Evaluating the Readability, Credibility, and Quality of Spanish-Language Online Educational Resources for Knee Arthroplasty: Implications for Patient Education and Health Disparities.

INTRODUCTION: Spanish-speaking individuals may experience language-based disparities related to elective orthopaedic procedures. Because patients often seek online health information, we assessed the readability, credibility, and quality of Spanish-language educational websites for knee arthroplasty. METHODS: We queried "Google," "Yahoo," and "Bing" using the term "reemplazo de rodilla" (knee replacement in Spanish) and extracted the top 50 websites per search engine. Websites were categorized by information source (physician/community hospital, university/academic, other) and presence of HONcode certification. Information was assessed for readability (Fernández-Huerta formula), credibility (Journal of the American Medical Association benchmark criteria), and quality (Brief DISCERN tool); scores were compared between the categories. RESULTS: A total of 77 unique websites were included (40.3% physician/community hospital, 35.1% university/academic). The median readability score was 59.4 (10th to 12th-grade reading level); no websites achieved the recommended level of ≤6th grade. The median Journal of the American Medical Association benchmark score was 2 (interquartile range 1 to 3), with only 7.8% of websites meeting all criteria. The median Brief DISCERN score was 16 (interquartile range 12 to 20), with 50.7% meeting the threshold for good quality. University/academic websites had better readability (P = 0.02) and credibility (P = 0.002) but similar quality (P > 0.05) compared with physician/community hospital websites. In addition, HONcode-certified websites had better quality scores (P = 0.045) but similar readability and credibility (P > 0.05) compared with noncertified websites. DISCUSSION: We identified limitations in readability, credibility, and quality of Spanish-language online educational resources for knee arthroplasty. Healthcare providers should be aware of these patient education barriers when counseling patients, and efforts should be made to support the online information needs of Spanish-speaking orthopaedic patients and mitigate language-based disparities.

Tranexamic Acid During Radical Cystectomy: A Randomized Clinical Trial.

Importance: Among cancer surgeries, patients requiring open radical cystectomy have the highest risk of red blood cell (RBC) transfusion. Prophylactic tranexamic acid (TXA) reduces blood loss during cardiac and orthopedic surgery, and it is possible that similar effects of TXA would be observed during radical cystectomy. Objective: To determine whether TXA, administered before incision and for the duration of radical cystectomy, reduced the number of RBC transfusions received by patients up to 30 days after surgery. Design, Setting, and Participants: The Tranexamic Acid During Cystectomy Trial (TACT) was a double-blind, placebo-controlled, randomized clinical trial with enrollment between June 2013 and January 2021. This multicenter trial was conducted in 10 academic centers. A consecutive sample of patients was eligible if the patients had a planned open radical cystectomy for the treatment of bladder cancer. Intervention: Before incision, patients in the intervention arm received a loading dose of intravenous TXA, 10 mg/kg, followed by a maintenance infusion of 5 mg/kg per hour for the duration of the surgery. In the control arm, patients received indistinguishable matching placebo. Main Outcomes and Measures: The primary outcome was receipt of RBC transfusion up to 30 days after surgery. Results: A total of 386 patients were assessed for eligibility, and 33 did not meet eligibility. Of 353 randomized patients (median [IQR] age, 69 [62-75] years; 263 male [74.5%]), 344 were included in the intention-to-treat analysis. RBC transfusion up to 30 days occurred in 64 of 173 patients (37.0%) in the TXA group and 64 of 171 patients (37.4%) in the placebo group (relative risk, 0.99; 95% CI, 0.83-1.18). There were no differences in secondary outcomes among the TXA group vs placebo group including mean (SD) number of RBC units transfused (0.9 [1.5] U vs 1.1 [1.8] U; P = .43), estimated blood loss (927 [733] mL vs 963 [624] mL; P = .52), intraoperative transfusion (28.3% [49 of 173] vs 24.0% [41 of 171]; P = .08), or venous thromboembolic events (3.5% [6 of 173] vs 2.9% [5 of 171]; P = .57). Non-transfusion-related adverse events were similar between groups. Conclusions and Relevance: Results of this randomized clinical trial reveal that TXA did not reduce blood transfusion in patients undergoing open radical cystectomy for bladder cancer. Based on this trial, routine use of TXA during open radical cystectomy is not recommended. Trial Registration: ClinicalTrials.gov Identifier: NCT01869413.

The Statistical Fragility of Patellar Resurfacing in Total Knee Arthroplasty: A Systematic Review of Randomized Controlled Trials.

INTRODUCTION: Randomized controlled trials (RCTs) evaluating patellar resurfacing in total knee arthroplasty (TKA) have conflicting findings, with some reporting its efficacy and others demonstrating no clinical significance. The fragility index (FI), reverse fragility index (rFI), and fragility quotient (FQ) evaluated statistical fragility of outcomes in RCTs evaluating patellar resurfacing in TKA. METHODS: The PubMed, Embase, and MEDLINE databases were systematically searched for RCTs (January 1, 2000, to August 1, 2023) assessing patellar resurfacing in TKA. Of 226 RCTs screened, 19 studies were included for analysis. We calculated FI and rFI, which represent the number of outcome event reversals required to alter statistical significance for significant and non-significant outcomes, respectively. The outcome categories of interest included anterior knee pain, complications/ adverse events, crepitus, reoperation, patient satisfaction, and clinical improvement. The FQ was determined by dividing the FI by the study sample size. RESULTS: Across 46 outcomes, the median FI was 5 (Interquartile Range (IQR) 3 to 8) with a median FQ of 0.041 (IQR 0.025 to 0.063). There were nine outcomes that were statistically significant, with a median FI of 3 (IQR 2 to 8) and a FQ of 0.011 (IQR 0.0044 to 0.039). There were 37 outcomes that were non-significant, with a median rFI of 5 (IQR 4 to 7) and FQ of 0.043 (IQR 0.031 to 0.062). Notably, in 47.8% of all outcomes, the number of patients lost-to-follow-up was greater than the outcome's respective FI or rFI. Outcomes regarding patient satisfaction (FI 4.5) and anterior knee pain (FI 5) were most fragile. CONCLUSION: The outcomes of interest regarding patellar resurfacing from RCTs are statistically fragile, particularly significant outcomes and patient satisfaction outcomes. Data surrounding patellar resurfacing remains inconclusive, and combining P-values with FI/FQ metrics may aid in interpreting patellar resurfacing findings. Future studies may mitigate fragility by obtaining higher follow-up rates and sample sizes.

Factors influencing the Central Nervous System (CNS) distribution of the ATR inhibitor elimusertib (BAY1895344): Implications for the treatment of CNS tumors.

Glioblastoma (GBM) is a disease of the whole brain, with infiltrative tumor cells protected by an intact BBB. GBM has a poor prognosis despite aggressive treatment, in part due to lack of adequate drug permeability at the BBB. Standard of care GBM therapies include radiation and cytotoxic chemotherapy that lead to DNA damage. Subsequent activation of DNA damage response (DDR) pathways can induce resistance. Various DDR inhibitors, targeting the key regulators of these pathways such as ataxia telangiectasia mutated and Rad3-related (ATR), are being explored as radio- and chemo-sensitizers. Elimusertib, a novel ATR kinase inhibitor, can prevent repair of damaged DNA, increasing efficacy of DNA damaging cytotoxic therapies. Robust synergy was observed in vitro when elimusertib was combined with the DNA-damaging agent, temozolomide, however, we did not observe improvement with this combination in in vivo efficacy studies in GBM orthotopic tumor-bearing mice. This in vitro - in vivo disconnect was explored to understand factors influencing CNS distribution of elimusertib and reasons for lack of efficacy. We observed that elimusertib is rapidly cleared from systemic circulation in mice and would not maintain adequate exposure in the CNS for efficacious combination therapy with temozolomide. CNS distribution of elimusertib is partially limited by P-gp efflux at the BBB, and high binding to CNS tissues leads to low levels of pharmacologically active (unbound) drug in the brain. Acknowledging the potential for inter-species differences in pharmacokinetics, these data suggest that clinical translation of elimusertib in combination with temozolomide for treatment of GBM may be limited. Significance Statement This study examined the disconnect between the in vitro synergy and in vivo efficacy of elimusertib/temozolomide combination therapy by exploring systemic and CNS distributional pharmacokinetics. Results indicate that the lack of improvement in in vivo efficacy in GBM PDX models could be attributed to inadequate exposure of pharmacologically active drug concentrations in the CNS. These observations can guide further exploration of elimusertib for the treatment of GBM, or other CNS tumors.

Patient Factors Associated With Reimplantation After Girdlestone Resection Arthroplasty for Treatment of Periprosthetic Joint Infections of the Hip.

INTRODUCTION: For patients unsuitable for prosthesis reimplantation or temporary spacer placement, Girdlestone resection arthroplasty (GRA) is a suitable option to eliminate infection. Using a large-scale database, this study aims to determine factors associated with reimplantation. METHODS: This study included patients who underwent GRA and subsequent total hip arthroplasty (2012 to 2015 Medicare Limited Data Set with ≥5-year follow-up). A mixed-effects model measured associations between patient characteristics and reimplantation. Odds ratios (OR) with 95% confidence intervals (CI) were reported. RESULTS: Among 2,772 GRA cases, 2,025 (73.1%) were reimplanted (median time to reimplantation 3.0 months). In multivariable analysis, patient factors associated with reduced odds of reimplantation were increased age (OR 0.96; CI, 0.94 to 0.97; P < 0.0001), Black race (OR, 0.58; CI, 0.37 to 0.90; P = 0.0149), obesity (OR, 0.74; CI, 0.58 to 0.94; P = 0.0150), and increased Deyo-Charlson comorbidities (1 comorbidity: OR, 0.78; CI, 0.61 to 0.99; P = 0.0453; two comorbidities: OR, 0.53; CI, 0.39 to 0.71; P < 0.0001; ≥3 comorbidities: OR, 0.69; CI, 0.49 to 0.95; P = 0.0244). Male (versus female) patients, however, had increased odds of reimplantation (OR, 1.64; CI, 1.32 to 2.02; P < 0.0001). DISCUSSION: Age, race, and comorbidities influence the likelihood of reimplantation after GRA. Owing to variability in patients who undergo additional surgery, additional studies should be conducted to determine the rationale of patient selection.

Associations Between Prehabilitation and Postoperative Healthcare Utilization for Total Hip or Total Knee Arthroplasty in Medicare Beneficiaries.

BACKGROUND: Prehabilitation has potential to improve outcomes in value-based care models. We examined the associations between the receipt of prehabilitation (physical therapy [PT] services within 30 days preoperatively) and postoperative healthcare utilization in a national cohort of fee-for-service Medicare beneficiaries. METHODS: This retrospective cohort study used the 5% fee-for-service claims from the Medicare limited data set to identify unilateral elective inpatient total hip arthroplasty (THA) procedures (n = 25,509) and total knee arthroplasty (TKA) procedures (n = 40,091) from January 1, 2016 to September 30, 2021. Associations between prehabilitation and postoperative healthcare utilization were analyzed in mixed-effects generalized linear models adjusting for patient-level and hospital-level factors. We report adjusted odds ratios (OR) or % differences. RESULTS: Prehabilitation (13.1% THA, 13.1% TKA) was not significantly associated with institutional postacute care discharge, 30-day emergency department visits, or 90-day readmissions. For TKA, prehabilitation was significantly associated with decreased odds of an extended hospital length of stay (OR = 0.86, P = 0.02) and reduced length of stay in an institutional postacute care facility (-5.71%, P = 0.004). In both THA and TKA, prehabilitation was associated with decreased use of 90-day home health physical and/or occupational therapy (THA: OR = 0.82, P = 0.001; TKA: OR = 0.67, P < 0.001). In contrast, prehabilitation in both cohorts was associated with the increased odds of receiving any 90-day outpatient PT (THA: OR = 2.08, P < 0.001; TKA: OR = 2.48, P < 0.001) and an increased number of 90-day outpatient PT visits (THA: +4.04%, P = 0.01; TKA: +5.21%, P < 0.001). CONCLUSION: Prehabilitation was associated with some decreases in postoperative healthcare utilization, particularly for TKA. Associations of preoperative PT with increased postoperative outpatient PT may reflect variation in referral patterns or patient access. These results highlight the importance of continued research into the impact of prehabilitation on healthcare utilization, patient outcomes, and episode costs. Additionally, further research should identify which patients would benefit the most from prehabilitation to increase the value of care.

Long-term continuous cropping reduces greenhouse gas emissions while sustaining crop yields.

Information is needed on the effect of long-term cropping systems on greenhouse gas (GHG) emissions in dryland conditions. The effect of 34 years of dryland cropping system was examined on N2O and CH4 emissions, greenhouse gas balance (GHGB), crop yield, and yield-scaled GHG balance (YSGB) from 2016-2017 to 2017-2018 in the US northern Great Plains. Cropping systems were no-till continuous spring wheat (Triticum aestivum L.) (NTCW), no-till spring wheat-pea (Pisum sativum L.) (NTWP), and conventional till spring wheat-fallow (CTWF). Gases were sampled twice a week to once a month throughout the year using a static chamber and flux determined. Soil C sequestration rate at 0-10 cm was determined from samples taken in 2012 and 2019. The N2O emissions occurred immediately after planting, fertilization, and intense rainfall from May to September in both years when the emissions greater for NTCW and NTWP than CTWF. The CH4 emissions were minimal and mostly negative throughout the year. Carbon sequestration rate was positive for NTCW and NTWP due to greater C input, but negative for CTWF due to rapid C mineralization. As a result, GHGB was 170%-362% lower for NTCW than NTWP and CTWF. Annualized crop yield was 23%-60% greater for NTWP than NTCW and CTWF in 2016-2017, but not different among cropping systems in 2017-2018. The YSGB was also 129%-132% lower for NTCW and NTWP than CTWF in both years. Because of greater annualized crop yield, but lower GHG emissions, NTWP is recommended for reducing GHG emissions while sustaining long-term dryland crop yields in the northern Great Plains.

Genome-Derived Ampullary Adenocarcinoma Classifier and Postresection Prognostication.

Importance: Ampullary adenocarcinoma (AA) is characterized by clinical and genomic heterogeneity. A previously developed genomic classifier defined biologically distinct phenotypes with greater accuracy than standard histologic classification. External validation is needed before routine clinical use. Objective: To test external validity of the prognostic value of the hidden genome classifier of AA. Design, Setting, and Participants: This retrospective cohort study took place at 6 international academic institutions. Consecutive patients (n = 192) who underwent curative-intent resection of histologically confirmed AA were included. The data were analyzed from January 2005 through July 2020. Exposures: The multilevel meta-feature regression model previously trained on a prospectively sequenced cohort of 3411 patients (1001 pancreatic adenocarcinoma, 165 distal bile duct adenocarcinoma, and 2245 colorectal adenocarcinoma) was applied to AA sequencing data to quantify the relative proportions of parental cell of origin. Main Outcome and Measures: Genomic classification was correlated with immunohistologic subtype (intestinal [INT] or pancreatobiliary [PB]) and with overall survival (OS), using the log-rank test and Cox proportional hazard models. Results: Among 192 patients with AA (median age, 69.0 [IQR, 60.0-74.0] years and 134 were male [64%]), concordance between immunohistologic and genomic subtypes was 55%. Most INT subtype tumors were categorized into the colorectal genomic subtype (43 of 57 [72.9%]). Of the 114 PB subtype tumors, 29 had a pancreatic genomic profile (25.4%) and 24 had a distal bile duct genomic profile (21.1%). Whereas the standard immunohistologic subtypes were not associated with survival (log rank P = .26), predicted genomic probabilities were correlated with survival probability. Genomic scores with higher colorectal probability were associated with higher survival probability; higher pancreatic and distal bile duct probabilities were associated with lower survival probability. Conclusions and Relevance: The AA genomic classifier is reproducible with available molecular testing in a diverse international cohort of patients and improves stratification of the divergent clinical outcomes beyond standard immunohistologic classification. These data provide a molecular classification that may be incorporated into clinical trials for prospective validation.

The association of antiplatelet agents with mortality among patients with non-COVID-19 community-acquired pneumonia: a systematic review and meta-analysis.

Background: Community-acquired pneumonia (CAP) triggers inflammatory and thrombotic host responses driving morbidity and mortality. Antiplatelet agents may favorably modulate these pathways; however, their role in non-COVID-19 CAP remains uncertain. Objectives: To evaluate the association of antiplatelet agents with mortality in hospitalized patients with non-COVID-19 CAP. Methods: We conducted a systematic review and meta-analysis of observational studies and randomized controlled trials (RCTs) of adult patients hospitalized for non-COVID-19 CAP exposed to antiplatelet agents (acetylsalicylic acid or P2Y12 inhibitors). We searched MEDLINE, Embase, and CENTRAL from inception to August 2023. Our primary outcome was all-cause mortality: meta-analyzed (random-effects models) separately for observational studies and RCTs. For observational studies, we used adjusted mortality estimates. Results: We included 13 observational studies (123,012 patients; 6 reported adjusted mortality estimates) and 2 RCTs (225 patients; both high risk of bias). In observational studies reporting hazard ratio, antiplatelet agents were associated with lower mortality (hazard ratio, 0.65; 95% CI, 0.46-0.91; I 2  = 85%; 4 studies, 91,430 patients). In studies reporting adjusted odds ratio, antiplatelet agent exposure was associated with reduced odds of mortality (odds ratio, 0.67; 95% CI, 0.45-1.00; I 2  = 0%; 2 studies, 24,889 patients). Among RCTs, there was a nonsignificant association with mortality (risk ratio, 0.66; 95% CI, 0.20-2.25; I 2  = 54%; 2 studies, 225 patients). By the Grading of Recommendations, Assessment, Development, and Evaluation criteria, the certainty of the evidence was low, primarily due to risk of bias. Conclusion: In hospitalized patients with non-COVID-19 CAP, antiplatelet agents may be associated with reduced mortality compared with usual care or placebo, but the certainty of evidence is low.

Does Preoperative Bisphosphonate Use Impact the Risk of Periprosthetic Fracture Following Total Hip Arthroplasty?

INTRODUCTION: Bisphosphonate (BP) use is not uncommon among total hip arthroplasty (THA) candidates. While the impact of BP therapy post-THA has been investigated, there is a paucity of literature discussing the impact of BP therapy pre-THA. Using a national dataset, we aimed to study the association between preoperative BP use and surgical outcomes in primary THA recipients. METHODS: This retrospective cohort study utilized a commercial claims and Medicare Supplemental Databases to identify adults aged ≥ 18 who had an index non-fracture-related primary THA from 2016 to 2020. The use of BP was defined as ≥ 6 months of BP therapy in the year prior to THA. Outcomes were 90-day all-cause readmission, 90-day readmission related to periprosthetic fracture (PPF), 90-day and 1-year all-cause revision, 1-year PPF-related revision, and 1-year diagnosis of PPF. In a 1:5 propensity-score matched analysis, each THA patient who had preoperative BP use was matched to five THA patients who did not have preoperative BP use. Logistic regression models were fitted; we report odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Of 91,907 THA patients, 1,018 (1.1%) used BP preoperatively. In the propensity-score-matched cohort (1,018 preoperative BP users, 5,090 controls), preoperative BP use was significantly associated with increased odds of 90-day all-cause revision surgery (OR 1.67; 95% CI 1.10 to 2.53; P = 0.02), 1-year PPF-related revision (OR 2.23; 95% CI 1.21 to 4.10; P = 0.01), and 1-year PPF diagnosis (OR 1.88; 95% CI 1.10 to 3.20; P = 0.02). There was no significant association between preoperative BP use and the other outcomes in the matched cohort. CONCLUSION: These findings suggest that preoperative BP use is associated with an increased risk of revision surgery and PPF in both the short and long term. This information can help in preoperative planning and patient counseling, potentially leading to improved surgical outcomes and reduced complication rates.

Distinct clinical outcomes and biological features of specific KRAS mutants in human pancreatic cancer.

KRAS mutations in pancreatic ductal adenocarcinoma (PDAC) are suggested to vary in oncogenicity but the implications for human patients have not been explored in depth. We examined 1,360 consecutive PDAC patients undergoing surgical resection and find that KRASG12R mutations are enriched in early-stage (stage I) disease, owing not to smaller tumor size but increased node-negativity. KRASG12R tumors are associated with decreased distant recurrence and improved survival as compared to KRASG12D. To understand the biological underpinnings, we performed spatial profiling of 20 patients and bulk RNA-sequencing of 100 tumors, finding enhanced oncogenic signaling and epithelial-mesenchymal transition (EMT) in KRASG12D and increased nuclear factor κB (NF-κB) signaling in KRASG12R tumors. Orthogonal studies of mouse KrasG12R PDAC organoids show decreased migration and improved survival in orthotopic models. KRAS alterations in PDAC are thus associated with distinct presentation, clinical outcomes, and biological behavior, highlighting the prognostic value of mutational analysis and the importance of articulating mutation-specific PDAC biology.

Getting slimmer without dieting or exercising: zebra finches can rapidly lose mass while maintaining food intake and decreasing activity.

It is widely accepted that birds can adaptively regulate body mass in different ecological contexts, but little is known about how birds monitor and interpret their body mass or the mechanisms that allow for rapid changes in mass. Using captive zebra finches (Taeniopygia guttata), we experimentally increased perceived mass via attachment of weighted backpacks and provided birds with either an ad libitum mixed-seed diet or supplementary high-fat diet to investigate: (1) how birds assess their own body mass and (2) the physiological and/or behavioral mechanisms birds may employ to rapidly adjust body mass. In both experiments, and independent of diet treatment, birds with weighted backpacks rapidly lost mass within 2 days of backpack attachment while reducing overall activity and maintaining food intake. Additionally, our data suggest that birds interpret body mass via a physical mechanosensory pathway rather than a physiological pathway: rapid loss of mass between days 0 and 2 was not linked to changes in plasma metabolites (glycerol or triglyceride concentrations). We found no evidence that mass loss was a consequence of stress associated with attachment of weighted backpacks (based on plasma corticosterone measures). Our results suggest that the processes of energy balance and mass regulation involve a greater array of mechanisms than simply matching 'energy in', through the amount of food consumed, to 'energy out', dictated by activity. Zebra finches were able to decrease body mass through other, unidentified, mechanisms even while maintaining dietary intake and reducing overall activity.

Acetabular Screws With Cement Augment for Tibial Plateau Defects in Dynamic Spacer Implantation: A Case of Recalcitrant Native Knee Septic Arthritis.

Treating tibial bone defects in the setting of recalcitrant native knee arthritis presents a challenging biomechanical problem for orthopaedic surgeons. A dynamic antibiotic spacer offers an effective solution to preserve patient function and manage infection. However, severe bone loss may compromise the fixation of the dynamic spacer. We describe the application of acetabular screws as rebar in a case of an Anderson Orthopaedic Research Institute type 3 defect of the medial tibial plateau. Additionally, we outline a facile method for fabricating the tibial stem component to ensure optimal fit within the intramedullary canal. Short-term follow-up (8 months) indicates successful fixation of the tibial component, absence of knee pain, and a knee range of motion up to 100 degrees.

Is Limited English Proficiency Associated With Differences in Care Processes and Treatment Outcomes in Patients Undergoing Orthopaedic Surgery? A Systematic Review.

BACKGROUND: Approximately 25 million people in the United States have limited English proficiency. Current developments in orthopaedic surgery, such as the expansion of preoperative education classes or patient-reported outcome collection in response to bundled payment models, may exacerbate language-related barriers. Currently, there are mixed findings of the associations between limited English proficiency and care processes and outcomes, warranting a cross-study synthesis to identify patterns of associations. QUESTIONS/PURPOSES: In this systematic review, we asked: Is limited English proficiency associated with (1) differences in clinical care processes, (2) differences in care processes related to patient engagement, and (3) poorer treatment outcomes in patients undergoing orthopaedic surgery in English-speaking countries? METHODS: On June 9, 2023, a systematic search of four databases from inception through the search date (PubMed, Ovid Embase, Web of Science, and Scopus) was performed by a medical librarian. Potentially eligible articles were observational studies that examined the association between limited English proficiency and the prespecified categories of outcomes among pediatric and adult patients undergoing orthopaedic surgery or receiving care in an orthopaedic surgery setting. We identified 10,563 records, of which we screened 6966 titles and abstracts after removing duplicates. We reviewed 56 full-text articles and included 29 peer-reviewed studies (outcome categories: eight for clinical care processes, 10 for care processes related to patient engagement, and 15 for treatment outcomes), with a total of 362,746 patients or encounters. We extracted data elements including study characteristics, definition of language exposure, specific outcomes, and study results. The quality of each study was evaluated using adapted Newcastle-Ottawa scales for cohort or cross-sectional studies. Most studies had a low (48%) or moderate (45%) risk of bias, but two cross-sectional studies had a high risk of bias. To answer our questions, we synthesized associations and no-difference findings, further stratified by adjusted versus unadjusted estimates, for each category of outcomes. No meta-analysis was performed. RESULTS: There were mixed findings regarding whether limited English proficiency is associated with differences in clinical care processes, with the strongest adjusted associations between non-English versus English as the preferred language and delayed ACL reconstruction surgery and receipt of neuraxial versus general anesthesia for other non-Spanish versus English primary language in patients undergoing THA or TKA. Limited English proficiency was also associated with increased hospitalization costs for THA or TKA but not opioid prescribing in pediatric patients undergoing surgery for fractures. For care processes related to patient engagement, limited English proficiency was consistently associated with decreased patient portal use and decreased completion of patient-reported outcome measures per adjusted estimates. The exposure was also associated with decreased virtual visit completion for other non-Spanish versus English language and decreased postoperative opioid refill requests after TKA but not differences in attendance-related outcomes. For treatment outcomes, limited English proficiency was consistently associated with increased hospital length of stay and nonhome discharge per adjusted estimates, but not hospital returns. There were mixed findings regarding associations with increased complications and worse postoperative patient-reported outcome measure scores. CONCLUSION: Findings specifically suggest the need to remove language-based barriers for patients to engage in care, including for patient portal use and patient-reported outcome measure completion, and to identify mechanisms and solutions for increased postoperative healthcare use. However, interpretations are limited by the heterogeneity of study parameters, including the language exposure. Future research should include more-precise and transparent definitions of limited English proficiency and contextual details on available language-based resources to support quantitative syntheses. LEVEL OF EVIDENCE: Level III, therapeutic study.

An intranasal nanoparticle STING agonist protects against respiratory viruses in animal models.

Respiratory viral infections cause morbidity and mortality worldwide. Despite the success of vaccines, vaccination efficacy is weakened by the rapid emergence of viral variants with immunoevasive properties. The development of an off-the-shelf, effective, and safe therapy against respiratory viral infections is thus desirable. Here, we develop NanoSTING, a nanoparticle formulation of the endogenous STING agonist, 2'-3' cGAMP, to function as an immune activator and demonstrate its safety in mice and rats. A single intranasal dose of NanoSTING protects against pathogenic strains of SARS-CoV-2 (alpha and delta VOC) in hamsters. In transmission experiments, NanoSTING reduces the transmission of SARS-CoV-2 Omicron VOC to naïve hamsters. NanoSTING also protects against oseltamivir-sensitive and oseltamivir-resistant strains of influenza in mice. Mechanistically, NanoSTING upregulates locoregional interferon-dependent and interferon-independent pathways in mice, hamsters, as well as non-human primates. Our results thus implicate NanoSTING as a broad-spectrum immune activator for controlling respiratory virus infection.

Low neighborhood socioeconomic status is associated with poor outcomes in young adults with colorectal cancer.

BACKGROUND: The incidence of early-onset colorectal cancer has increased markedly over the past decade. Although established for older adults, there are limited data on socioeconomic and racial disparities in screening, treatment, and outcomes in this distinct group. METHODS: Adults with primary colorectal cancer diagnosed at age <50 were identified from the Surveillance, Epidemiology, and End Results database. The exposure of interest was neighborhood socioeconomic status based on the Yost Index, a census-tract level composite score of neighborhood economic health. Univariate analysis was performed with χ2 analyses. Logistic regression models were created to evaluate the association of neighborhood socioeconomic status (Yost Index quintile) with metastasis at presentation and surgical intervention. Kaplan-Meier and Cox proportional hazards models were created. RESULTS: In total, 45,660 early-onset colorectal cancer patients were identified; 16.8% (7,679) were in the lowest quintile of neighborhood socioeconomic status. Patients with the lowest neighborhood socioeconomic status were 1.13 times (95% confidence interval 1.06-1.21) more likely to present with metastases and had lower survival (hazard ratio 1.45, 95% confidence interval 1.37-1.53) compared to those with the highest neighborhood socioeconomic status. Non-Hispanic Black patients were more likely to present with metastatic disease (odds ratio 1.11, 95% confidence interval 1.05-1.19), less likely to undergo surgery for localized or regional disease (odds ratio 0.48, 95% confidence interval 0.43-0.53), and had lower survival (hazard ratio 1.21, 95% confidence interval 1.15-1.27) than non-Hispanic White patients. CONCLUSION: Socioeconomic and racial disparities in early-onset colorectal cancer span diagnosis, treatment, and survival. As the disease burden of early-age onset colorectal cancer increases, interventions to boost early diagnosis and access to surgery are necessary to improve survival among minorities and patients with low neighborhood socioeconomic status.

Heparin Dose Intensity and Organ Support-Free Days in Patients Hospitalized for COVID-19.

Background: Clinical trials suggest that therapeutic-dose heparin may prevent critical illness and vascular complications due to COVID-19, but knowledge gaps exist regarding the efficacy of therapeutic heparin including its comparative effect relative to intermediate-dose anticoagulation. Objectives: The authors performed 2 complementary secondary analyses of a completed randomized clinical trial: 1) a prespecified per-protocol analysis; and 2) an exploratory dose-based analysis to compare the effect of therapeutic-dose heparin with low- and intermediate-dose heparin. Methods: Patients who received initial anticoagulation dosed consistently with randomization were included. The primary outcome was organ support-free days (OSFDs), a combination of in-hospital death and days free of organ support through day 21. Results: Among 2,860 participants, 1,761 (92.8%) noncritically ill and 857 (89.1%) critically ill patients were treated per-protocol. Among noncritically ill per-protocol patients, the posterior probability that therapeutic-dose heparin improved OSFDs as compared with usual care was 99.3% (median adjusted OR: 1.36; 95% credible interval [CrI]: 1.07-1.74). Therapeutic heparin had a high posterior probability of efficacy relative to both low- (94.6%; adjusted OR: 1.26; 95% CrI: 0.95-1.64) and intermediate- (99.8%; adjusted OR: 1.80; 95% CrI: 1.22-2.62) dose thromboprophylaxis. Among critically ill per-protocol patients, the posterior probability that therapeutic heparin improved outcomes was low. Conclusions: Among noncritically ill patients hospitalized for COVID-19 who were randomized to and initially received therapeutic-dose anticoagulation, heparin, compared with usual care, was associated with improved OSFDs, a combination of in-hospital death and days free of organ support. Therapeutic heparin appeared superior to both low- and intermediate-dose thromboprophylaxis.

ATM inhibition exploits checkpoint defects and ATM-dependent double strand break repair in TP53-mutant glioblastoma.

Determining the balance between DNA double strand break repair (DSBR) pathways is essential for understanding treatment response in cancer. We report a method for simultaneously measuring non-homologous end joining (NHEJ), homologous recombination (HR), and microhomology-mediated end joining (MMEJ). Using this method, we show that patient-derived glioblastoma (GBM) samples with acquired temozolomide (TMZ) resistance display elevated HR and MMEJ activity, suggesting that these pathways contribute to treatment resistance. We screen clinically relevant small molecules for DSBR inhibition with the aim of identifying improved GBM combination therapy regimens. We identify the ATM kinase inhibitor, AZD1390, as a potent dual HR/MMEJ inhibitor that suppresses radiation-induced phosphorylation of DSBR proteins, blocks DSB end resection, and enhances the cytotoxic effects of TMZ in treatment-naïve and treatment-resistant GBMs with TP53 mutation. We further show that a combination of G2/M checkpoint deficiency and reliance upon ATM-dependent DSBR renders TP53 mutant GBMs hypersensitive to TMZ/AZD1390 and radiation/AZD1390 combinations. This report identifies ATM-dependent HR and MMEJ as targetable resistance mechanisms in TP53-mutant GBM and establishes an approach for simultaneously measuring multiple DSBR pathways in treatment selection and oncology research.

Hospital policy of tranexamic acid to reduce transfusion in major non-cardiac surgery (TRACTION): protocol for a phase IV randomised controlled trial.

INTRODUCTION: Tranexamic acid (TXA) is an inexpensive and widely available medication that reduces blood loss and red blood cell (RBC) transfusion in cardiac and orthopaedic surgeries. While the use of TXA in these surgeries is routine, its efficacy and safety in other surgeries, including oncologic surgeries, with comparable rates of transfusion are uncertain. Our primary objective is to evaluate whether a hospital-level policy implementation of routine TXA use in patients undergoing major non-cardiac surgery reduces RBC transfusion without increasing thrombotic risk. METHODS AND ANALYSIS: A pragmatic, registry-based, blinded, cluster-crossover randomised controlled trial at 10 Canadian sites, enrolling patients undergoing non-cardiac surgeries at high risk for RBC transfusion. Sites are randomised in 4-week intervals to a hospital policy of intraoperative TXA or matching placebo. TXA is administered as 1 g at skin incision, followed by an additional 1 g prior to skin closure. Coprimary outcomes are (1) effectiveness, evaluated as the proportion of patients transfused RBCs during hospital admission and (2) safety, evaluated as the proportion of patients diagnosed with venous thromboembolism within 90 days. Secondary outcomes include: (1) transfusion: number of RBC units transfused (both at a hospital and patient level); (2) safety: in-hospital diagnoses of myocardial infarction, stroke, deep vein thrombosis or pulmonary embolism; (3) clinical: hospital length of stay, intensive care unit admission, hospital survival, 90-day survival and the number of days alive and out of hospital to day 30; and (4) compliance: the proportion of enrolled patients who receive a minimum of one dose of the study intervention. ETHICS AND DISSEMINATION: Institutional research ethics board approval has been obtained at all sites. At the completion of the trial, a plain language summary of the results will be posted on the trial website and distributed in the lay press. Our trial results will be published in a peer-reviewed scientific journal. TRIAL REGISTRATION NUMBER: NCT04803747.