A stable atmospheric-pressure plasma for extreme-temperature synthesis.

Plasmas can generate ultra-high-temperature reactive environments that can be used for the synthesis and processing of a wide range of materials1,2. However, the limited volume, instability and non-uniformity of plasmas have made it challenging to scalably manufacture bulk, high-temperature materials3-8. Here we present a plasma set-up consisting of a pair of carbon-fibre-tip-enhanced electrodes that enable the generation of a uniform, ultra-high temperature and stable plasma (up to 8,000 K) at atmospheric pressure using a combination of vertically oriented long and short carbon fibres. The long carbon fibres initiate the plasma by micro-spark discharge at a low breakdown voltage, whereas the short carbon fibres coalesce the discharge into a volumetric and stable ultra-high-temperature plasma. As a proof of concept, we used this process to synthesize various extreme materials in seconds, including ultra-high-temperature ceramics (for example, hafnium carbonitride) and refractory metal alloys. Moreover, the carbon-fibre electrodes are highly flexible and can be shaped for various syntheses. This simple and practical plasma technology may help overcome the challenges in high-temperature synthesis and enable large-scale electrified plasma manufacturing powered by renewable electricity.

IL-18-secreting multiantigen targeting CAR T cells eliminate antigen-low myeloma in an immunocompetent mouse model.

ABSTRACT: Multiple myeloma is a plasma cell malignancy that is currently incurable with conventional therapies. Following the success of CD19-targeted chimeric antigen receptor (CAR) T cells in leukemia and lymphoma, CAR T cells targeting B-cell maturation antigen (BCMA) more recently demonstrated impressive activity in relapsed and refractory myeloma patients. However, BCMA-directed therapy can fail due to weak expression of BCMA on myeloma cells, suggesting that novel approaches to better address this antigen-low disease may improve patient outcomes. We hypothesized that engineered secretion of the proinflammatory cytokine interleukin-18 (IL-18) and multiantigen targeting could improve CAR T-cell activity against BCMA-low myeloma. In a syngeneic murine model of myeloma, CAR T cells targeting the myeloma-associated antigens BCMA and B-cell activating factor receptor (BAFF-R) failed to eliminate myeloma when these antigens were weakly expressed, whereas IL-18-secreting CAR T cells targeting these antigens promoted myeloma clearance. IL-18-secreting CAR T cells developed an effector-like T-cell phenotype, promoted interferon-gamma production, reprogrammed the myeloma bone marrow microenvironment through type-I/II interferon signaling, and activated macrophages to mediate antimyeloma activity. Simultaneous targeting of weakly-expressed BCMA and BAFF-R with dual-CAR T cells enhanced T-cell:target-cell avidity, increased overall CAR signal strength, and stimulated antimyeloma activity. Dual-antigen targeting augmented CAR T-cell secretion of engineered IL-18 and facilitated elimination of larger myeloma burdens in vivo. Our results demonstrate that combination of engineered IL-18 secretion and multiantigen targeting can eliminate myeloma with weak antigen expression through distinct mechanisms.

CLDN18.2 BiTE Engages Effector and Regulatory T Cells for Antitumor Immune Response in Preclinical Models of Pancreatic Cancer.

BACKGROUND & AIMS: BiTE (bispecific T-cell engager) immune therapy has demonstrated clinical activity in multiple tumor indications, but its influence in the tumor microenvironment remains unclear. CLDN18.2 is overexpressed in solid tumors including gastric cancer (GC) and pancreatic ductal adenocarcinoma (PDAC), both of which are characterized by the presence of immunosuppressive cells, including regulatory T cells (Tregs) and few effector T cells (Teffs). METHODS: We evaluated the activity of AMG 910, a CLDN18.2-targeted half-life extended (HLE) BiTE molecule, in GC and PDAC preclinical models and cocultured Tregs and Teffs in the presence of CLDN18.2-HLE-BiTE. RESULTS: AMG 910 induced potent, specific cytotoxicity in GC and PDAC cell lines. In GSU and SNU-620 GC xenograft models, AMG 910 engaged human CD3+ T cells with tumor cells, resulting in significant antitumor activity. AMG 910 monotherapy, in combination with a programmed death-1 (PD-1) inhibitor, suppressed tumor growth and enhanced survival in an orthotopic Panc4.14 PDAC model. Moreover, Treg infusion enhanced the antitumor efficacy of AMG 910 in the Panc4.14 model. In syngeneic KPC models of PDAC, treatment with a mouse surrogate CLDN18.2-HLE-BiTE (muCLDN18.2-HLE-BiTE) or the combination with an anti-PD-1 antibody significantly inhibited tumor growth. Tregs isolated from mice bearing KPC tumors that were treated with muCLDN18.2-HLE-BiTE showed decreased T cell suppressive activity and enhanced Teff cytotoxic activity, associated with increased production of type I cytokines and expression of Teff gene signatures. CONCLUSIONS: Our data suggest that BiTE molecule treatment converts Treg function from immunosuppressive to immune enhancing, leading to antitumor activity in immunologically "cold" tumors.

National trends and outcomes of total proctocolectomy and completion proctectomy ileal pouch-anal anastomosis procedures for ulcerative colitis.

AIM: The purpose of this study is to assess US operative trends and outcomes of ulcerative colitis (UC) patients undergoing total proctocolectomy with ileal pouch-anal anastomosis (TPC-IPAA) or completion proctectomy with IPAA (CP-IPAA). METHODS: Adult UC patients who underwent TPC-IPAA or CP-IPAA were analysed retrospectively using the 2016-2020 American College of Surgeons National Surgical Quality Improvement Program database. Factors associated with 30-day overall and serious morbidity were identified using multivariable logistic regression. RESULTS: A total of 1696 patients were identified, with 958 patients (56.5%) undergoing TPC-IPAA and 738 (43.5%) undergoing CP-IPAA. A greater proportion of TPC-IPAAs were performed each year (except in 2019) compared to CP-IPAAs over the study period (P trend <0.001). Unadjusted analysis showed comparable rates of overall (20.8% vs. 24.4%, P = 0.076) and serious morbidity (14.3% vs. 12.7%, P = 0.352) between TPC-IPAA and CP-IPAA patients. Robotic TPC-IPAA had no differences in complications compared to laparoscopic and open approaches. Robotic CP-IPAA had higher anastomotic leak rates and longer hospital length of stay compared to laparoscopic and open approaches. Obesity was associated with increased odds of overall and serious morbidity for patients who underwent TPC-IPAA. Steroid/immunosuppressive therapy was associated with increased odds of overall and serious morbidity for patients who underwent CP-IPAA. CONCLUSIONS: Obese patients should be informed of their increased morbidity risk and offered counselling on weight loss prior to surgery when feasible. Patients on steroid/immunosuppressive therapy within 30 days preoperatively should not undergo CP-IPAA or should delay surgery until they can be safely off those medications.

Prevalence of cannabis use disorder and perioperative outcomes in adult colectomy patients: A propensity score-matched analysis.

BACKGROUND: The decriminalization of cannabis across the United States has led to an increased number of patients reporting cannabis use prior to surgery. However, it is unknown whether preoperative cannabis use disorder (CUD) increases the risk of postoperative complications among adult colectomy patients. METHODS: Adult patients undergoing an elective colectomy were retrospectively analyzed from the National Inpatient Sample database (2004-2018). To control for potential confounders, patients with CUD, defined using ICD-9/10 codes, were propensity score matched to patients without CUD in a 1:1 ratio. The association between preoperative CUD and composite morbidity, the primary outcome of interest, was assessed. Subgroup analyses were performed after stratification by age (≥50 years). RESULTS: Among 432,018 adult colectomy patients, 816 (0.19%) reported preoperative CUD. The prevalence of CUD increased nearly three-fold during the study period from 0.8/1000 patients in 2004 to 2.0/1000 patients in 2018 (P-trend<0.001). After propensity score matching, patients with CUD exhibited similar rates of composite morbidity (140 of 816; 17.2%) as those without CUD (151 of 816; 18.5%) (p = 0.477). Patients with CUD also had similar anastomotic leak rates (CUD: 5.64% vs. No CUD: 6.25%; p = 0.601), hospital lengths of stay (CUD: 5 days, IQR 4-7 vs. No CUD: 5 days, IQR 4-7) (p = 0.415), and hospital charges as those without CUD. Similar findings were seen among patients aged ≥50 years in the subgroup analysis. CONCLUSIONS: Though the prevalence of CUD has increased drastically over the past 15 years, preoperative CUD was not associated with an increased risk of composite morbidity among adult patients undergoing an elective colectomy.

Colorectal Surgery Outcomes in the United States During the COVID-19 Pandemic.

INTRODUCTION: The purpose of this study was to assess colorectal surgery outcomes, discharge destination, and readmission in the United States during the COVID-19 pandemic. METHODS: Adult colorectal surgery patients in the American College of Surgeons National Surgical Quality Improvement Program database (2019-2020) and its colectomy and proctectomy procedure-targeted files were included. The prepandemic time period was defined from April 1, 2019 to December 31, 2019. The pandemic time period was defined from April 1, 2020 to December 31, 2020 in quarterly intervals (Q2 April-June; Q3 July-September; Q4 October-December). Factors associated with morbidity and in-hospital mortality were assessed using multivariable logistic regression. RESULTS: Among 62,393 patients, 34,810 patients (55.8%) underwent colorectal surgery prepandemic and 27,583 (44.2%) during the pandemic. Patients who had surgery during the pandemic had higher American Society of Anesthesiologists class and presented more frequently with dependent functional status. The proportion of emergent surgeries increased (12.7% prepandemic versus 15.2% pandemic, P < 0.001), with less laparoscopic cases (54.0% versus 51.0%, P < 0.001). Higher rates of morbidity with a greater proportion of discharges to home and lesser proportion of discharges to skilled care facilities were observed with no considerable differences in length of stay or worsening readmission rates. Multivariable analysis demonstrated increased odds of overall and serious morbidity and in-hospital mortality, during Q3 and/or Q4 of the 2020 pandemic. CONCLUSIONS: Differences in hospital presentation, inpatient care, and discharge disposition of colorectal surgery patients were observed during the COVID-19 pandemic. Pandemic responses should emphasize balancing resource allocation, educating patients and providers on timely medical workup and management, and optimizing discharge coordination pathways.

Simultaneous resection of colorectal cancer and synchronous colorectal liver metastases: A risk stratified analysis of the NSQIP database.

BACKGROUND AND OBJECTIVES: Over 25% of patients diagnosed with colorectal cancer (CRC) will develop colorectal liver metastases (CRLM). Controversy exists over the surgical management of these patients. This study aims to investigate the safety of a simultaneous surgical approach by stratifying patients based on procedure risk and operative approach. METHODS: Using ACS-NSQIP (2016-2020), patients with CRC who underwent isolated colorectal, isolated hepatic, or simultaneous resections were identified. Colorectal and hepatic procedures were stratified by morbidity risk (high vs. low) and operative approach (open vs. minimally invasive). Thirty-day overall morbidity was compared between risk matched isolated and simultaneous resection groups. RESULTS: A total of 65 417 patients were identified, with 1550 (2.4%) undergoing simultaneous resections. A total of 1207 (77.9%) underwent a low-risk colorectal and low-risk liver resection. On multivariate analysis, there was no significant difference in overall morbidity between patients who had a simultaneous open high-risk colorectal/low-risk hepatic procedure compared to patients who had an isolated open high-risk colorectal procedure (odds ratio: 1.19; 95% confidence interval: 0.94-1.50; p = 0.148). All other combinations of simultaneous procedures had statistically significant higher rates of morbidity than the isolated group. CONCLUSIONS: Simultaneous resection of colorectal and synchronous CRLM is associated with an increased risk of morbidity in most circumstances in a risk stratified analysis, although rates of readmission and reoperation were not increased. Minimally invasive surgical approaches may significantly mitigate this morbidity.

The Effects of Chronic Steroid Use on Postoperative Complications Following Thyroidectomy.

BACKGROUND: Patients undergoing thyroidectomy are sometimes on chronic steroids for underlying disease. This study examined the postoperative risk profile of thyroidectomy patients on chronic steroids. METHODS: Patients in the National Surgical Quality Improvement Program (NSQIP) database who underwent thyroidectomy were sorted by presence or absence of chronic steroid use. Clinicodemographics, comorbidities, and postoperative complications were recorded and compared between the two. Univariate and multivariate analyses compared the groups and calculated odds ratios (OR). RESULTS: We identified 42,857 patients. 41,903 (97.8%) patients were not on chronic steroids, while 954 (2.2%) were. Most underwent total thyroidectomy (18,748, 43.75%) or total lobectomy (16,323, 38.09%). Following univariate and multivariate analyses, patients on chronic steroids had increased risk of postoperative bleeding and transfusions (OR = 0.375, p = 0.046, 95% CI 0.223-0.988), open wound infection (OR = 0.226, p < 0.001, 95% CI 0.117-0.437), pulmonary embolism (OR = 0.312, p = 0.034, 95% CI 0.106-0.918), and ventilator use > 48 h (OR = 0.401, p < 0.008, 95% CI 0.205-0.785). CONCLUSIONS: Chronic steroid use prior to thyroidectomy is an independent risk factor for multiple postoperative complications, namely postoperative bleeding and transfusions, open wound infection, pulmonary embolism, and ventilator use over 48 h. Patients on chronic steroids should be medically optimized before thyroidectomy to reduce the risk of potentially life-threatening complications.

Safety and Feasibility of ≤24-h Short-Stay Right Colectomies for Primary Colon Cancer.

BACKGROUND: Hospital length of stay (LOS) has been used as a surgical quality metric. This study seeks to determine the safety and feasibility of right colectomy as a ≤24-h short-stay procedure for colon cancer patients. METHODS: This was a retrospective cohort study using the ACS-NSQIP database and its Procedure Targeted Colectomy database (2012-2020). Adult patients with colon cancer who underwent right colectomies were identified. Patients were categorized into LOS ≤1 day (≤24-h short-stay), LOS 2-4 days, LOS 5-6 days, and LOS ≥7 days groups. Primary outcomes were 30-day overall and serious morbidity. Secondary outcomes were 30-day mortality, readmission, and anastomotic leak. The association between LOS and overall and serious morbidity was assessed using multivariable logistic regression. RESULTS: 19,401 adult patients were identified, with 371 patients (1.9%) undergoing short-stay right colectomies. Patients undergoing short-stay surgery were generally younger with fewer comorbidities. Overall morbidity for the short-stay group was 6.5%, compared to 11.3%, 23.4%, and 42.0% for LOS 2-4 days, LOS 5-6 days, and LOS ≥7 days groups, respectively (p < 0.001). There were no differences in anastomotic leak, mortality, and readmission rates in the short-stay group compared to patients with LOS 2-4 days. Patients with LOS 2-4 days had increased odds of overall morbidity (OR 1.71, 95% CI 1.10-2.65, p = 0.016) compared to patients with short-stay but no differences in odds of serious morbidity (OR 1.20, 95% CI 0.61-2.36, p = 0.590). CONCLUSIONS: ≤24-h short-stay right colectomy is safe and feasible for a highly-select group of colon cancer patients. Optimizing patients preoperatively and implementing targeted readmission prevention strategies may aid patient selection.

High-fat diet prevents the development of autoimmune diabetes in NOD mice.

AIMS: Type 1 diabetes (T1D) has a strong genetic predisposition and requires an environmental trigger to initiate the beta-cell autoimmune destruction. The rate of childhood obesity has risen in parallel to the proportion of T1D, suggesting high-fat diet (HFD)/obesity as potential environmental triggers for autoimmune diabetes. To explore this, non-obese diabetic (NOD) mice were subjected to HFD and monitored for the development of diabetes, insulitis and beta-cell stress. MATERIALS AND METHODS: Four-week-old female NOD mice were placed on HFD (HFD-NOD) or standard chow-diet. Blood glucose was monitored weekly up to 40 weeks of age, and glucose- and insulin-tolerance tests performed at 4, 10 and 15 weeks. Pancreata and islets were analysed for insulin secretion, beta-cell mass, inflammation, insulitis and endoplasmic reticulum stress markers. Immune cell levels were measured in islets and spleens. Stool microbiome was analysed at age 4, 8 and 25 weeks. RESULTS: At early ages, HFD-NOD mice showed a significant increase in body weight, glucose intolerance and insulin resistance; but paradoxically, they were protected from developing diabetes. This was accompanied by increased insulin secretion and beta-cell mass, decreased insulitis, increased splenic T-regulatory cells and altered stool microbiome. CONCLUSIONS: This study shows that HFD protects NOD mice from autoimmune diabetes and preserves beta-cell mass and function through alterations in gut microbiome, increased T-regulatory cells and decreased insulitis. Further studies into the exact mechanism of HFD-mediated prevention of diabetes in NOD mice could potentially lead to interventions to prevent or delay T1D development in humans.

Development and validation of the motivations to Eat Meat Inventory.

Previous research suggests that there are four primary motives to eat meat: that it is natural, normal, necessary, or nice. However, these motives have not yet been distinguished empirically; the lack of a measurement tool that can distinguish these motives has contributed to a literature that focuses primarily on meat-eating motivation or justification in general, as opposed to differences between these motives. We developed a 19-item measure, the Motivations to Eat Meat Inventory (MEMI), that fit a four-factor model in three samples (total N = 2175), including one with a large number of vegetarians. Using this instrument, we generated psychological profiles associated with each motive, and showed that the structure and correlates of meat-eating motives is highly similar for omnivores and vegetarians. This research provides a valuable tool for studying variation in psychological motives for eating meat among both meat-eaters and vegetarians and provides an initial framework for understanding the underpinnings of these different motivations.

DATA 2000 waiver training for medical students: Lessons learned from a medical school experience.

BACKGROUND: In the midst of this national opioid crisis, it has become apparent that there is a large shortage in the workforce of treatment providers equipped to deliver evidence-based care for opioid use disorders (OUD). Medications for opioid use disorder (MOUD), such as buprenorphine, are crucial in reducing mortality in those with OUD, and yet prescribers must meet federal waiver requirements under the Drug Addiction Treatment Act of 2000 (DATA 2000). There are now several pathways for medical schools to satisfy these waiver requirements for all graduates, but this has not yet become widespread. We propose that including a DATA 2000 waiver training within the medical school curriculum is a feasible and effective way to meet eligibility requirements to prescribe buprenorphine. Methods: As part of a longitudinal opioid curriculum requirement, we implemented a DATA 2000 waiver training for all rising Year 4 medical students. One hundred sixty-nine students completed a hybrid (online and in-person) waiver training. The majority completed a pre- and post-survey. Results: The pre-training survey showed 93% of rising Year 4 medical students (112/120) reported participation in care of patients with OUD. Students six month post-training reported a rise in confidence (1.94 to 2.45; p < 0.01) and knowledge (2.27 to 2.76; p < 0.01) regarding MOUD. They also reported their plans to apply for the buprenorphine waiver once licensed and reported being more likely to prescribe buprenorphine for OUD as a result of the training (mean = 3.35; SD = 1.36; 0 = extremely unlikely to 5 = extremely likely). Conclusions: We successfully implemented a DATA 2000 waiver training as a mandatory requirement for the medical school curriculum. Further studies are needed to determine optimal timing, best format, and frequency of reinforcement of MOUD educational content across the undergraduate and graduate medical education continuum.

Treatment Strategies and Survival Trends for Anorectal Melanoma: Is it Time for a Change?

BACKGROUND: Immunotherapy advances for the treatment of cutaneous melanoma question its efficacy in treating anorectal mucosal melanoma (ARMM). We aimed to identify the prevalence, current management, and overall survival (OS) for ARMM. METHODS: Review of patients with ARMM from 2004 to 2015 National Cancer Database. Factors associated with immunotherapy were identified using multivariable logistic regression. The primary outcome was 2- and 5-year OS. Subgroup analysis by treatment type was performed. RESULTS: A total of 1331 patients were identified with a significant increase in prevalence (2004: 6.99%, 2015: 10.53%). ARMM patients were older, white, on Medicare, and from the South. The most common treatment was surgery (48.77%), followed by surgery + radiation (11.75%), surgery + immunotherapy (8.68%), and surgery + chemotherapy (8.68%). 16.93% of patients received immunotherapy, with utilization increasing (7.24%: 2004, 21.27%: 2015, p < 0.001). Patients who received immunotherapy had a significantly better 2-year OS (42.47% vs. 49.21%, p < 0.001), and other therapies did not reveal a significant difference. Adjusted analysis showed no difference in 2- and 5-year OS based on therapy type. CONCLUSION: The prevalence of ARMM has increased. The use of immunotherapy has increased substantially. Some survival benefit with the administration of immunotherapy may exist that has yet to be revealed. A more aggressive treatment paradigm is warranted.

Readmission Adversely Affects Survival in Surgical Rectal Cancer Patients.

BACKGROUND: Readmission has received attention as a potential healthcare quality metric. No studies have investigated the relationship between readmission and survival in patients undergoing rectal cancer surgery. The aims of this study were to identify factors associated with 30-day readmission after rectal cancer surgery and to determine the impact of readmission on overall survival (OS). METHODS: Patients who underwent surgical treatment for rectal/rectosigmoid adenocarcinoma stages I-IV were identified using the National Cancer Database (2004-2014). Multivariable logistic regression was used to identify factors for readmission. 2:1 nearest neighbor caliper matching without replacement was used to ensure similarity of patients being compared. Survival analyses were performed using Kaplan-Meier method along with log-rank test and Cox proportional hazards model. RESULTS: Of 110,167 patients, 7045 (6.39%) were readmitted. Factors associated with readmission included higher Charlson comorbidity score, non-private or no insurance, procedure type, hospitals in the Northeast, South, and Midwest regions, and prolonged length of stay. Within the matched cohort (13,756 non-readmitted and 6878 readmitted), readmitted patients had worse 5- and 10-year OS regardless of cancer stage (p < 0.001) and procedure type. Five- and 10-year OS were 58.98% and 41.01% for readmitted patients, 64.96% and 43.50% for non-readmitted patients. Readmitted patients had shorter OS by 13.14 months and increased risk of mortality (HR 1.20, 95% CI 1.15-1.25, p < 0.001). CONCLUSIONS: Thirty-day readmission after rectal cancer surgery is associated with decreased OS. Efforts to reduce readmissions should be considered to advance cancer care and enhance the potential for improved patient survival.

Assessing the Financial Burden Associated With Treatment Options for Resectable Pancreatic Cancer.

OBJECTIVE: The aim of this study is to assess the financial burden associated with treatment options for resectable pancreatic cancer. BACKGROUND: As the volume of cancer care increases in the United States, there is growing interest among both clinicians and policy-makers to reduce its financial impact on the healthcare system. However, costs relative to the survival benefit for differing treatment modalities used in practice have not been described. METHODS: Patients undergoing resection for pancreatic cancer were identified in the Truven Health MarketScan database. Associations between chemoradiation therapies and survival were performed using parameterized multivariable accelerated failure time models. Median payments over time were calculated for surgery, chemoradiation, and subsequent hospitalizations. RESULTS: A total of 2408 patients were included. Median survival among all patients was 21.1 months [95% confidence interval (CI): 19.8-22.5 months], whereas median follow-up time was 25.1 months (95% CI: 23.5-26.5 months). After controlling for comorbidity, receipt of neoadjuvant therapy, and nodal involvement, a longer survival was associated with undergoing combination gemcitabine and nab-paclitaxel [time ratio (TR) = 1.26, 95% CI: 1.02-1.57, P = 0.035) or capecitabine and radiation (TR = 1.25, 95% CI: 1.04-1.51, P = 0.018). However, median cumulative payments for gemcitabine with nab-paclitaxel were highest overall [median $74,051, interquartile range (IQR): $38,929-$133,603). CONCLUSIONS: Total payments for an episode of care relative to improvement in survival vary significantly by treatment modality. These data can be used to inform management decisions about pursuing further care for pancreatic cancer. Future investigations should seek to refine estimates of the cost-effectiveness of different treatments.