Noninferiority Trial Design: Opportunities and Challenges.

Defining treatment effectiveness is the foundation of evidence-based practice. Most studies comparing the effectiveness of treatment options involve superiority designs in which a treatment is compared against a placebo, standard care, or an alternative treatment. However, in scenarios in which it is not ethical to consider these options, noninferiority designs can be considered. Noninferiority (NI) trials aim to demonstrate that a new treatment is not unacceptably worse than a standard treatment. Noninferiority is determined relative to a noninferiority margin, which is the difference between the test and active control treatment that is not unacceptably clinically inferior. However, there are important considerations with respect to the design, analysis, and interpretation of NI studies, which differ from superiority trials. This review will outline the key components of NI trials, how to interpret the findings, and understand their nuances and potential limitations.

Prospective cohort study on the trajectory and association of perioperative anxiety and postoperative opioid-related outcomes.

INTRODUCTION: Although perioperative anxiety is common, its trajectory and influence on postoperative pain and opioid use are not well understood. We sought to examine the association and trajectory of perioperative anxiety, pain and opioid use following common surgical procedures. METHODS: We conducted a prospective cohort study of 1771 patients undergoing elective surgical procedures. Self-reported opioid use, pain (Brief Pain Inventory) and anxiety (Patient-Reported Outcome Measurement Information System (PROMIS) Anxiety) were recorded on the day of surgery and at 1 month, 3 months and 6 months postsurgery. Clinically significant anxiety was defined as a PROMIS Anxiety T-score ≥55. We examined postoperative opioid use in the context of surgical site pain and anxiety using mixed-effects regression models adjusted for covariates, and examined anxiety as a mediator between pain and opioid use. RESULTS: In this cohort, 65% of participants completed all follow-ups and 30% reported clinically significant anxiety at baseline. Anxiety and surgical site pain were highest on the day of surgery (anxiety: mean=49.3, SD=9.0; pain: mean=4.3, SD=3.3) and declined in the follow-up period. Those with anxiety reported higher opioid use (OR=1.40; 95% CI 1.0, 1.9) and 1.14-point increase in patient-reported surgical pain (95% CI 1.0, 1.3) compared with those without anxiety. Anxiety had no significant mediation effect on the relationship of pain and opioid use. DISCUSSION: Anxiety is an independent risk factor for increased pain and opioid use after surgery. Future studies examining targeted behavioral therapies to reduce anxiety during the perioperative period may positively impact postoperative pain and opioid use.

Norbornadiene Chain-End Functional Polymers as Stable, Readily Available Precursors to Cyclopentadiene Derivatives.

A novel method for facile postpolymerization functionalization of synthetic polymers using terminal norbornadiene (NBD) building blocks is presented. Incorporation of the NBD functionality streamlines the synthesis of a wide array of block polymers utilizing multistep click chemistry strategies. Previously, the use of NBD-functionalized initiators produced polymers that underwent a cascade of Diels-Alder (DA) reactions to unveil a reactive cyclopentadiene (Cp) chain end. When coupled with a maleimide-bearing counterpart, a highly efficient DA cycloaddition with the terminal Cp can occur. To extend this concept to a range of polyacrylates and commercially available poly(ethylene glycol) systems, we developed a novel NBD acid building block for postpolymerization functionalization. Employing this process, we have demonstrated straightforward access to a library of block polymers that leverage this NBD click platform.

Nickel(IV)-Catalyzed C-H Trifluoromethylation of (Hetero)arenes.

This Article describes the development of a stable NiIV complex that mediates C(sp2)-H trifluoromethylation reactions. This reactivity is first demonstrated stoichiometrically and then successfully translated to a NiIV-catalyzed C-H trifluoromethylation of electron-rich arene and heteroarene substrates. Both experimental and computational mechanistic studies support a radical chain pathway involving NiIV, NiIII, and NiII intermediates.

Norbornadienes: Robust and Scalable Building Blocks for Cascade "Click" Coupling of High Molecular Weight Polymers.

Herein, we report the development of a scalable and synthetically robust building block based on norbornadiene (NBD) that can be broadly incorporated into a variety of macromolecular architectures using traditional living polymerization techniques. By taking advantage of a selective and rapid deprotection with tetrazine, highly reactive "masked" cyclopentadiene (Cp) functionalities can be introduced into synthetic polymers as chain-end groups in a quantitative and efficient manner. The orthogonality of this platform further enables a cascade "click" process where the "unmasked" Cp can rapidly react with dienophiles, such as maleimides, through a conventional Diels-Alder reaction. Coupling proceeds with quantitative conversions allowing high molecular weight star and dendritic block copolymers to be prepared in a single step under ambient conditions.

Endo and Exo Diels-Alder Adducts: Temperature-Tunable Building Blocks for Selective Chemical Functionalization.

The development and application of a novel endo furan-protected maleimide building block is reported. The endo isomer undergoes deprotection at temperatures ∼50 °C below the exo derivative. This enables a simple and powerful approach to quantitatively and selectively introduce functional maleimide groups via temperature modulation.