The GPCR-Gαs-PKA signaling axis promotes T cell dysfunction and cancer immunotherapy failure.

Immune checkpoint blockade (ICB) targeting PD-1 and CTLA-4 has revolutionized cancer treatment. However, many cancers do not respond to ICB, prompting the search for additional strategies to achieve durable responses. G-protein-coupled receptors (GPCRs) are the most intensively studied drug targets but are underexplored in immuno-oncology. Here, we cross-integrated large singe-cell RNA-sequencing datasets from CD8+ T cells covering 19 distinct cancer types and identified an enrichment of Gαs-coupled GPCRs on exhausted CD8+ T cells. These include EP2, EP4, A2AR, ß1AR and ß2AR, all of which promote T cell dysfunction. We also developed transgenic mice expressing a chemogenetic CD8-restricted Gαs-DREADD to activate CD8-restricted Gαs signaling and show that a Gαs-PKA signaling axis promotes CD8+ T cell dysfunction and immunotherapy failure. These data indicate that Gαs-GPCRs are druggable immune checkpoints that might be targeted to enhance the response to ICB immunotherapies.

To Revise or Not Revise? Isolated Margin Positivity in Localized Pancreatic Ductal Adenocarcinoma.

BACKGROUND: The study determined the proportion of patients with pancreatic adenocarcinoma (PDAC) who had margin-positive disease and no other adverse pathologic findings (APF) using institutional and administrative datasets. METHODS: Patients with clinical stage I or II PDAC in the National Cancer Database (NCDB 2010-2020) and those who underwent pancreatectomy at the authors' institution (2010-2021) were identified. Isolated margin positivity (IMP) was defined as a positive surgical margin with no APF (negative nodes, no lymphovascular/perineural invasion). RESULTS: The study included 225 patients from the authors' institution and 23,598 patients from the NCDB. The margin-positive rates were 21.8% and 20.3%, and the IMP rates were 0.4% and 0.5%, respectively. In the institutional cohort, 68.4% of the patients had recurrence, and most of the patients (65.6%) had distant recurrences. The median recurrence-free survival (RFS) was 63.3 months for no APF, not reached for IMP, 14.8 months for negative margins & 1 APF, 20.3 months for positive margins & 2 APFs, and 12.9 months with all APF positive. The patients in the NCDB with IMP had a lower median OS than the patients with no APF (20.5 vs 390 months), but a higher median OS than those with margin positivity plus 1 APF (20.5 vs 18.0 months) or all those with APF positivity (20.5 vs 15.4 months). Based on institutional rates of IMP, any margin positivity, neck margin positivity (NMP), and no APF, the fraction of patients who might benefit from neck margin revision was 1 in 100,000, and those likely to benefit from any margin revision was 1 in 18,500. In the NCDB, those estimated to derive potential benefit from margin revision was 1 in 25,000. CONCLUSIONS: Isolated margin positivity in resected PDAC is rare, and most patients experience distant recurrence. Revision of IMP appears unlikely to confer benefit to most patients.

Outcomes of Hepatic Artery-Based Therapies and Systemic Multiagent Chemotherapy in Unresectable Colorectal Liver Metastases: A Systematic Review and Meta-analysis.

BACKGROUND: Treatment of unresectable colorectal liver metastases (UCRLM) includes locoregional and systemic therapy. A comprehensive analysis capturing long-term outcomes of these treatment options has not been performed. OBJECTIVE: A systematic review and meta-analysis was performed to calculate pooled outcomes of hepatic artery infusion with systemic chemotherapy (HAI-S), transarterial chemoembolization with systemic chemotherapy (TACE-S), transarterial radioembolization with systemic chemotherapy (TARE-S), doublet (FOLFOX, FOLFIRI), and triplet chemotherapy (FOLFOXIRI). METHODS: Outcomes included overall survival (OS), progression-free survival (PFS), rate of conversion to resection (CTR), and response rate (RR). RESULTS: A total of 32, 7, 9, and 14 publications were included in the HAI-S, TACE-S, and TARE-S chemotherapy arms. The 6/12/24/36-month OS estimates for HAI-S, TACE-S, TARE-S, FOLFOX, FOLFIRI, and FOLFOXIRI were 97%/80%/54%/35%, 100%/83%/40%/14%, 82%/61%/34%/21%, 96%/83%/53%/36%, and 96%/93%/72%/55%. Similarly, the 6/12/24/36-month PFS estimates were 74%/44%/19%/14%, 66%/20%/9%/3%, 57%/23%/10%/3%, 69%/30%/12%/7%, and 88%/55%/18%/11%. The corresponding CTR and RR rates were 31, 20%, unmeasurable (TARE-S), 35, 53; and 49, 45, 45, 50, 80%, respectively. The majority of chemotherapy studies included first-line therapy and liver-only metastases, whereas most HAI-S studies were pretreated. On subgroup analysis in first-line setting with liver-only metastases, the HAI-S arm had comparable outcomes to FOLFOXIRI and outperformed doublet chemotherapy regimens. Although triplet chemotherapy appeared to outperform other arms, high toxicity and inclusion of potentially resectable patients must be considered while interpreting results. CONCLUSIONS: HAI-S and multiagent chemotherapy are effective therapies for UCRLM. To make definitive conclusions, a randomized trial with comparable patient characteristics and line of therapy will be required. The upcoming EA2222 PUMP trial may help to address this question.

Association between socioeconomic deprivation and presentation with a ruptured abdominal aortic aneurysm.

OBJECTIVE: Given the ongoing nature of research in the social determinants space and urges to improve United States Preventive Services Task Force screening efforts for abdominal aortic aneurysms (AAAs), this project aims to characterize the association between the level of socioeconomic deprivation, rurality, and ruptured AAA (rAAA) presentation across the United States. METHODS: We queried the Vascular Quality Initiative registry (2010-2019) for patients with AAAs. The area deprivation index (ADI) is an index from 1 to 100 used to capture socioeconomic status. ADI was grouped into quintiles, with the most deprived regions being quintile 5 and having the highest ADI index. Multivariable logistic regression assessed the association between ADI, rurality, and rAAA presentation overall and before age 65. RESULTS: Of the 82,909 patients included, 11,458 patients (14%) resided in the most socioeconomically deprived regions, and 18,083 patients (22%) lived in rural regions. Overall, 6831 patients (8.2%) experienced an rAAA, with 4696 patients (69%) residing in the three most deprived quintiles. Most patients underwent endovascular repair (n = 67,933; 82%), followed by open repair (n = 14,976; 18%). On multivariable analysis, residence in the most socioeconomically deprived region was associated with a near 1.5-fold increased odds of presenting with an rAAA compared with a residence in the least deprived regions (odds ratio [OR], 1.46; 95% confidence interval [CI], 1.31-1.63; P < .001), whereas urban residence was associated with a decreased odds to present with an rAAA compared with rural residence (OR, 0.84; 95% CI, 0.79-0.89; P < .001). When stratifying the study population by the United States Preventive Services Task Force recommended age for AAA screening (65 years old), 14,147 patients (17%) were under 65. Of those under 65, 1381 patients (9.8%) experienced a rAAA, and 9955 patients (71%) resided in the three most deprived quintiles. Residence in the most socioeconomically deprived region was associated with an increased odds of presenting with an rAAA compared with residence in the least deprived region (OR, 1.31; 95% CI, 1.01-1.69; P = .042). However, there were no significant associations between rural residence and increased rAAA presentation among individuals under 65 (OR, 1.07; 95% CI, 0.93-1.23; P = .36). CONCLUSIONS: Among all patients in this study, patients residing in highly socioeconomically deprived or rural regions were more likely to present with an rAAA, but among those under 65, only residence in a socioeconomically deprived area was associated with increased odds of rAAA presentation. Understanding the effects of socioeconomic deprivation on rAAA presentation can identify at-risk populations for early AAA screening before rupture.

Patient Navigation in Cancer Treatment: A Systematic Review.

PURPOSE OF REVIEW: Patient navigation promotes access to timely treatment of chronic diseases by eliminating barriers to care. Patient navigation programs have been well-established in improving screening rates and diagnostic resolution. This systematic review aimed to characterize the multifaceted role of patient navigators within the realm of cancer treatment. RECENT FINDINGS: A comprehensive electronic literature review of PubMed and Embase databases was conducted to identify relevant studies investigating the role of patient navigators in cancer treatment from August 1, 2009 to March 27, 2023. Fifty-nine articles were included in this review. Amongst studies focused on cancer treatment initiation, 70% found a significant improvement in treatment initiation amongst patients who were enrolled in patient navigation programs, 71% of studies focused on treatment adherence demonstrated significant improvements in treatment adherence, 87% of studies investigating patient satisfaction showed significant benefits, and 81% of studies reported a positive impact of patient navigators on quality care indicators. Three palliative care studies found beneficial effects of patient navigation. Thirty-seven studies investigated disadvantaged populations, with 76% of them concluded that patient navigators made a positive impact during treatment. This systematic review provides compelling evidence supporting the value of patient navigation programs in cancer treatment. The findings suggest that patient navigation plays a crucial role in improving access to care and optimizing treatment outcomes, especially for disadvantaged cancer patients. Incorporating patient navigation into standard oncology practice can reduce disparities and improve the overall quality of cancer care.

Single-nanometer iron oxide nanoparticles as tissue-permeable MRI contrast agents.

Magnetic nanoparticles are robust contrast agents for MRI and often produce particularly strong signal changes per particle. Leveraging these effects to probe cellular- and molecular-level phenomena in tissue can, however, be hindered by the large sizes of typical nanoparticle contrast agents. To address this limitation, we introduce single-nanometer iron oxide (SNIO) particles that exhibit superparamagnetic properties in conjunction with hydrodynamic diameters comparable to small, highly diffusible imaging agents. These particles efficiently brighten the signal in T1-weighted MRI, producing per-molecule longitudinal relaxation enhancements over 10 times greater than conventional gadolinium-based contrast agents. We show that SNIOs permeate biological tissue effectively following injection into brain parenchyma or cerebrospinal fluid. We also demonstrate that SNIOs readily enter the brain following ultrasound-induced blood-brain barrier disruption, emulating the performance of a gadolinium agent and providing a basis for future biomedical applications. These results thus demonstrate a platform for MRI probe development that combines advantages of small-molecule imaging agents with the potency of nanoscale materials.

Discordance Between Conventional and Detailed Lymph Node Analysis in Resected, Node-negative Pancreatic or Ampullary Adenocarcinomas and Association With Adverse Survival Outcomes: A Single-institution Analysis.

OBJECTIVE: To assess the frequency of occult metastases (OM) in patients with resected pancreatic ductal adenocarcinoma (PDAC) or ampullary adenocarcinoma (AA) discovered on detailed pathologic examination on lymph nodes (LNs) previously considered negative by conventional analysis and to examine the association between OM and overall survival (OS). BACKGROUND: Poor prognosis of patients with no pathologic evidence of LN metastases may be due to OM that is not detected on conventional LN analysis. METHODS: Patients with LN-negative resected PDAC or AA (2010-2020) were identified from our institutional database. Original hematoxylin and eosin ( H and E ) slides were reanalyzed. In addition, selected LN were analyzed by H and E (3 sections/LN) and pan-cytokeratin (AE1-AE3/PCK26) immunohistochemistry. RESULTS: A total of 598 LNs from 74 LN-negative patients were reexamined. Nineteen patients (25.7%) had OM; 9 (47.4%) were found with immunohistochemistry but not on H and E . The number of positive LNs ranged from 1 to 3. No clinicodemographic, pathologic, or treatment-related factors were associated with OM. On conventional LN analysis, 3/19 patients (15.8%) had stage IA, 9/34 (26.5%) had stage IB, and 7/19 (36.8%) had stage IIA. On detailed LN analysis, 11/19 patients (57.9%) were upstaged to IIB, whereas 8/19 (42.1%) had isolated tumor cells only (N0i+). OM was associated with shorter OS (median OS: 22.3 vs 50.5 months; hazard ratio=3.95, 95% CI: 1.58-9.86). CONCLUSIONS: There is a 26% discordance rate between conventional and detailed LN pathologic analysis in resected PDAC and AA. The presence of OM is associated with shorter OS.

Why the Treatment Sequence Matters: Interplay Between Chemotherapy Cycles Received, Cumulative Dose Intensity, and Survival in Resected Early-stage Pancreas Cancer.

OBJECTIVE: To define the optimal threshold of perioperative chemotherapy completion and relative dose intensity (RDI) for patients with resected pancreatic ductal adenocarcinoma (PDAC). BACKGROUND: Many patients who undergo pancreatectomy for PDAC fail to initiate or complete recommended perioperative chemotherapy. The association between the amount of perioperative chemotherapy received and overall survival (OS) is not well-defined. METHODS: Single-institution analysis of 225 patients who underwent pancreatectomy for stage I/II PDAC (2010-2021). Associations between OS, chemotherapy cycles completed, and RDI were analyzed. RESULTS: Regardless of treatment sequence, completion of ≥67% of recommended cycles was associated with improved OS compared with no chemotherapy [median OS: 34.5 vs 18.1 months; hazard ratio (HR): 0.43; 95% CI: 0.25-0.74] and <67% of cycles (median OS: 17.9 months; HR: 0.39; 95% CI: 0.24-0.64). A near-linear relationship existed between cycles completed and the RDI received (ß = 0.82). A median RDI of 56% corresponded to the completion of 67% of cycles. Receipt of ≥56% RDI was associated with improved OS compared with no chemotherapy (median OS: 35.5 vs 18.1 months; HR: 0.44; 95% CI: 0.23-0.84) and <56% RDI (median OS: 27.2 months; HR: 0.44; 95% CI: 0.20-0.96). Neoadjuvant chemotherapy is associated with increased odds of receiving ≥67% of recommended cycles (odds ratio: 2.94; 95% CI: 1.45-6.26) and ≥56% RDI (odds ratio: 4.47; 95% CI: 1.72-12.50). CONCLUSIONS: Patients with PDAC who received ≥67% of recommended chemotherapy cycles or ≥56% cumulative RDI had improved OS. Neoadjuvant therapy was associated with increased odds of receiving ≥67% of cycles and ≥56% cumulative RDI and should be considered in all patients with resectable PDAC.

Do discussions of financial burdens decrease long-term financial toxicity in adolescent and young adult cancer survivors?

PURPOSE: This study aims to evaluate the associations between patient-provider cost discussions with patient-reported out-of-pocket (OOP) spending and long-term financial toxicity (FT) among adolescent and young adult (AYA; 15-39 years old) cancer survivors. METHODS: Using a cross-sectional survey, we assessed the themes and quality of patient discussions with providers about financial needs and general survivorship preparation, quantified patients' levels of FT, and evaluated patient-reported OOP spending. We determined the association between cancer treatment cost discussion and FT using multivariable analysis. In a subset of survivors (n = 18), we conducted qualitative interviews and used thematic analysis to characterize responses. RESULTS: Two hundred forty-seven AYA survivors completed the survey at a mean of 7 years post treatment and with a median COST score of 13. 70% of AYA survivors did not recall having any cost discussion about their cancer treatment with a provider. Having any cost discussion with a provider was associated with decreased FT (ß = 3.00; p = 0.02) but not associated with reduced OOP spending (χ2 = 3.77; p = 0.44). In a second adjusted model, with OOP spending included as a covariate, OOP spending was a significant predictor of FT (ß = - 1.40; p = 0.002). Key qualitative themes included survivors' frustration about the lack of communication related to financial issues throughout treatment and in survivorship, feeling unprepared, and reluctance to seek help. CONCLUSION: AYA patients are not fully informed about the costs of cancer care and FT; the dearth of cost discussions between patients and providers may represent a missed opportunity to reduce costs.

Do Patients Reporting Fractures Experience Food Insecurity More Frequently Than the General Population?

BACKGROUND: The economic burden of traumatic injuries forces families into difficult tradeoffs between healthcare and nutrition, particularly among those with a low income. However, the epidemiology of food insecurity among individuals reporting having experienced fractures is not well understood. QUESTIONS/PURPOSES: (1) Do individuals in the National Health Interview Survey reporting having experienced fractures also report food insecurity more frequently than individuals in the general population? (2) Are specific factors associated with a higher risk of food insecurity in patients with fractures? METHODS: This retrospective, cross-sectional analysis of the National Health Interview Survey was conducted to identify patients who reported a fracture within 3 months before survey completion. The National Health Interview Survey is an annual serial, cross-sectional survey administered by the United States Centers for Disease Control, involving approximately 90,000 individuals across 35,000 American households. The survey is designed to be generalizable to the civilian, noninstitutionalized United States population and is therefore well suited to evaluate longitudinal trends in physical, economic, and psychosocial health factors nationwide. We analyzed data from 2011 to 2017 and identified 1399 individuals who reported sustaining a fracture during the 3 months preceding their survey response. Among these patients, 27% (384 of 1399) were older than 65 years, 77% (1074) were White, 57% (796) were women, and 14% (191) were uninsured. A raw score compiled from 10 food security questions developed by the United States Department of Agriculture was used to determine the odds of 30-day food insecurity for each patient. A multivariate logistic regression analysis was performed to determine factors associated with food insecurity among patients reporting fractures . In the overall sample of National Health Interview Survey respondents, approximately 0.6% (1399 of 239,168) reported a fracture. RESULTS: Overall, 17% (241 of 1399) of individuals reporting broken bones or fractures in the National Health Interview Survey also reported food insecurity. Individuals reporting fractures were more likely to report food insecurity if they also were aged between 45 and 64 years (adjusted odds ratio 4.0 [95% confidence interval 2.1 to 7.6]; p < 0.001), had a household income below USD 49,716 (200% of the federal poverty level) per year (adjusted OR 3.1 [95% CI 1.9 to 5.1]; p < 0.001), were current tobacco smokers (adjusted OR 2.8 [95% CI 1.6 to 5.1]; p < 0.001), and were of Black race (adjusted OR 1.9 [95% CI 1.1 to 3.4]; p = 0.02). CONCLUSION: Among patients with fractures, food insecurity screening and routine nutritional assessments may help to direct financially vulnerable patients toward available community resources. Such screening programs may improve adherence to nutritional recommendations in the trauma recovery period and improve the physiologic environment for adequate soft tissue and bone healing. Future research may benefit from the inclusion of clinical nutritional data, a broader representation of high-energy injuries, and a prospective study design to evaluate cost-efficient avenues for food insecurity interventions in the context of locally available social services networks. LEVEL OF EVIDENCE: Level III, prognostic study.

Do Americans Lacking a Local Orthopaedic Surgeon Have Adequate Broadband for Telehealth?

BACKGROUND: Although telehealth holds promise in expanding access to orthopaedic surgical care, high-speed internet connectivity remains a major limiting factor for many communities. Despite persistent federal efforts to study and address the health information technology needs of patients, there is limited information regarding the current high-speed internet landscape as it relates to access to orthopaedic surgical care. QUESTIONS/PURPOSES: (1) What is the distribution of practicing orthopaedic surgeons in the United States relative to the presence of broadband internet access? (2) What geographic, demographic, and socioeconomic factors are associated with the absence of high-speed internet and access to a local orthopaedic surgeon? METHODS: The Federal Communications Commission (FCC) Mapping Broadband in America interactive tool was used to determine the proportion of county residents with access to broadband-speed internet for all 3141 US counties. Data regarding the geographic distribution of orthopaedic surgeons and county-level characteristics were obtained from the 2015 Physician Compare National Downloadable File and the Area Health Resource File, respectively. The FCC mapping broadband public use files are considered the most comprehensive datasets describing high-speed internet infrastructure within the United States. The year 2015 represents the most recently available FCC data for which county-level broadband penetration estimates are available. Third-party audits of the FCC data have shown that broadband expansion has been slow over the past decade and that many large improvements have been driven by changes in the reporting methodology. Therefore, we believe the 2015 FCC data still hold relevance. The primary outcome measure was the simultaneous absence of at least 50% broadband penetration and at least one orthopaedic surgeon practicing in county limits. Statistical analyses using Kruskal-Wallis tests and multivariable logistic regression were conducted to assess for factors associated with inaccessibility to orthopaedic telehealth. All statistical tests were two-sided with a significance threshold of p < 0.05. RESULTS: In 2015, 14% (448 of 3141) of counties were considered "low access" in that they both had no orthopaedic surgeons and possessed less than 50% broadband access. A total of 4,660,559 people lived within these low-access counties, representing approximately 1.4% (4.6 million of 320.7 million) of the US population. After controlling for potential confounding variables, such as the age, sex, income level, and educational attainment, lower population density per square mile (OR 0.92 [95% confidence interval (CI) 0.90 to 0.94]; p < 0.01), a lower number of primary care physicians per 100,000 (OR 0.88 [95% CI 0.81 to 0.97]; p < 0.01), a higher unemployment level (OR 1.3 [95% CI 1.2 to 1.4]; p < 0.01), and greater number preventable hospital stays per 100,000 (OR 1.01 [95% CI 1.01 to 1.02]; p < 0.01) were associated with increased odds of being a low-access county (though the effect size of the finding was small for population density and number of primary care physicians). Stated another way, each additional person per square mile was associated with an 8% (95% CI 6% to 10%; p < 0.01) decrease in the odds of being a low-access county, and each additional percentage point of unemployment was associated with a 30% (95% CI 20% to 40%) increase in the odds of being a low-access county. CONCLUSION: Despite the potential for telehealth programs to improve the delivery of high-quality orthopaedic surgical care, broadband internet access remains a major barrier to implementation. Until targeted investments are made to expand broadband infrastructure across the country, health systems, policymakers, and surgeon leaders must capitalize on existing federal subsidy programs, such as the lifeline or affordability connectivity initiatives, to reach unemployed patients living in economically depressed regions. The incorporation of internet access questions into clinic-based social determinants screening may facilitate the development of alternative follow-up protocols for patients unable to participate in synchronous videoconferencing. CLINICAL RELEVANCE: Some orthopaedic patients lack the broadband capacity necessary for telehealth visits, in which case surgeons may pursue alternative methods of follow-up such as mobile phone-based surveillance of postoperative wounds, surgical sites, and clinical symptoms.

Use of intraoperative technology in total knee arthroplasty is not associated with reductions in postoperative pain.

PURPOSE: Our systematic review and meta-analysis sought to assess how technology-assistance impacts (1) post-operative pain and (2) opioid use in patients undergoing primary total knee arthroplasty (TKA). METHODS: Four online databases were queried for studies published up to October 2021 that reported on pain and opioid usage between technology-assisted and manual TKA (mTKA) patients. Mantel-Haenszel (M-H) models were utilized to calculate pooled mean difference (MDs) and 95% confidence interval (CIs). Subgroup analyses were conducted to isolate robotic-arm assisted (RAA) and computed-assisted navigation (CAN) cohorts. Risk of bias was assessed for all included non-randomized studies with the Methodological Index for Non-Randomized Studies (MINORS) tool. For the randomized control trials included in our study, the Detsky scale was applied. RESULTS: Our analysis included 31 studies, reporting on a total of 761,300 TKAs (mTKA: n = 753,554; Computer-Assisted Navigation (CAN): n = 1,309; Robotic-Arm Assisted (RAA): n = 6437). No differences were demonstrated when evaluating WOMAC (MD: 0.00, 95% CI - 0.69 to 0.69; p = 1.00), KSS (MD: 0.01, 95% CI - 1.46 to 1.49; p = 0.99), KOOS (MD - 2.91, 95% CI - 6.17 to 0.34; p = 0.08), and VAS (MD - 0.54, 95% CI - 1.01 to - 0.007; p = 0.02) pain scores between cohorts. There was mixed evidence regarding how opioid consumption differed between TKA techniques. CONCLUSION: The present analysis demonstrated no difference in terms of pain across a variety of utilized patient-reported pain measurements. However, there were mixed results regarding how opioid consumption varied between manual and technology-assisted cohorts, particularly in the immediate post-operative period. LEVEL OF EVIDENCE: III.

Impact of social disadvantage among total knee arthroplasty places of service on procedural volume: a nationwide Medicare analysis.

INTRODUCTION: As recent analyses have indicated that low-volume hospitals experience higher rates of complications following total knee arthroplasty (TKA), it remains important to evaluate how area deprivation index (ADI) of hospitals impacts the quantity of TKA performed. Our analysis sought to evaluate how the ADI of orthopedic surgeon's place of service influences TKA utilization. MATERIALS AND METHODS: The Medicare Provider Utilization and Payment Data Public Use File (MPUP-PUF) was queried to identify claims between 2013 and 2019 associated with Healthcare Common Procedure Coding System (HCPCS) code 27447 (TKA). The MPUP-PUF file was linked with publicly available ADI information as well as information regarding each provider's practice location. The Mann-Kendall trend test was used to analyze significant differences in TKA volume between ADI quintiles and differences in TKA volume overall between the years 2013 and 2019. An adjusted multivariable linear regression analysis was conducted to evaluate how ADI, and practice-specific characteristics, influenced TKA utilization volume. RESULTS: When isolating by ADI quintiles, no significant changes in TKA volume were demonstrated for Quintile 4 (Kendall's τ = 0.524; p = 0.13) and Quintile 5 (Kendall's τ = 0.524; p = 0.13) between 2013 and 2019. However, a significant increase in TKA volume over the study period was observed in Quintile 1 (Kendall's τ = 0.714 p = 0.034), Quintile 2 (Kendall's τ = 0.714 p = 0.034), and Quintile 3 (Kendall's τ = 0.905 p = 0.007). The adjusted multivariable linear regression model demonstrated that each increase in ADI quintile was associated with significantly lower TKA utilization (ß-estimate - 1.16; 95% CI - 2.04 to - 0.29; p = 0.009). CONCLUSIONS: Our findings suggest that resource deprivation contributes to disparities in TKA utilization. With the ongoing recognition of how social and neighborhood-level deprivation may influence access to end-stage osteoarthritis care and related perioperative outcomes, the present study serves to encourage continued efforts at ensuring equity in orthopedic care.

Illuminating the Onco-GPCRome: Novel G protein-coupled receptor-driven oncocrine networks and targets for cancer immunotherapy.

G protein-coupled receptors (GPCRs) are the largest gene family of cell membrane-associated molecules mediating signal transmission, and their involvement in key physiological functions is well-established. The ability of GPCRs to regulate a vast array of fundamental biological processes, such as cardiovascular functions, immune responses, hormone and enzyme release from endocrine and exocrine glands, neurotransmission, and sensory perception (e.g. vision, odor, and taste), is largely due to the diversity of these receptors and the layers of their downstream signaling circuits. Dysregulated expression and aberrant functions of GPCRs have been linked to some of the most prevalent human diseases, which renders GPCRs one of the top targets for pharmaceutical drug development. However, the study of the role of GPCRs in tumor biology has only just begun to make headway. Recent studies have shown that GPCRs can contribute to the many facets of tumorigenesis, including proliferation, survival, angiogenesis, invasion, metastasis, therapy resistance, and immune evasion. Indeed, GPCRs are widely dysregulated in cancer and yet are underexploited in oncology. We present here a comprehensive analysis of GPCR gene expression, copy number variation, and mutational signatures in 33 cancer types. We also highlight the emerging role of GPCRs as part of oncocrine networks promoting tumor growth, dissemination, and immune evasion, and we stress the potential benefits of targeting GPCRs and their signaling circuits in the new era of precision medicine and cancer immunotherapies.

Associations Among Household Chaos, School Belonging and Risk Behaviors in Adolescents.

We examined the associations between adolescent risk behaviors and household chaos, and whether associations varied by adolescents' sense of school belonging. We collected data from 801 Chilean adolescents from working-class families (M age 16.2 years). Approximately, one-quarter of participants reported past-month cigarette use, and 8% and 9% reported past-month binge drinking and marijuana use, respectively. More than half of youth reported having sex (52%), 23% of youth reported having unprotected sex at their last encounter, and 14% reported having multiple sex partners. Within the past year, 16%, 36%, and 23% reported carrying a weapon, physically attacking someone, and threatening to physically hurt someone, respectively. Greater household chaos was related to increased odds of each risk behavior except unprotected sex. These associations did not vary significantly by level of school belonging. Results are compared to previously reported results using a U.S., largely Latinx sample in attempts to replicate findings across culture and context.

Associations Among Mothers' Depression, Emotional and Learning-Material Support to Their Child, and Children's Cognitive Functioning: A 16-Year Longitudinal Study.

This study examined the associations among maternal depression, mothers' emotional and material investment in their child, and children's cognitive functioning. Middle-class Chilean mothers and children (N = 875; 52% males) were studied when children were 1, 5, 10, and 16 years (1991-2007). Results indicated that highly depressed mothers provided less emotional and material support to their child across all ages, which related to children's lower IQ. Children with lower mental abilities at age 1 received less learning-material support at age 5, which led to mothers' higher depression at child age 10. Mothers' low support was more strongly linked to maternal depression as children got older. Findings elucidate the dynamic and enduring effects of depression on mothers' parenting and children's development.

Waiting for Aπαταω: 250 Years Later.

Scientific articles have been traditionally written from single points of view. In contrast, new knowledge is derived strictly from a dialectical process, through interbreeding of partially disparate perspectives. Dialogues, therefore, present a more veritable form for representing the process behind knowledge creation. They are also less prone to dogmatically disseminate ideas than monologues, alongside raising awareness of the necessity for discussion and challenging of differing points of view, through which knowledge evolves. Here we celebrate 250 years since the discovery of the chemical identity of the inorganic component of bone in 1769 by Johan Gottlieb Gahn through one such imaginary dialogue between two seasoned researchers and aficionados of this material. We provide the statistics on ups and downs in the popularity of this material throughout the history and also discuss important achievements and challenges associated with it. The shadow of Samuel Beckett's Waiting for Godot is cast over the dialogue, acting as its frequent reference point and the guide. With this dialogue presented in the format of a play, we provide hope that conversational or dramaturgical compositions of scientific articles - albeit virtually prohibited from the scientific literature of the day - may become more pervasive in the future.

Is there a relationship between solubility and resorbability of different calcium phosphate phases in vitro?

BACKGROUND: Does chemistry govern biology or it is the other way around - that is a broad connotation of the question that this study attempted to answer. METHOD: Comparison was made between the solubility and osteoclastic resorbability of four fundamentally different monophasic calcium phosphate (CP) powders with monodisperse particle size distributions: alkaline hydroxyapatite (HAP), acidic monetite (DCP), ß-calcium pyrophosphate (CPP), and amorphous CP (ACP). Results With the exception of CPP, the difference in solubility between different CP phases became neither mitigated nor reversed, but augmented in the resorptive osteoclastic milieu. Thus, DCP, a phase with the highest solubility, was also resorbed more intensely than any other CP phase, whereas HAP, a phase with the lowest solubility, was resorbed least. CPP becomes retained inside the cells for the longest period of time, indicating hindered digestion of only this particular type of CP. Osteoclastogenesis was mildly hindered in the presence of HAP, ACP and DCP, but not in the presence of CPP. The most viable CP powder with respect to the mitochondrial succinic dehydrogenase activity was the one present in natural biological bone tissues: HAP. CONCLUSION: Chemistry in this case does have a direct effect on biology. Biology neither overrides nor reverses the chemical propensities of inorganics with which it interacts, but rather augments and takes a direct advantage of them. SIGNIFICANCE: These findings set the fundamental basis for designing the chemical makeup of CP and other biosoluble components of tissue engineering constructs for their most optimal resorption and tissue regeneration response.