Mechanochemical Approaches to Fundamental Studies in Soft-Matter Physics.

Stretching a segment of a polymer beyond its contour length makes its (primarily backbone) bonds more dissociatively labile, which enables polymer mechanochemistry. Integrating some backbone bonds into suitably designed molecular moieties yields mechanistically and kinetically diverse chemistry, which is becoming increasingly exploitable. Examples include, most prominently, attempts to improve mechanical properties of bulk polymers, as well as prospective applications in drug delivery and synthesis. This review aims to highlight an emerging effort to apply the concepts and experimental tools of mechanochemistry to fundamental physical questions in soft matter. A succinct summary of the state-of-the-knowledge of the field, with emphasis on foundational concepts and generalizable observations, is followed by analysis of 3 recent examples of mechanochemistry yielding molecular-level details of elastomer failure, macromolecular chain dynamics in elongational flows and kinetic allostery. We conclude with reasons to assume that the highlighted approaches are generalizable to a broader range of physical problems than considered to date.

Coumarin Dimer Is an Effective Photomechanochemical AND Gate for Small-Molecule Release.

Stimulus-responsive gating of chemical reactions is of considerable practical and conceptual interest. For example, photocleavable protective groups and gating mechanophores allow the kinetics of purely thermally activated reactions to be controlled optically or by mechanical load by inducing the release of small-molecule reactants. Such release only in response to a sequential application of both stimuli (photomechanochemical gating) has not been demonstrated despite its unique expected benefits. Here, we describe computational and experimental evidence that coumarin dimers are highly promising moieties for realizing photomechanochemical control of small-molecule release. Such dimers are transparent and photochemically inert at wavelengths >300 nm but can be made to dissociate rapidly under tensile force. The resulting coumarins are mechanochemically and thermally stable, but rapidly release their payload upon irradiation. Our DFT calculations reveal that both strain-free and mechanochemical kinetics of dimer dissociation are highly tunable over an unusually broad range of rates by simple substitution. In head-to-head dimers, the phenyl groups act as molecular levers to allow systematic and predictable variation in the force sensitivity of the dissociation barriers by choice of the pulling axis. As a proof-of-concept, we synthesized and characterized the reactivity of one such dimer for photomechanochemically controlled release of aniline and its application for controlling bulk gelation.

Sacrificial Mechanical Bond is as Effective as a Sacrificial Covalent Bond in Increasing Cross-Linked Polymer Toughness.

Sacrificial chemical bonds have been used effectively to increase the toughness of elastomers because such bonds dissociate at forces significantly below the fracture limit of the primary load-bearing bonds, thereby dissipating local stress. This approach owes much of its success to the ability to adjust the threshold force at which the sacrificial bonds fail at the desired rate, for example, by selecting either covalent or noncovalent sacrificial bonds. Here, we report experimental and computational evidence that a mechanical bond, responsible for the structural integrity of a rotaxane or a catenane, increases the elastomer's fracture strain, stress, and energy as much as a covalent bond of comparable mechanochemical dissociation kinetics. We synthesized and studied 6 polyacrylates cross-linked by either difluorenylsuccinonitrile (DFSN), which is an established sacrificial mechanochromic moiety; a [2]rotaxane, whose stopper allows its wheel to dethread on the same subsecond time scale as DFSN dissociates when either is under tensile force of 1.5-2 nN; a structurally homologous [2]rotaxane with a much bulkier stopper that is stable at force >5.5 nN; similarly stoppered [3]rotaxanes containing DFSN in their axles; and a control polymer with aliphatic nonsacrificial cross-links. Our data suggest that mechanochemical dethreading of a rotaxane without failure of any covalent bonds may be an important, hitherto unrecognized, contributor to the toughness of some rotaxane-cross-linked polymers and that sacrificial mechanical bonds provide a mechanism to control material fracture behavior independently of the mechanochemical response of the covalent networks, due to their distinct relationships between structure and mechanochemical reactivity.

Selective ortho-C-H Activation in Arenes without Functional Groups.

Aromatic C-H activation in alkylarenes is a key step for the synthesis of functionalized organic molecules from simple hydrocarbon precursors. Known examples of such C-H activations often yield mixtures of products resulting from activation of the least hindered C-H bonds. Here we report highly selective ortho-C-H activation in alkylarenes by simple iridium complexes. We demonstrate that the capacity of the alkyl substituent to override the typical preference of metal-mediated C-H activation for the least hindered aromatic C-H bonds results from transient insertion of iridium into the benzylic C-H bond. This enables fast iridium insertion into the ortho-C-H bond, followed by regeneration of the benzylic C-H bond by reductive elimination. Bulkier alkyl substituents increase the ortho selectivity. The described chemistry represents a conceptually new alternative to existing approaches for aromatic C-H bond activation.

Advances in AAC intervention: some contributions related to applied behavior analysis.

This article extends Dr. Bob Remington's call for collaborations between those supporting behavioral approaches and those supporting more natural developmental approaches to beginning communication intervention. This article expands areas previously discussed by Dr. Remington. Topics that are addressed include pivotal behaviors that may facilitate communication acquisition, matching law and response efficiency, generalization, maintenance, and the related topics of general case instruction (which involves an understanding of stimulus and response classes). These topics reflect contemporary areas of research that could be better integrated into translational research and have not been extensively integrated into augmentative and alternative communication (AAC) practice. Dr. Remington's article discussed the value of behavioral approaches and corresponding methodology to AAC researchers and practitioners. We agree and discuss the need for greater interaction among proponents of varying approaches to intervention.

A Bivalent Meningococcal B Vaccine in Adolescents and Young Adults.

BACKGROUND: MenB-FHbp is a licensed meningococcal B vaccine targeting factor H-binding protein. Two phase 3 studies assessed the safety of the vaccine and its immunogenicity against diverse strains of group B meningococcus. METHODS: We randomly assigned 3596 adolescents (10 to 18 years of age) to receive MenB-FHbp or hepatitis A virus vaccine and saline and assigned 3304 young adults (18 to 25 years of age) to receive MenB-FHbp or saline at baseline, 2 months, and 6 months. Immunogenicity was assessed in serum bactericidal assays that included human complement (hSBAs). We used 14 meningococcal B test strains that expressed vaccine-heterologous factor H-binding proteins representative of meningococcal B epidemiologic diversity; an hSBA titer of at least 1:4 is the accepted correlate of protection. The five primary end points were the proportion of participants who had an increase in their hSBA titer for each of 4 primary strains by a factor of 4 or more and the proportion of those who had an hSBA titer at least as high as the lower limit of quantitation (1:8 or 1:16) for all 4 strains combined after dose 3. We also assessed the hSBA responses to the primary strains after dose 2; hSBA responses to the 10 additional strains after doses 2 and 3 were assessed in a subgroup of participants only. Safety was assessed in participants who received at least one dose. RESULTS: In the modified intention-to-treat population, the percentage of adolescents who had an increase in the hSBA titer by a factor of 4 or more against each primary strain ranged from 56.0 to 85.3% after dose 2 and from 78.8 to 90.2% after dose 3; the percentages of young adults ranged from 54.6 to 85.6% and 78.9 to 89.7%, after doses 2 and 3, respectively. Composite responses after doses 2 and 3 in adolescents were 53.7% and 82.7%, respectively, and those in young adults were 63.3% and 84.5%, respectively. Responses to the 4 primary strains were predictive of responses to the 10 additional strains. Most of those who received MenB-FHbp reported mild or moderate pain at the vaccination site. CONCLUSIONS: MenB-FHbp elicited bactericidal responses against diverse meningococcal B strains after doses 2 and 3 and was associated with more reactions at the injection site than the hepatitis A virus vaccine and saline. (Funded by Pfizer; ClinicalTrials.gov numbers, NCT01830855 and NCT01352845 ).

Immune activation by DNA damage predicts response to chemotherapy and survival in oesophageal adenocarcinoma.

OBJECTIVE: Current strategies to guide selection of neoadjuvant therapy in oesophageal adenocarcinoma (OAC) are inadequate. We assessed the ability of a DNA damage immune response (DDIR) assay to predict response following neoadjuvant chemotherapy in OAC. DESIGN: Transcriptional profiling of 273 formalin-fixed paraffin-embedded prechemotherapy endoscopic OAC biopsies was performed. All patients were treated with platinum-based neoadjuvant chemotherapy and resection between 2003 and 2014 at four centres in the Oesophageal Cancer Clinical and Molecular Stratification consortium. CD8 and programmed death ligand 1 (PD-L1) immunohistochemical staining was assessed in matched resection specimens from 126 cases. Kaplan-Meier and Cox proportional hazards regression analysis were applied according to DDIR status for recurrence-free survival (RFS) and overall survival (OS). RESULTS: A total of 66 OAC samples (24%) were DDIR positive with the remaining 207 samples (76%) being DDIR negative. DDIR assay positivity was associated with improved RFS (HR: 0.61; 95% CI 0.38 to 0.98; p=0.042) and OS (HR: 0.52; 95% CI 0.31 to 0.88; p=0.015) following multivariate analysis. DDIR-positive patients had a higher pathological response rate (p=0.033), lower nodal burden (p=0.026) and reduced circumferential margin involvement (p=0.007). No difference in OS was observed according to DDIR status in an independent surgery-alone dataset.DDIR-positive OAC tumours were also associated with the presence of CD8+ lymphocytes (intratumoural: p<0.001; stromal: p=0.026) as well as PD-L1 expression (intratumoural: p=0.047; stromal: p=0.025). CONCLUSION: The DDIR assay is strongly predictive of benefit from DNA-damaging neoadjuvant chemotherapy followed by surgical resection and is associated with a proinflammatory microenvironment in OAC.

Carbon nanohorn modified platinum electrodes for improved immobilisation of enzyme in the design of glutamate biosensors.

Electrochemical enzymatic biosensors are the subject of research due to their potential for in vivo monitoring of glutamate, which is a key neurotransmitter whose concentration is related to healthy brain function. This study reports the use of biocompatible oxidised carbon nanohorns (o-CNH) with a high surface area, to enhance the immobilization of glutamate oxidase (GluOx) for improved biosensor performance. Two families of biosensors were designed to interact with the anionic GluOx. Family-1 consists of covalently functionalised o-CNH possessing hydrazide (HYZ) and amine (PEG-NH2) terminated surfaces and Family-2 comprised non-covalently functionalised o-CNH with different loadings of polyethyleneimine (PEI) to form a cationic hybrid. Amperometric detection of H2O2 formed by enzymatic oxidation of glutamate revealed a good performance from all designs with the most improved performance by the PEI hybrid systems. The best response was from a o-CNH : PEI ratio of 1 : 10 mg mL-1, which yielded a glutamate calibration plateau, JMAX, of 55 ± 9 µA cm-2 and sensitivity of 111 ± 34 µA mM-1 cm-2. The low KM of 0.31 ± 0.05 mM indicated the retention of the enzyme function, and a limit of detection of 0.02 ± 0.004 µM and a response time of 0.88 ± 0.13 s was determined. The results demonstrate the high sensitivity of these biosensors and their potential for future use for the detection of glutamate in vivo.

Characterization of Biosensors Based on Recombinant Glutamate Oxidase: Comparison of Crosslinking Agents in Terms of Enzyme Loading and Efficiency Parameters.

Amperometric l-glutamate (Glu) biosensors, based on both wild-type and a recombinant form of l-glutamate oxidase (GluOx), were designed and characterized in terms of enzyme-kinetic, sensitivity and stability parameters in attempts to fabricate a real-time Glu monitoring device suitable for future long-term detection of this amino acid in biological and other complex media. A comparison of the enzyme from these two sources showed that they were similar in terms of biosensor performance. Optimization of the loading of the polycationic stabilization agent, polyethyleneimine (PEI), was established before investigating a range of crosslinking agents under different conditions: glutaraldehyde (GA), polyethylene glycol (PEG), and polyethylene glycol diglycidyl ether (PEGDE). Whereas PEI-free biosensor designs lost most of their meager Glu sensitivity after one or two days, configurations with a 2:5 ratio of dip-evaporation applications of PEI(1%):GluOx(400 U/mL) displayed a 20-fold increase in their initial sensitivity, and a decay half-life extended to 10 days. All the crosslinkers studied had no effect on initial Glu sensitivity, but enhanced biosensor stability, provided the crosslinking procedure was carried out under well-defined conditions. The resulting biosensor design based on the recombinant enzyme deposited on a permselective layer of poly-(ortho-phenylenediamine), PoPD/PEI2/GluOx5/PEGDE, displayed good sensitivity (LOD < 0.2 µM), response time (t90% < 1 s) and stability over a 90-day period, making it an attractive candidate for future long-term monitoring of Glu concentration dynamics in complex media.

Multiplicity in confirmatory clinical trials: a case study with discussion from a JSM panel.

An invited panel session was conducted in the 2012 Joint Statistical Meetings, San Diego, California, USA, to stimulate the discussion on multiplicity issues in confirmatory clinical trials for drug development. A total of 11 expert panel members were invited and 9 participated. Prior to the session, a case study was previously provided to the panel members to facilitate the discussion, focusing on the key components of the study design and multiplicity. The Phase 3 development program for this new experimental treatment was based on a single randomized controlled trial alone. Each panelist was asked to clarify if he or she responded as if he or she were a pharmaceutical drug sponsor, an academic panelist or a health regulatory scientist.

Electropolymerized phenol derivatives as permselective polymers for biosensor applications.

Amperometric biosensors are often coated with a polymeric permselective film to avoid electroactive interference by reducing agents present in the target medium. Phenylenediamine and phenol monomers are commonly used to form these permselective films in the design of microsensors and biosensors. This paper aims to evaluate the permselectivity, stability and lifetime of polymers electrosynthesized using either constant potential amperometry (CPA) or cyclic voltammetry (CV) from naturally occurring phenylpropanoids in monomeric and dimeric forms (eugenol, isoeugenol, dehydrodieugenol and magnolol). Sensors were characterized by scanning electron microscopy and permselectivity analysis. Magnolol formed an electro-deposited polymer with a more defined three-dimensional texture in comparison with the other films. The phenol-derived films showed different permselectivity towards H2O2 over ascorbic acid and dopamine, likely to be related to the thickness and compactness of the polymer. The CV-derived films had a better permselectivity compared to the CPA-corresponding polymers. Based on these results, the permselectivity, stability and lifetime of a biosensor for glucose were studied when a magnolol coating was electro-deposited. The structural principles governing the permselectivity of the magnolol-derived film are suggested to be mainly related to the conformational flexibility of this monomer. Newly designed biosensors, coated with electropolymerized natural phenol derivatives, may represent promising analytical devices for different application fields.

Simultaneous telemetric monitoring of brain glucose and lactate and motion in freely moving rats.

A new telemetry system for simultaneous detection of extracellular brain glucose and lactate and motion is presented. The device consists of dual-channel, single-supply miniature potentiostat-I/V converter, a microcontroller unit, a signal transmitter, and a miniaturized microvibration sensor. Although based on simple and inexpensive components, the biotelemetry device has been used for accurate transduction of the anodic oxidation currents generated on the surface of implanted glucose and lactate biosensors and animal microvibrations. The device was characterized and validated in vitro before in vivo experiments. The biosensors were implanted in the striatum of freely moving animals and the biotelemetric device was fixed to the animal's head. Physiological and pharmacological stimulations were given in order to induce striatal neural activation and to modify the motor behavior in awake, untethered animals.

Further in-vitro characterization of an implantable biosensor for ethanol monitoring in the brain.

Ethyl alcohol may be considered one of the most widespread central nervous system (CNS) depressants in Western countries. Because of its toxicological and neurobiological implications, the detection of ethanol in brain extracellular fluid (ECF) is of great importance. In a previous study, we described the development and characterization of an implantable biosensor successfully used for the real-time detection of ethanol in the brain of freely-moving rats. The implanted biosensor, integrated in a low-cost telemetry system, was demonstrated to be a reliable device for the short-time monitoring of exogenous ethanol in brain ECF. In this paper we describe a further in-vitro characterization of the above-mentioned biosensor in terms of oxygen, pH and temperature dependence in order to complete its validation. With the aim of enhancing ethanol biosensor performance, different enzyme loadings were investigated in terms of apparent ethanol Michaelis-Menten kinetic parameters, viz. IMAX, KM and linear region slope, as well as ascorbic acid interference shielding. The responses of biosensors were studied over a period of 28 days. The overall findings of the present study confirm the original biosensor configuration to be the best of those investigated for in-vivo applications up to one week after implantation.

Experimental quantitation of molecular conditions responsible for flow-induced polymer mechanochemistry.

Fragmentation of macromolecular solutes in rapid flows is of considerable fundamental and practical importance. The sequence of molecular events preceding chain fracture is poorly understood, because such events cannot be visualized directly but must be inferred from changes in the bulk composition of the flowing solution. Here we describe how analysis of same-chain competition between fracture of a polystyrene chain and isomerization of a chromophore embedded in its backbone yields detailed characterization of the distribution of molecular geometries of mechanochemically reacting chains in sonicated solutions. In our experiments the overstretched (mechanically loaded) chain segment grew and drifted along the backbone on the same timescale as, and in competition with, the mechanochemical reactions. Consequently, only <30% of the backbone of a fragmenting chain is overstretched, with both the maximum force and the maximum reaction probabilities located away from the chain centre. We argue that quantifying intrachain competition is likely to be mechanistically informative for any flow fast enough to fracture polymer chains.

Allosteric control of olefin isomerization kinetics via remote metal binding and its mechanochemical analysis.

Allosteric control of reaction thermodynamics is well understood, but the mechanisms by which changes in local geometries of receptor sites lower activation reaction barriers in electronically uncoupled, remote reaction moieties remain relatively unexplored. Here we report a molecular scaffold in which the rate of thermal E-to-Z isomerization of an alkene increases by a factor of as much as 104 in response to fast binding of a metal ion to a remote receptor site. A mechanochemical model of the olefin coupled to a compressive harmonic spring reproduces the observed acceleration quantitatively, adding the studied isomerization to the very few reactions demonstrated to be sensitive to extrinsic compressive force. The work validates experimentally the generalization of mechanochemical kinetics to compressive loads and demonstrates that the formalism of force-coupled reactivity offers a productive framework for the quantitative analysis of the molecular basis of allosteric control of reaction kinetics. Important differences in the effects of compressive vs. tensile force on the kinetic stabilities of molecules are discussed.

An obscure cause of gastrointestinal bleeding: Recurrent duodenal variceal hemorrhage treated with intramuscular octreotide in the absence of portal hypertension.

Duodenal varices (DVs) are ectopic gastrointestinal varices (ECVs) associated with portal hypertension (PH). We present the case of an 82-year-old woman who presented with symptomatic anemia secondary to DV hemorrhage diagnosed on oesophagogastroduodenoscopy. This lesion was treated with endoscopic adrenaline injection and clip application. The patient re-presented on multiple occasions with bleeding recurrence localized to the duodenum, which was managed with intramuscular octreotide and oral beta-blockade resulting in sustained remission of bleeding. This case highlights a rare cause of upper gastrointestinal hemorrhage and highlights the value of somatostatin analogues for conservative treatment of DVs.

Delabeling, safety, and impact of ß-lactam allergy testing: A systematic review.

Background: To improve ß-lactam delabeling outcomes, we need to understand current practice and the evidence base regarding its outcomes, safety, and impact. Objectives: We sought to assess the existing published evidence reporting on the effectiveness of penicillin allergy testing and delabeling. Methods: We conducted a systematic review of studies reporting ß-lactam delabeling practices and outcomes after testing, including ß-lactam use and patient understanding of the delabeling result. Searches of the PubMed, Scopus, and Embase databases; clinical trial registries; and websites of professional organizations were conducted. Data were extracted from the included studies in duplicate, with a third extraction if discrepancies remained. Results: We included 284 publications (covering 98,316 participants); 173 were prospective studies, with no randomized controlled trials. The overall study quality was low. In all, 95.6% of individuals who underwent provocation testing were delabeled. Factors associated with successful delabeling could not be determined because of significant heterogeneity between studies. Anaphylaxis due to testing occurred in 0.3% of participants (95 of 31,667). Subjects who did not undergo skin testing (6,980 patients in 31 studies) before challenge had higher rates of provocation test positivity (8.8% vs 4.1% [P < .0001]) and anaphylaxis (15.9% vs 2.7% [P < .0001]) than those subjects who underwent skin testing (51,607 patients in 177 studies). Six studies (2.1%) followed patients after testing to assess their adherence to prescribing recommendations. In all, 136 participants (20.6%) were actively avoiding ß-lactams despite delabeling. Conclusions: The available data suggest that penicillin allergy testing is safe and effective in delabeling most individuals, but the evidence base is incomplete and more work is required to assess the role of skin testing and the impact that delabeling is having on prescribing habits.

Teaching argument writing in math class: challenges and solutions to improve the performance of 4th and 5th graders with disabilities.

Incorporating argument writing as a learning activity has been found to increase students' mathematics performance. However, teachers report receiving little to no preservice or inservice preparation to use writing to support students' learning. This is especially concerning for special education teachers who provide highly specialized mathematics instruction (i.e., Tier 3) to students with mathematics disabilities (MLD). The purpose of this study was to examine the effectiveness of teachers providing content-focused open-ended questioning strategies, which included both argument writing and foundational fraction content, using Practice-Based Professional Development (PBPD) and Self-Regulated Strategy Development (SRSD) for implementing a writing-to-learn strategy called FACT-R2C2. We report the relative number of higher-order mathematical content questions that teachers asked during instruction, from among three different-level question types: Level 1: yes/no questions focused on the mathematics content; Level 2: one-word responses focused on the mathematics content; and Level 3: higher-order open-ended responses centered around four mathematical practices from the Common Core State Standards for Mathematics. Within a well-controlled single-case multiple-baseline design, seven special education teachers were randomly assigned to each PBPD + FACT-R2C2 intervention tier. Results indicated that: (1) teachers' relative use of Level 3 questions increased following the introduction of the FACT intervention; (2) this increase was apart from the professional development training that the teachers had initially received; and (3) students' writing quality improved to some extent with the increase in teachers' relative use of Level 3 questions. Implications and future directions are discussed.

Immunogenicity and safety of a pentavalent meningococcal ABCWY vaccine in adolescents and young adults: an observer-blind, active-controlled, randomised trial.

BACKGROUND: Meningococcal serogroups A, B, C, W, and Y cause nearly all meningococcal disease, and comprehensive protection requires vaccination against all five serogroups. We aimed to assess the immunogenicity and safety of a pentavalent MenABCWY vaccine comprising two licensed vaccines-meningococcal serogroup B-factor H binding protein vaccine (MenB-FHbp) and a quadrivalent meningococcal serogroup ACWY tetanus toxoid conjugate vaccine (MenACWY-TT)-compared with two doses of MenB-FHbp and a single dose of quadrivalent meningococcal serogroup ACWY CRM197-conjugate vaccine (MenACWY-CRM) as the active control. We previously reported the primary safety and immunogenicity data relating to the two-dose MenB-FHbp schedule. Here we report secondary outcomes and ad-hoc analyses relating to MenABCWY immunogenicity and safety. METHODS: We did an observer-blind, active-controlled trial at 68 sites in the USA, Czech Republic, Finland, and Poland. Healthy individuals (aged 10-25 years) who had or had not previously received a MenACWY vaccine were randomly assigned (1:2) using an interactive voice or web-based response system, stratified by previous receipt of a MenACWY vaccine, to receive 0·5 mL of MenABCWY (months 0 and 6) and placebo (month 0) or MenB-FHbp (months 0 and 6) and MenACWY-CRM (month 0) via intramuscular injection into the upper deltoid. All individuals were masked to group allocation, except staff involved in vaccine dispensation, preparation, and administration; and protocol adherence. Endpoints for serogroups A, C, W, and Y included the proportion of participants who achieved at least a four-fold increase in serum bactericidal antibody using human complement (hSBA) titres between baseline and 1 month after each vaccination. For serogroup B, secondary endpoints included the proportion of participants who achieved at least a four-fold increase in hSBA titres from baseline for each of four primary test strains and the proportion of participants who achieved titres of at least the lower limit of quantitation against all four test strains combined at 1 month after the second dose. Endpoints for serogroups A, C, W, and Y were assessed in the modified intent-to-treat (mITT) population, which included all randomly assigned participants who received at least one vaccine dose and had at least one valid and determinate MenB or serogroup A, C, W, or Y assay result before vaccination up to 1 month after the second dose, assessed in ACWY-experienced and ACWY-naive participants separately. Secondary endpoints for serogroup B were analysed in the evaluable immunogenicity population, which included all participants in the mITT population who were randomly assigned to the group of interest, received all investigational products as randomly assigned, had blood drawn for assay testing within the required time frames, had at least one valid and determinate MenB assay result after the second vaccination, and had no important protocol deviations; outcomes were assessed in both ACWY-experienced and ACWY-naive populations combined. Non-inferiority of MenABCWY to MenACWY-CRM and MenB-FHbp was determined using a -10% non-inferiority margin for these endpoints. Reactogenicity and adverse events were assessed among all participants who received at least one vaccine dose and who had available safety data. This trial is registered with Clinicaltrials.gov, NCT03135834, and is complete. FINDINGS: Between April 24 and November 10, 2017, 1610 participants (809 MenACWY-naive; 801 MenACWY-experienced) were randomly assigned: 544 to receive MenABCWY and placebo (n=272 MenACWY-naive; n=272 MenACWY-experienced) and 1066 to receive MenB-FHbp and MenACWY-CRM (n=537 MenACWY-naive; n=529 MenACWY-experienced). Among MenACWY-naive or MenACWY-experienced MenABCWY recipients, 75·5% (95% CI 69·8-80·6; 194 of 257; serogroup C) to 96·9% (94·1-98·7; 254 of 262; serogroup A) and 93·0% (88·4-96·2; 174 of 187; serogroup Y) to 97·4% (94·4-99·0; 224 of 230; serogroup W) achieved at least four-fold increases in hSBA titres against serogroups ACWY after dose 1 or 2, respectively, in ad-hoc analyses. Additionally, 75·8% (71·5-79·8; 320 of 422) to 94·7% (92·1-96·7; 396 of 418) of MenABCWY and 67·4% (64·1-70·6; 563 of 835) to 95·0% (93·3-96·4; 782 of 823) of MenB-FHbp recipients achieved at least four-fold increases in hSBA titres against MenB strains after dose 2 in secondary analyses; 79·9% (334 of 418; 75·7-83·6) and 74·3% (71·2-77·3; 605 of 814), respectively, achieved composite responses. MenABCWY was non-inferior to MenACWY-CRM (single dose) and to MenB-FHbp in ad-hoc analyses based on the proportion of participants with at least a four-fold increase in hSBA titres from baseline and (for MenB-FHbp only) composite responses. Reactogenicity events after vaccination were similarly frequent across groups, were mostly mild or moderate, and were unaffected by MenACWY experience. No adverse events causing withdrawals were related to the investigational product. Serious adverse events were reported in four (1·5%; 0·4-3·7) MenACWY-naive individuals in the MenABCWY group versus six (2·2%; 0·8-4·8) among MenACWY-experienced individuals in the MenABCWY group and 14 (1·3%; 0·7-2·2) in the active control group (MenACWY-experienced and MenACWY-naive individuals combined); none of these were considered related to the investigational product. INTERPRETATION: MenABCWY immune responses were robust and non-inferior to MenACWY-CRM and MenB-FHbp administered separately, and MenABCWY was well tolerated. The favourable benefit-risk profile supports further MenABCWY evaluation as a simplified schedule compared with current adolescent meningococcal vaccination programmes. FUNDING: Pfizer.