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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.
Accumulating evidence shows that an increasing number of children and young people (CYP) are reporting mental health problems.
Aims
To investigate emotional disorders (anxiety or depression) among CYP in England between 2004 and 2017, and to identify which disorders and demographic groups have experienced the greatest increase.
Method
Repeated cross-sectional, face-to-face study using data from the Mental Health of Children and Young People surveys conducted in 2004 and 2017, allowing use of nationally representative probability samples of CYP aged 5–16 years in England. A total of 13 561 CYP were included across both survey waves (6898 in 2004 and 6663 in 2017). We assessed the prevalence of any emotional, anxiety and depressive disorder assessed using the Development and Well-Being Assessment and classified according to ICD-10 criteria.
Results
The prevalence of emotional disorders increased from 3.9% in 2004 to 6.0% in 2017, a relative increase of 63% (relative ratio 1.63, 95% CI 1.38, 1.91). This was largely driven by anxiety disorders, which increased from 3.5 to 5.4% (relative ratio 1.63, 95% CI 1.37, 1.93). The largest relative changes were for panic disorder, separation anxiety, social phobia and post-traumatic stress disorder. Changes were similar for different genders and socioeconomic groups, but differed by ethnicity: the most pronounced increase was among White CYP (relative ratio 1.88, 95% CI 1.59, 2.24), compared with no clear change for Black and minority ethnic CYP (relative ratio 0.85, 95% CI 0.52, 1.39). Comorbid psychiatric conditions were present in over a third of CYP with emotional disorders, with the most common being conduct disorder.
Conclusions
Between 2004 and 2017, the increase in emotional disorders among CYP in England was largely driven by anxiety disorders. Socioeconomic inequalities did not narrow. Disaggregating by ethnicity, change was evident only in White CYP, suggesting differential trends in either risk exposure, resilience or reporting by ethnicity.
Children and adolescents with a history of adverse childhood experiences (ACEs) are more likely than their peers to develop mental health difficulties, but not enough is known about their help-seeking behaviours and preferences. We aimed to determine whether ACEs are associated with access to and perceived unmet need for mental health services and support amongst secondary school students.
Methods
We used multi-level logistic regression with data from the 2020 OxWell Student Survey to assess whether ACEs were associated with (1) prior access to mental health support and (2) perceived unmet need for mental health services in a community sample of English secondary school students. We assessed ACEs as a cumulative score from the Center for Youth Wellness Adverse Childhood Experiences Questionnaire: Teen Self-Report version and accounted for current mental health difficulties as measured by the 25-item Revised Children’s Anxiety and Depression Scale (RCADS).
Results
Our analysis included 2018 students across 64 schools, of whom 29.9% (598/2002) reported prior access to mental health support. Of those not reporting prior access, 34.1% (469/1377) reported a perceived unmet need for services. In the unadjusted models, cumulative ACE scores were significantly positively associated with both prior access to mental health support (odds ratio (OR) = 1.36; 95% confidence interval (CI): 1.29–1.43) and perceived unmet need for mental health services (OR = 1.47; 95% CI: 1.37–1.59), meaning that students who had experienced adversity had a greater chance of having previously accessed support as well as perceiving an unmet need for services. After adjusting for mental health difficulties and other sociodemographic variables, cumulative ACE scores were positively associated with prior access (adjusted OR (aOR) = 1.25; 95% CI: 1.17–1.34 with a significant interaction between RCADS and ACE scores, aOR = 0.88; 95% CI: 0.84–0.93) as well as perceived unmet need (aOR = 1.32; 95% CI: 1.21–1.43 with a significant interaction between RCADS and ACE scores, aOR = 0.85; 95% CI: 0.78–0.91).
Conclusions
Although it is encouraging that adolescents with experience of adversity are more likely than their peers with similar levels of depression and anxiety symptoms to have accessed mental health support, there remains a concern that those who have not accessed support are more likely to perceive an as-yet unmet need for it. Mental health support must be available, accessible and acceptable to all who need it, especially for those groups that traditionally have not accessed services, including the more marginalised and vulnerable populations.
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.
The fundamental nature of turbulent density fluctuations in standard Wendelstein 7-X (W7-X) stellarator discharges is investigated experimentally via phase contrast imaging (PCI) in combination with gyrokinetic simulations with the code GENE. We find that density fluctuations are ion-temperature-gradient-driven and radially localised in the outer half of the plasma. It is shown that the line-integrated PCI measurements cover the right range of wavenumbers and a favourable toroidal and poloidal location to capture some of the strongest density fluctuations in W7-X. Due to the radial localisation of fluctuations, measured wavenumber–frequency spectra exhibit a dominant phase velocity, which can be related to the $\boldsymbol {E\times B}$ rotation velocity at the radial position of a well in the neoclassical radial electric field. The match is robust against variations of heating power and line-integrated density, which is partly due to the localisation of fluctuations and partly due to effects of the radial gradient in the $\boldsymbol {E\times B}$ velocity profile on the wavenumber–frequency spectrum. The latter effect is studied with a newly built synthetic PCI diagnostic and global gyrokinetic simulations with GENE-3D.
Exposure to glucocorticoid levels higher than appropriate for current developmental stages induces offspring metabolic dysfunction. Overfed/obese (OB) ewes and their fetuses display elevated blood cortisol, while fetal Adrenocorticotropic hormone (ACTH) remains unchanged. We hypothesized that OB pregnancies would show increased placental 11β hydroxysteroid dehydrogenase 2 (11β-HSD2) that converts maternal cortisol to fetal cortisone as it crosses the placenta and increased 11β-HSD system components responsible for peripheral tissue cortisol production, providing a mechanism for ACTH-independent increase in circulating fetal cortisol. Control ewes ate 100% National Research Council recommendations (CON) and OB ewes ate 150% CON diet from 60 days before conception until necropsy at day 135 gestation. At necropsy, maternal jugular and umbilical venous blood, fetal liver, perirenal fat, and cotyledonary tissues were harvested. Maternal plasma cortisol and fetal cortisol and cortisone were measured. Fetal liver, perirenal fat, cotyledonary 11β-HSD1, hexose-6-phosphate dehydrogenase (H6PD), and 11β-HSD2 protein abundance were determined by Western blot. Maternal plasma cortisol, fetal plasma cortisol, and cortisone were higher in OB vs. CON (p < 0.01). 11β-HSD2 protein was greater (p < 0.05) in OB cotyledonary tissue than CON. 11β-HSD1 abundance increased (p < 0.05) in OB vs. CON fetal liver and perirenal fat. Fetal H6PD, an 11β-HSD1 cofactor, also increased (p < 0.05) in OB vs. CON perirenal fat and tended to be elevated in OB liver (p < 0.10). Our data provide evidence for increased 11β-HSD system components responsible for peripheral tissue cortisol production in fetal liver and adipose tissue, thereby providing a mechanism for an ACTH-independent increase in circulating fetal cortisol in OB fetuses.
An experimental study of bluff bodies in confinement is presented. Two Reynolds matched rigs (pipe diameters: $D=40~\text{mm}$ and $D=194~\text{mm}$) are used to derive a picture of the flow topology of the primary-shedding mode (Kármán vortex, mode-I). Confined bluff bodies create an additional spectral mode (mode-II). This is caused by the close coupling of the shedder blockage and the wall and is unique to the confined bluff-body problem. Under certain conditions, modes-I and II can interact, resulting in a lock-on, wherein the modes cease to exist at independent frequencies. The topological effects of mode interaction are demonstrated using flow visualisation. Furthermore, the scaling of mode-II is explored. The two experimental facilities span Reynolds numbers (based on the shedder diameter, $d$) $10^{4}<Re_{d}<10^{5}$ and bulk Mach numbers $0.02<M_{b}<0.4$. Bluff bodies with a constant blockage ratio ($d/D$), forebody shape and various splitter-plate lengths ($l$) and thicknesses ($t$) are used. Results indicate that the flow topology changes substantially between short ($l<d$) and long ($l>d$) tailed geometries. Surface flow visualisation indicates that the primary vortex becomes anchored on the tail when $l\gtrsim 3h$ ($2h=d-t$). This criterion prohibits the development of such a topology for short-tailed geometries. When mode interaction occurs, which it does exclusively in long-tailed cases, the tail-anchored vortex pattern is disrupted. The onset of mode-II occurs at approximately the same Reynolds number in both rigs, although the associated dimensionless frequency is principally a function of Mach number. Accordingly, mode interaction is avoided in the larger-scale rig, due to the increased separation of the modal frequencies.
Inefficiencies in the national clinical research infrastructure have been apparent for decades. The National Center for Advancing Translational Science—sponsored Clinical and Translational Science Award (CTSA) program is able to address such inefficiencies. The Trial Innovation Network (TIN) is a collaborative initiative with the CTSA program and other National Institutes of Health (NIH) Institutes and Centers that addresses critical roadblocks to accelerate the translation of novel interventions to clinical practice. The TIN’s mission is to execute high-quality trials in a quick, cost-efficient manner. The TIN awardees are composed of 3 Trial Innovation Centers, the Recruitment Innovation Center, and the individual CTSA institutions that have identified TIN Liaison units. The TIN has launched a national scale single (central) Institutional Review Board system, master contracting agreements, quality-by-design approaches, novel recruitment support methods, and applies evidence-based strategies to recruitment and patient engagement. The TIN has received 113 submissions from 39 different CTSA institutions and 8 non-CTSA Institutions, with projects associated with 12 different NIH Institutes and Centers across a wide range of clinical/disease areas. Already more than 150 unique health systems/organizations are involved as sites in TIN-related multisite studies. The TIN will begin to capture data and metrics that quantify increased efficiency and quality improvement during operations.
Group housing of gestating sows benefits their welfare by allowing them freedom of movement and the opportunity for social interaction. However, social life could also bring disadvantages for individuals who receive direct aggression or are displaced from the feeder. The aim of this study was to investigate associations between social behaviour, body condition and live weight. Gestating sows (n=298) were investigated on a commercial farm. Sows were housed in mixed parity groups where two single space, ad libitum trough feeders served 12 animals. Sows were weighed, body condition scored and had their back fat layer measured at mixing, 4 weeks after insemination and again before farrowing. Social status was estimated based on the numbers of won and lost agonistic interactions at mixing and at the end of gestation. In addition, tear staining was scored before the farrowing and reproductive performance data were collected. With the aid of video recordings, 100 to 150 interactions per group were observed. Winning percentage at mixing and at the end of gestation were associated (P<0.05) and appeared relatively stable within individuals. Tear staining scores and litter sizes were not associated with winning percentage at the end of gestation. However, live weight, relative weight, body condition and back fat thickness were associated with winning percentage (P<0.05), giving heavier animals an advantage. Low winning percentage related to lower live weight gain, probably due to poorer success in competition for feed. Live weight within a mixed parity group could be used as a proxy measure for social status. Sows with low body condition score and submissive sows might need special attention with regard to group dynamics and housing to alleviate the effects of competition in group housing.
Phased Array Feed (PAF) technology is the next major advancement in radio astronomy in terms of combining high sensitivity and large field of view. The Focal L-band Array for the Green Bank Telescope (FLAG) is one of the most sensitive PAFs developed so far. It consists of 19 dual-polarization elements mounted on a prime focus dewar resulting in seven beams on the sky. Its unprecedented system temperature of ~17 K will lead to a 3 fold increase in pulsar survey speeds as compared to contemporary single pixel feeds. Early science observations were conducted in a recently concluded commissioning phase of the FLAG where we clearly demonstrated its science capabilities. We observed a selection of normal and millisecond pulsars and detected giant pulses from PSR B1937+21.
Faster eating rates are associated with increased energy intake, but little is known about the relationship between children’s eating rate, food intake and adiposity. We examined whether children who eat faster consume more energy and whether this is associated with higher weight status and adiposity. We hypothesised that eating rate mediates the relationship between child weight and ad libitum energy intake. Children (n 386) from the Growing Up in Singapore Towards Healthy Outcomes cohort participated in a video-recorded ad libitum lunch at 4·5 years to measure acute energy intake. Videos were coded for three eating-behaviours (bites, chews and swallows) to derive a measure of eating rate (g/min). BMI and anthropometric indices of adiposity were measured. A subset of children underwent MRI scanning (n 153) to measure abdominal subcutaneous and visceral adiposity. Children above/below the median eating rate were categorised as slower and faster eaters, and compared across body composition measures. There was a strong positive relationship between eating rate and energy intake (r 0·61, P<0·001) and a positive linear relationship between eating rate and children’s BMI status. Faster eaters consumed 75 % more energy content than slower eating children (Δ548 kJ (Δ131 kcal); 95 % CI 107·6, 154·4, P<0·001), and had higher whole-body (P<0·05) and subcutaneous abdominal adiposity (Δ118·3 cc; 95 % CI 24·0, 212·7, P=0·014). Mediation analysis showed that eating rate mediates the link between child weight and energy intake during a meal (b 13·59; 95 % CI 7·48, 21·83). Children who ate faster had higher energy intake, and this was associated with increased BMI z-score and adiposity.
Although repeatedly associated with white matter microstructural alterations, bipolar disorder (BD) has been relatively unexplored using complex network analysis. This method combines structural and diffusion magnetic resonance imaging (MRI) to model the brain as a network and evaluate its topological properties. A group of highly interconnected high-density structures, termed the ‘rich-club’, represents an important network for integration of brain functioning. This study aimed to assess structural and rich-club connectivity properties in BD through graph theory analyses.
Method
We obtained structural and diffusion MRI scans from 42 euthymic patients with BD type I and 43 age- and gender-matched healthy volunteers. Weighted fractional anisotropy connections mapped between cortical and subcortical structures defined the neuroanatomical networks. Next, we examined between-group differences in features of graph properties and sub-networks.
Results
Patients exhibited significantly reduced clustering coefficient and global efficiency, compared with controls globally and regionally in frontal and occipital regions. Additionally, patients displayed weaker sub-network connectivity in distributed regions. Rich-club analysis revealed subtly reduced density in patients, which did not withstand multiple comparison correction. However, hub identification in most participants indicated differentially affected rich-club membership in the BD group, with two hubs absent when compared with controls, namely the superior frontal gyrus and thalamus.
Conclusions
This graph theory analysis presents a thorough investigation of topological features of connectivity in euthymic BD. Abnormalities of global and local measures and network components provide further neuroanatomically specific evidence for distributed dysconnectivity as a trait feature of BD.
A computational method is presented for solving numerically the three dimensional Euler equations for transonic flow around practical aircraft forebodies. The Euler solver is pseudo-time dependent, split and cast in finite volume form. Shock waves are captured crisply without the need for additional smoothing by means of an operator-switching facility which more accurately reflects the direction of propagation of signals.
The method is illustrated by examples of computed external, axisymmetric flows and some, simulated, realistic aircraft fore-bodies. The computational meshes employed in the three dimensional cases are essentially of cylindrical polar, flow conforming, type and relatively coarse. Closer attention to the mesh generation is expected to refine the results presented here. The method is versatile, robust, and holds promise for treating complex three dimensional geometries within economically viable run times.
Accurate and complete reporting of study methods, results and interpretation are essential components for any scientific process, allowing end-users to evaluate the internal and external validity of a study. When animals are used in research, excellence in reporting is expected as a matter of continued ethical acceptability of animal use in the sciences. Our primary objective was to assess completeness of reporting for a series of studies relevant to mitigation of pain in neonatal piglets undergoing routine management procedures. Our second objective was to illustrate how authors can report the items in the Reporting guidElines For randomized controLled trials for livEstoCk and food safety (REFLECT) statement using examples from the animal welfare science literature. A total of 52 studies from 40 articles were evaluated using a modified REFLECT statement. No single study reported all REFLECT checklist items. Seven studies reported specific objectives with testable hypotheses. Six studies identified primary or secondary outcomes. Randomization and blinding were considered to be partially reported in 21 and 18 studies, respectively. No studies reported the rationale for sample sizes. Several studies failed to report key design features such as units for measurement, means, standard deviations, standard errors for continuous outcomes or comparative characteristics for categorical outcomes expressed as either rates or proportions. In the discipline of animal welfare science, authors, reviewers and editors are encouraged to use available reporting guidelines to ensure that scientific methods and results are adequately described and free of misrepresentations and inaccuracies. Complete and accurate reporting increases the ability to apply the results of studies to the decision-making process and prevent wastage of financial and animal resources.
The ITRACK study explored the process and predictors of transition between Child and Adolescent Mental Health Services (CAMHS) and Adult Mental Health Services (AMHS) in the Republic of Ireland.
Method
Following ethical approval, clinicians in each of Ireland’s four Health Service Executive (HSE) areas were contacted, informed about the study and were invited to participate. Clinicians identified all cases who had reached the transition boundary (i.e. upper age limit for that CAMHS team) between January and December 2010. Data were collected on clinical and socio-demographic details and factors that informed the decision to refer or not refer to the AMHS, and case notes were scrutinised to ascertain the extent of information exchanged between services during transition.
Results
A total of 62 service users were identified as having crossed the transition boundary from nine CAMHS [HSE Dublin Mid-Leinster (n=40, 66%), HSE South (n=18, 30%), HSE West (n=2, 3%), HSE Dublin North (n=1, 2%)]. The most common diagnoses were attention deficit hyperactivity disorder (ADHD; n=19, 32%), mood disorders (n=16, 27%), psychosis (n=6, 10%) and eating disorders (n=5, 8%). Forty-seven (76%) of those identified were perceived by the CAMHS clinician to have an ‘on-going mental health service need’, and of these 15 (32%) were referred, 11 (23%) young people refused and 21 (45%) were not referred, with the majority (12, 57%) continuing with the CAMHS for more than a year beyond the transition boundary. Young people with psychosis were more likely to be referred [χ2 (2, 46)=8.96, p=0.02], and those with ADHD were less likely to be referred [χ2 (2, 45)=8.89, p=0.01]. Being prescribed medication was not associated with referral [χ2 (2, 45)=4.515, p=0.11]. In referred cases (n=15), there was documented evidence of consent in two cases (13.3%), inferred in another four (26.7%) and documented preparation for transition in eight (53.3%). Excellent written communication (100%) was not supported by face-to-face planning meetings (n=2, 13.3%), joint appointments (n=1, 6.7%) or telephone conversations (n=1, 6.7%) between corresponding clinicians.
Conclusions
Despite perceived on-going mental health (MH) service need, many young people are not being referred or are refusing referral to the AMHS, with those with ADHD being the most affected. CAMHS continue to offer on-going care past the transition boundary, which has resource implications. Further qualitative research is warranted to understand, in spite of perceived MH service need, the reason for non-referral by the CAMHS clinicians and refusal by the young person.
Depression is common and the efficacy of antidepressants is suboptimal. High plasma homocysteine has been consistently associated with depression, and treatment with certain B vitamins demonstrably reduces its concentration.
Aims
To determine whether vitamins B6, B12 and folic acid enhance response to antidepressant treatment over 52 weeks.
Method
Randomised, double-blind, placebo-controlled trial of citalopram (20–40 g) together with 0.5mg of vitamin B12, 2mg of folic acid and 25mg of vitamin B6 for 52 weeks (Australian and New Zealand Clinical Trials Registry: 12609000256279). Participants were community-dwelling adults aged 50 years or over with DSM-IV-TR major depression. We measured severity of symptoms with the Montgomery–åsberg Depression Rating Scale (MADRS). The primary outcome was remission of the depressive episode after 12, 26 and 52 weeks. Secondary outcomes included reduction of MADRS scores over time and relapse of major depression after recovery by week 12.
Results
In total, 153 people were randomised (76 placebo, 77 vitamins). Remission of symptoms was achieved by 78.1 and 79.4% of participants treated with placebo and vitamins by week 12 (P = 0.840), by 76.5 and 85.3% at week 26 and 75.8 and 85.5% at week 52 (effect of intervention over 52 weeks: odds ratio (OR) = 2.49, 95% CI 1.12–5.51). Group differences in MADRS scores over time were not significant (P = 0.739). The risk of subsequent relapse among those who had achieved remission of symptoms at week 12 was lower in the vitamins than placebo group (OR = 0.33, 95% CI 0.12–0.94).
Conclusions
B vitamins did not increase the 12-week efficacy of antidepressant treatment, but enhanced and sustained antidepressant response over 1 year. Replication of these findings would mandate that treatment guidelines adopt the adjunctive use of B vitamins as a safe and inexpensive strategy to manage major depression in middle-aged and older adults.
A survey of the Milky Way disk and the Magellanic System at the wavelengths of the 21-cm atomic hydrogen (H i) line and three 18-cm lines of the OH molecule will be carried out with the Australian Square Kilometre Array Pathfinder telescope. The survey will study the distribution of H i emission and absorption with unprecedented angular and velocity resolution, as well as molecular line thermal emission, absorption, and maser lines. The area to be covered includes the Galactic plane (|b| < 10°) at all declinations south of δ = +40°, spanning longitudes 167° through 360°to 79° at b = 0°, plus the entire area of the Magellanic Stream and Clouds, a total of 13 020 deg2. The brightness temperature sensitivity will be very good, typically σT≃ 1 K at resolution 30 arcsec and 1 km s−1. The survey has a wide spectrum of scientific goals, from studies of galaxy evolution to star formation, with particular contributions to understanding stellar wind kinematics, the thermal phases of the interstellar medium, the interaction between gas in the disk and halo, and the dynamical and thermal states of gas at various positions along the Magellanic Stream.