A mixed methods evaluation of patient perspectives on the implementation of an electronic health record-integrated patient-reported symptom and needs monitoring program in cancer care.

BACKGROUND: As cancer centers have increased focus on patient-centered, evidenced-based care, implementing efficient programs that facilitate effective patient-clinician communication remains critical. We implemented an electronic health record-integrated patient-reported symptom and needs monitoring program ('cPRO' for cancer patient-reported outcomes). To aid evaluation of cPRO implementation, we asked patients receiving care in one of three geographical regions of an academic healthcare system about their experiences. METHODS: Using a sequential mixed-methods approach, we collected feedback in two waves. Wave 1 included virtual focus groups and interviews with patients who had completed cPRO. In Wave 2, we administered a structured survey to systematically examine Wave 1 themes. All participants had a diagnosed malignancy and received at least 2 invitations to complete cPRO. We used rapid and traditional qualitative methods to analyze Wave 1 data and focused on identifying facilitators and barriers to cPRO implementation. Wave 2 data were analyzed descriptively. RESULTS: Participants (n = 180) were on average 62.9 years old; were majority female, White, non-Hispanic, and married; and represented various cancer types and phases of treatment. Wave 1 participants (n = 37) identified facilitators, including cPRO's perceived value and favorable usability, and barriers, including confusion about cPRO's purpose and various considerations for responding. High levels of clinician engagement with, and patient education on, cPRO were described as facilitators while low levels were described as barriers. Wave 2 (n = 143) data demonstrated high endorsement rates of cPRO's usability on domains such as navigability (91.6%), comprehensibility (98.7%), and relevance (82.4%). Wave 2 data also indicated low rates of understanding cPRO's purpose (56.7%), education from care teams about cPRO (22.5%), and discussing results of cPRO with care teams (16.3%). CONCLUSIONS: While patients reported high value and ease of use when completing cPRO, they also reported areas of confusion, emphasizing the importance of patient education on the purpose and use of cPRO and clinician engagement to sustain participation. These results guided successful implementation changes and will inform future improvements.

Hypothermic and cryogenic preservation of cardiac tissue-engineered constructs.

Cardiac tissue engineering (cTE) has already advanced towards the first clinical trials, investigating safety and feasibility of cTE construct transplantation in failing hearts. However, the lack of well-established preservation methods poses a hindrance to further scalability, commercialization, and transportation, thereby reducing their clinical implementation. In this study, hypothermic preservation (4 °C) and two methods for cryopreservation (i.e., a slow and fast cooling approach to -196 °C and -150 °C, respectively) were investigated as potential solutions to extend the cTE construct implantation window. The cTE model used consisted of human induced pluripotent stem cell-derived cardiomyocytes and human cardiac fibroblasts embedded in a natural-derived hydrogel and supported by a polymeric melt electrowritten hexagonal scaffold. Constructs, composed of cardiomyocytes of different maturity, were preserved for three days, using several commercially available preservation protocols and solutions. Cardiomyocyte viability, function (beat rate and calcium handling), and metabolic activity were investigated after rewarming. Our observations show that cardiomyocytes' age did not influence post-rewarming viability, however, it influenced construct function. Hypothermic preservation with HypoThermosol® ensured cardiomyocyte viability and function. Furthermore, fast freezing outperformed slow freezing, but both viability and function were severely reduced after rewarming. In conclusion, whereas long-term preservation remains a challenge, hypothermic preservation with HypoThermosol® represents a promising solution for cTE construct short-term preservation and potential transportation, aiding in off-the-shelf availability, ultimately increasing their clinical applicability.

Proteus mirabilis UreR coordinates cellular functions required for urease activity.

A hallmark of Proteus mirabilis infection of the urinary tract is the formation of stones. The ability to induce urinary stone formation requires urease, a nickel metalloenzyme that hydrolyzes urea. This reaction produces ammonia as a byproduct, which can serve as a nitrogen source and weak base that raises the local pH. The resulting alkalinity induces the precipitation of ions to form stones. Transcriptional regulator UreR activates expression of urease genes in a urea-dependent manner. Thus, urease genes are highly expressed in the urinary tract where urea is abundant. Production of mature urease also requires the import of nickel into the cytoplasm and its incorporation into the urease apoenzyme. Urease accessory proteins primarily acquire nickel from one of two nickel transporters and facilitate incorporation of nickel to form mature urease. In this study, we performed a comprehensive RNA-seq to define the P. mirabilis urea-induced transcriptome as well as the UreR regulon. We identified UreR as the first defined regulator of nickel transport in P. mirabilis. We also offer evidence for the direct regulation of the Ynt nickel transporter by UreR. Using bioinformatics, we identified UreR-regulated urease loci in 15 Morganellaceae family species across three genera. Additionally, we located two mobilized UreR-regulated urease loci that also encode the ynt transporter, implying that UreR regulation of nickel transport is a conserved regulatory relationship. Our study demonstrates that UreR specifically regulates genes required to produce mature urease, an essential virulence factor for P. mirabilis uropathogenesis. IMPORTANCE: Catheter-associated urinary tract infections (CAUTIs) account for over 40% of acute nosocomial infections in the USA and generate $340 million in healthcare costs annually. A major causative agent of CAUTIs is Proteus mirabilis, an understudied Gram-negative pathogen noted for its ability to form urinary stones via the activity of urease. Urease mutants cannot induce stones and are attenuated in a murine UTI model, indicating this enzyme is essential to P. mirabilis pathogenesis. Transcriptional regulation of urease genes by UreR is well established; here, we expand the UreR regulon to include regulation of nickel import, a function required to produce mature urease. Furthermore, we reflect on the role of urea catalysis in P. mirabilis metabolism and provide evidence for its importance.

Beetroot juice supplementation and exercise performance: is there more to the story than just nitrate?

This mini-review summarizes the comparative effects of different sources of dietary nitrate (NO3-), beetroot juice (BRJ) and nitrate salts (NIT), on physiological function and exercise capacity. Our objectives were to determine whether BRJ is superior to NIT in enhancing exercise-related outcomes, and to explore the potential contribution of other putatively beneficial compounds in BRJ beyond NO3-. We conducted a comparative analysis of recent studies focused on the impact of BRJ versus NIT on submaximal oxygen consumption (VO2), endurance performance, adaptations to training, and recovery from muscle-damaging exercise. While both NO3- sources provide benefits, there is some evidence that BRJ may offer additional advantages, specifically in reducing VO2 during high-intensity exercise, magnifying performance improvements with training, and improving recovery post-exercise. These reported differences could be due to the hypothesized antioxidant and/or anti-inflammatory properties of BRJ resulting from the rich spectrum of phytonutrients it contains. However, significant limitations to published studies directly comparing BRJ and NIT make it quite challenging to draw any firm conclusions. We provide recommendations to help guide further research into the important question of whether there is more to the story of BRJ than just NO3-.

Crystal structure and biophysical characterization of IspD from Burkholderia thailandensis and Mycobacterium paratuberculosis.

The methylerythritol phosphate (MEP) pathway is a metabolic pathway that produces the isoprenoids isopentyl pyrophosphate and dimethylallyl pyrophosphate. Notably, the MEP pathway is present in bacteria and not in mammals, which makes the enzymes of the MEP pathway attractive targets for discovering new anti-infective agents due to the reduced chances of off-target interactions leading to side effects. There are seven enzymes in the MEP pathway, the third of which is IspD. Two crystal structures of Burkholderia thailandensis IspD (BtIspD) were determined: an apo structure and that of a complex with cytidine triphosphate (CTP). Comparison of the CTP-bound BtIspD structure with the apo structure revealed that CTP binding stabilizes the loop composed of residues 13-19. The apo structure of Mycobacterium paratuberculosis IspD (MpIspD) is also reported. The melting temperatures of MpIspD and BtIspD were evaluated by circular dichroism. The moderate Tm values suggest that a thermal shift assay may be feasible for future inhibitor screening. Finally, the binding affinity of CTP for BtIspD was evaluated by isothermal titration calorimetry. These structural and biophysical data will aid in the discovery of IspD inhibitors.

Covalent Grafting of Functionalized MEW Fibers to Silk Fibroin Hydrogels to Obtain Reinforced Tissue Engineered Constructs.

Hydrogels are ideal materials to encapsulate cells, making them suitable for applications in tissue engineering and regenerative medicine. However, they generally do not possess adequate mechanical strength to functionally replace human tissues, and therefore they often need to be combined with reinforcing structures. While the interaction at the interface between the hydrogel and reinforcing structure is imperative for mechanical function and subsequent biological performance, this interaction is often overlooked. Melt electrowriting enables the production of reinforcing microscale fibers that can be effectively integrated with hydrogels. Yet, studies on the interaction between these micrometer scale fibers and hydrogels are limited. Here, we explored the influence of covalent interfacial interactions between reinforcing structures and silk fibroin methacryloyl hydrogels (silkMA) on the mechanical properties of the construct and cartilage-specific matrix production in vitro. For this, melt electrowritten fibers of a thermoplastic polymer blend (poly(hydroxymethylglycolide-co-ε-caprolactone):poly(ε-caprolactone) (pHMGCL:PCL)) were compared to those of the respective methacrylated polymer blend pMHMGCL:PCL as reinforcing structures. Photopolymerization of the methacrylate groups, present in both silkMA and pMHMGCL, was used to generate hybrid materials. Covalent bonding between the pMHMGCL:PCL blend and silkMA hydrogels resulted in an elastic response to the application of torque. In addition, an improved resistance was observed to compression (∼3-fold) and traction (∼40-55%) by the scaffolds with covalent links at the interface compared to those without these interactions. Biologically, both types of scaffolds (pHMGCL:PCL and pMHMGCL:PCL) showed similar levels of viability and metabolic activity, also compared to frequently used PCL. Moreover, articular cartilage progenitor cells embedded within the reinforced silkMA hydrogel were able to form a cartilage-like matrix after 28 days of in vitro culture. This study shows that hybrid cartilage constructs can be engineered with tunable mechanical properties by grafting silkMA hydrogels covalently to pMHMGCL:PCL blend microfibers at the interface.

Reductive Metallation of Dendralenes and Myrcene Using Dimagnesium(I) Compounds: A Facile Route to Unsaturated Organomagnesium Compounds.

The two-electron reduction of 2,3-dimethylbuta-1,3-diene (DMB) with ß-diketiminate and guanidinate substituted dimagnesium(I) compounds has given complexes in which two bidentate amido-magnesium fragments are bridged through the π-system of the DMB dianion, viz. [(LMg)2 (µ-DMB)] (L=Xyl Nacnac, [HC(MeCNXyl)2 ]- , Xyl=2,6-xylyl; or Priso=[(DipN)2 CNPri 2 ]- , Dip=2,6-diisopropylphenyl). Similar double reductions of [4]dendralene (4dend) have afforded the complexes, [(LMg)2 (µ-4dend)] (L=Ar Nacnac, Ar=Xyl or mesityl (Mes); or Priso) in which the 4dend dianion is π-coordinated to the bidentate amido-magnesium fragments. Treatment of several such complexes with THF leads to Z- to E-isomerization of the dendralene fragment, and formation of purely σ-bonded Mg-C interactions in the THF coordinated products [{(Ar Nacnac)(THF)Mg}2 (µ-4dend)] (Ar=Xyl, Mes or Dip). Reaction of myrcene (Myr) with [{(Xyl Nacnac)Mg}2 ] proceeds via reductive coupling of Myr to give a previously unknown acyclic, branched C20 tetra-olefin dianion complex [{(Xyl Nacnac)(THF)Mg}2 (µ-Myr)2 ]. Preliminary reactions of [(LMg)2 (µ-DMB)] with H2 and/or CO yielded a series of products, including novel magnesium hydride compounds, products derived from couplings of CO with the reduced DMB fragment (viz. magnesium dimethylcyclohexadienediolates), and one magnesium cyclopropanetriolate complex from the magnesium(I) induced coupling of DMB with H2 and CO.

Automated human induced pluripotent stem cell culture and sample preparation for 3D live-cell microscopy.

To produce abundant cell culture samples to generate large, standardized image datasets of human induced pluripotent stem (hiPS) cells, we developed an automated workflow on a Hamilton STAR liquid handler system. This was developed specifically for culturing hiPS cell lines expressing fluorescently tagged proteins, which we have used to study the principles by which cells establish and maintain robust dynamic localization of cellular structures. This protocol includes all details for the maintenance, passage and seeding of cells, as well as Matrigel coating of 6-well plastic plates and 96-well optical-grade, glass plates. We also developed an automated image-based hiPS cell colony segmentation and feature extraction pipeline to streamline the process of predicting cell count and selecting wells with consistent morphology for high-resolution three-dimensional (3D) microscopy. The imaging samples produced with this protocol have been used to study the integrated intracellular organization and cell-to-cell variability of hiPS cells to train and develop deep learning-based label-free predictions from transmitted-light microscopy images and to develop deep learning-based generative models of single-cell organization. This protocol requires some experience with robotic equipment. However, we provide details and source code to facilitate implementation by biologists less experienced with robotics. The protocol is completed in less than 10 h with minimal human interaction. Overall, automation of our cell culture procedures increased our imaging samples' standardization, reproducibility, scalability and consistency. It also reduced the need for stringent culturist training and eliminated culturist-to-culturist variability, both of which were previous pain points of our original manual pipeline workflow.

Longitudinal study of stream ecology pre- and post- dam removal: Physical, chemical, and biological changes to a northern Michigan stream.

Over the past two decades, dam removal has become an increasingly important aspect of aquatic ecology. As a result of this work, ecological studies have arisen that monitor the changes to riverine ecosystems as a result of removal. Unfortunately, given the uncertain nature of funding and public concerns over dam removal, long term longitudinal studies that cover multiple trophic levels are difficult to find. Fortunately, the University of Michigan Biological Station has been involved in the ecological monitoring of a headwater river (the Maple River) in the northern part of the lower peninsula of Michigan. The physical, chemical, and some biological aspects of this river's ecology was measured for eight years prior to dam removal, during dam removal, and for two years post-dam removal. The results presented here show that the ecology of the river recovered within this two-year period, but had a different ecological set point. This new habitat is primarily driven by increases in flow, ammonia, silica, and increases in the populations of two macroinvertebrate feeding guilds. Discharge increased seven-fold in the year that the dam was removed in two sampling sites furthest from the dam but returned to pre-dam removal conditions a year after removal occurred. Turbidity followed this same temporal pattern as turbidity increased during dam removal but decreased to pre-removal levels once the dam was removed. pH decreased at all sites post-removal. In addition, ammonia showed a five-fold increase following dam removal at the two most upstream sites, while phosphate increased at all sites. Last, the number of filterers and shredders increased at all sampling sites, though the significance of increase varied spatially for each guild. The results and observations presented here may provide some guidance for other long term monitoring studies.

Air Tolerant Cadiot-Chodkiewicz and Sonogashira Cross-Couplings.

Cadiot-Chodkiewicz cross-couplings generate an unsymmetric buta-1,3-diyne by way of a Cu(I)-catalyzed coupling between a terminal alkyne and a 1-haloalkyne. Despite their widespread use, Cadiot-Chodkiewicz reactions are plagued by the generation of symmetric buta-1,3-diyne side products, formed through competing: (a) formal reductive homo-coupling of the 1-haloalkyne and (b) oxidative (Glaser-Hay/Eglinton) homo-coupling of the terminal alkyne. To overcome this issue, a large excess of one of the two reacting alkynes is commonly deployed, and difficult separations of cross- and homo-coupled products are often encountered. Here, we demonstrate that the use of ascorbate as a reductant leads to a suppression of these unwanted side reactions, hence permitting excellent yields with a roughly stoichiometric ratio of reactants. The procedure also avoids an inert gas atmosphere and uses a sustainable solvent. A similar approach is effective for cross-couplings involving a Pd(0)/Pd(II) catalytic cycle, with air tolerant Sonogashira couplings also established.

Actin cytoskeleton remodeling disrupts physical barriers to infection and presents entry receptors to respiratory syncytial virus.

RSV is the leading cause of infant hospitalizations and a significant cause of paediatric and geriatric morbidity worldwide. Recently, we reported that insulin-like growth factor 1 receptor (IGF1R) was a receptor for respiratory syncytial virus (RSV) in airway epithelial cells and that activation of IGF1R recruited the coreceptor, nucleolin (NCL), to the cell surface. Cilia and mucus that line the airways pose a significant barrier to viral and bacterial infection. The cortical actin cytoskeleton has been shown by others to mediate RSV entry, so we studied the roles of the RSV receptors and actin remodelling during virus entry. We found that IGF1R expression and phosphorylation were associated with the ability of RSV to infect cells. Confocal immunofluorescence imaging showed that actin projections, a hallmark of macropinocytosis, formed around viral particles 30 min after infection. Consistent with prior reports we also found that virus particles were internalized into early endosome antigen-1 positive endosomes within 90 min. Inhibiting actin polymerization significantly reduced viral titre by approximately ten-fold. Inhibiting PI3 kinase and PKCζ in stratified air-liquid interface (ALI) models of the airway epithelium had similar effects on reducing the actin remodelling observed during infection and attenuating viral entry. Actin projections were associated with NCL interacting with RSV particles resting on apical cilia of the ALIs. We conclude that macropinocytosis-like actin projections protrude through normally protective cilia and mucus layers of stratified airway epithelium that helps present the IGF1R receptor and the NCL coreceptor to RSV particles waiting at the surface.

Comparison of phage-derived recombinases for genetic manipulation of Pseudomonas species.

IMPORTANCE: The Pseudomonas genus contains many members currently being investigated for applications in biodegradation, biopesticides, biocontrol, and synthetic biology. Though several strains have been identified with beneficial properties, chromosomal manipulations to further improve these strains for commercial applications have been limited due to the lack of efficient genetic tools that have been tested across this genus. Here, we test the recombineering efficiencies of five phage-derived recombinases across three biotechnologically relevant Pseudomonas strains: P. putida KT2440, P. protegens Pf-5, and P. protegens CHA0. These results demonstrate a method to generate targeted mutations quickly and efficiently across these strains, ideally introducing a method that can be implemented across the Pseudomonas genus and a strategy that may be applied to develop analogous systems in other nonmodel bacteria.

Venous thromboembolism prevention in cancer care: implementation strategies to address underuse.

Background: Evidenced-based interventions have been developed to prevent venous thromboembolism (VTE) in ambulatory patients with cancer, including VTE-risk assessment for all patients and targeted primary thromboprophylaxis for high-risk patients. Despite supportive evidence and recommendations, oncologists rarely assess VTE risk or provide primary prophylaxis. Our previous work identified barriers and facilitators to using VTE prevention interventions in oncology practice. Objectives: To identify potential strategies that address the identified barriers and leverage facilitators to achieve successful implementation of evidence-based interventions for VTE prevention in oncology practice. Methods: We used the Implementation Research Logic Model, an implementation science framework, to map the relationships among barriers and facilitators, feasible and effective implementation strategies, and implementation and clinical outcomes that will be used to evaluate the implementation strategies. Results: We identified 12 discrete implementation strategies (eg, conducting clinician education and training and staged implementation scale-up) that address barriers and leverage facilitators through their mechanisms of action (eg, increased clinician awareness of evidence and targeting the highest effectiveness). We identified key implementation (eg, penetration, adoption, acceptability, fidelity, appropriateness, and sustainability), system (eg, integration of VTE-risk assessment into clinical workflow), and clinical (eg, lower VTE rates) outcomes targeted by the selected strategies. Conclusion: Using the Implementation Research Logic Model framework and building on our knowledge of barriers and facilitators, we identified implementation strategies and important outcomes to evaluate these strategies. We will use these results to test and measure the strategies to improve the uptake of evidence-based recommendations for VTE prevention in oncology practice.

Delayed esophageal anastomotic complication and ramucirumab therapy: A case report.

Current NCCN guidelines for second-line therapy in recurrent or metastatic esophago-gastric cancers recommend the use of VEGF inhibitors such as ramucirumab. VEGF inhibitors have been shown to be associated with gastrointestinal perforation in clinical trials and late colorectal anastomotic leaks in a few case reports. Here, we present a case of late esophageal anastomotic leak in a patient receiving ramucirumab. Case information was obtained from our institution's electronic medical records. The patient was found to have T4N1M0, poorly differentiated invasive adenocarcinoma and subsequently received neoadjuvant chemoradiation followed by hybrid Ivor-Lewis esophagectomy 6 weeks later. He recovered well with no leak or perioperative complications. The patient had disease progression 9 months postoperatively on CT and PET imaging. Sixteen months after surgery he began paclitaxel and ramucirumab and 16 weeks after ramucirumab initiation, he was found to have an esophago-pulmonary fistula in the region of the anastomosis. Biopsies were negative for recurrence at the anastomosis. He died one week later from progressive pneumonia despite stenting. In conclusion, this is the only known report of delayed esophageal anastomotic complication associated with ramucirumab. VEGF inhibitor therapies such as bevacizumab have been associated with late (greater than 3 months postoperative) colorectal anastomotic complications including fistulas and leaks. Risk factors that have been associated are perioperative radiotherapy and history of early postoperative leak. These findings raise concern whether VEGF inhibitor therapy should be used in post-esophagectomy patients with recurrence if these rare but catastrophic events are likely to be terminal.

Serum Cartilage Oligomeric Matrix Protein Concentration Increases More After Running Than Swimming for Older People.

BACKGROUND: Knee osteoarthritis is common in older people. Serum cartilage oligomeric matrix protein (sCOMP) is a biomarker of knee articular cartilage metabolism. The purpose of this study was 2-fold: to (1) determine acute effects of running and swimming on sCOMP concentration in older people; and (2) investigate relationships between sCOMP concentration change due to running and swimming and measures of knee health in older people. HYPOTHESES: Running would result in greater increase in sCOMP concentration than swimming, and increase in sCOMP concentration due to running and swimming would associate positively with measures of poor knee health. STUDY DESIGN: Cross-sectional. LEVEL OF EVIDENCE: Level 3. METHODS: A total of 20 participants ran 5 km and 19 participants swam 1500 m. sCOMP concentration was measured immediately before, immediately after, and 15, 30, and 60 minutes after running or swimming. sCOMP concentration change due to running and swimming was compared. Correlations between sCOMP concentration change due to running and swimming, and other measures of knee health were evaluated, including the Tegner Activity Scale and Knee injury and Osteoarthritis Outcome Score. RESULTS: sCOMP concentration increased 29% immediately after running, relative to baseline, but only 6% immediately after swimming (P < 0.01). No significant relationship was observed between acute sCOMP change due to running and swimming, and observed measures of knee health (P > 0.05). Participants with clinically relevant knee symptoms exhibited greater sCOMP concentration before and after running and swimming (P = 0.03) and had greater body mass (P = 0.04). CONCLUSION: Running results in greater acute articular cartilage metabolism than swimming; however, the chronic effects of this are unclear. Older people with clinically relevant knee symptoms possess greater sCOMP concentration and are heavier, independent of exercise mode and physical activity level. CLINICAL RELEVANCE: These results describe the effects of exercise (running and swimming) for older physically active persons, with and without knee pain.

Drug-Inducible Gene Therapy Effectively Reduces Spontaneous Seizures in Kindled Rats but Creates Off-Target Side Effects in Inhibitory Neurons.

Over a third of patients with temporal lobe epilepsy (TLE) are not effectively treated with current anti-seizure drugs, spurring the development of gene therapies. The injection of adeno-associated viral vectors (AAV) into the brain has been shown to be a safe and viable approach. However, to date, AAV expression of therapeutic genes has not been regulated. Moreover, a common property of antiepileptic drugs is a narrow therapeutic window between seizure control and side effects. Therefore, a long-term goal is to develop drug-inducible gene therapies that can be regulated by clinically relevant drugs. In this study, a first-generation doxycycline-regulated gene therapy that delivered an engineered version of the leak potassium channel Kcnk2 (TREK-M) was injected into the hippocampus of male rats. Rats were electrically stimulated until kindled. EEG was monitored 24/7. Electrical kindling revealed an important side effect, as even low expression of TREK M in the absence of doxycycline was sufficient to cause rats to develop spontaneous recurring seizures. Treating the epileptic rats with doxycycline successfully reduced spontaneous seizures. Localization studies of infected neurons suggest seizures were caused by expression in GABAergic inhibitory neurons. In contrast, doxycycline increased the expression of TREK-M in excitatory neurons, thereby reducing seizures through net inhibition of firing. These studies demonstrate that drug-inducible gene therapies are effective in reducing spontaneous seizures and highlight the importance of testing for side effects with pro-epileptic stressors such as electrical kindling. These studies also show the importance of evaluating the location and spread of AAV-based gene therapies in preclinical studies.

Computational and Experimental Confirmation of the Diradical Character of para-Quinonedimethide.

The ground-state structure of the parent para-quinonedimethide (p-QDM) molecule is generally represented in its closed shell form, i.e., as a cyclic, nonaromatic, through-conjugated/cross-conjugated hybrid comprising four C═C bonds. Nonetheless, p-QDM has been theorized to contain a contribution from its open-shell aromatic singlet diradical form. VBSCF calculations identify an open-shell contribution of 29% to the structure, while CASPT2(16,16)/def2-TZVP and ωB97XD/aug-cc-pVTZ calculations predict that dimerization proceeds along an open-shell singlet diradical pathway with a low (77 kJ/mol) barrier toward dimerization, which occurs by way of C-C bond formation between the exocyclic methylene carbons. A similar low (98 kJ/mol) barrier exists toward the reaction between a p-QDM molecule and the radical trap TEMPO. These predictions are verified experimentally through the isolation of bis-TEMPO-trapped p-QDM, its C-C coupled dimer, and by demonstrating that a mixture of p-QDM and TEMPO can initiate the radical polymerization of n-butyl acrylate at ambient temperature. In contrast to p-QDM, tetracyanoquinone (TCNQ) neither dimerizes nor reacts with TEMPO, despite having a similar diradical character to p-QDM. This lack of reactivity is consistent with both a higher kinetic barrier and a thermodynamically unfavorable process, which is ascribed to destabilizing steric clashes and polar effects.

Anticoagulation in emergency general surgery: Who bleeds more? The EAST multicenter trials ACES study.

BACKGROUND: While direct oral anticoagulant (DOAC) use is increasing in the Emergency General Surgery (EGS) patient population, our understanding of their bleeding risk in the acute setting remains limited. Therefore, the objective of this study was to determine the prevalence of perioperative bleeding complications in patients using DOACs versus warfarin and AP therapy requiring urgent/emergent EGS procedures (EGSPs). METHODS: This was a prospective observational trial, conducted between 2019 and 2022, across 21 centers. Inclusion criteria were 18 years or older, DOAC, warfarin/AP use within 24 hours of requiring an urgent/emergent EGSP. Demographics, preoperative, intraoperative, and postoperative data were collected. ANOVA, χ 2 , and multivariable regression models were used to conduct the analysis. RESULTS: Of the 413 patients enrolled in the study, 261 (63%) reported warfarin/AP use and 152 (37%) reported DOAC use. Appendicitis and cholecystitis were the most frequent indication for operative intervention in the warfarin/AP group (43.4% vs. 25%, p = 0.001). Small bowel obstruction/abdominal wall hernias were the main indication for operative intervention in the DOAC group (44.7% vs. 23.8%, p = 0.001). Intraoperative, postoperative, and perioperative bleeding complications and in-hospital mortality were similar between the two groups. After adjusting for confounders, a history of chemotherapy (odds ratio [OR], 4.3; p = 0.015) and indication for operative intervention including occlusive mesenteric ischemia (OR, 4.27; p = 0.016), nonocclusive mesenteric ischemia (OR, 3.13; p = 0.001), and diverticulitis (OR, 3.72; p = 0.019) were associated with increased perioperative bleeding complications. The need for an intraoperative transfusion (OR, 4.87; p < 0.001), and intraoperative vasopressors (OR, 4.35; p = 0.003) were associated with increased in-hospital mortality. CONCLUSION: Perioperative bleeding complications and mortality are impacted by the indication for EGSPs and patient's severity of illness rather than a history of DOAC or warfarin/AP use. Therefore, perioperative management should be guided by patient physiology and indication for surgery rather than the concern for recent antiplatelet or anticoagulant use. LEVEL OF EVIDENCE: Prognostic and Epidemiologic; Level III.