TLR agonists polarize interferon responses in conjunction with dendritic cell vaccination in malignant glioma: a randomized phase II Trial.

In this randomized phase II clinical trial, we evaluated the effectiveness of adding the TLR agonists, poly-ICLC or resiquimod, to autologous tumor lysate-pulsed dendritic cell (ATL-DC) vaccination in patients with newly-diagnosed or recurrent WHO Grade III-IV malignant gliomas. The primary endpoints were to assess the most effective combination of vaccine and adjuvant in order to enhance the immune potency, along with safety. The combination of ATL-DC vaccination and TLR agonist was safe and found to enhance systemic immune responses, as indicated by increased interferon gene expression and changes in immune cell activation. Specifically, PD-1 expression increases on CD4+ T-cells, while CD38 and CD39 expression are reduced on CD8+ T cells, alongside an increase in monocytes. Poly-ICLC treatment amplifies the induction of interferon-induced genes in monocytes and T lymphocytes. Patients that exhibit higher interferon response gene expression demonstrate prolonged survival and delayed disease progression. These findings suggest that combining ATL-DC with poly-ICLC can induce a polarized interferon response in circulating monocytes and CD8+ T cells, which may represent an important blood biomarker for immunotherapy in this patient population.Trial Registration: ClinicalTrials.gov Identifier: NCT01204684.

The Variability of MCID, SCB, PASS, and MOI Thresholds for PROMs in the Reverse Total Shoulder Arthroplasty Literature: A Systematic Review.

BACKGROUND: Reverse total shoulder arthroplasty (RTSA) is a common procedure utilized to address degenerative pathologies of the glenohumeral joint and rotator cuff. Increased reliance on patient-reported outcome measures (PROMs) has placed emphasis on the utilization of the minimum clinically important difference (MCID), substantial clinical benefit (SCB), patient acceptable symptom state (PASS), and maximal outcome improvement (MOI) thresholds to assess the clinical efficacy of RTSA. In this study, we systematically reviewed the MCID, SCB, PASS, and MOI thresholds reported for PROMs following RTSA. METHODS: PubMed, Embase, MEDLINE, Cochrane Library, and Google Scholar were queried for articles from Jan. 1, 2000-Aug. 31, 2023 reporting MCID, SCB, PASS, or MOI values for PROMs following RTSA. Patient demographic data, study characteristics, MCID/SCB/PASS/MOI thresholds, and threshold calculation methods were extracted. RESULTS: 141 articles were screened with 39 ultimately included, comprising 11,984 total patients that underwent RTSA. 34 (87%) studies reported MCID thresholds, 20 (51%) reported SCB, 5 (13%) reported PASS, and 2 (5%) reported MOI. 25/39 (64%) studies referenced a previous study when reporting MCID, SCB, PASS, or MOI values, 11 (28%) used an anchor-based method to calculate threshold values, 1 (3%) used a distribution-based method, and 2 (5%) used both anchor and distribution methods. There were 19 newly calculated MCID (11), SCB (5), PASS (1), and MOI (2) thresholds. For five of the six most utilized PROMs (ASES, SST, Constant, UCLA, SPADI), the range of reported MCID values exceeded 50% of the most common threshold. For three of the six, the range of SCB values exceeded 25% of the most common threshold. CONCLUSION: There is substantial variability in the MCID and SCB threshold values reported in the RTSA literature. Standardizing the methodologic calculation and utilization of MCID, SCB, PASS, and MOI thresholds for RTSA may allow for improved assessment of PROMs.

Transgender Women Exhibit a Distinct Stress Echocardiography Profile Compared to Age-Matched Cisgender Counterparts: The Mayo Clinic Women's Heart Clinic Experience.

BACKGROUND: Stress echocardiography (SE) is an important modality in cardiovascular risk stratification and obstructive coronary artery disease (CAD) assessment. Binary sex-based parameters are classically used for interpretation of these studies, even among transgender women (TGW). CAD is a leading cause of morbidity and mortality in this population. Yet, it remains unclear whether TGW exhibit a distinct stress testing profile from their cisgender counterparts. METHODS: Using a matched case-control study design, we compared the echocardiographic stress testing profiles of TGW (n=43) with those of matched cisgender men (CGM, n=84) and cisgender women (CGW, n=86) at a single center. Relevant data, including demographics, comorbidities, and cardiac testing data were manually extracted from the patients' charts. RESULTS: The prevalence of hypertension and dyslipidemia was similar between TGW and CGW and lower than that of CGM (p= .003 and .009, respectively). The majority of comorbidities and lab values were similar. On average, TGW had higher heart rates than CGM (p=.002) and had lower blood pressures than CGM and CGW (p<.05). The TGW's double product and metabolic equivalents were similar to those among CGW and lower than those of CGM (p=.016, p=.018, respectively). On echocardiography, the left ventricular end-diastolic and end-systolic diameters among TGW were similar to those of CGW but lower than CGM's (p=.023, p=.018, respectively). Measures of systolic and diastolic function, except for the exercise mitral valve E:e' ratio which was lower in TGW than CGW (p=.029), were largely similar among the three groups. There was no difference in the wall motion score index, and therefore, no difference in the percentage of positive SE tests. CONCLUSION: Our study shows, for the first time, that TGW have a SE profile that is distinct from that of their cisgender counterparts. Larger, multicenter, prospective studies are warranted to further characterize the SE profile of TGW.

Utilizing median and maximum QTc values improves prediction of breakthrough cardiac events in pediatric long QT syndrome.

INTRODUCTION: Although prior studies indicate that a QTc > 500 ms on a single baseline 12-lead electrocardiogram (ECG) is associated with significantly increased risk of arrhythmic events in long QT syndrome (LQTS), less is known about the risk of persistent QT prolongation. We sought to determine QTc persistence and its prognostic effect on breakthrough cardiac events (BCEs) among pediatric patients treated for LQTS. METHODS: We performed a retrospective analysis of 433 patients with LQTS evaluated, risk-stratified, and undergoing active guideline-based LQTS treatment between 1999 and 2019. BCEs were defined as arrhythmogenic syncope/seizure, sudden cardiac arrest (SCA), appropriate VF-terminating ICD shock, and sudden cardiac death (SCD). RESULTS: During the median follow-up of 5.5 years (interquartile range [IQR] = 3-9), 32 (7%) patients experienced a total of 129 BCEs. A maximum QTc threshold of 520 ms and median QTc threshold of 490 ms were determined to be strong predictors for BCEs. A landmark analysis controlling for age, sex, genotype, and symptomatic status demonstrated models utilizing both the median QTc and maximum QTc demonstrated the highest discriminatory value (c-statistic = 0.93-0.95). Patients in the high-risk group (median QTc > 490 ms and maximum QTc > 520 ms) had a significantly lower BCE free survival (70%-81%) when compared to patients in both medium-risk (93%-97%) and low-risk (98%-99%) groups. CONCLUSIONS: The risk of BCE among patients treated for LQTS increases not only based upon their maximum QTc, but also their median QTc (persistence of QTc prolongation). Patients with a maximum QTc > 520 ms and median QTc > 490 ms over serial 12-lead ECGs are at the highest risk of BCE while on guideline-directed medical therapy.

Outcomes of Surgical Septal Myectomy for Obstructive Hypertrophic Cardiomyopathy After Prior Septal Reduction Therapy.

OBJECTIVE: To compare early and late outcomes of septal myectomy in patients with obstructive hypertrophic cardiomyopathy who presented with residual or recurrent left ventricular outflow tract (LVOT) obstruction following prior septal reduction therapy (SRT). METHODS: From January 1989 to March 2022, 145 patients underwent reintervention by septal myectomy for residual LVOT obstruction following prior SRT; 72 patients had prior alcohol septal ablation (ASA), and 73 had prior surgical septal myectomy (SM). Baseline patient characteristics, echocardiographic parameters, and surgical outcomes were compared between these two groups. RESULTS: Patients who had prior ASA were more likely to be male (50.0% vs 30.1%; P=0.015), older (median age 57.5 years vs. 48.3 years; P<0.001) and have a greater body mass index (32.7 kg/m2vs. 30.0 kg/m2; P=0.011). After repeat SRT by septal myectomy, there was no significant difference in the incidence of postoperative complete heart block (CHB), necessitating permanent pacemaker, between the two groups (8.3% vs. 2.7%; P=0.151). One (0.7%) patient died within 30 days of surgery. Over a median follow-up of 7.5 years (IQR 3.0-13.8), there were 20 deaths. Kaplan-Meier 5-, 10-, and 15-year survival rates were 100%, 91%, and 76% for the prior SM group, and 93%, 81%, and 64% for the prior ASA group (P=0.207). CONCLUSION: Septal myectomy for residual or recurrent LVOT obstruction in patients who had prior ASA is safe with an acceptably low rate of postoperative CHB. Surgical outcomes and late survival rates in patients with prior ASA were satisfactory and comparable to patients who underwent repeat myectomy.

Dobutamine-Induced Myoclonus in a Patient With Advanced Heart Failure and Chronic Kidney Disease.

Dobutamine is a positive inotropic agent often used in treatment of cardiogenic shock. Although there are well-documented adverse effects, dobutamine-induced myoclonus is a rarely reported phenomenon. Our case offers a direct and temporally related description of myoclonus, with onset observed within hours of dobutamine initiation and complete resolution within minutes of discontinuation.

Decisional Regret Surrounding Dialysis Initiation: A Comparative Analysis.

Rationale & Objective: Dialysis comes with a substantial treatment burden, so patients must select care plans that align with their preferences. We aimed to deepen the understanding of decisional regret with dialysis choices. Study Design: This study had a mixed-methods explanatory sequential design. Setting & Participants: All patients from a single academic medical center prescribed maintenance in-center hemodialysis or presenting for home hemodialysis or peritoneal dialysis check-up during 3 weeks were approached for survey. A total of 78 patients agreed to participate. Patients with the highest (15 patients) and lowest decisional regret (20 patients) were invited to semistructured interviews. Predictors: Decisional regret scale and illness intrusiveness scale were used in this study. Analytical Approach: Quantitatively, we examined correlations between the decision regret scale and illness intrusiveness scale and sorted patients into the highest and lowest decision regret scale quartiles for further interviews; then, we compared patient characteristics between those that consented to interview in high and low decisional regret. Qualitatively, we used an adapted grounded theory approach to examine differences between interviewed patients with high and low decisional regret. Results: Of patients invited to participate in the interviews, 21 patients (8 high regret, 13 low regret) agreed. We observed that patients with high decisional regret displayed resignation toward dialysis, disruption of their sense of self and social roles, and self-blame, whereas patients with low decisional regret demonstrated positivity, integration of dialysis into their identity, and self-compassion. Limitations: Patients with the highest levels of decisional regret may have already withdrawn from dialysis. Patients could complete interviews in any location (eg, home, dialysis unit, and clinical office), which may have influenced patient disclosure. Conclusions: Although all patients experienced disruption after dialysis initiation, patients' approach to adversity differs between patients experiencing high versus low regret. This study identifies emotional responses to dialysis that may be modifiable through patient-support interventions.

As part of a quality improvement initiative in our dialysis practice, a patient stated, "I wish I never started dialysis." This quote served as the catalyst for embarking on a research project with the aim to understand why patients living with end-stage kidney disease have regret about starting and continuing dialysis, a lifesaving but time-intensive measure. We surveyed and interviewed patients on the topic and learned that patients experiencing regret had a disrupted sense of self and blamed themselves for their need of dialysis. Patients with little to no regret demonstrated positivity and self-compassion. These findings will help health care professionals as they work with patients considering dialysis or having newly started dialysis.

Primary Arthroscopic Repair for Massive Rotator Cuff Tears Results in Good Shoulder Function, Low Pain, and Satisfactory Outcomes at 2-Year Minimum Follow-Up.

PURPOSE: To evaluate outcomes of patients who underwent primary arthroscopic repair for massive rotator cuff tears (MRCTs). METHODS: Patients with MRCTs (full-thickness tear of 2 or more tendons or full-thickness tear ≥5 cm) who underwent arthroscopic repair with a minimum follow-up of 2 years were retrospectively reviewed (n = 51). All patients had preoperative magnetic resonance imaging used to characterize pattern of tear, degree of fatty degeneration (Goutallier classification), and degree of rotator cuff arthropathy (Hamada classification). Outcomes were determined by American Shoulder and Elbow Surgeons (ASES) scores and Penn Shoulder Scores (PSS). RESULTS: A total of 51 patients with a minimum 2.3-year follow-up (mean, 5.4 years; range, 2.3-9.7 years) were included in this study. Mean ASES score was 46.1 ± 7.8 (95% CI, 43.9-48.3) for pain and 39.4 ± 12.1 (95% CI, 36.0-42.8) for function. Total ASES score averaged 85.5 ± 18.4 (95% CI, 80.4-90.7). PSS had a mean pain score of 26.8 ± 4.4 (95% CI, 25.4-28.1), a mean satisfaction score of 7.9 ± 2.9 (95% CI, 7.0-8.2), and a mean function score of 48.5 ± 13.5 (95% CI, 44.7-52.3). Total PSS averaged 83.2 ± 19.6 (95% CI, 77.7-87.7). No correlation was found between Goutallier grade and ASES/PSS scores or between Hamada grade and ASES/PSS scores. Three patients underwent reoperation after primary arthroscopic repair of an MRCT (5.9%). CONCLUSIONS: Patients with MRCTs who undergo primary arthroscopic repair have postoperative outcome scores indicative of good shoulder function, low pain, and high satisfaction. The rate of reoperation for individuals who underwent primary arthroscopic repair with MRCTs was low at 6%. LEVEL OF EVIDENCE: Level IV, retrospective case series.

Sensor-Integrated Chairs for Lower Body Strength and Endurance Assessment.

This paper describes an automated method and device to conduct the Chair Stand Tests of the Fullerton Functional Test Battery. The Fullerton Functional Test is a suite of physical tests designed to assess the physical fitness of older adults. The Chair Stand Tests, which include the Five Times Sit-to-Stand Test (5xSST) and the 30 Second Sit-to-Stand Test (30CST), are the standard for measuring lower-body strength in older adults. However, these tests are performed manually, which can be labor-intensive and prone to error. We developed a sensor-integrated chair that automatically captures the dynamic weight and distribution on the chair. The collected time series weight-sensor data is automatically uploaded for immediate determination of the sit-to-stand timing and counts, as well as providing a record for future comparison of lower-body strength progression. The automatic test administration can provide significant labor savings for medical personnel and deliver much more accurate data. Data from 10 patients showed good agreement between the manually collected and sensor-collected 30CST data (M = 0.5, SD = 1.58, 95% CI = 1.13). Additional data processing will be able to yield measurements of fatigue and balance and evaluate the mechanisms of failed standing attempts.

Variability of MCID, SCB, and PASS Thresholds in Studies Assessing Patient-Reported Outcomes After Rotator Cuff Repair: A Systematic Review.

BACKGROUND: An increasing reliance on patient-reported outcomes has led to greater emphasis on minimal clinically important difference (MCID), substantial clinical benefit (SCB), and Patient Acceptable Symptom State (PASS) thresholds in assessing rotator cuff repairs. PURPOSE: To review the MCID, SCB, and PASS thresholds reported for patient-reported outcome measures (PROMs) after rotator cuff repair. STUDY DESIGN: Systematic review; Level of evidence, 4. METHODS: The PubMed, Embase, Ovid, Cochrane, and Google Scholar databases were queried for full-text journal articles in English published between January 1, 2000, and May 31, 2022. Studies with MCID, SCB, and PASS thresholds reported for patients with rotator cuff repair and a minimum of 12 months of follow-up were included. Reported MCID, SCB, and PASS thresholds and associated calculation methods were extracted. RESULTS: There were 41 unique studies (6331 shoulders) that met the inclusion criteria. Of these, 37 (90%) reported MCID; 16 (39%), PASS; and 11 (27%), SCB values. The most common PROMs were the American Shoulder and Elbow Surgeons score and the Constant-Murley score. In total, 71% (29/41) of these studies referenced values in the literature, usually studies of patients undergoing rotator cuff repair (21/29). Twelve studies calculated MCID, SCB, or PASS thresholds using anchor-based approaches, whereas 6 studies also calculated thresholds using distribution-based methods. The use of MCID, SCB, and PASS in the rotator cuff repair literature is increasing, with half of the included studies published within the final 17 months of the studied period. CONCLUSION: Significant variability was seen in the reporting of MCID, SCB, and PASS threshold values after rotator cuff repair. Researchers should prioritize studies that report clinical outcome thresholds calculated using anchor-based methods and should critically review both the anchor question and its response choices. Standardization of MCID, SCB, and PASS values and calculation methods will allow for a more reliable assessment of PROMs in rotator cuff repair moving forward.

Analysis of Anemia, Transfusions, and CABG Outcomes in The Society of Thoracic Surgeons National Database.

BACKGROUND: This study characterized the association of preoperative anemia and intraoperative red blood cell (RBC) transfusion on outcomes of elective coronary artery bypass grafting (CABG). METHODS: Data from 53,856 patients who underwent CABG included in The Society of Thoracic Surgeons (STS) Adult Cardiac Database in 2019 were used. The primary outcome was operative mortality. Secondary outcomes were postoperative complications. The association of anemia with outcomes was analyzed with multivariable regression models. The influence of intraoperative RBC transfusion on the effect of preoperative anemia on outcomes was studied using mediation analysis. RESULTS: Anemia was present in 25% of patients. Anemic patients had a higher STS Predicted Risk of Operative Mortality (1.2% vs 0.7%; P < .001). Anemia was associated with operative mortality (odds ratio [OR], 1.27; 99.5% CI, 1.00-1.61; P = .047), postoperative RBC transfusion (OR, 2.28; 99.5% CI, 2.12-2.44; P < .001), dialysis (OR, 1.58; 99.5% CI, 1.19-2.11; P < .001), and prolonged intensive care unit and hospital length of stay. Intraoperative RBC transfusion largely mediated the effects of anemia on mortality (76%), intensive care unit stay (99%), and hospital stay, but it only partially mediated the association with dialysis (34.9%). CONCLUSIONS: Preoperative anemia is common in patients who undergo CABG and is associated with increased postoperative risks of mortality, complications, and RBC transfusion. However, most of the effect of anemia on mortality is mediated through intraoperative RBC transfusion.

Fragile Statistical Findings in Randomized Controlled Trials Evaluating Autograft Versus Allograft Use in Anterior Cruciate Ligament Reconstruction: A Systematic Review.

PURPOSE: To analyze the statistical stability of randomized controlled trials (RCTs) evaluating the surgical management of autografts versus allografts in the anterior cruciate ligament reconstruction (ACLR) literature and calculate the fragility index (FI) and fragility quotient and explore a subgroup analysis by calculating the proportion of outcome events where the FI was less than the number of patients lost to follow-up. METHODS: Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we conducted a systematic search in the PubMed and Cochrane databases to identify RCTs published between 2000 and 2022 that investigated the use of autografts versus allografts in ACLR literature and reported dichotomous data. The fragility index of each dichotomous variable was calculated through the reversal of a single outcome event until significance was reversed. The fragility quotient was calculated by dividing each fragility index by the study sample size. The interquartile range also was calculated. RESULTS: Of the 4407 articles screened, 23 met the search criteria, with 11 RCTs evaluating ALCR using autografts and allografts included for analysis. Two hundred and 18 outcome events with 32 significant (P < .05) outcomes and 186 nonsignificant (P ≥ .05) outcomes were identified. The overall fragility index and fragility quotient for all 218 outcomes were 6 subjects (interquartile range 5-8) and 0.058 (interquartile range 0.039-0.077). Fragility analysis of statistically significant outcomes and nonsignificant outcomes had a fragility index of 3.5 (interquartile range 1-5.5) and 6 (interquartile range 5-8), respectively. All of the studies reported a loss to follow-up where 45.5% (5) reported a loss to follow-up greater or equal to 6. CONCLUSIONS: The RCTs in the ACLR peer-reviewed literature evaluating autograft versus allograft use are vulnerable to a small number of outcome event reversals and exemplify significant statistical fragility in statistically significant findings. LEVEL OF EVIDENCE: Level I, systematic review of Level I studies.

Identifying sports chiropractic global research priorities: an international Delphi study of sports chiropractors.

Objectives: Developing a research agenda is one method to facilitate broad research planning and prioritise research within a discipline. Despite profession-specific agendas, none have specifically addressed the research needs of the specialty of sports chiropractic. This study determined consensus on research priorities to inform a global sports chiropractic research agenda. Methods: A Delphi consensus methodology was used to integrate expert opinions. Clinicians, academics and leaders from the international sports chiropractic specialty were recruited using purposive sampling to participate in (1) a Delphi panel involving three voting rounds to determine consensus on research priorities and (2) a priority importance ranking of the items that reached consensus. Results: We identified and contacted 141 participants, with response rates for rounds 1, 2 and 3, of 44%, 31% and 34%, respectively. From the original 149 research priorities, 66 reached consensus in round 1, 63 in round 2 and 45 items in round 3. Research priorities reaching consensus were collapsed by removing redundancies, and priority ranking identified 20 research priorities, 11 related to collaboration and 6 to research themes. Conclusions: The top-ranked items for research priorities, research themes and collaborations included the effects of interventions on performance, recovery and return to play; clinical research in sport; and collaborations with researchers in chiropractic educational institutions, respectively. Implications: The prioritisation of research items can be evaluated by key stakeholders (including athletes) and implemented to develop the first international research agenda for sports chiropractic.

Dendritic Cell Vaccination in Conjunction with a TLR Agonist Polarizes Interferon Immune Responses in Malignant Glioma Patients.

Autologous tumor lysate-pulsed dendritic cell (ATL-DC) vaccination is a promising immunotherapy for patients with high grade gliomas, but responses have not been demonstrated in all patients. To determine the most effective combination of autologous tumor lysate-pulsed DC vaccination, with or without the adjuvant toll-like receptor (TLR) agonists poly-ICLC or resiquimod, we conducted a Phase 2 clinical trial in 23 patients with newly diagnosed or recurrent WHO Grade III-IV malignant gliomas. We then performed deep, high-dimensional immune profiling of these patients to better understand how TLR agonists may influence the systemic immune responses induced by ATL-DC vaccination. Bulk RNAseq data demonstrated highly significant upregulation of type 1 and type 2 interferon gene expression selectively in patients who received adjuvant a TLR agonist together with ATL-DC. CyTOF analysis of patient peripheral blood mononuclear cells (PBMCs) showed increased expression of PD-1 on CD4+ T-cells, decreases in CD38 and CD39 on CD8+ T cells and elevated proportion of monocytes after ATL-DC + TLR agonist administration. In addition, scRNA-seq demonstrated a higher expression fold change of IFN-induced genes with poly-ICLC treatment in both peripheral blood monocytes and T lymphocytes. Patients who had higher expression of interferon response genes lived significantly longer and had longer time to progression compared to those with lower expression. The results suggest that ATL-DC in conjunction with adjuvant poly-ICLC induces a polarized interferon response in circulating monocytes and specific activation of a CD8+ T cell population, which may represent an important blood biomarker for immunotherapy in this patient population. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01204684.

Axitinib in patients with advanced/metastatic soft tissue sarcoma (Axi-STS): an open-label, multicentre, phase II trial in four histological strata.

BACKGROUND: Axitinib is an oral vascular endothelial growth factor receptor inhibitor with anti-tumour activity in renal, thyroid, and pancreatic cancer. METHODS: Axi-STS was a pathologically-stratified, non-randomised, open-label, multi-centre, phase II trial of continuous axitinib treatment in patients ≥16 years, performance status ≤2, with pathologically-confirmed advanced/metastatic soft tissue sarcoma (STS). Patients were recruited within four tumour strata, each analysed separately: angiosarcoma, leiomyosarcoma, synovial sarcoma, or other eligible STSs. The primary outcome was progression-free survival at 12 weeks (PFS12). A Simon's two-stage design with activity defined as PFS12 rate of 40% determined a sample size of 33 patients per strata. RESULTS: Between 31-August-2010 and 29-January-2016, 145 patients were recruited: 38 angiosarcoma, 37 leiomyosarcoma, 36 synovial sarcoma, and 34 other subtypes. PFS12 rate for each stratum analysed was 42% (95% lower confidence interval (LCI); 29), 45% (95% LCI; 32), 57% (95% LCI; 42), and 33% (95% LCI; 21), respectively. There were 74 serious adverse events including two treatment-related deaths of pulmonary haemorrhage and gastrointestinal bleeding. Fatigue and hypertension were the most common grade 3 adverse events. CONCLUSIONS: Axitinib showed clinical activity in all STS strata investigated. The adverse event profile was acceptable, supporting further investigation in phase III trials. CLINICAL TRIAL REGISTRATION: ISRCTN 60791336.

Immune checkpoint blockade induces distinct alterations in the microenvironments of primary and metastatic brain tumors.

In comparison with responses in recurrent glioblastoma (rGBM), the intracranial response of brain metastases (BrM) to immune checkpoint blockade (ICB) is less well studied. Here, we present an integrated single-cell RNA-Seq (scRNA-Seq) study of 19 ICB-naive and 9 ICB-treated BrM samples from our own and published data sets. We compared them with our previously published scRNA-Seq data from rGBM and found that ICB led to more prominent T cell infiltration into BrM than rGBM. These BrM-infiltrating T cells exhibited a tumor-specific phenotype and displayed greater activated/exhausted features. We also used multiplex immunofluorescence and spatial transcriptomics to reveal that ICB reduced a distinct CD206+ macrophage population in the perivascular space, which may modulate T cell entry into BrM. Furthermore, we identified a subset of progenitor exhausted T cells that correlated with longer overall survival in BrM patients. Our study provides a comprehensive immune cellular landscape of ICB's effect on metastatic brain tumors and offers insights into potential strategies for improving ICB efficacy for brain tumor patients.

The proteomic landscape of soft tissue sarcomas.

Soft tissue sarcomas (STS) are rare and diverse mesenchymal cancers with limited treatment options. Here we undertake comprehensive proteomic profiling of tumour specimens from 321 STS patients representing 11 histological subtypes. Within leiomyosarcomas, we identify three proteomic subtypes with distinct myogenesis and immune features, anatomical site distribution and survival outcomes. Characterisation of undifferentiated pleomorphic sarcomas and dedifferentiated liposarcomas with low infiltrating CD3 + T-lymphocyte levels nominates the complement cascade as a candidate immunotherapeutic target. Comparative analysis of proteomic and transcriptomic profiles highlights the proteomic-specific features for optimal risk stratification in angiosarcomas. Finally, we define functional signatures termed Sarcoma Proteomic Modules which transcend histological subtype classification and show that a vesicle transport protein signature is an independent prognostic factor for distant metastasis. Our study highlights the utility of proteomics for identifying molecular subgroups with implications for risk stratification and therapy selection and provides a rich resource for future sarcoma research.

Factors Associated With COVID-19 Vaccine Acceptance Among Patients Receiving Care at a Federally Qualified Health Center.

BACKGROUND: COVID-19 vaccine hesitancy in the United States is high, with at least 63 million unvaccinated individuals to date. Socioeconomically disadvantaged populations experience lower COVID-19 vaccination rates despite facing a disproportionate COVID-19 burden. OBJECTIVE: To assess the factors associated with COVID-19 vaccine acceptance among under-resourced, adult patients. METHODS: Participants were patients receiving care at a Federally Qualified Health Center (FQHC) in St. Paul, Minnesota. Data were collected via multiple modes over 2 phases in 2020 (self-administered electronic survey) and 2021 (study team-administered survey by telephone, self-administered written survey) to promote diversity and inclusion for study participation. The primary outcome was COVID-19 vaccine acceptance. Using logistic regression analysis, associations between vaccine acceptance and factors including risk perception, concerns about the COVID-19 vaccine, social determinants of health (SDOH), co-morbidities, pandemic-induced hardships, and stress were assessed by adjusted odds ratios (AORs) and 95% confidence intervals (CI). RESULTS: One hundred sixty-eight patients (62.5% female; mean age [SD]: 49.9 [17.4] years; 32% <$20 000 annual household income; 69%

Paraneoplastic syndrome of arthropathies as presenting sign for non-small cell lung cancer.

The aim of this study is to showcase an example of paraneoplastic syndrome, so other healthcare providers can be aware of early NSCLC manifestations. This is also important so providers do not dismiss review of symptoms that may not seem pertinent.