Can Brain Volume-Driven Characteristic Features Predict the Response of Alzheimer's Patients to Repetitive Transcranial Magnetic Stimulation? A Pilot Study.

This study is a post-hoc examination of baseline MRI data from a clinical trial investigating the efficacy of repetitive transcranial magnetic stimulation (rTMS) as a treatment for patients with mild-moderate Alzheimer's disease (AD). Herein, we investigated whether the analysis of baseline MRI data could predict the response of patients to rTMS treatment. Whole-brain T1-weighted MRI scans of 75 participants collected at baseline were analyzed. The analyses were run on the gray matter (GM) and white matter (WM) of the left and right dorsolateral prefrontal cortex (DLPFC), as that was the rTMS application site. The primary outcome measure was the Alzheimer's disease assessment scale-cognitive subscale (ADAS-Cog). The response to treatment was determined based on ADAS-Cog scores and secondary outcome measures. The analysis of covariance showed that responders to active treatment had a significantly lower baseline GM volume in the right DLPFC and a higher GM asymmetry index in the DLPFC region compared to those in non-responders. Logistic regression with a repeated five-fold cross-validated analysis using the MRI-driven features of the initial 75 participants provided a mean accuracy of 0.69 and an area under the receiver operating characteristic curve of 0.74 for separating responders and non-responders. The results suggest that GM volume or asymmetry in the target area of active rTMS treatment (DLPFC region in this study) may be a weak predictor of rTMS treatment efficacy. These results need more data to draw more robust conclusions.

Repetitive transcranial magnetic stimulation as a treatment for Alzheimer's disease: A randomized placebo-controlled double-blind clinical trial.

We report results of a large multisite double-blind randomized trial investigating the short and long-term efficacy of repetitive transcranial magnetic stimulation (rTMS) applied to patients with Alzheimer's disease (AD) at mild to moderate stages, in doses of either 2 or 4 weeks of treatment (5 days/week), whilst compared with 4 weeks of sham rTMS. Randomization to treatment group was stratified based on age and severity. The objectives of this study were to: 1) investigate the efficacy of active rTMS versus sham, 2) investigate the effect of dose of treatment (2 or 4 weeks), and 3) investigate the length of benefits from treatment. The rTMS pulses (20 â€‹Hz, 30 pulses/train, 25 trains, 10-s intertrain interval) were applied serially to the left and right dorsolateral prefrontal cortex using neuro-navigation. We compared the primary outcome measure's (ADAS-Cog) score changes from pre- to post-treatment, with assessments at baseline and 4 more times up to 6 months post-treatment. Data of 135 patients were analyzed. The mean total ADAS-Cog score at baseline did not differ between the active and sham treatment groups, nor across the three study sites. The overall results show significant cognitive improvement after treatment up to two months post-treatment with either sham or active coils. The results show both short and long-term benefits of active rTMS treatment but also show similar benefits for sham coil treatment of mild/moderate AD. We discuss this finding in the context of the existing literature on rTMS therapy for AD, as well as evidence of the sham coil's potential to induce a low-level current in the brain. TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT02908815.

Damage Tolerance of Superhydrophobic Coatings with Binary Cooperative Cells for Water Harvesting.

Multifunction superhydrophobic coatings that facilitate water harvesting are attractive for addressing the daunting water crisis, yet, they are caught in a double bind when their durability is considered, as durable coatings will require both tough micro-textures to survive concentrated stress and high-surface-energy chemistry to form chemical bonds within the matrix. To date, a universal bulk-phase coating that combines multifunctionality, ultra-durability, and fabrication feasibility remains challenging. Here, a binary cooperative cell design is reported that can solve the contradiction between the multifunctionality and durability requirements of superhydrophobic coatings. In this strategy, mechanochemically tailored cells with releasable nanoseeds are infused in the common matrix, which serves both as a versatile chemical bridge to achieve strong bonds within the coating building blocks, and as an instantaneous self-repairing generator to improve durability. Such a strategy significantly boosted the wear resistance and outdoor stability of the coatings by over 30-100 and 18 folds, respectively, compared with conventional coatings. The coating is applied to the sustainable application, i.e., enhancing the water collection efficiency by at least 1000% even after harsh abrasion. The strategy will broaden the vision in handling the dilemma properties among functional coatings and promote the application of superhydrophobic coatings in extreme environments.

Construction of a Bi2WO6/BiVO4 photocatalytic system for efficient visible light degradation of tetracycline drugs.

A Bi2WO6/BiVO4 composite photocatalytic material was synthesized by the hydrothermal method, and achieved the effective degradation of oxytetracycline (OTC) and tetracycline (TC) under visible light. The compositions, structures, chemical states and optoelectronic properties of Bi2WO6, BiVO4 and Bi2WO6/BiVO4 composites were characterized by systematic characterization. The results show that the existence of the heterojunction interface facilitates the separation of photogenerated carriers. Compared with the pure catalyst of Bi2WO6 and BiVO4, the Bi2WO6/BiVO4 composite material significantly improves the degradation efficiency of OTC and TC. The degradation rate is 6.22 and 3.02 times higher than that of Bi2WO6 and BiVO4, respectively. Through the free radical quenching experiments, it is known that photogenerated holes (h+) and superoxide anion free radicals (·O2 -) are the main active substances in the degradation of OTC. By analyzing the process of photocatalytic degradation of OTC, there are mainly six intermediates during the process. Their possible degradation pathways are also inferred in this paper.

Controllable CO2 Reduction or Hydrocarbon Oxidation Driven by Entire Solar via Silver Quantum Dots Direct Photocatalysis.

The current solar-chemical-industry based on semiconductor photocatalyst is impractical. Metal catalysts are extensively employed in thermal- and electro-catalysis industries, but unsuitable for direct-driven photocatalysis. Herein, silver quantum dots (Ag-QDs) are synthesized on support via an in situ photoreduction method, and in situ photocatalysis temperature programmed dynamics chemisorption desorption analyses are designed to demonstrate that Ag-QDs should be the actual photocatalytic sites. The surface plasmon resonance of Ag-QDs could harvests entire visible solar, and the plasmon-driven charge-transfer exhibits opposite directions at the interface when supports are different. Consequently, Ag-QDs could be alternatively regulated as oxidation or reduction active centers. Furthermore, Ag-QDs excite electron tunneling transfer with adsorbate, which does not generate high-energy free-radical intermediates. As a result, the efficiencies of hydrocarbon photooxidation and CO2 photoreduction are improved in several orders of magnitude. Evidently, the Ag-QDs direct photocatalytic technology greatly promotes solar-chemical-industry applications.

Uptake, Translocation, and Fate of Carcinogenic Aristolochic Acid in Typical Vegetables in Soil-Plant Systems.

When Aristolochia plants wilt and decay, aristolochic acids (AAs) are released into the soil, causing soil contamination. It has been demonstrated that aristolochic acid can be accumulated and enriched in crops through plant uptake. However, there is a lack of systematic studies on the migration and accumulation of AAs in a realistic simulated soil environment. In this study, Aristolochia herbal extracts were mixed with soil for growing three typical vegetables: lettuce, celery, and tomato. The contents of AAs in the above-mentioned plants were determined by an established highly sensitive LC-MS/MS method to study the migration and accumulation of AAs. We found that AAs in the soil can be transferred and accumulated in plants. AAs first entered the roots, which were more likely to accumulate AAs, and partially entered the above-ground parts. This further confirms that AAs can enter the food chain through plants and can have serious effects on human health. It was also shown that plants with vigorous growth and a large size absorbed AAs from the soil at a faster rate. The more AAs present in the soil, the more they accumulated in the plant.

Construction of a double heterojunction between graphite carbon nitride and anatase TiO2 with co-exposed (101) and (001) faces for enhanced photocatalytic degradation.

This study aimed to promote the separation of photogenerated carriers and improve the redox performance of graphite carbon nitride (g-C3N4) by synthesizing a double-heterojunction-structure photocatalyst, g-C3N4/(101)-(001)-TiO2, through the solvothermal method. The photocatalyst comprised a Z-system formed from g-C3N4 and the (101) plane of TiO2, as well as a surface heterojunction formed from the (101) and (001) planes of TiO2. The results showed that g-C3N4/(101)-(001)-TiO2 had strong photocatalytic activity and stable performance in the photodegradation of paracetamol. The active species ·O2 - and ·OH were found to play important roles in the photocatalytic degradation of paracetamol through a radical-quenching experiment. The charge-transfer mechanism was also described in detail. Overall, this work provided a new strategy for the Z-system heterojunction and opened up the application of this structure in the degradation of organic pollutants.

Subscribing to big data at scale.

Today, data is being actively generated by a variety of devices, services, and applications. Such data is important not only for the information that it contains, but also for its relationships to other data and to interested users. Most existing Big Data systems focus on passively answering queries from users, rather than actively collecting data, processing it, and serving it to users. To satisfy both passive and active requests at scale, application developers need either to heavily customize an existing passive Big Data system or to glue one together with systems like Streaming Engines and Pub-sub services. Either choice requires significant effort and incurs additional overhead. In this paper, we present the BAD (Big Active Data) system as an end-to-end, out-of-the-box solution for this challenge. It is designed to preserve the merits of passive Big Data systems and introduces new features for actively serving Big Data to users at scale. We show the design and implementation of the BAD system, demonstrate how BAD facilitates providing both passive and active data services, investigate the BAD system's performance at scale, and illustrate the complexities that would result from instead providing BAD-like services with a "glued" system.

Repeated Transcranial Magnetic Stimulation for Improving Cognition in Alzheimer Disease: Protocol for an Interim Analysis of a Randomized Controlled Trial.

BACKGROUND: Many clinical trials investigating treatment efficacy require an interim analysis. Recently we have been running a large, multisite, randomized, placebo-controlled, double-blind clinical trial investigating the effect of repetitive transcranial magnetic stimulation (rTMS) treatment for improving or stabilizing the cognition of patients diagnosed with Alzheimer disease. OBJECTIVE: The objectives of this paper are to report on recruitment, adherence, and adverse events (AEs) to date, and to describe in detail the protocol for interim analysis of the clinical trial data. The protocol will investigate whether the trial is likely to reach its objectives if continued to the planned maximum sample size. METHODS: The specific requirements of the analytic protocol are to (1) ensure the double-blind nature of the data while doing the analysis, (2) estimate the predictive probabilities of success (PPoSs), (3) estimate the numbers needed to treat, (4) re-estimate the initial required sample size. The initial estimate of sample size was 208. The interim analysis will be based on 150 patients who will be enrolled in the study and finish at least 8 weeks of the study. Our protocol for interim analysis, at the very first stage, is to determine the response rate for each participant to the treatment (either sham or active), while ensuring the double-blind nature of the data. The blinded data will be analyzed by a statistician to investigate the treatment efficacy. We will use Bayesian PPoS to predict the success rate and determine whether the study should continue. RESULTS: The enrollment has been slowed significantly due to the COVID-19 pandemic and lockdown. Nevertheless, so far 133 participants have been enrolled, while 22 of these have been withdrawn or dropped out for various reasons. In general, rTMS has been found tolerable with no serious AE. Only 2 patients dropped out of the study due to their intolerability to rTMS pulses. CONCLUSIONS: Overall, the study with the same protocol is going as expected with no serious AE or any major protocol deviation. TRIAL REGISTRATION: ClinicalTrials.gov NCT02908815; https://clinicaltrials.gov/ct2/show/NCT02908815. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/31183.

Repeated Transcranial Magnetic Stimulation for Improving Cognition in Patients With Alzheimer Disease: Protocol for a Randomized, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Alzheimer disease has no known cure. As existing pharmacologic interventions only modestly slow cognitive decline, there is a need for new treatments. Recent trials of repetitive transcranial magnetic stimulation (rTMS) have reported encouraging results for improving or stabilizing cognition in patients diagnosed with Alzheimer dementia. However, owing to small samples and lack of a well-controlled double-blind design, the results to date are inconclusive. This paper presents the protocol for a large placebo-controlled double-blind study designed with sufficient statistical rigor to measure the efficacy of rTMS treatment in patients with Alzheimer dementia. OBJECTIVE: The objectives are to (1) recruit and enroll up to 200 eligible participants, (2) estimate the difference in treatment effects between active treatment and sham treatment, (3) estimate the difference in treatment effects between two doses of rTMS applications, (4) estimate the duration of treatment effects among responders to active rTMS treatment, and (5) estimate the effect of dementia severity on treatment outcomes among patients receiving active rTMS treatment. METHODS: We have designed our study to be a double-blind, randomized, placebo-controlled clinical trial investigating the short- and long-term (up to 6 months) benefits of active rTMS treatment at two doses (10 sessions over 2 weeks and 20 sessions over 4 weeks) compared with sham rTMS treatment. The study will include patients aged ≥55 years who are diagnosed with Alzheimer disease at an early to moderate stage and have no history of seizures and no major depression. The primary outcome measure is the change in the Alzheimer Disease Assessment Scale-Cognitive Subscale score from pretreatment to posttreatment. Secondary outcomes are changes in performance on tests of frontal lobe functioning (Stroop test and verbal fluency), changes in neuropsychiatric symptoms (Neuropsychiatric Inventory Questionnaire), and changes in activities of daily living (Alzheimer Disease Co-operative Study-Activities of Daily Living Inventory). Tolerability of the intervention will be assessed using a modification of the Treatment Satisfaction Questionnaire for Medication. We assess participants at baseline and 3, 5, 8, 16, and 24 weeks after the intervention. RESULTS: As of November 1, 2020, we have screened 523 individuals, out of which 133 were eligible and have been enrolled. Out of the 133 individuals, 104 have completed the study. Moreover, as of November 1, 2020, there has been no serious adverse event. We anticipate that rTMS will considerably improve cognitive function, with effects lasting up to 3 months. Moreover, we expect rTMS to be a well-tolerated treatment with no serious side effect. CONCLUSIONS: This protocol design will allow to address both the rTMS active treatment dose and its short- and long-term effects compared with sham treatment in large samples. TRIAL REGISTRATION: ClinicalTrials.gov NCT02908815; https://clinicaltrials.gov/ct2/show/NCT02908815. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/25144.

Anatase TiO2 with Co-exposed (001) and (101) Surface-Based Photocatalytic Materials for Energy Conversion and Environmental Purification.

Anatase TiO2 with co-exposed (001) and (101) surfaces [(001)-(101)-TiO2 ], as a semiconductor photocatalyst in crystal plane control engineering, has become a research hotspot in environmental purification and energy conversion due to its strong physicochemical stability, non-toxic and harmless, and low production cost. This review briefly introduces the basic principles and influencing factors of [(001)-(101)-TiO2 ]. On this basis, the effect of heterostructures formed by different materials and modification methods on its photocatalytic activity are elaborated in detail. Mainly formed heterostructures mentioned in this review include oxygen vacancy/Ti3+ -[(001)-(101)-TiO2 ] heterostructures, noble metal-[(001)-(101)-TiO2 ] heterostructures, metal sulfide-[(001)-(101)-TiO2 ] heterostructures, metal oxide-[(001)-(101)-TiO2 ] heterostructures and carbon material-[(001)-(101)-TiO2 ] heterostructures. The light absorption range and charge separation mechanism of (001)-(101)-TiO2 after modification are discussed. Moreover, the application of photocatalytic redox reaction in simulating photosynthesis to prepare new energy (hydrogen evolution and CO2 reduction), environmental purification and sterilization is introduced in detail. Finally, various measures of designing (001)-(101)-TiO2 nanostructures for further applications in energy production and environmental remediation are discussed.

Effects of Particle Size on the Structure and Photocatalytic Performance by Alkali-Treated TiO2.

Particle size of nanomaterials has significant impact on their photocatalyst properties. In this paper, TiO2 nanoparticles with different crystalline sizes were prepared by adjusting the alkali-hydrothermal time (0-48 h). An annealing in N2 atmosphere after hydrothermal treatment caused TiO2 reduction and created defects, resulting in the visible light photocatalytic activity. The evolution of physicochemical properties along with the increase of hydrothermal time at a low alkali concentration has been revealed. Compared with other TiO2 samples, TiO2-24 showed higher photocatalytic activity toward degrading Rhodamine B and Sulfadiazine under visible light. The radical trapping and ESR experiments revealed that O2•- is the main reactive specie in TiO2-24. Large specific surface areas and rapid transfer of photogenerated electrons are responsible for enhancing photocatalytic activity. The above findings clearly demonstrate that particle size and surface oxygen defects can be regulated by alkali-hydrothermal method. This research will deepen the understanding of particle size on the nanomaterials performance and provide new ideas for designing efficient photocatalysts.

QuEChERS pretreatment combined with high-performance liquid chromatography-tandem mass spectrometry for determination of aristolochic acids I and II in Chinese herbal patent medicines.

Aristolochic acid I and II (AA I and II), a kind of nephrotoxic and carcinogenic compound, are widely added in Chinese herbal patent medicines though they have been banned due to their toxicity. However, the traditional sample pre-treatment combined with the LC-MS analysis system is not effective to determine AAs in such complicated patent medicines. The QuEChERS pretreatment method possesses some merits such as being quick and effective. In this work, the modified QuEChERS method was first used to determine AA I and II in Chinese herbal patent medicines combined with the HPLC-MS/MS analysis system. Extraction and removal of target analytes from powder, tablet, and capsule samples were conducted using the modified QuEChERS pretreatment. The liquid extracts of Chinese herbal patent medicines could be analyzed directly. The method optimization results show that average recoveries ranged from 96.6% to 110.3% with relative standard deviations ranging from 4.2% to 13.0%. The quantization limits of the three selected matrices are estimated as follows (AA I/II): 2.8/6.5 ng mL-l in liquid herbal extract, 6.5/12.5 ng g-1 in tablets, and 22.1/42.1 ng g-1 in capsules. This method was conducted to investigate the presence of AAs, which are a type of nephrotoxic and carcinogenic carboxylic acid, in 30 herbal products sold through the Internet in China. AA I and II were detected in 53% and 20%, respectively, of tested samples.

Correction: QuEChERS pretreatment combined with high-performance liquid chromatography-tandem mass spectrometry for determination of aristolochic acids I and II in Chinese herbal patent medicines.

[This corrects the article DOI: 10.1039/D0RA03200J.].

Effective Magnetic Field Regulation of the Radical Pair Spin States in Electrocatalytic CO2 Reduction.

Regulation of the radical pair spin states allows effective optimization of the electrocatalytic CO2 reduction reaction. This study for the first time reports an experimental observation of significantly boosting the catalytic activity of tin nanoparticle catalysts by an external magnetic field for electrocatalytic CO2 reduction to formate/formic acid. We reveal that enhancing the amount of singlet radical pairs via magnetic field-facilitated triplet → singlet spin evolution can significantly increase the catalytic activity toward an efficient overall electrochemical CO2 reduction reaction. When a common Sn nanoparticle electrode was used as an example, in a constant applied magnetic field (about 0.9 T), the yield of formic acid can be nearly doubled compared to that of zero magnetic field. This finding suggests the merits of radical pair spin states in the electron-transfer process and paves the way toward high formate production in electrocatalytic reduction of CO2.

Engineering the Dimensional Interface of BiVO4-2D Reduced Graphene Oxide (RGO) Nanocomposite for Enhanced Visible Light Photocatalytic Performance.

Graphene as a two-dimensional (2D) nanoplatform is beneficial for assembling a 2D heterojunction photocatalytic system to promote electron transfer in semiconductor composites. Here a BiVO4 nanosheets/reduced graphene oxide (RGO) based 2D-2D heterojunction photocatalytic system as well as 0D-2D BiVO4 nanoparticles/RGO and 1D-2D BiVO4 nanotubes/RGO nanocomposites are fabricated by a feasible solvothermal process. During the synthesis; the growth of BiVO4 and the intimate interfacial contact between BiVO4 and RGO occur simultaneously. Compared to 0D-2D and 1D-2D heterojunctions, the resulting 2D-2D BiVO4 nanosheets/RGO composites yield superior chemical coupling; leading to exhibit higher photocatalytic activity toward the degradation of acetaminophen under visible light irradiation. Photoluminescence (PL) and photocurrent experiments revealed that the apparent electron transfer rate in 2D-2D BiVO4 nanosheets/RGO composites is faster than that in 0D-2D BiVO4 nanoparticles/RGO composites. The experimental findings presented here clearly demonstrate that the 2D-2D heterojunction interface can highlight the optoelectronic coupling between nanomaterials and promote the electron-hole separation. This study will motivate new developments in dimensionality factors on designing the heterojunction photocatalysts and promote their photodegradation photocatalytic application in environmental issues.

A Pilot Randomised Double-Blind Study of the Tolerability and efficacy of repetitive Transcranial Magnetic Stimulation on Persistent Post-Concussion Syndrome.

This study investigates the effect of Repetitive Transcranial Magnetic Stimulation (rTMS) on persistent post-concussion syndrome (PCS). The study design was a randomized (coin toss), placebo controlled, and double-blind study. Thirty-seven participants with PCS were assessed for eligibility; 22 were randomised and 18 completed the study requirements. Half the participants with PCS were given an Active rTMS intervention and the other half given Sham rTMS over 3 weeks. Follow ups were at the end of treatment and at 30 and 60 days. The primary outcome measure was the Rivermead Post-Concussion Symptoms Questionnaire (RPQ3 & RPQ13). The results indicate participants with more recent injuries (<12 month), who received Active rTMS, showed significant improvements compared to those of: 1) the same subgroup who received Sham, and 2) those with a longer duration of injury (>14 months) who received Active rTMS. This improvement predominantly manifested in RPQ13 in the follow up periods 1 and 2 months after the intervention (RPQ13 change (mean ± SD): at 1 month, Active = -21.8 ± 6.6, Sham = -2.2 ± 9.8; at 2 months, Active = -21.2 ± 5.3, Sham = -5.4 ± 13.7). No improvement was found in the subgroup with longer duration injuries. The results support rTMS as a tolerable and potentially effective treatment option for individuals with a recent (<1 year) concussion.

Low-Temperature Stable α-Phase Inorganic Perovskite Compounds via Crystal Cross-Linking.

Inorganic perovskite compounds hold promise to improve the stability of perovskite solar cells (PSCs). However, the phase instability and high annealing temperature process of these metastable structural polymorphs such as α-phase CsPbI3- xBr x hinder their further development. Herein, we demonstrated the successful reduction of temperature from 250 to 100 °C during the growth of stable and high-crystallinity α-phase CsPbI2Br via crystal cross-linking. 4-Aminobenzoic acid (ABA) was used as a nonvolatile additive with slight solubility in water to bridge the adjacent CsPbI2Br to form a grain-interconnected film. The interaction between ABA and perovskite grains leads to the growth of highly crystalline perovskite films. The optimized PSC based on ABA-incorporated CsPbI2Br using a TiO2/Al2O3/NiO/carbon architecture exhibits an efficiency of 8.44%. More importantly, the additive enables significant improvement of phase stability against moisture. The good performance highlights the chemical modification via cross-linking to achieve efficient and stable inorganic perovskite devices.

Beetle-like droplet-jumping superamphiphobic coatings for enhancing fog collection of sheet arrays.

Fog collection from atmosphere is an effective way to solve the water resource crisis in arid or semi-arid areas. Inspired by the bumpy surface of the desert beetle, this work provides a beetle-like superamphiphobic coating by adding silicon carbide particles to nano-SiO2 superamphiphobic coating in proportion, which shows excellent superamphiphobic performance, high nucleation rate, efficient drop removal efficiency and recommendable fog collection effect. In this work, drop removal is facilitated by the collisions of water droplets between the array sheets, and when the as-prepared samples are placed parallel to each other and with a space of ∼2 mm, the jumping drop collisions between two sample surfaces could promote the departure of droplets, and the water collection rate of the collision surface increased by ∼217% compared to that of the non-collision surface, which provides a new idea to promote water droplet removal. This work findings are instrumental in water collection and have wide application prospects in desalination, heat transfer, anti-fogging and other fields.

Considerations for adaptive design in pediatric clinical trials: study protocol for a systematic review, mixed-methods study, and integrated knowledge translation plan.

BACKGROUND: Although children have historically been excluded from clinical trials (CTs), many require medicines tested and approved in CTs, forcing health care providers to treat their pediatric patients based on extrapolated data. Unfortunately, traditional randomized CTs can be slow and resource-intensive, and they often require multi-center collaboration. However, an adaptive design (AD) framework for CTs could be used to increase the efficiency of pediatric CTs by incorporating prospectively planned modifications to CT methods without undermining the integrity or validity of the study. There are many possible adaptations, but each will have ethical, logistical, and statistical implications. It remains unclear which adaptations (or combinations thereof) will lead to real-world improvements in pediatric CT efficiency. This study will identify, evaluate, and synthesize the various regulatory, ethical, logistical, and statistical considerations and emerging issues of AD in CTs that could be used to evaluate the use of drugs in children. METHODS/DESIGN: Following the development of a peer-reviewed search strategy, a systematic review on AD in CTs will be conducted. Data on regulatory, ethical, logistic, and statistical considerations as well as population and trial design characteristics will be synthesized. A mixed-methods study including surveys and focus groups with regulators, research ethics board members, biostatisticians, clinicians, and scientists, as well as representatives from patient groups and the public will evaluate the opportunities and challenges in applying AD in trials enrolling children and propose recommendations on best practices. DISCUSSION: This study will deliver practical recommendations on the use of AD in pediatric CTs. Collaboration and consultation with national and global partners will ensure that our results meet the needs of researchers, regulators, and patients, both locally and globally, and that they remain current and relevant by engaging a wide variety of stakeholders. Overall, this research will enrich the knowledge base regarding if, how, and when AD can be used to answer research questions with fewer resources while still meeting the highest ethical standards and regulatory requirements for CTs. In turn, this will result in increased high-quality clinical research needed by health care providers so they have access to appropriate, population-specific evidence regarding the safe and effective use of medicines in children.