Generating human artery and vein cells from pluripotent stem cells highlights the arterial tropism of Nipah and Hendra viruses.

Stem cell research endeavors to generate specific subtypes of classically defined "cell types." Here, we generate >90% pure human artery or vein endothelial cells from pluripotent stem cells within 3-4 days. We specified artery cells by inhibiting vein-specifying signals and vice versa. These cells modeled viral infection of human vasculature by Nipah and Hendra viruses, which are extraordinarily deadly (∼57%-59% fatality rate) and require biosafety-level-4 containment. Generating pure populations of artery and vein cells highlighted that Nipah and Hendra viruses preferentially infected arteries; arteries expressed higher levels of their viral-entry receptor. Virally infected artery cells fused into syncytia containing up to 23 nuclei, which rapidly died. Despite infecting arteries and occupying ∼6%-17% of their transcriptome, Nipah and Hendra largely eluded innate immune detection, minimally eliciting interferon signaling. We thus efficiently generate artery and vein cells, introduce stem-cell-based toolkits for biosafety-level-4 virology, and explore the arterial tropism and cellular effects of Nipah and Hendra viruses.

Antibody Lineages with Vaccine-Induced Antigen-Binding Hotspots Develop Broad HIV Neutralization.

The vaccine-mediated elicitation of antibodies (Abs) capable of neutralizing diverse HIV-1 strains has been a long-standing goal. To understand how broadly neutralizing antibodies (bNAbs) can be elicited, we identified, characterized, and tracked five neutralizing Ab lineages targeting the HIV-1-fusion peptide (FP) in vaccinated macaques over time. Genetic and structural analyses revealed two of these lineages to belong to a reproducible class capable of neutralizing up to 59% of 208 diverse viral strains. B cell analysis indicated each of the five lineages to have been initiated and expanded by FP-carrier priming, with envelope (Env)-trimer boosts inducing cross-reactive neutralization. These Abs had binding-energy hotspots focused on FP, whereas several FP-directed Abs induced by immunization with Env trimer-only were less FP-focused and less broadly neutralizing. Priming with a conserved subregion, such as FP, can thus induce Abs with binding-energy hotspots coincident with the target subregion and capable of broad neutralization.

A DNA unwinding equilibrium serves as a checkpoint for CRISPR-Cas12a target discrimination.

CRISPR-associated proteins such as Cas9 and Cas12a are programable RNA-guided nucleases that have emerged as powerful tools for genome manipulation and molecular diagnostics. However, these enzymes are prone to cleaving off-target sequences that contain mismatches between the RNA guide and DNA protospacer. In comparison to Cas9, Cas12a has demonstrated distinct sensitivity to protospacer-adjacent-motif (PAM) distal mismatches, and the molecular basis of Cas12a's enhanced target discrimination is of great interest. In this study, we investigated the mechanism of Cas12a target recognition using a combination of site-directed spin labeling, fluorescent spectroscopy, and enzyme kinetics. With a fully matched RNA guide, the data revealed an inherent equilibrium between a DNA unwound state and a DNA-paired duplex-like state. Experiments with off-target RNA guides and pre-nicked DNA substrates identified the PAM-distal DNA unwinding equilibrium as a mismatch sensing checkpoint prior to the first step of DNA cleavage. The finding sheds light on the distinct targeting mechanism of Cas12a and may better inform CRISPR based biotechnology developments.

A neural network solves, explains, and generates university math problems by program synthesis and few-shot learning at human level.

We demonstrate that a neural network pretrained on text and fine-tuned on code solves mathematics course problems, explains solutions, and generates questions at a human level. We automatically synthesize programs using few-shot learning and OpenAI's Codex transformer and execute them to solve course problems at 81% automatic accuracy. We curate a dataset of questions from Massachusetts Institute of Technology (MIT)'s largest mathematics courses (Single Variable and Multivariable Calculus, Differential Equations, Introduction to Probability and Statistics, Linear Algebra, and Mathematics for Computer Science) and Columbia University's Computational Linear Algebra. We solve questions from a MATH dataset (on Prealgebra, Algebra, Counting and Probability, Intermediate Algebra, Number Theory, and Precalculus), the latest benchmark of advanced mathematics problems designed to assess mathematical reasoning. We randomly sample questions and generate solutions with multiple modalities, including numbers, equations, and plots. The latest GPT-3 language model pretrained on text automatically solves only 18.8% of these university questions using zero-shot learning and 30.8% using few-shot learning and the most recent chain of thought prompting. In contrast, program synthesis with few-shot learning using Codex fine-tuned on code generates programs that automatically solve 81% of these questions. Our approach improves the previous state-of-the-art automatic solution accuracy on the benchmark topics from 8.8 to 81.1%. We perform a survey to evaluate the quality and difficulty of generated questions. This work automatically solves university-level mathematics course questions at a human level and explains and generates university-level mathematics course questions at scale, a milestone for higher education.

p38 MAPK and MKP-1 control the glycolytic program via the bifunctional glycolysis regulator PFKFB3 during sepsis.

Hyperlactatemia often occurs in critically ill patients during severe sepsis/septic shock and is a powerful predictor of mortality. Lactate is the end product of glycolysis. While hypoxia due to inadequate oxygen delivery may result in anaerobic glycolysis, sepsis also enhances glycolysis under hyperdynamic circulation with adequate oxygen delivery. However, the molecular mechanisms involved are not fully understood. Mitogen-activated protein kinase (MAPK) families regulate many aspects of the immune response during microbial infections. MAPK phosphatase (MKP)-1 serves as a feedback control mechanism for p38 and JNK MAPK activities via dephosphorylation. Here, we found that mice deficient in Mkp-1 exhibited substantially enhanced expression and phosphorylation of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB) 3, a key enzyme that regulates glycolysis following systemic Escherichia coli infection. Enhanced PFKFB3 expression was observed in a variety of tissues and cell types, including hepatocytes, macrophages, and epithelial cells. In bone marrow-derived macrophages, Pfkfb3 was robustly induced by both E. coli and lipopolysaccharide, and Mkp-1 deficiency enhanced PFKFB3 expression with no effect on Pfkfb3 mRNA stability. PFKFB3 induction was correlated with lactate production in both WT and Mkp-1-/- bone marrow-derived macrophage following lipopolysaccharide stimulation. Furthermore, we determined that a PFKFB3 inhibitor markedly attenuated lactate production, highlighting the critical role of PFKFB3 in the glycolysis program. Finally, pharmacological inhibition of p38 MAPK, but not JNK, substantially attenuated PFKFB3 expression and lactate production. Taken together, our studies suggest a critical role of p38 MAPK and MKP-1 in the regulation of glycolysis during sepsis.

Modeling interactions between Heparan sulfate and proteins based on the Heparan sulfate microarray analysis.

Heparan sulfate (HS), a sulfated polysaccharide abundant in the extracellular matrix, plays pivotal roles in various physiological and pathological processes by interacting with proteins. Investigating the binding selectivity of HS oligosaccharides to target proteins is essential, but the exhaustive inclusion of all possible oligosaccharides in microarray experiments is impractical. To address this challenge, we present a hybrid pipeline that integrates microarray and in silico techniques to design oligosaccharides with desired protein affinity. Using fibroblast growth factor 2 (FGF2) as a model protein, we assembled an in-house dataset of HS oligosaccharides on microarrays and developed two structural representations: a standard representation with all atoms explicit and a simplified representation with disaccharide units as "quasi-atoms." Predictive Quantitative Structure-Activity Relationship (QSAR) models for FGF2 affinity were developed using the Random Forest (RF) algorithm. The resulting models, considering the applicability domain, demonstrated high predictivity, with a correct classification rate of 0.81-0.80 and improved positive predictive values (PPV) up to 0.95. Virtual screening of 40 new oligosaccharides using the simplified model identified 15 computational hits, 11 of which were experimentally validated for high FGF2 affinity. This hybrid approach marks a significant step toward the targeted design of oligosaccharides with desired protein interactions, providing a foundation for broader applications in glycobiology.

ALT to qHBsAg ratio predicts long-term HBsAg seroclearance after entecavir cessation in Chinese patients with chronic hepatitis B.

BACKGROUND & AIMS: Factors predicting HBsAg seroclearance after treatment cessation, irrespective of nucleos(t)ide analogue (NA) resumption, have important clinical implications. We evaluated predictors of long-term HBsAg seroclearance after entecavir cessation. METHODS: This study followed-up Chinese patients with chronic hepatitis B from two previous studies of entecavir cessation. All patients were non-cirrhotic, HBeAg-negative, with undetectable HBV DNA (<20 IU/ml) at end-of-treatment (EOT). They were monitored closely for 48 weeks with regular HBV DNA, quantitative HBsAg (qHBsAg) and alanine aminotransferase (ALT) measurements. Entecavir was resumed at HBV DNA >2,000 IU/ml, irrespective of ALT levels. After the initial 48 weeks, patients were assessed every 6 months, regardless of entecavir resumption, to monitor for HBsAg seroclearance. RESULTS: A total of 194 patients (63.4% male, mean age 49.9 years, on entecavir for a median of 47.2 months) were recruited; 94 (48.5%) and 158 (81.4%) patients had EOT qHBsAg <100 IU/ml and <1,000 IU/ml, respectively; 151 (77.8%) patients were eventually resumed on entecavir. After follow-up for a median of 70.7 (51.0-118.2) months, 28 (14.4%) patients had HBsAg seroclearance. qHBsAg levels at weeks 36 and 48 after EOT independently predicted HBsAg seroclearance (both p <0.01), whereas qHBsAg from EOT to week 24 only trended towards statistical significance. The ratio of ALT/qHBsAg at all time points from EOT to week 48 independently predicted HBsAg seroclearance (hazard ratios ranging from 1.003-1.028, all p <0.01) with excellent diagnostic performance (area under the receiver-operating characteristic curve 0.799-0.933, negative predictive value >90% at different time points), regardless of whether entecavir was resumed. CONCLUSIONS: The ALT/qHBsAg ratio after entecavir cessation predicts HBsAg seroclearance, even in patients who were resumed on treatment. Its use may mitigate the risk of severe hepatitis flares in patients managed by observation without treatment resumption. IMPACT AND IMPLICATIONS: Current predictors of HBsAg seroclearance after finite nucleos(t)ide analogue (NA) therapy have suboptimal predictive value. We demonstrated that the ALT/qHBsAg ratio may be able to reflect the balance between host control and virological activity. The ALT/qHBsAg ratio at different time points from end-of-treatment till week 48 independently and accurately predicted HBsAg seroclearance in patients who have stopped entecavir. The ALT/qHBsAg ratio may be utilized by clinicians for patient selection and retreatment decisions in finite NA therapy.

Endocuff With or Without Artificial Intelligence-Assisted Colonoscopy in Detection of Colorectal Adenoma: A Randomized Colonoscopy Trial.

INTRODUCTION: Both artificial intelligence (AI) and distal attachment devices have been shown to improve adenoma detection rate and reduce miss rate during colonoscopy. We studied the combined effect of Endocuff and AI on enhancing detection rates of various colonic lesions. METHODS: This was a 3-arm prospective randomized colonoscopy study involving patients aged 40 years or older. Participants were randomly assigned in a 1:1:1 ratio to undergo Endocuff with AI, AI alone, or standard high-definition (HD) colonoscopy. The primary outcome was adenoma detection rate (ADR) between the Endocuff-AI and AI groups while secondary outcomes included detection rates of polyp (PDR), sessile serrated lesion (sessile detection rate [SDR]), and advanced adenoma (advanced adenoma detection rate) between the 2 groups. RESULTS: A total of 682 patients were included (mean age 65.4 years, 52.3% male), with 53.7% undergoing diagnostic colonoscopy. The ADR for the Endocuff-AI, AI, and HD groups was 58.7%, 53.8%, and 46.3%, respectively, while the corresponding PDR was 77.0%, 74.0%, and 61.2%. A significant increase in ADR, PDR, and SDR was observed between the Endocuff-AI and AI groups (ADR difference: 4.9%, 95% CI: 1.4%-8.2%, P = 0.03; PDR difference: 3.0%, 95% CI: 0.4%-5.8%, P = 0.04; SDR difference: 6.4%, 95% CI: 3.4%-9.7%, P < 0.01). Both Endocuff-AI and AI groups had a higher ADR, PDR, SDR, and advanced adenoma detection rate than the HD group (all P < 0.01). DISCUSSION: Endocuff in combination with AI further improves various colonic lesion detection rates when compared with AI alone.

Intravenous tranexamic acid reduces complications following surgical treatment of pathologic fractures of the lower extremity.

BACKGROUND AND OBJECTIVES: This study aimed to evaluate the postoperative complications associated with administering intravenous (IV) tranexamic acid (TXA) in patients undergoing surgical fixation for neoplastic pathologic fractures of the lower extremities. METHODS: Patients ≥18 years old who underwent surgical intervention for neoplastic pathologic lower extremity fractures from 2015 to 2021 were identified using the Premier Healthcare Database. This cohort was divided by TXA receipt on the index surgery day. Patient demographics, hospital factors, patient comorbidities, and 90-day complications were assessed and compared between the cohorts. RESULTS: From 2015 to 2021, 4497 patients met inclusion criteria (769 TXA[+] and 3728 TXA[-]). Following propensity score matching, patients who received TXA had a significantly shorter length of stay than those who did not (7.6 ± 7.3 days vs. 9.0 ± 15.2, p = 0.036). Between the two cohorts, there were no significant differences in comorbidities. Regarding differences in postoperative complications, TXA(+) patients had significantly decreased odds of deep vein thrombosis (DVT) (1.87% vs. 5.46%; odds ratio [OR]:0.33; 95% confidence interval: 0.17-0.62; p = 0.001). CONCLUSION: Administration of IV TXA may be associated with a decreased risk of postoperative DVT without an increased risk of other complications. Orthopedic surgeons should consider the utilization of IV TXA in patients treated surgically for neoplastic pathologic fractures of the lower extremity.

Prescription drug monitoring programs and prescription pain medication misuse among U.S. high school students-2019.

BACKGROUND: Prescription drug monitoring programs (PDMPs) are state-level databases that track and inform prescribing practices to reduce prescription drug diversion and misuse. To our knowledge, only three studies have examined the impact of PDMPs on opioid-related outcomes among adolescents, and none have focused on prescription pain medication misuse among adolescents. METHODS: This study leveraged data from the 2019 National Youth Risk Behavior Survey (YRBS) to explore the associations between five categories of PDMP dimensions and the prevalence of self-reported prescription pain medication misuse. Demographic factors' associations with self-reported prescription pain medication misuse were also examined. RESULTS: In 2019, none of the PDMP dimensions were associated with self-reported prescription pain medication misuse among U.S. high school students, adjusting for gender, grade, race/ethnicity, and sexual orientation. CONCLUSIONS: None of the five PDMP dimensions were associated with lower prescription pain medication misuse, however further research is needed, especially as new YRBS data become available.

Surgical management of vocal cord nodules in children: Trends and outcomes.

OBJECTIVES: Vocal cord nodules (VCNs) are the most common cause of dysphonia in school-aged children, with potential negative impacts on quality of life including diminished self-esteem and academic performance. The standard of care for VCNs is conservative management which ranges from voice hygiene to speech therapy with a focus on voice otherwise known as voice therapy, with surgical excision reserved for refractory cases. Thus, few studies have analyzed outcomes of surgical management of VCNs. The purpose of this study is to assess the prevalence and efficacy of surgical excision of VCNs when compared to speech therapy. METHODS: Children with VCNs seen at a single tertiary care institution between 2015 and 2020 were identified by ICD-9 code 478.5 and ICD-10 code J38.2. Demographics, objective voice assessment, intervention, and follow-up assessment data were reviewed. Frequencies, medians, and interquartile ranges were calculated. Time to resolution and improvement were assessed by Cox proportional hazards model. Univariate logistic regression was performed. A P value of <0.05 was considered statistically significant. RESULTS: Three hundred sixty-eight patients diagnosed with VCNs were identified. 169 patients received intervention for VCNs, with 159 (43.2 %) receiving speech therapy alone and 5 (1.4 %) receiving surgery alone. On bivariate analysis, there was no significant difference in demographic features between treatment groups, however speech therapy patients did have a longer follow-up time. 154 patients underwent objective voice assessment at the time of VCN diagnosis. Among these patients, 95 (61.7 %) received speech therapy and 59 (40.3 %) received no intervention. Speech therapy patients had significantly higher pVHI scores, however there was no significant difference in CAPE-V Overall Severity scores or computerized voice assessment analysis. On Cox proportional hazards analysis, surgical intervention was associated with faster resolution and faster improvement of dysphonic symptoms. On binary logistic regression, surgery was associated with a significantly greater proportion of patients reporting resolution of dysphonic symptoms, however there was no significant difference in proportion of patients reporting improvement of dysphonia. CONCLUSION: For most patients with VCNs, conservative measures such as voice hygiene and speech therapy remain first line, however certain patients may benefit from the rapid improvement and resolution of symptoms that surgical intervention may provide.

Shoulder arthroplasty for inflammatory arthritis is associated with higher rates of medical and surgical complications: a nationwide matched cohort analysis from 2016-2020.

BACKGROUND: Inflammatory arthritis (IA) represents a less common indication for anatomic and reverse total shoulder arthroplasty (TSA) than osteoarthritis (OA). The safety and efficacy of anatomic and reverse TSA in this population has not been as well studied compared to OA. We analyzed the differences in outcomes between IA and OA patients undergoing TSA. METHODS: Patients who underwent primary anatomic total shoulder arthroplasty (aTSA) and reverse total shoulder arthroplasty (rTSA) from 2016-2020 were identified in the Premier Healthcare Database. Inflammatory arthritis (IA) patients were identified using International Classification of Diseases, Tenth Revision, diagnosis codes and compared to osteoarthritis controls. Patients were matched in a 1:8 fashion by age (±3 years), sex, race, and presence of pertinent comorbidities. Patient demographics, hospital factors, and patient comorbidities were compared. Multivariate regression was performed following matching to account for any residual confounding and 90-day complications were compared between the 2 cohorts. Descriptive statistics and regression analysis were employed with significance set at P < .05. RESULTS: Prior to matching, 5685 IA cases and 93,539 OA controls were identified. Patients with IA were more likely to be female, have prolonged length of stay and increased total costs (P < .0001). After matching and multivariate analysis, 4082 IA cases and 32,656 controls remained. IA patients were at increased risk of deep wound infection (OR 3.14, 95% CI 1.38-7.16, P = .006), implant loosening (OR 4.11, 95% CI 1.17-14.40, P = .027), and mechanical complications (OR 6.34, 95% CI 1.05-38.20, P = .044), as well as a decreased risk of postoperative stiffness (OR 0.36, 95% CI 0.16-0.83, P = .002). Medically, IA patients were at increased risk of PE (OR 2.97, 95% CI 1.52-5.77, P = .001) and acute blood loss anemia (OR 1.27, 95% CI 1.12-1.44, P < .0001). DISCUSSION AND CONCLUSION: Inflammatory arthritis represents a distinctly morbid risk profile compared to osteoarthritis patients with multiple increased surgical and postoperative medical complications in patients undergoing aTSA and rTSA. Surgeons should consider these potential complications and employ a multidisciplinary approach in preoperative risk stratification of IA undergoing shoulder replacement.

Total Hip and Total Knee Arthroplasty Outpatient Case Volume During the 2020 COVID-19 Pandemic in New York and California.

BACKGROUND: Inpatient total hip and total knee arthroplasty were substantially impacted by the SARS-CoV-2 (COVID-19) pandemic. We sought to characterize the transition of total joint arthroplasty (TJA) to the outpatient setting in 2 large state health systems during this pandemic. METHODS: Adult patients who underwent primary elective TJA between January 1, 2016 and December 31, 2020 were retrospectively reviewed using the New York Statewide Planning and Research Cooperative System and California Department of Health Care Access and Information datasets. Yearly inpatient and outpatient case volumes and patient demographics, including age, sex, race, and payer coverage, were recorded. Continuous and categorical variables were compared using descriptive statistics. Significance was set at P < .05. RESULTS: In New York during 2020, TJA volume decreased 16% because 22,742 fewer inpatient TJAs were performed. Much of this lost volume (46.6%) was offset by a 166% increase in outpatient TJA. In California during 2020, TJA volume decreased 20% because 34,114 fewer inpatient TJAs were performed. Much of this lost volume (37%) was offset by a 47% increase in outpatient TJA. CONCLUSIONS: This present study demonstrates a marked increase in the proportion of TJA being performed on an outpatient basis in both California and New York. In both states, despite a decrease in overall TJA volume in 2020, outpatient TJA volume increased markedly. LEVEL OF EVIDENCE: Therapeutic Level IV, Retrospective Cohort Study.

Risk Factors for Peripheral Nerve Injury Following Revision Total Knee Arthroplasty in 132,960 Patients.

BACKGROUND: Peripheral nerve injury (PNI) following revision total knee arthroplasty (rTKA) is a potentially devastating injury for patients. This study assessed the frequency of and risk factors for postoperative PNI following rTKA. METHODS: Patients who underwent rTKA from 2003 to 2015 were identified using the National Inpatient Sample. Demographics, medical histories, surgical details, and complications were compared between patients who sustained a PNI and those who did not to identify risk factors for the development of PNI after rTKA. RESULTS: Overall, 132,960 patients who underwent rTKA were identified, and 737 (0.56%) sustained a postoperative PNI. After adjusting for confounders, patients with a history of a spine condition (adjusted odds ratio [aOR]: 1.7, 95%-confidence interval 1.2 to 2.4, P = .003) and postoperative anemia (aOR: 1.3, 95%-CI: 1.1 to 1.5, P = .004) had higher risk of PNI following rTKA. Intraoperative periprosthetic fracture (aOR: 1.3, 0.78 to 2.2, P = .308), rheumatoid arthritis (aOR: 1.0, 95%-CI: 0.68 to 1.6, P = .865), and history of knee dislocation (aOR: 1.1, 95%-CI: 0.85 to 1.5, P = .412), were not significantly associated with higher risk for PNI. CONCLUSIONS: This study found a 0.56% incidence of PNI following rTKA, and patients who had preexisting spine conditions or postoperative anemia were at an increased risk for this complication. Orthopedic surgeons may use the results of this study to appropriately counsel patients on the potential for a PNI following rTKA.

Same-Day Total Joint Arthroplasty in the United States From 2016 to 2020: The Impact of the Medicare Inpatient Only List and the COVID-19 Pandemic.

BACKGROUND: Same-day total hip arthroplasty (THA) and total knee arthroplasty (TKA) continue to gain popularity in the United States. The present study sought to quantify recent same-day outpatient trends taking into consideration the COVID-19 pandemic as well as the removal of these procedures from the Medicare inpatient only (IPO) list. METHODS: Patients undergoing primary elective TKA and THA were identified using the Nationwide Ambulatory Surgery Sample and the National Inpatient Sample from January 1, 2016, to December 31, 2020. The same-day cohort included Nationwide Ambulatory Surgery Sample and National Inpatient Sample patients with a length of stay = 0 days. The inpatient cohort included patients with length of stay ≥1 day. National estimates were extrapolated using weight functions. RESULTS: From January 2016 to December 2020, the proportion of same-day TKA increased from 1.2 (719) to 62.4% (31,293) and the proportion of same-day THA increased from 2.0 (599) to 54.5% (18,252). Following removal from the Medicare IPO list, same-day TKAs increased from 3.2% (1,895) in December 2017 to 13.8% (9,269) in January 2018, and same-day THAs increased from 10.7% (4,295) in December 2019 to 22.5% (8,708) in January 2020. Between February and March 2020, same-day TKAs increased from 42.4 (26,148) to 44.4% (16,972) and same-day THAs increased from 28.5 (10,729) to 30.2% (7,409). CONCLUSIONS: The proportion of same-day TKA and THA dramatically increased following removal from the Medicare IPO list and in response to the COVID-19 pandemic. By December 2020, same-day TKA and THA accounted for >50% of all cases performed in the United States.

Perioperative Dexamethasone is Associated With a Decreased Risk of Pulmonary Embolism and Deep Vein Thrombosis Following Total Joint Arthroplasty: An Analysis of 70,000 High-Risk Patients.

BACKGROUND: Dexamethasone (DEX) has demonstrated promise with respect to decreasing postoperative thromboembolic complications following total joint arthroplasty (TJA). Therefore, the aim of this study was to investigate the effects of perioperative intravenous DEX on rates of pulmonary embolism (PE) and deep vein thrombosis (DVT) after primary TJA in patients who have a history of venous thromboembolism (VTE). METHODS: Patients who have a history of VTE who underwent primary elective TJA from 2015 to 2021 were identified using a commercial health care database. Patients were divided based on receipt of perioperative intravenous DEX [DEX(+) versus DEX(-)] on the day of index TJA. Patient demographics and hospital factors were collected. The 90-day risk of postoperative complications, readmission, and in-hospital mortality were compared. RESULTS: Overall, 70,147 patients who had a history of VTE underwent TJA, of which 40,607 (57.89%) received DEX and 29,540 (42.11%) did not. The DEX(+) patients were younger (67 ± 9.8 versus 68 ± 9.9 years, P < .001) and had a significantly shorter length of stay compared to the DEX(-) patients (1.8 ± 1.6 versus 2.2 ± 1.8 days, P < .001). The DEX(+) patients demonstrated lower rates of PE (1.37 versus 1.75%, P < .001) and DVT (2.37 versus 3.01%, P < .001) compared to DEX(-) patients. The DEX(+) patients experienced a lower risk of PE (adjusted odds ratio: 0.78, 95% confidence interval: 0.66 to 0.93, P = .006) and DVT (adjusted odds ratio: 0.84, 95% confidence interval: 0.74 to 0.95, P = .006) compared to DEX(-) patients. The DEX(+) patients demonstrated no differences in the odds of surgical site infection, periprosthetic joint infection, or sepsis compared to the DEX(-) patients (P > .05). CONCLUSIONS: The administration of DEX was associated with a decreased risk of PE and DVT in patients who have a history of VTE who underwent TJA. These data warrant further study investigating the postoperative benefits of perioperative DEX administration for high-risk patients undergoing TJA. LEVEL OF EVIDENCE: Level III.

Dexamethasone-Associated Hyperglycemia is Not Associated With Infectious Complications After Total Joint Arthroplasty in Diabetic Patients.

BACKGROUND: Postoperative infection is a devastating complication of total joint arthroplasty (TJA). Perioperative use of dexamethasone in patients who have diabetes mellitus (DM) remains controversial due to concern for increased infection risk. This study aimed to evaluate the association between dexamethasone and infection risk among patients who have DM undergoing TJA. METHODS: This was a retrospective cohort study conducted on adult patients who underwent primary, elective total knee arthroplasty (TKA) or total hip arthroplasty (THA) between January 2016 and December 2021 using a large national database. We identified 110,568 TJA patients (TKA: 66.6%; THA: 33.4%), 31.0% (34,298) of which had DM. Patients who received perioperative dexamethasone were compared to those who did not. The primary end points were the 90-day risk of postoperative periprosthetic joint infection, surgical site infection (SSI), and other non-SSI (urinary tract infection, pneumonia, sepsis). RESULTS: When modeling the association between dexamethasone exposure and study outcomes while accounting for the interaction between dexamethasone and morning blood glucose levels, dexamethasone administration conferred no increased odds of postoperative periprosthetic joint infection nor SSI in diabetics. However, dexamethasone significantly lowered the adjusted odds of other postoperative infections in diabetic patients (TKA: adjusted odds ratio = 09, 95% confidence interval = 0.8 to 1.0, P = .030; THA: adjusted odds ratio = 0.7, 95% confidence interval = 0.6 to 0.9, P = .001); specifically in patients with morning blood glucose levels between 110 to 248 mg/dL in TKA and ≤ 172 mg/dL in THA. CONCLUSIONS: This study provides strong evidence against withholding dexamethasone in diabetic patients undergoing TJA based on concern for infection. Instead, short-course perioperative dexamethasone reduced infection risk in select patients. The narrative surrounding dexamethasone should shift away from questions about whether dexamethasone is appropriate for diabetic patients, and instead focus on how best to optimize its use.

Risk of Postcolonoscopy Thromboembolic Events: A Real-World Cohort Study.

BACKGROUND& AIMS: Although antithrombotic agents could increase the risk of postpolypectomy bleeding, interruption of these agents also increases the risk of thromboembolism (TE). We assessed the risks of postcolonoscopy TE events and their association with the interruption of antithrombotic agents. METHODS: This was a retrospective cohort study including consecutive patients undergoing colonoscopy between January 2016 and March 2021. We determined the rates of postcolonoscopy TE events in patients taking various antithrombotic agents (with or without interruption), and in different patient groups according to indications for colonoscopy, underlying TE, and bleeding risks. RESULTS: Of the 6220 patients, 1755 (28.2%) were on antithrombotics. Overall, 20 patients (0.32%) developed TE events, and 25 (0.80%) of 3134 patients with polypectomy experienced major episodes of bleeding. Among all patients on antithrombotic agents, the highest rates of TE events were observed in patients on dual-antiplatelet therapy (4.65%; adjusted odds ratio [aOR], 28.0; 95% CI, 3.77-142.1) and clopidogrel (2.78%; aOR, 12.2; 95% CI, 2.10-57.0), compared with 0.11% among those not on antithrombotics. In patients interrupting anti-thrombotic agents, the risk of TE was increased compared to those on no agent as follows: stopping 2 or more antithrombotic agents (4.55%; aOR, 22.5; 95% CI, 1.09-158.0), monotherapy with clopidogrel (3.06%; aOR, 15.5; 95% CI, 2.86-69.6), warfarin (1.33%; aOR, 6.96; 95% CI, 1.14-33.5), or direct-acting oral anticoagulants (0.87%; aOR, 6.23; 95% CI, 1.22-26.8). Having an underlying high TE risk (aOR, 16.8; 95% CI, 6.33-46.6) was associated with higher postcolonoscopy TE events. CONCLUSIONS: The risk of post-colonoscopy thromboembolic events is low. However, the temporary interruption of antithrombotic agents, particularly stopping 2 or more agents, clopidogrel, warfarin, or direct-acting oral anticoagulants was associated with higher postcolonoscopy TE events, particularly in high-risk patients.

Blue-light imaging or narrow-band imaging for proximal colonic lesions: a prospective randomized tandem colonoscopy study.

BACKGROUND AND AIMS: Blue-light imaging (BLI) is a new image-enhanced endoscopy with a wavelength filter similar to narrow-band imaging (NBI). We compared the 2 with white-light imaging (WLI) on proximal colonic lesion detection and miss rates. METHODS: In this 3-arm prospective randomized study with tandem examination of the proximal colon, we enrolled patients aged ≥40 years. Eligible patients were randomized in 1:1:1 ratio to receive BLI, NBI, or WLI during the first withdrawal from the proximal colon. The second withdrawal was performed using WLI in all patients. Primary outcomes were proximal polyp (pPDRs) and adenoma (pADRs) detection rates. Secondary outcomes were miss rates of proximal lesions found on tandem examination. RESULTS: Of 901 patients included (mean age, 64.7 years; 52.9% men), 48.1% underwent colonoscopy for screening or surveillance. The corresponding pPDRs of the BLI, NBI, and WLI groups were 45.8%, 41.6, and 36.6%, whereas the corresponding pADRs were 36.6%, 33.8%, and 28.3%. There was a significant difference in pPDR and pADR between BLI and WLI groups (difference, 9.2% [95% confidence interval {CI}, 3.3-16.9] and 8.3% [95% CI, 2.7-15.9]) and between NBI and WLI groups (difference, 5.0% [95% CI, 1.4-12.9] and 5.6% [95% CI, 2.1-13.3]). Proximal adenoma miss rates were significantly lower with BLI (19.4%) than with WLI (27.4%; difference, -8.0%; 95% CI, -15.8 to -.1) but not between NBI (27.2%) and WLI. CONCLUSIONS: Both BLI and NBI were superior to WLI on detecting proximal colonic lesions, but only BLI had lower proximal adenoma miss rates than WLI. (Clinical trial registration number: NCT03696992.).

"Per protocol" practice patterns for Children's Oncology Group trials within the radiation oncology community.

Little is known about the prevalence of pediatric radiation oncologists treating patients off study according to Children's Oncology Group (COG) trials before data are available regarding toxicity and efficacy of novel radiotherapy regimens. We conducted a 12-question survey of 358 pediatric radiation oncologists to characterize practice patterns regarding ongoing and completed COG protocols off study. With 130 responses (40.3%), the prevalence of providing treatment per protocol, but off study, before data are available in abstract or peer-reviewed form varied from 9.1% (for ACNS1422) to 88.1% (for AHOD1331). Future studies are needed to understand the effects of these practice patterns on outcomes.