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Tumor-associated macrophages (TAMs) represent an important cellular subset within the glioblastoma (WHO grade IV) microenvironment and are a potential therapeutic target. TAMs display a continuum of different polarization states between antitumorigenic M1 and protumorigenic M2 phenotypes, with a lower M1/M2 ratio correlating with worse prognosis. Here, we investigated the effect of macrophage polarization on anti-CD47 antibody-mediated phagocytosis of human glioblastoma cells in vitro, as well as the effect of anti-CD47 on the distribution of M1 versus M2 macrophages within human glioblastoma cells grown in mouse xenografts. Bone marrow-derived mouse macrophages and peripheral blood-derived human macrophages were polarized in vitro toward M1 or M2 phenotypes and verified by flow cytometry. Primary human glioblastoma cell lines were offered as targets to mouse and human M1 or M2 polarized macrophages in vitro. The addition of an anti-CD47 monoclonal antibody led to enhanced tumor-cell phagocytosis by mouse and human M1 and M2 macrophages. In both cases, the anti-CD47-induced phagocytosis by M1 was more prominent than that for M2. Dissected tumors from human glioblastoma xenografted within NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice and treated with anti-CD47 showed a significant increase of M1 macrophages within the tumor. These data show that anti-CD47 treatment leads to enhanced tumor cell phagocytosis by both M1 and M2 macrophage subtypes with a higher phagocytosis rate by M1 macrophages. Furthermore, these data demonstrate that anti-CD47 treatment alone can shift the phenotype of macrophages toward the M1 subtype in vivo.

In silico quantification of cell proportions from mixed-cell transcriptomics data (deconvolution) requires a reference expression matrix, called basis matrix. We hypothesize that matrices created using only healthy samples from a single microarray platform would introduce biological and technical biases in deconvolution. We show presence of such biases in two existing matrices, IRIS and LM22, irrespective of deconvolution method. Here, we present immunoStates, a basis matrix built using 6160 samples with different disease states across 42 microarray platforms. We find that immunoStates significantly reduces biological and technical biases. Importantly, we find that different methods have virtually no or minimal effect once the basis matrix is chosen. We further show that cellular proportion estimates using immunoStates are consistently more correlated with measured proportions than IRIS and LM22, across all methods. Our results demonstrate the need and importance of incorporating biological and technical heterogeneity in a basis matrix for achieving consistently high accuracy. Cell type deconvolution from bulk expression data rely on a reference expression matrix. Here, the authors introduce a basis matrix built using data from both healthy and diseased samples profiled on 42 platforms, reducing biases introduced by single-platform matrices built using healthy samples.

Telemedicine plays an important role in the delivery of medical care, and will become increasingly prominent going forward. Current medical students are among the first generation of \"digital natives\" who are well versed in the incorporation of technology into social interaction. These students are well positioned to apply advances in communications to patient care. Even so, providers require training to effectively leverage these opportunities. Therefore, we recommend introducing telemedicine training into medical school curricula and propose a model for incorporation.

Glioblastoma multiforme (GBM) is a highly aggressive malignant brain tumor with fatal outcome. Tumor-associated macrophages and microglia (TAMs) have been found to be major tumor-promoting immune cells in the tumor microenvironment. Hence, modulation and reeducation of tumor-associated macrophages and microglia in GBM is considered a promising antitumor strategy. Resident microglia and invading macrophages have been shown to have distinct origin and function. Whereas yolk sac-derived microglia reside in the brain, blood-derived monocytes invade the central nervous system only under pathological conditions like tumor formation. We recently showed that disruption of the SIRPα-CD47 signaling axis is efficacious against various brain tumors including GBM primarily by inducing tumor phagocytosis. However, most effects are attributed to macrophages recruited from the periphery but the role of the brain resident microglia is unknown. Here, we sought to utilize a model to distinguish resident microglia and peripheral macrophages within the GBM-TAM pool, using orthotopically xenografted, immunodeficient, and syngeneic mouse models with genetically color-coded macrophages (Ccr2 RFP) and microglia (Cx3cr1 GFP). We show that even in the absence of phagocytizing macrophages (Ccr2 RFP/RFP), microglia are effector cells of tumor cell phagocytosis in response to anti-CD47 blockade. Additionally, macrophages and microglia show distinct morphological and transcriptional changes. Importantly, the transcriptional profile of microglia shows less of an inflammatory response which makes them a promising target for clinical applications.

Circulating tumor DNA (ctDNA) is a component of cell-free DNA that is shed by malignant tumors into the bloodstream and other bodily fluids. Levels of ctDNA are typically low, particularly in patients with localized disease, requiring highly sophisticated methods for detection and quantification. Multiple liquid biopsy methods have been developed for ctDNA analysis in solid tumor malignancies and are now enabling detection and assessment of earlier stages of disease, post-treatment molecular residual disease (MRD), resistance to targeted systemic therapy, and tumor mutational burden. Understanding ctDNA biology, mechanisms of release, and clearance and size characteristics, in conjunction with the application of molecular barcoding and targeted error correction, have increased the sensitivity and specificity of ctDNA detection techniques. Combinatorial approaches including integration of ctDNA data with circulating protein biomarkers may further improve assay sensitivity and broaden the scope of ctDNA applications. Circulating viral DNA may be utilized to monitor disease in some virally induced malignancies. In spite of increasingly accurate methods of ctDNA detection, results need to be interpreted with caution given that somatic mosaicisms such as clonal hematopoiesis of indeterminate potential (CHIP) may give rise to genetic variants in the bloodstream unrelated to solid tumors, and the limited concordance observed between different commercial platforms. Overall, highly precise ctDNA detection and quantification methods have the potential to transform clinical practice via non-invasive monitoring of solid tumor malignancies, residual disease detection at earlier timepoints than standard clinical and/or imaging surveillance, and treatment personalization based on real-time assessment of the tumor genomic landscape.

Chronic pain affects more than 80% of individuals with spinal cord injury (SCI), profoundly impairing mobility, rehabilitation, and quality of life. Conventional pharmacologic and non-pharmacologic treatments often fail to achieve adequate relief. Spinal cord stimulation (SCS) has emerged as a potential neuromodulatory therapy for neuropathic pain; however, its role in SCI remains insufficiently defined. A systematic review was conducted in accordance with PRISMA 2020 guidelines and registered with PROSPERO (CRD42024541622). Comprehensive searches of PubMed, Embase, Web of Science, and the Cochrane Library were performed through April 2024. Eligible studies evaluated SCS for chronic pain in adults with SCI and reported validated pain or patient-reported outcomes. Screening, eligibility assessment, and data extraction were performed in duplicate. Risk of bias and certainty of evidence were evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework and the MethodologicAl STandards for Epidemiological Research (MASTER) tool. From 1064 records, 10 studies involving 43 participants met inclusion criteria. Most were case reports or small case series, with one prospective cohort study. All studies reported pain improvement after SCS using heterogenous outcome formats; minor adverse events were reported in 3 studies, and the remaining 7 studies reported none. The overall certainty of evidence was rated very low due to small sample sizes, heterogeneity in study design, and methodological limitations. Three ongoing clinical trials evaluating SCS for pain in SCI were also identified. Preliminary, very low-certainty evidence indicates that SCS may be a promising option for chronic pain after SCI, with limited reported complications in the available literature. Higher-quality studies are required to confirm benefit, characterize risks, and guide patient selection and programming. CRD42024541622.

Abstract BACKGROUND Idiopathic intracranial hypertension results in increased intracranial pressure leading to headache and visual loss. This disease frequently requires surgical intervention through lumboperitoneal (LP) or ventriculoperitoneal (VP) shunting. OBJECTIVE To compare postoperative outcomes between LP and VP shunts, including failure and complication rates. METHODS A retrospective analysis was conducted using a national administrative database (MarketScan) to identify idiopathic intracranial hypertension (IIH) patients who underwent LP or VP shunting from 2007 to 2014. Multivariate logistic and Cox regressions were performed to compare rates of shunt failure and time to shunt failure between LP and VP shunts while controlling for demographics and comorbidities. RESULTS The analytic cohort included 1082 IIH patients, 347 of whom underwent LP shunt placement at index hospitalization and 735 of whom underwent VP shunt placement. Rates of shunt failure were similar among patients with LP and VP shunt (34.6% vs 31.7%; P = .382). Among patients who experienced shunt failure, the mean number of shunt failures was 2.1 ± 1.6 and was similar between LP and VP cohorts. Ninety-day readmission rates, complication rates, and costs did not differ significantly between LP and VP shunts. Patients who experienced more than two shunt failures tended to have an earlier time to first shunt failure (hazard ratio 1.41; 95% confidence interval 1.08-1.85; P = .013). CONCLUSION These findings suggest that LP and VP shunts may have comparable rates of shunt failure and complication. Regardless of shunt type, earlier time to first shunt failure may be associated with multiple shunt failures. Graphical Abstract Graphical Abstract

To estimate global surgical volume in 2012 and compare it with estimates from 2004. For the 194 Member States of the World Health Organization, we searched PubMed for studies and contacted key informants for reports on surgical volumes between 2005 and 2012. We obtained data on population and total health expenditure per capita for 2012 and categorized Member States as very-low, low, middle and high expenditure. Data on caesarean delivery were obtained from validated statistical reports. For Member States without recorded surgical data, we estimated volumes by multiple imputation using data on total health expenditure. We estimated caesarean deliveries as a proportion of all surgery. We identified 66 Member States reporting surgical data. We estimated that 312.9 million operations (95% confidence interval, CI: 266.2-359.5) took place in 2012, an increase from the 2004 estimate of 226.4 million operations. Only 6.3% (95% CI: 1.7-22.9) and 23.1% (95% CI: 14.8-36.7) of operations took place in very-low- and low-expenditure Member States representing 36.8% (2573 million people) and 34.2% (2393 million people) of the global population of 7001 million people, respectively. Caesarean deliveries comprised 29.6% (5.8/19.6 million operations; 95% CI: 9.7-91.7) of the total surgical volume in very-low-expenditure Member States, but only 2.7% (5.1/187.0 million operations; 95% CI: 2.2-3.4) in high-expenditure Member States. Surgical volume is large and growing, with caesarean delivery comprising nearly a third of operations in most resource-poor settings. Nonetheless, there remains disparity in the provision of surgical services globally.

Summary Little is known regarding osteoporosis management between Traditional Medicare (TM) and Medicare Advantage (MA). MA beneficiaries had higher rates of osteoporosis testing and higher rates of osteoporosis drug treatment initiation rates. Following an osteoporotic fragility fracture, MA beneficiaries were more likely to be prescribed osteoporosis treatment. While osteoporosis testing and treatment initiation rates are low in both TM and MA, rates tended to be higher in MA. Purpose Osteoporosis represents a substantial clinical challenge in the United States, particularly for older women, and requires effective care coordination. Medicare Advantage (MA) plans have financial incentives in the form of star ratings to improve osteoporosis testing and treatment. The objective of this study was to compare osteoporosis management practices between Traditional Medicare (TM) beneficiaries and MA female enrollees. Methods We conducted a cross-sectional study using a nationally representative 20% sample of 2017–2019 TM claims and MA encounter records. We identified 2,994,203 female TM beneficiaries and 1,924,132 MA enrollees. The exposure was enrollment in MA. The primary outcomes were the rates of guideline-recommended bone mineral density (BMD) testing and osteoporosis drug initiation following a new osteoporosis diagnosis and after a new osteoporotic fragility fracture. Results MA beneficiaries had higher unadjusted (22.0% vs. 19.8% in TM; P  < 0.001) and adjusted rates (0.8 percentage points [p.p.] higher; P  < 0.001) of BMD testing. Osteoporosis drug treatment initiation rates were higher in the MA cohort, both unadjusted (24.9% vs. 20.3% in TM; P  < 0.001) and adjusted (4.0 p.p. higher; P  < 0.001). Following an osteoporotic fragility fracture, MA beneficiaries were more likely to be prescribed pharmacologic treatment (28.7% vs. 21.1% in TM; P  < 0.001), with an adjusted increase of 5.9 p.p ( P  < 0.001). Conclusion Overall osteoporosis testing and treatment initiation rates in both TM and MA enrollees were low, with improved rates in MA compared to TM.

Grade III spinal ependymomas are rare central nervous system tumors with poor prognoses and limited treatment guidance. This study aimed to identify predictors of long-term mortality using a national dataset. The National Cancer Database was queried for patients diagnosed with grade III spinal ependymomas from 2004 to 2017. Demographic, clinical, and treatment variables were analyzed with traditional statistics and machine learning models. Model performance was evaluated with C-index and Integrated Brier Score (IBS), and SHAP analysis was used for feature interpretation. A total of 2,011 patients were included. Surgical resection was performed in 83% of cases, with gross total resection in 96% of those. Radiation was given to 33% (mean 41.4 Gy), and chemotherapy to 18%. Ten-year survival was 75%. Long-term survivors were younger (42 vs. 52 years, P  < 0.001), had fewer comorbidities ( P  < 0.001), and were more often privately insured. Mortality was higher among those receiving radiation (56% vs. 24%, P  < 0.001) or chemotherapy (37% vs. 12%, P  < 0.001). Random Survival Forest was the best-performing model (C-index 0.724; IBS 0.176), identifying tumor size, radiation, chemotherapy, and surgery as key correlates of mortality. Kaplan-Meier analysis showed reduced survival with radiation and chemotherapy, but improved survival with surgery. Stratified analyses revealed diminished surgical benefit in pediatric patients and small tumors. Tumor size emerged as the strongest correlate of mortality. Surgery improves survival, though benefit varies by age and tumor features. Chemotherapy and radiation correlated with higher mortality, underscoring the need for individualized treatment planning and prospective validation.