Citations

Ultrafast oscillations (UFOs) are brief bursts of high-frequency (2–8 kHz) activity recorded using depth electrodes in epileptic brain tissue. While reliably detected at small scales using microelectrodes, UFOs have thus far likely not been observed at larger scales using macroelectrodes. Here we show that faint echoes of these bursting patterns can be detected in macroelectrode signals using a model of cross-scale propagation. To model this cross-scale effect, we extend the classical damped wave equation to include an explicit scale coordinate governed by the dilation operator. We then use Green's functions to obtain an expression for the spectral echo expected at the macroelectrode scale. This echo takes the form of a carrier envelope modulated by the temporal structure of the original microscale bursting event. We test the predicted signature echo pattern in human intracranial recordings from eleven epilepsy patients implanted with both micro- and macroelectrodes. Statistically significant echoes are confirmed in two out of eleven patients, appearing in 2% of all tested micro-macro pairs.

Abstract Deep mutational scanning (DMS) has proven effective for mapping protein–protein interactions (PPIs), but it cannot provide complete coverage of the mutation landscape, particularly for multi‐mutant variants. To address this limitation, we trained machine‐learning (ML) models on previously generated DMS data for a stabilized amyloid precursor protein inhibitor (APPI) binding to either of two serine proteases, mesotrypsin and kallikrein‐6 (KLK6), which are implicated in various human disorders. We combined the models to accurately predict the binding selectivity of APPI variants, including double‐mutant variants, for the two serine proteases. We achieved a Pearson correlation of 0.937 between predicted log 2 selectivity enrichment ratios and DMS‐derived values. We further validated the predictions of our combined model by yeast‐surface‐display measurements and inhibition assays of purified APPI variants and revealed epistatic interactions that shape protease selectivity. Guided by binding selectivity predictions, we identified highly selective APPI variants, including the most selective mesotrypsin inhibitor reported to date. Together, these findings support the use of DMS and ML as a framework for predicting PPI selectivity and prioritizing selective therapeutic protein variants.

Purpose: To describe the refractive results of cataract surgery in patients with high corneal astigmatism treated with implantation of custom-made toric intraocular lenses (IOLs). Methods: This retrospective cohort analysis of eyes implanted with high-cylinder (≥6.75 diopters [D]) custom-made toric IOLs was conducted at Rabin Medical Center, Petach Tikva, Israel. A control group of eyes implanted with standard toric IOLs (1.50 to 3.75 D) was also included. Postoperative IOL misalignment, uncorrected distance visual acuity (UDVA), residual refractive astigmatism (RA), and the prediction error (PE) of the toric IOL calculation using the Barrett Toric Calculator were assessed. Results: Twenty-two eyes of 22 patients were included. The mean ± standard deviation toric power was 9.67 ± 3.51 D (range: 6.75 to 19.00 D). Diagnoses included pellucid marginal degeneration (n = 7), keratoconus (n = 4), post-keratoplasty astigmatism (n = 3), and previous pterygium excision (n = 2). The mean postoperative UDVA was 0.28 ± 0.19 logarithm of the minimum angle of resolution (Snellen: 20/38). Mean absolute astigmatism decreased from 7.88 ± 3.15 D preoperatively (corneal) to 0.76 ± 0.87 D postoperatively (refractive) ( P < .001). One eye required redialing due to a 17° misalignment. Compared with the control group (41 eyes), the high-cylinder toric IOL group showed a slightly lower UDVA (20/30, P = .024) and a non-significant trend toward higher RA (0.58 ± 0.50, P = .930), as well as a significantly worse RA-PE, in both vector magnitude (1.47 vs. 0.62, P = .027) and vector dispersion (total bivariate variance 2.67 vs 0.40, px < 0.001 and py = 0.006). Conclusions: Customized high-cylinder toric IOLs significantly improve UDVA and reduce RA in eyes with extreme corneal astigmatism. Although slightly inferior to standard toric IOLs, they provide an effective treatment option for astigmatic correction in complex corneal pathologies with a central and relatively regular astigmatic component.

Summary Human spaceflight has historically been led by government agencies, but the emergence of commercial organizations is enabling broader participation and new research opportunities. In this study, we present a comprehensive molecular characterization of early human responses to spaceflight, leveraging multi-omics data across the first three weeks of two commercial missions. Biospecimens from six individuals, four from the Axiom 2 mission (10 days) and two from Axiom 3 (21 days), were analyzed using single-cell and bulk RNA sequencing, alongside proteomic profiling. Individual and integrative analyses of these datasets reveal systemic changes in cell types, transcripts, and proteins related to immune regulation, osteoclast differentiation, NF-κB signaling, and blood homeostasis pathways. Importantly, several of the detected pathways align with physiological patterns observed in longer-duration missions. This work establishes a foundational resource for understanding early adaptation to spaceflight at the cellular and molecular levels, providing insights to reduce future space-travel health risks. Highlights First integrated multi-omics analysis using single-cell, bulk RNA sequencing and proteomic profiling of early human spaceflight responses across two commercial missions (Ax-2 and Ax-3). Distinct PBMC clustering was observed across Ax-2 and Ax-3, and post-flight samples. It showed fewer monocytes, dendritic cells, and megakaryocytes with increased naïve CD4⁺ and cytotoxic T cells. Multi-omics integration identifies shared biological signatures, including osteoclast differentiation, metabolic stress, and coagulation changes. These findings lay the foundation for developing countermeasures to protect immune, skeletal, and vascular health during spaceflight.

Background Delirium is a frequent and serious complication in critically ill patients and associated with adverse outcomes. Automated pupillometry has emerged as a potential diagnostic tool for the detection of delirium. However, pupillometric parameters are also influenced by pain, potentially confounding their relationship to delirium. The aim of this study was to evaluate the association between automated pupillometry parameters and delirium in patients with high risk of pain (surgical patients) admitted to intensive care units (ICU). Methods This prospective multicenter observational study included adult surgical patients admitted to an ICU between April 2023 and August 2025. Delirium was assessed every 6 h after admission using CAM-ICU. Automated pupillometry together with pain intensity scores (VAS, CPOT, BPS) were performed concurrent with CAM-ICU. To account for repeated measurements within individual patients, a generalized linear mixed-effects model (GLMM) with patient as a random effect was used to evaluate the association between pupillometric parameters and diagnosed delirium. Results Forty-nine patients were included, yielding 417 measurements, of which 48 (12%) were done in patients who were simultaneously CAM-ICU positive. Among pupillometric variables, only average pupillary latency (LAT avg) was significantly shorter in patients with delirium ( p = 0.01). In the mixed-effects model adjusted for sedation depth, level of consciousness, and pain intensity, LAT avg. was independently associated with delirium (OR 1.55 per 0.01; 95% CI 1.13–2.13; p = 0.007). Conclusion In surgical ICU patients, shortened pupillary light reflex latency is associated with delirium. Automated pupillometry may serve as a useful tool for detection of delirium in this population. Clinical trial registration https://clinicaltrials.gov/study/ Identifier: NCT05811208.

7011 Background: Up to 40% of pts with diffuse large B-cell lymphoma (DLBCL) will relapse or have refractory disease following 1L treatment (Tx) with SOC chemoimmunotherapy regimens R-CHOP or Pola-RCHP. High risk (HR) populations include those with International Prognostic Index (IPI) score 3–5 and IPI 1–2 with either ≥1 lesion ≥7 cm or baseline LDH >1.3×ULN. GOLCA is a potential, first-in-class, oral CELMoD designed for the Tx of lymphoma, with preferential distribution to lymphoid organs and enhanced activity in lymphoma cell lines. GOLCA induces rapid and deep degradation of Ikaros and Aiolos, leading to direct cell killing and immunomodulatory activity. GOLCA 0.4 mg + R-CHOP has shown promising safety, a ≥90% minimal residual disease (MRD) negativity rate, and durable efficacy (24-mo PFS, 79%) in 1L a-BCL (Nowakowski et al, ASH 2025, 476) and is being evaluated in the Phase (Ph) 3 study GOLSEEK-1 (NCT06356129). We report initial Ph1b results with GOLCA + Pola-RCHP in 1L a-BCL. Methods: Pts aged ≥18 y with ECOG PS ≤2, IPI 0–5 (Part 2A) or 2–5 (Part 2B), and newly diagnosed a-BCL with measurable tumorous disease were included. Pts were treated with GOLCA + Pola-RCHP for six 21-day (D) cycles or until disease progression/unacceptable toxicity/study withdrawal. In dose escalation, GOLCA was dosed at 0.2 and 0.4 mg D1–7. In dose expansion, pts were randomized 1:1 to Pola-RCHP + GOLCA 0.2 or 0.4 mg. Primary endpoint: safety; efficacy was a secondary endpoint. Results: At data cutoff, 57 pts were treated with GOLCA + Pola-RCHP (0.2 mg, n=28; 0.4 mg, n=29). Median age was 63 y. Most pts had HR disease (86%) and DLBCL not otherwise specified histology (84%). For known cell of origin (COO), 47% were germinal center B cell (GCB) and 39% non-GCB by Hans algorithm. Forty-seven pts (83%) completed Tx and 52 (91%) entered the follow-up (f/u) period. Grade 3/4 Tx-emergent adverse events occurred in 95% of pts, most frequently neutropenia (86%; an on-target side effect of GOLCA) and anemia (39%). Median relative dose intensity for GOLCA and Pola-RCHP components was >95%. At 15.5 mo median f/u, end of Tx (EOT) complete metabolic response (CMR) rate was 69% at 0.2 mg, 82% at 0.4 mg, and similar across COO subtypes. EOT CMR was consistent in HR pts (65% at 0.2 mg, 83% at 0.4 mg). The 12-mo DOR and PFS rates were 92% and 88% at 0.2 mg, and 96% and 96% at 0.4 mg. In pts with both pre-Tx and EOT ctDNA analysis, 65% and 83% at 0.2 and 0.4 mg achieved MRD negativity (PhasED-Seq) at EOT. Conclusions: GOLCA + Pola-RCHP demonstrated a predictable and manageable safety profile, and addition of GOLCA did not compromise median dose intensity of Pola-RCHP. GOLCA 0.4 mg + Pola-RCHP resulted in a high rate of durable CMRs, high rate of MRD negativity, and a promising 12-mo PFS rate. These data continue to show that GOLCA + SOC regimens R-CHOP and Pola-RCHP has potential to improve outcomes in 1L HR a-BCL. Clinical trial information: NCT04884035 .

Introduction Studies have revealed circadian rhythms affect many organ systems and time of injury can impact healing, lung function, and inflammation. We hypothesized operative time may impact post-operative risk. Accordingly, the aim of this study was to compare post-operative complications in patients whose surgery started and finished before 12pm (Group 1); after 12pm (Group 2); and started before 12pm and finished after 12pm (Group 3). Methods Patients from two previous prospective studies were included in this post-hoc analysis. Inclusion criteria were indication for lung resection surgery (confirmed or highly suspicious tumor), age ≥18 and ability to undergo cardiopulmonary exercise testing (CPET). Exclusion criterion was inability to perform surgery (either low predicted postoperative oxygen consumption or inoperability). All patients underwent pre-operative CPET and spirometry. Post-operative pulmonary (PPC) and cardiovascular complications (PCC) were prospectively assessed from the hospital stay up to 30 days. Results Data from 497 patients were analyzed. On comparison of groups, there were differences in BMI (highest in Group 3), surgery duration (lowest in Group 1) and frequency of lobectomies (lowest in Group 1). Incidence of PPC was lowest in Group 1 (n=17; 9%) compared to n=17 (21%) in Group 2 and n=37 (17%) in Group 3 (p=0.01). Incidence of PCC was lowest in Group 1 n=25 (13%) compared to n=19 (23%) in Group 2 and n=46 (21%) in Group 3 (p=0.05). Multivariate logistic regression adjusted for confounders (BMI, surgery duration and lobectomy) showed time of surgery after 12pm was independently associated with PPC with OR = 2.17 (95% CI 1.07-4.41); p=0.03. Conclusion Time of surgery may impact the incidence of PPC in lung resection surgery patients with highest risk in patients undergoing the surgery after 12pm.

ABSTRACT Multistate models offer a powerful framework for studying disease processes and can be used to formulate intensity‐based and more descriptive marginal regression models. They also represent a natural foundation for the construction of joint models for disease processes and dynamic marker processes, as well as joint models incorporating random censoring and intermittent observation times. This article reviews the ways multistate models can be formed and fitted to life history data. Recent work on pseudo‐values and the incorporation of random effects to model dependence on the process history and between‐process heterogeneity are also discussed. The software available to facilitate such analyses is listed.

Abstract Background Fibroblast growth factor receptors inhibitors (FGFRi) are approved treatments for various malignancies. FGFRi-associated retinopathy is a class effect of FGFRi, including erdafitinib, pemigatinib, infigratinib, and rogaratinib. Patients and Methods We summarized FGFRi-associated retinopathy with erdafitinib across 5 clinical studies in patients with metastatic urothelial cancer (mUC pooled studies) and one study in patients with advanced solid tumors (RAGNAR). We also present changes in visual acuity, retinal pigment epithelial elevation, and subretinal fluid in RAGNAR. Results One hundred and three (21.5%) of 479 patients in the mUC pooled studies and 43/314 (13.7%) patients in RAGNAR experienced FGFRi-associated retinopathy. Most FGFRi-associated retinopathy were Grade 1/2 events. Grade 3 FGFRi-associated retinopathy were infrequent (mUC pooled studies, 11/479 [2.3%]; RAGNAR, 3/314 [1.0%]). No Grade 4 events occurred. Most FGFRi-associated retinopathy events (mUC pooled studies, 81/103 [78.6%]; RAGNAR, 30/43 [70.0%]) occurred within 90 days of treatment initiation and were managed with erdafitinib dose interruption (mUC pooled studies, 41/479 [8.6%]; RAGNAR, 23/314 [7.3%]) or reduction (mUC pooled studies, 58/479 [12.1%]; RAGNAR, 21/314 [6.7%]); few required treatment discontinuation (mUC pooled studies, 14/479 [2.9%]; RAGNAR, 3/314 [1.0%]). By the data cutoff, 63.1% (65/103) patients in the mUC pooled studies and 65.1% (28/43) patients in RAGNAR had their FGFRi-associated retinopathy events resolve. Most unresolved FGFRi-associated retinopathy events were persistent Grade 1 events. In RAGNAR, 92.0% of patients had their visual acuity return to baseline and 78.5% of patients had their retinal pigment epithelial elevation resolve. Conclusions FGFRi-associated retinopathy with erdafitinib can be managed with dose reductions, interruptions, or discontinuations. Proactive collaboration between oncologists and ophthalmologists is required to ensure that erdafitinib delivers clinical benefit to patients while managing their potential adverse symptoms of FGFRi-associated retinopathy.