Traumatic middle meningeal arteriovenous fistulas (MMAVFs): an exploratory systematic review.

This study aims to systematically review case reports and case series in order to compare the postoperative course of conservative, endovascular and surgical treatments for traumatic dural arteriovenous fistulas predominantly supplied by the middle meningeal artery (MMAVFs), which usually occur following head trauma or iatrogenic causes. We conducted a comprehensive search of PubMed, Embase, Scopus, Web of Science, and Google Scholar until June 23rd, 2024. Three cohorts were defined based on the treatment modality employed. The primary outcomes were the rates of overall obliteration and postoperative complications, with all-cause mortlality considered as secondary outcome. A total of 61 studies encompassing 78 pooled MMAVFs were included in the qualitative analysis. The predominant demographic consisted of males (53.9%) with a median age of 50.5 (IQR: 33.5-67.5) years. The main etiologies for fistula formation were head trauma (75.6%), cranial neurosurgical procedures (11.5%) and endovascular embolization (8.97%). Venous drainage patterns were categorized as follows based on anatomical confluence: Class I (16.7%), II (14.1%), III (12.8%), IV (14.1%), V (7.7%), and VI (3.9%). Regarding treatment efficacy, the overall obliteration rate was 89.74%, achieved through endovascular (95.83%), surgical (64.29%) or conservative (93.75%) approaches. In terms of safety, the overall postoperative complication rate was 6.49% with an all-cause mortality rate of 8.97%, predominantly observed in the surgical group (35.71%). Our systematic review highlights the challenging management of traumatic MMAVFs, frequently associated with head injuries. Endovascular therapy has emerged as the predominant treatment modality, demonstrating markedly higher rates of fistula obliteration, reduced all-cause mortality, and fewer postoperative complications.

Utilizing risk factors to guide treatment decisions in chronic lymphocytic leukemia.

INTRODUCTION: In the era of chemo-immunotherapy, high-risk factors unequivocally predicted inferior outcomes for patients with CLL. The widespread adoption of BTK inhibitors has challenged the practical implications of such testing, as many patients have improved outcomes despite the presence of high-risk features. The impact of adverse prognostic factors, such as unmutated IGHV, on survival has been ameliorated by continuous treatment with BTK inhibitors, but not by finite-duration therapy with venetoclax-based combinations. Furthermore, TP53 abnormalities continue to be associated with worse outcomes in the era of novel agents. New treatment modalities, such as pirtobrutinib, lisocabtagene maraleucel, and ongoing studies combining BTK inhibitors with venetoclax, raise new questions on the significance of prognostic factors of survival for patients with CLL. AREAS COVERED: Herein, we summarized the available literature on patients with CLL harboring high-risk biomarkers, with a focus on data from key clinical trials. EXPERT OPINION: Testing for prognostic biomarkers will remain relevant to identify patients who may have increased benefit from novel therapeutic strategies, such as combination therapies and novel agents. Patients with high-risk disease should be encouraged to participate in clinical trials.

Improved technical outcomes with converting thrombectomy techniques after failed first pass recanalization.

BACKGROUND: A higher number of recanalization attempts reduces the efficacy of endovascular thrombectomy (EVT) for acute ischemic stroke secondary to large vessel occlusion (LVO). We assessed the impact of switching EVT techniques after a failed first pass on procedural and clinical outcomes. METHODS: This multicenter international study, conducted between January 2013 and December 2022, included patients undergoing EVT for anterior circulation LVO (internal carotid artery or M1 segments) with failed first pass recanalization. Propensity score matching identified a 1:1 matched cohort of patients in whom EVT technique was changed after a failed first pass and those with the same technique repeated. The primary outcome was successful recanalization at second attempt defined as Thrombolysis in Cerebral Ischemia (TICI) score of 2B or higher. Secondary outcomes were 90-day modified Rankin Score (mRS) and postprocedural hemorrhage. RESULTS: Among 2167 patients, converting to an alternative technique after a failed first pass was associated with higher odds of successful recanalization (adjusted OR (aOR)=1.5, p=0.041), and higher odds of mRS 0-2 at 90 days (aOR=1.6, p=0.005) without additional risk of symptomatic hemorrhage (p=0.379). Using a propensity score matched cohort of 490 patients, technique conversion at second attempt increased odds of successful recanalization at second attempt (aOR=1.32, p=0.006) and 90-day mRS 0-2 (aOR=1.38, p=0.008). CONCLUSIONS: Early conversion to an alternative EVT technique after a failed first pass recanalization in patients with AIS is associated with better technical success and clinical outcomes.

Angiomyolipomatous Lesions of the Nasal Cavity (Sinonasal Angioleiomyoma with Adipocytic Differentiation): A Multi-Institutional Immunohistochemical and Molecular Study.

Purpose: Mesenchymal neoplasms composed of vascular, smooth muscle, and adipocytic components are uncommon in the nasal cavity. While angioleiomyoma (AL) is a smooth muscle tumor in the Head & Neck WHO classification, it is considered of pericytic origin in the Skin as well as Soft Tissue and Bone classifications. For nasal AL with an adipocytic component, the terms AL with adipocytic differentiation and angiomyolipoma (AML) have been applied, among others. AML is a type of perivascular epithelioid cell tumor (PEComa), most often arising in the kidney, sometimes associated with the tuberous sclerosis complex (TSC). It is uncertain whether nasal cavity AML and AL are best considered hamartomas or neoplasms, as their genetics are largely unexplored. Methods: We performed a multi-institutional retrospective study of nasal cavity mesenchymal lesions. Patient demographics, clinical histories, and histologic and immunohistochemical findings were collected. DNA and RNA were extracted from formalin-fixed, paraffin-embedded tissue and analyzed by SNP-based chromosomal microarray, targeted RNA fusion sequencing, and whole-exome sequencing. Results: Fifteen lesions (3 to 42 mm) were identified predominantly in male (87%) patients with a median age of 60. Patients typically presented with obstructive symptoms, and none had a history of TSC. One AL was a recurrence from six years prior; 11 cases showed no recurrence (median 4.7 years, range: 0.88-12.4). Morphologically, 11 AMLs contained 30-80% smooth muscle, 10-25% vasculature, and 2-60% adipose tissue, while four ALs contained 70-80% smooth muscle and 20-30% vasculature. Other histologic observations included surface ulceration, vascular thrombosis, chronic inflammation, and myxoid change; no well-developed epithelioid cell morphology was identified. Immunohistochemically, all cases were positive for smooth muscle markers (actin and/or desmin) and negative for melanocytic markers. Molecular analysis revealed loss of 3p and 11q in a single AML. No other known pathogenic copy number or molecular alterations were seen, including in TSC1/2, TFE3, or NOTCH2. Conclusion: Nasal cavity AML lacks morphologic, immunophenotypic, and genetic features of PEComa family AMLs. The significant histologic overlap between nasal AML and AL without distinguishing molecular features in either entity suggests "sinonasal angioleiomyoma with adipocytic differentiation" may be the most appropriate terminology for hybrid vascular and smooth muscle lesions containing adipocytic components.

Extracorporeal Shockwave Therapy for Greater Trochanteric Pain Syndrome: A Systematic Review with Meta-Analysis of Randomized Clinical Trials.

BACKGROUND: Greater trochanteric pain syndrome (GTPS) affects 17.6% of adults aged 50 to 79 years, particularly women. While exercise therapy and corticosteroid injections (CSIs) are common treatments, their limitations include inadequate pain control and potential tendon weakening. Extracorporeal shockwave therapy (ESWT) is an emerging alternative for GTPS. This systematic review assessed ESWT's efficacy in GTPS by evaluating pain and functional outcomes at different follow-up intervals. METHODS: A literature search of PubMed, Embase, and Web of Science for randomized clinical trials (RCTs) was conducted comparing ESWT with other GTPS treatments up to March 1, 2024. Two reviewers independently extracted data, assessing study quality using the Cochrane risk-of-bias tool. A random-effects pairwise meta-analysis compared ESWT with other treatments. RESULTS: Eight RCTs involving 754 patients (169 male, 585 female patients) were included. Seven RCTs were deemed high risk of bias, and 1 RCT had some concerns. Five RCTs investigated focused on focused ESWT, and 3 examined radial ESWT. ESWT provided significantly lower pain scores than other treatments at 2 to 4 months (standardized mean difference = -0.431; 95% confidence interval [CI], -0.82 to -0.039; I2 = 83%). Functional improvement (Lower Extremity Functional Scale) was significantly higher at 6 months (weighted mean difference = 6.68; 95% CI, 3.11-10.25; I2 = 0%) but did not exceed the minimal clinically important difference. Focused ESWT provided greater pain reduction than radial ESWT. CONCLUSION: Three weekly ESWT sessions offer short-term pain relief at 2 to 4 months for patients with GTPS, especially with focused ESWT. Functional improvements at 6 months were notable but not clinically significant. These findings suggest ESWT may complement or serve as an alternative to CSIs and exercise. However, caution is needed when interpreting these results due to high risk of bias with the included RCTs and heterogeneity across the studies. Further high-quality trials are needed to confirm ESWT's long-term benefits over other treatments. LEVEL OF EVIDENCE: Level II. See Instructions for Authors for a complete description of levels of evidence.

Correction: Water adsorption lifts the (2 × 1) reconstruction of calcite(104).

Correction for 'Water adsorption lifts the (2 × 1) reconstruction of calcite(104)' by Jonas Heggemann et al., Phys. Chem. Chem. Phys., 2024, 26, 21365-21369, https://doi.org/10.1039/D3CP01408H.

Specific locations of myocardial inflammation and fibrosis are associated with higher risk of events in cardiac sarcoidosis.

BACKGROUND: 18F-FDG-PET/MR can identify inflammation and fibrosis, high-risk features in cardiac sarcoidosis. OBJECTIVE: To evaluate whether the involvement of certain myocardial segments is associated with higher risk compared to others. METHODS: 124 patients with suspected clinical sarcoidosis underwent 18F-FDG-PET/MR. Late gadolinium enhancement (LGE) and focal 18F-FDG uptake were evaluated globally and in the 16 myocardial segments. Presence of LGE was defined when the percentage of LGE exceeded 5.7% globally (relative to myocardial volume) and in each myocardial segment. Patients were followed up for 5.5 years. Events were defined as ventricular arrhythmia (VA, including sustained ventricular tachycardia, ventricular fibrillation, and appropriate ICD discharge), heart failure hospitalization, or all-cause death. RESULTS: Mean age was 57.1±8.9 years, and 39.5% were female; 22 patients (17.6%) had an event at follow-up, and 9 (7.2%) presented VA. LGE and 18F-FDG uptake were more frequent in patients with than without events (36.4% vs 7.8%, p=0.001). Presence of LGE or 18F-FDG in the basal anterior segment were independent predictors for events after adjustment by left ventricular ejection fraction and relative enhanced volume (LGE: OR 10.5[1.2-92.4]; p=0.034;18F-FDG: OR 5.5[1.1-27.5], p=0.038). LGE presence in basal to mid anterior, mid anteroseptal, and basal to mid inferoseptal segments was an independent predictor for VA. Presence of 18F-FDG in basal to mid anterior, mid inferoseptal and mid inferior segments was an independent predictor for VA. CONCLUSION: Involvement of specific myocardial segments, particularly basal to mid anterior and mid septal segments, is associated with higher rates of events in patients with suspected cardiac sarcoidosis.

Hyperferritinemia Screening to Aid Identification and Differentiation of Patients with Hyperinflammatory Disorders.

High ferritin is an important and sensitive biomarker for the various forms of hemophagocytic lymphohistiocytosis (HLH), a diverse and deadly group of cytokine storm syndromes. Early action to prevent immunopathology in HLH often includes empiric immunomodulation, which can complicate etiologic work-up and prevent collection of early/pre-treatment research samples. To address this, we instituted an alert system at UPMC Children's Hospital where serum ferritin > 1000 ng/mL triggered real-time chart review, assessment of whether the value reflected "inflammatory hyperferritnemia (IHF)", and biobanking of remnant samples from consenting IHF patients. We extracted relevant clinical data; periodically measured serum total IL-18, IL-18 binding protein (IL-18BP), and CXCL9; retrospectively classified patients by etiology into infectious, rheumatic, or immune dysregulation; and subjected a subgroup of samples to a 96-analyte biomarker screen. 180 patients were identified, 30.5% of which had IHF. Maximum ferritin levels were significantly higher in patients with IHF than with either hemoglobinopathy or transplant, and highly elevated total IL-18 levels were distinctive to patients with Stills Disease and/or Macrophage Activation Syndrome (MAS). Multi-analyte analysis showed elevation in proteins associated with cytotoxic lymphocytes in all IHF samples when compared to healthy controls and depression of proteins such as ANGPT1 and VEGFR2 in samples from hyperferritinemic sepsis patients relative to non-sepsis controls. This real-time IFH screen proved feasible and efficient, validated prior observations about the specificity of IL-18, enabled early sample collection from a complex population, suggested a unique vascular biomarker signature in hyperferritinemic sepsis, and expanded our understanding of IHF heterogeneity.

Stat3 Inhibitors TTI-101 and SH5-07 Suppress Bladder Cancer Cell Survival in 3D Tumor Models.

Bladder cancer (BCa) is one of the most lethal genitourinary malignancies owing to its propensity for recurrence and poor survival. The biochemical pathway, signal transducer and activator of transcription 3 (STAT3), has gained significance as a molecular pathway that promotes proliferation, invasion, and chemoresistance. In this study, we explored the targeting of STAT3 with TTI-101 and SH5-07 in BCa and elucidated the mechanisms in three-dimensional (3D) spheroid and organoid models. We optimized the growth of spheroids from human, rat, and mouse BCa cell lines (J82, NBT-II, and MB49 respectively) and organoids from BBN (N-butyl-N-(4-hydroxybutyl)-nitrosamine)-induced rat bladder tumors. Cell viability was assessed using MTT and trypan blue assays. Intracellular ATP production, ROS production, and calcium AM (CA)/EtBr staining were used to measure the spheroid and organoid inhibition and mitochondrial function. Western blot analysis was performed to evaluate the pharmacodynamic markers involved in cell proliferation, apoptosis, cancer stem cells (CSCs), and STAT3 signaling in BCa. We found that targeting STAT3 (using TTI-101 and SH5-07) significantly reduced the proliferation of BCa spheroids and organoids, which was accompanied by decreased expression of pSTAT3, Cyclin D1, and PCNA. Our data also demonstrated that treatment with STAT3 inhibitors induced ROS production and cell death in BCa spheroids and organoids. STAT3 inhibition-induced cell death was associated with the activation of caspase 3/7 and PARP cleavage. Moreover, TTI-101 and SH5-07 target cancer stem cells by downregulating the expression of CD44 and CD133 in 3D models. This study provides the first evidence for the prevention of BCa with small-molecule inhibitors TTI-101 and SH5-07 via suppression of CSCs and STAT3 signaling.

Integrated clinical risk prediction of type 2 diabetes with a multifactorial polygenic risk score.

Combining information from multiple GWASs for a disease and its risk factors has proven a powerful approach for development of polygenic risk scores (PRSs). This may be particularly useful for type 2 diabetes (T2D), a highly polygenic and heterogeneous disease where the additional predictive value of a PRS is unclear. Here, we use a meta-scoring approach to develop a metaPRS for T2D that incorporated genome-wide associations from both European and non-European genetic ancestries and T2D risk factors. We evaluated the performance of this metaPRS and benchmarked it against existing genome-wide PRS in 620,059 participants and 50,572 T2D cases amongst six diverse genetic ancestries from UK Biobank, INTERVAL, the All of Us Research Program, and the Singapore Multi-Ethnic Cohort. We show that our metaPRS was the most powerful PRS for predicting T2D in European population-based cohorts and had comparable performance to the top ancestry-specific PRS, highlighting its transferability. In UK Biobank, we show the metaPRS had stronger predictive power for 10-year risk than all individual risk factors apart from BMI and biomarkers of dysglycemia. The metaPRS modestly improved T2D risk stratification of QDiabetes risk scores for 10-year risk prediction, particularly when prioritising individuals for blood tests of dysglycemia. Overall, we present a highly predictive and transferrable PRS for T2D and demonstrate that the potential for PRS to incrementally improve T2D risk prediction when incorporated into UK guideline-recommended screening and risk prediction with a clinical risk score.

Adjunctive Intravenous Argatroban or Eptifibatide for Ischemic Stroke.

BACKGROUND: Intravenous thrombolysis is a standard treatment of acute ischemic stroke. The efficacy and safety of combining intravenous thrombolysis with argatroban (an anticoagulant agent) or eptifibatide (an antiplatelet agent) are unclear. METHODS: We conducted a phase 3, three-group, adaptive, single-blind, randomized, controlled clinical trial at 57 sites in the United States. Patients with acute ischemic stroke who had received intravenous thrombolysis within 3 hours after symptom onset were assigned to receive intravenous argatroban, eptifibatide, or placebo within 75 minutes after the initiation of thrombolysis. The primary efficacy outcome, the utility-weighted 90-day modified Rankin scale score (range, 0 to 10, with higher scores reflecting better outcomes), was assessed by means of centralized adjudication. The primary safety outcome was symptomatic intracranial hemorrhage within 36 hours after randomization. RESULTS: A total of 514 patients were assigned to receive argatroban (59 patients), eptifibatide (227 patients), or placebo (228 patients). All the patients received intravenous thrombolysis (70% received alteplase, and 30% received tenecteplase), and 225 patients (44%) underwent endovascular thrombectomy. At 90 days, the mean (±SD) utility-weighted modified Rankin scale scores were 5.2±3.7 with argatroban, 6.3±3.2 with eptifibatide, and 6.8±3.0 with placebo. The posterior probability that argatroban was better than placebo was 0.002 (posterior mean difference in utility-weighted modified Rankin scale score, -1.51±0.51) and that eptifibatide was better than placebo was 0.041 (posterior mean difference, -0.50±0.29). The incidence of symptomatic intracranial hemorrhage was similar in the three groups (4% with argatroban, 3% with eptifibatide, and 2% with placebo). Mortality at 90 days was higher in the argatroban group (24%) and the eptifibatide group (12%) than in the placebo group (8%). CONCLUSIONS: In patients with acute ischemic stroke treated with intravenous thrombolysis within 3 hours after symptom onset, adjunctive treatment with intravenous argatroban or eptifibatide did not reduce poststroke disability and was associated with increased mortality. (Funded by the National Institute of Neurological Disorders and Stroke; MOST ClinicalTrials.gov number, NCT03735979.).

An Acute Bout of Whole-Body Vibration Does Not Improve Jumping Performance in Those With Anterior Cruciate Ligament Reconstruction.

CONTEXT: Individuals with anterior cruciate ligament reconstruction (ACLR) often fail to return to their previous level of sport performance. Although multifaceted, this inability to regain preinjury performance may be influenced by impaired plyometric ability attributable to chronic quadriceps dysfunction. Whole-body vibration (WBV) acutely improves quadriceps function and biomechanics after ACLR, but its effects on jumping performance outcomes such as jump height, the reactive strength index (RSI), and knee work and power are unknown. OBJECTIVE: To evaluate the acute effects of WBV on measures of jumping performance in those with ACLR. DESIGN: Crossover study design. SETTING: Research laboratory. PATIENTS OR OTHER PARTICIPANTS: Thirty-six individuals with primary, unilateral ACLR. INTERVENTION(S): Participants stood on a WBV platform in a mini-squat position while vibration or no vibration (control) was applied during six 60-second bouts with 2 minutes of rest between bouts. MAIN OUTCOME MEASURE(S): Double-leg jumping tasks were completed preintervention and postintervention (WBV or control) and consisted of jumping off a 30-cm box to 2 force plates half the participant's height away. The jumping task required participants to maximally jump vertically upon striking the force plates. RESULTS: Whole-body vibration did not produce significant improvements in any of the study outcomes (ie, jump height, RSI, and knee work and power) in either limb (P = .053-.839). CONCLUSIONS: These results suggest that a single bout of WBV is insufficient for improving jumping performance in individuals with ACLR. As such, using WBV to acutely improve jumping performance post-ACLR is likely not warranted. Future research should evaluate the effects of repeated exposure to WBV in combination with other plyometric interventions on jumping performance.

Hearing preservation and quality of life in small to medium sized vestibular schwannomas after a wait and scan approach or stereotactic radiosurgery: a systematic review and meta-analysis.

BACKGROUND: The management of vestibular schwannomas (VS) encompasses a choice between conservative "wait-and-scan" (WAS) approach, stereotactic radiosurgery (SRS) or open microsurgical resection. Currently, there is no consensus on the optimal management approach for small to medium sized VS. This study aims to compared outcomes related to hearing in patients with small and medium sized VS who underwent initial treatment with WAS versus SRS. METHODS: A systematic review of the available literature was conducted using PubMed/MEDLINE, Embase, and Cochrane up December 08, 2023. Meta-analysis was performed using a random-effect model to calculate mean difference (MD) and relative risk (RR). A leave-one-out analysis was conducted. The risk of bias was assessed via the Risk of Bias in Non-randomized Studies-Interventions (ROBINS-I) and Cochrane Risk of Bias assessment tool (RoB-2). Ultimately, the certainty of evidence was evaluated using the GRADE assessment. The primary outcomes were serviceable hearing, and pure-tone average (PTA). The secondary outcome was the Penn Acoustic Neuroma Quality of Life Scale (PANQOL) total score. RESULTS: Nine studies were eligible for inclusion, comprising a total of 1,275 patients. Among these, 674 (52.86%) underwent WAS, while 601 patients (47.14%) received SRS. Follow-up duration ranged from two to eight years. The meta-analysis indicated that WAS had a better outcome for serviceable hearing (0.47; 95% CI: 0.32 - 0.68; p < 0.001), as well as for postoperative functional measures including PTA score (MD 13.48; 95% CI 3.83 - 23.13; p < 0.01), and PANQOL total score (MD 3.83; 95% CI 0.42 - 7.25; p = 0.03). The overall certainty of evidence ranged from "very low" to "moderate". CONCLUSIONS: Treating small to medium sized VS with WAS increases the likelihood of preserving serviceable hearing and optimized PANQOL overall postoperative score compared to SRS. Nevertheless, the limited availability of literature and the methodological weakness observed in existing studies outline the need for higher-quality studies.

Snapshot of cyclooctyne ring-opening to a tethered alkylidene cyclic polymer catalyst.

Cyclooctyne reacts with the trianionic pincer ligand supported alkylidyne [ t BuOCO]WCC(CH3)3(THF)2 (1) to yield tungstacyclopropene (3) and tungstacyclopentadiene (4) complexes. The ratio of 3 and 4 in the reaction mixture depends on the stoichiometry of the reaction. The maximum concentration of 3 occurs with one equiv. of cyclooctyne and 4 is the exclusive product of the reaction above three equivalents. Both complexes 3 and 4 convert to the cyclooctyne ring-opened product 5 upon heating. While the conversion of 4 to 5 is accompanied by formation of polycyclooctyne as a white precipitate during the reaction, conversion of 3 to 5 is homogeneous. Exhibiting Ring Expansion Polymerization (REP), complexes 4 and 5 initiate the polymerization of phenylacetylene to generate cyclic poly(phenylacetylene) (c-PPA).

External validation of a deep learning model for automatic segmentation of skeletal muscle and adipose tissue on abdominal computed tomography images.

BACKGROUND: Body composition assessment using computed tomography (CT) images at the L3-level is increasingly applied in cancer research. Robust high-throughput automated segmentation is key to assess large patient cohorts and to support implementation of body composition analysis into routine clinical practice. We trained and externally validated a deep learning neural network (DLNN) to automatically segment L3-CT images. METHODS: Expert-drawn segmentations of visceral and subcutaneous adipose tissue (VAT/SAT) and skeletal muscle (SM) of L3-CT-images of 3,187 patients undergoing abdominal surgery were used to train a DLNN. The external validation cohort was comprised of 2,535 patients with abdominal cancer. DLNN performance was evaluated with (geometric) Dice Similarity (DS) and Lin's Concordance Correlation Coefficient. RESULTS: There was a strong concordance between automatic and manual segmentations with median DS for SM, VAT, and SAT of 0.97 (interquartile range, IQR: 0.95-0.98), 0.98 (IQR: 0.95-0.98), and 0.95 (IQR: 0.92-0.97), respectively. Concordance correlations were excellent: SM 0.964 (0.959-0.968), VAT 0.998 (0.998-0.998), and SAT 0.992 (0.991-0.993). Bland-Altman metrics indicated only small and clinically insignificant systematic offsets; SM radiodensity: 0.23 hounsfield units (0.5%), SM: 1.26 cm2.m-2 (2.8%), VAT: -1.02 cm2.m-2 (1.7%), and SAT: 3.24 cm2.m-2 (4.6%). CONCLUSION: A robustly-performing and independently externally validated DLNN for automated body composition analysis was developed. ADVANCES IN KNOWLEDGE: CT-based body composition analysis is highly prognostic for long-term overall survival in oncology. This DLNN was succesfully trained and externally validated on several large patient cohorts and will therefore enable large scale population studies and implementation of body composition analysis into clinical practice.

Clinical features and outcomes in carriers of pathogenic desmoplakin variants.

BACKGROUND AND AIMS: Pathogenic variants in the desmoplakin (DSP) gene are associated with the development of a distinct arrhythmogenic cardiomyopathy phenotype not fully captured by either dilated cardiomyopathy (DCM), non-dilated left ventricular cardiomyopathy (NDLVC), or arrhythmogenic right ventricular cardiomyopathy (ARVC). Prior studies have described baseline DSP cardiomyopathy genetic, inflammatory, and structural characteristics. However, cohort sizes have limited full clinical characterization and identification of clinical and demographic predictors of sustained ventricular arrhythmias (VAs), heart failure (HF) hospitalizations, and transplant/death. In particular, the relevance of acute myocarditis-like episodes for subsequent disease course is largely unknown. METHODS: All patients with pathogenic/likely pathogenic (P/LP) DSP variants in the worldwide DSP-ERADOS Network (26 academic institutions across nine countries) were included. The primary outcomes were the development of sustained VA and HF hospitalizations during follow-up. Fine-Gray regressions were used to test association between clinical and instrumental parameters and the development of outcomes. RESULTS: Eight hundred patients [40.3 ± 17.5 years, 47.5% probands, left ventricular ejection fraction (LVEF) 49.5 ± 13.9%] were included. Over 3.7 [1.4-7.1] years, 139 (17.4%, 3.9%/year) and 72 (9.0%, 1.8%/year) patients experienced sustained VA and HF episodes, respectively. A total of 32.5% of individuals did not fulfil diagnostic criteria for ARVC, DCM, or NDLVC; their VA incidence was 0.5%/year. In multivariable regression, risk features associated with the development of VA were female sex [adjusted hazard ratio (aHR) 1.547; P = .025], prior non-sustained ventricular tachycardia (aHR 1.721; P = .009), prior sustained VA (aHR 1.923; P = .006), and LVEF ≤ 50% (aHR: 1.645; P = .032), while for HF, they were the presence of T-wave inversion in 3+ electrocardiogram leads (aHR 2.036, P = .007) and LVEF ≤ 50% (aHR 3.879; P < .001). Additionally, 70 (8.8%) patients experienced a myocardial injury episode at presentation or during follow-up. These episodes were associated with an increased risk of VA and HF thereafter (HR 2.394; P < .001, and HR 5.064, P < .001, respectively). CONCLUSIONS: Patients with P/LP DSP variants experience high rates of sustained VA and HF hospitalizations. These patients demonstrate a distinct clinical phenotype (DSP cardiomyopathy), whose most prominent risk features associated with adverse clinical outcomes are the presence of prior non-sustained ventricular tachycardia or sustained VA, T-wave inversion in 3+ leads on electrocardiogram, LVEF ≤ 50%, and myocardial injury events.

Multi-dimensional immunotyping of human NF1-associated peripheral nerve sheath tumors uncovers tumor-associated macrophages as key drivers of immune evasion in the tumor microenvironment.

PURPOSE: Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft tissue sarcomas and the leading cause of mortality in individuals with neurofibromatosis type 1 (NF1). Despite many clinical trials, outcomes for patients with MPNST have remained stagnant and most succumb to their disease; thus, novel therapeutic approaches are needed. A better understanding of the MPNST immune ecosystem will aid in the development of strategies to activate the immune system against the tumor. Herein, we profile the tumor immune microenvironment (TIME) in NF1-associated peripheral nerve sheath tumors (PNST) to discover insights on the role that tumor-infiltrating immune cells play in malignant transformation. EXPERIMENTAL DESIGN: Utilizing fresh and formalin-fixed, paraffin-embedded tissue from patients diagnosed with NF1-PNST, we dissected the TIME by using immunohistochemistry, multiparameter flow cytometry, and comparative transcriptomic studies. RESULTS: Immunophenotyping confirmed increased immune cells infiltration during malignant progression, with a predominance of infiltrating myeloid cells, particularly CD163+ tumor-associated macrophages (TAM). The T cells within MPNST exhibited signs of tumor activation, characterized by high PD-1 expression. Additionally, MPNST specimens demonstrated elevated levels of immunosuppressive TAM, with heightened PD-L1 expression. The proportion of CD163+ myeloid cells within the TIME correlated with poorer progression free survival. Notably, loss of H3K27 trimethylation correlated with low immune cell infiltration in MPNST. CONCLUSIONS: Malignant transformation of NF1-PNST is characterized by an immunosuppressive microenvironment comprising of TAM with high expression of PD-L1, which are associated with inferior outcomes. These findings suggest a clinical potential of immune modulating therapeutics that can unleash an anti-tumor immune response.

Cardiovascular Disease Mortality Trends, 2010-2022: An Update with Final Data.

INTRODUCTION: Age-adjusted mortality rates (AAMR) for cardiovascular diseases (CVD) increased in 2020 and 2021, and provisional data indicated an increase in 2022, resulting in substantial excess CVD deaths during the COVID-19 pandemic. Updated estimates using final data for 2022 are needed. METHODS: The National Vital Statistics System's final Multiple Cause of Death files were analyzed in 2024 to calculate AAMR from 2010 to 2022 and excess deaths from 2020 to 2022 for US adults aged ≥35 years, with CVD as the underlying cause of death. RESULTS: The CVD AAMR among adults aged ≥35 years in 2022 was 434.6 deaths per 100,000 (95% CI: 433.8, 435.5), which was lower than in 2021 (451.8 deaths per 100,000; 95% CI: 450.9, 452.7). The most recent year with a similarly high CVD AAMR as in 2022 was 2012 (434.7 deaths per 100,000 population, 95% CI: 433.8, 435.7). The CVD AAMR for 2022 calculated using provisional data over-estimated the AAMR calculated using final data by 4.6% (95% CI: 4.3%, 4.9%) or 19.9 (95% CI: 18.6, 21.2) deaths per 100,000 population. From 2020 to 2022, an estimated 190,661 (95% CI: 158,139, 223,325) excess CVD deaths occurred. CONCLUSIONS: In 2022, the CVD AAMR among adults aged ≥35 years did not increase, but rather declined from a peak in 2021, signaling improvements in adverse mortality trends that began in 2020, amid the COVID-19 pandemic. However, the 2022 CVD AAMR remains higher than observed before the COVID-19 pandemic, indicating an ongoing need for cardiovascular disease prevention, detection, and management.

Changes in blood pressure measurement prevalence among United States adults with hypertension before and during the COVID-19 pandemic.

Background: The Coronavirus Disease 2019 (COVID-19) pandemic disrupted health care, with particularly profound effects on persons with chronic conditions like hypertension. Objectives: In this study, we examined changes in the prevalence of blood pressure (BP) measurements by a healthcare professional among adults aged ≥ 18 years with hypertension before and during the COVID-19 pandemic in the United States (US). Methods: This study utilized the National Health Interview Survey data from April to December of the 2019 and 2021 modules of the survey. A total of 15,855 participants were included in the analytic sample. The prevalence of BP measurements taken by a health professional was calculated and the association between survey year and BP measurements was evaluated using adjusted and unadjusted logistic regression models. Results: Overall, the prevalence of BP measurements by a health professional among US adults with hypertension decreased from 95.9 % in the pre-pandemic period to 94.7 % in the pandemic period. Adults with hypertension were less likely (OR: 0.76, 95 % CI: 0.63-0.91) to report having had a BP measurement taken by a health professional during the pandemic compared to before the pandemic. Conclusion: Self-measured BP monitoring with clinical support could ensure continuous and improved care of individuals with hypertension, especially when circumstances could interrupt healthcare access.

Magrolimab Plus Rituximab with/without Chemotherapy in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma.

Patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) ineligible for available salvage therapies have limited options for long-term disease control, necessitating novel treatments. Previously, magrolimab (anti-cluster-of-differentiation-47 antibody) plus rituximab (M+R) demonstrated ability to induce complete responses (CR) in R/R DLBCL. Here we report 3-year follow-up data from this phase 1b/2 study (NCT02953509) assessing long-term safety and efficacy of M+R, and initial safety and efficacy of M+R plus gemcitabine-oxaliplatin (M+R-GemOx), in R/R DLBCL. After magrolimab priming, 4 M+R patient groups received 10-45 mg/kg magrolimab with 375 mg/m2 rituximab; M+R-GemOx patients received 30 or 45 mg/kg magrolimab with 375 mg/m2 rituximab, 1000 mg/m2 gemcitabine, and 100 mg/m2 oxaliplatin. Primary endpoints were treatment-emergent adverse events (TEAEs) and objective response rate (ORR). Secondary endpoints included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Of 132 patients treated, 99 received M+R and 33 received M+R-GemOx. Most common any-grade TEAEs were fatigue (M+R, 40%; M+R-GemOx, 70%), infusion-related reactions (M+R, 39%), or anemia (M+R-GemOx, 70%). Treatment-related TEAEs led to magrolimab discontinuation in 7% (M+R) and 6% (M+R-GemOx). One death was considered treatment related (M+R-GemOx, colitis). M+R ORR was 24% (CR, 12%), and median DOR was 9.3 months. Median PFS and OS were 1.8 and 9.2 months, respectively. M+R-GemOx ORR was 52% (CR, 39%); 12-month DOR rate was 66.6% (95% CI, 33.1-86.1%). Median PFS and OS were 3.9 months and not reached, respectively. These results demonstrate that M+R with/without GemOx is well tolerated, and M+R-GemOx has clinical activity in patients with R/R DLBCL.