Pre-Admission (NAPA) Workshop. The Student-led NAPA Workshop has resulted in an additional, culturally sensitive pathway for increased recruitment of NA medical students, the most underrepresented group in medicine, furthering OSUCOM’s mission to recruit, train, and retain physicians serving rural and tribal communitie

A Novel Molecular Solution for Ultraviolet Light Detection in Caenorhabditis elegans

For many organisms the ability to transduce light into cellular signals is crucial for survival. Light stimulates DNA repair and metabolism changes in bacteria, avoidance responses in single-cell organisms, attraction responses in plants, and both visual and nonvisual perception in animals. Despite these widely differing responses, in all of nature there are only six known families of proteins that can transduce light. Although the roundworm Caenorhabditis elegans has none of the known light transduction systems, we show here that C. elegans strongly accelerates its locomotion in response to blue or shorter wavelengths of light, with maximal responsiveness to ultraviolet light. Our data suggest that C. elegans uses this light response to escape the lethal doses of sunlight that permeate its habitat. Short-wavelength light drives locomotion by bypassing two critical signals, cyclic adenosine monophosphate (cAMP) and diacylglycerol (DAG), that neurons use to shape and control behaviors. C. elegans mutants lacking these signals are paralyzed and unresponsive to harsh physical stimuli in ambient light, but short-wavelength light rapidly rescues their paralysis and restores normal levels of coordinated locomotion. This light response is mediated by LITE-1, a novel ultraviolet light receptor that acts in neurons and is a member of the invertebrate Gustatory receptor (Gr) family. Heterologous expression of the receptor in muscle cells is sufficient to confer light responsiveness on cells that are normally unresponsive to light. Our results reveal a novel molecular solution for ultraviolet light detection and an unusual sensory modality in C. elegans that is unlike any previously described light response in any organism