A protein-based machine learning approach to the identification of inflammatory subtypes in pancreatic ductal adenocarcinoma.

BACKGROUND/OBJECTIVES: The inherently immunosuppressive tumor microenvironment along with the heterogeneity of pancreatic ductal adenocarcinoma (PDAC) limits the effectiveness of available treatment options and contributes to the disease lethality. Using a machine learning algorithm, we hypothesized that PDAC may be categorized based on its microenvironment inflammatory milieu. METHODS: Fifty-nine tumor samples from patients naïve to treatment were homogenized and probed for 41 unique inflammatory proteins using a multiplex assay. Subtype clustering was determined using t-distributed stochastic neighbor embedding (t-SNE) machine learning analysis of cytokine/chemokine levels. Statistics were performed using Wilcoxon rank sum test and Kaplan-Meier survival analysis. RESULTS: t-SNE analysis of tumor cytokines/chemokines revealed two distinct clusters, immunomodulating and immunostimulating. In pancreatic head tumors, patients in the immunostimulating group (N = 26) were more likely to be diabetic (p = 0.027), but experienced less intraoperative blood loss (p = 0.0008). Though there were no significant differences in survival (p = 0.161), the immunostimulating group trended toward longer median survival by 9.205 months (11.28 vs. 20.48 months). CONCLUSION: A machine learning algorithm identified two distinct subtypes within the PDAC inflammatory milieu, which may influence diabetes status as well as intraoperative blood loss. Opportunity exists to further explore how these inflammatory subtypes may influence treatment response, potentially elucidating targetable mechanisms of PDAC's immunosuppressive tumor microenvironment.

Obesity and Associated Outcomes for Blunt vs Penetrating Mechanism in Trauma Laparotomy Patients.

Obesity in trauma patients is an established risk factor contributing to postoperative complications, but the relationship between body mass index (BMI) and trauma patient outcomes is not well-defined, especially when stratified by mechanism of injury. We surveyed the trauma laparotomy registry at an academic level 1 trauma center over a 3-year period to identify mortality, injury severity score, and hospital length of stay (hLOS) outcome measures across BMI classes, with further stratification by mechanism of injury: blunt vs penetrating trauma. A total of 442 patients were included with mean age 44.6 (SD = 18.7) and mean BMI 28.55 (SD = 7.37). These were subdivided into blunt trauma (n = 313) and penetrating trauma (n = 129). Within the blunt trauma subgroup, the hLOS among patients who survived hospitalization significantly increased 9% for each successive BMI class (P = .022, 95% CI = 1.29-17.5). We conclude that successive increase in BMI class is associated with longer hospital stay for blunt trauma patient survivors requiring laparotomy, though additional analysis is needed to establish this relationship to other outcome measures and among penetrating trauma patients.

Obesity Associated With Increased Mortality and Hospital Length of Stay in Trauma Laparotomy Patients.

Although obesity in trauma patients is accepted as a risk factor for postoperative complications, recent literature offers conflicting evidence regarding the effect of body mass index (BMI) on mortality in trauma patients undergoing laparotomy. To address this question, we examined the patient population of a Level 1 Trauma Center during a 3-year period to compare mortality rates and other outcomes between BMI groups undergoing laparotomy. Through retrospective chart review of electronic medical records, with subsequent stratification of data based on BMI, we found that mortality, injury severity score, and hospital length of stay all increase significantly with each incremental increase in BMI class. From these data, we concluded that higher BMI class leads to greater morbidity and mortality in trauma patients undergoing laparotomy at this institution.

Call to action: overcoming enrollment disparities in cancer clinical trials with modernized eligibility criteria.

Traditional clinical trial eligibility criteria restrict study populations, perpetuating enrollment disparities. We aimed to assess implementation of modernized eligibility criteria guidelines among pancreatic cancer (PC) clinical trials. Interventional PC trials in the United States since January 1, 2014, were identified via clinicaltrials.gov with December 31, 2017, as the transition for pre- and postguidance eras. Trials were assessed for guideline compliance and compared using Fisher exact test. In total, 198 trials were identified: 86 (43.4%) were pre- and 112 (56.6%) postguidance era. Improvements were seen in allowing patients with history of HIV (8.6% vs 43.8%; P < .0001), prior cancer (57.0% vs 72.3%; P = .034), or concurrent and/or stable cancer (2.1% vs 31.1%; P < .0001) to participate. Most (>95%) trials were compliant with laboratory reference ranges, QT interval corrected for heart rate (QTc) cutoffs, and rationalizing excluding prior therapies both pre- and postguidance eras. However, overall compliance with modernized criteria remains poor. We advocate for stakeholders to update protocols and scrutinize traditionally restrictive eligibility criteria.

Diversification of Academic Surgery, Its Leadership, and the Importance of Intersectionality.

Importance: Diversity in academic surgery is lacking, particularly among positions of leadership. Objective: To evaluate trends among racial/ethnical minority groups stratified by gender along the surgical pipeline, as well as in surgical leadership. Design, Setting, and Participants: This cross-sectional and longitudinal analysis assessed US surgical faculty census data obtained from the Association of American Medical Colleges faculty roster in the Faculty Administrative Management Online User System database. Surgical faculty members captured in census data from December 31, 2013, to December 31, 2019, were included in the analysis. Faculty were identified from the surgery category of the faculty roster, which includes general surgeons and subspecialists, neurosurgeons, and urologists. Main Outcomes and Measures: Gender and race/ethnicity were obtained for surgical faculty stratified by rank. Descriptive statistics with annual percentage of change in representation are reported based on faculty rank. Results: A total of 15 653 US surgical faculty, including 3876 women (24.8%), were included in the data set for 2019. Female faculty from racial/ethnic minority groups experienced an increase in representation at instructor and assistant and associate professorship appointments, with a more favorable trajectory than male faculty from racial/ethnic minority groups across nearly all ranks. White faculty maintain most leadership positions as full professors (3105 of 3997 [77.7%]) and chairs (294 of 380 [77.4%]). The greatest magnitude of underrepresentation along the surgical pipeline has been among Black (106 of 3997 [2.7%]) and Hispanic/Latinx (176 of 3997 [4.4%]) full professors. Among full professors, although Black and Hispanic/Latinx male representation increased modestly (annual change, 0.07% and 0.10%, respectively), Black female representation remained constant (annual change, 0.00004%) and Hispanic/Latinx female representation decreased (annual change, -0.16%). Overall Hispanic/Latinx (20 of 380 [5.3%]) and Black (13 of 380 [3.4%]) representation as chairs has not changed, with only 1 Black and 1 Hispanic/Latinx woman ascending to chair from 2013 to 2019. Conclusions and Relevance: A disproportionately small number of faculty from minority groups obtain leadership positions in academic surgery. Intersectionality may leave female members of racial/ethnic minority groups more disadvantaged than their male colleagues in achieving leadership positions. These findings highlight the urgency to diversify surgical leadership.

Elevated acute phase proteins reflect peripheral inflammation and disease severity in patients with amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a multifactorial, multisystem pro-inflammatory neuromuscular disorder compromising muscle function resulting in death. Neuroinflammation is known to accelerate disease progression and accentuate disease severity, but peripheral inflammatory processes are not well documented. Acute phase proteins (APPs), plasma proteins synthesized in the liver, are increased in response to inflammation. The objective of this study was to provide evidence for peripheral inflammation by examining levels of APPs, and their contribution to disease burden and progression rates. Levels of APPs, including soluble CD14 (sCD14), lipopolysaccharide binding protein (LBP), and C-reactive protein (CRP), were elevated in sera, and correlated positively with increased disease burden and faster progression. sCD14 was also elevated in patients' CSF and urine. After a 3 year follow-up, 72% of the patients with sCD14 levels above the receiver operating characteristics cutoff were deceased whereas only 28% below the cutoff were deceased. Furthermore, disease onset sites were associated with disease progression rates and APP levels. These APPs were not elevated in sera of patients with Alzheimer's Disease, frontotemporal dementia, or Parkinson's Disease. These collective APPs accurately reflect disease burden, progression rates, and survival times, reinforcing the concept of ALS as a disorder with extensive systemic pro-inflammatory responses.

Antibacterial Properties of Charged TiN Surfaces for Dental Implant Application.

The formation and characterization of positively surface charged TiN surfaces were investigated for improving dental implant survival. Surface nitrogen atoms of a traditional TiN implant were converted to a positive charge by a quaternization reaction which greatly increased the antibacterial efficiency. Ti, TiN, and quaternized TiN samples were incubated with human patient subgingival bacteria for 4 hours at 37°C in an anaerobic environment with an approximate 40% reduction in counts on the quaternized surface over traditional Ti and TiN. The samples were challenged with Streptococcus Mutans and fluorescent imaging confirmed significant reduction in the quaternized TiN over the traditional Ti and TiN. Contact angle measurement and X-Ray Photoelectron Spectroscopy (XPS) were utilized to confirm the surface chemistry changes. The XPS results found the charged quaternized nitrogen peak at 399.75 eV that is unique to the quaternized sample.

Decreased incidence of venous thromboembolism after spine surgery with early multimodal prophylaxis: Clinical article.

OBJECT: Venous thromboembolism (VTE) represents a significant complication after spine surgery, with reported rates as high as 2%-4%. Published institutional practices for VTE prophylaxis are highly variable. In 2008, the authors implemented a departmental protocol for early VTE prophylaxis consisting of combined compressive devices and subcutaneous heparin initiated either preoperatively or on the same day of surgery. In this study, the authors compared the incidence of VTE in spine surgery patients before and after implementing this protocol. METHODS: An institutional review board-approved retrospective review of outcomes in patients undergoing spine surgery 2 years before protocol implementation (representing the preprotocol group) and of outcomes in patients treated 2 years thereafter (the postprotocol group) was conducted. Inclusion criteria were that patients were 18 years or older and had been admitted for 1 or more days. Before 2008 (preprotocol), VTE prophylaxis was variable and provider dependent without any uniform protocol. Since 2008 (postprotocol), a new VTE-prophylaxis protocol was administered, starting either preoperatively or on the same day of surgery and continuing throughout hospitalization. The new protocol consisted of 5000 U heparin administered subcutaneously 3 times daily, except in patients older than 75 years or weighing less than 50 kg, who received this dose twice daily. All patients also received sequential compression devices (SCDs). The incidence of VTE in the 2 protocol phases was identified by codes of the International Classification of Diseases, Ninth Revision (ICD-9) codes for deep vein thrombosis (DVT) and pulmonary embolus (PE). Bleeding complications arising from anticoagulation treatments were evaluated by the Current Procedural Terminology (CPT) code for postoperative epidural hematoma (EDH) requiring evacuation. RESULTS: In total, 941 patients in the preprotocol group met the inclusion criteria: 25 had DVT (2.7%), 6 had PE (0.6%), and 6 had postoperative EDH (0.6%). In the postprotocol group, 992 patients met the criteria: 10 had DVT (1.0%), 5 had PE (0.5%), and 4 had postoperative EDH (0.4%). This reduction in DVT after the protocol's implementation was statistically significant (p = 0.009). Despite early aggressive prophylaxis, the incidence of postoperative EDH did not increase and compared favorably to the published literature. CONCLUSIONS: At a high-volume tertiary center, an aggressive protocol for early VTE prophylaxis after spine surgery decreases VTE incidence without increasing morbidity.

Rationale for treating unruptured intracranial aneurysms: actuarial analysis of natural history risk versus treatment risk for coiling or clipping based on 14,050 patients in the Nationwide Inpatient Sample database.

OBJECTIVE: The treatment of small unruptured intracranial aneurysms has been questioned based on the results of the International Study of Unruptured Intracranial Aneurysms. Our objective was to compare natural history rupture risk versus treatment risk for coiling and clipping small unruptured aneurysms using data in the Nationwide Inpatient Sample database. METHODS: Data for clipping and coiling of unruptured aneurysms was collected from the Nationwide Inpatient Sample from 2002-2008. Treatment risks were adjusted for age, gender, and medical comorbidities. Logistic regression models were used to create curves depicting the estimated probability of poor outcome as a function of patient age for clipping and coiling. These treatment risk curves were compared against natural history actuarial risk curves calculated from four prominent studies. RESULTS: There were 14,050 hospitalizations: 7439(53%) coiling; 6611(47%) clipping. For patients who underwent coiling or clipping, the mortality rate was 2.17% and 2.66%, and the morbidity rate was 2.16% and 4.75%, respectively. The adjusted risk of poor outcome from clipping and coiling, when modeled against most natural history studies, demonstrates a treatment benefit for clipping for patients <70 years and for coiling patients <81 years. Models using the International Study of Unruptured Intracranial Aneurysms data demonstrate a treatment benefit for clipping for patients <61 years and for coiling for patients <70 years. CONCLUSIONS: Both clipping and coiling of unruptured intracranial aneurysms are safe. This analysis demonstrates rationale for clipping small unruptured aneurysms in patients <61-70 years and coiling small unruptured aneurysms in patients <70-80 years. Treatment beyond these age ranges is associated with increased risk of poor outcome.

Higher complications and no improvement in mortality in the ACGME resident duty-hour restriction era: an analysis of more than 107,000 neurosurgical trauma patients in the Nationwide Inpatient Sample database.

BACKGROUND: The Accreditation Council for Graduate Medical Education resident duty-hour restrictions were implemented in July 2003 based on the supposition that resident fatigue contributes to medical errors. OBJECTIVE: To examine the effect of duty-hour restrictions on outcome in neurotrauma patients. METHODS: The Nationwide Inpatient Sample database was analyzed for a time period with no restrictions (years 1999-2002) compared with a period with restrictions (years 2005-2008) for (1) mortality and (2) complications. We analyzed both teaching and nonteaching hospitals to account for potential differences attributed to non-resident-related factors. RESULTS: There were 107,006 teaching hospital and 115,604 nonteaching hospital admissions for neurotrauma. Multivariate logistic regression demonstrated significantly more complications in the time period with restrictions in teaching hospitals. In nonteaching hospitals, there was no difference in complications. In both teaching and nonteaching hospitals, there was no difference in mortality between the 2 time periods. For teaching and nonteaching hospitals, there was no difference in hospital length of stay, but hospital charges were significantly higher in the period with restrictions. The occurrence of a complication was significantly associated with longer hospital length of stay and higher hospital charges in both time periods in both teaching and nonteaching hospitals. CONCLUSION: The implementation of the Accreditation Council for Graduate Medical Education resident duty-hour restrictions was associated with increased complications and no change in mortality for neurotrauma patients in teaching hospitals. In nonteaching hospitals, there was no change in complications and mortality. The occurrence of a complication was associated with longer length of stay and higher hospital charges in both time periods in both teaching and nonteaching hospitals.