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.).

Digital Image Sensor Evolution and New Frontiers.

This article reviews nearly 60 years of solid-state image sensor evolution and identifies potential new frontiers in the field. From early work in the 1960s, through the development of charge-coupled device image sensors, to the complementary metal oxide semiconductor image sensors now ubiquitous in our lives, we discuss highlights in the evolutionary chain. New frontiers, such as 3D stacked technology, photon-counting technology, and others, are briefly discussed.

Beware of the Iceberg Phenomenon: A Case Report of Chest Wall Fibrous Dysplasia.

Thoracic fibrous dysplasia (FD) is a benign, osseous chest wall tumor. It originates from bone marrow and accounts for 30-50% of all benign osseous neoplasms in the chest wall. In FD, normal bone marrow is replaced by fibrous stroma and immature bone. We present a rare case in which massive intrathoracic polyostotic FD originating from the rib was diagnosed and treated. The extrathoracic part of the tumor appeared stable and unalarming for decades; however, in hindsight, the intrathoracic part significantly progressed, eventually leading to symptoms. The tumor was removed through a hemi-clamshell approach, which allowed adequate visualization and control of mediastinal structures. After establishing the diagnosis of FD, regular follow-up imaging is crucial for timing of a surgical intervention to prevent symptoms, impairment of quality of life, and unnecessarily complex resections.

KIR2DS2+ NK cells in cancer patients demonstrate high activation in response to tumour-targeting antibodies.

Strategies to mobilise natural killer (NK) cells against cancer include tumour-targeting antibodies, NK cell engagers (NKCEs) and the adoptive transfer of ex vivo expanded healthy donor-derived NK cells. Genetic and functional studies have revealed that expression of the activating killer immunoglobulin-like receptor KIR2DS2 is associated with enhanced function in NK cells from healthy donors and improved outcome in several different malignancies. The optimal strategy to leverage KIR2DS2+ NK cells therapeutically is however currently unclear. In this study, we therefore evaluated the response of KIR2DS2-expressing NK cells to activation against cancer with clinically relevant tumour-targeting antibodies and following ex vivo expansion. We identified that KIR2DS2high NK cells from patients with chronic lymphocytic leukaemia and hepatocellular carcinoma had enhanced activation in response to tumour-targeting antibodies compared to KIR2DS2- NK cells. However, the superior function of healthy donor derived KIR2DS2high NK cells was lost following ex vivo expansion which is required for adoptive transfer-based therapeutic strategies. These data provide evidence that targeting KIR2DS2 directly in cancer patients may allow for the utilisation of their enhanced effector function, however such activity may be lost following their ex vivo expansion.

Will Transformers change gastrointestinal endoscopic image analysis? A comparative analysis between CNNs and Transformers, in terms of performance, robustness and generalization.

Gastrointestinal endoscopic image analysis presents significant challenges, such as considerable variations in quality due to the challenging in-body imaging environment, the often-subtle nature of abnormalities with low interobserver agreement, and the need for real-time processing. These challenges pose strong requirements on the performance, generalization, robustness and complexity of deep learning-based techniques in such safety-critical applications. While Convolutional Neural Networks (CNNs) have been the go-to architecture for endoscopic image analysis, recent successes of the Transformer architecture in computer vision raise the possibility to update this conclusion. To this end, we evaluate and compare clinically relevant performance, generalization and robustness of state-of-the-art CNNs and Transformers for neoplasia detection in Barrett's esophagus. We have trained and validated several top-performing CNNs and Transformers on a total of 10,208 images (2,079 patients), and tested on a total of 7,118 images (998 patients) across multiple test sets, including a high-quality test set, two internal and two external generalization test sets, and a robustness test set. Furthermore, to expand the scope of the study, we have conducted the performance and robustness comparisons for colonic polyp segmentation (Kvasir-SEG) and angiodysplasia detection (Giana). The results obtained for featured models across a wide range of training set sizes demonstrate that Transformers achieve comparable performance as CNNs on various applications, show comparable or slightly improved generalization capabilities and offer equally strong resilience and robustness against common image corruptions and perturbations. These findings confirm the viability of the Transformer architecture, particularly suited to the dynamic nature of endoscopic video analysis, characterized by fluctuating image quality, appearance and equipment configurations in transition from hospital to hospital. The code is made publicly available at: https://github.com/BONS-AI-VCA-AMC/Endoscopy-CNNs-vs-Transformers.

Esophageal Expert Development of a Preliminary Question Prompt List for Adults With Eosinophilic Esophagitis: A Modified Delphi Study.

BACKGROUND: Question prompt lists (QPLs) are structured sets of disease-specific questions intended to encourage question-asking by patients and enhance patient-physician communication. To date, an EoE-specific QPL has not been developed for EoE patients. AIM: To develop a preliminary QPL specific to adults with EoE by incorporating input from international esophageal experts. METHODS: Sixteen experts were invited to generate QPL content through a modified Delphi (RAND/University of California, Los Angeles, CA) method consisting of 2 rounds of independent ratings. In round 1, experts provided 5 answers to the prompts "what general questions should patients ask when being seen for EoE?" and "what questions do I not hear patients asking but given my experience, I believe they should be asking?" In round 2, experts rated each question on a 5-point Likert scale, and responses rated as "essential" or "important" (determined by an a priori median threshold of ≥ 4.0) were accepted for the EoE QPL. RESULTS: Ten esophageal experts participated in both rounds. Round 1 generated 100 questions. Questions were combined and modified to reduce redundancy, yielding 57 questions. After round 2, 51 questions (85%) were accepted for inclusion (median value ≥ 4.0) in the final QPL. Questions were then divided into 4 themes based on disease domains: (1) "What is EoE?," (2) "Treatment Options," (3) "Follow-up Surveillance and Long-term Risks," and (4) "Allergy and Genetic Testing." The largest number of questions covered was "What is EoE?" (16/51 or 31%). Questions with the highest agreement median (5.0) included examples such as "what should I do if I get a food impaction?" and "what are the treatment options?" CONCLUSION: This is the first preliminary EoE QPL developed in the field of medicine. We hope implementation enhances effective patient-physician communication by encouraging patients to ask relevant questions that experts prioritized. Future studies will aim to modify this communication tool by incorporating patient perspectives.

Preoperative Vascular Imaging in Lower Extremity Free Flap Reconstruction: Comparison Between Imaging Modalities.

BACKGROUND: Adequate vascular anatomy and perfusion status are essential for successful lower extremity free tissue transfer. Computed tomography angiography (CTA) is widely available, minimally invasive, and enables visualization of soft tissues and bones. Angiography permits temporal evaluation of flow, identifies potential needs for concurrent endovascular interventions, and enhances visibility in the setting of hardware. Despite widespread availability of these imaging modalities, no standardized algorithm for preoperative imaging prior to lower extremity free flap reconstruction exists. METHODS: Current Procedural Terminology (CPT) codes identified patients undergoing free flap reconstruction of the lower extremity over an 18-year period (2002-2020). Electronic medical records were reviewed for patient, treatment, and imaging characteristics, and pre- and post-imaging laboratory values. Outcomes included imaging findings and related complications and surgical outcomes. RESULTS: In total, 405 patients were identified, with 59% (n = 238) undergoing preoperative imaging with angiography, 10% (n = 42) with CTA, 7.2% (n = 29) with both imaging modalities, and 24% (n = 96) with neither performed. Forty percent (122 of 309) of patients who underwent preoperative imaging had less than 3-vessel runoff. Four patients developed contrast-induced nephropathy (CIN) after angiography only and one after having both CTA and angiography. Vessel runoff on CTA and angiography demonstrated moderate correlation. CONCLUSION: Most patients undergoing lower extremity free tissue transfer underwent preoperative imaging with angiography and/or CTA, 40% of which had less than 3-vessel runoff. Both angiography and CTA had low complication rates, with no statistically significant risk factors identified. Specifically, the incidence of CIN was not found to be significant using either modality. We discuss our institutional algorithm to aid in decision-making for preoperative imaging prior to lower extremity free flap reconstruction. Specifically, we recommend angiography for patients with peripheral vascular disease, internal hardware, or distal defects secondary to trauma.

Studies of the Energy Dependence of Diboson Polarization Fractions and the Radiation-Amplitude-Zero Effect in WZ Production with the ATLAS Detector.

This Letter presents the first study of the energy dependence of diboson polarization fractions in WZ→ℓνℓ^{'}ℓ^{'}(ℓ,ℓ^{'}=e,µ) production. The dataset used corresponds to an integrated luminosity of 140 fb^{-1} of proton-proton collisions at a center-of-mass energy of 13 TeV recorded by the ATLAS detector. Two fiducial regions with an enhanced presence of events featuring two longitudinally polarized bosons are defined. A nonzero fraction of events with two longitudinally polarized bosons is measured with an observed significance of 5.3 standard deviations in the region with 100200 GeV, where p_{T}^{Z} is the transverse momentum of the Z boson. This Letter also reports the first study of the radiation-amplitude-zero effect. Events with two transversely polarized bosons are analyzed for the ΔY(ℓ_{W}Z) and ΔY(WZ) distributions defined respectively as the rapidity difference between the lepton from the W boson decay and the Z boson and the rapidity difference between the W boson and the Z boson. Significant suppression of events near zero is observed in both distributions. Unfolded ΔY(ℓ_{W}Z) and ΔY(WZ) distributions are also measured and compared to theoretical predictions.

Combination of Searches for Higgs Boson Pair Production in pp Collisions at sqrt[s]=13 TeV with the ATLAS Detector.

This Letter presents results from a combination of searches for Higgs boson pair production using 126-140 fb^{-1} of proton-proton collision data at sqrt[s]=13 TeV recorded with the ATLAS detector. At 95% confidence level (CL), the upper limit on the production rate is 2.9 times the standard model (SM) prediction, with an expected limit of 2.4 assuming no Higgs boson pair production. Constraints on the Higgs boson self-coupling modifier κ_{λ}=λ_{HHH}/λ_{HHH}^{SM}, and the quartic HHVV coupling modifier κ_{2V}=g_{HHVV}/g_{HHVV}^{SM}, are derived individually, fixing the other parameter to its SM value. The observed 95% CL intervals are -1.2<κ_{λ}<7.2 and 0.6<κ_{2V}<1.5, respectively, while the expected intervals are -1.6<κ_{λ}<7.2 and 0.4<κ_{2V}<1.6 in the SM case. Constraints obtained for several interaction parameters within Higgs effective field theory are the strongest to date, offering insights into potential deviations from SM predictions.

Referral to hepatology is lower in patients with excessive alcohol use who have mental health disorders despite a high fibrosis-4 index.

BACKGROUND: Alcohol use disorder (AUD) is a multifaceted disease, and integration of AUD treatment between mental health and hepatology is necessary to improve outcomes. We aimed to ascertain whether patients with excessive alcohol use (EAU) and high FIB-4, which is a non-invasive method to identify advanced liver disease, are appropriately referred to hepatology and detect which clinical barriers, if any, might pertain. METHODS: Records of patients with excessive alcohol use between 2013 and 2023 were extracted from a large public system. Demographics, alcohol-related hospitalizations, mental health conditions, Charlson comorbidity index (CCI) and referral patterns were evaluated. Comparisons were made between those referred to hepatology versus not. RESULTS: 1131 subjects showed evidence of EAU but on further review, 189 were in alcohol-remission. The remaining 942 (636 men, age 55.7 ± 14.5 years, 548 white, 363 black, 19 Hispanic) subjects with CCI 2.61 ± 2.23 were further analyzed for FIB-4 score and referral patterns. 316 patients had active EAU and a high FIB-4, of whom only 116 (37%) were referred to hepatology. Patients with alcohol-related mental health concerns and admitted for trauma were less likely to be referred. Logistic regression showed referral was higher with alcohol-related liver hospitalizations (OR: 9.25, 95% CI: 4.90-17.47, p < 0.001), higher CCI (OR: 6.23, 95% CI: 3.00-12.94, p < 0.0001) and lower with mental health admissions (OR: 0.36, 95% CI: 0.15-0.48, p < 0.001) or mental health diagnoses (OR: 0.36, 95% CI: 0.15-0.82, p = 0.02) and increasing age (OR: 0.95, 95% CI: 0.92-0.97, p < 0.001). CONCLUSIONS: In a large public health system, almost 63% of patients with EAU and FIB-4 >2.67 are not referred to hepatology for evaluation. Patients not referred were more likely to have alcohol-related mental-health hospitalizations and mental health diagnoses, while those with liver-related hospitalizations and comorbidities were more likely to be referred. Greater education of mental health providers and for teams taking care of inpatients admitted with alcohol-related mental health concerns would better integrate care and improve outcomes for patients with higher risk for advanced liver disease.

Deep Brain Stimulation (DBS) in Treatment-Resistant Depression (TRD): Hope and Concern.

In this chapter, we explore the historical evolution, current applications, and future directions of Deep Brain Stimulation (DBS) for Treatment-Resistant Depression (TRD). We begin by highlighting the early efforts of neurologists and neurosurgeons who laid the foundations for today's DBS techniques, moving from controversial lobotomies to the precision of stereotactic surgery. We focus on the advent of DBS, emphasizing its emergence as a significant breakthrough for movement disorders and its extension to psychiatric conditions, including TRD. We provide an overview of the neural networks implicated in depression, detailing the rationale for the choice of common DBS targets. We also cover the technical aspects of DBS, from electrode placement to programming and parameter selection. We then critically review the evidence from clinical trials and open-label studies, acknowledging the mixed outcomes and the challenges posed by placebo effects and trial design. Safety and ethical considerations are also discussed. Finally, we explore innovative directions for DBS research, including the potential of closed-loop systems, dual stimulation strategies, and noninvasive alternatives like ultrasound neuromodulation. In the last section, we outline recommendations for future DBS studies, including the use of alternative designs for placebo control, the collection of neural and behavioral recordings, and the application of machine-learning approaches.

Odontogenic Myxomas Harbor Recurrent Copy Number Alterations and a Distinct Methylation Signature.

Odontogenic myxoma is a rare, benign, and locally aggressive tumor that develops in the tooth-bearing areas of the jaw. The molecular mechanisms underlying odontogenic myxomas are unknown and no diagnostic markers are available to date. The aim of this study was to analyze DNA methylation and copy number variations in odontogenic myxomas to identify new molecular signatures for diagnostic decision-making. We collected a cohort of 16 odontogenic myxomas from 2006 to 2021 located in the mandible (n = 10) and maxilla (n = 6) with available formalin-fixed paraffin-embedded or fresh frozen tumor tissue from a biopsy or resection material. Genome-wide DNA methylation and copy number variation data were generated from 12 odontogenic myxomas using the Illumina Infinium Methylation EPIC array, interrogating >850,000 CpG sites. Unsupervised clustering and dimensionality reduction (Uniform Manifold Approximation and Projection) revealed that odontogenic myxomas formed a distinct DNA methylation class. Copy number profiling showed recurrent whole-chromosome gains (trisomies) of chromosomes 5, 8, and 20 in all cases, and of chromosomes 10, 12, and 17 in all except one case. In conclusion, odontogenic myxomas harbor recurrent copy number patterns and a distinct DNA methylation profile, which can be used as an additional diagnostic tool in the appropriate clinical and radiologic context. Further research is needed to explain the genetic mechanisms caused by these alterations that drive these locally aggressive neoplasms.

8-OxodG: A Potential Biomarker for Chronic Oxidative Stress Induced by High-LET Radiation.

Oxidative stress-mediated biomolecular damage is a characteristic feature of ionizing radiation (IR) injury, leading to genomic instability and chronic health implications. Specifically, a dose- and linear energy transfer (LET)-dependent persistent increase in oxidative DNA damage has been reported in many tissues and biofluids months after IR exposure. Contrary to low-LET photon radiation, high-LET IR exposure is known to cause significantly higher accumulations of DNA damage, even at sublethal doses, compared to low-LET IR. High-LET IR is prevalent in the deep space environment (i.e., beyond Earth's magnetosphere), and its exposure could potentially impair astronauts' health. Therefore, the development of biomarkers to assess and monitor the levels of oxidative DNA damage can aid in the early detection of health risks and would also allow timely intervention. Among the recognized biomarkers of oxidative DNA damage, 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-OxodG) has emerged as a promising candidate, indicative of chronic oxidative stress. It has been reported to exhibit differing levels following equivalent doses of low- and high-LET IR. This review discusses 8-OxodG as a potential biomarker of high-LET radiation-induced chronic stress, with special emphasis on its potential sources, formation, repair mechanisms, and detection methods. Furthermore, this review addresses the pathobiological implications of high-LET IR exposure and its association with 8-OxodG. Understanding the association between high-LET IR exposure-induced chronic oxidative stress, systemic levels of 8-OxodG, and their potential health risks can provide a framework for developing a comprehensive health monitoring biomarker system to safeguard the well-being of astronauts during space missions and optimize long-term health outcomes.

Psychosocial and functional impact of successful digital replantation - A cohort study of 36 patients with a median follow-up of 6 years.

INTRODUCTION: This study aims to evaluate the long-term psychosocial and functional outcomes of successful digital replantation following traumatic amputation. METHODS: Patients that underwent successful replantation (i.e. no secondary amputation following replantation) of one or more traumatically amputated digits between January 2009 and April 2019 were invited to participate in this study. In addition to a custom questionnaire on psychosocial and socioeconomic aspects of life, various Patient-Reported Outcomes Measurement Information System (PROMIS) questionnaires regarding global health, upper extremity function, and depressive symptoms were completed. Bivariate analyses were performed to identify significant associations between outcomes and explanatory variables. RESULTS: Thirty-six patients were successfully enrolled and completed the questionnaires at a median follow-up of 6.1 years. The median PROMIS score for Upper Extremity Function (40.6) was considerably different from the score that is typically found in the general population (all PROMIS instruments are calibrated with a control group score of 50.0), but the median PROMIS scores for Global Health - Physical (49.0), Global Health - Mental (50.7), and Depression (45.6) were comparable to those among the general population. Dominant hand injury, a greater number of injured digits, higher age at the time of injury, and the need for neuropathic pain medication were associated with lower Upper Extremity Function scores (all p < 0.05). Additionally, the presence of neuroma was associated with negative changes in both household finances and mental well-being (p < 0.05). CONCLUSIONS: At long-term follow-up, a majority of patients that underwent replantation of traumatically amputated digits seem to cope well based on psychosocial and functional outcomes. However, neuropathic pain and the presence of neuroma are strong negative factors. Specific attention to digital nerves at the time of surgery is crucial in the management of traumatic amputations.

LacdiNAc to LacNAc: remodelling of bovine α-lactalbumin N-glycosylation during the transition from colostrum to mature milk.

α -Lactalbumin, an abundant protein present in the milk of most mammals, is associated with biological, nutritional and technological functionality. Its sequence presents N-glycosylation motifs, the occupancy of which is species-specific, ranging from no to full occupancy. Here, we investigated the N-glycosylation of bovine α-lactalbumin in colostrum and milk sampled from four individual cows, each at 9 time points starting from the day of calving up to 28.0 d post-partum. Using a glycopeptide-centric mass spectrometry-based glycoproteomics approach, we identified N-glycosylation at both Asn residues found in the canonical Asn-Xxx-Ser/Thr motif, i.e. Asn45 and Asn74 of the secreted protein. We found similar glycan profiles in all four cows, with partial site occupancies, averaging at 35% and 4% for Asn45 and Asn74, respectively. No substantial changes in occupancy occurred over lactation at either site. Fucosylation, sialylation, primarily with N-acetylneuraminic acid (Neu5Ac), and a high ratio of N,N'-diacetyllactosamine (LacdiNAc)/N-acetyllactosamine (LacNAc) motifs were characteristic features of the identified N-glycans. While no substantial changes occurred in site occupancy at either site during lactation, the glycoproteoform (i.e. glycosylated form of the protein) profile revealed dynamic changes; the maturation of the α-lactalbumin glycoproteoform repertoire from colostrum to mature milk was marked by substantial increases in neutral glycans and the number of LacNAc motifs per glycan, at the expense of LacdiNAc motifs. While the implications of α-lactalbumin N-glycosylation on functionality are still unclear, we speculate that N-glycosylation at Asn74 results in a structurally and functionally different protein, due to competition with the formation of its two intra-molecular disulphide bridges.

Impact of Partial Body Shielding from Very High Dose Rates on Untargeted Metabolomics in Biodosimetry.

A realistic exposure to ionizing radiation (IR) from an improvised nuclear device will likely include individuals who are partially shielded from the initial blast delivered at a very high dose rate (VHDR). As different tissues have varying levels of radiosensitivity, e.g., hematopoietic vs gastrointestinal tissues, the effects of shielding on radiation biomarkers need to be addressed. Here, we explore how biofluid (urine and serum) metabolite signatures from male and female C57BL/6 mice exposed to VHDR (5-10 Gy/s) total body irradiation (TBI, 0, 4, and 8 Gy) compare to individuals exposed to partial body irradiation (PBI) (lower body irradiated [LBI] or upper body irradiated [UBI] at an 8 Gy dose) using a data-independent acquisition untargeted metabolomics approach. Although sex differences were observed in the spatial groupings of urine signatures from TBI and PBI mice, a metabolite signature (N6,N6,N6-trimethyllysine, carnitine, propionylcarnitine, hexosamine-valine-isoleucine, taurine, and creatine) previously developed from variable dose rate experiments was able to identify individuals with high sensitivity and specificity, irrespective of radiation shielding. A panel of serum metabolites composed from previous untargeted studies on nonhuman primates had excellent performance for separating irradiated cohorts; however, a multiomic approach to complement the metabolome could increase dose estimation confidence intervals. Overall, these results support the inclusion of small-molecule markers in biodosimetry assays without substantial interference from the upper or lower body shielding.

Pembrolizumab plus enzalutamide for metastatic castration-resistant prostate cancer progressing on enzalutamide: cohorts 4 and 5 of the phase 2 KEYNOTE-199 study.

BACKGROUND: KEYNOTE-199 (NCT02787005) is a multicohort phase 2 study evaluating pembrolizumab in patients with metastatic castration-resistant prostate cancer (mCRPC). Results from cohorts 4 (C4) and 5 (C5) are presented. METHODS: Eligible patients had not received chemotherapy for mCRPC and had responded to enzalutamide prior to developing resistance as defined by Prostate Cancer Clinical Trials Working Group 3 guidelines. Patients with RECIST-measurable disease were enrolled in C4, and patients with bone-only or bone-predominant disease were enrolled in C5. All patients received pembrolizumab 200 mg every 3 weeks for ≤35 cycles with ongoing enzalutamide until progression, unacceptable toxicity, or withdrawal. The primary end point was objective response rate (ORR) per RECIST v1.1 by blinded independent central review in C4. Secondary end points included disease control rate (DCR), overall survival, and safety in each cohort and both cohorts combined. RESULTS: A total of 126 patients were treated (C4, n = 81; C5, n = 45). Median age was 72 years (range 43-92), and 87.3% had received ≥6 months of enzalutamide prior to study entry. Confirmed ORR was 12.3% (95% CI 6.1-21.5%) for C4. Median duration of response in C4 was 8.1 months (range, 2.5+ to 15.2), and 5 of these patients experienced an objective response lasting ≥6 months. DCR was 53.1% (95% CI 41.7-64.3%) in C4 and 51.1% (95% CI 35.8-66.3%) in C5. Median overall survival was 17.6 months (95% CI 14.0-22.6) in C4 and 20.8 months (95% CI 14.1-28.9) in C5. Grade ≥3 treatment-related adverse events occurred in 35 patients (27.8%); 2 patients in C4 died from immune-related adverse events (myasthenic syndrome and Guillain-Barré syndrome). CONCLUSIONS: The addition of pembrolizumab to ongoing enzalutamide treatment in patients with mCRPC that progressed on enzalutamide after initial response demonstrated modest antitumor activity with a manageable safety profile. CLINICAL TRIAL REGISTRY AND ID: ClinicalTrials.gov, NCT02787005.

Probing recombinant AAV capsid integrity and genome release after thermal stress by mass photometry.

Adeno-associated viruses (AAVs) are gaining traction as delivery vehicles for gene therapy although the molecular understanding of AAV-transgene release is still limited. Typically, the process of viral uncoating is investigated (in vitro) through thermal stress, revealing capsid disintegration at elevated temperatures. To assess the (in)stability of different empty and filled AAV preparations, we used the light-scattering-based interferometric microscopy technique of mass photometry that, on a single-particle basis, determines the molecular weight of AAVs. By introducing a heat-stable DNA plasmid as an internal standard, we quantitatively probed the impact of heat on AAVs. Generally, empty AAVs exhibited greater heat resistance than genome-filled particles. Our data also indicate that upon DNA release, the capsids do not transform into empty AAVs, but seem to aggregate or disintegrate. Strikingly, some AAVs exhibited an intermediate state with disrupted capsids but preserved bound genome, a feature that experimentally only emerged following incubation with a nuclease. Our data demonstrate that the thermal uncoating process is highly AAV specific (i.e., can be influenced by serotype, genome, host system). We argue that nuclease treatment in combination with MP can be used as an additional analytical tool for assessing structural integrity of recombinant and/or clinical AAV vectors.

Rasmussen's encephalitis: structural, functional, and clinical correlates of contralesional epileptiform activity.

Progressive inflammation of one hemisphere characterises Rasmussen's encephalitis (RE), but contralesional epileptiform activity has been repeatedly reported. We aimed to quantify contralesional epileptiform activity in RE and uncover its functional and structural underpinnings. We retrospectively ascertained people with RE treated between 2000 and 2018 at a tertiary centre (Centre 1) and reviewed all available EEG datasets. The temporal occurrence of preoperative contralesional epileptiform activity (interictal/ictal) was evaluated using mixed-effects logistic regression. Cases with/without contralesional epileptiform activity were compared for cognition, inflammation (ipsilesional brain biopsies), and MRI (cortical and fixel-based morphometry). EEG findings were validated in a second cohort treated at another tertiary centre (Centre 2) between 1995 and 2020. We included 127 people with RE and 687 EEG samples. Preoperatively, contralesional epileptiform activity was seen in 30/68 (44%, Centre 1) and 8/59 (14%, Centre 2). In both cohorts, this activity was associated with younger onset age (OR = 0.9; 95% CI 0.83-0.97; P = 0.006). At centre 1, contralesional epileptiform activity was associated with contralesional MRI alterations, lower intelligence (OR = 5.19; 95% CI 1.28-21.08; P = 0.021), and impaired verbal memory (OR = 10.29; 95% CI 1.97-53.85; P = 0.006). After hemispherotomy, 11/17 (65%, Centre 1) and 28/37 (76%, Centre 2) were seizure-free. Contralesional epileptiform activity was persistent postoperatively in 6/12 (50%, Centre 1) and 2/34 (6%, Centre 2). Preoperative contralesional epileptiform activity reduced the chance of postoperative seizure freedom in both cohorts (OR = 0.69; 95% CI 0.50-0.95; P = 0.029). Our findings question the concept of strict unilaterality of RE and provide the evidence of contralesional epileptiform activity as a possible EEG predictor for persisting postoperative seizures.

Statistical Combination of ATLAS Run 2 Searches for Charginos and Neutralinos at the LHC.

Statistical combinations of searches for charginos and neutralinos using various decay channels are performed using 139 fb^{-1} of pp collision data at sqrt[s]=13 TeV with the ATLAS detector at the Large Hadron Collider. Searches targeting pure-wino chargino pair production, pure-wino chargino-neutralino production, or Higgsino production decaying via standard model W, Z, or h bosons are combined to extend the mass reach to the produced supersymmetric particles by 30-100 GeV. The depth of the sensitivity of the original searches is also improved by the combinations, lowering the 95% C.L. cross-section upper limits by 15%-40%.