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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.
The aerodynamic performance of an ultra-high aspect ratio strut-braced wing design is assessed for flight at cruise. The sensitivity of a selected airframe design from a recent CleanSky2 project to operating conditions around the design point is quantified using the adaptive-cut high-dimensional model representation (HDMR) method, which allows for the decomposition of the parameter space into smaller subdomains to isolate the parameter interactions and influence on the aerodynamic forces. A comparative analysis with a cantilever wing configuration is performed to identify the role of the strut on the sensitivity of the design. Insight into the transonic performance is gained by characterisation of buffet limits and drag rise. Results show that, for the selected optimised airframe configuration, small changes in freestream parameters can lead to significant reduction in performance due to drag divergence triggered by the shock wave generated at the strut-wing junction and at the fuselage-strut intersection. Cruise conditions can be achieved without buffet onset throughout much of the parameter space. Safety margins associated with buffeting are satisfied, but sensible limits are imposed on the flight envelope for this configuration.
Adolescence is a key developmental period associated with an increased risk of experiencing cannabis-related problems. Identifying modifiable risk factors prior to the onset of cannabis use could help inform preventative interventions.
Method
Analysis nested within a UK prospective birth cohort study, the Avon Longitudinal Study of Parents and Children. Participants (n = 6,049) provided data on cannabis use and symptoms of cannabis problems using the Cannabis Abuse Screening Test at two or more time points between the ages of 15–24 years. Risk factors included internalizing and externalizing disorders assessed at age 10 years, and cognitive function assessed at age 8 years via short-term memory, emotion recognition, divided attention, and listening comprehension.
Results
Participants were mostly female (59.1%) and white (95.73%). Five patterns of adolescent cannabis use problems were identified using longitudinal latent class analysis: stable-no problems (n = 5,157, 85%), early-onset high (n = 104, 2%), late-onset high (n = 153, 3%), early onset low (n = 348, 6%), and late-onset low (n = 287, 5%). In adjusted models, externalizing disorders were associated with early-onset high [RR, 95% CI: 2.82 (1.72, 4.63)], late-onset high [RR, 95% CI: 1.62 (1.02, 2.57)], and early-onset low [RR, 95% CI: 1.82 (1.30, 2.55)] compared to the stable-no problems class. Internalizing disorders were associated with late-onset low only [RR, 95% CI: .50 (.26, .96)], and short-term memory with late-onset high only [RR, 95% CI: 1.09 (1.01, 1.18) compared to the stable-no problems class.
Conclusions
Childhood externalizing disorders were consistently associated with increased risk of problematic patterns of cannabis use over adolescence, particularly early-onset and high levels of problems.
The Hippoboscidae are ectoparasites of birds and mammals, which, as a group, are known to vector multiple diseases. Avipoxvirus (APV) is mechanically vectored by various arthropods and causes seasonal disease in wild birds in the United Kingdom (UK). Signs of APV and the presence of louse flies (Hippoboscidae) on Dunnocks Prunella modularis were recorded over a 16·5-year period in a rural garden in Somerset, UK. Louse flies collected from this site and other sites in England were tested for the presence of APV DNA and RNA sequences. Louse flies on Dunnocks were seen to peak seasonally three weeks prior to the peak of APV lesions, an interval consistent with the previously estimated incubation period of APV in Dunnocks. APV DNA was detected on 13/25 louse flies, Ornithomya avicularia and Ornithomya fringillina, taken from Dunnocks, both with and without lesions consistent with APV, at multiple sites in England. Collectively these data support the premise that louse flies may vector APV. The detection of APV in louse flies, from apparently healthy birds, and from sites where disease has not been observed in any host species, suggests that the Hippoboscidae could provide a non-invasive and relatively cheap method of monitoring avian diseases. This could provide advanced warnings of disease, including zoonoses, before they become clinically apparent.
The primary purpose of this study was to assess perceived burdens and benefits of participating in implementation research among staff employed in resource-constrained healthcare settings. Another objective was to use findings to generate considerations for engaging staff in research across different phases of implementation research.
Methods:
This qualitative focus group and consensus building study involved researchers affiliated with the National Cancer Institute Implementation Science Centers in Cancer Control program and nine Community Health Centers (CHCs) in Massachusetts. Six focus groups (n = 3 with CHC staff; n = 3 with researchers) assessed barriers and facilitators to staff participation in implementation research. During consensus discussions, we used findings to develop considerations for engaging staff as participants and partners throughout phases of implementation research.
Results:
Sixteen researchers and 14 staff participated in separate focus groups; nine researchers and seven staff participated in separate consensus discussions. Themes emerged across participant groups in three domains: (1) influences on research participation; (2) research burdens and benefits; and (3) ways to facilitate staff participation in research. Practical considerations included: (a) aligning research with organizational and staff values and priorities; (b) applying user-centered design to research methods; (c) building organizational and individual research capacity; and (d) offering equitable incentives for staff participation.
Conclusions:
Engaging staff as participants and partners across different phases of implementation research requires knowledge about what contributes to research burden and benefits and addressing context-specific burdens and benefits.
Previous studies identified clusters of first-episode psychosis (FEP) patients based on cognition and premorbid adjustment. This study examined a range of socio-environmental risk factors associated with clusters of FEP, aiming a) to compare clusters of FEP and community controls using the Maudsley Environmental Risk Score for psychosis (ERS), a weighted sum of the following risks: paternal age, childhood adversities, cannabis use, and ethnic minority membership; b) to explore the putative differences in specific environmental risk factors in distinguishing within patient clusters and from controls.
Methods
A univariable general linear model (GLS) compared the ERS between 1,263 community controls and clusters derived from 802 FEP patients, namely, low (n = 223) and high-cognitive-functioning (n = 205), intermediate (n = 224) and deteriorating (n = 150), from the EU-GEI study. A multivariable GLS compared clusters and controls by different exposures included in the ERS.
Results
The ERS was higher in all clusters compared to controls, mostly in the deteriorating (β=2.8, 95% CI 2.3 3.4, η2 = 0.049) and the low-cognitive-functioning cluster (β=2.4, 95% CI 1.9 2.8, η2 = 0.049) and distinguished them from the cluster with high-cognitive-functioning. The deteriorating cluster had higher cannabis exposure (meandifference = 0.48, 95% CI 0.49 0.91) than the intermediate having identical IQ, and more people from an ethnic minority (meandifference = 0.77, 95% CI 0.24 1.29) compared to the high-cognitive-functioning cluster.
Conclusions
High exposure to environmental risk factors might result in cognitive impairment and lower-than-expected functioning in individuals at the onset of psychosis. Some patients’ trajectories involved risk factors that could be modified by tailored interventions.
Vaccines have revolutionised the field of medicine, eradicating and controlling many diseases. Recent pandemic vaccine successes have highlighted the accelerated pace of vaccine development and deployment. Leveraging this momentum, attention has shifted to cancer vaccines and personalised cancer vaccines, aimed at targeting individual tumour-specific abnormalities. The UK, now regarded for its vaccine capabilities, is an ideal nation for pioneering cancer vaccine trials. This article convened experts to share insights and approaches to navigate the challenges of cancer vaccine development with personalised or precision cancer vaccines, as well as fixed vaccines. Emphasising partnership and proactive strategies, this article outlines the ambition to harness national and local system capabilities in the UK; to work in collaboration with potential pharmaceutic partners; and to seize the opportunity to deliver the pace for rapid advances in cancer vaccine technology.
Making informed clinical decisions based on individualised outcome predictions is the cornerstone of precision psychiatry. Prediction models currently employed in psychiatry rely on algorithms that map a statistical relationship between clinical features (predictors/risk factors) and subsequent clinical outcomes. They rely on associations that overlook the underlying causal structures within the data, including the presence of latent variables, and the evolution of predictors and outcomes over time. As a result, predictions from sparse associative models from routinely collected data are rarely actionable at an individual level. To be actionable, prediction models should address these shortcomings. We provide a brief overview of a general framework for the rationale for implementing causal and actionable predictions using counterfactual explanations to advance predictive modelling studies, which has translational implications. We have included an extensive glossary of terminology used in this paper and the literature (Supplementary Box 1) and provide a concrete example to demonstrate this conceptually, and a reading list for those interested in this field (Supplementary Box 2).
Stigma of mental health conditions hinders recovery and well-being. The Honest, Open, Proud (HOP) program shows promise in reducing stigma but there is uncertainty about the feasibility of a randomized trial to evaluate a peer-delivered, individual adaptation of HOP for psychosis (Let's Talk).
Methods
A multi-site, Prospective Randomized Open Blinded Evaluation (PROBE) design, feasibility randomised controlled trial (RCT) comparing the peer-delivered intervention (Let's Talk) to treatment as usual (TAU). Follow-up was 2.5 and 6 months. Randomization was via a web-based system, with permuted blocks of random size. Up to 10 sessions of the intervention over 10 weeks were offered. The primary outcome was feasibility data (recruitment, retention, intervention attendance). Primary outcomes were analyzed by intention to treat. Safety outcomes were reported by as treated status. The study was prospectively registered: https://doi.org/10.1186/ISRCTN17197043.
Results
149 patients were referred to the study and 70 were recruited. 35 were randomly assigned to intervention + TAU and 35 to TAU. Recruitment was 93% of the target sample size. Retention rate was high (81% at 2.5 months primary endpoint), and intervention attendance rate was high (83%). 21% of 33 patients in Let's talk + TAU had an adverse event and 16% of 37 patients in TAU. One serious adverse event (pre-randomization) was partially related and expected.
Conclusions
This is the first trial to show that it is feasible and safe to conduct a RCT of HOP adapted for people with psychosis and individual delivery. An adequately powered trial is required to provide robust evidence.
Cannabis use severely affects the outcome of people with psychotic disorders, yet there is a lack of treatments. To address this, in 2019 the National Health Service (NHS) Cannabis Clinic for Psychosis (CCP) was developed to support adults suffering from psychosis to reduce and/or stop their cannabis use.
Aims
Examine outcome data from the first 46 individuals to complete the CCP's intervention.
Method
The sample (N = 46) consisted of adults (aged ≥ 18) with psychosis under the care of the South London and Maudsley NHS Foundation Trust, referred to the CCP between January 2020 and February 2023, who completed their intervention by September 2023. Clinical and functional measures were collected before (T0) and after (T1) the CCP intervention (one-to-one sessions and peer group attendance). Primary outcomes were changes in the Cannabis Use Disorders Identification Test-Revised (CUDIT-R) score and pattern of cannabis use. Secondary outcomes included T0–T1 changes in measures of delusions, paranoia, depression, anxiety and functioning.
Results
A reduction in the mean CUDIT-R score was observed between T0 (mean difference = 17.10, 95% CI = 15.54–18.67) and T1, with 73.91% of participants achieving abstinence and 26.09% reducing the frequency and potency of their use. Significant improvements in all clinical and functional outcomes were observed, with 90.70% being in work or education at T1 compared with 8.70% at T0. The variance in CUDIT-R scores explained between 34 and 64% of the variance in our secondary measures.
Conclusions
The CCP intervention is a feasible strategy to support cannabis use cessation/reduction and improve clinical and functional outcomes of people with psychotic disorders.
The association between cannabis and psychosis is established, but the role of underlying genetics is unclear. We used data from the EU-GEI case-control study and UK Biobank to examine the independent and combined effect of heavy cannabis use and schizophrenia polygenic risk score (PRS) on risk for psychosis.
Methods
Genome-wide association study summary statistics from the Psychiatric Genomics Consortium and the Genomic Psychiatry Cohort were used to calculate schizophrenia and cannabis use disorder (CUD) PRS for 1098 participants from the EU-GEI study and 143600 from the UK Biobank. Both datasets had information on cannabis use.
Results
In both samples, schizophrenia PRS and cannabis use independently increased risk of psychosis. Schizophrenia PRS was not associated with patterns of cannabis use in the EU-GEI cases or controls or UK Biobank cases. It was associated with lifetime and daily cannabis use among UK Biobank participants without psychosis, but the effect was substantially reduced when CUD PRS was included in the model. In the EU-GEI sample, regular users of high-potency cannabis had the highest odds of being a case independently of schizophrenia PRS (OR daily use high-potency cannabis adjusted for PRS = 5.09, 95% CI 3.08–8.43, p = 3.21 × 10−10). We found no evidence of interaction between schizophrenia PRS and patterns of cannabis use.
Conclusions
Regular use of high-potency cannabis remains a strong predictor of psychotic disorder independently of schizophrenia PRS, which does not seem to be associated with heavy cannabis use. These are important findings at a time of increasing use and potency of cannabis worldwide.
Introduction: Dementia continues to be a global health concern owed to its increasing prevalence and coupled with physical and psychological burden. It is also the most feared diagnosis amongst older adults which may contribute to underdiagnosis. Pre-assessment counselling (PAC) may reduce fear and increase diagnoses when people with suspected cognitive impairment are empowered with choice and feel in control of their diagnosis journey.
Methods: This study recruited 10 clinicians from an NHS memory clinic in England, UK, and, using semi-structured interviews, sought to understand the mechanisms and effectiveness of PAC.
Results: Using reflective thematic analysis, 3 themes were found. 1. The person with dementia (PwD) is central in their diagnosis journey. 2. Candid conversations build strong therapeutic alliances. 3. Patients are more than their diagnoses.
Discussion: Clinicians emphasized the importance of timely diagnosis for the wellbeing of PwD, while also recognizing the need for patient-centred and collaborative approaches. Additionally, the study highlighted the significance of empowering PwD in decision-making processes, fostering resilience through comprehensive support, and addressing stigma through candid conversations to improve diagnostic outcomes and enhance patient engagement in dementia care. The study indicates that PAC is effective in enabling timely diagnoses, but there is a lack of dedicated appointments in NHS Trusts where PwD are empowered to manage their dementia journey and subsequent care.
Cannabis use and familial vulnerability to psychosis have been associated with social cognition deficits. This study examined the potential relationship between cannabis use and cognitive biases underlying social cognition and functioning in patients with first episode psychosis (FEP), their siblings, and controls.
Methods
We analyzed a sample of 543 participants with FEP, 203 siblings, and 1168 controls from the EU-GEI study using a correlational design. We used logistic regression analyses to examine the influence of clinical group, lifetime cannabis use frequency, and potency of cannabis use on cognitive biases, accounting for demographic and cognitive variables.
Results
FEP patients showed increased odds of facial recognition processing (FRP) deficits (OR = 1.642, CI 1.123–2.402) relative to controls but not of speech illusions (SI) or jumping to conclusions (JTC) bias, with no statistically significant differences relative to siblings. Daily and occasional lifetime cannabis use were associated with decreased odds of SI (OR = 0.605, CI 0.368–0.997 and OR = 0.646, CI 0.457–0.913 respectively) and JTC bias (OR = 0.625, CI 0.422–0.925 and OR = 0.602, CI 0.460–0.787 respectively) compared with lifetime abstinence, but not with FRP deficits, in the whole sample. Within the cannabis user group, low-potency cannabis use was associated with increased odds of SI (OR = 1.829, CI 1.297–2.578, FRP deficits (OR = 1.393, CI 1.031–1.882, and JTC (OR = 1.661, CI 1.271–2.171) relative to high-potency cannabis use, with comparable effects in the three clinical groups.
Conclusions
Our findings suggest increased odds of cognitive biases in FEP patients who have never used cannabis and in low-potency users. Future studies should elucidate this association and its potential implications.
Childhood bullying is a public health priority. We evaluated the effectiveness and costs of KiVa, a whole-school anti-bullying program that targets the peer context.
Methods
A two-arm pragmatic multicenter cluster randomized controlled trial with embedded economic evaluation. Schools were randomized to KiVa-intervention or usual practice (UP), stratified on school size and Free School Meals eligibility. KiVa was delivered by trained teachers across one school year. Follow-up was at 12 months post randomization. Primary outcome: student-reported bullying-victimization; secondary outcomes: self-reported bullying-perpetration, participant roles in bullying, empathy and teacher-reported Strengths and Difficulties Questionnaire. Outcomes were analyzed using multilevel linear and logistic regression models.
Findings
Between 8/11/2019–12/02/2021, 118 primary schools were recruited in four trial sites, 11 111 students in primary analysis (KiVa-intervention: n = 5944; 49.6% female; UP: n = 5167, 49.0% female). At baseline, 21.6% of students reported being bullied in the UP group and 20.3% in the KiVa-intervention group, reducing to 20.7% in the UP group and 17.7% in the KiVa-intervention group at follow-up (odds ratio 0.87; 95% confidence interval 0.78 to 0.97, p value = 0.009). Students in the KiVa group had significantly higher empathy and reduced peer problems. We found no differences in bullying perpetration, school wellbeing, emotional or behavioral problems. A priori subgroup analyses revealed no differences in effectiveness by socioeconomic gradient, or by gender. KiVa costs £20.78 more per pupil than usual practice in the first year, and £1.65 more per pupil in subsequent years.
Interpretation
The KiVa anti-bullying program is effective at reducing bullying victimization with small-moderate effects of public health importance.
Funding
The study was funded by the UK National Institute for Health and Care Research (NIHR) Public Health Research program (17-92-11). Intervention costs were funded by the Rayne Foundation, GwE North Wales Regional School Improvement Service, Children's Services, Devon County Council and HSBC Global Services (UK) Ltd.
Sex biases in prevalence of disease are often attributed to intrinsic factors, such as physiological differences while a proximate role of extrinsic factors such as behavioural or ecological differences may be more difficult to establish. We combined large-scale screening for the presence and lineage identity of avian malaria (haemosporidian) parasites, in 1234 collared flycatchers (Ficedula albicollis) with life-history information from each bird to establish the location and timing of infection. We found an overall infection rate of 36.2% ± 0.03 (95% CI) with 25 distinct malaria lineages. Interestingly, first-year breeding males and females had similar infection prevalence while females accrued a significantly higher infection rate than males later in life. The sex difference in infection rate was driven by the most abundant Haemoproteus, lineage, hPHSIB1, while the infection rate of Plasmodium lineages was similar in males and females. Furthermore, when infections were assigned to an apparent transmission location, we found that the sex difference in infection rate trend was driven by lineages transmitted in Europe, more specifically by one lineage (the hPHSIB1), while no similar pattern was found in African lineages. We deduce that the observed infection patterns are likely to be caused by differences in breeding behaviour, with incubating females (and nestling individuals of both sexes) being easy targets for the biting insects that are the vectors of avian malaria parasites. Overall, our results are most consistent with ecological factors rather than intrinsic factors underlying the observed sex-biased infection rate of avian malaria in collared flycatchers.
Hypertension and depression are increasingly common noncommunicable diseases in Ghana and worldwide, yet both are poorly controlled. We sought to understand how healthcare workers in rural Ghana conceptualize the interaction between hypertension and depression, and how care for these two conditions might best be integrated. We conducted a qualitative descriptive study involving in-depth interviews with 34 healthcare workers in the Kassena-Nankana districts of the Upper East Region of Ghana. We used conventional content analysis to systematically review interview transcripts, code the data content and analyze codes for salient themes. Respondents detailed three discrete conceptual models. Most emphasized depression as causing hypertension: through both emotional distress and unhealthy behavior. Others posited a bidirectional relationship, where cardiovascular morbidity worsened mood, or described a single set of underlying causes for both conditions. Nearly all proposed health interventions targeted their favored root cause of these disorders. In this representative rural Ghanaian community, healthcare workers widely agreed that cardiovascular disease and mental illness are physiologically linked and warrant an integrated care response, but held diverse views regarding precisely how and why. There was widespread support for a single primary care intervention to treat both conditions through counseling and medication.
Early life stress (ELS) and a Western diet (WD) promote mood and cardiovascular disorders, however, how these risks interact in disease pathogenesis is unclear. We assessed effects of ELS with or without a subsequent WD on behaviour, cardiometabolic risk factors, and cardiac function/ischaemic tolerance in male mice. Fifty-six new-born male C57BL/6J mice were randomly allocated to a control group (CON) undisturbed before weaning, or to maternal separation (3h/day) and early (postnatal day 17) weaning (MSEW). Mice consumed standard rodent chow (CON, n = 14; MSEW, n = 15) or WD chow (WD, n = 19; MSEW + WD, n = 19) from week 8 to 24. Fasted blood was sampled and open field test and elevated plus maze (EPM) tests undertaken at 7, 15, and 23 weeks of age, with hearts excised at 24 weeks for Langendorff perfusion (evaluating pre- and post-ischaemic function). MSEW alone transiently increased open field activity at 7 weeks; body weight and serum triglycerides at 4 and 7 weeks, respectively; and final blood glucose levels and insulin resistance at 23 weeks. WD increased insulin resistance and body weight gain, the latter potentiated by MSEW. MSEW + WD was anxiogenic, reducing EPM open arm activity vs. WD alone. Although MSEW had modest metabolic effects and did not influence cardiac function or ischaemic tolerance in lean mice, it exacerbated weight gain and anxiogenesis, and improved ischaemic tolerance in WD fed animals. MSEW-induced increases in body weight (obesity) in WD fed animals in the absence of changes in insulin resistance may have protected the hearts of these mice.
We assessed adverse events in hospitalized patients receiving selected vesicant antibiotics or vasopressors administered through midline catheters or peripherally inserted central catheters (PICC). The rates of catheter-related bloodstream infections, thrombosis, and overall events were similar across the two groups, while occlusion was higher in the PICC group.