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Multicenter clinical trials are essential for evaluating interventions but often face significant challenges in study design, site coordination, participant recruitment, and regulatory compliance. To address these issues, the National Institutes of Health’s National Center for Advancing Translational Sciences established the Trial Innovation Network (TIN). The TIN offers a scientific consultation process, providing access to clinical trial and disease experts who provide input and recommendations throughout the trial’s duration, at no cost to investigators. This approach aims to improve trial design, accelerate implementation, foster interdisciplinary teamwork, and spur innovations that enhance multicenter trial quality and efficiency. The TIN leverages resources of the Clinical and Translational Science Awards (CTSA) program, complementing local capabilities at the investigator’s institution. The Initial Consultation process focuses on the study’s scientific premise, design, site development, recruitment and retention strategies, funding feasibility, and other support areas. As of 6/1/2024, the TIN has provided 431 Initial Consultations to increase efficiency and accelerate trial implementation by delivering customized support and tailored recommendations. Across a range of clinical trials, the TIN has developed standardized, streamlined, and adaptable processes. We describe these processes, provide operational metrics, and include a set of lessons learned for consideration by other trial support and innovation networks.
Studies using the dietary inflammatory index often perform complete case analyses (CCA) to handle missing data, which may reduce the sample size and increase the risk of bias. Furthermore, population-level socio-economic differences in the energy-adjusted dietary inflammatory index (E-DII) have not been recently studied. Therefore, we aimed to describe socio-demographic differences in E-DII scores among American adults and compare the results using two statistical approaches for handling missing data, i.e. CCA and multiple imputation (MI).
Design:
Cross-sectional analysis. E-DII scores were computed using a 24-hour dietary recall. Linear regression was used to compare the E-DII scores by age, sex, race/ethnicity, education and income using both CCA and MI.
Setting:
USA.
Participants:
This study included 34 547 non-Hispanic White, non-Hispanic Black and Hispanic adults aged ≥ 20 years from the 2005–2018 National Health and Nutrition Examination Survey.
Results:
The MI and CCA subpopulations comprised 34 547 and 23 955 participants, respectively. Overall, 57 % of the American adults reported 24-hour dietary intakes associated with inflammation. Both methods showed similar patterns wherein 24-hour dietary intakes associated with high inflammation were commonly reported among males, younger adults, non-Hispanic Black adults and those with lower education or income. Differences in point estimates between CCA and MI were mostly modest at ≤ 20 %.
Conclusions:
The two approaches for handling missing data produced comparable point estimates and 95 % CI. Differences in the E-DII scores by age, sex, race/ethnicity, education and income suggest that socio-economic disparities in health may be partially explained by the inflammatory potential of diet.
Auditory verbal hallucinations (AVHs) in schizophrenia have been suggested to arise from failure of corollary discharge mechanisms to correctly predict and suppress self-initiated inner speech. However, it is unclear whether such dysfunction is related to motor preparation of inner speech during which sensorimotor predictions are formed. The contingent negative variation (CNV) is a slow-going negative event-related potential that occurs prior to executing an action. A recent meta-analysis has revealed a large effect for CNV blunting in schizophrenia. Given that inner speech, similar to overt speech, has been shown to be preceded by a CNV, the present study tested the notion that AVHs are associated with inner speech-specific motor preparation deficits.
Objectives
The present study aimed to provide a useful framework for directly testing the long-held idea that AVHs may be related to inner speech-specific CNV blunting in patients with schizophrenia. This may hold promise for a reliable biomarker of AVHs.
Methods
Hallucinating (n=52) and non-hallucinating (n=45) patients with schizophrenia, along with matched healthy controls (n=42), participated in a novel electroencephalographic (EEG) paradigm. In the Active condition, they were asked to imagine a single phoneme at a cue moment while, precisely at the same time, being presented with an auditory probe. In the Passive condition, they were asked to passively listen to the auditory probes. The amplitude of the CNV preceding the production of inner speech was examined.
Results
Healthy controls showed a larger CNV amplitude (p = .002, d = .50) in the Active compared to the Passive condition, replicating previous results of a CNV preceding inner speech. However, both patient groups did not show a difference between the two conditions (p > .05). Importantly, a repeated measure ANOVA revealed a significant interaction effect (p = .007, ηp2 = .05). Follow-up contrasts showed that healthy controls exhibited a larger CNV amplitude in the Active condition than both the hallucinating (p = .013, d = .52) and non-hallucinating patients (p < .001, d = .88). No difference was found between the two patient groups (p = .320, d = .20).
Conclusions
The results indicated that motor preparation of inner speech in schizophrenia was disrupted. While the production of inner speech resulted in a larger CNV than passive listening in healthy controls, which was indicative of the involvement of motor planning, patients exhibited markedly blunted motor preparatory activity to inner speech. This may reflect dysfunction in the formation of corollary discharges. Interestingly, the deficits did not differ between hallucinating and non-hallucinating patients. Future work is needed to elucidate the specificity of inner speech-specific motor preparation deficits with AVHs. Overall, this study provides evidence in support of atypical inner speech monitoring in schizophrenia.
Improving the quality and conduct of multi-center clinical trials is essential to the generation of generalizable knowledge about the safety and efficacy of healthcare treatments. Despite significant effort and expense, many clinical trials are unsuccessful. The National Center for Advancing Translational Science launched the Trial Innovation Network to address critical roadblocks in multi-center trials by leveraging existing infrastructure and developing operational innovations. We provide an overview of the roadblocks that led to opportunities for operational innovation, our work to develop, define, and map innovations across the network, and how we implemented and disseminated mature innovations.
Significant progress has been made in designing magnetic fields that provide excellent confinement of the guiding-centre trajectories of alpha particles using quasisymmetry (QS). Given the reduction in this transport channel, we assess the impact of resonant Alfvén eigenmodes (AEs) on the guiding-centre motion. The AE amplitudes are chosen to be consistent with experimental measurements and large-scale simulations. We evaluate the drift resonance condition, phase-space island width and island overlap criterion for quasisymmetric configurations. Kinetic Poincaré plots elucidate features of the transport, including stiff transport above a critical perturbation amplitude. Our analysis highlights key departures from the AE-driven transport in tokamaks, such as the avoidance of phase-space island overlap in quasihelical configurations and the enhanced transport due to wide phase-space islands in low magnetic shear configurations. In configurations that are closer to QS, with QS deviations $\delta B/B_0 \lesssim 10^{-3}$, the transport is primarily driven by the AE, while configurations that are further from QS, $\delta B/B_0 \sim 10^{-2}$, experience significant transport due to the QS-breaking fields in addition to the AE.
Despite their documented efficacy, substantial proportions of patients discontinue antidepressant medication (ADM) without a doctor's recommendation. The current report integrates data on patient-reported reasons into an investigation of patterns and predictors of ADM discontinuation.
Methods
Face-to-face interviews with community samples from 13 countries (n = 30 697) in the World Mental Health (WMH) Surveys included n = 1890 respondents who used ADMs within the past 12 months.
Results
10.9% of 12-month ADM users reported discontinuation-based on recommendation of the prescriber while 15.7% discontinued in the absence of prescriber recommendation. The main patient-reported reason for discontinuation was feeling better (46.6%), which was reported by a higher proportion of patients who discontinued within the first 2 weeks of treatment than later. Perceived ineffectiveness (18.5%), predisposing factors (e.g. fear of dependence) (20.0%), and enabling factors (e.g. inability to afford treatment cost) (5.0%) were much less commonly reported reasons. Discontinuation in the absence of prescriber recommendation was associated with low country income level, being employed, and having above average personal income. Age, prior history of psychotropic medication use, and being prescribed treatment from a psychiatrist rather than from a general medical practitioner, in comparison, were associated with a lower probability of this type of discontinuation. However, these predictors varied substantially depending on patient-reported reasons for discontinuation.
Conclusion
Dropping out early is not necessarily negative with almost half of individuals noting they felt better. The study underscores the diverse reasons given for dropping out and the need to evaluate how and whether dropping out influences short- or long-term functioning.
New technologies and disruptions related to Coronavirus disease-2019 have led to expansion of decentralized approaches to clinical trials. Remote tools and methods hold promise for increasing trial efficiency and reducing burdens and barriers by facilitating participation outside of traditional clinical settings and taking studies directly to participants. The Trial Innovation Network, established in 2016 by the National Center for Advancing Clinical and Translational Science to address critical roadblocks in clinical research and accelerate the translational research process, has consulted on over 400 research study proposals to date. Its recommendations for decentralized approaches have included eConsent, participant-informed study design, remote intervention, study task reminders, social media recruitment, and return of results for participants. Some clinical trial elements have worked well when decentralized, while others, including remote recruitment and patient monitoring, need further refinement and assessment to determine their value. Partially decentralized, or “hybrid” trials, offer a first step to optimizing remote methods. Decentralized processes demonstrate potential to improve urban-rural diversity, but their impact on inclusion of racially and ethnically marginalized populations requires further study. To optimize inclusive participation in decentralized clinical trials, efforts must be made to build trust among marginalized communities, and to ensure access to remote technology.
One challenge for multisite clinical trials is ensuring that the conditions of an informative trial are incorporated into all aspects of trial planning and execution. The multicenter model can provide the potential for a more informative environment, but it can also place a trial at risk of becoming uninformative due to lack of rigor, quality control, or effective recruitment, resulting in premature discontinuation and/or non-publication. Key factors that support informativeness are having the right team and resources during study planning and implementation and adequate funding to support performance activities. This communication draws on the experience of the National Center for Advancing Translational Science (NCATS) Trial Innovation Network (TIN) to develop approaches for enhancing the informativeness of clinical trials. We distilled this information into three principles: (1) assemble a diverse team, (2) leverage existing processes and systems, and (3) carefully consider budgets and contracts. The TIN, comprised of NCATS, three Trial Innovation Centers, a Recruitment Innovation Center, and 60+ CTSA Program hubs, provides resources to investigators who are proposing multicenter collaborations. In addition to sharing principles that support the informativeness of clinical trials, we highlight TIN-developed resources relevant for multicenter trial initiation and conduct.
Predeath grief conceptualizes complex feelings of loss experienced for someone who is still living and is linked to poor emotional well-being. The Road Less Travelled program aimed to help carers of people with rarer dementias identify and process predeath grief. This study evaluated the feasibility, acceptability, and preliminary effectiveness of this program.
Design:
Pre–post interventional mixed methods study.
Setting:
Online videoconference group program for carers across the UK held in 2021.
Participants:
Nine family carers of someone living with a rare form of dementia. Eight were female and one male (mean age 58) with two facilitators.
Intervention:
The Road Less Travelled is an online, facilitated, group-based program that aims to help carers of people with rarer dementias to explore and accept feelings of grief and loss. It involved six fortnightly 2-hour sessions.
Measurements:
We collected measures for a range of well-being outcomes at baseline (T1), post-intervention (T2), and 3 months post-intervention (T3). We conducted interviews with participants and facilitators at T2.
Results:
Participant attendance was 98% across all sessions. Findings from the semistructured interviews supported the acceptability of the program and identified improvements in carer well-being. Trends in the outcome measures suggested an improvement in quality of life and a reduction in depression.
Conclusion:
The program was feasible to conduct and acceptable to participants. Qualitative reports and high attendance suggest perceived benefits to carers, including increased acceptance of grief, and support the need for a larger-scale pilot study to determine effectiveness.
Childhood adversities (CAs) predict heightened risks of posttraumatic stress disorder (PTSD) and major depressive episode (MDE) among people exposed to adult traumatic events. Identifying which CAs put individuals at greatest risk for these adverse posttraumatic neuropsychiatric sequelae (APNS) is important for targeting prevention interventions.
Methods
Data came from n = 999 patients ages 18–75 presenting to 29 U.S. emergency departments after a motor vehicle collision (MVC) and followed for 3 months, the amount of time traditionally used to define chronic PTSD, in the Advancing Understanding of Recovery After Trauma (AURORA) study. Six CA types were self-reported at baseline: physical abuse, sexual abuse, emotional abuse, physical neglect, emotional neglect and bullying. Both dichotomous measures of ever experiencing each CA type and numeric measures of exposure frequency were included in the analysis. Risk ratios (RRs) of these CA measures as well as complex interactions among these measures were examined as predictors of APNS 3 months post-MVC. APNS was defined as meeting self-reported criteria for either PTSD based on the PTSD Checklist for DSM-5 and/or MDE based on the PROMIS Depression Short-Form 8b. We controlled for pre-MVC lifetime histories of PTSD and MDE. We also examined mediating effects through peritraumatic symptoms assessed in the emergency department and PTSD and MDE assessed in 2-week and 8-week follow-up surveys. Analyses were carried out with robust Poisson regression models.
Results
Most participants (90.9%) reported at least rarely having experienced some CA. Ever experiencing each CA other than emotional neglect was univariably associated with 3-month APNS (RRs = 1.31–1.60). Each CA frequency was also univariably associated with 3-month APNS (RRs = 1.65–2.45). In multivariable models, joint associations of CAs with 3-month APNS were additive, with frequency of emotional abuse (RR = 2.03; 95% CI = 1.43–2.87) and bullying (RR = 1.44; 95% CI = 0.99–2.10) being the strongest predictors. Control variable analyses found that these associations were largely explained by pre-MVC histories of PTSD and MDE.
Conclusions
Although individuals who experience frequent emotional abuse and bullying in childhood have a heightened risk of experiencing APNS after an adult MVC, these associations are largely mediated by prior histories of PTSD and MDE.
The non-selective serotonin 2A (5-HT2A) receptor agonist lysergic acid diethylamide (LSD) holds promise as a treatment for some psychiatric disorders. Psychedelic drugs such as LSD have been suggested to have therapeutic actions through their effects on learning. The behavioural effects of LSD in humans, however, remain incompletely understood. Here we examined how LSD affects probabilistic reversal learning (PRL) in healthy humans.
Methods
Healthy volunteers received intravenous LSD (75 μg in 10 mL saline) or placebo (10 mL saline) in a within-subjects design and completed a PRL task. Participants had to learn through trial and error which of three stimuli was rewarded most of the time, and these contingencies switched in a reversal phase. Computational models of reinforcement learning (RL) were fitted to the behavioural data to assess how LSD affected the updating (‘learning rates’) and deployment of value representations (‘reinforcement sensitivity’) during choice, as well as ‘stimulus stickiness’ (choice repetition irrespective of reinforcement history).
Results
Raw data measures assessing sensitivity to immediate feedback (‘win-stay’ and ‘lose-shift’ probabilities) were unaffected, whereas LSD increased the impact of the strength of initial learning on perseveration. Computational modelling revealed that the most pronounced effect of LSD was the enhancement of the reward learning rate. The punishment learning rate was also elevated. Stimulus stickiness was decreased by LSD, reflecting heightened exploration. Reinforcement sensitivity differed by phase.
Conclusions
Increased RL rates suggest LSD induced a state of heightened plasticity. These results indicate a potential mechanism through which revision of maladaptive associations could occur in the clinical application of LSD.
Hospital readmission is unsettling to patients and caregivers, costly to the healthcare system, and may leave patients at additional risk for hospital-acquired infections and other complications. We evaluated the association between comorbidities present during index coronavirus disease 2019 (COVID-19) hospitalization and the risk of 30-day readmission.
Design, setting, and participants:
We used the Premier Healthcare database to perform a retrospective cohort study of COVID-19 hospitalized patients discharged between April 2020 and March 2021 who were followed for 30 days after discharge to capture readmission to the same hospital.
Results:
Among the 331,136 unique patients in the index cohort, 36,827 (11.1%) had at least 1 all-cause readmission within 30 days. Of the readmitted patients, 11,382 (3.4%) were readmitted with COVID-19 as the primary diagnosis. In the multivariable model adjusted for demographics, hospital characteristics, coexisting comorbidities, and COVID-19 severity, each additional comorbidity category was associated with an 18% increase in the odds of all-cause readmission (adjusted odds ratio [aOR], 1.18; 95% confidence interval [CI], 1.17–1.19) and a 10% increase in the odds of readmission with COVID-19 as the primary readmission diagnosis (aOR, 1.10; 95% CI, 1.09–1.11). Lymphoma (aOR, 1.86; 95% CI, 1.58–2.19), renal failure (aOR, 1.32; 95% CI, 1.25–1.40), and chronic lung disease (aOR, 1.29; 95% CI, 1.24–1.34) were most associated with readmission for COVID-19.
Conclusions:
Readmission within 30 days was common among COVID-19 survivors. A better understanding of comorbidities associated with readmission will aid hospital care teams in improving postdischarge care. Additionally, it will assist hospital epidemiologists and quality administrators in planning resources, allocating staff, and managing bed-flow issues to improve patient care and safety.
The literature on the internalized stigma (or self-stigma) of mental illness has been expanding rapidly. We review the key findings of two meta-analyses of the correlates and consequences that occurred a decade apart (Livingston & Boyd, 2010, Del Rosal et al., 2020), showing that internalized stigma is related to less self-esteem, quality of life, and hope; and related to greater experienced stigma, perceived stigma, and symptom severity. For empowerment, the relationship of internalized stigma was somewhat weaker in 2020 than in 2010. Neither found significant relationships with sociodemographic variables. Although more longitudinal studies are needed to better test the causal direction of these relationships, the overall findings are consistent with the idea that internalized stigma impedes recovery and adds to the burden of mental illness. While, more work needs to be done to understand the effects of internalized stigma on people with a variety of intersectional identities. we briefly describe the literature on a few contrasting types of marginalized identities: gender (female and transgender), race/ethnicity (African Americans), and profession (mental health professionals with a lived experience of mental illness). These summaries highlight that the consequences of internalized stigma may vary across intersectional identities. We conclude with suggestions for future research.
Research among non-industrial societies suggests that body kinematics adopted during running vary between groups according to the cultural importance of running. Among groups in which running is common and an important part of cultural identity, runners tend to adopt what exercise scientists and coaches consider to be good technique for avoiding injury and maximising performance. In contrast, among groups in which running is not particularly culturally important, people tend to adopt suboptimal technique. This paper begins by describing key elements of good running technique, including landing with a forefoot or midfoot strike pattern and leg oriented roughly vertically. Next, we review evidence from non-industrial societies that cultural attitudes about running associate with variation in running techniques. Then, we present new data from Tsimane forager–horticulturalists in Bolivia. Our findings suggest that running is neither a common activity among the Tsimane nor is it considered an important part of cultural identity. We also demonstrate that when Tsimane do run, they tend to use suboptimal technique, specifically landing with a rearfoot strike pattern and leg protracted ahead of the knee (called overstriding). Finally, we discuss processes by which culture might influence variation in running techniques among non-industrial societies, including self-optimisation and social learning.
The aim of the social and behavioral sciences is to understand human behavior across a wide array of contexts. Our theories often make sweeping claims about human nature, assuming that our ancestors or offspring will be prone to the same biases and preferences. Yet we gloss over the fact that our research is often based in a single temporal context with a limited set of stimuli. Political and moral psychology are domains in which the context and stimuli are likely to matter a great deal (Van Bavel, Mende-Siedlecki, Brady, & Reinero, 2016). In response to Yarkoni (see BBS issue), we delve into topics related to political and moral psychology that likely depend on features of the research. These topics include understanding differences between liberals and conservatives, when people are willing to sacrifice someone to save others, the behavior of political leaders, and the dynamics of intergroup conflict.
Accurate estimation of tuber size distribution (TSD) parameters in discretely categorized potato (Solanum tuberosum L) yield samples is desirable for estimating modal tuber sizes, which is fundamental to yield prediction. In the current work, systematic yield digs were conducted on five commercial fields (N = 119) to compare the Weibull, Gamma and Gaussian distribution functions for relative-likelihood-based goodness-of-fit to the observed discrete distributions. Parameters were estimated using maximum likelihood estimation (MLE) for the three distributions but were also derived using the percentiles approach for the Weibull distribution to compare accuracy against the MLE approaches. The relationship between TSD and soil nutrient variability was examined using the best-fitting model's parameters. The percentiles approach had lower overall relative likelihood than the MLE approaches across five locations, but had consistently lower Root Mean Square Error in the marketable tuber size range. Negative relationships were observed between the percentile-based shape parameter and the concentrations of Phosphorus and Nitrogen, with significant (non-zero-overlapping 95% confidence interval) regression coefficients for P (−0.74 ± 0.33 for distribution of proportional tuber numbers and −1.3 ± 0.62 for tuber weights). Stem density was negatively associated with the scale and mode of tuber number (regression coefficients −0.98 ± 0.63 and −1.08 ± 0.78 respectively) and tuber weight (regression coefficients −0.99 ± 0.78 and −1.04 ± 0.69 respectively) distributions. Phosphorus is negatively related to the scale of the tuber-number-based distribution while positively associating with the tuber weight distribution. The results suggest that excess P application was associated with the increase in small tubers that did not contribute significant weight to the final yield.
The Clinical and Translational Science Award Program (CTSA) Trial Innovation Network (TIN) was launched in 2016 to increase the efficiency and effectiveness of multisite trials by supporting the development of national infrastructure. With the advent of the COVID-19 pandemic, it was therefore well-positioned to support clinical trial collaboration. The TIN was leveraged to support two initiatives: (1) to create and evaluate a mechanism for coordinating Data and Safety Monitoring Board (DSMB) activities among multiple ongoing trials of the same therapeutic agents, and (2) to share data across clinical trials so that smaller, likely underpowered studies, could be combined to produce meaningful and actionable data through pooled analyses. The success of these initiatives was understood to be dependent upon the willingness of investigators, study teams, and US National Institutes of Health research networks to collaborate and share information.
Methods:
To inform these two initiatives, we conducted semistructured interviews with members of CTSA hubs and clinical research stakeholders that probed barriers and facilitators to collaboration. Thematic analysis identified topics relevant across institutions, individuals, and DSMBs.
Results:
The DSMB coordination initiative was viewed as less controversial, while the data pooling initiative was seen as complex because of its potential impact on publication, authorship, and the rewards of discovery. Barriers related to resources, centralization, and technical work were significant, but interviewees suggested these could be handled by the provision of central funding and supportive frameworks. The more intractable findings were related to issues around credit and ownership of data.
Conclusion:
Based on our interviews, we conclude with nine recommended actions that can be implemented to support collaboration.
The most common treatment for major depressive disorder (MDD) is antidepressant medication (ADM). Results are reported on frequency of ADM use, reasons for use, and perceived effectiveness of use in general population surveys across 20 countries.
Methods
Face-to-face interviews with community samples totaling n = 49 919 respondents in the World Health Organization (WHO) World Mental Health (WMH) Surveys asked about ADM use anytime in the prior 12 months in conjunction with validated fully structured diagnostic interviews. Treatment questions were administered independently of diagnoses and asked of all respondents.
Results
3.1% of respondents reported ADM use within the past 12 months. In high-income countries (HICs), depression (49.2%) and anxiety (36.4%) were the most common reasons for use. In low- and middle-income countries (LMICs), depression (38.4%) and sleep problems (31.9%) were the most common reasons for use. Prevalence of use was 2–4 times as high in HICs as LMICs across all examined diagnoses. Newer ADMs were proportionally used more often in HICs than LMICs. Across all conditions, ADMs were reported as very effective by 58.8% of users and somewhat effective by an additional 28.3% of users, with both proportions higher in LMICs than HICs. Neither ADM class nor reason for use was a significant predictor of perceived effectiveness.
Conclusion
ADMs are in widespread use and for a variety of conditions including but going beyond depression and anxiety. In a general population sample from multiple LMICs and HICs, ADMs were widely perceived to be either very or somewhat effective by the people who use them.
The inaugural data from the first systematic program of sea-ice observations in Kotzebue Sound, Alaska, in 2018 coincided with the first winter in living memory when the Sound was not choked with ice. The following winter of 2018–19 was even warmer and characterized by even less ice. Here we discuss the mass balance of landfast ice near Kotzebue (Qikiqtaġruk) during these two anomalously warm winters. We use in situ observations and a 1-D thermodynamic model to address three research questions developed in partnership with an Indigenous Advisory Council. In doing so, we improve our understanding of connections between landfast ice mass balance, marine mammals and subsistence hunting. Specifically, we show: (i) ice growth stopped unusually early due to strong vertical ocean heat flux, which also likely contributed to early start to bearded seal hunting; (ii) unusually thin ice contributed to widespread surface flooding. The associated snow ice formation partly offset the reduced ice growth, but the flooding likely had a negative impact on ringed seal habitat; (iii) sea ice near Kotzebue during the winters of 2017–18 and 2018–19 was likely the thinnest since at least 1945, driven by a combination of warm air temperatures and a persistent ocean heat flux.