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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.
We live in a time of significant global risk. Some research has focused on understanding systemic sources of this risk, while other research has focused on possible worst-case outcomes. In this article, we bring together these two areas of research and provide a simple conceptual framework that shows how emergent features of the global system contribute to the risk of global catastrophe.
Technical summary
Humanity faces a complex and dangerous global risk landscape, and many different terms and concepts have been used to make sense of it. One broad strand of research characterises how risk emerges within the complex global system, using concepts like systemic risk, Anthropocene risk, synchronous failure, negative social tipping points, and polycrisis. Another focuses on possible worst-case outcomes, using concepts like global catastrophic risk (GCR), existential risk, and extinction risk. Despite their clear relevance to each other, connections between these two strands remain limited. Here, we provide a simple conceptual framework that synthesises these research strands and shows how emergent properties of the global system contribute to the risk of global catastrophic outcomes. In particular, we show that much of GCR stems from the interaction of hazards and vulnerabilities that arise endogenously within the global system, and how ‘systems thinking’ and complex adaptive systems theory can help illuminate this. We also highlight some unique challenges that systemic sources of GCR pose for risk assessment and mitigation, discuss insights for policy, and outline potential paths forward.
Social media summary
The global system is generating global catastrophic risk.
Major depressive disorder (MDD) is a serious and often chronic illness that requires early and urgent treatment. Failing to provide effective treatment of MDD can worsen the illness trajectory, negatively impact physical health, and even alter brain structure. Early optimized treatment (EOT) of MDD, with a measurement-based approach to diagnosis, rapid treatment initiation with medication dosage optimization, frequent monitoring, and prompt adjustments in treatment planning when indicated, should proceed with a sense of urgency. In this article, we describe common barriers to providing an EOT approach to treating MDD at each phase of care, along with strategies for navigating these obstacles. Approaching the treatment of MDD with a greater sense of urgency increases the likelihood of symptom reduction in MDD, facilitating full functional recovery and a return to life engagement.
Concentrating on Canadian experience, specifically litigation under the Canadian Charter of Rights and Freedoms (the ‘Charter’), this article seeks to reconcile the access to justice benefits of summary procedures with the government litigant's duty to act in the public interest (or as a ‘model litigant’) and uphold the rule of law. Though acknowledging the benefits that can result from the use of summary procedures to end litigation, the authors observe that compliance with strict requirements in procedural law are frequently dispensed with in the Charter context. In fact, summary procedures can have a devastating effect on the development of Charter rights. The authors ultimately posit that the government should have a duty of restraint in using summary procedures to end public law litigation, and courts should be reluctant to permit the government to preclude such litigation aimed at advancing the evolution of the Charter from reaching hearings on the merits.
Alexandrov’s estimate states that if $\Omega $ is a bounded open convex domain in $\mathbb {R}^n$ and $u:\bar \Omega \to \mathbb {R}$ is a convex solution of the Monge-Ampère equation $\det D^2 u = f$ that vanishes on $\partial \Omega $, then
We establish a variety of improvements of this, depending on the geometry of $\partial \Omega $. For example, we show that if the curvature is bounded away from $0$, then the estimate remains valid if $\omega (\delta )$ is replaced by $C_\Omega \delta ^{\frac 12 + \frac 1{2n}}$. We determine the sharp constant $C_\Omega $ when $n=2$, and when $n\ge 3$ and $\partial \Omega $ is $C^2$, we determine the sharp asymptotics of the optimal modulus of continuity $\omega _\Omega (\delta )$ as $\delta \to 0$. For arbitrary convex domains, we characterize the scaling of the optimal modulus $\omega _\Omega $. Our results imply in particular that unless $\partial \Omega $ has a flat spot, $\omega _\Omega (\delta ) = o(\delta ^{1/n})$ as $\delta \to 0$, and under very mild nondegeneracy conditions, they yield the improved Hölder estimate, $\omega _\Omega (\delta ) \le C \delta ^\alpha $ for some $\alpha>1/n$.
To investigate the potential application of replacing a proportion of a perennial ryegrass (PRG) silage diet with press cake on productivity and enteric methane (CH4) emissions in late lactation and non-lactating spring-calving dairy cows, a study was undertaken in which control cows (n = 21) were offered PRG silage, while treatment cows (n = 21) were offered a diet consisting of 60% PRG press cake and 40% of the same PRG silage. Although treatment cows had higher group average dry matter intakes (DMI) and produced more enteric CH4, carbon dioxide (CO2), milk solids, protein, fat- and protein-corrected milk yield (FPCM) in late lactation, the magnitude of the difference between treatment and control cows varied from week to week (P < 0.050). When enteric CH4 per kg of milk yield, milk solids and FPCM were considered, there was no significant difference between treatment and control. Absolute enteric CH4 was higher for cows fed press cake during the non-lactating period but this tended to vary from week to week. Similarly, CO2 (P < 0.001) and hydrogen (H2; P = 0.023) differed from week to week for cows offered press cake, and cows offered PRG silage in the non-lactating period. Although there was no significant effect of diet on body weight (BW) and body condition score (BCS), when enteric CH4 was expressed on a per kg BW basis, cows offered press cake tended to produce more enteric CH4 in both late lactation and during the dry period.
The sorption of water, at 490°C and ca. 23–24 torr, on clay mineral surfaces has been studied using thermogravimetry and infrared absorption spectroscopy. Results from a series of synthetic hectorites, with and without lattice fluoride (see Granquist and Pollack, 1960), point to the presence of F− in the clay lattice as an important condition for the sorption. Similar studies on natural hectorite and montmorillonite, synthetic interstratified montmorillonite/mica with and without fluoride, and Al2F6 support this interpretation of the role of the F− ion and show that dioctahedral 2:1 clays sorb more water at 490°C than do trioctahedral 2:1 clays. The infrared spectra demonstrate that the sorbed water is for the most part hydrogen-bonded to the surface.
n-3 fatty acid consumption during pregnancy is recommended for optimal pregnancy outcomes and offspring health. We examined characteristics associated with self-reported fish or n-3 supplement intake.
Design:
Pooled pregnancy cohort studies.
Setting:
Cohorts participating in the Environmental influences on Child Health Outcomes (ECHO) consortium with births from 1999 to 2020.
Participants:
A total of 10 800 pregnant women in twenty-three cohorts with food frequency data on fish consumption; 12 646 from thirty-five cohorts with information on supplement use.
Results:
Overall, 24·6 % reported consuming fish never or less than once per month, 40·1 % less than once a week, 22·1 % 1–2 times per week and 13·2 % more than twice per week. The relative risk (RR) of ever (v. never) consuming fish was higher in participants who were older (1·14, 95 % CI 1·10, 1·18 for 35–40 v. <29 years), were other than non-Hispanic White (1·13, 95 % CI 1·08, 1·18 for non-Hispanic Black; 1·05, 95 % CI 1·01, 1·10 for non-Hispanic Asian; 1·06, 95 % CI 1·02, 1·10 for Hispanic) or used tobacco (1·04, 95 % CI 1·01, 1·08). The RR was lower in those with overweight v. healthy weight (0·97, 95 % CI 0·95, 1·0). Only 16·2 % reported n-3 supplement use, which was more common among individuals with a higher age and education, a lower BMI, and fish consumption (RR 1·5, 95 % CI 1·23, 1·82 for twice-weekly v. never).
Conclusions:
One-quarter of participants in this large nationwide dataset rarely or never consumed fish during pregnancy, and n-3 supplement use was uncommon, even among those who did not consume fish.
Identifying neuroimaging biomarkers of antidepressant response may help guide treatment decisions and advance precision medicine.
Aims
To examine the relationship between anhedonia and functional neurocircuitry in key reward processing brain regions in people with major depressive disorder receiving aripiprazole adjunct therapy with escitalopram.
Method
Data were collected as part of the CAN-BIND-1 study. Participants experiencing a current major depressive episode received escitalopram for 8 weeks; escitalopram non-responders received adjunct aripiprazole for an additional 8 weeks. Functional magnetic resonance imaging (on weeks 0 and 8) and clinical assessment of anhedonia (on weeks 0, 8 and 16) were completed. Seed-based correlational analysis was employed to examine the relationship between baseline resting-state functional connectivity (rsFC), using the nucleus accumbens (NAc) and anterior cingulate cortex (ACC) as key regions of interest, and change in anhedonia severity after adjunct aripiprazole.
Results
Anhedonia severity significantly improved after treatment with adjunct aripiprazole.
There was a positive correlation between anhedonia improvement and rsFC between the ACC and posterior cingulate cortex, ACC and posterior praecuneus, and NAc and posterior praecuneus. There was a negative correlation between anhedonia improvement and rsFC between the ACC and anterior praecuneus and NAc and anterior praecuneus.
Conclusions
Eight weeks of aripiprazole, adjunct to escitalopram, was associated with improved anhedonia symptoms. Changes in functional connectivity between key reward regions were associated with anhedonia improvement, suggesting aripiprazole may be an effective treatment for individuals experiencing reward-related deficits. Future studies are required to replicate our findings and explore their generalisability, using other agents with partial dopamine (D2) agonism and/or serotonin (5-HT2A) antagonism.
The structural and physical effects of partially substituting Cd for Fe in goethite have been investigated. The solubility of Cd2+ in goethite is ∼10 mol.%, i.e. Fe0.905Cd0.095OOH. The structures of the substituted goethites have been refined, using the Rietveld method, from synchrotron X-ray powder diffraction data. There is a progressive increase in the size of the unit-cell parameters and unit-cell volume, upon the incorporation of much larger Cd2+ ion (0.95 Å) compared with Fe3+ (0.645 Å) in the goethite structure, together with a reduction in crystallinity. Transmission electron microscopy measurements confirm the crystallite size decreases as the Cd2+ content increases in goethite structure.
The morphology, dehydroxylation, and dissolution properties of single- and multi-metal (Cr, Zn, Cd, and Pb)-substituted goethites prepared using hydrothermal methods are reported. The crystal morphology varied with the nature and the number of metals present in the system. The presence of Cr produced broader crystals while Zn, Cd, and Pb produced narrower crystals than pure goethite. The presence of multiple metals retards the crystal growth of the mineral. Metal substitution caused changes in the unit-cell parameters and the infrared (IR) spectra of the samples. The IR spectra were also sensitive to the morphology of the crystals. The separation of γO and δOH bending frequencies increased with increase in area and aspect ratio of the (100) crystal face. The dissolution-kinetics studies (1 M HCl, 40ºC) of single-metal-substituted goethite provided the following dissolution rate order: Zn- > Pb(II)- ≥ Pb(IV)- > unsubstituted > Cd- > Cr-goethite. More complex results were obtained for the multi-metal-substituted samples. In the di-metal-substituted goethites, incorporation of Cr suppressed the dissolution rate of Zn-substituted goethite by 85% and Cd suppressed the dissolution rate of Zn-substituted goethite by 53%. Similarly, incorporated Cr and Cd suppressed the dissolution rate of Pb(II)-substituted goethite by 50%. The dissolution rates of multi-metal-substituted goethite were linearly related to the steric strains derived from the lattice parameters of the mineral. Dissolution studies also showed that Cr, Zn, Cd, and Pb(IV) were distributed homogeneously throughout goethite crystals while Pb(II) was enriched in the near-surface regions of the crystals. Incorporation of Cr and Pb(II) increased, while Zn and Pb(IV) decreased the dehydroxylation temperature of single-metal-substituted goethites. Incorporation of Zn suppressed the effect of Cr on the dehydroxylation temperature in multi-metal-substituted goethites.
To examine patterns of cognitive function among a clinical sample of patients seeking treatment for Post-Acute Sequelae of COVID-19 (PASC).
Participants and Methods:
One hundred nineteen patients each completed a baseline neuropsychological evaluation, including clinical diagnostic interview, cognitive assessments, and a comprehensive battery of self-report questionnaires. Patients had a mean age of 50 years (range:18 to 74, SD=10.1) and a mean of 15.5 years (SD=2.54) of formal education. Patients were primarily female (74%) and of White/Caucasian race (75%). Hierarchical agglomerative clustering was used to partition the data into groups based on cognitive performance. Euclidean distance was used as the similarity measure for the continuous variables and within-cluster variance was minimized using Ward’s method. The optimal number of clusters was determined empirically by fitting models with 1 to 15 clusters, with the best number of clusters selected using the silhouette index. All analyses were conducted using the NbClust package, an R package for determining the relevant number of clusters in a data set.
Results:
Clustering yielded two distinct clusters of cognitive performance. Group 1 (n=57) performed worse than Group 2 (n=62) on most cognitive variables (including a brief cognitive screener and tests of attention/working memory, executive function, processing speed, learning and delayed recall). Of note, there were no significant differences between groups on an infection severity scale, hospitalizations/ICU admissions, initial or current COVID-19 symptoms, or prior comorbidities. Groups did not differ in age or gender, but Group 1 had a lower education level than Group 2 (M=14.7, SD=2.45 vs. M=16.2, SD=2.42; p=.001). Group 1 also had significantly more minorities than Group 2 (40% vs. 8%; p<.001). No other demographic differences (income, living arrangement, or marital status) were observed. In comparison to Group 2 patients, Group 1 patients self-reported significantly higher levels of anxiety and depression and functional impairment (Functional Activities Questionnaire: M=11.3, SD=8.33 vs. M=7.65, SD=7.97), perceived stress (Perceived Stress Scale: M=24.7, SD=7.90 vs. M=20.3, SD=7.89), insomnia (Insomnia Severity Index: M=16.0, SD=6.50 vs. M=13.1, SD=6.76), and subjective cognitive functioning (Cognitive Failures Questionnaire: M=58.8, SD=16.9 vs. M=50.3, SD=18.6; p’s<.05).
Conclusions:
Findings indicate two predominant subtypes of patients seeking treatment for PASC, with one group presenting as more cognitively impaired and reporting greater levels of anxiety, depression, insomnia, perceived stress, functional limitations, and subjective cognitive impairment. Future directions include follow-up assessments with these patients to determine cognitive trajectories over time and tailoring treatment adjuncts to address mood symptoms, insomnia, functional ability, and lifestyle variables. Understanding mechanisms of differences in cognitive and affective symptoms is needed in future work. Limitations to the study were that patients were referred for evaluation based on the complaint of “brain fog” and the sample was a homogenous, highly educated, younger group of individuals who experienced generally mild COVID-19 course.
During the peak of his contemporary popularity, F. Scott Fitzgerald lived abroad – mostly in France – for five years and eight months, much of that time pursuing a frenzied social life that impeded his literary work. His European travels included lengthy stays from May 1924 through the end of 1926 and then from March 1929 through September 1931, as well as a five-month sojourn in mid-1928. On foreign shores he experienced misery and elation: his wife Zelda's romance with French aviator Edouard Jozan; completion, publication, and celebration of his third novel, The Great Gatsby (1925); new friendships with Ernest Hemingway and with Gerald and Sara Murphy; innumerable alcoholic binges and embarrassments; false starts on a fourth novel and increasing self-doubts; domestic rivalry and acrimony; Zelda's first nervous breakdown and treatment; his hotel life and fugitive magazine fiction. Only after returning to the United States did Fitzgerald publish Tender Is the Night (1934), a work that despite its flaws plumbs the paradoxes of desire more profoundly than did Gatsby. Understandably, Tender has preoccupied scholars and biographers seeking insight into the author's life abroad, for its thinly veiled treatment of the Fitzgeralds' domestic calamities, set against the crazy violence of postwar Europe, reveals much about the author's own identification with expatriate culture. But the many short stories set at least partly in Europe likewise merit closer attention, less for their biographical connections than for their representations of the American migration to Europe after World War I.
The WHO has urged member states to develop preparedness plans for infant and young child feeding (IYCF) during emergencies. Ireland has no such plan. We aimed to identify the needs of caregivers in Ireland with regards IYCF during the COVID-19 pandemic.
Design:
Online survey conducted in May–June 2020.
Setting:
Ireland, during the first period of severely restricted movement due to COVID-19 (lockdown).
Participants:
Respondents (n 745) were primary caregivers of a child under 2 years; they were primarily well educated and likely of higher socio-economic status.
Results:
Among those who breastfed, being unable to access breast-feeding support groups and being unable to access in-person, one-to-one breast-feeding assistance were the biggest challenges reported. Nearly three quarters of those who had their babies during lockdown reported these challenges: 72·8 % and 68·8 %, respectively. For those using formula, the main challenges were structural in nature; approximately two-thirds of those who had their baby prior to lockdown feared there would be formula shortages and a third were unable to purchase formula due to shortages.
Conclusions:
Regardless of how their babies were fed, parents in Ireland experienced multiple challenges with infant feeding during the COVID-19 crisis. Breast-feeding should be protected, supported and promoted, particularly during an infectious disease pandemic. Additionally, assurances around supply of infant formula could reduce parental stress during a pandemic or emergency. An IYCF in emergencies plan would clearly set out how we could best support and protect the nutrition of the most vulnerable members of our population.
Cardiovascular disease (CVD) is excessively prevalent and premature in bipolar disorder (BD), even after controlling for traditional cardiovascular risk factors. The increased risk of CVD in BD may be subserved by microvascular dysfunction. We examined coronary microvascular function in relation to youth BD.
Methods
Participants were 86 youth, ages 13–20 years (n = 39 BD, n = 47 controls). Coronary microvascular reactivity (CMVR) was assessed using quantitative T2 magnetic resonance imaging during a validated breathing-paradigm. Quantitative T2 maps were acquired at baseline, following 60-s of hyperventilation, and every 10-s thereafter during a 40-s breath-hold. Left ventricular structure and function were evaluated based on 12–15 short- and long-axis cardiac-gated cine images. A linear mixed-effects model that controlled for age, sex, and body mass index assessed for between-group differences in CMVR (time-by-group interaction).
Results
The breathing-paradigm induced a significant time-related increase in T2 relaxation time for all participants (i.e. CMVR; β = 0.36, p < 0.001). CMVR was significantly lower in BD v. controls (β = −0.11, p = 0.002). Post-hoc analyses found lower T2 relaxation time in BD youth after 20-, 30-, and 40 s of breath-holding (d = 0.48, d = 0.72, d = 0.91, respectively; all pFDR < 0.01). Gross left ventricular structure and function (e.g. mass, ejection fraction) were within normal ranges and did not differ between groups.
Conclusion
Youth with BD showed evidence of subclinically impaired coronary microvascular function, despite normal gross cardiac structure and function. These results converge with prior findings in adults with major depressive disorder and post-traumatic stress disorder. Future studies integrating larger samples, prospective follow-up, and blood-based biomarkers are warranted.
The Ontario Review Board (ORB) makes and reviews dispositions that limit the freedoms of individuals found not criminally responsible (NCR) due to a “mental disorder.” Their dispositions must be responsive to the risk NCR individuals pose to the public. To assess how risk is measured, the authors studied twenty-six publicly accessible court files pertaining to the appeal of ORB dispositions. The authors studied hospital reports, the ORB’s dispositions, and transcripts of ORB hearings found in the court files. In this paper, the authors draw on institutional ethnography and critical legal theories of jurisdiction to analyze how certain citational practices—namely citation of closely related statutes and the ORB’s procedures—participate in structuring the ORB’s analysis of risk. The authors argue that risk becomes legible to participants in the NCR process through the intertextual mediation of these citations, which legitimize and naturalize the NCR individuals’ dependence on forensic institutions.