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The goal of cystic fibrosis transmembrane conductance regulator (CFTR) modulators is to reach normal CFTR function in people with cystic fibrosis. Vanzacaftor–tezacaftor–deutivacaftor restored CFTR function in vitro and in phase 2 trials in participants aged 18 years and older resulting in improvements in CFTR function, as measured by sweat chloride concentrations and lung function as measured by spirometry. We aimed to evaluate the efficacy and safety of vanzacaftor–tezacaftor–deutivacaftor compared with standard of care elexacaftor–tezacaftor–ivacaftor in individuals with cystic fibrosis aged 12 years and older. more...

Long-term risks of gene therapy are not fully understood. In this study, we evaluated safety outcomes in 783 patients over more than 2,200 total patient-years of observation from 38 T cell therapy trials. The trials employed integrating gammaretroviral or lentiviral vectors to deliver engineered receptors to target HIV-1 infection or cancer. Eighteen patients (2.3%) developed secondary malignancies after treatment, with a median onset of 1.94 years (range: 51 d to 14 years). Where possible, incident tumor samples were analyzed for vector copy number, revealing no evidence of high-level marking or other indications of insertional mutagenesis. One T cell lymphoma was detected, but malignant T cells were not marked by vector integration. Analysis of vector integration sites in 176 patients revealed no pathological insertions linked to secondary malignancies, although, in some cases, integration in or near specific genes, including tumor suppressor genes, was associated with modest clonal expansion and sustained T cell persistence. These findings highlight the safety of engineered T cell therapies. more...

We consider the problem of dynamic channel allocation (DCA) in cognitive communication networks with the goal of maximizing a global signal-to-interference-plus-noise ratio (SINR) measure under a specified target quality of service (QoS)-SINR for each network. The shared bandwidth is partitioned into K channels with frequency separation. In contrast to the majority of existing studies that assume perfect orthogonality or a one-to-one user-channel allocation mapping, this paper focuses on practical systems experiencing inter-carrier interference (ICI) and channel reuse by multiple large-scale networks. This realistic scenario significantly increases the problem dimension, rendering existing algorithms inefficient. We propose a novel multi-agent reinforcement learning (RL) framework for distributed DCA, named Channel Allocation RL To Overlapped Networks (CARLTON). The CARLTON framework is based on the Centralized Training with Decentralized Execution (CTDE) paradigm, utilizing the DeepMellow value-based RL algorithm. To ensure robust performance in the interference-laden environment we address, CARLTON employs a low-dimensional representation of observations, generating a QoS-type measure while maximizing a global SINR measure and ensuring the target QoS-SINR for each network. Our results demonstrate exceptional performance and robust generalization, showcasing superior efficiency compared to alternative state-of-the-art methods, while achieving a marginally diminished performance relative to a fully centralized approach. more...

The protein homeostasis (proteostasis) network encompasses a myriad of mechanisms that maintain the integrity of the proteome by controlling various biological functions, including protein folding and degradation. Alas, ageing-associated decline in the efficiency of this network enables protein aggregation and consequently the development of late-onset neurodegenerative disorders, such as Alzheimer’s disease. Accordingly, the maintenance of proteostasis through late stages of life bears the promise to delay the emergence of these devastating diseases. Yet the identification of proteostasis regulators is needed to assess the feasibility of this approach. Here we report that knocking down the activity of the nucleolar FIB-1–NOL-56 complex protects model nematodes from proteotoxicity of the Alzheimer’s disease-causing amyloid-β peptide and of abnormally long poly-glutamine stretches. This mechanism promotes proteostasis across tissues by modulating the activity of TGFβ signalling and by enhancing proteasome activity. Our findings point at research avenues towards the development of proteostasis-promoting therapies for neurodegenerative maladies. more...

AbstractInterviews with 22 home-based primary care (HBPC) clinicians revealed that infectious disease physicians and clinical pharmacists facilitate infection management and antibiotic selection, respectively, and that local initiatives within programs support antibiotic prescribing decisions. Interventions that facilitate specialist engagement and tailored approaches that address the unique challenges of HBPC are needed. more...

•B-cell maturation antigen–directed CAR-T therapy in patients with MM and CNS involvement is feasible without excess neurotoxicity.•Data support CNS myeloma screening, optimized bridging, and CNS-targeted treatment before CAR-T therapy in high-risk patients. more...

•Patients with FL experiencing POD24 with retained follicular histology have a short median EFS of 9.8 months and 5-year OS of 71%.•After POD24, cause of death in patients with FL is predominantly due to lymphoma despite infrequent subsequent transformation events. more...

In recent years, the large electric field enhancement and tight spatial confinement supported by the so-called epsilon near-zero (ENZ) mode has attracted significant attention for the realization of efficient nonlinear optical devices. Here, we experimentally demonstrate ENZ photonic gap antennas (PGAs), which consist of a dielectric pillar within which a thin slab of indium tin oxide (ITO) material is embedded. In ENZ PGAs, hybrid dielectric-ENZ modes emerge from strong coupling between the dielectric antenna modes and the ENZ bulk plasmon resonance. These hybrid modes efficiently couple to free space and allow for large enhancements of the incident electric field over nearly an octave bandwidth, without the stringent lateral nanofabrication requirements of conventional plasmonic or dielectric nanoantennas. To understand the modal features, we probe the linear response of single ENZ PGAs with dark field scattering and interpret the results in terms of a simple coupled oscillator framework. Third harmonic generation (THG) is used to probe the ITO local fields and large enhancements are observed in the THG efficiency over a broad spectral range. Surprisingly, sharp peaks emerge on top of the nonlinear response, which were not predicted by full wave calculations. These peaks are attributed to the ENZ material’s nonlocal response, which once included using a hydrodynamic model for the ITO permittivity improves the agreement of our calculations for both the linear and nonlinear response. This proof of concept demonstrates the potential of ENZ PGAs, which we have previously shown can support electric field enhancements of up to 100–200×, and the importance of including nonlocal effects when describing the response of thin ENZ layers. Importantly, inclusion of the ITO nonlocality leads to increases in the predicted field enhancement, as compared to the local calculation. more...

ABSTRACTIntroductionThe history of treating chronic lymphocytic leukemia (CLL) inflected in 2014 with the Food and Drug Administration’s (FDA) approval of ibrutinib, the first-in-class small molecule inhibitor of the Bruton’s tyrosine kinase (BTK). Zanubrutinib is a 2ndgeneration covalent BTK inhibitor developed and manufactured by BeiGene.Areas coveredIn this review, the authors trace the arc of zanubrutinib development from the preclinical phase through the two landmark phase 3 studies in the CLL space, ALPINE and SEQUOIA. The authors cover contemporary management strategies in CLL and highlight the areas of need that zanubrutinib was designed to mitigate.Expert opinionZanubrutinib entered a fray of novel, exciting therapies for CLL. As the second of two 2ndgeneration covalent BTK inhibitors its path to prominence in CLL management was narrow. Emphasis during development on kinase selectivity and enhanced bioavailability identified a molecule with superior efficacy and tolerability; hierarchical endpoints in trial design allowed for efficient acquisition of comparative data. Zanubrutinib is endorsed by the National Comprehensive Cancer Network as a preferred, category 1 recommended treatment choice for CLL. Future efforts in combination therapies and response-directed treatment breaks will hopefully lead to still further improvements in use. more...

Objective: To determine whether screening for social determinants of health (SDoH) in a level IV neonatal intensive care unit (NICU) could uncover additional family needs. Methods: Secondary analysis of a prospective study in a level IV NICU. Participants filled out the Protocol for Responding to and Assessing Patients’ Assets, Risks and Experiences (PRAPARE) tool, which includes economic, housing, transportation, and safety questions. Questionnaires were completed via secure tablet; the research team notified social workers of reported needs. Illness and demographic characteristics were compared between families who did and did not report resource needs. Manual chart review assessed subsequent response to reported SDoH needs. Results: Of 319 respondents, 61(19%) reported resource needs. Of 61 families, 88% received repeat social work encounters to re-assess for resources; 59% received new resource referrals. Conclusions: Systematic SDoH screening can identify needs throughout the NICU stay, even among families already connected to social work support. more...

We examined the acute effects of intranasal insulin on cognitive function and brain glutathione (GSH), a central factor in resistance to oxidative stress, in both participants with early psychosis and healthy control (HC) participants. more...

Autologous haematopoietic stem cell transplantation (AHSCT) is a treatment option for relapsing forms of multiple sclerosis (MS) that are refractory to disease-modifying therapy (DMT). AHSCT after failure of high-efficacy DMT in aggressive forms of relapsing–remitting MS is a generally accepted indication, yet the optimal placement of this approach in the treatment sequence is not universally agreed upon. Uncertainties also remain with respect to other indications, such as in rapidly evolving, severe, treatment-naive MS, progressive MS, and neuromyelitis optica spectrum disorder (NMOSD). Furthermore, treatment and monitoring protocols, rehabilitation and other supportive care before and after AHSCT need to be optimized. To address these issues, we convened a European Committee for Treatment and Research in Multiple Sclerosis Focused Workshop in partnership with the European Society for Blood and Marrow Transplantation Autoimmune Diseases Working Party, in which evidence and key questions were presented and discussed by experts in these diseases and in AHSCT. Based on the workshop output and subsequent written interactions, this Consensus Statement provides practical guidance and recommendations on the use of AHSCT in MS and NMOSD. Recommendations are based on the available evidence, or on consensus when evidence was insufficient. We summarize the key evidence, report the final recommendations, and identify areas for further research. more...

T-cell redirecting therapy (TCRT), specifically chimeric antigen receptor T-cell therapy (CAR T-cells) and bispecific T-cell engagers (TCEs) represent a remarkable advance in the treatment of multiple myeloma (MM). There are several products available around the world and several more in development targeting primarily B-cell maturation antigen (BCMA) and G protein–coupled receptor class C group 5 member D (GRPC5D). The relatively rapid availability of multiple immunotherapies brings the necessity to understand how a certain agent may affect the safety and efficacy of a subsequent immunotherapy so MM physicians and patients can aim at optimal sequential use of these therapies. The International Myeloma Working Group conveyed panel of experts to review patient and disease-related factors affecting efficacy and safety of immunotherapy, summarize existing information on sequencing therapy and provide a series of core recommendations. more...

IMPORTANCE: Increasing rates of sexually transmitted infections (STIs) have been associated with rises in serious morbidity. While doxycycline postexposure prophylaxis (doxyPEP), a strategy in which individuals take doxycycline, 200 mg, after condomless sex to prevent bacterial STIs, has been shown to be efficacious in randomized clinical trials, doxyPEP’s potential effect on population-level STI incidence is unknown. OBJECTIVE: To assess the association of citywide doxyPEP guideline release with reported chlamydia, gonorrhea, and early syphilis cases in men who have sex with men (MSM) and in transgender women in San Francisco, California. DESIGN, SETTING, AND PARTICIPANTS: This population-level interrupted time series analysis of reported San Francisco STI cases measured monthly cases of chlamydia, gonorrhea, and early syphilis prior to (July 2021-October 2022) and after (November 2022-November 2023) release of citywide doxyPEP guidelines in October 2022. All reported chlamydia, gonorrhea, and early syphilis cases among MSM and transgender women in San Francisco during the period of analysis were included. Data were analyzed November 2023 to July 2024. EXPOSURE: Release of doxyPEP citywide guidelines. MAIN OUTCOMES AND MEASURES: The primary outcome was the percentage change between projected and observed chlamydia, gonorrhea, and early syphilis cases in the 13-month postexposure period. RESULTS: Citywide, there were 6694 cases of chlamydia, 9603 cases of gonorrhea, and 2121 cases of early syphilis among MSM and transgender women during the analytic period. STI cases among MSM and transgender women decreased significantly compared with model projections for chlamydia (−6.58% per month; 95% CI, −7.99% to −5.16%) and early syphilis (−2.68% per month; 95% CI, −3.75% to −1.60%) after doxyPEP implementation. By the end of the 13-month postperiod in November 2023, chlamydia and early syphilis cases decreased −49.64% (95% CI, −59.05% to −38.06%) and −51.39% (95% CI, −58.21% to −43.46%), respectively, compared with projected cases. There was a significant increase in monthly gonorrhea cases compared with projections (1.77% per month; 95% CI, 0.87% to 2.67%). CONCLUSIONS AND RELEVANCE: This study suggests that San Francisco’s doxyPEP guideline release was associated with decreases in reported cases of chlamydia and early syphilis, but not gonorrhea, among MSM and transgender women in San Francisco. Further analyses are needed to assess whether declines are sustained and monitor for adverse consequences, including antimicrobial resistance. Supporting doxyPEP implementation for MSM and transgender women at risk for STIs could have a significant impact on the nationwide STI epidemic. more...

A 39 year-old female with a history of Roux-en-Y gastric bypass underwent emergent partial colectomy. Her postoperative analgesic management of a transversus abdominus plane block administered with a combination of bupivacaine and liposomal bupivacaine was ineffective. A bupivacaine thoracic epidural was then placed, which provided significant pain relief. This use of a bupivacaine thoracic epidural infusion following liposomal bupivacaine regional anesthesia demonstrated a case of effective analgesia without the development of local anesthetic systemic toxicity symptoms in a remote hospital setting, where certain laboratory analyses were not readily available. more...

Urinary collection over 24 h is a cornerstone in the care of patients with nephrolithiasis, obesity, hypertension, and chronic kidney disease (CKD). The completeness of 24-h urinary collection is assessed by urinary creatinine excretion, which reflects the muscle mass. Hence, it is of paramount importance to define expected values of daily urinary creatinine excretion to correctly interpret urinary collection. These references are available for the general population. We hypothesized that these reference values might not be applicable to individuals with obesity whose body composition is different from general population. more...

Understanding gene–environment interactions associated with vitamin D status may refine nutrition and public health strategies for vitamin D deficiency. Recent methodological advances have enabled the identification of variance quantitative trait loci (vQTLs) where gene–environment interactions are enriched. more...

Global harmonization of biosimilar developmental requirements will facilitate development leading to increased patient and societal benefits. However, there are several technical and regulatory hurdles that must be addressed to harmonize the regulatory requirements in different countries and regions. At times, there is a requirement for use of locally sourced reference product, forcing biosimilar developers to repeat analytical or clinical comparability studies against reference product batches sourced from within a given country. While most health authorities no longer require comparative animal toxicology studies of the proposed biosimilar and reference product, these are still required in several countries, forcing biosimilar companies to conduct such studies or risk non-approval of their product. At times, different health authorities request different clinical study designs. In some jurisdictions there is a requirement to generate clinical data in local ethnic populations. Some health authorities require a hybrid label that combines clinical data from the reference biologic and the biosimilar, in the patient leaflet. Recommendations are provided to address each of these hurdles to facilitate global regulatory harmonization of biosimilars. Overcoming these barriers will ultimately increase patient access to these medicines in all regions while providing financial relief to healthcare systems. more...

As interstitial lung abnormalities (ILAs) are increasingly recognized on imaging and in clinical practice, identification and appropriate management are critical. We propose an algorithmic approach to the identification and management of patients with ILAs. more...

Polymer-grafted metal–organic frameworks (MOFs) can be used to form free-standing self-assembled MOF monolayers (SAMMs). Polymer chains can be introduced onto MOF surfaces through either the ligands or metal nodes using both grafting-to and grafting-from approaches. However, controlling the grafting density of polymer-grafted MOFs has not yet been achieved, because a means to control the density of grafting sites on the MOF surface has not been developed. In this study, the grafting density of polymer-grafted UiO-66 (UiO = University of Oslo) was controlled by functionalizing a portion of the Zr(IV) secondary building units (SBUs) on a UiO-66 surface with a so-called blocking agent. The remaining sites on the UiO-66 SBUs were functionalized with polymerization initiation groups, and polymers were grown from these sites to obtain particles with variable grafting densities and chain lengths that form SAMMs at an air–water interface. Even under conditions of low grafting density, these materials retain the ability to form SAMMs and their free-standing ability. Changes in particle arrangement within the monolayers were investigated using SEM imaging, and the toughness of the monolayers was evaluated using a film-on-water (FOW) method. Furthermore, coarse-grained molecular dynamics simulations were carried out to elucidate the morphology and mechanical properties of the monolayers. Findings from both experiments and simulations indicate that the toughness of SAMMs is more heavily influenced by the chain length of the grafted polymers than by the overall polymer content in the composite. more...

ABSTRACTVenous thromboembolism (VTE), consisting of both deep vein thrombosis (DVT) and pulmonary embolism (PE), is an extremely common condition both in the United States and worldwide. Not only is the diagnosis associated with significant morbidity and mortality for patients but it also imposes a deleterious financial burden on the US healthcare system. Diagnosis may be challenging due to variability in clinical presentation and requires a sequential workup including assessment of clinical pretest probability for VTE, D-dimer testing, and imaging. Following diagnosis, proper risk stratification is necessary to determine the appropriate treatment as well as the need for inpatient care. Elucidation of underlying major or minor risk factors at the time of diagnosis is essential as the presence of which may influence the duration of therapy. First-line treatment for most patients is anticoagulation with a direct oral anticoagulant (DOAC) for a minimum of 3–6 months. In multiple clinical trials, DOACs have proven to be non-inferior to vitamin K antagonists for the treatment of VTE with a lower risk of bleeding. Special consideration should be taken in the choice of agent and duration of treatment for patients who have underlying thrombophilias or malignancy and who are pregnant. more...

IMPORTANCE: Improving patients’ health status is a key goal of treating tricuspid regurgitation (TR). The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a heart failure disease-specific health status measure used to capture the health status impact of TR and the benefit of transcatheter tricuspid valve intervention (TTVI), but its validity in this clinical setting is unknown. OBJECTIVE: To evaluate the psychometric properties of the KCCQ in patients with TR. DESIGN, SETTING, AND PARTICIPANTS: Data were pooled from patients with severe TR enrolled in 11 manufacturer-sponsored trials of TTVI. The data were transferred to the US Food and Drug Administration to harmonize and anonymize prior to analysis by an independent center. Data were collected from December 2015 to April 2023, and data analysis was performed from July to October 2023. MAIN OUTCOMES AND MEASURES: Prespecified analyses included evaluation of internal consistency, reproducibility, responsiveness, construct validity, and predictive validity. Outcomes were determined using Cronbach α, score comparisons, intraclass correlation, Cohen d, Spearman correlations with best available reference measures, and association of scores and changes in scores with risk of subsequent clinical events. RESULTS: The study cohort was composed of 2693 patients enrolled in either single-arm (n = 1517) or randomized (n = 1176) investigations of TTVI. Mean (SD) patient age was 78.6 (8.0) years, 1658 of 2693 patients (61.6%) were female, and the mean (SD) baseline KCCQ Overall Summary (KCCQ-OS) score was 50 (23). There was strong internal consistency within individual domains (Cronbach α, .77-.83). Among clinically stable patients between 1 and 6 months, there were small mean changes in KCCQ domain and summary scores (differences of −0.1 to 1.9 points), demonstrating reproducibility. In contrast, domain and summary scores of patients who underwent TTVI showed large improvements at 1 month after treatment (mean changes, 12.1-21.4 points), indicating excellent perceived responsiveness. Construct validity was moderately strong when domains were compared with best available reference measures (Spearman correlations, 0.47-0.69). In both cross-sectional and longitudinal analyses, the KCCQ-OS was associated with clinical events, with lower scores associated with an increased risk of mortality (hazard ratio, 1.34 per 10-point decrement; 95% CI, 1.22-1.47) and heart failure hospitalization (hazard ratio, 1.24 per 10-point decrement; 95% CI, 1.17-1.31). CONCLUSIONS AND RELEVANCE: In this cohort study, the KCCQ had strong psychometric properties in patients with severe TR, including reliability, responsiveness, and validity. These data support use of the KCCQ in patients with severe TR as a measure of their symptoms, function, and quality of life and also for assessing the impact of interventions, such as TTVI, in rigorously controlled trials. more...

Background:Hypertension (HTN) is a common side effect of tacrolimus (Tac), the first-line antirejection medication for kidney transplant recipients. The impact of immediate-release tacrolimus (Tac IR) dosed twice daily versus extended-release tacrolimus (Tac ER) dosed once daily on long-term blood pressure control in kidney transplant recipients remains understudied. This study aims to compare the use of Tac IR versus Tac ER in kidney transplant recipients and evaluate the effects of the different formulations on systolic blood pressure (SBP), diastolic blood pressure (DBP), and HTN crisis. Methods:This retrospective cohort study at a single institution collected baseline characteristics, time-varying exposure to Tac IR versus Tac ER, SBP, DBP, HTN crisis, and confounders at each posttransplant visit. A marginal structural linear mixed-effects model was employed to analyze the longitudinal blood pressure control in kidney transplant recipients receiving Tac IR and Tac ER. Results:The final analysis included 654 patients, with mean ages of 52.0 years for Tac IR and 50.3 years for Tac ER. Males constituted 56.7% in Tac IR and 55.0% in Tac ER. Notably, the black population had 2.44 times higher odds of receiving Tac ER after adjusting for the rest of the baseline characteristics. No difference was found between longitudinal SBP (p= 0.386, 95% CI: −1.00, 2.57) or DBP (p= 0.797, 95% CI: −1.38, 1.06). Conclusion:Our study indicates that posttransplant patients taking Tac ER exhibit no difference in chronic SBP and DBP controls compared to Tac IR. more...

•What is the primary question addressed by this study?This primary question addressed by this brief report is whether a newly developed course increased confidence in key competencies for medical experts in estate litigation.•What is the main finding of this study?This study found that confidence in assessing testamentary capacity retrospectively and, to a lesser extent, contemporaneously increased among course participants. The main finding of this study was a significant improvement in the overall mean score of related key competencies after participation in the course.•What is the meaning of the finding?The meaning of these findings is that, amid an increasing need for medical expertise in the assessment of testamentary and related capacities, the course addresses a gap in training and formal education opportunities for physicians in this area. more...

Gastric cancer is a leading cause of cancer and cancer-related mortality worldwide, especially in East Asia. It is often diagnosed at an advanced stage, which carries a poor prognosis. Patients with advanced gastric cancer typically receive systemic therapy and best supportive care. For patients with locally advanced gastric cancer, a combination of systemic therapy and surgical resection is recommended, while surgical resection-alone is recommended for patients with early-stage localized tumors. Surgical resection, including total gastrectomy, distal gastrectomy, and proximal gastrectomy, is recommended for resection of localized tumors based on tumor location. Herein, the authors provide an overview of open gastrectomy resection and reconstruction techniques. more...

Transarterial chemoembolisation (TACE) is standard of care for patients with unresectable hepatocellular carcinoma that is amenable to embolisation; however, median progression-free survival is still approximately 7 months. We aimed to assess whether adding durvalumab, with or without bevacizumab, might improve progression-free survival. more...

Collective optical properties can emerge from an ordered ensemble of emitters due to interactions between the individual units. Superlattices of halide perovskite nanocrystals exhibit collective light emission, influenced by dipole–dipole interactions between simultaneously excited nanocrystals. This coupling changes both the emission energy and rate compared to the emission of uncoupled nanocrystals. We demonstrate how quantum confinement governs the nature of the coupling between the nanocrystals in the ensemble. The extent of confinement is modified by controlling the nanocrystal size or by compositional control over the Bohr radius. In superlattices made of weakly confined nanocrystals, the collective emission is red-shifted with a faster emission rate, showing the key characteristics of superfluorescence. In contrast, the collective emission of stronger quantum-confined nanocrystals is blue-shifted with a slower emission rate. Both types of collective emission exhibit correlative multiphoton emission bursts, showing distinct photon bunching emission statistics. The quantum confinement changes the preferred alignment of transition dipoles within the nanocrystal and switches the relative dipole orientation between neighbors, resulting in opposite collective optical behaviors. Our results extend these collective effects to relatively high temperatures and provide a better understanding of exciton interactions and collective emission phenomena at the solid state. more...

Poly(ethylene glycol) diacrylate (PEGDA) hydrogels are biocompatible and photo-cross-linkable, with accessible values of elastic modulus ranging from kPa to MPa, leading to their wide use in biomedical and soft material applications. However, PEGDA gels possess complex microstructures, limiting the use of standard polymer theories to describe them. As a result, we lack a foundational understanding of how to relate their composition, processing, and mechanical properties. To address this need, we use a data-driven approach to develop an empirical predictive framework based on high-quality data obtained from uniaxial compression tests and validated using prior data found in the literature. The developed framework accurately predicts the hydrogel shear modulus and the strain-stiffening coefficient using only synthesis parameters, such as the molecular weight and initial concentration of PEGDA, as inputs. These results provide simple and reliable experimental guidelines for precisely controlling both the low-strain and high-strain mechanical responses of PEGDA hydrogels, thereby facilitating their design for various applications. more...

High-harmonic generation (HHG) is a nonlinear process in which a material sample is irradiated by intense laser pulses, causing the emission of high harmonics of incident light. HHG has historically been explained by theories employing a classical electromagnetic field, successfully capturing its spectral and temporal characteristics. However, recent research indicates that quantum-optical effects naturally exist or can be artificially induced in HHG, such as entanglement between emitted harmonics. Even though the fundamental equations of motion for quantum electrodynamics (QED) are well-known, a unifying framework for solving them to explore HHG is missing. So far, numerical solutions have employed a wide range of basis-sets, methods, and untested approximations. Based on methods originally developed for cavity polaritonics, here we formulate a numerically accurate QED model consisting of a single active electron and a single quantized photon mode. Our framework can, in principle, be extended to higher electronic dimensions and multiple photon modes to be employed in ab initiocodes for realistic physical systems. We employ it as a model of an atom interacting with a photon mode and predict a characteristic minimum structure in the HHG yield vs phase-squeezing. We find that this phenomenon, which can be used for novel ultrafast quantum spectroscopies, is partially captured by a multitrajectory Ehrenfest dynamics approach, with the exact minima position sensitive to the level of theory. On the one hand, this motivates using multitrajectory approaches as an alternative for costly exact calculations. On the other hand, it suggests an inherent limitation of the multitrajectory formalism, indicating the presence of entanglement and true quantum effects (especially prominent for atomic and molecular resonances). Our work creates a roadmap for a universal formalism of QED-HHG that can be employed for benchmarking approximate theories, predicting novel phenomena for advancing quantum applications, and for the measurements of entanglement and entropy. more...

Lack of Herpes Simplex Virus (HSV) vaccine, low vaccination rates of Influenza viruses, waning immunity and viral transmission after vaccination underscore the need to reduce viral loads at their transmission sites. Oral virus transmission is several orders of magnitude higher than nasal transmission. Therefore, in this study, we evaluated neutralization of viruses using a natural viral trap protein (FRIL) formulated in clinical-grade chewing gum. FRIL is highly stable in the lablab bean powder (683 days) and in chewing gum (790 days), and fully functional (794 days) when stored at ambient temperature. They passed the bioburden test with no aerobic bacteria, yeasts/molds, with minimal moisture content (1.28–5.9%). Bean gum extracts trapped HSV-1/HSV-2 75–94% in a dose-dependent manner through virus self-aggregation. Mastication simulator released >50% release of FRIL within 15 min of chewing the bean gum. In plaque reduction assays, >95% neutralization of H1N1 and H3N2 required ∼40 mg/mL, HSV-1 160 mg/mL, and HSV-2 74 mg/mL of bean gum for 1,000 copies/mL virus particles. Therefore, a 2000 mg bean gum tablet has more than adequate potency for clinical evaluation and is safe with no detectable levels of glycosides. These observations augur well for evaluating bean gum in human clinical studies to minimize virus infection/transmission. more...

Early data from the DYNAMIC study of circulating tumor DNA (ctDNA)-guided adjuvant chemotherapy (ACT) versus standard approach met its primary outcome demonstrating reduced ACT use without compromising 2-year recurrence-free survival (RFS) for stage II colon cancer. We report here other prespecified analyses of overall survival, ctDNA clearance and ctDNA level. At a median follow-up of 59.7 months, 5-year RFS was 88% and 87% with ctDNA-guided and standard management, respectively (difference 1.1%, 95% confidence interval −5.8% to 8.0%), and 5-year overall survival is similar (93.8% versus 93.3%, hazard ratio (HR) 1.05; P= 0.887). For treated ctDNA-positive patients, ctDNA clearance was observed at the end of ACT (EOT) in 35 out of 40 patients (87.5%). A higher than median postoperative tumor-derived mutant molecules per milliliter plasma was associated with worse 5-year RFS (HR 10.62; P= 0.005). For treated ctDNA-positive patients, post hoc analysis of ctDNA clearance at EOT assessed by a new assay that evaluated an average of 29 tumor-derived mutations per patient predicted for a favorable 5-year recurrence-free probability of 97% versus 0% for ctDNA persistence (P< 0.001). Mature DYNAMIC outcome data support a ctDNA-guided approach to ACT for stage II colon cancer, with potential to further risk stratify ctDNA-positive patients based on ctDNA burden and EOT results. Australian New Zealand Clinical Trials Registry Identifier: ACTRN12615000381583. more...

Optical space-ground communication is regarded as the next leap in global connectivity. However, in such free-space optical communication links, atmospheric turbulence causes fluctuations in the intensity and phase of the received light signal, significantly impairing the link budget and rendering the system impractical. This paper presents a novel communication technique designed to mitigate turbulence-induced intensity fluctuations-specifically signal fading and phase distortions-resulting from multipath interference, while still enabling high-order coherent modulation schemes and dual polarization. Spatial distortions can be simultaneously corrected using established adaptive optics techniques. The proposed method is based on transmitting ultra-short pulses, on the order of picoseconds or hundreds of femtoseconds, through a turbulent atmosphere and utilizing a unique detection scheme known as the dynamic coherent all-optical matched filter (DCOF). The system concept, including the atmospheric channel, was evaluated through Monte Carlo simulations. Core photonic engines within this concept were further tested in an experimental laboratory setting, demonstrating the ability to generate and modulate ultra-short pulses, perform coherent detection by mixing two synchronized pulse trains, and optimize detection performance via spectral phase encoding. Both experimental and simulation results indicate the feasibility of a robust coherent free-space optical communication system capable of supporting high-speed data rates. more...

BackgroundClinical trials for rare disorders have unique challenges due to low prevalence, patient phenotype variability and high expectations. These challenges are highlighted by our study on clonazepam in ARID1Bpatients, a common cause of intellectual disability. Previous studies on Arid1b-haploinsufficient mice showed positive effects of clonazepam on various cognitive aspects.MethodsThis study used a randomised, double-blinded, placebo-controlled, two-way crossover study (RCT), followed by an N-of-1 design. In the crossover study, ARID1Bpatients received clonazepam (max 0.5 mg, two times per day) or a placebo for 22 days with a 3-week washout period. Assessments included safety, tolerability, pharmacokinetics, pharmacodynamics on neurocognitive tasks, behaviour and cognitive function. During phase I of the N-of-1 trial the optimal dosage and individual treatment goals were determined. Phase II evaluated the treatment effect. This phase was composed of three periods: an open-label period with placebo (4 weeks), followed by a double-blinded period (6 weeks), followed by an open-label period in which the patient received clonazepam (4 weeks).ResultsIn the clonazepam group (n=16, 15 completing both periods), seven (44%) reported improvement on Clinician Global Impression of Improvement versus two (13%) on placebo. 13 (87%) showed ‘no change’ after placebo (two (13%) on clonazepam), while seven (44%) on clonazepam reported deterioration, often linked to side effects (n=6), suggesting potential benefit from lower dosing. Three N-of-1 trials with RCT responders saw two patients improve on clonazepam during double-blinding, but clinical evaluation deemed the improvements insufficient.ConclusionsOur approach shows the feasibility and strength of combining conventional RCT and N-of-1 studies for therapeutic studies in populations with intellectual disabilities, distinguishing real treatment effects from expectation bias. Our findings suggest that clonazepam has no additional therapeutic value in ARID1Bpatients.Trial registration numberEUCTR2019-003558-98, ISRCTN11225608. more...