CXCL12 chemokine dimer signaling modulates acute myelogenous leukemia cell migration through altered receptor internalization.

Acute myeloid leukemia (AML) is a malignancy of immature myeloid blast cells with stem-like and chemoresistant cells being retained in the bone marrow through CXCL12-CXCR4 signaling. Current CXCR4 inhibitors mobilize AML cells into the bloodstream where they become more chemosensitive have failed to improve patient survival, likely reflecting persistent receptor localization on target cells. Here we characterize the signaling properties of CXCL12-locked dimer (CXCL12-LD), a bioengineered variant of the dimeric CXCL12 structure. CXCL12-LD binding resulted in lower levels of G protein, ß-arrestin, and intracellular calcium mobilization, consistent with the locked dimer being a partial agonist of CXCR4. Further, CXCL12-LD failed to induce chemotaxis in AML cells. Despite these partial agonist properties, CXCL12-LD increased CXCR4 internalization compared to wildtype and locked-monomer forms of CXCL12. Analysis of a previously published AML transcriptomic data showed CXCR4 positive AML cells co-express genes involved in chemoresistance and maintenance of a blast-like state. The CXCL12-LD partial agonist effectively mobilized stem cells into the bloodstream in mice suggesting a potential role for their use in targeting CXCR4. Together, our results suggest that enhanced internalization by CXCL12-LD partial agonist signaling can avoid pharmacodynamic tolerance and may identify new avenues to better target GPCRs.

An INSULIN and IAPP dual reporter enables tracking of functional maturation of stem cell-derived insulin producing cells.

OBJECTIVE: Human embryonic stem cell (hESC; SC)-derived pancreatic ß cells can be used to study diabetes pathologies and develop cell replacement therapies. Although current differentiation protocols yield SCß cells with varying degrees of maturation, these cells still differ from deceased donor human ß cells in several respects. We sought to develop a reporter cell line that could be used to dynamically track SCß cell functional maturation. METHODS: To monitor SCß cell maturation in vitro, we created an IAPP-2A-mScar and INSULIN-2A-EGFP dual fluorescent reporter (INS2A-EGFP/+;IAPP2A-mScarlet/+) hESC line using CRISPR/Cas9. Pluripotent SC were then differentiated using a 7-stage protocol to islet-like cells. Immunohistochemistry, flow cytometry, qPCR, GSIS and electrophysiology were used to characterise resulting cell populations. RESULTS: We observed robust expression of EGFP and mScarlet fluorescent proteins in insulin- and IAPP-expressing cells without any compromise to their differentiation. We show that the proportion of insulin-producing cells expressing IAPP increases over a 4-week maturation period, and that a subset of insulin-expressing cells remain IAPP-free. Compared to this IAPP-free population, we show these insulin- and IAPP-expressing cells are less polyhormonal, more glucose-sensitive, and exhibit decreased action potential firing in low (2.8 mM) glucose. CONCLUSIONS: The INS2A-EGFP/+;IAPP2A-mScarlet/+ hESC line provides a useful tool for tracking populations of maturing hESC-derived ß cells in vitro. This tool has already been shared with 3 groups and is freely available to all.

What Is the Carbon Footprint of Adult Spinal Deformity Surgery?

Background/Objectives: While the economic cost of adult spinal deformity (ASD) surgery has been studied extensively, its environmental impact is unknown. The aim of this study is to determine the carbon footprint (CF) associated with ASD surgery. Methods: ASD patients who underwent > four levels of corrective surgery between 2017 and 2021 were included. The open group included a posterior-only, single-stage technique, while the minimally invasive surgery (MIS) group was defined as the use of lateral interbody fusion and percutaneous posterior screw fixation. The two groups were propensity-score matched to adjust for baseline demographic, surgical, and radiographic characteristics. Data on all disposables and reusable instruments, anesthetic gas, and non-gas medications used during surgery were collected from medical records. The CF of transporting, using, and disposing of each product and the footprint of energy use in operating rooms were calculated. The CF produced was evaluated using the carbon dioxide equivalent (CO2e), which is relative to the amount of CO2 with an equivalent global warming potential. Results: Of the 175 eligible patients, 15 pairs (65 ± 9 years, 47% female) were properly matched and analyzed for all variables. The average CF generated per case was 147.7 ± 37.3 kg-CO2e, of which 54% was attributable to energy used to sterilize reusable instruments, followed by anesthetic gas released into the environment (17%) and operating room air conditioning (15%). Conclusions: The CF generated during ASD surgery should be reduced using a multidisciplinary approach, taking into account that different surgical procedures have different impacts on carbon emission sources.

Post-Operative Hyperextension Bracing Has the Potential to Reduce Proximal Junctional Kyphosis: A Propensity Matched Analysis of Braced versus Non-braced Cohorts.

STUDY DESIGN: Retrospective cohort. OBJECTIVE: Determine effects of bracing on proximal junctional kyphosis (PJK) after adult deformity correction. METHODS: Patients were identified from a single-surgeon dataset of posterior-only fusions for ASD (pelvis to UIV of T9-12) with a minimum of 1-year follow up. Starting in 2021, all lower thoracic fusions were braced using a hyperextension brace. Patients wore the brace at all times (unless in bed) for the first 6 weeks after surgery. A 1:1 propensity-match was performed based on age, number of levels, 3 column osteotomies, and magnitude of correction to identify a comparative non-braced cohort. RESULTS: 141 patients (113 non-brace, 28 brace) were evaluated. After matching, 56 patients were identified to form similar cohorts. Non-matched and matched groups had no statistically significant differences in demographics, comorbid conditions, surgical characteristics (except shorter operative time and lower EBL in the braced group), and preoperative radiographic parameters. For the overall cohort, the change in proximal junctional angle at 1-year was higher in the non-braced group (7.6° vs 8.1°, P = .047), and non-braced patients had a higher incidence of PJK at 1-year in both the overall cohort (36% vs 14%, P = .045) and matched cohort (43% vs 14%, P = .038). There was no difference in proximal junctional failure between groups. CONCLUSION: This pilot study shows that our protocol for extension bracing may reduce rates of PJK. These findings can form the basis for future multi-center trials examining the effect of extension bracing on junctional complications.

Return to sporting activities following long fusions to the pelvis in adult spinal deformity.

BACKGROUND CONTEXT: Returning to recreational sporting activities after adult spinal deformity (ASD) correction may significantly impact the patient's perceived quality of life. PURPOSE: This study sought to characterize participation in sporting activities before and after ASD surgery, and to identify factors associated with impaired return to sports. STUDY DESIGN: Cross-sectional survey and retrospective review of prospectively collected data. PATIENT SAMPLE: Patients who underwent posterior-only thoracolumbar ASD surgery between 2016 and 2021 with ≥1 year follow-up and ≥3 levels of fusion to the pelvis were included. OUTCOME MEASURES: Preoperative and postoperative participation in sports, timing of return to these activities, and reasons for limited sports participation postoperatively were assessed. METHODS: A survey was used to evaluate outcome measures. Differences in demographic, surgical, and perioperative variables between patients who reported improved, unchanged, or worsened activity tolerance were evaluated. RESULTS: Ninety-five patients were included (mean age: 64.3±10.1 years; BMI: 27.3±6.1 kg/m2; median levels fused: 7). The survey was completed at an average of 43.5±15.9 months after surgery. Sixty-eight (72%) patients participated in sports preoperatively. The most common sports were swimming (n=33, 34.7%), yoga (n=23, 24.2%), weightlifting (n=20, 21.1%), elliptical (n=19, 20.0%), and golf (n=11, 11.6%). Fifty-seven (83.8%) returned to at least one sport postoperatively, most commonly 6-12 months after surgery (45%). Elliptical had the highest rate of equal or improved participation (53%). Patients generally returned below their preoperative level to all other sports. Reasons for reduced sporting activities included physical limitation (51.4%), fear (20.0%), pain (17.1%), and surgeon advice (8.6%). There were no differences in the demographic, surgical, or perioperative characteristics between those who returned to sports at the same or better level compared with those who returned at a lower level. CONCLUSIONS: About 84% of patients successfully resumed sporting activities after undergoing fusion to the sacrum/pelvis for ASD. However, this return is typically at a lower level of participation than their preoperative participation, particularly in higher demand sports. Understanding trends in sporting activity may be valuable for counseling patients and setting expectations.

Hyperspectral imaging and dynamic region of interest tracking approaches to quantify localized cAMP signals.

Cyclic adenosine monophosphate (cAMP) is a ubiquitous second messenger known to orchestrate a myriad of cellular functions over a wide range of timescales. In the last 20 years, a variety of single-cell sensors have been developed to measure second messenger signals including cAMP, Ca2+, and the balance of kinase and phosphatase activities. These sensors utilize changes in fluorescence emission of an individual fluorophore or Förster resonance energy transfer (FRET) to detect changes in second messenger concentration. cAMP and kinase activity reporter probes have provided powerful tools for the study of localized signals. Studies relying on these and related probes have the potential to further revolutionize our understanding of G protein-coupled receptor signaling systems. Unfortunately, investigators have not been able to take full advantage of the potential of these probes due to the limited signal-to-noise ratio of the probes and the limited ability of standard epifluorescence and confocal microscope systems to simultaneously measure the distributions of multiple signals (e.g. cAMP, Ca2+, and changes in kinase activities) in real time. In this review, we focus on recently implemented strategies to overcome these limitations: hyperspectral imaging and adaptive thresholding approaches to track dynamic regions of interest (ROI). This combination of approaches increases signal-to-noise ratio and contrast, and allows identification of localized signals throughout cells. These in turn lead to the identification and quantification of intracellular signals with higher effective resolution. Hyperspectral imaging and dynamic ROI tracking approaches offer investigators additional tools with which to visualize and quantify multiplexed intracellular signaling systems.

Postoperative racial disparities following spine surgery are less pronounced in the outpatient setting.

BACKGROUND CONTEXT: Racial disparities in spine surgery have been thoroughly documented in the inpatient (IP) setting. However, despite an increasing proportion of procedures being performed as same-day surgeries, whether similar differences have developed in the outpatient (OP) setting remains to be elucidated. PURPOSE: This study aimed to investigate racial differences in postoperative outcomes between Black and White patients following OP and IP lumbar and cervical spine surgery. STUDY DESIGN/SETTING: Retrospective cohort study. PATIENT SAMPLE: Patients who underwent IP or OP microdiscectomy, laminectomy, anterior cervical discectomy and fusion (ACDF), or cervical disc replacement (CDR) between 2017 and 2021. OUTCOME MEASURES: Thirty-day rates of serious and minor adverse events, readmission, reoperation, nonhome discharge, and mortality. METHODS: A retrospective review of patients who underwent IP or OP microdiscectomy, laminectomy, anterior cervical discectomy and fusion (ACDF), or cervical disc replacement (CDR) between 2017 and 2021 was conducted using the National Surgical Quality Improvement Program (NSQIP) database. Disparities between Black and White patients in (1) adverse event rates, (2) readmission rates, (3) reoperation rates, (4) nonhome discharge rates, (5) mortality rates, (6) operative times, and (7) hospital LOS between Black and White patients were measured and compared between IP and OP surgical settings. Multivariable logistic regression analyses were used to adjust for potential effects of baseline demographic and clinical differences. RESULTS: Of 81,696 total surgeries, 49,351 (60.4%) were performed as IP and 32,345 (39.6%) were performed as OP procedures. White patients accounted for a greater proportion of IP (88.2% vs 11.8%) and OP (92.7% vs 7.3%) procedures than Black patients. Following IP surgery, Black patients experienced greater odds of serious (OR 1.214, 95% CI 1.077-1.370, p=.002) and minor adverse events (OR 1.377, 95% CI 1.113-1.705, p=.003), readmission (OR 1.284, 95% CI 1.130-1.459, p<.001), reoperation (OR 1.194, 95% CI 1.013-1.407, p=.035), and nonhome discharge (OR 2.304, 95% CI 2.101-2.528, p<.001) after baseline adjustment. Disparities were less prominent in the OP setting, as Black patients exhibited greater odds of readmission (OR 1.341, 95% CI 1.036-1.735, p=.026) but were no more likely than White patients to experience adverse events, reoperation, individual complications, nonhome discharge, or death (p>.050 for all). CONCLUSIONS: Racial inequality in postoperative complications following spine surgery is evident, however disparities in complication rates are relatively less following OP compared to IP procedures. Further work may be beneficial in elucidating the causes of these differences to better understand and mitigate overall racial disparities within the inpatient setting. These decreased differences may also provide promising indication that progress towards reducing inequality is possible as spine care transitions to the OP setting.

Differences in total shoulder arthroplasty utilization and 30-day outcomes among White, Black, and Hispanic patients: do disparities exist in the outpatient setting?

BACKGROUND: In the United States, efforts to improve efficiency and reduce healthcare costs are shifting more total shoulder arthroplasty (TSA) surgeries to the outpatient setting. However, whether racial and ethnic disparities in access to high-quality outpatient TSA care exist remains to be elucidated. The purpose of this study was to assess racial/ethnic differences in relative outpatient TSA utilization and perioperative outcomes using a large national surgical database. METHODS: White, Black, and Hispanic patients who underwent TSA between 2017 and 2021 were identified from the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database. Baseline demographic and clinical characteristics were collected, and rates of outpatient utilization, adverse events, readmission, reoperation, nonhome discharge, and mortality within 30 days of surgery were compared between racial/ethnic groups. Race/ethnicity-specific trends in utilization of outpatient TSA were assessed, and multivariable logistic regression was used to adjust for baseline demographic factors and comorbidities. RESULTS: A total of 21,186 patients were included, consisting of 19,135 (90.3%) White, 1093 (5.2%) Black, and 958 (4.5%) Hispanic patients and representing 17,649 (83.3%) inpatient and 3537 (16.7%) outpatient procedures. Black and Hispanic patients were generally younger and less healthy than White patients, yet incidences of complications, nonhome discharge, readmission, reoperation, and death within 30 days were similar across groups following outpatient TSA (P > .050 for all). Relative utilization of outpatient TSA increased by 28.7% among White patients, 29.5% among Black patients, and 38.6% among Hispanic patients (ptrend<0.001 for all). Hispanic patients were 64% more likely than White patients to undergo TSA as an outpatient procedure across the study period (OR: 1.64, 95% CI 1.40-1.92, P < .001), whereas odds did not differ between Black and White patients (OR: 1.04, 95% CI 0.87-1.23, P = .673). CONCLUSION: Relative utilization of outpatient TSA remains highest among Hispanic patients but has been significantly increasing across all racial and ethnic groups, now accounting for more than one-third of all TSA procedures. Considering outpatient TSA is associated with fewer complications and lower costs, increasing utilization may represent a promising avenue for reducing disparities in orthopedic shoulder surgery.

Decisional regret following corrective adult spinal deformity surgery: a single institution study of incidence and risk factors.

PURPOSE: To assess the characteristics and risk factors for decisional regret following corrective adult spinal deformity (ASD) surgery at our hospital. METHODS: This is a retrospective cohort study of a single-surgeon ASD database. Adult patients (> 40 years) who underwent ASD surgery from May 2016 to December 2020 with minimum 2-year follow-up were included (posterior-only, ≥ 4 levels fused to the pelvis) (n = 120). Ottawa decision regret questionnaires, a validated and reliable 5-item Likert scale, were sent to patients postoperatively. Regret scores were defined as (1) low regret: 0-39 (2) medium to high regret: 40-100. Risk factors for medium or high decisional regret were identified using multivariate models. RESULTS: Ninety patients were successfully contacted and 77 patients consented to participate. Nonparticipants were older, had a higher incidence of anxiety, and higher ASA class. There were 7 patients that reported medium or high decisional regret (9%). Ninety percentage of patients believed that surgery was the right decision, 86% believed that surgery was a wise choice, and 87% would do it again. 8% of patients regretted the surgery and 14% believed that surgery did them harm. 88% of patients felt better after surgery. On multivariate analysis, revision fusion surgery was independently associated with an increased risk of medium or high decisional regret (adjusted odds ratio: 6.000, 95% confidence interval: 1.074-33.534, p = 0.041). CONCLUSIONS: At our institution, we found a 9% incidence of decisional regret. Revision fusion was associated with increased decisional regret. Estimates for decisional regret should be based on single-institution experiences given differences in patient populations.

Esophagectomy Enhanced Recovery After Surgery Initiative Results in Improved Outcomes.

BACKGROUND: Esophagectomy for esophageal cancer is a procedure with high morbidity and mortality. This study developed a Multidisciplinary Esophagectomy Enhanced Recovery Initiative (MERIT) pathway and analyzed implementation outcomes in a single institution. METHODS: The MERIT pathway was developed as a practice optimization and quality improvement initiative. Patients were studied from November 1, 2021 to June 20, 2022 and were compared with historical control subjects. The Wilcoxon rank sum test and the Fisher exact test were used for statistical analysis. RESULTS: The study compared 238 historical patients (January 17, 2017 to December 30, 2020) with 58 consecutive MERIT patients. There were no significant differences between patient characteristics in the 2 groups. In the MERIT group, 49 (85%) of the patients were male, and their mean age was 65 years (range, 59-71 years). Most cases were performed for esophageal cancer after neoadjuvant therapy. Length of stay improved by 27% from 11 to 8 days (P = .27). There was a 12% (P = .05) atrial arrhythmia rate reduction, as well as a 9% (P = .01) decrease in postoperative ileus. Overall complications were reduced from 54% to 35% (-19%; P = .01). CONCLUSIONS: This study successfully developed and implemented an enhanced recovery after surgery pathway for esophagectomy. In the first year, study investigators were able to reduce overall complications, specifically atrial arrhythmias, and postoperative ileus.

Sublobar Resection, Stereotactic Body Radiation Therapy, and Percutaneous Ablation Provide Comparable Outcomes for Lung Metastasis-Directed Therapy.

BACKGROUND: Prolonged survival of patients with metastatic disease has furthered interest in metastasis-directed therapy (MDT). RESEARCH QUESTION: There is a paucity of data comparing lung MDT modalities. Do outcomes among sublobar resection (SLR), stereotactic body radiation therapy (SBRT), and percutaneous ablation (PA) for lung metastases vary in terms of local control and survival? STUDY DESIGN AND METHODS: Medical records of patients undergoing lung MDT at a single cancer center between January 2015 and December 2020 were reviewed. Overall survival, local progression, and toxicity outcomes were collected. Patient and lesion characteristics were used to generate multivariable models with propensity weighted analysis. RESULTS: Lung MDT courses (644 total: 243 SLR, 274 SBRT, 127 PA) delivered to 511 patients were included with a median follow-up of 22 months. There were 47 local progression events in 45 patients, and 159 patients died. Two-year overall survival and local progression were 80.3% and 63.3%, 83.8% and 9.6%, and 4.1% and 11.7% for SLR, SBRT, and PA, respectively. Lesion size per 1 cm was associated with worse overall survival (hazard ratio, 1.24; P = .003) and LP (hazard ratio, 1.50; P < .001). There was no difference in overall survival by modality. Relative to SLR, there was no difference in risk of local progression with PA; however, SBRT was associated with a decreased risk (hazard ratio, 0.26; P = .023). Rates of severe toxicity were low (2.1%-2.6%) and not different among groups. INTERPRETATION: This study performs a propensity weighted analysis of SLR, SBRT, and PA and shows no impact of lung MDT modality on overall survival. Given excellent local control across MDT options, a multidisciplinary approach is beneficial for patient triage and longitudinal management.

Patient specific quality assurance of volumetric modulated arc therapy of synchronous bilateral breast cancer.

Synchronous bilateral breast cancers (SBBC) present a considerable issue in external beam radiotherapy because of large fields size and large target volumes. Mono-isocentric volumetric modulated arc therapy (VMAT) appears as an appropriate irradiation technique for these types of tumors. The aim of this study was to demonstrate the utility of a 3D DVH pretreatment quality assurance program in VMAT of SBBC cases. Twenty SBBC patients who underwent radiation therapy in our department were retrospectively enrolled in this study. Fifteen patients were treated exclusively to the mammary glands. Five patients benefited from a dose boost on the tumor bed (60Gy). Nine patients were irradiated on the supraclavicular nodes (50Gy). This dose was delivered in 25 fractions and integrated boost was used when appropriate. Depending on the complexity of the treatment plans; 2 or 4 arcs VMAT plans were used in a mono-isocentric technique. The patient specific quality assurance (PSQA) was evaluated using COMPASS measured data, COMPASS reconstructed (CR) and COMPASS computed (CC) dose compared to treatment planning system (TPS) dose. Clinical evaluation was based on DVH metrics for target volumes and organ at risks. The maximum average dose deviation between TPS, CC, and CR was below 3%. The paired t-test between TPS, CC, and CR shows a strong agreement (p < 0.001). The 3DVH dose distribution comparison between TPS and COMPASS were also performed with good gamma score for global analysis. COMPASS was successfully evaluated as a 3DVH pretreatment system for SBBC despite the large fields size and complex target volumes. It allows the verification of the plan in 3D patient anatomy and the evaluation of dose discrepancies.

Extensive Aortic Dissection in a Low-Risk Male Causing Acute Kidney Injury: A Case Report.

Aortic dissection is a major differential diagnosis in an elderly male with severe chest pain radiating to the back who has a history of hypertension, smoking, or connective tissue disorders such as Marfan and Ehlers-Danlos syndromes. It is a medical emergency with a high mortality rate if undetected and untreated. This report describes the case of a patient presenting with extensive aortic dissection with no significant risk factors who was diagnosed following a CT angiogram of the aorta. He was subsequently managed medically before being transferred for definitive surgical management with a good outcome.

Mepitel Film for the prevention of acute radiation dermatitis in head and neck cancer: a systematic review and meta-analysis of randomized controlled trials.

PURPOSE: This systematic review and meta-analysis evaluates the efficacy of Mepitel Film in preventing acute radiation dermatitis (RD) in patients with head and neck cancer (HNC) across randomized controlled trials (RCTs). METHODS: Embase, MEDLINE, and Cochrane Central Register of Controlled Trials were searched on 5 March 2023 to identify relevant RCTs. RD assessment tools and outcomes were compared across studies. Pooled effect sizes and 95% confidence intervals (CI) were estimated based on random-effects analysis using RevMan 5.4. RESULTS: Three RCTs conducted between 2018 and 2020 were included. Mepitel Film decreased RD severity when compared to Sorbolene or Biafine but not when compared to mometasone. A per-protocol analysis of two of the trials revealed that, overall, Mepitel Film significantly reduced the incidence of grade 2-3 RD (odds ratio (OR), 0.24; 95% CI, 0.09-0.65; p = 0.005) and moist desquamation (OR, 0.21; 95% CI, 0.10-0.46; p < 0.0001) and decreased average patient, researcher, and combined components of the Radiation-Induced Skin Reaction Assessment Scale (the standardized mean difference (SMD) for patient ratings, - 2.56; 95% CI, - 3.15 to - 1.96, p < 0.00001; SMD for researcher ratings, - 3.47; 95% CI, - 6.63 to - 0.31, p = 0.03; SMD for combined scores, - 3.68; 95% CI, - 6.43 to - 0.92, p = 0.009). Noted issues with Mepitel Film included itchiness and poor adherence. CONCLUSION: While there were discrepancies across studies, Mepitel Film demonstrated a decrease in the incidence of grade 2-3 RD and moist desquamation. These findings emphasize the need for further examining Mepitel Film's efficacy across diverse patient groups and the importance of standardizing RD severity assessment methodologies and control arms.

NMR indicates the N-termini of PSGL1 and CCR7 bind competitively to the chemokine CCL21.

Chemokines are from a family of secreted cytokines that direct the trafficking of immune cells to coordinate immune responses. Chemokines are involved in numerous disease states, including responding to infections, autoimmune disorders, and cancer metastasis. Ther are chemokines, like CCL21, that signal for cellular migration through the activation of G protein-coupled receptors, like CCR7, through interaction with the receptor's extracellular N-terminus, loops, and core of the receptor. CCL21 is involved in routine immune surveillance but can also attract metastasizing cancer cells to lymph nodes. P-selectin glycoprotein ligand 1 (PSGL1) has a role in cellular adhesion during chemotaxis and is a transmembrane signaling molecule. PSGL1 expression enhances chemotactic responses of T cells to CCL21. Here NMR studies indicate the binding sites on CCL21 for the N-termini or PSGL1 and CCR7 overlap, and binding of the N-termini of PSGL1 and CCR7 is competitive.

Nativity Status Predicts Tobacco Use: A Comparative Analysis of US-Born and Foreign-Born Adults From the Health Information National Trends Survey (HINTS).

Introduction Tobacco smoking remains one of the leading causes of morbidity and mortality globally and in the United States (USA). We hypothesize that US-born naturals have higher odds of tobacco smoking compared to their foreign-born counterparts, and our study aims to assess the relationship between nativity status and odds of tobacco smoking using a nationally representative sample. Methods We utilized the Health Information National Trends Survey (HINTS) 5 Cycle 1 (2017) and Cycle 2 (2018) for this study. Our main outcome variable was smoking status divided as ever smoker and never smoker. The main predictor was US birth status. We controlled for sociodemographic characteristics such as age, race, gender, educational status, and marital status. We performed weighted descriptive statistics and bivariate analysis with chi-square for our variables. Unadjusted and adjusted logistic regression was used to ascertain the odds of our outcome given our predictor. Significance was set at 95% confidence, and the alpha level was set to 0.05. All analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA). Results Our final sample consisted of 5,677 individuals (weighted: 429,613,693). Of our sample, 36.89% were ever smokers, females were 50.73%, and the majority (57.90%) were high school graduates. In terms of nativity status, those born in the USA were 85.65%, while the non-US-born population was 14.35%. After adjusting for confounders, we found that non-US-born respondents had 42% lower odds of being ever smokers compared to their US-born counterparts (adjusted odds ratio (AOR) = 0.576; 95% confidence interval (CI) = 0.388-0.854; P = 0.0062). Females were 24% less likely to be ever smokers compared to males (AOR = 0.758; 95% CI = 0.644-0.893; P = 0.0010). Having a bachelor's degree or a graduate degree was associated with 42% and 53% lower odds of being ever smokers compared to high school graduates (AOR = 0.583; 95% CI = 0.474-0.717; P < 0.0001) (AOR = 0.471; 95% CI = 0.377-0.588; P < 0.0001). Whites had 97% higher odds of being ever smokers compared to Hispanics (AOR = 1.977; 95% CI = 1.459-2.679; P < 0.0001). Conclusion Our finding of lower odds of tobacco use among foreign-born nationals compared to US-born nationals is consistent with previous studies and suggests the need for equity in tobacco use prevention between the two populations assessed in our study. This is poised to improve overall tobacco use burden, morbidity, and mortality.

Human A2-CAR T Cells Reject HLA-A2 + Human Islets Transplanted Into Mice Without Inducing Graft-versus-host Disease.

BACKGROUND: Type 1 diabetes is an autoimmune disease characterized by T-cell-mediated destruction of pancreatic beta-cells. Islet transplantation is an effective therapy, but its success is limited by islet quality and availability along with the need for immunosuppression. New approaches include the use of stem cell-derived insulin-producing cells and immunomodulatory therapies, but a limitation is the paucity of reproducible animal models in which interactions between human immune cells and insulin-producing cells can be studied without the complication of xenogeneic graft-versus-host disease (xGVHD). METHODS: We expressed an HLA-A2-specific chimeric antigen receptor (A2-CAR) in human CD4 + and CD8 + T cells and tested their ability to reject HLA-A2 + islets transplanted under the kidney capsule or anterior chamber of the eye of immunodeficient mice. T-cell engraftment, islet function, and xGVHD were assessed longitudinally. RESULTS: The speed and consistency of A2-CAR T-cell-mediated islet rejection varied depending on the number of A2-CAR T cells and the absence/presence of coinjected peripheral blood mononuclear cells (PBMCs). When <3 million A2-CAR T cells were injected, coinjection of PBMCs accelerated islet rejection but also induced xGVHD. In the absence of PBMCs, injection of 3 million A2-CAR T cells caused synchronous rejection of A2 + human islets within 1 wk and without xGVHD for 12 wk. CONCLUSIONS: Injection of A2-CAR T cells can be used to study rejection of human insulin-producing cells without the complication of xGVHD. The rapidity and synchrony of rejection will facilitate in vivo screening of new therapies designed to improve the success of islet-replacement therapies.

The Association of Lumbar Plexus Lengthening with Neurologic Deficit After Adult Spinal Deformity Surgery.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: This study aimed to evaluate the association between nerve lengthening after adult deformity correction and motor deficits dervied from the upper lumbar plexus or femoral nerve. SUMMARY OF BACKGROUND DATA: Adult spinal deformity (ASD) surgery is associated with high rates of neurological deficits. Certain postoperative deficits may be related to lengthening of the upper lumbar plexus (ULP) and/or femoral nerve (FN) after correction of lumbar deformity. METHODS: Patients with ASD who underwent posterior-only corrective surgery from the sacrum to L3 or above were included. The length of each lumbar nerve root (NR) was calculated geometrically using the distance from the foramen to the midpoint between the anterosuperior iliac crest and pubic symphysis on AP and lateral radiographs. The mean lengths of the L1-3 and L2-4 NRs were used to define the lengths of the ULP and FN, respectively. Pre- to postoperative changes in nerve length were calculated. Neurological examination was performed at discharge. Proximal weakness (PW) was defined as the presence of weakness compared to baseline in either hip flexors or knee extensors. Multiple linear regression analysis was used for estimating the postoperative lengthening according to the magnitude of preoperative curvature and postoperative correction angles. RESULTS: A total of 202 sides were analyzed in 101 patients, and PW was present on 15 (7.4%) sides in 10 patients. Excluding the 10 cases with three-column osteotomies, those with PW had a significantly higher rate of pure sagittal deformity (P<.001) and greater nerve lengthening than those without PW (ULP 24 vs 15 mm, P=0.02; FN 18 vs 11 mm, P=0.05). No patient had advanced imaging showing neural compression, and complete recovery of PW occurred in 8 patients at 1-year follow-up. CONCLUSIONS: After ASD surgery, lengthening of the ULP was associated with PW. In preoperative planning, surgeons must consider how the type of correction may influence the risk for nerve lengthening, which may contribute to postoperative neurologic deficit. LEVEL OF EVIDENCE: 3.

Engineering of 3D printed personalized polypills for the treatment of the metabolic syndrome.

Metabolic syndrome is a collection of abnormalities, including at least three of the following insulin resistance, hypertension, dyslipidemia, type 2 diabetes, obesity, inflammation, and non-alcoholic fatty liver disease. 3D printed solid dosage forms have emerged as a promising tool enabling the fabrication of personalized medicines and offering solutions that cannot be achieved by industrial mass production. Most attempts found in the literature to manufacture polypills for this syndrome contain just two drugs. However, most fixed-dose combination (FDC) products in clinical practice required the use of three or more drugs. In this work, Fused deposition modelling (FDM) 3D printing technology coupled with hot-melt extrusion (HME) has been successfully applied in the manufacture of polypills containing nifedipine (NFD), as an antihypertensive drug, simvastatin (SMV), as an antihyperlipidemic drug, and gliclazide (GLZ) as an antiglycemic drug. Hanssen solubility parameters (HSPs) were utilized as predictors to guide the formation of amorphous solid dispersion between drug and polymer to ensure miscibility and enhanced oral bioavailability. The HSP varied from 18.3 for NFD, 24.6 for SMV, and 7.0 for GLZ while the total solubility parameter for the excipient mixture was 27.30.5. This allowed the formation of an amorphous solid dispersion in SMV and GLZ 3D printed tablets compared to NFD which was partially crystalline. Popypill showed a dual release profile combining a faster SMV release (< 6h) with a 24 h sustained release for NDF and GLZ. This work demonstrated the transformation of FDC into dynamic dose-personalized polypills.

Infection promotes Ser-214 phosphorylation important for generation of cytotoxic tau variants.

Patients who recover from hospital-acquired pneumonia exhibit a high incidence of end-organ dysfunction following hospital discharge, including cognitive deficits. We have previously demonstrated that pneumonia induces the production and release of cytotoxic oligomeric tau from pulmonary endothelial cells, and these tau oligomers can enter the circulation and may be a cause of long-term morbidities. Endothelial-derived oligomeric tau is hyperphosphorylated during infection. The purpose of these studies was to determine whether Ser-214 phosphorylation of tau is a necessary stimulus for generation of cytotoxic tau variants. The results of these studies demonstrate that Ser-214 phosphorylation is critical for the cytotoxic properties of infection-induced oligomeric tau. In the lung, Ser-214 phosphorylated tau contributes to disruption of the alveolar-capillary barrier, resulting in increased permeability. However, in the brain, both the Ser-214 phosphorylated tau and the mutant Ser-214-Ala tau, which cannot be phosphorylated, disrupted hippocampal long-term potentiation suggesting that inhibition of long-term potentiation was relatively insensitive to the phosphorylation status of Ser-214. Nonetheless, phosphorylation of tau is essential to its cytotoxicity since global dephosphorylation of the infection-induced cytotoxic tau variants rescued long-term potentiation. Collectively, these data demonstrate that multiple forms of oligomeric tau are generated during infectious pneumonia, with different forms of oligomeric tau being responsible for dysfunction of distinct end-organs during pneumonia.