Thrombectomy and stenting of pseudoaneurysm from transcarotid artery revascularization.

Background: Transcarotid artery revascularization (TCAR) is becoming an increasingly popular treatment of carotid stenosis. Despite this rapid adoption, little in the literature describes the associated complications of this procedure. Case Description: We report a case of a left M1 large-vessel occlusion following treatment of symptomatic, high-grade carotid stenosis with a TCAR procedure approximately three weeks earlier. The initial angiography demonstrated a pseudoaneurysm in the left common carotid artery at the site of TCAR access with a distal clot in the carotid stent. The clot within the stent was aspirated, and a mechanical thrombectomy was performed with a combination of a stent-retriever and aspiration catheter for thrombolysis in cerebral infarction 2B revascularization. Conclusion: The TCAR procedure offers a novel method for revascularization of carotid lesions; it does include its complications. While generally safe, access site complications such as pseudoaneurysms can always occur. Knowledge of this risk allows for appropriate surveillance and management should it occur.

Competing Risks for Monomorphic versus Non-Monomorphic Ventricular Arrhythmias in Primary Prevention Implantable Cardioverter Defibrillator Recipients: Global Electrical Heterogeneity and Clinical Outcomes (GEHCO) Study.

BACKGROUND AND AIMS: Ablation of monomorphic ventricular tachycardia (MMVT) has been shown to reduce shock frequency and improve survival. We aimed to compare cause-specific risk factors of MMVT and polymorphic ventricular tachycardia (PVT)/ventricular fibrillation (VF) and to develop predictive models. METHODS: The multicenter retrospective cohort study included 2,668 patients (age 63.1±13.0 y; 23% female; 78% white; 43% nonischemic cardiomyopathy, left ventricular ejection fraction 28.2±11.1%). Cox models were adjusted for demographic characteristics, heart failure severity and treatment, device programming, and ECG metrics. Global electrical heterogeneity was measured by spatial QRS-T angle (QRSTa), spatial ventricular gradient elevation (SVGel), azimuth, magnitude (SVGmag), and sum absolute QRST integral (SAIQRST). We compared the out-of-sample performance of the lasso and elastic net for Cox proportional hazards and the Fine-Gray competing risk model. RESULTS: During a median follow-up of 4 years, 359 patients experienced their first sustained MMVT with appropriate ICD therapy, and 129 patients had their first PVT/VF with appropriate ICD shock. The risk of MMVT was associated with wider QRSTa (HR 1.16; 95%CI 1.01-1.34), larger SVGel (HR 1.17; 95%CI 1.05-1.30), and smaller SVGmag (HR 0.74; 95%CI 0.63-0.86) and SAIQRST (HR 0.84; 95%CI 0.71-0.99). The best-performing 3-year competing risk Fine-Gray model for MMVT (ROC(t)AUC 0.728; 95%CI 0.668-0.788) identified high-risk (> 50%) patients with 75% sensitivity, 65% specificity, and PVT/VF prediction model had ROC(t)AUC 0.915 (95%CI 0.868-0.962), both satisfactory calibration. CONCLUSION: We developed and validated models to predict the competing risks of MMVT or PVT/VF that could inform procedural planning and future RCTs of prophylactic VT ablation.

Longitudinal Fluctuations in Protein Concentrations and Higher-Order Structures in the Plasma Proteome of Kidney Failure Patients Subjected to a Kidney Transplant.

Using proteomics and complexome profiling, we evaluated in a year-long study longitudinal variations in the plasma proteome of kidney failure patients, prior to and after a kidney transplantation. The post-transplant period was complicated by bacterial infections, resulting in dramatic changes in the proteome, attributed to an acute phase response (APR). As positive acute phase proteins (APPs), being elevated upon inflammation, we observed the well-described C-reactive protein and Serum Amyloid A (SAA), but also Fibrinogen, Haptoglobin, Leucine-rich alpha-2-glycoprotein, Lipopolysaccharide-binding protein, Alpha-1-antitrypsin, Alpha-1-antichymotrypsin, S100, and CD14. As negative APPs, being downregulated upon inflammation, we identified the well-documented Serotransferrin and Transthyretin, but added Kallistatin, Heparin cofactor 2, and interalpha-trypsin inhibitor heavy chain H1 and H2 (ITIH1, ITIH2). For the patient with the most severe APR, we performed plasma complexome profiling by SEC-LC-MS on all longitudinal samples. We observed that several plasma proteins displaying alike concentration patterns coelute and form macromolecular complexes. By complexome profiling, we expose how SAA1 and SAA2 become incorporated into high-density lipid particles, replacing largely Apolipoprotein (APO)A1 and APOA4. Overall, our data highlight that the combination of in-depth longitudinal plasma proteome and complexome profiling can shed further light on correlated variations in the abundance of several plasma proteins upon inflammatory events.

A high-resolution large-area detector for quality assurance in radiotherapy.

Hadron therapy is an advanced radiation modality for treating cancer, which currently uses protons and carbon ions. Hadrons allow for a highly conformal dose distribution to the tumour, minimising the detrimental side-effects due to radiation received by healthy tissues. Treatment with hadrons requires sub-millimetre spatial resolution and high dosimetric accuracy. This paper discusses the design, fabrication and performance tests of a detector based on Gas Electron Multipliers (GEM) coupled to a matrix of thin-film transistors (TFT), with an active area of 60 × 80 mm2 and 200 ppi resolution. The experimental results show that this novel detector is able to detect low-energy (40 kVp X-rays), high-energy (6 MeV) photons used in conventional radiation therapy and protons and carbon ions of clinical energies used in hadron therapy. The GEM-TFT is a compact, fully scalable, radiation-hard detector that measures secondary electrons produced by the GEMs with sub-millimetre spatial resolution and a linear response for proton currents from 18 pA to 0.7 nA. Correcting known detector defects may aid in future studies on dose uniformity, LET dependence, and different gas mixture evaluation, improving the accuracy of QA in radiotherapy.

Multi-modality imaging for assessment of the microcirculation in peripheral artery disease: Bench to clinical practice.

Peripheral artery disease (PAD) is a highly prevalent disorder with a high risk of mortality and amputation despite the introduction of novel medical and procedural treatments. Microvascular disease (MVD) is common among patients with PAD, and despite the established role as a predictor of amputations and mortality, MVD is not routinely assessed as part of current standard practice. Recent pre-clinical and clinical perfusion and molecular imaging studies have confirmed the important role of MVD in the pathogenesis and outcomes of PAD. The recent advancements in the imaging of the peripheral microcirculation could lead to a better understanding of the pathophysiology of PAD, and result in improved risk stratification, and our evaluation of response to therapies. In this review, we will discuss the current understanding of the anatomy and physiology of peripheral microcirculation, and the role of imaging for assessment of perfusion in PAD, and the latest advancements in molecular imaging. By highlighting the latest advancements in multi-modality imaging of the peripheral microcirculation, we aim to underscore the most promising imaging approaches and highlight potential research opportunities, with the goal of translating these approaches for improved and personalized management of PAD in the future.

Not All Arms of IgM Are Equal: Following Hinge-Directed Cleavage by Online Native SEC-Orbitrap-Based CDMS.

Immunoglobulins M (IgM) are key natural antibodies produced initially in humoral immune response. Due to their large molecular weights and extensive glycosylation loads, IgMs represent a challenging target for conventional mass analysis. Charge detection mass spectrometry (CDMS) may provide a unique approach to tackle heterogeneous IgM assemblies, although this technique can be quite laborious and technically challenging. Here, we describe the use of online size exclusion chromatography (SEC) to automate buffer exchange and sample introduction, and demonstrate its adaptability with Orbitrap-based CDMS. We discuss optimal experimental parameters for online SEC-CDMS experiments, including ion activation, choice of column, and resolution. Using this approach, CDMS histograms containing hundreds of individual ion signals can be obtained in as little as 5 min from single injections of <1 µg of sample. To demonstrate the unique utility of online SEC-CDMS, we performed real-time kinetic monitoring of pentameric IgM digestion by the protease IgMBRAZOR, which cleaves specifically in the hinge region of IgM. Several digestion intermediates corresponding to processive losses of F(ab')2 subunits could be mass-resolved and identified by SEC-CDMS. Interestingly, we find that for the J-chain linked IgM pentamer, cleavage of one of the F(ab')2 subunits is much slower than the other four F(ab')2 subunits, which we attribute to the symmetry-breaking interactions of the J-chain within the pentameric IgM structure. The online SEC-CDMS methodologies described here open new avenues into the higher throughput automated analysis of heterogeneous, high-mass protein assemblies by CDMS.

Proteogenomic characterization of difficult-to-treat breast cancer with tumor cells enriched through laser microdissection.

BACKGROUND: Breast cancer (BC) is the most commonly diagnosed cancer and the leading cause of cancer death among women globally. Despite advances, there is considerable variation in clinical outcomes for patients with non-luminal A tumors, classified as difficult-to-treat breast cancers (DTBC). This study aims to delineate the proteogenomic landscape of DTBC tumors compared to luminal A (LumA) tumors. METHODS: We retrospectively collected a total of 117 untreated primary breast tumor specimens, focusing on DTBC subtypes. Breast tumors were processed by laser microdissection (LMD) to enrich tumor cells. DNA, RNA, and protein were simultaneously extracted from each tumor preparation, followed by whole genome sequencing, paired-end RNA sequencing, global proteomics and phosphoproteomics. Differential feature analysis, pathway analysis and survival analysis were performed to better understand DTBC and investigate biomarkers. RESULTS: We observed distinct variations in gene mutations, structural variations, and chromosomal alterations between DTBC and LumA breast tumors. DTBC tumors predominantly had more mutations in TP53, PLXNB3, Zinc finger genes, and fewer mutations in SDC2, CDH1, PIK3CA, SVIL, and PTEN. Notably, Cytoband 1q21, which contains numerous cell proliferation-related genes, was significantly amplified in the DTBC tumors. LMD successfully minimized stromal components and increased RNA-protein concordance, as evidenced by stromal score comparisons and proteomic analysis. Distinct DTBC and LumA-enriched clusters were observed by proteomic and phosphoproteomic clustering analysis, some with survival differences. Phosphoproteomics identified two distinct phosphoproteomic profiles for high relapse-risk and low relapse-risk basal-like tumors, involving several genes known to be associated with breast cancer oncogenesis and progression, including KIAA1522, DCK, FOXO3, MYO9B, ARID1A, EPRS, ZC3HAV1, and RBM14. Lastly, an integrated pathway analysis of multi-omics data highlighted a robust enrichment of proliferation pathways in DTBC tumors. CONCLUSIONS: This study provides an integrated proteogenomic characterization of DTBC vs LumA with tumor cells enriched through laser microdissection. We identified many common features of DTBC tumors and the phosphopeptides that could serve as potential biomarkers for high/low relapse-risk basal-like BC and possibly guide treatment selections.

Difference in early all-cause mortality among patients having hip arthroplasty a Swedish perioperative registry study 2013-2022.

INTRODUCTION: Hip arthroplasty is a common orthopaedic procedure worldwide. There is an ongoing debate related to the fixation and anaesthesia impact on the 30-day mortality, particularly in the aging population with higher American Society of Anaesthesiology (ASA) Physical-Status. AIM: To study the 30-day all-cause mortality in patients undergoing primary hip arthroplasty, with regards to the impact of age, ASA-class, anaesthesia techniques, indication for surgery and fixation techniques. MATERIALS AND METHODS: Perioperative data for primary hip arthroplasty procedures for osteoarthritis and hip fractures registered in the Swedish Perioperative Registry (SPOR) between 2013 and June 2022 were collected. Binary logistic regressions were performed to assess the impact of age, ASA-class, anaesthetic technique, indication for surgery and fixation on odds ratio for 30-day mortality in Sweden. RESULTS: In total, 79,114 patients, 49,565 with osteoarthritis and 29,549 with hip fractures were included in the main study cohort. Mortality was significantly higher among hip fracture patients compared with osteoarthritis, cumulative 8.2% versus 0.1% at 30-days respectively (p < 0.001). Age above 80 years (OR3.7), ASA 3-5 (OR3.3) and surgery for hip fracture (OR 21.5) were associated with significantly higher odds ratio, while hybrid fixation was associated with a significantly lower odds ratio (OR0.4) of 30-day mortality. In the same model, for the subgroups of osteoarthritis and hip fracture, only age (OR 3.7) and ASA-class (OR 3.3) had significant impact, increasing the odds ratio for 30-day mortality. Hemi arthroplasty was commonly used among the hip fracture patients 20.453 (69.2%), and associated with a significantly higher odds ratio for all-cause 30-day mortality as compared to total hip arthroplasty when adjusting for age and ASA-class and fixation 2.3 (95%CI 1.9-2.3, p < 0.001). CONCLUSIONS: All-cause 30-day mortality associated with arthroplasty differed significantly between the two cohorts, hip fracture, and osteoarthritis (8.2% and 0.1% respectively) and mortality expectedly increased with age and higher ASA-class. Anaesthetic method and cement-fixation did not impact the odds ratio for all-cause 30-day mortality after adjustment for age and ASA-class.

Host microbiome depletion attenuates biofluid metabolite responses following radiation exposure.

Development of novel biodosimetry assays and medical countermeasures is needed to obtain a level of radiation preparedness in the event of malicious or accidental mass exposures to ionizing radiation (IR). For biodosimetry, metabolic profiling with mass spectrometry (MS) platforms has identified several small molecules in easily accessible biofluids that are promising for dose reconstruction. As our microbiome has profound effects on biofluid metabolite composition, it is of interest how variation in the host microbiome may affect metabolomics based biodosimetry. Here, we 'knocked out' the microbiome of male and female C57BL/6 mice (Abx mice) using antibiotics and then irradiated (0, 3, or 8 Gy) them to determine the role of the host microbiome on biofluid radiation signatures (1 and 3 d urine, 3 d serum). Biofluid metabolite levels were compared to a sham and irradiated group of mice with a normal microbiome (Abx-con mice). To compare post-irradiation effects in urine, we calculated the Spearman's correlation coefficients of metabolite levels with radiation dose. For selected metabolites of interest, we performed more detailed analyses using linear mixed effect models to determine the effects of radiation dose, time, and microbiome depletion. Serum metabolite levels were compared using an ANOVA. Several metabolites were affected after antibiotic administration in the tryptophan and amino acid pathways, sterol hormone, xenobiotic and bile acid pathways (urine) and lipid metabolism (serum), with a post-irradiation attenuative effect observed for Abx mice. In urine, dose×time interactions were supported for a defined radiation metabolite panel (carnitine, hexosamine-valine-isoleucine [Hex-V-I], creatine, citric acid, and Nε,Nε,Nε-trimethyllysine [TML]) and dose for N1-acetylspermidine, which also provided excellent (AUROC ≥ 0.90) to good (AUROC ≥ 0.80) sensitivity and specificity according to the area under the receiver operator characteristic curve (AUROC) analysis. In serum, a panel consisting of carnitine, citric acid, lysophosphatidylcholine (LysoPC) (14:0), LysoPC (20:3), and LysoPC (22:5) also gave excellent to good sensitivity and specificity for identifying post-irradiated individuals at 3 d. Although the microbiome affected the basal levels and/or post-irradiation levels of these metabolites, their utility in dose reconstruction irrespective of microbiome status is encouraging for the use of metabolomics as a novel biodosimetry assay.

Dupilumab provides sustained effectiveness on patient-reported outcomes and favorable safety in patients with moderate-to-severe atopic dermatitis: Up to 5-year results from the daily practice BioDay registry.

BACKGROUND: Long-term daily practice data on patient-reported benefits of dupilumab for atopic dermatitis (AD) remains limited. OBJECTIVE: To evaluate patient-reported outcome measures (PROMs) and the safety of dupilumab in patients with moderate-to-severe AD over a follow-up period of up to 5 years. METHODS: Data were extracted from the prospective, multicenter BioDay registry (October 2017-2022) of patients with moderate-to-severe AD treated with dupilumab in daily practice. RESULTS: In total 1223 patients, 1108 adults and 115 pediatric patients were included. After ≥1 year of treatment, mean Patient-Oriented Eczema Measure (POEM), Dermatology Life Quality Index (DLQI), Numeric rating scale (NRS)-pruritus ranged between 7.8 and 8.7, 3.5 and 4.2, and 2.9 and 3.1 in adults, respectively, whilst these patient-reported outcome measures (PROMs) ranged between 8.9 and 10.9, 4.4 and 6.4, and 3.0 and 3.7 in pediatric patients, respectively. At follow-up, overall work impairment decreased from 40.1% to 16.3% to 13.3% in adults. Furthermore, class I obesity and itch-dominant patients generally had less favorable treatment response. Of all patients, 66.8% reported ≥1 adverse event, with conjunctivitis being the most common (33.7%). LIMITATIONS: The overall percentage of missing values for selected PROMs was 26% in adults and 46% in pediatric patients. CONCLUSION: In addition to favorable safety, dupilumab has demonstrated sustained effectiveness across various PROMs, underscoring the treatment benefits from patients' perspectives.

Focal Distal Esophageal Dilation (Blown-Out Myotomy) After Achalasia Treatment: Prevalence and Associated Symptoms.

INTRODUCTION: Peroral endoscopic myotomy (POEM) may result in a distended distal esophagus, referred to as a blown-out myotomy (BOM), the relevance of which is uncertain. The aim of this study was to investigate the prevalence, risk factors, and associated symptoms of BOM after achalasia treatment. METHODS: A data set of the locally treated patients in a randomized controlled trial comparing POEM with pneumatic dilation (PD) was analyzed. A BOM is defined as a >50% increase in esophageal diameter at its widest point in the distal esophagus between the lower esophageal sphincter and 5 cm above. RESULTS: Seventy-four patients were treated in our center, and 5-year follow-up data were available in 55 patients (32 patients [58%] randomized to POEM, 23 [42%] PD). In the group initially treated with POEM, the incidence of BOM increased from 11.5% (4/38) at 3 months, to 21.1% (8/38) at 1 year, 27.8% (10/36) at 2 years, and 31.3% (10/32) at 5 years. None of the patients treated with PD alone developed a BOM. Patients who developed a BOM had a higher total Eckardt score and Eckardt regurgitation component compared with patients who underwent POEM without BOM development (3 [2.75-3.25] vs 2 [1.75-3], P = 0.032, and 1 [0.75-1] vs 0 [0-1], P = 0.041). POEM patients with a BOM more often report reflux symptoms (85% [11/13] vs 46% [2/16], P = 0.023) and had a higher acid exposure time (24.5% [8-47] vs 6% [1.2-18.7], P = 0.027). DISCUSSION: Thirty percent of the patients treated with POEM develop a BOM, which is associated with a higher acid exposure, more reflux symptoms, and symptoms of regurgitation.

Developing a Computer Vision Model to Automate Quantitative Measurement of Hip-Knee-Ankle Angle in Total Hip and Knee Arthroplasty Patients.

BACKGROUND: Increasing deformity of the lower extremities, as measured by the hip-knee-ankle angle (HKAA), is associated with poor patient outcomes after total hip and knee arthroplasty (THA, TKA). Automated calculation of HKAA is imperative to reduce the burden on orthopaedic surgeons. We proposed a detection-based deep learning (DL) model to calculate HKAA in THA and TKA patients and assessed the agreement between DL-derived HKAAs and manual measurement. METHODS: We retrospectively identified 1,379 long-leg radiographs (LLRs) from patients scheduled for THA or TKA within an academic medical center. There were 1,221 LLRs used to develop the model (randomly split into 70% training, 20% validation, and 10% held-out test sets); 158 LLRs were considered "difficult," as the femoral head was difficult to distinguish from surrounding tissue. There were 2 raters who annotated the HKAA of both lower extremities, and inter-rater reliability was calculated to compare the DL-derived HKAAs with manual measurement within the test set. RESULTS: The DL model achieved a mean average precision of 0.985 on the test set. The average HKAA of the operative leg was 173.05 ± 4.54°; the nonoperative leg was 175.55 ± 3.56°. The inter-rater reliability between manual and DL-derived HKAA measurements on the operative leg and nonoperative leg indicated excellent reliability (intraclass correlation (2,k) = 0.987 [0.96, 0.99], intraclass correlation (2, k) = 0.987 [0.98, 0.99, respectively]). The standard error of measurement for the DL-derived HKAA for the operative and nonoperative legs was 0.515° and 0.403°, respectively. CONCLUSIONS: A detection-based DL algorithm can calculate the HKAA in LLRs and is comparable to that calculated by manual measurement. The algorithm can detect the bilateral femoral head, knee, and ankle joints with high precision, even in patients where the femoral head is difficult to visualize.

DeepFLAIR: A neural network approach to mitigate signal and contrast loss in temporal lobes at 7 Tesla FLAIR images.

BACKGROUND AND PURPOSE: Higher magnetic field strength introduces stronger magnetic field inhomogeneities in the brain, especially within temporal lobes, leading to image artifacts. Particularly, T2-weighted fluid-attenuated inversion recovery (FLAIR) images can be affected by these artifacts. Here, we aimed to improve the FLAIR image quality in temporal lobe regions through image processing of multiple contrast images via machine learning using a neural network. METHODS: Thirteen drug-resistant MR-negative epilepsy patients (age 29.2 ± 9.4y, 5 females) were scanned on a 7 T MRI scanner. Magnetization-prepared (MP2RAGE) and saturation-prepared with 2 rapid gradient echoes, multi-echo gradient echo with four echo times, and the FLAIR sequence were acquired. A voxel-wise neural network was trained on extratemporal-lobe voxels from the acquired structural scans to generate a new FLAIR-like image (i.e., deepFLAIR) with reduced temporal lobe inhomogeneities. The deepFLAIR was evaluated in temporal lobes through signal-to-noise (SNR), contrast-to-noise (CNR) ratio, the sharpness of the gray-white matter boundary and joint-histogram analysis. Saliency mapping demonstrated the importance of each input image per voxel. RESULTS: SNR and CNR in both gray and white matter were significantly increased (p < 0.05) in the deepFLAIR's temporal ROIs, compared to the FLAIR. The gray-white matter boundary sharpness was either preserved or improved in 10/13 right-sided temporal regions and was found significantly increased in the ROIs. Multiple image contrasts were influential for the deepFLAIR reconstruction with the MP2RAGE second inversion image being the most important. CONCLUSIONS: The deepFLAIR network showed promise to restore the FLAIR signal and reduce contrast attenuation in temporal lobe areas. This may yield a valuable tool, especially when artifact-free FLAIR images are not available.

Posterior circulation collaterals as predictors of outcome in basilar artery occlusion: a sub-analysis of the BASICS randomized trial.

Introduction and purpose: Basilar artery occlusion (BAO) is still one of the most devastating neurological conditions associated with high morbidity and mortality. In the present study, we aimed to assess the role of posterior circulation collaterals as predictors of outcome in the BASICS trial and to compare two grading systems (BATMAN score and PC-CS) in terms of prognostic value. Methods: We performed a sub-analysis of the BASICS trial. Baseline clinical and imaging variables were analyzed. For the imaging analysis, baseline CT and CTA were analyzed by a central core lab. Only those patients with good or moderate quality of baseline CTA and with confirmed BAO were included. Multivariable binary logistic regression analysis was used to test the independent association of clinical and imaging characteristics with a favorable outcome at 3 months (defined as a modified Rankin Score of ≤3). ROC curve analysis was used to assess and compare accuracy between the two collateral grading systems. Results: The mean age was 67.0 (±12.5) years, 196 (65.3%) patients were males and the median NIHSS was 21.5 (IQR 11-35). Median NCCT pc-ASPECTS was 10 (IQR10-10) and median collateral scores for BATMAN and PC-CS were 8 (IQR 7-9) and 7 (IQR 6-8) respectively. Collateral scores were associated with favorable outcome at 3 months for both BATMAN and PC-CS but only with a modest accuracy on ROC curve analysis (AUC 0.62, 95% CI [0.55-0.69] and 0.67, 95% CI [0.60-0.74] respectively). Age (OR 0.97, 95% CI [0.95-1.00]), NIHSS (OR 0.91, 95% CI [0.89-0.94]) and collateral score (PC-CS - OR 1.2495% CI [1.02-1.51]) were independently associated with clinical outcome. Conclusion: The two collateral grading systems presented modest prognostic accuracy. Only the PC-CS was independently associated with a favorable outcome at 3 months.

Study of High-Transverse-Momentum Higgs Boson Production in Association with a Vector Boson in the qqbb Final State with the ATLAS Detector.

This Letter presents the first study of Higgs boson production in association with a vector boson (V=W or Z) in the fully hadronic qqbb final state using data recorded by the ATLAS detector at the LHC in proton-proton collisions at sqrt[s]=13 TeV and corresponding to an integrated luminosity of 137 fb^{-1}. The vector bosons and Higgs bosons are each reconstructed as large-radius jets and tagged using jet substructure techniques. Dedicated tagging algorithms exploiting b-tagging properties are used to identify jets consistent with Higgs bosons decaying into bb[over ¯]. Dominant backgrounds from multijet production are determined directly from the data, and a likelihood fit to the jet mass distribution of Higgs boson candidates is used to extract the number of signal events. The VH production cross section is measured inclusively and differentially in several ranges of Higgs boson transverse momentum: 250-450, 450-650, and greater than 650 GeV. The inclusive signal yield relative to the standard model expectation is observed to be µ=1.4_{-0.9}^{+1.0} and the corresponding cross section is 3.1±1.3(stat)_{-1.4}^{+1.8}(syst) pb.

TFE3-Rearranged PEComa/PEComa-like Neoplasms: Report of 25 New Cases Expanding the Clinicopathologic Spectrum and Highlighting its Association With Prior Exposure to Chemotherapy.

Since their original description as a distinctive neoplastic entity, ~50 TFE3-rearranged perivascular epithelioid cell tumors (PEComas) have been reported. We herein report 25 new TFE3-rearranged PEComas and review the published literature to further investigate their clinicopathologic spectrum. Notably, 5 of the 25 cases were associated with a prior history of chemotherapy treatment for cancer. This is in keeping with prior reports, based mainly on small case series, with overall 11% of TFE3-rearranged PEComas being diagnosed postchemotherapy. The median age of our cohort was 38 years. Most neoplasms demonstrated characteristic features such as nested architecture, epithelioid cytology, HMB45 positive, and muscle marker negative immunophenotype. SFPQ was the most common TFE3 fusion partner present in half of the cases, followed by ASPSCR1 and NONO genes. Four of 7 cases in our cohort with meaningful follow-up presented with or developed systemic metastasis, while over half of the reported cases either recurred locally, metastasized, or caused patient death. Follow-up for the remaining cases was limited (median 18.5 months), suggesting that the prognosis may be worse. Size, mitotic activity, and necrosis were correlated with aggressive behavior. There is little evidence that treatment with MTOR inhibitors, which are beneficial against TSC-mutated PEComas, is effective against TFE3-rearranged PEComas: only one of 6 reported cases demonstrated disease stabilization. As co-expression of melanocytic and muscle markers, a hallmark of conventional TSC-mutated PEComa is uncommon in the spectrum of TFE3-rearranged PEComa, an alternative terminology may be more appropriate, such as "TFE3-rearranged PEComa-like neoplasms," highlighting their distinctive morphologic features and therapeutic implications.

Incidence and risk factors of reflux esophagitis after peroral endoscopic myotomy.

BACKGROUND: Peroral endoscopic myotomy (POEM) is an effective and safe treatment for achalasia, but often leads to posttreatment gastroesophageal reflux disease. The aim of this study was to examine the incidence and severity of reflux esophagitis after POEM and to identify associated predictive factors. METHODS: Patients who underwent POEM between August 2011 and December 2022 were included. Multivariate logistic regression was used to assess predictive factors for reflux esophagitis after POEM. KEY RESULTS: In total, 252 patients were included; of which, 46% were female and age ranged between 18 and 87 years. Reflux esophagitis within 1 year after POEM was observed in 131 patients (52%), which was severe in 29 patients (LA grade C/D, 12%). Length of full-thickness myotomy (cm; OR 1.11, 95% CI 1.02-1.21), Eckardt scores before POEM (OR 0.84, 95% CI 0.74-0.96), previous pneumatic dilation (OR 0.51, 95% CI 0.29-0.91), and previous laparoscopic Heller myotomy (LHM; OR 0.44, 95% CI 0.23-0.86) were associated with reflux esophagitis after POEM. Alcohol use (none vs > 7 units per week; OR 3.51, 95% CI 1.35-9.11) and overweight (BMI ≥25 kg/m2; OR 2.67, 95% CI 1.17-6.09) were positive predictive factors and previous LHM (OR 0.13, 95% CI 0.02-0.95) was a negative predictive factor for severe reflux esophagitis after POEM (LA grade C/D). CONCLUSION: About half of the patients develop reflux esophagitis after POEM and 12% is graded as severe. Recognizing predictive factors of reflux esophagitis after POEM treatment leads to better patient selection before POEM and provides an opportunity to take preventive measures or start preemptive treatment.

Baseline gut microbiome and metabolites are correlated with alcohol consumption in a zonisamide clinical trial of heavy drinking alcoholic civilians.

Development and severity of alcohol use disorder (AUD) has been linked to variations in gut microbiota and their associated metabolites in both animal and human studies. However, the involvement of the gut microbiome in alcohol consumption of individuals with AUD undergoing treatment remains unclear. To address this, stool samples (n=48) were collected at screening (baseline) and trial completion from a single site of a multi-site double-blind, placebo-controlled trial of Zonisamide in individuals with AUD. Alcohol consumption, gamma-glutamyl transferase (GGT), and phosphatidylethanol (PEth)levels were measured both at baseline and endpoint of 16-week trial period. Fecal microbiome was analyzed via 16S rRNA sequencing and metabolome via untargeted LC-MS. Both sex (p = 0.003) and psychotropic medication usage (p = 0.025) are associated with baseline microbiome composition. The relative abundance of 12 genera at baseline was correlated with percent drinking reduction, baseline and endpoint alcohol consumption, and changes in GGT and PeTH over the course of treatment (p.adj < 0.05). Overall microbiome community structure at baseline differed between high and low responders (67-100% and 0-33% drinking reduction, respectively; p = 0.03). A positive relationship between baseline fecal GABA levels and percent drinking reduction (R=0.43, p < 0.05) was identified by microbiome function prediction and confirmed by ELISA and metabolomics. Predicted microbiome function and metabolomics analysis have found that tryptophan metabolic pathways are over-represented in low responders. These findings highlight importance of baseline microbiome and metabolites in alcohol consumption in AUD patients undergoing zonisamide treatment.

Protein-Centric Analysis of Personalized Antibody Repertoires Using LC-MS-Based Fab-Profiling on a timsTOF.

Endogenous antibodies, or immunoglobulins (Igs), abundantly present in body fluids, represent some of the most challenging samples to analyze, largely due to the immense variability in their sequences and concentrations. It has been estimated that our body can produce billions of different Ig proteins with different isotypes, making their individual analysis seemingly impossible. However, recent advances in protein-centric proteomics using LC-MS coupled to Orbitrap mass analyzers to profile intact Fab fragments formed by selective cleavage at the IgG-hinge revealed that IgG repertoires may be less diverse, albeit unique for each donor. Serum repertoires seem to be dominated by a few hundred clones that cumulatively make up 50-95% of the total IgG content. Enabling such analyses required careful optimization of the chromatography and mass analysis, as all Fab analytes are highly alike in mass (46-51 kDa) and sequence. To extend the opportunities of this mass-spectrometry-based profiling of antibody repertoires, we here report the optimization and evaluation of an alternative MS platform, namely, the timsTOF, for antibody repertoire profiling. The timsTOF mass analyzer has gained traction in recent years for peptide-centric proteomics and found wide applicability in plasma proteomics, affinity proteomics, and HLA peptidomics, to name a few. However, for protein-centric analysis, this platform has been less explored. Here, we demonstrate that the timsTOF platform can be adapted to perform protein-centric LC-MS-based profiling of antibody repertoires. In a side-by-side comparison of the timsTOF and the Orbitrap we demonstrate that the extracted serum antibody repertoires are alike qualitatively and quantitatively, whereby in particular the sensitivity of the timsTOF platform excels. Future incorporation of advanced top-down capabilities on the timsTOF may make this platform a very valuable alternative for protein-centric proteomics and top-down proteomics and thus also for personalized antibody repertoire profiling.

Racial/Ethnic Disparities: Discrimination's Impact on Health-Related Quality of Life-An All of Us Cancer Survivors' Cross-sectional Study.

BACKGROUND: Discrimination is associated with worse mental and physical health outcomes. However, the associations among cancer survivors are limited. OBJECTIVE: We examined whether discrimination is associated with HRQoL and whether adjusting for it reduces racial/ethnic disparities in HRQoL among cancer survivors. METHODS: Cross-sectional data from adult cancer survivors who completed surveys on discrimination in the medical settings (DMS), everyday perceived discrimination (PD), and HRQoL in the "All of Us" Program from 2018 to 2022 were assessed. We created a binary indicator for fair-to-poor vs. good-to-excellent physical health and mental health. PD and DMS scores were a continuous measure with higher scores reflecting more discrimination. Multivariable logistic regression models tested whether DMS and PD are associated with HRQoL and whether they differently affect the association between race/ethnicity and HRQoL. RESULTS: The sample (N = 16,664) of cancer survivors was predominantly White (86%) and female (59%), with a median age of 69. Every 5-unit increase in DMS and PD scores was associated with greater odds of fair-to-poor physical health (DMS: OR [95%CI] = 1.66 [1.55, 1.77], PD: 1.33 [1.27, 1.40]) and mental health (DMS: 1.57 [1.47, 1.69], PD: 1.33 [1.27, 1.39]). After adjusting for DMS or PD, Black and Hispanic survivors had a decreased likelihood of fair-to-poor physical health and mental health (decrease estimate range: - 6 to - 30%) compared to White survivors. This effect was greater for Black survivors when adjusting for PD, as the odds of fair-to-poor mental health compared to White survivors were no longer statistically significant (1.78 [1.32, 2.34] vs 1.22 [0.90, 1.64]). CONCLUSION: Experiences of discrimination are associated with lower HRQoL and reducing it may mitigate racial/ethnic disparities in HRQoL.