Proteomic discovery of chemical probes that perturb protein complexes in human cells.

Most human proteins lack chemical probes, and several large-scale and generalizable small-molecule binding assays have been introduced to address this problem. How compounds discovered in such "binding-first" assays affect protein function, nonetheless, often remains unclear. Here, we describe a "function-first" proteomic strategy that uses size exclusion chromatography (SEC) to assess the global impact of electrophilic compounds on protein complexes in human cells. Integrating the SEC data with cysteine-directed activity-based protein profiling identifies changes in protein-protein interactions that are caused by site-specific liganding events, including the stereoselective engagement of cysteines in PSME1 and SF3B1 that disrupt the PA28 proteasome regulatory complex and stabilize a dynamic state of the spliceosome, respectively. Our findings thus show how multidimensional proteomic analysis of focused libraries of electrophilic compounds can expedite the discovery of chemical probes with site-specific functional effects on protein complexes in human cells.

Intrinsic glassy-metallic transport in an amorphous coordination polymer.

Conducting organic materials, such as doped organic polymers1, molecular conductors2,3 and emerging coordination polymers4, underpin technologies ranging from displays to flexible electronics5. Realizing high electrical conductivity in traditionally insulating organic materials necessitates tuning their electronic structure through chemical doping6. Furthermore, even organic materials that are intrinsically conductive, such as single-component molecular conductors7,8, require crystallinity for metallic behaviour. However, conducting polymers are often amorphous to aid durability and processability9. Using molecular design to produce high conductivity in undoped amorphous materials would enable tunable and robust conductivity in many applications10, but there are no intrinsically conducting organic materials that maintain high conductivity when disordered. Here we report an amorphous coordination polymer, Ni tetrathiafulvalene tetrathiolate, which displays markedly high electronic conductivity (up to 1,200 S cm-1) and intrinsic glassy-metallic behaviour. Theory shows that these properties are enabled by molecular overlap that is robust to structural perturbations. This unusual set of features results in high conductivity that is stable to humid air for weeks, pH 0-14 and temperatures up to 140 °C. These findings demonstrate that molecular design can enable metallic conductivity even in heavily disordered materials, raising fundamental questions about how metallic transport can exist without periodic structure and indicating exciting new applications for these materials.

Remodeling oncogenic transcriptomes by small molecules targeting NONO.

Much of the human proteome is involved in mRNA homeostasis, but most RNA-binding proteins lack chemical probes. Here we identify electrophilic small molecules that rapidly and stereoselectively decrease the expression of transcripts encoding the androgen receptor and its splice variants in prostate cancer cells. We show by chemical proteomics that the compounds engage C145 of the RNA-binding protein NONO. Broader profiling revealed that covalent NONO ligands suppress an array of cancer-relevant genes and impair cancer cell proliferation. Surprisingly, these effects were not observed in cells genetically disrupted for NONO, which were instead resistant to NONO ligands. Reintroduction of wild-type NONO, but not a C145S mutant, restored ligand sensitivity in NONO-disrupted cells. The ligands promoted NONO accumulation in nuclear foci and stabilized NONO-RNA interactions, supporting a trapping mechanism that may prevent compensatory action of paralog proteins PSPC1 and SFPQ. These findings show that NONO can be co-opted by covalent small molecules to suppress protumorigenic transcriptional networks.

Early Interventional Treatment of High Output Chyle Leak After Esophagectomy is Associated With Improved Survival.

OBJECTIVE: To investigate overall survival and length of stay (LOS) associated with differing management for high output (>1 L over 24 hours) leaks (HOCL) after cancer-related esophagectomy. BACKGROUND: Although infrequent, chyle leak after esophagectomy is an event that can lead to significant perioperative sequelae. Low-volume leaks appear to respond to nonoperative measures, whereas HOCLs often require invasive therapeutic interventions. METHODS: From a prospective single-institution database, we retrospectively reviewed patients treated from 2001 to 2021 who underwent esophagectomy for esophageal cancer. Within that cohort, we focused on a subgroup of patients who manifested a HOCL postoperatively. Clinicopathologic and operative characteristics were collected, including hospital LOS and survival data. RESULTS: A total of 53/2299 patients manifested a HOCL. These were mostly males (77%), with a mean age of 62 years. Of this group, 15 patients received nonoperative management, 15 patients received prompt (<72 hours from diagnosis) interventional management, and 23 received late interventional management. Patients in the late intervention group had longer LOSs compared with early intervention (slope = 9.849, 95% CI: 3.431-16.267). Late intervention (hazard ratio: 4.772, CI: 1.384-16.460) and nonoperative management (hazard ratio: 4.731, CI: 1.294-17.305) were associated with increased mortality compared with early intervention. Patients with early intervention for HOCL had an overall survival similar to patients without chyle leaks in survival analysis. CONCLUSIONS: Patients with HOCL should receive early intervention to possibly reverse the prognostic implications of this potentially detrimental complication.

Relationship of Surgical Approach With Financial Toxicity in Patients With Resected Lung Cancer.

INTRODUCTION: Minimally invasive surgery (MIS) reduces lengths of stay, complications, and potentially perioperative hospital costs. However, the impact of MIS on financial toxicity (FT), defined as the costs resulting from oncologic care and their negative effects on quality of life, in patients with lung cancer is unknown. Our objective was to investigate the association between surgical approach and FT in this population. METHODS: A single-institution study was performed evaluating resected lung cancer patients (2016-2021). FT was assessed using the Comprehensive Score for Financial Toxicity (COST) questionnaire. The relationship between surgical approach (MIS vs. thoracotomy) and FT was evaluated using propensity score-matched (PSM) regression analysis. A sensitivity analysis involving the entire cohort was also performed using an inverse probability-weighted generalized linear model. RESULTS: As reported previously, of 1477 patients surveyed, 463 responded (31.3%) with FT reported in 196 patients (42.3%). Resection was performed by thoracotomy in 53.3% (n = 247), and by MIS in the remainder (n = 216, 46.7%; video-assisted thoracoscopic surgery [VATS] = 115; robotic-assisted = 101). There was no difference in FT in patients who underwent VATS and robotic-assisted surgery (p = 0.515). In the PSM analysis, MIS was not associated with FT (odds ratio [OR]: 0.980, 95% confidence interval [CI]: 0.628-1.533, p = 0.929). Similar results were found on sensitivity analysis (OR: 1.488, CI: 0.931-2.378, p = 0.096). CONCLUSIONS: Compared to MIS, thoracotomy was not associated with FT in patients with resected lung cancer. Though there are several benefits from MIS, it does not appear to be a meaningful strategy to alleviate FT in this population.

Do resected colorectal cancer patients need early chest imaging? Impact of clinicopathologic characteristics on time to development of pulmonary metastases.

BACKGROUND AND OBJECTIVES: For patients with colorectal cancer (CRC), the lung is the most common extra-abdominal site of distant metastasis. However, practices for chest imaging after colorectal resection vary widely. We aimed to identify characteristics that may indicate a need for early follow-up imaging. METHODS: We retrospectively reviewed charts of patients who underwent CRC resection, collecting clinicopathologic details and oncologic outcomes. Patients were grouped by timing of pulmonary metastases (PM) development. Analyses were performed to investigate odds ratio (OR) of PM diagnosis within 3 months of CRC resection. RESULTS: Of 1600 patients with resected CRC, 233 (14.6%) developed PM, at a median of 15.4 months following CRC resection. Univariable analyses revealed age, receipt of systemic therapy, lymph node ratio (LNR), lymphovascular and perineural invasion, and KRAS mutation as risk factors for PM. Furthermore, multivariable regression showed neoadjuvant therapy (OR: 2.99, p < 0.001), adjuvant therapy (OR: 6.28, p < 0.001), LNR (OR: 28.91, p < 0.001), and KRAS alteration (OR: 5.19, p < 0.001) to predict PM within 3 months post-resection. CONCLUSIONS: We identified clinicopathologic characteristics that predict development of PM within 3 months after primary CRC resection. Early surveillance in such patients should be emphasized to ensure timely identification and treatment of PM.

Octreotide's role in the management of post-esophagectomy chylothorax.

The use of octreotide in managing intrathoracic chyle leak following esophagectomy has gained popularity in the adult population. While the benefits of octreotide have been confirmed in the pediatric population, there remains limited evidence to support its use in the adults post-esophagectomy. Thus, we performed a single-institution cohort study to characterize its efficacy. The study was performed using a prospective, single-center database, from which clinicopathologic characteristics were extracted of patients who had post-esophagectomy chyle leaks. Kaplan-Meier and multivariable Cox regression analyses were performed to investigate the effect of octreotide use on chest tube duration (CTD), hospital length of stay (LOS), and overall survival (OS). In our cohort, 74 patients met inclusion criteria, among whom 27 (36.5%) received octreotide. Kaplan-Meier revealed no significant effect of octreotide on CTD (P = 0.890), LOS (P = 0.740), or OS (P = 0.570). Multivariable Cox regression analyses further corroborated that octreotide had no effect on CTD (HR = 0.62, 95% confidence interval [CI]: 0.32-1.20, P = 0.155), LOS (HR = 0.64, CI: 0.34-1.21, P = 0.168), or OS (1.08, CI: 0.53-2.19, P = 0.833). Octreotide use in adult patients with chyle leak following esophagectomy lacks evidence of association with meaningful clinical outcomes. Level 1 evidence is needed prior to further consideration in this population.

How Has the Total Hip Arthroplasty Patient Population Changed? A Ten-Year Analysis of Total Hip Arthroplasty Patients From 2013 to 2022: A Retrospective, Single-Center Study.

BACKGROUND: Over the past decades, utilization of total hip arthroplasty (THA) has steadily increased. Understanding the demographic trends of THA patients can assist in projecting access to care. This study sought to assess the temporal trends in THA patient baseline characteristics and socioeconomic factors. METHODS: We retrospectively analyzed 16,296 patients who underwent primary elective THA from January 1, 2013, to December 31, 2022. Demographic data, including age, sex, race, body mass index (BMI), Charlson comorbidity index, insurance, and socioeconomic status, as determined by median income by patients' zip code, were collected. The trends of these data were analyzed using the Mann-Kendall test. RESULTS: Over the past decade at our institution, patient age (2013: 62.1 years to 2022: 65.1 years, P = .001), BMI (2013: 29.0 to 2022: 29.5, P = .020), and mean Charlson comorbidity index (2013: 2.4 to 2022: 3.1, P = .001) increased. The proportion of Medicare patients increased from 48.4% in 2013 to 54.9% in 2022 (P = .001). The proportion of African American patients among the THA population increased from 11.3% in 2013 to 13.0% in 2022 (P = .012). Over this period, 90-day readmission and 1-year revision rates did not significantly change (2013: 4.8 and 3.0% to 2022: 3.4 and 1.4%, P = .107 and P = .136, respectively). The proportion of operations using robotic devices also significantly increased (2013: 0% to 2022: 19.1%; P < .001). CONCLUSIONS: In the past decade, the average age, BMI, and comorbidity burden of THA patients have significantly increased, suggesting improved access to care for these populations. Similarly, there have been improvements in access to care for African American patients. Along with these changes in patient demographics, we found no change in 90-day readmission or 1-year revision rates. Continued characterization of the THA patient population is vital to understanding this demographic shift and educating future strategies and improvements in patient care.

Library Screening, In Vivo Confirmation, and Structural and Bioinformatic Analysis of Pentapeptide Sequences as Substrates for Protein Farnesyltransferase.

Protein farnesylation is a post-translational modification where a 15-carbon farnesyl isoprenoid is appended to the C-terminal end of a protein by farnesyltransferase (FTase). This process often causes proteins to associate with the membrane and participate in signal transduction pathways. The most common substrates of FTase are proteins that have C-terminal tetrapeptide CaaX box sequences where the cysteine is the site of modification. However, recent work has shown that five amino acid sequences can also be recognized, including the pentapeptides CMIIM and CSLMQ. In this work, peptide libraries were initially used to systematically vary the residues in those two parental sequences using an assay based on Matrix Assisted Laser Desorption Ionization-Mass Spectrometry (MALDI-MS). In addition, 192 pentapeptide sequences from the human proteome were screened using that assay to discover additional extended CaaaX-box motifs. Selected hits from that screening effort were rescreened using an in vivo yeast reporter protein assay. The X-ray crystal structure of CMIIM bound to FTase was also solved, showing that the C-terminal tripeptide of that sequence interacted with the enzyme in a similar manner as the C-terminal tripeptide of CVVM, suggesting that the tripeptide comprises a common structural element for substrate recognition in both tetrapeptide and pentapeptide sequences. Molecular dynamics simulation of CMIIM bound to FTase further shed light on the molecular interactions involved, showing that a putative catalytically competent Zn(II)-thiolate species was able to form. Bioinformatic predictions of tetrapeptide (CaaX-box) reactivity correlated well with the reactivity of pentapeptides obtained from in vivo analysis, reinforcing the importance of the C-terminal tripeptide motif. This analysis provides a structural framework for understanding the reactivity of extended CaaaX-box motifs and a method that may be useful for predicting the reactivity of additional FTase substrates bearing CaaaX-box sequences.

Parahydrogen-Induced Polarization of 14N Nuclei.

Hyperpolarization techniques provide a dramatic increase in sensitivity of nuclear magnetic resonance spectroscopy and imaging. In spite of the outstanding progress in solution-state hyperpolarization of spin-1/2 nuclei, hyperpolarization of quadrupolar nuclei remains challenging. Here, hyperpolarization of quadrupolar 14N nuclei with natural isotopic abundance of >99 % is demonstrated. This is achieved via pairwise addition of parahydrogen to tetraalkylammonium salts with vinyl or allyl unsaturated moieties followed by a subsequent polarization transfer from 1H to 14N nuclei at high magnetic field using PH-INEPT or PH-INEPT+ radiofrequency pulse sequence. Catalyst screening identified water-soluble rhodium complex [Rh(P(m-C6H4SO3Na)3)3Cl] as the most efficient catalyst for hyperpolarization of the substrates under study, providing up to 1.3 % and up to 6.6 % 1H polarization in the cases of vinyl and allyl precursors, respectively. The performance of PH-INEPT and PH-INEPT+ pulse sequences was optimized with respect to interpulse delays, and the resultant experimental dependences were in good agreement with simulations. As a result, 14N NMR signal enhancement of up to 760-fold at 7.05 T (corresponding to 0.15 % 14N polarization) was obtained.

Broad Electronic Modulation of Two-Dimensional Metal-Organic Frameworks over Four Distinct Redox States.

Two-dimensional (2D) inorganic materials have emerged as exciting platforms for (opto)electronic, thermoelectric, magnetic, and energy storage applications. However, electronic redox tuning of these materials can be difficult. Instead, 2D metal-organic frameworks (MOFs) offer the possibility of electronic tuning through stoichiometric redox changes, with several examples featuring one to two redox events per formula unit. Here, we demonstrate that this principle can be extended over a far greater span with the isolation of four discrete redox states in the 2D MOFs LixFe3(THT)2 (x = 0-3, THT = triphenylenehexathiol). This redox modulation results in 10,000-fold greater conductivity, p- to n-type carrier switching, and modulation of antiferromagnetic coupling. Physical characterization suggests that changes in carrier density drive these trends with relatively constant charge transport activation energies and mobilities. This series illustrates that 2D MOFs are uniquely redox flexible, making them an ideal materials platform for tunable and switchable applications.

Financial Toxicity in Patients With Resected Lung Cancer.

OBJECTIVES: To describe financial toxicity (FT) in patients with resected lung cancer and identify risk factors in this population. BACKGROUND: FT describes the financial burden associated with cancer care and its impact on the quality of survivorship. Few prior studies have examined FT in patients with lung cancer. METHODS: Patients who underwent lung cancer resection at our institution between January 1, 2016 and December 31, 2021, were surveyed to gather demographic information and evaluate FT using a validated questionnaire. A multivariable model was built to identify risk factors for FT. RESULTS: Of the total, 1477 patients were contacted, of whom 463 responded (31.3%). Most patients were stage I (n = 349, 75.4%) and lobectomy was performed often (n = 290, 62.8%). There were 196 patients (42.3%) who experienced FT. Upon multivariable analyses, divorced marital status [odds ratio (OR) = 3.658, 95% CI: 1.180-11.337], household income <$40,000 (OR = 2.544, 95% CI: 1.003-6.455), credit score below 739 (OR = 2.744, 95% CI: 1.326-5.679), clinical stage >I (OR = 2.053, 95% CI: 1.088-3.877), and change in work hours or work cessation (all P < 0.05) were associated with FT. Coping mechanisms, such as decreased spending on food or clothing and increased use of savings or borrowing money, were more likely to be reported by patients experiencing FT than those who did not ( P < 0.001). CONCLUSIONS: Patients undergoing lung cancer resection often experienced significant financial stress with several identifiable risk factors. FT should be considered early in the care of these patients to alleviate detrimental coping mechanisms and enhance their quality of survivorship.

High-Risk Features of Esophageal Adenocarcinoma Following Neoadjuvant Chemoradiation: Patients for Whom Surgery Should Not Be Delayed.

OBJECTIVE: Clinical predictors of pathological complete response have not reliably identified patients for whom an organ-sparing approach following neoadjuvant chemoradiation be undertaken for esophageal cancer patients. We sought to identify high-risk predictors of residual carcinoma that may preclude patients from a selective surgical approach. BACKGROUND: Patients treated with neoadjuvant chemoradiation followed by esophagectomy for esophageal adenocarcinoma were identified. PATIENTS AND METHODS: Correlation between clinical and pathologic complete responses were examined. Regression models and recursive partitioning were utilized to identify features associated with residual carcinoma. External validation of these high-risk factors was performed on a data set from an independent institution. RESULTS: A total of 326 patients were identified, in whom clinical complete response was noted in 104/326 (32%). Pathologic complete response was noted in only 33/104 (32%) of these clinical complete responders. Multivariable analysis identified that the presence of stricture ( P =0.011), positive biopsy ( P =0.010), and signet ring cell histology ( P =0.019) were associated with residual cancer. Recursive partitioning corroborated a 94% probability of residual disease, or greater, for each of these features. The positive predictive value was >90% for these characteristics. A SUV max >5.4 at the esophageal primary in the absence of esophagitis was also a high-risk factor for residual carcinoma. External validation confirmed these high-risk factors to be implicated in the finding of residual carcinoma. CONCLUSIONS: Clinical parameters of response are poor predictors of complete pathologic response leading to challenges in selecting candidates for active surveillance. However, we characterize several high-risk features for residual carcinoma which indicate that esophagectomy should not be delayed.

Colonization of the Caenorhabditis elegans gut with human enteric bacterial pathogens leads to proteostasis disruption that is rescued by butyrate.

Protein conformational diseases are characterized by misfolding and toxic aggregation of metastable proteins, often culminating in neurodegeneration. Enteric bacteria influence the pathogenesis of neurodegenerative diseases; however, the complexity of the human microbiome hinders our understanding of how individual microbes influence these diseases. Disruption of host protein homeostasis, or proteostasis, affects the onset and progression of these diseases. To investigate the effect of bacteria on host proteostasis, we used Caenorhabditis elegans expressing tissue-specific polyglutamine reporters that detect changes in the protein folding environment. We found that colonization of the C. elegans gut with enteric bacterial pathogens disrupted proteostasis in the intestine, muscle, neurons, and the gonad, while the presence of bacteria that conditionally synthesize butyrate, a molecule previously shown to be beneficial in neurodegenerative disease models, suppressed aggregation and the associated proteotoxicity. Co-colonization with this butyrogenic strain suppressed bacteria-induced protein aggregation, emphasizing the importance of microbial interaction and its impact on host proteostasis. Further experiments demonstrated that the beneficial effect of butyrate depended on the bacteria that colonized the gut and that this protective effect required SKN-1/Nrf2 and DAF-16/FOXO transcription factors. We also found that bacteria-derived protein aggregates contribute to the observed disruption of host proteostasis. Together, these results reveal the significance of enteric infection and gut dysbiosis on the pathogenesis of protein conformational diseases and demonstrate the potential of using butyrate-producing microbes as a preventative and treatment strategy for neurodegenerative disease.

Neoadjuvant versus definitive chemoradiation in locally advanced esophageal cancer for patients of advanced age or significant comorbidities.

The addition of surgery to chemoradiation for esophageal cancer has not shown a survival benefit in randomized trials. Patients with more comorbidities or advanced age are more likely to be given definitive chemoradiation due to surgical risk. We aimed to identify subsets of patients in whom the addition of surgery to chemoradiation does not provide an overall survival (OS) benefit. The National Cancer Database was queried for patients with locally advanced esophageal cancer who received either definitive chemoradiation or neoadjuvant chemoradiation followed by surgery. Bivariate analysis was used to assess the association between patient characteristics and treatment groups. Log-rank tests and Cox proportional hazards models were performed to assess for differences in survival. A total of 15,090 with adenocarcinoma and 5,356 with squamous cell carcinoma met the inclusion criteria. Patients treated with neoadjuvant chemoradiation and surgery had significantly improved survival by Cox proportional hazards model regardless of histology if <50, 50-60, 61-70, or 71-80 years old. There was no significant benefit or detriment in patients 81-90 years old. Survival advantage was also significant with a Charlson/Deyo comorbidity condition score of 0, 1, 2, and ≥3 in adenocarcinoma squamous cell carcinoma with scores of 2 or ≥3 had no significant benefit or detriment. Patients 81-90 years old or with squamous cell carcinoma and a Charlson/Deyo comorbidity score ≥ 2 lacked an OS benefit from neoadjuvant chemoradiation followed by surgery compared with definitive chemoradiation. Careful consideration of esophagectomy-specific surgical risks should be used when recommending treatment for these patients.

Development of an evidence-based model for predicting patient, provider, and appointment factors that influence no-shows in a rural healthcare system.

BACKGROUND: No-show appointments pose a significant challenge for healthcare providers, particularly in rural areas. In this study, we developed an evidence-based predictive model for patient no-shows at the Marshfield Clinic Health System (MCHS) rural provider network in Wisconsin, with the aim of improving overbooking approaches in outpatient settings and reducing the negative impact of no-shows in our underserved rural patient populations. METHODS: Retrospective data (2021) were obtained from the MCHS scheduling system, which included 1,260,083 total appointments from 263,464 patients, as well as their demographic, appointment, and insurance information. We used descriptive statistics to associate variables with show or no-show status, logistic regression, and random forests utilized, and eXtreme Gradient Boosting (XGBoost) was chosen to develop the final model, determine cut-offs, and evaluate performance. We also used the model to predict future no-shows for appointments from 2022 and onwards. RESULTS: The no-show rate was 6.0% in both the train and test datasets. The train and test datasets both yielded 5.98. Appointments scheduled further in advance (> 60 days of lead time) had a higher (7.7%) no-show rate. Appointments for patients aged 21-30 had the highest no-show rate (11.8%), and those for patients over 60 years of age had the lowest (2.9%). The model predictions yielded an Area Under Curve (AUC) of 0.84 for the train set and 0.83 for the test set. With the cut-off set to 0.4, the sensitivity was 0.71 and the positive predictive value was 0.18. Model results were used to recommend 1 overbook for every 6 at-risk appointments per provider per day. CONCLUSIONS: Our findings demonstrate the feasibility of developing a predictive model based on administrative data from a predominantly rural healthcare system. Our new model distinguished between show and no-show appointments with high performance, and 1 overbook was advised for every 6 at-risk appointments. This data-driven approach to mitigating the impact of no-shows increases treatment availability in rural areas by overbooking appointment slots on days with an elevated risk of no-shows.

Considerations for Surgical Treatment of Neurogenic Thoracic Outlet Syndrome: A Meta-Analysis of Patient-Reported Outcomes.

PURPOSE: It remains unclear whether first rib resection (FRR), performed via a supraclavicular (SCFRR) or transaxillary (TAFRR) approach, is necessary for patients with neurogenic thoracic outlet syndrome (nTOS). In a systematic review and meta-analysis, we performed a direct comparison of patient-reported functional outcomes following different surgical approaches for nTOS. METHODS: The authors searched PubMed, Embase, Web of Science, Cochrane Library, PROSPERO, Google Scholar, and the gray literature. Data were extracted based on the procedure type. Well-validated patient-reported outcome measures were analyzed in separate time intervals. Random-effects meta-analysis and descriptive statistics were used where appropriate. RESULTS: Twenty-two articles were included, with 11 discussing SCFRR (812 patients), 6 discussing TAFRR (478 patients), and 5 discussing rib-sparing scalenectomy (RSS; 720 patients). The mean difference between preoperative and postoperative Disabilities of the Arm, Shoulder and Hand score was significantly different comparing RSS (43.0), TAFRR (26.8), and SCFRR (21.8). The mean difference between preoperative and postoperative visual analog scale scores was significantly higher for TAFRR (5.3) compared to SCFRR (3.0). Derkash scores were significantly worse for TAFRR compared to RSS or SCFRR. RSS had a success rate of 97.4% based on Derkash score, followed by SCFRR and TAFRR at 93.2% and 87.9%, respectively. RSS had a lower complication rate compared to SCFRR and TAFRR. There was a difference in complication rates: 8.7%, 14.5%, and 3.6% for SCFRR, TAFRR, and RSS, respectively. CONCLUSIONS: Mean differences in Disabilities of the Arm, Shoulder and Hand scores and Derkash scores were significantly better for RSS. Higher complication rates were reported after FRR. Our findings suggest that RSS is an effective option for the treatment of nTOS. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Preserved ß-adrenergic-mediated vasodilation in skeletal muscle of young adults with obesity despite shifts in cyclooxygenase and nitric oxide synthase.

Central adiposity is associated with greater sympathetic support of blood pressure. ß-adrenergic receptors (ß-AR) buffer sympathetically mediated vasoconstriction and ß-AR-mediated vasodilation is attenuated in preclinical models of obesity. With this information, we hypothesized ß-AR vasodilation would be lower in obese compared with normal weight adults. Because ß-AR vasodilation in normal weight adults is limited by cyclooxygenase (COX) restraint of nitric oxide synthase (NOS), we further explored the contributions of COX and NOS to ß-AR vasodilation in this cohort. Forearm blood flow (FBF, Doppler ultrasound) and mean arterial blood pressure (MAP, brachial arterial catheter) were measured and forearm vascular conductance (FVC) was calculated (FVC = FBF/MAP). The rise in FVC from baseline (ΔFVC) was quantified during graded brachial artery infusion of isoproterenol (Iso, 1-12 ng/100 g/min) in normal weight (n = 36) and adults with obesity (n = 22) (18-40 yr old). In a subset of participants, Iso-mediated vasodilation was examined before and during inhibition of NOS [NG-monomethyl-l-arginine (l-NMMA)], COX (ketorolac), and NOS + COX (l-NMMA + ketorolac). Iso-mediated increases in FVC did not differ between groups (P = 0.57). l-NMMA attenuated Iso-mediated ΔFVC in normal weight (P = 0.03) but not adults with obesity (P = 0.27). In normal weight adults, ketorolac increased Iso-mediated ΔFVC (P < 0.01) and this response was lost with concurrent l-NMMA (P = 0.67). In contrast, neither ketorolac (P = 0.81) nor ketorolac + l-NMMA (P = 0.40) altered Iso-mediated ΔFVC in adults with obesity. Despite shifts in COX and NOS, ß-AR vasodilation is preserved in young adults with obesity. These data highlight the presence of a compensatory shift in microvascular control mechanisms in younger humans with obesity.NEW & NOTEWORTHY We examined ß-adrenergic receptor-mediated vasodilation in skeletal muscle of humans with obesity and normal weight. Results show that despite shifts in the contribution of cyclooxygenase and nitric oxide synthase, ß-adrenergic-mediated vasodilation is relatively preserved in young, otherwise healthy adults with obesity. These data highlight the presence of subclinical changes in microvascular control mechanisms early in the obesity process and suggest duration of obesity and/or the addition of primary aging may be necessary for overt dysfunction.

The Role of Surgery in the Treatment of Melanoma Pulmonary Metastases in the Modern Era.

INTRODUCTION: The lung represents a frequent site of spread for metastatic melanoma, which has historically been managed with surgical resection achieving promising outcomes. We hypothesized that the role of surgery in the management of melanoma pulmonary metastases (MPM) is evolving among the development of less invasive diagnostic and novel systemic therapeutic strategies. MATERIALS AND METHODS: A single-center thoracic surgery database was reviewed and patients who underwent surgical resection of MPM between 1998 and 2019 were identified. Demographic, clinicopathologic, and surgical data were collected and analyzed, as were the annual volumes and indications for surgical resection. A Cochran-Armitage test was used to assess the trend in surgical indication. RESULTS: Three hundred and seventy seven surgical procedures for MPM were performed during the years of study in the care of 347 patients. Patients were predominantly male, with a mean age of 59.3 y. The mean number of annual resections was 17 and while this number initially increased from six in 1998 to a peak of 39 cases in 2008, a decline was subsequently observed. Diagnostic resection decreased from 22% in 1998-1999 to 5% at the peak of procedures in 2008-2009 and to 0 in 2018-2019 (P = 0.02). Curative resection increased from 44% in 1998-1999 to 73% in 2008-2009 (P < 0.001) and remained the dominant reason for surgery in later years. CONCLUSIONS: Surgical indications in the management of MPM have transformed in conjunction with systemic modalities, and the volume of resections has decreased in the modern era. Despite innovations in systemic management and shifting goals of operative interventions, surgeons continue to play a vital role in caring for these patients with an advanced disease.

Evaluation of Psychiatric Rehospitalization of Individuals Treated at a Federally Qualified Health Center.

At a federally qualified health center which often receives discharge referrals from the local hospital, rehospitalization rates and reasons were unknown yet pertinent information for assuring timely follow-up appointments. This study examined psychiatric discharge and rehospitalization between August 2020 and January 2021. Between August and October 2020, all adult patients of the FQHC were investigated who presented to or were discharged from the hospital. Those who received a primary psychiatric diagnosis were then examined retrospectively (between November 2020 and January 2021) to determine readmission status. During the study period, 36 patients were hospitalized with primary psychiatric diagnoses, 81% of whom did not establish behavioral health care subsequent to their initial hospitalization. The overall 90-day readmission rate of the sample was 41.7% with 80% of these individuals returning within 30 days.