Additional Delay Research Articles

Multi-synchronization of coupled multi-stable memristive Cohen–Grossberg neural networks with mixed time-delays

This paper investigates the multi-synchronization issue for a class of coupled multi-stable memristive Cohen–Grossberg neural networks with both additive time delays and distributed delays. First, the multi-stability of the isolated subnetwork with a general class of activation function is analyzed. By employing state-space decomposition, M-matrix and fixed point theory, some sufficient conditions are deduced to ensure that each subnetwork of the coupled networks has (r+1)n locally exponential stable equilibrium states. In the scenario where the time delays are continuously differentiable, a unique Lyapunov–Krasovskii function is established and some sufficient conditions are derived for the coupled system to achieve multi-synchronization under feedback control. Additionally, in circumstances where the time delays are immeasurable or discontinuous, a new feedback controller is constructed based on the system’s model parameters, and a delay-independent finite-time multi-synchronization criterion is proposed. Finally, three numerical examples are provided to illustrate the effectiveness of the proposed methods.

Missing Data Filling of Model Based on Neural Network

Today’s society has entered the pace of information development era. All kinds of information are digitized, while the loss of information data also directly affects the normal operation of the application system and has become the biggest obstacle to the development of information technology. The existing missing filling methods do not take into account the time-series information of the data set. Based on the neural network method for filling missing data in time series, an end-to-end missing data filling method for time series based on the residual of regression equation is proposed. Under the assumption that the activation function and the noise diffusion coefficient function are satisfied, the exponential stability of the complex-valued stochastic inertial neural network systems with additive time-varying delays is studied. The bipartite graph model of the time series data missing value filling method of the countermeasure network and the filling cyclic neural unit are generated. According to the end-to-end time series data missing value filling method of the self encoder, the corresponding low-dimensional feature vector can be automatically generated for each time series data. It avoids overfitting by using nonlinear methods directly in low-dimensional space. Experiments show that the method proposed in this paper uses Monte Carlo to fill data missing at different proportions. In data gap filling process, the coefficient variance is less than 0.05, which enhances the rationality of filling data. It is of great research value and practical significance to reasonably fill in the missing values of time series data. The research can accelerate the improvement of big data system, improve the level and effectiveness of database management, and is an important means of computing capacity of existing data centers.

A Simulation-Free Replacement Solution for Radiation Therapy Immobilization Devices Using Computer Numerical Control (CNC) -Milled Polystyrene Molds

In radiation therapy (RT), if an immobilization device is lost or damaged, the patient may need to be brought back for resimulation, device fabrication, and treatment planning, causing additional imaging radiation exposure, inconvenience, cost, and delay. We describe a simulation-free method for replacing lost or damaged RT immobilization devices. Replacement immobilization devices were fabricated using existing simulation scans as design templates by computer numerical control (CNC) milling of molds made from extruded polystyrene (XPS). XPS material attenuation and bolusing properties were evaluated, a standard workflow was established, and 12 patients were treated. Setup reproducibility was analyzed postfacto using Dice similarity coefficient (DSC) and mean distance to agreement (MDA) calculations comparing onboard treatment imaging with computed tomography (CT) simulations. Results showed that XPS foam material had less dosimetric impact (attenuation and bolusing) than materials used for our standard immobilization devices. The average direct cost to produce each replacement mold was $242.17, compared with over $2000 for standard resimulation. Hands-on time to manufacture was 86.3 minutes, whereas molds were delivered in as little as 4 hours and mostly within 24 hours, compared with a week or more required for standard resimulation. Each mold was optically scanned after production and was measured to be within 2-mm tolerance (pointwise displacement) of design input. All patients were successfully treated using the CNC-milled foam mold replacements, and pretreatment imaging verified satisfactory clinical setup reproduction for each case. The external body contours from the setup cone beam CT and the original CT simulation with matching superior-inferior extent were compared by calculating the DSC and MDA. DSC average was 0.966 (SD, 0.011), and MDA average was 2.694 mm (SD, 0.986). CNC milling of XPS foam is a quicker and more convenient solution than traditional resimulation for replacing lost or damaged RT immobilization devices. Satisfactory patient immobilization, low dosimetric impact compared with standard immobilization devices, and strong correlation of onboard contours with CT simulations are shown. We share our clinical experience, workflow, and manufacturing guide to help other clinicians who may want to adopt this solution.

A lightweight packet forwarding verification in SDN using sketch

By decoupling the control plane and the data plane, Software Defined Networking (SDN) has reshaped the ossified network architecture and improved the programmability of the network. However, SDN is also susceptible to malicious injection, tampering, dropping and hijacking attacks against forwarding packets, and the SDN architecture cannot perceive the real behavior of switches in the data plane. Packet forwarding verification and exception localization are recognized as effective and promising methods, enabling reliable packet delivery in the data plane and allowing the controller in SDN to identify abnormal links. While existing mechanisms embed the linear-scale cryptographic tags into the packet header space as the transmission path lengthens to realize packet verification and exception localization, which cannot achieve a feasible tradeoff between efficiency and security. Leveraging the central controllability of SDN, we propose a lightweight packet forwarding verification mechanism. This mechanism splits the runtime of a flow into consecutive epochs by address hopping. The switches in the data plane forward packets based on hopping address, collecting the information of packets forwarded in a compact data structure, namely traffic sketch. The controller verifies traffic sketches and localizes exception in the epoch. We further prototype the proposed mechanism based on simulation network. The analysis and experiments demonstrate that the cost of proposed scheme is lower than the similar mechanisms, introducing no more than 9 % additional forwarding delay and less than 8 % throughput degradation.

De novo variation in ARID1B gene causes Coffin-Siris syndrome 1 in a Chinese family with excessive early-onset high myopia

Coffin-Siris syndrome (CSS) is a rare autosomal dominant inheritance disorder characterized by distinctive facial features, hypoplasia of the distal phalanx or nail of the fifth and additional digits, developmental or cognitive delay of varying degree, hypotonia, hirsutism/hypertrichosis, sparse scalp hair and varying kind of congenital anomalies. CSS can easily be misdiagnosed as other syndromes or disorders with a similar clinical picture because of their genetic and phenotypic heterogeneity. We describde the genotype-phenotype correlation of one patient from a healthy Chinese family with a novel genotype underlying CSS, who was first diagnosed in the ophthalmology department as early-onset high myopia (eoHM). Comprehensive ophthalmic tests as well as other systemic examinations were performed on participants to confirm the phenotype. The genotype was identified using whole exome sequencing, and further verified the results among other family members by Sanger sequencing. Real-time quantitative PCR (RT-qPCR) technology was used to detect the relative mRNA expression levels of candidate genes between proband and normal family members. The pathogenicity of the identified variant was determined by The American College of Medical Genetics and Genomics (ACMG) guidelines. STRING protein-protein interactions (PPIs) network analysis was used to detect the interaction of candidate gene-related proteins with high myopia gene-related proteins. The patient had excessive eoHM, cone-rod dystrophy, coarse face, excessive hair growth on the face, sparse scalp hair, developmental delay, intellectual disability, moderate hearing loss, dental hypoplasia, patent foramen ovale, chronic non-atrophic gastritis, bilateral renal cysts, cisterna magna, and emotional outbursts with aggression. The genetic assessment revealed that the patient carries a de novo heterozygous frameshift insertion variant in the ARID1B c.3981dup (p.Glu1328ArgfsTer5), which are strongly associated with the typical clinical features of CSS patients. The test results of RT-qPCR showed that mRNA expression of the ARID1B gene in the proband was approximately 30% lower than that of the normal control in the family, suggesting that the variant had an impact on the gene function at the level of mRNA expression. The variant was pathogenic as assessed by ACMG guidelines. Analysis of protein interactions in the STRING online database revealed that the ARID1A protein interacts with the high myopia gene-related proteins FGFR3, ASXL1, ERBB3, and SOX4, whereas the ARID1A protein antagonizes the ARID1B protein. Therefore, in this paper, we are the first to report a de novo heterozygous frameshift insertion variant in the ARID1B gene causing CSS with excessive eoHM. Our study extends the genotypic and phenotypic spectrums for ARID1B-CSS and supplies evidence of significant association of eoHM with variant in ARID1B gene. As CSS has high genetic and phenotypic heterogeneity, our findings highlight the importance of molecular genetic testing and an interdisciplinary clinical diagnostic workup to avoid misdiagnosis as some disorders with similar manifestations of CSS.

Assessment of efficacy and safety of dose-dense doxorubicin and cyclophosphamide (ddAC) in combination with immunotherapy in early-stage triple-negative breast cancer

PurposeThis study aimed to assess safety and efficacy of a modified KEYNOTE 522 protocol, which incorporated pembrolizumab every 6 weeks, allowing for concomitant dose-dense (14 day) doxorubicin and cyclophosphamide (ddAC). By optimizing this dosing, the intention of this modified protocol was to improve pathologic complete response (pCR) rates in a population associated with a poorer prognosis.MethodsThis was a retrospective, single-center, cohort study. Patients were included if they had early stage, triple-negative breast cancer, and received at least one dose of AC. The entire cohort received neoadjuvant chemotherapy including weekly carboplatin and paclitaxel with pembrolizumab every 3 weeks for 12 weeks (4 cycles). The group then received either ddAC with pembrolizumab 400 mg every 6 weeks, or AC with pembrolizumab 200 mg every 3 weeks. The primary objective was pCR rate at time of surgery.ResultsThis study assessed outcomes in 25 patients over 34 months. The pCR rate in the pembrolizumab, AC 3-week cohort was 64.3% versus 81.8% in the ddAC and 6-week pembrolizumab group. No pembrolizumab-associated grade 3–4 adverse events occurred in the either cohort. Despite seeing an increased incidence of grade 3–4 toxicities in the ddAC arm, this did not result in additional chemotherapy delays or dose reductions.ConclusionThis study demonstrated tolerability and a potential for favorable outcomes with this patient population, making this modified KEYNOTE 522 protocol a reasonable treatment approach. Larger, prospective studies are warranted to assess the feasibility of this dosing and true optimization of patient outcomes given the small sample size of this study.

NDNOTA: NDN One-Time Authentication

Named Data Networking (NDN) stands out as a prominent architectural framework for the future Internet, aiming to address deficiencies present in IP networks, specifically in the domain of security. Although NDN packets containing requested content are signed with the publisher’s signature which establishes data provenance for content, the NDN domain still requires more holistic frameworks that address consumers’ identity verification while accessing protected contents or services using producer/publisher-preapproved authentication servers. In response, this paper introduces the NDN One-Time Authentication (NDNOTA) framework, designed to authenticate NDN online services, applications, and data in real time. NDNOTA comprises three fundamental elements: the consumer, producer, and authentication server. Employing a variety of security measures such as single sign-on (SSO), token credentials, certified asymmetric keys, and signed NDN packets, NDNOTA aims to reinforce the security of NDN-based interactions. To assess the effectiveness of the proposed framework, we validate and evaluate its impact on the three core elements in terms of time performance. For example, when accessing authenticated content through the entire NDNOTA process, consumers experience an additional time overhead of 70 milliseconds, making the total process take 83 milliseconds. In contrast, accessing normal content that does not require authentication does not incur this delay. The additional NDNOTA delay is mitigated once the authentication token is generated and stored, resulting in a comparable time frame to unauthenticated content requests. Additionally, obtaining private content through the authentication process requires 10 messages, whereas acquiring public data only requires two messages.

Abstract PO5-01-10: Evaluating a computer-aided platform for predicting recurrence and survival in an Oncotype Dx tested breast cancer cohort

Abstract Background: Oncotype DX Breast Recurrence ScoreÒ (ODXRS) is a widely used predictive measure of breast cancer recurrence risk and chemotherapy benefit for patients with estrogen receptor positive (ER+), human epidermal growth factor receptor-2 negative (HER2-) breast cancers. ODXRS testing incurs additional costs and delays. These drawbacks could be obviated by innovative computer-aided technologies within digital pathology workflows. Such technologies could be developed to perform a wide variety of diagnostic and prognostic tests on digital whole slide images (WSIs) of hematoxylin and eosin (H&E)-stained tissue alone. This would save time, cost, and sample tissue whilst still providing critical prognostic information for patient management. Q-Plasia OncoReader Breast (QPORB) is a computer-aided solution which extracts information from H&E WSIs to provide diagnostic and prognostic information for breast cancer specimens. Aims: The aim of this study was to identify whether the computer aided QPROB platform could successfully predict breast cancer recurrence from H&E WSIs alone in line with recurrence predicted by ODXRS. Methods: H&E slides corresponding to tissue blocks sent for ODXRS testing from primary breast cancer resection/excision specimens from St James’s University Hospital, Leeds, UK (n=137 cases, 1 slide per case) were collected, anonymized, and scanned at x20 magnification on an Aperio AT2 scanner. Relevant pathological and clinical data were collected from electronic pathology reports and patient records. These data included ODXRS and recurrence events. QPORB analyzed each case/slide and generated a digital biomarker profile from the H&E images alone, combining statistical physics and tumor biology to quantify malignant cell cycle deformation. QPORB’s biomarker profile and ODXRS for each case was compared to disease-free survival (DFS) and overall survival (OS). Kaplan-Meier survival analyses were performed. Confounding factors (age, tumor grade, invasive tumor size and Charlson Comorbidity Index) were accounted for. Results: Results of three QPORB-generated indices - two putatively associated with overall cell cycle signature and one with G1 deformation, and their combined overall biomarker profile did not predict DFS in this cohort. However, with regards to OS, all three indices and the combined biomarker profile predicted OS over a median follow-up period of 5 years (P=0.044). 5% of WSIs (7/137) did not meet the criteria to be analyzed by QPORB and 4% (6/137) could not be analyzed by QPORB (attrition). While ODXRS similarly predicted OS but not DFS, the follow-up duration was suboptimal. Conclusion: While QPORB indices evaluated in this work, putatively associated with overall cell cycle signature and G1 deformation, did not predict breast cancer recurrence on a par with ODXRS, it has shown promising results as potential adjunct device to provide an estimate of OS for breast cancer patients eligible for ODXRS testing. Future work will expand on this observational cohort, blindly validate these findings, and extend the work to encompass all breast cancer molecular subtypes. Citation Format: Satabhisa Mukhopadhyay, Elizabeth Walsh, Rebecca Millican-Slater, Andrew Hanby, Joanne Stephenson, Tathagata Dasgupta, Nicolas Orsi. Evaluating a computer-aided platform for predicting recurrence and survival in an Oncotype Dx tested breast cancer cohort [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-01-10.

О связи между ослаблением и временем запаздывания узкополосного сигнала в диспергирующей среде

The 1D problem of propagation of a narrowband signal in a homogeneous dispersing medium is considered. It is shown that there is a direct and immediate relationship between the additional (to vacuum) delay time of the signal and its attenuation during propagation in an absorbing medium. It is shown that with an additional delay time of more than several tens of coherence times of uniformly broadened spectral lines of the medium, the signal weakens by hundreds of decibels and therefore practically disappears. On the other hand, when the delay of the signal is less than the coherence time of the medium, its absorption is small. A similar situation arises in an amplifying (thermodynamically nonequilibrium) environment – of course, with the replacement of signal attenuation with its amplification and the replacement of signal delay with its advance. As an example, the propagation of a narrowband signal, the carrier frequency of which is outside the gain band of the space maser, is considered. It is shown that in this case, due to the long lifetime of the excited states of interstellar gas molecules, the signal propagates at superluminal velocity with practically no change in amplitude, which is very rare in problems of this type.

Mortality impact of further delays in active targeted antibiotic therapy in bacteraemic patients that did not receive initial active empiric treatment: Results from the prospective, multicentre cohort PROBAC

ObjectivesThe early initiation of the empirical antibiotic treatment and its impact on mortality in patients with bacteraemia has been extensively studied. However, information on the impact of precocity of the targeted antibiotic treatment is scarce. We aimed to study the impact of further delay in active antibiotic therapy on 30-day mortality among patients with bloodstream infection who had not received appropriate empirical therapy. DesignWe worked with PROBAC cohort (prospective and compound by patients from 26 different Spanish hospitals). We selected a total of 1703 patients, who survived to day 2 without having received any active antibiotic therapy against the causative pathogen. ResultsThe 30-day mortality was 14% (238 patients). The adjusted odds of mortality increased for every day of delay, from 1.53 (95% confidence interval (CI) 1.13-2.08) for day 3 or after to 11.38 (95% CI 7.95-16.38) for day 6 or after. ConclusionWe concluded that among patients who had not received active treatment within the first 2 days of blood culture collection, additional delays in active targeted therapy were associated with increased mortality. These results emphasize the importance of active interventions in the management of patients with bloodstream infections.

Cosmology-Independent Photon Mass Limits from Localized Fast Radio Bursts by Using Artificial Neural Networks

A hypothetical photon mass mγ can produce a frequency-dependent vacuum dispersion of light, which leads to an additional time delay between photons with different frequencies when they propagate through a fixed distance. The dispersion measure and redshift measurements of fast radio bursts (FRBs) have been widely used to constrain the rest mass of the photon. However, all current studies analyzed the effect of the frequency-dependent dispersion for massive photons in the standard ΛCDM cosmological context. In order to alleviate the circularity problem induced by the presumption of a specific cosmological model based on the fundamental postulate of the masslessness of photons, here we employ a new model-independent smoothing technique, artificial neural network (ANN), to reconstruct the Hubble parameter H(z) function from 34 cosmic-chronometer measurements. By combining observations of 32 well-localized FRBs and the H(z) function reconstructed by ANN, we obtain an upper limit of mγ ≤ 3.5 × 10−51 kg, or equivalently mγ ≤ 2.0 × 10−15 eV/c2 (mγ ≤ 6.5 × 10−51 kg, or equivalently mγ ≤ 3.6 × 10−15 eV/c2) at the 1σ (2σ) confidence level. This is the first cosmology-independent photon mass limit derived from extragalactic sources.

Minimizing delays to hemodialysis access maturation: A quality improvement analysis.

Pre-operative process optimization can expedite time-to-intervention and reduce overall health care costs. We hypothesized that the longest delay to hemodialysis (HD) access creation would be from pre-operative vessel mapping (mandatory in our practice), and that this would be correlated with increased catheter days. One hundred thirty patients (24 inpatients, 106 outpatients) who received initial hemodialysis (HD) access from 01/01/2017 to 12/31/2021, at the Veterans Affairs Puget Sound, Seattle, Washington, were identified. Median time differences between pre-operative events were compared between inpatients and outpatients using the Mann-Whitney U test. Outpatients were then stratified by time of catheter-based HD initiation (no catheter, pre-referral catheter, post-referral catheter) and compared. The impacts of mapping-related delays on catheter use were evaluated using regression. Inpatients had shorter referral to access maturation times (125 days inpatient vs 146 days outpatient; p = 0.03). This was driven by shorter referral to mapping (2 days inpatient vs 27 days outpatient; p < 0.01) and mapping to pre-surgical evaluation (1-day inpatient vs 6 days outpatients; p < 0.01) times. Pre-surgical evaluation to OR times represented the longest pre-operative delay in both groups (51 days inpatient vs 29 days outpatient; p = 0.59). Among outpatients, tunneled catheter placement post-referral resulted in longer maturation times (74 days no catheter vs 67 days pre-referral vs 149 days post-referral; p < 0.01) but not additional pre-operative delays. No trend existed between increased mapping times and catheter-based dialysis duration (R2 = 0.08). Preoperative vein mapping contributed up to 21% of referral to maturation times but was not associated with increased tunneled catheter duration. While tunneled catheter placement impacted access maturation it did not cause additional pre-operative delays. Earlier referrals for access creation and reduction of outpatient wait-time from referral to OR and increased AV graft placement may minimize catheter days in our system thereby mitigating the added delays caused by pre-operative vein mapping.

Orbit and clock products for quad-system satellites with undifferenced ambiguity fixing approach

Integer Ambiguity Resolution (IAR) can significantly improve the accuracy of GNSS Precise Orbit Determination (POD). Traditionally, the IAR in POD is achieved at the Double Differenced (DD) level. In this contribution, we develop an Un-Differenced (UD) IAR method for Global Positioning System (GPS)+ BeiDou Navigation Satellite System (BDS) + Galileo navigation satellite system (Galileo)+ Global'naya Navigatsionnaya Sputnikovaya Sistema (GLONASS) quad-system POD by calibrating UD ambiguities in the raw carrier phase and generating the so-called carrier range. Based on this method, we generate the UD ambiguity-fixed orbit and clock products for the Wuhan Innovation Application Center (IAC) of the International GNSS Monitoring and Assessment System (iGMAS). One-year observations in 2020 from 150 stations are employed to investigate performance of orbit and clock products. Notably, the UD Ambiguity Resolution (AR) yields more resolved integer ambiguities than the traditional DD AR, scaling up to 9%, attributable to its avoidance of station baseline formation. Benefiting from the removal of ambiguity parameters, the computational efficiency of parameter estimation undergoes a substantial 70% improvement. Compared with the float solution, the orbit consistencies of UD AR solution achieve the accuracy of 1.9, 5.2, 2.8, 2.1, and 2.7 cm for GPS, BeiDou-2 Navigation Satellite System (BDS-2), BeiDou-3 Navigation Satellite System (BDS-3), Galileo, and GLONASS satellites respectively, reflecting enhancements of 40%, 24%, 54%, 34%, and 42%. Moreover, the standard deviations of Satellite Laser Ranging (SLR) residuals are spanning 2.5–3.5 cm, underscoring a comparable accuracy to the DD AR solution, with discrepancies below 5%. A notable advantage of UD AR lies in its capability to produce the Integer Recovered Clock (IRC), facilitating Precise Point Positioning (PPP) AR without requiring additional Uncalibrated Phase Delay (UPD) products. To assess the performance of quad-system kinematic PPP based on IRC, a network comprising 120 stations is utilized. In comparison to the float solution, the IRC-based PPP AR accelerates convergence time by 31% and enhance positioning accuracy in the east component by 54%.

How Positioning Wearable Haptic Interfaces on Limbs Influences Virtual Embodiment.

With increasing use of computer applications and robotic devices in our everyday life, and with the advent of metaverse, there is an urgent need of developing new types of interfaces that facilitate a more intuitive interaction in physical and virtual space. In this work, we investigate the influence of the location of haptic feedback devices on embodiment of virtual hands and user load during an interactive pick-and-place task. To do this, we conducted a user study with a 3x2 repeated measure experiment design: feedback position is varied between the distal phalanx of the index finger and the thumb, the proximal phalanx of the index finger and the thumb, and the wrist. These conditions of feedback are tested with the stimuli applied synchronously to the participant in one case, and with an additional delay of 350 ms in the second case. The results show that the location of the haptic feedback device does not affect embodiment, whereas the delay, i.e., whether the feedback is applied synchronously or asynchronously, affects embodiment. This suggests that for pick-and-place tasks, haptic feedback devices can be placed on the user's wrist without compromising performance making the hands to remain free, allowing unobstructed hand visibility for precise motion tracking, thereby improving accuracy.

Quantitative systems pharmacology-based exploration of relevant anti-amyloid therapy challenges in clinical practice.

Addressing practical challenges in clinical practice after the recent approvals of amyloid antibodies in Alzheimer's disease (AD) will benefit more patients. However, generating these answers using clinical trials or real-world evidence is not practical, nor feasible. Here we use a Quantitative Systems Pharmacology (QSP) computational model of amyloid aggregation dynamics, well validated with clinical data on biomarkers and amyloid-related imaging abnormality-edema (ARIA-E) liability of six amyloid antibodies in clinical trials to explore various clinical practice challenges. Treatment duration to reach amyloid negativity ranges from 12 to 44, 16 to 40, and 6 to 20 months for lecanemab, aducanumab, and donanemab, respectively, for baseline central amyloid values between 50 and 200 Centiloids (CL). Changes in plasma cerebrospinal fluid Aβ42 and the plasma Aβ42/ Aβ40 ratio-fluid biomarkers to detect central amyloid negativity-is greater for lecanemab than for aducanumab and donanemab, indicating that these fluid amyloid biomarkers are only suitable for lecanemab. After reaching amyloid negativity an optimal maintenance schedule consists of a 24-month, 48-month and 64-month interval for 10mg/kg (mpk) lecanemab, 10mpk aducanumab, and 20mpk donanemab, respectively, to keep central amyloid negative for 10 years. Cumulative ARIA-E liability could be reduced to almost half by introducing a drug holiday in the first months. For patients experiencing ARIA-E, restarting treatment with a conservative titration strategy resulted in an additional delay ranging between 3 and 4 months (donanemab), 5 months (lecanemab), and up to 7 months (aducanumab) for reaching amyloid negativity, depending upon the timing of the incident. Clinical trial designs for Down syndrome patients suggested the same rank order for central amyloid reduction, but higher ARIA-E liability especially for donanemab, which can be significantly mitigated by adopting a longer titration period. This QSP platform could support clinical practice challenges to optimize real-world treatment paradigms for new and existing amyloid drugs.

Energy fluxes and vertical heat transfer in the Southern Baltic Sea

IntroductionThis study investigates the dynamics of energy fluxes and vertical heat transfer in the Southern Baltic Sea, emphasizing the significant role of the dicothermal layer in modulating the penetration of the thermocline and the propagation rates of thermal energy. The research aims to elucidate the complex patterns of solar energy absorption, its conversion into sea surface temperature (SST), and the transference of this energy deeper into the marine environment.MethodsData were collected through 93 monitoring cruises by the Institute of Oceanology of the Polish Academy of Sciences (IOPAN) from 1998 to 2023, using a high-resolution towed probe technique alongside Argo floats data for the Baltic Proper from 2020 to 2023. ERA5 climate reanalysis dataset and NEMOv4.0 ocean model forecasts were also utilized for a comprehensive analysis of VITE, Top Net Short-Wave Radiation, SST, and energy budget across the Southern Baltic Sea.Results and discussionThe Southern Baltic Sea functions as a net energy sink, with an average energy budget of 5.48 W m-2, predominantly absorbing energy during daylight and emitting it from September to February. A 59-day lag between peak solar energy and VITE peak was observed, followed by an additional 6-day delay before peak SST. The study further reveals a 15-day delay in temperature phase shift per 10 meters depth due to the dicothermal layer's influence on thermal energy propagation, extending to 35 days in the Central and Northern Baltic. Heat transfer is significantly affected by the levels of the thermocline and halocline, with regional variations in advection-driven seasonal signals. The pronounced thermal inertia and the critical role of the dicothermal layer underscore the complexity of thermal energy distribution in the Southern Baltic Sea.

Abstract 2879: Spatiotemporal fractionation: An innovative concept of fractionated radiotherapy

Abstract Impressive outcomes in therapeutic radiation oncology have been achieved in the past decade through the development of advanced computer technology and imaging methods, such as intensity modulated radiotherapy. Ideally, radiotherapy treatment delivers a high dose to the tumor while sparing the surrounding healthy tissues and organs at risk from radiation damage. Spatiotemporal Fractionated Radiotherapy has emerged as an innovative technique that delivers different dose distributions to different parts of the tumor in order to achieve high doses to the target while ensuring a low dose-bath in the surrounding normal tissue. Spatiotemporally fractionated regimens showed in silico up to 10 - 15% sparing of normal tissue from radiation damage, while ensuring isoeffective tumor control compared to conventionally fractionated regimens. However, prior to advancing spatiotemporal fractionation to the clinical level, it is important to probe the validity of the main assumption of spatiotemporal fractionation derived from the Biologically Effective Dose (BED) model: two different fractionation schemes that implement a high and a low dose will lead to equivalent clinical effects, regardless of dose-treatment sequence. A tumor growth delay study was performed in a subcutaneous immunocompetent murine tumor model (MC38-tumor cell derived) receiving two different fractionation regimens. Particularly, tumors belonging to the two treatment groups received the same dose combination - a high (12 Gy) and a low (6 Gy) dose fraction separated by 72 hours - with the doses delivered in opposite order in the two treatment groups. The same experimental outline was performed in a subcutaneous immunodeficient murine tumor model derived from the same tumor cells. Tumors were also characterized by immunophenotyping analysis seven days after first irradiation. Even though the two regimens deliver the same physical dose to the tumor - and would be considered equivalent according to the BED model - different tumor growth delays were observed in a time window of 30 days after first irradiation depending on the treatment group. Such differences were observed in the immunocompetent model but not in the immunodeficient model. The immunophenotyping results showed immunostimulatory vs immunosuppressive phenotypes of the tumor microenvironment depending on the order of the treatment doses. An additional tumor growth delay study including immune checkpoint inhibitors confirmed the fundamental role of the immune system with the differential efficacy outcomes of the two regimens. Overall, these intriguing results suggest that a differential radiotherapy-induced immune response to different doses of ionizing radiation plays an important role in the treatment outcome and asks for re-evaluation of the BED model taking scheduling-dependent parameters into consideration. Citation Format: Irene Vetrugno, Irma Telarovic, Nathan Torelli, Jan Unkelbach, Martin Pruschy. Spatiotemporal fractionation: An innovative concept of fractionated radiotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2879.

Abstract 1353: Potentiating salvage radiotherapy in radiorecurrent prostate cancer through anti-CTLA4 therapy: Implications from a syngeneic model

Abstract Background: Advanced prostate cancer (PCa) is a leading cause in cancer death and can elicit significant morbidity and mortality. A common treatment modality for advanced PCa is radiation therapy (RT). Currently, salvage of local disease recurrence after RT is a major clinical problem. Emerging evidence indicates the importance of the immune system in governing RT response. In support of this, immune checkpoint inhibitors (ICIs), which enhance immune activation, have demonstrated clinical therapeutic promise in combination with RT in certain advanced cancers. Irradiation (IR) combined with ICIs may prime the immune system to recognize and target recurrent cancer. Purpose: Investigate the therapeutic efficacy of ICIs in combination with RT for radiorecurrent PCa in a syngeneic pre-clinical model. Methods: TRAMP-C2 cells were treated with 10 Gy of radiation over 5 fractions (similar to clinical hypofractionated (HF) schedule) to generate TRAMP-C2 HF cells. Immune-competent mice were transplanted subcutaneously with TRAMP-C2 HF cells. Once tumors reached palpable size, mice were administered either ICIs (anti-PDL1 or anti-CTLA4) alone or in combination with RT. Tumor volume was monitored to determine the treatment effect. Correlative studies on excised tumors and secondary lymphoid organs included flow cytometry and NanoString gene expression panel to evaluate immunological mechanisms that contribute to anti-tumor effects. Results: TRAMP-C2 HF cells were validated for radiation resistance and exhibited a more aggressive phenotype (reduction in senescence, increase in clonogenicity) similar to clinically recurrent PCa. Radiation resistance of TRAMP-C2 HF tumors was validated in vivo. Administration of anti-PDL1 and anti-CTLA4 as monotherapy or in combination did not achieve significant tumor growth delay compared to control. IR alone produced an observable tumor growth delay compared to ICIs alone. The combination of anti-PDL1 and IR did not yield additional growth delay compared to IR alone. Strikingly, significant tumor growth delay was seen with the combination of IR and anti-CTLA4 compared to IR alone, while also resulting in complete cure in a third of the mice. mice. Lymph nodes and tumors from mice treated with IR and anti-CTLA4 vs. IR and isotype control demonstrated differential expression of genes in T cell functions and enrichment in both CD4+ and CD8+ T cell populations. Conclusion: We generated the first syngeneic radiorecurrent PCa model and demonstrated that combining anti-CTLA4 and IR results in synergistic tumor response. Combined therapy resulted in augmented immune response, most notably enhancement of CD8 T cell activity. Significance: These findings contribute to our understanding of immunological events associated with RT and ICIs in the context of radiorecurrent PCa and support new avenues for salvage therapy in clinical trials. Citation Format: Hanzhi Wang, Linsey Gong, Xiaoyong Huang, Stephanie D. White, Hanz T. Chung, Danny Vesprini, Tera N. Petchiny, Emmanouil Fokas, Hansen He, Robert S. Kerbel, Stanley K. Liu. Potentiating salvage radiotherapy in radiorecurrent prostate cancer through anti-CTLA4 therapy: Implications from a syngeneic model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1353.

Grand theft API: A forensic analysis of vehicle cloud data

Modern vehicles such as cars, trucks and motorcycles contain an increasing number of embedded computers that continuously exchange telemetry data like current mileage, tire pressure, expected range and geolocation to the manufacturer's cloud. Vehicle owners can access this data via Vehicle Assistant Apps (VAA). Naturally, this data is of increasing interest to law enforcement in criminal investigations. While manufacturers must comply with local laws requiring them to hand over the data of suspects upon the issuance of a warrant, this process can be time-consuming and cause an additional delay in a case. Making use of novel API-based access methods in cloud forensic investigations, we present a method to get permanent access to a vehicle's cloud data by directly accessing cloud servers given suspects' credentials. We analysed a set of 23 different VAAs and pointed out the potentially accessible data categories. With our proof of concept tool gta.py in combination with six provided vehicles from BMW, Dacia, Ford, Hyundai, Mercedes and Tesla, we verified the accessibility of the data categories. Our findings demonstrate that the API-based forensic acquisition and analysis of vehicle cloud data provides important insights to be considered in future digital forensic investigations of vehicles.

Modified SiP single-polarization CADD receiver.

In cost-sensitive application scenarios, increasing the data rate per channel under a limited receiver bandwidth is critical, and thus, the transceivers with low costs and high electrical spectral efficiencies (ESEs) are highly desirable. In this Letter, we demonstrate a modified silicon photonic (SiP) carrier-assisted differential detection (CADD) receiver with a record ESE for single polarization. The ESE of the conventional CADD is mainly limited by the transfer function that originated from the optical delay and hybrid. We modify the transfer function of the CADD by placing an additional delay in parallel to the original delay path. Consequently, the modified transfer function exhibits a sharper slope around the zero frequency, leading to a higher ESE. Here we employ complementary metal-oxide-semiconductor-compatible SiP integration to further reduce the cost and footprint of the modified CADD receiver. In the experiment, 280-Gb/s raw rate (net 226-Gb/s) 16-QAM OFDM signal after 80-km SMF transmission was detected using a 36.5-GHz SiP modified CADD receiver, with a bit error ratio below the 24% SD-FEC threshold. To our best knowledge, we achieve a record net 6.2-b/s/Hz ESE for an integrated single-polarization DD receiver with a 16-QAM format.