Development of the Nova Scotia Potential Donor Audit (PDA) Tool and 2020 Historic Performance Database: Lessons Learned From the First 1000 Medical Record Reviews.

Background: Legislation and accountability frameworks are key components of high-performing deceased-donation systems. In 2021, Nova Scotia (NS), Canada, became the first jurisdiction in North America to enact deemed consent legislation and concurrently implemented mandatory referral legislation similar to that found in other Canadian provinces. Frontline financial resources were provided by the government to support the development of program infrastructure, including implementation of means to evaluate system performance. Methods: The Organ Donation Program (ODP), in collaboration with other stakeholders, developed a Potential Donor Audit (PDA) tool and database for referral intake and manual performance audits. Medical record reviews of deaths in the year before legislative change were conducted to pilot and revise the PDA and evaluate missed donation opportunities. Results: The NS PDA was piloted on 1028 patient deaths. Of 518 patients (50.4%) who met clinical triggers for referral to the ODP, 72 (13.9%) were referred (86.1% missed referral rate). One hundred sixty-three patients met the NS definition of a potential donor; 53 (32.5%) were referred (110 missed potential donors). Referral consent rates reached 71.7% (n = 38 of 53 approaches). The actualized donation rate reported by Canadian Blood Services was 29.9 donors per million population (n = 34 donors). Discussion: We documented high rates of missed referrals and missed potential donors before the enactment of mandatory referral and deemed consent legislation. Conclusions: The ODP has intentionally broadened clinical criteria for referral to shift the responsibility of identifying medically suitable potential donors from bedside clinicians to organ donation specialists. Lessons learned from our experience developing a PDA include the importance of early involvement of multiple stakeholders and ongoing modification of fields and workflow based on data availability and utility for clinical, educational, research, and reporting purposes.

Extubation to High-Flow Nasal Cannula in Infants Following Cardiac Surgery: A Retrospective Cohort Study.

High-flow nasal cannula (HFNC) therapy is commonly used in the pediatric intensive care unit (PICU) for postextubation respiratory support. This hypothesis-generating retrospective cohort study aimed to compare postextubation PICU length of stay in infants extubated to HFNC and low flow oxygen (LF) in PICU following cardiac surgery. Of 136 infants (newborn to 1 year) who were intubated and mechanically ventilated in PICU following cardiac surgery, 72 (53%) were extubated to HFNC and 64 (47%) to LF. Compared with patients extubated to LF, those extubated to HFNC had significantly longer durations of cardiopulmonary bypass (152 vs. 109 minutes; p = 0.002), aortic cross-clamp (90 vs. 63 minutes; p = 0.003), and invasive mechanical ventilation (3.2 vs. 1.6 days; p < 0.001), although demographic and preoperative clinical variables were similar. No significant difference was observed in postextubation PICU length of stay between HFNC and LF groups in unadjusted analysis (3.3 vs. 2.6 days, respectively; p = 0.19) and after controlling for potential confounding variables (F [1,125] = 0.17, p = 0.68, R 2 = 0.16). Escalation of therapy was similar between HFNC and LF groups (8.3 vs. 14.1%; p = 0.41). HFNC was effective as rescue therapy for six patients in the LF group requiring escalation of therapy. Need for reintubation was similar between HFNC and LF groups (8.3 vs. 4.7%; p = 0.5). Although extubation to HFNC was associated with a trend toward longer postextubation PICU length of stay and was successfully used as rescue therapy for several infants extubated to LF, our results must be interpreted with caution given the limitations of our study.

Clinical utility of the pediatric respiratory rate-oxygenation index.

A recently published study evaluated the pediatric respiratory rate-oxygenation index to predict high-flow nasal cannula therapy failure in children. This commentary outlines limitations to the clinical applicability of the study results and suggestions for future research.

Urotensin II((4-11)) Azasulfuryl Peptides: Synthesis and Biological Activity.

Cyclic azasulfuryl (As) peptide analogs of the urotensin II (UII, 1, H-Glu-Thr-Pro-Asp-c[Cys-Phe-Trp-Lys-Tyr-Cys]-Val-OH) fragment 4-11 were synthesized to explore the influences of backbone structure on biological activity. N-Aminosulfamides were inserted as surrogates of the Trp(7) and Lys(8) residues in the biologically relevant Trp-Lys-Tyr triad. A combination of solution- and solid-phase methods were used to prepare novel UII((4-11)) analogs 6-11 by routes featuring alkylation of azasulfuryl-glycine tripeptide precursors to install various side chains. The pharmacological profiles of derivatives 6-11 were tested in vitro using a competitive binding assay and ex vivo using a rat aortic ring bioassay. Although the analogs exhibited weak affinity for the urotensin II receptor (UT) without agonistic activity, azasulfuryl-UII((4-11)) derivatives 7-9 reduced up to 50% of the effects of UII and urotensin II-related peptide (URP) without affecting their potency.

De Novo Conception of Small Molecule Modulators Based on Endogenous Peptide Ligands: Pyrrolodiazepin-2-one γ-Turn Mimics That Differentially Modulate Urotensin II Receptor-Mediated Vasoconstriction ex Vivo.

A proof-of-concept library of pyrrolodiazepinone small molecules was designed based on the Bip-Lys-Tyr motif found in a recently described modulator of the urotensinergic system. Solid-phase synthesis provided 13 analogues, which were tested for their ability to modulate selectively and differentially the potency (EC50) and efficacy (E(max)) of hUII and URP ex vivo in a rat aortic ring bioassay. Notably, at 14 µM, pyrrolodiazepinone R-4a inhibited completely hUII-induced contractions and increased URP-associated vasoconstriction. Pyrrolodiazepinone R-4a represents, to the best of our knowledge, a first-in-class small molecule that exerts a probe-dependent effect on hUII and URP biological activities and proves that UT modulators of the urotensin II receptor (UT) can be rationally designed. The importance of the UT system in the pathogenesis and progression of cardiovascular diseases highlights the utility of pyrrolodiazepinones such as R-4a, which exhibit promising potential as tools for differentiating the respective roles, signaling pathways, and phenotypic outcomes of UII and URP in the UT system.

Pyrrolo[3,2-e][1,4]diazepin-2-one synthesis: a head-to-head comparison of soluble versus insoluble supports.

Aryldiazepin-2-ones are known as "privileged structures", because they bind to multiple receptor types with high affinity. Toward the development of a novel class of aryldiazepin-2-one scaffolds, the synthesis of pyrrolo[3,2-e][1,4]diazepin-2-ones on a support was explored starting from N-(PhF)-4-hydroxyproline and featuring an acid-catalyzed Pictet-Spengler reaction to form the diazepine ring. Three supports [Wang resin, tetraarylphosphonium (TAP) soluble support, and Merrifield resin] were examined in the synthesis of the heterocycle and exhibited different advantages and disadvantages. Wang resin proved effective for exploratory optimization of the synthesis by identification of intermediates after resin cleavage under mild conditions; however, the acidic conditions of the Pictet-Spengler reaction caused premature loss of resin-bound material. Direct monitoring of reactions by TLC, RP-HPLC-MS, and in certain cases NMR spectroscopy was possible with the TAP support, which facilitated purification of intermediates by precipitation; however, incomplete precipitation of material led to overall yields lower than those from solid-phase approaches on resin. Merrifield resin proved stable to the conditions for the synthesis of the pyrrolo[3,2-e][1,4]diazepin-2-one targets and would be amenable to "split-and-mix" chemistry; however, relatively harsh conditions were necessary for final product cleavage. Perspective for the application of different solid-phase approaches in heterocycle library synthesis was thus obtained by demonstration of the respective utility of the three supports for preparation of pyrrolo[3,2-e][1,4]diazepin-2-one.