Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700

Characterization of a Water–Solid Interaction in a Partially Ordered System

GNE068-PC, a developmental compound, was previously characterized to be mesomorphous, i.e. having long-range order associated with significant local molecular disorder (Chakravarty et. al., <i>Mol. Pharmaceutics</i>, accepted). The compound was exposed to moisture under different relative humidity conditions ranging from 11% to 60% RH at room temperature (RT) for 7 days, and the resultant product phases were characterized. The partially ordered sample progressively lost crystallinity (long-range order) and birefringence (orientational order) upon exposure to increasing RH conditions, leading to the formation of a completely disordered amorphous phase at 60% RH (RT). Long-range positional order was irrecoverable even after moisture removal from the sample exposed to 60% RH. This was attributed to replacement of residual ethyl acetate by water, the former being critical for maintenance of long-range order in the material. In addition, water sorption appeared to irreversibly alter the molecular orientation, thereby affecting sample birefringence. Solid-state NMR revealed increases in ¹H and ¹³C spin–lattice relaxation times (<i>T</i>₁) going from the mesomorphous phase to the fully amorphous phase. This was indicative of reduction in lattice mobility, likely due to the decreased motion of the aromatic portions of the molecule, in particular C17, which showed the most dramatic increase in ¹³C <i>T</i>₁. This is likely due to decrease in available free volume upon water sorption. Drying of the hydrated disordered phase showed somewhat greater mobility than the hydrated phase, likely due to increased relative free volume through removal of water. A water–solid interaction therefore irreversibly changed the solid-state makeup of GNE068-PC

Magic angle spinning dynamic nuclear polarization solid-state NMR spectroscopy of γ-irradiated molecular organic solids

In the past 15 years, magic angle spinning (MAS) dynamic nuclear polarization (DNP) has emerged as a method to increase the sensitivity of high-resolution solid-state NMR spectroscopy experiments. Recently, γ-irradiation has been used to generate significant concentrations of homogeneously distributed free radicals in a variety of solids, including quartz, glucose, and cellulose. Both γ-irradiated quartz and glucose previously showed significant MAS DNP enhancements. Here, γ-irradiation is applied to twelve small organic molecules to test the applicability of γ-irradiation as a general method of creating stable free radicals for MAS DNP experiments on organic solids and pharmaceuticals. Radical concentrations in the range of 0.25 ​mM–10 ​mM were observed in irradiated glucose, histidine, malic acid, and malonic acid, and significant 1H DNP enhancements of 32, 130, 19, and 11 were obtained, respectively, as measured by 1H→13C CPMAS experiments. However, concentrations of free radicals below 0.05 ​mM were generally observed in organic molecules containing aromatic rings, preventing sizeable DNP enhancements. DNP sensitivity gains for several of the irradiated compounds exceed that which can be obtained with the relayed DNP approach that uses exogeneous polarizing agent solutions and impregnation procedures. In several cases, significant 1H DNP enhancements were realized at room temperature. This study demonstrates that in many cases γ-irradiation is a viable alternative to addition of stable exogenous radicals for DNP experiments on organic solids.This is a manuscript of an article published as Carnahan, Scott L., Yunhua Chen, James F. Wishart, Joseph W. Lubach, and Aaron J. Rossini. "Magic angle spinning dynamic nuclear polarization solid-state NMR spectroscopy of γ-irradiated molecular organic solids." Solid State Nuclear Magnetic Resonance (2022): 101785. DOI: 10.1016/j.ssnmr.2022.101785. Copyright 2022 Elsevier Inc. Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0). Posted with permission

Carbon-deuterium rotational-echo double-resonance NMR spectroscopy of lyophilized aspartame formulations

In this study, changes in the local conformation of aspartame were observed in annealed lyophilized glasses by monitoring changes in the distance between two labeled sites using C–2H rotational-echo double-resonance (REDOR) nuclear magnetic resonance (NMR) spectroscopy. Confirmation that the REDOR experiments were producing accurate distance measurement was ensured by measuring the 13C–15N distance in glycine. The experiment was further verified by measuring the REDOR dephasing curve on 13C–2H methionine. 13C–2H REDOR dephasing curves were then measured on lyophilized aspartame–disaccharide formulations. In aspartame–sucrose formulation, the internuclear distances increased upon annealing, which correlated with decreased chemical reactivity. By contrast, annealing had only a minimal effect on the dephasing curve in aspartame–trehalose formulation. The results show that stability is a function of both mobility and local structure (conformation), even in a small molecule system such as lyophilized aspartame–sucrose. © 2011 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:283–290, 201

Attached Nitrogen Test by 13C–14N Solid-State NMR Spectroscopy for the Structure Determination of Heterocyclic Isomers

Differentiation of heterocyclic isomers by solution 1H, 13C, and 15N NMR spectroscopy is often challenging due to similarities in their spectroscopic signatures. Here, 13C{14N} solid-state NMR spectroscopy experiments are shown to operate as an “attached nitrogen test”, where heterocyclic isomers are easy to distinguish based on one-dimensional nitrogen-filtered 13C solid-state NMR. We anticipate that these NMR experiments will facilitate the assignment of heterocyclic isomers during synthesis and natural product discovery.This document is the unedited Author’s version of a Submitted Work that was subsequently accepted for publication in Organic Letters, copyright © 2022 American Chemical Society after peer review. To access the final edited and published work see DOI: 10.1021/acs.orglett.2c01576. Posted with permission

Impact of Supramolecular Aggregation on the Crystallization Kinetics of Organic Compounds from the Supercooled Liquid State

Despite numerous challenges in their theoretical description and practical implementation, amorphous drugs are of growing importance to the pharmaceutical industry. One such challenge is to gain molecular level understanding of the propensity of a molecule to form and remain as a glassy solid. In this study, a series of structurally similar diarylamine compounds was examined to elucidate the role of supramolecular aggregation on crystallization kinetics from supercooled liquid state. The structural similarity of the compounds makes it easier to isolate the molecular features that affect crystallization kinetics and glass forming ability of these compounds. To examine the role of hydrogen-bonded aggregation and motifs on crystallization kinetics, a combination of thermal and spectroscopic techniques was employed. Using variable temperature FTIR, Raman, and solid-state NMR spectroscopies, the presence of hydrogen bonding in the melt and glassy state was examined and correlated with observed phase transition behaviors. Spectroscopic results revealed that the formation of hydrogen-bonded aggregates involving carboxylic acid and pyridine nitrogen (acid–pyridine aggregates) between neighboring molecules in the melt state impedes crystallization, while the presence of carboxylic acid dimers (acid–acid dimers) in the melt favors crystallization. This study suggests that glass formation of small molecules is influenced by the type of intermolecular interactions present in the melt state and the kinetics associated with the molecules to assemble into a crystalline lattice. For the compounds that form acid–pyridine aggregates, the formation of energy degenerate chains, produced due to conformational flexibility of the molecules, presents a kinetic barrier to crystallization. The poor crystallization tendency of these aggregates stems from the highly directional hydrogen-bonding interactions needed to form the acid–pyridine chains. Conversely, for the compounds that form acid–acid dimers, the nondirectional van der Waals forces needed to construct a nucleus promote rapid assembly and crystallization