Quaternary Center Research Articles

Triphasic Learning Curve of Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy.

Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) is an effective but costly procedure for select patients with peritoneal malignancies. The impact of progression along a learning curve on the cost of these procedures is unknown. We performed a retrospective cohort study of patients undergoing CRS-HIPEC from 2016 to 2022 at a single quaternary center. Our study cohort was temporally divided into four equally sized volume quartiles (A, B, C, and D). We utilized cumulative sum plots and split-group analysis to characterize the institutional learning curve based on cost, operative time, length of stay, and morbidity. Multivariable linear regression was performed to estimate costs after adjusting for covariates. Bivariate analysis was performed using a Kruskal-Wallis test to compare continuous variables and a χ2 test to compare categorical variables. Of 201 patients, the median age [interquartile range (IQR)] was 57 (47-65) years, 113 (56%) patients were female, 143 (71%) were white, and 107 (53%) had private insurance. Median operating room charge [US$42,639 (US$32,477-54,872), p < 0.001] varied between volume quartiles, peaking in quartile C. Stabilization was achieved for 86 cases for operating room cost, 88 cases for routine cost, 96 cases for length of stay, 103 cases for operative time, 120 cases for intensive care unit length of stay, and 150 cases for overall and serious morbidity. The actual operating room and routine costs were similar to predicted costs at the end of the study period. The CRS-HIPEC learning curve is triphasic, with cost stability achieved relatively early compared with other markers of surgical proficiency.

Asymmetric Rh‐Catalyzed [2+2+2] Cycloaddition: Synthesis of N‐Alkenylindoles with both Axial and Central Chirality

Axially chiral Indoline‐based scaffolds are virtually universal in biological and pharmaceutical compounds. Here we demonstrate an atroposelective Rh‐catalyzed 1,6‐enynes with steric hindered N‐alkynyl indoles, which enables simultaneous construction of both axial and central chirality, containing a quaternary carbon center, in one step. Notable features of these reactions include excellent chemo‐, regio‐, diastereo‐ and enantioselectivity, 100% atom‐economy, easily available Segphos ligand, and mild conditions.

Formation of All-Carbon Quaternary Centers via Enantioselective Pd-Catalyzed α-Vinylation of γ-Lactams.

Herein, we report an enantioselective vinylation of α-substituted γ-lactams that forges quaternary centers in up to 59% yield with 94% ee. The use of canonically inactive vinyl chloride electrophiles afforded the highest yields and levels of stereoselectivity, and a range of trisubstituted vinyl chlorides were found to be proficient in promoting this transformation. These stereogenic products could be further elaborated to functionally rich scaffolds, thereby highlighting the synthetic utility of this process.

Pyridine-Catalyzed Chemoselective Four-Component Cascade Reaction of Aromatic Aldehydes, Malononitrile/Cyanoacetates, MBH Carbonates, and Alcohols.

An efficient pyridine-catalyzed chemoselective four-component cascade reaction of aromatic aldehydes, malononitrile/cyanoacetates, Morita-Baylis-Hillman (MBH) carbonates, and alcohols has been established. This one-pot reaction progressed in an unusual reaction with solvent participation via a Knoevenagel condensation/oxa-Michael addition/SN2' substitution sequence. This method allowed for facile access to an array of functionalized chain alkylbenzenes and dihydroquinolinones bearing one all-carbon quaternary center in moderate to excellent yields. It is worth noting that the configuration of the all-carbon quaternary center could be modulated by changing only the electron-withdrawing groups via a tandem reduction/cyclization reaction.

Serial transverse enteroplasty in adults with parenteral nutrition dependence: A case series.

Serial transverse enteroplasty is used to treat patients with chronic intestinal failure owing to short bowel syndrome. Current literature lacks discussion of its role for other etiologies of intestinal failure and its impact on adult patients' nutrition support needs and quality of life. We performed a case series on adults with parenteral nutrition (PN) dependence who underwent serial transverse enteroplasty at Emory University Hospital, a quaternary referral center between 2011 and 2022. Data collected included demographics, operative technique, and preoperative and postoperative PN requirements. A phone survey was administered to evaluate the impact of PN and the operation on quality of life. Ten patients underwent the procedure of interest during the study period. Indications included short bowel syndrome following multiple abdominal operations or intra-abdominal catastrophe and chronic partial bowel obstruction with dysmotility. Bowel length increased by a median of 83%. All patients were discharged home after a median hospital stay of 21 days. At 1-year follow-up, survival was 100%, two (20%) patients fully weaned from PN, three others (30%) reduced PN frequency, and six (60%) decreased their daily parenteral energy requirement. Two additional patients fully weaned from PN by 18 months postoperatively. This represents one of the largest case series of serial transverse enteroplasty in adults. Small intestinal length nearly doubled, and PN dependence was reduced in most patients. Given the low morbidity and good quality of life observed in this series, this procedure should be more widely investigated for patients with chronic intestinal failure.

Friedel–crafts alkylations of indoles, furans, and thiophenes with arylmethyl acetates promoted by trimethylsilyl trifluoromethanesulfonate

Various indoles undergo Friedel–Crafts alkylation at the 3-position when treated with secondary arylmethyl acetates in the presence of trimethylsilyl trifluoromethanesulfonate (TMSOTf) and 2,6-lutidine. Tertiary benzylic alcohols are also effective alkylating agents, undergoing TMSOTf-promoted activation to yield alkylated indoles that feature quaternary centers. A related study shows that benzofuran reacts under similar conditions to yield 2-alkylated benzofurans when treated with similar alkylating agents, and the reaction has been extended to include other representative heteroarenes. Yields for these Friedel–Crafts alkylation products range from 43%–99% over a wide range of substrate combinations.

233. UTILITY OF SINGLE TRANSHIATAL CHEST DRAINAGE AFTER MINIMALLY INVASIVE OESOPHAGECTOMY: A PROPENSITY-SCORE MATCHED STUDY OF FEASIBILITY

Abstract Background The routine placement of intercostal chest drains remains common practice following minimally invasive oesophagectomy (MIO). Chest drains may contribute to increased post-operative pain and morbidity. The aim of this study was to compare the outcomes of transhiatal chest drain with intercostal chest drain. We analysed use of analgesia, length of hospital stay, and postoperative pulmonary morbidity following MIO. Methods This was a retrospective case-control study of patients undergoing elective MIO at a quaternary centre in Western Australia between September 2016 and September 2023. To reduce confounding, propensity score matching was performed. All patients were identified from a prospectively maintained database. In patients undergoing MIO with exclusive transhiatal drainage, a 19 French Blake’s drain was advanced through the hiatus into the right pleural cavity and positioned adjacent to the anastomosis. Results Thirty patients were included in the study, fifteen of whom had exclusively transhiatal drain placement. Mean total daily oral morphine dose equivalent was significantly lower in the transhiatal drain group (58mg+/-35.8) compared with intercostal drain group (100.8mg+/-64.0) on day 1 (p=0.04). There is no statistically significant difference between the total oral morphine use on days 3 (p=0.44) and 6 (p=0.97). No significant difference was observed in reintervention rate (p=1.00), length of stay (p=0.78) or postoperative pulmonary complications (p=1.00). Conclusion The results of this study suggest that transhiatal drain placement following MIO is associated with a reduction in post-operative pain and no increase in pulmonary complications or length of stay. Larger, prospective studies are needed to further evaluate the safety of single transhiatal chest drain placement following MIO.

Integration of Diagnostic Lung Ultrasound Into Clinical Practice by Hospitalists in an Academic Medical Center: A Retrospective Chart Review.

Background Point-of-care lung ultrasound (LUS) is a guideline-recommended imaging modality that has been shown to be more accurate than chest radiography for multiple causes of dyspnea. This study was conducted to understand the impact of LUS on real-world clinical decision-making among hospitalists. Methods A retrospective chart review was conducted of patients who received a LUS while hospitalized at a quaternary care academic medical center between July 2020 and June 2022. Data was extracted from the electronic health record (EHR) into a standardized REDCap form. Cases were defined as patients who had received a LUS that (1) had images archived and accessible to viewing through the EHR and (2) had an imaging report documented in the EHR. Results Of the 820 LUSs reviewed, 297 (36.2%) were performed to evaluate for appropriateness of thoracentesis, 205 (25%) for diagnosing or monitoring of pneumonia related to COVID-19, 169 (20.6%) for volume status assessment, 136 (16.6%) for worsening respiratory status, 114 (13.9%) for monitoring pleural effusions, 64 (7.8%) for diagnosing or monitoring of pneumonia not related to COVID-19, and 12 (1.5%) for monitoring of diuresis. Documentation was sufficient to determine clinical decision-making in 730 (89%) of LUSs reviewed, 739 (90.1%) were considered to be diagnostically useful, and 327 (39.9%) changed management. Conclusions These findings suggest LUS was diagnostically useful and routinely changed management in hospitalist practice. Further, documentation in the EHR was sufficient to allow for the evaluation of real-world clinical decision-making using LUS, which is an important gap in both the education and health services research literature.

The role of cytokines in acute and chronic postsurgical pain after major musculoskeletal surgeries in a quaternary pediatric center

Study ObjectiveTo determine if baseline cytokines/chemokines and their changes over postoperative days 0–2 (POD0-2) predict acute and chronic postsurgical pain (CPSP) after major surgery. DesignProspective, observational, longitudinal nested study. SettingUniversity-affiliated quaternary children’s hospital. PatientsSubjects (≥8 years old) with idiopathic scoliosis undergoing spine fusion or pectus excavatum undergoing Nuss procedure. MeasurementsDemographics, surgical, psychosocial measures, pain scores, and opioid use over POD0-2 were collected. Cytokine concentrations were analyzed in serial blood samples collected before and up to two weeks after surgery, using Luminex bead arrays. After data preparation, relationships between pre- and post-surgical cytokine concentrations with acute (% time in moderate-severe pain over POD0-2) and chronic (pain score > 3/10 beyond 3 months post-surgery) post-surgical pain were analyzed using univariable and multivariable regression analyses with adjustment for covariates and mixed effects models were used to associate longitudinal cytokine concentrations with pain outcomes. Main ResultsAnalyses included 3,164 repeated measures of 16 cytokines/chemokines from 112 subjects (median age 15.3, IQR 13.5–17.0, 54.5 % female, 59.8 % pectus). Acute postsurgical pain was associated with higher baseline concentrations of GM-CSF (β = 0.95, SE 0.31; p = 0.003), IL-1β (β = 0.84, SE 0.36; p = 0.02), IL-2 (β = 0.78, SE 0.34; p = 0.03), and IL-12 p70 (β = 0.88, SE 0.40; p = 0.03) and longitudinal postoperative elevations in GM-CSF (β = 1.38, SE 0.57; p = 0.03), IFNγ (β = 1.36, SE 0.6; p = 0.03), IL-1β (β = 1.25, SE 0.59; p = 0.03), IL-7 (β = 1.65, SE 0.7; p = 0.02), and IL-12 p70 (β = 1.17, SE 0.58; p = 0.04). In contrast, CPSP was associated with lower baseline concentration of IL-8 (β = -0.39, SE 0.17; p = 0.02), and the risk of developing CPSP was elevated in patients with lower longitudinal postoperative concentrations of IL-6 (β = -0.57, SE 0.26; p = 0.03), IL-8 (β = -0.68, SE 0.24; p = 0.006), and IL-13 (β = -0.48, SE 0.22; p = 0.03). Covariates female (vs. male) sex and surgery type (pectus surgery vs. spine) were associated with higher odds for CPSP in baseline adjusted cytokine-CPSP association models for IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, TNFα, and IL-8, IL-10, respectively. ConclusionWe identified pro-inflammatory cytokine profiles associated with higher risk of acute postoperative pain. Interestingly, pleiotropic cytokine IL-6, chemokine IL-8 (which promotes neutrophil infiltration and monocyte differentiation), and monocyte-released anti-inflammatory cytokine IL-13, were associated with lower CPSP risk. Our results suggest heterogenous outcomes of cytokine/chemokine signaling that can both promote and protect against post-surgical pain. These may serve as predictive and prognostic biomarkers of pain outcomes following surgery.

Construction of new quaternary carbon center of fluorinated isoxazolines at C5 position via C-F bond cleavage

A substitution reaction of O-, S-, or N-nucleophiles onto fluorinated isoxazolines via carbon–fluorine (C-F) bond cleavage was achieved. The C-F bond at the C5 position of fluorinated isoxazolines was dissociated by using SnCl4 for the generation of a carbocation intermediate in this reaction. Subsequently, various nucleophiles such as alcohols, thiols, and amines were introduced, enabling the conversion to CO, C-S, or CN bonds and the formation of a new quaternary carbon center.

En Route to Enantioenriched Quaternary Stereocenters via Lewis Base/Palladium Cooperative Catalysis

AbstractThe prevalence of quaternary stereogenic centers in bioactive molecules coupled with innate challenges associated with their enantioselective preparation continues to provide powerful impetus for the development of catalytic asymmetric methods capable of their construction. Herein, we describe a cooperative isothiourea Lewis base‐palladium catalyst system that enables the enantioselective alkylation of α‐substituted‐α‐cyano esters with allyl methanesulfonate. While the levels of enantioselection are modest, this study represents the first time we have successfully constructed quaternary‐substituted stereogenic centers using this Lewis base‐palladium cooperative catalysis scheme. Further, this strategy constitutes a departure from ligand‐based enantiocontrol and suggests that, when using acidic pro‐nucleophiles, the development of protocols where Lewis base catalysis can outcompete direct deprotonation might be within reach.

Silver-Catalyzed Single-Carbon Insertion of Indoles with Acetophenone N-Triftosylhydrazones.

Here, we report a silver carbene-enabled single-carbon insertion reaction of indoles via a one-pot, two-step sequence to deliver a dearomative quaternary center quinoline scaffold in a modular fashion. Specifically, we used N-triftosylhydrazones as masked donor-donor carbene precursors that facilitate the insertion of carbon atoms bearing various functional groups to the library of functionalized quinoline. Experimental and DFT evidence support the transient presence of a cyclopropane species and removal of protecting groups.

A magnetic nanocatalyst based on Bronsted acid and Lewis acid centers for the efficient synthesis of polycyclic melting 1,5-benzodiazepines

In this study, 3-(Triethoxysilyl)propyl chloride (CPTES) was used to modify the surface of magnetic nanoparticles Fe3O4@SiO2, and aminomethylphosphonic acid (AMPA) was further anchored on the surface. Then, Ce (III) was used as the ligand to immobilize the surface of the modified material with N/O as the donor. Magnetic nanocatalysts (Fe3O4@SiO2@CPTES@AMPA@CeCl3) were successfully prepared. The prepared catalysts were characterized by infrared spectroscopy (FT-IR), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM), transmission electron microscopy (TEM), nitrogen absorption-desorption experiment (BET), vibrating sample magnetometer (VSM), energy dispersive spectroscopy (EDS) and inductively coupled plasma atomic emission spectrometry (ICP-AES). A synergetic effect of Brønsted and Lewis acid (AMPA and CeCl3) of the magnetic nanocatalyst was examined to active carbonyl, imine or enamine bonds for the synthesis of polycyclic fused 1,5-benzodiazepine with quaternary carbon centers or quinoxaline ring in a one-pot method. It was found that this catalyst exhibited excellent catalytic activities (TON up to 111368, TOF up to 110232 h−1) and high selectivities in the synthesis of fused 1,5-benzodiazepine compounds (22 examples, 85–96 % yields). The mechanism for the synthesis of polycyclic fused 1,5-benzodiazepine catalyzed by Fe3O4@SiO2@CPTES@AMPA@CeCl3 was proposed. The nanocatalyst was readily recovered by simple magnetic decantation and can be recyclable without obviously reducing catalytic activity up to seven times.

Review of Outpatient Pediatric Ethics Consults at an Academic Medical Center.

Limited data exist in the specific content of pediatric outpatient ethics consults as compared to inpatient ethics consults. Given the fundamental differences in outpatient and inpatient clinical care, we aimed to describe the distinctive nature of ethics consultation in the ambulatory setting. This is a retrospective review at a large, quaternary academic center of all outpatient ethics consults in a 6-year period. Encounter-level demographic data was recorded, and primary ethical issue and contextual features were identified using qualitative conceptual content analysis. A total of 48 consults were identified representing 44 unique patients. The most common primary ethical issue was beneficence and best interest concern comprising 20 (42%) consults, followed by refusal of recommended treatment comprising 11 (23%) consults and patient preference/assent comprising 5 (10%) consults. The most common contextual features were staff-family communication dispute/conflict comprising 28 (58%) consults, followed by legal involvement comprising 25 (52%) consults and quality of life comprising 19 (40%) consults. The most common consulting specialty was hematology/oncology. Ethical issues encountered in the provision of outpatient pediatric care are distinct and differ from those in inpatient consults. Further research is necessary to identify strategies and educational gaps in outpatient ethics consultation to increase its effectiveness and utilization.

Construction of remote cyano-substituted quaternary carbon centers via nickel-catalyzed migratory hydrocyanation of unconjugated dienes

Construction of remote cyano-substituted quaternary carbon centers via nickel-catalyzed migratory hydrocyanation of unconjugated dienes

Association Between Persistent Hypothermia After Cardiopulmonary Bypass in Neonates and Odds of Serious Complications.

Persistent hypothermia after cardiopulmonary bypass (CPB) in neonates with congenital heart defects (CHD) has been historically considered benign despite lack of evidence on its prognostic significance. Examine associations between the magnitude and pattern of unintentional postoperative hypothermia and odds of complications in neonates with CHD undergoing CPB. Retrospective cohort study. Single northeastern U.S., urban pediatric quaternary care center with an established cardiac surgery program. Population-based sample of neonates greater than or equal to 34 weeks gestation undergoing their first CPB between 2015 and 2019. None. Hourly temperature measurements for the first 48 postoperative hours were extracted from inpatient medical records, and clinical characteristics and outcomes were accessed through the local patient registry. Group-based trajectory modeling (GBTM) identified latent temporal temperature trajectories. Associations of trajectories with outcomes were assessed using multivariable binary logistic regression. Outcomes (postoperative complications) were manually adjudicated by experts or were predefined by the patient registry. Four hundred fifty neonates met inclusion criteria. Their mean (sd) gestational age was 38 weeks (1.3), mean (sd) birth weight was 3.19 kilograms (0.55), median (interquartile range) surgical age was 4.7 days (3.3-7.0), 284 of 450 (63%) were male, and 272 of 450 (60%) were White. GBTM identified three distinct curvilinear temperature trajectories: persistent hypothermia (n = 38, 9%), resolving hypothermia (n = 233, 52%), and normothermia (n = 179, 40%). Compared with the normothermic group, those with persistent hypothermia had significantly higher odds of cardiac arrest, actionable arrhythmia, delayed first successful extubation, prolonged cardiac ICU length of stay, very poor weight gain, and 30-day hospital mortality. The persistent hypothermia group was characterized by greater odds of having a lower gestational age, more prevalent neurologic abnormalities, more unplanned reoperations, and a low surgical mortality risk assessment. Persistent postoperative hypothermia in neonates after CPB is independently associated with having greater odds of complications. Recovery patterns from postoperative hypothermia may be a clinically useful marker to identify patient instability in neonates. Additional research is needed for causal modeling and prospective validation before clinical adoption.

Mechanical Thromboprophylaxis and Hospital-Acquired Venous Thromboembolism Among Critically Ill Adolescents: A U.S. Pediatric Health Information Systems Registry Study, 2016-2023.

To estimate the rate of mechanical thromboprophylaxis (mTP) prescription among critically ill adolescents using a multicenter administrative database and determine whether mTP prescription is inversely associated with hospital-acquired venous thromboembolism. Multicenter, observational, retrospective study of the Pediatric Health Information Systems (PHIS) Registry cohort, January 2016 to December 2023. Thirty PICUs located within quaternary pediatric referral centers in the United States. Critically ill children 12-17 years old, excluding encounters with a principal diagnosis at admission of venous thromboembolism. mTP prescription within the first 24 hours of hospitalization. A total of 107,804 children met the study criteria, of which 21,124 (19.6%) were prescribed mTP. Hospital center prescribing rates ranged from 1.4% to 65.4% and decreased by 1.6% per year from 28.2% in 2016 to 17.1% in 2023. As compared with those without mTP, those with mTP more frequently had a concurrent central venous catheter (17.2% vs. 9.4%, p < 0.001), underwent invasive mechanical ventilation (37.4% vs. 24.8%, p < 0.001), were admitted for a primary surgical indication (30.9% vs. 12.7%, p < 0.001), and experienced a longer median duration of hospitalization (7 [interquartile range (IQR): 4-15] vs. 4 [IQR: 2-9] d, p < 0.001). Hospital-acquired venous thromboembolism occurred in 2.7% of the study sample and was more common among those with, as compared with without, prescription of mTP (4% vs. 2.4%, p < 0.001). In multivariable logistic regression models for hospital-acquired venous thromboembolism adjusting for salient prothrombotic risk factors, we failed to identify an association between mTP and greater odds of hospital-acquired venous thromboembolism (HA-VTE) among low-, moderate-, and high-risk tiers. However, we cannot exclude the possibility of 17-50% greater odds of HA-VTE in this population. In the multicenter PHIS cohort, 2016-2023, the prescribing patterns for mTP among critically ill adolescents showed a low rate of mTP prescription (19.6%) that varied widely across institutions, decreased annually over the study period by 1.6%/year, and was not independently associated with HA-VTE risk reduction.

Palladium-Catalyzed Regio- and Diastereoselective Hydro(hetero)arylation for Rapid Construction of Quaternary Center Containing Cyclobutanes.

Herein we report a Pd-catalyzed regio- and diastereoselective hydro(hetero)arylation of inactivated alkylidenecyclobutanes. This protocol provides a rapid and atom-economical route to access 3-cyclobutyl (hetero)arenes with good functionalities toleration. With the assistance of the directing group, nucleophilic attack happened on the bulkier γ-position to form the quaternary carbon center. Furthermore, the selected products exhibited antitumor bioactivities.

Zinc‐Mediated Carbamoyl Amination of Alkylidenecyclopropane‐Tethered Carbamoyl Chlorides: Synthesis of Functionalized 2‐Quinolones

The transition metal catalyzed cyclization of alkene‐tethered carbamoyl chloride has now emerged as a vital tool to construct oxindoles bearing all carbon quaternary centers. However, most of these reactions proceed via carbometalation‐initiated 5‐exo‐trig cyclization followed by nucleophilic trapping of the resulting σ alkyl‐metal species to achieve diverse functionalized oxindoles. The 6‐endo‐trig type cyclization of alkene‐tethered carbamoyl chloride has been rarely reported. Herein, a zinc‐mediated carbamoyl amination of alkylidenecyclopropane‐tethered carbamoyl chlorides with anilines for the synthesis of functionalized 2‐quinolones was developed. A range of different substituted 2‐quinolones were prepared in 65‐89% yields from alkylidenecyclopropane‐tethered carbamoyl chlorides and aniline derivatives using Zn/TMSCl system.

Construction of Vicinal Quaternary Centers via Ru-Catalyzed Enantiospecific Allylic Substitution with Lithium Ester Enolates.

The installation of vicinal quaternary centers with absolute stereocontrol constitutes a considerable challenge in organic synthesis. Herein, we introduce a novel [Cp*Ru(MeCN)3]PF6/phenoxythiazoline catalyst system that achieves enantiospecific allylic substitution of tertiary carbonates with α,α-disubstituted lithium ester enolates to give products containing vicinal quaternary centers. Noteworthy features include the direct use of nonstabilized ester enolates, a class of nucleophiles which has rarely been used in transition metal-catalyzed allylic substitution reactions. The approach is demonstrated for a broad scope of tertiary electrophiles as well as ester enolates and accomplishes stereoretentive substitution with excellent conservation of ee (89-99%) and branched/linear regioselectivities (up to 40:1).