Abstract
Background
Adolescent mental health (AMH) needs in England have increased dramatically and needs exceed treatment availability. This study undertook a comparative assessment of the health ...and economic return on investment (ROI) of interventions to prevent and treat mental disorders among adolescents (10–19 years) and examined intervention affordability and readiness.
Methods
Interventions were identified following a review of published and grey literature. A Markov model followed a simulated adolescent cohort to estimate implementation costs and health, education, and economic benefits. Intervention affordability was assessed, comparing annual cost per adolescent with NHS England per capita spending, and an expert panel assessed intervention readiness using a validated framework.
Results
Over 10- and 80-year horizons, interventions to treat mild anxiety and mild depression were most cost-effective, with the highest individual lifetime ROI (GBP 5822 GBP 1 and GBP 257: GBP 1). Preventing anxiety and depression was most affordable and ‘implementation ready’ and offered the highest health and economic benefits. A priority package (anxiety and depression prevention; mild anxiety and mild depression treatment) would avert 5 million disability-adjusted life-years (DALYS) and achieve an ROI of GBP 15: GBP 1 over 10 years or 11.5 million DALYs (ROI of GBP 55: GBP 1) over 80 years.
Conclusion
The economic benefits from preventing and treating common adolescent mental disorders equivalent to 25% of NHS England’s annual spending in 2021 over 10 years and 91% over 80 years. Preventing and early treatment for anxiety and depression had the highest ROIs and strong implementation readiness.
There is a dearth of biospecimen repositories available to perinatal researchers. In order to address this need, here we describe the methodology used to establish such a resource.
With the ...collaboration of MedSci.net, we generated an online perinatal database with 847 fields of clinical information. Simultaneously, we established a biospecimen repository of the same clinical participants.
The demographic and clinical outcomes data are described for the first 10 000 participants enrolled. The demographic characteristics are consistent with the demographics of the delivery hospitals. Quality analysis of the biospecimens reveals variation in very few analytes. Furthermore, since the creation of PeriBank, we have demonstrated validity of the database and tissue integrity of the biospecimen repository.
Here we establish that the creation of a universal perinatal database and biospecimen collection is not only possible, but allows for the performance of state-of-the-science translational perinatal research and is a potentially valuable resource to academic perinatal researchers.
Nuclear reactor process control is typically monitored for pure β-emitting radionuclides via manual sampling followed by laboratory analysis, leading to delays in data availability and response ...times. The development of an in situ microfluidic Lab on Chip (LoC) system with integrated detection capable of measuring pure β-emitting radionuclides presents a promising solution, enabling a reduction in occupational exposure and cost of monitoring whilst providing improved temporal resolution through near real-time data acquisition. However, testing prototypes with radioactive sources is time-consuming, requires specialist facilities/equipment, generates contaminated waste, and cannot rapidly evaluate a wide range of designs or configurations. Despite this, modelling multiple design parameters and testing their impact on detection with non-radioactive substitutes has yet to be adopted as best practice. The measurement of pure β emitters in aqueous media relies on the efficient transport of photons generated by the Cherenkov effect or liquid scintillators to the detector. Here we explore the role of numerical modelling to assess the impact of optical cell geometry and design on photon transmission and detection through the microfluidic system, facilitating improved designs to realise better efficiency of integrated detectors and overall platform design. Our results demonstrate that theoretical modelling and an experimental evaluation using non-radiogenic chemiluminescence are viable for system testing design parameters and their impact on photon transport. These approaches enable reduced material consumption and requirement for specialist facilities for handling radioactive materials during the prototyping process. This method establishes proof of concept and the first step towards numerical modelling approaches for the design optimisation of microfluidic LoC systems with integrated detectors for the measurement of pure β emitting radionuclides via scintillation-based detection.
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•Numerical modelling leads to the more efficient development of Lab-On-Chip radiometric sensors.•Novel prototyping approach reduces the need for radioactive materials, equipment, facilities and specialist labour.•Validation is achieved with good agreement between experimental and theoretical modelled results.•Outlines the foundations of best practices for optimising Lab-on-Chip prototypes using optical detection.
The acrotelm–catotelm model of peatland hydrological and biogeochemical processes posits that the permeability of raised bogs is largely homogenous laterally but varies strongly with depth through ...the soil profile; uppermost peat layers are highly permeable while deeper layers are, effectively, impermeable. We measured down‐core changes in peat permeability, plant macrofossil assemblages, dry bulk density and degree of humification beneath two types of characteristic peatland microform – ridges and hollows – at a raised bog in Wales. Six ¹⁴C dates were also collected for one hollow and an adjacent ridge. Contrary to the acrotelm–catotelm model, we found that deeper peat can be as highly permeable as near‐surface peat and that its permeability can vary by more than an order of magnitude between microforms over horizontal distances of 1–5 m. Our palaeoecological data paint a complicated picture of microform persistence. Some microforms can remain in the same position on a bog for millennia, growing vertically upwards as the bog grows. However, adjacent areas on the bog (< 10 m distant) show switches between microform type over time, indicating a lack of persistence. Synthesis. We suggest that the acrotelm–catotelm model should be used cautiously; spatial variations in peatland permeability do not fit the simple patterns suggested by the model. To understand how peatlands as a whole function both hydrologically and ecologically, it is necessary to understand how patterns of peat physical properties and peatland vegetation develop and persist.
Magnetic resonance enterography and enteric ultrasonography are used to image Crohn's disease patients. Their diagnostic accuracy for presence, extent and activity of enteric Crohn's disease was ...compared.
To compare diagnostic accuracy, observer variability, acceptability, diagnostic impact and cost-effectiveness of magnetic resonance enterography and ultrasonography in newly diagnosed or relapsing Crohn's disease.
Prospective multicentre cohort study.
Eight NHS hospitals.
Consecutive participants aged ≥ 16 years, newly diagnosed with Crohn's disease or with established Crohn's disease and suspected relapse.
Magnetic resonance enterography and ultrasonography.
The primary outcome was per-participant sensitivity difference between magnetic resonance enterography and ultrasonography for small bowel Crohn's disease extent. Secondary outcomes included sensitivity and specificity for small bowel Crohn's disease and colonic Crohn's disease extent, and sensitivity and specificity for small bowel Crohn's disease and colonic Crohn's disease presence; identification of active disease; interobserver variation; participant acceptability; diagnostic impact; and cost-effectiveness.
Out of the 518 participants assessed, 335 entered the trial, with 51 excluded, giving a final cohort of 284 (133 and 151 in new diagnosis and suspected relapse cohorts, respectively). Across the whole cohort, for small bowel Crohn's disease extent, magnetic resonance enterography sensitivity 80%, 95% confidence interval (CI) 72% to 86% was significantly greater than ultrasonography sensitivity (70%, 95% CI 62% to 78%), with a 10% difference (95% CI 1% to 18%;
= 0.027). For small bowel Crohn's disease extent, magnetic resonance enterography specificity (95%, 95% CI 85% to 98%) was significantly greater than ultrasonography specificity (81%, 95% CI 64% to 91%), with a 14% difference (95% CI 1% to 27%). For small bowel Crohn's disease presence, magnetic resonance enterography sensitivity (97%, 95% CI 91% to 99%) was significantly greater than ultrasonography sensitivity (92%, 95% CI 84% to 96%), with a 5% difference (95% CI 1% to 9%). For small bowel Crohn's disease presence, magnetic resonance enterography specificity was 96% (95% CI 86% to 99%) and ultrasonography specificity was 84% (95% CI 65% to 94%), with a 12% difference (95% CI 0% to 25%). Test sensitivities for small bowel Crohn's disease presence and extent were similar in the two cohorts. For colonic Crohn's disease presence in newly diagnosed participants, ultrasonography sensitivity (67%, 95% CI 49% to 81%) was significantly greater than magnetic resonance enterography sensitivity (47%, 95% CI 31% to 64%), with a 20% difference (95% CI 1% to 39%). For active small bowel Crohn's disease, magnetic resonance enterography sensitivity (96%, 95% CI 92% to 99%) was significantly greater than ultrasonography sensitivity (90%, 95% CI 82% to 95%), with a 6% difference (95% CI 2% to 11%). There was some disagreement between readers for both tests. A total of 88% of participants rated magnetic resonance enterography as very or fairly acceptable, which is significantly lower than the percentage (99%) of participants who did so for ultrasonography. Therapeutic decisions based on magnetic resonance enterography alone and ultrasonography alone agreed with the final decision in 122 out of 158 (77%) cases and 124 out of 158 (78%) cases, respectively. There were no differences in costs or quality-adjusted life-years between tests.
Magnetic resonance enterography and ultrasonography scans were interpreted by practitioners blinded to clinical data (but not participant cohort), which does not reflect use in clinical practice.
Magnetic resonance enterography has higher accuracy for detecting the presence, extent and activity of small bowel Crohn's disease than ultrasonography does. Both tests have variable interobserver agreement and are broadly acceptable to participants, although ultrasonography produces less participant burden. Diagnostic impact and cost-effectiveness are similar. Recommendations for future work include investigation of the comparative utility of magnetic resonance enterography and ultrasonography for treatment response assessment and investigation of non-specific abdominal symptoms to confirm or refute Crohn's disease.
Current Controlled Trials ISRCTN03982913.
This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in
; Vol. 23, No. 42. See the NIHR Journals Library website for further project information.
Antibody-drug conjugates (ADCs) have begun to fulfil their promise as targeted cancer therapeutics with ten clinical approvals to date. As the field matures, much attention has focused upon the key ...factors required to produce safe and efficacious ADCs. Recently the role that linker-payload reagent design has on the properties of ADCs has been highlighted as an important consideration for developers. We have investigated the effect of incorporating hydrophilic macrocycles into reagent structures on the
in vitro
and
in vivo
behavior of ADCs.
Bis
-sulfone based disulfide rebridging reagents bearing Val-Cit-PABC-MMAE linker-payloads were synthesized with a panel of cyclodextrins and crown ethers integrated into their structures
via
a glutamic acid branching point. Brentuximab was selected as a model antibody and ten ADCs with a drug-to-antibody ratio (DAR) of 4 were prepared for biological evaluation.
In vitro
, the ADCs prepared showed broadly similar potency (range: 16–34 pM) and were comparable to Adcetris
®
(16 pM).
In vivo
, the cyclodextrin containing ADCs showed greater efficacy than Adcetris
®
and the most efficacious variant (incorporating a 3′-amino-α-cyclodextrin component) matched a 24-unit poly(ethylene glycol) (PEG) containing comparator. The ADCs bearing crown ethers also displayed enhanced
in vivo
efficacy compared to Adcetris
®
, the most active variant (containing a 1-aza-42-crown-14 macrocycle) was superior to an analogous ADC with a larger 24-unit PEG chain. In summary, we have demonstrated that hydrophilic macrocycles can be effectively incorporated into ADC reagent design and offer the potential for enhanced alternatives to established drug-linker architectures.
Magnetic resonance enterography (MRE) and ultrasound are used to image Crohn's disease, but their comparative accuracy for assessing disease extent and activity is not known with certainty. ...Therefore, we did a multicentre trial to address this issue.
We recruited patients from eight UK hospitals. Eligible patients were 16 years or older, with newly diagnosed Crohn's disease or with established disease and suspected relapse. Consecutive patients had MRE and ultrasound in addition to standard investigations. Discrepancy between MRE and ultrasound for the presence of small bowel disease triggered an additional investigation, if not already available. The primary outcome was difference in per-patient sensitivity for small bowel disease extent (correct identification and segmental localisation) against a construct reference standard (panel diagnosis). This trial is registered with the International Standard Randomised Controlled Trial, number ISRCTN03982913, and has been completed.
284 patients completed the trial (133 in the newly diagnosed group, 151 in the relapse group). Based on the reference standard, 233 (82%) patients had small bowel Crohn's disease. The sensitivity of MRE for small bowel disease extent (80% 95% CI 72–86) and presence (97% 91–99) were significantly greater than that of ultrasound (70% 62–78 for disease extent, 92% 84–96 for disease presence); a 10% (95% CI 1–18; p=0·027) difference for extent, and 5% (1–9; p=0·025) difference for presence. The specificity of MRE for small bowel disease extent (95% 85–98) was significantly greater than that of ultrasound (81% 64–91); a difference of 14% (1–27; p=0·039). The specificity for small bowel disease presence was 96% (95% CI 86–99) with MRE and 84% (65–94) with ultrasound (difference 12% 0–25; p=0·054). There were no serious adverse events.
Both MRE and ultrasound have high sensitivity for detecting small bowel disease presence and both are valid first-line investigations, and viable alternatives to ileocolonoscopy. However, in a national health service setting, MRE is generally the preferred radiological investigation when available because its sensitivity and specificity exceed ultrasound significantly.
National Institute of Health and Research Health Technology Assessment.
Background: Men who have sex with men (MSM) who use stimulants are at increased risk for HIV infection. Adherence to pre-exposure prophylaxis (PrEP) reduces the risk of HIV infection. We evaluated ...the efficacy of the individualized Texting for Adherence Building (iTAB) intervention for PrEP adherence compared to standard of care (SoC) among 119 MSM who use stimulants (cocaine, methamphetamine and/or other amphetamine) from the California Collaborative Treatment Group 595 randomized control trial.
Method: Three ordered levels of PrEP adherence (non-adherence, adequate adherence, and near-perfect adherence) were compared between intervention arms across study visits (weeks 12 and 48) using ordinal logistic regressions.
Results: The effect of intervention arm was not significant in the final model; however, there was a 38% decrease in odds (OR = 0.62, p=.023) of having near-perfect adherence (versus non-adherence or adequate adherence) at week 48 compared to week 12, indicating a significant effect of time. In a follow-up analysis examining week 48 only, logistic regression examining PrEP adherence showed that receiving iTAB (compared to SoC) trended toward higher odds of near-perfect adherence relative to adequate adherence (OR = 2.48, p=.061). Higher HIV knowledge resulted in higher odds (OR = 1.72, p=.020) of near-perfect adherence (versus non-adherence or adequate adherence).
Conclusion: HIV knowledge may influence PrEP adherence, and most notably, the iTAB intervention may support near-perfect adherence relative to adequate adherence.
The conjugation of monomethyl auristatin E (MMAE) to trastuzumab using a reduction bis-alkylation approach that is capable of rebridging reduced (native) antibody interchain disulfide bonds has been ...previously shown to produce a homogeneous and stable conjugate with a drug-to-antibody ratio (DAR) of 4 as the major product. Here, we further investigate the potency of the DAR 4 conjugates prepared by bis-alkylation by comparing to lower drug loaded variants to maleimide linker based conjugates possessing typical mixed DAR profiles. Serum stability, HER2 receptor binding, internalization, in vitro potency, and in vivo efficacy were all evaluated. Greater stability compared with maleimide conjugation was observed with no significant decrease in receptor/FcRn binding. A clear dose–response was obtained based on drug loading (DAR) with the DAR 4 conjugate showing the highest potency in vitro and a much higher efficacy in vivo compared with the lower DAR conjugates. Finally, the DAR 4 conjugate demonstrated superior efficacy compared to trastuzumab–DM1 (T-DM1, Kadcyla), as evaluated in a low HER2 expressing JIMT-1 xenograft model.
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