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In this paper we consider a tumor-immune system interaction model with immune response delay, in which a nonmonotonic function is used to describe immune response to the tumor burden and a time delay is used to represent the time for the immune system to respond and take effect. It is shown that the model may have one, two or three tumor equilibria, respectively, under different conditions. Time delay can only affect the stability of the low tumor equilibrium and local Hopf bifurcation occurs when the time delay passes through a critical value. The direction and stability of the bifurcating periodic solutions are also determined. Moreover, the global existence of periodic solutions is established by using a global Hopf bifurcation theorem. We also observe the existence of relaxation oscillations and complex oscillating patterns driven by the time delay. Numerical simulations are presented to illustrate the theoretical results.

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The neuropsychiatric syndrome of apathy is now recognized to be a common and disabling condition in Huntington's disease (HD). However, the mechanisms underlying it are poorly understood. One way to investigate apathy is to utilise a theoretical framework of normal motivated behaviour, to determine where breakdown has occurred in people with this behavioural disruption. A fundamental computation underlying motivated, goal-directed behaviour across species is weighing up the costs and rewards associated with actions. Here, we asked whether people with apathy are more sensitive to costs of actions (physical effort and time delay), less sensitive to rewarding outcomes, or both. Based on the unique anatomical substrates associated with HD pathology, we hypothesised that a general hypersensitivity to costs would underpin HD apathy. Genetically confirmed carriers of the expanded Huntingtin gene (premanifest to mild motor manifest disease (n=53) were compared to healthy controls (n = 38). Participants performed a physical effort-based decision-making task (Apple Gathering Task) and a delay discounting task (Money Choice Questionnaire). Choice data was analysed using linear regression and drift diffusion models that also accounted for the time taken to make decisions. Apathetic people with HD accepted fewer offers overall on the Apple Gathering Task, specifically driven by increased sensitivity to physical effort costs, and not explained by motor severity, mood, cognition, or medication. Drift diffusion modelling provided further evidence of effort hypersensitivity, with apathy associated with a faster drift rate towards rejecting offers as a function of varying effort. Increased delay sensitivity was also associated with apathy, both when analysing raw choice and also drift rate, where there was moderate evidence of HD apathy drifting faster towards the immediately available (low cost) option. Furthermore, the effort and delay sensitivity parameters from these tasks were positively correlated. The results demonstrate a clear mechanism for apathy in HD, cost hypersensitivity, which manifests in both the effort and time costs associated with actions towards rewarding goals. This suggests that HD pathology may cause a domain-general disruption of cost processing, which is distinct to apathy occurrence in other brain disorders, and may require different therapeutic approaches.

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For nonlinear systems with uncertain state time delays, an adaptive neural optimal tracking control method based on finite time is designed. With the help of the appropriate LKFs, the time-delay problem is handled. A novel nonquadratic Hamilton-Jacobi-Bellman (HJB) function is defined, where finite time is selected as the upper limit of integration. This function contains information on the state time delay, while also maintaining the basic information. To meet specific requirements, the integral reinforcement learning method is employed to solve the ideal HJB function. Then, a tracking controller is designed to ensure finite-time convergence and optimization of the controlled system. This involves the evaluation and execution of gradient descent updates of neural network weights based on a reinforcement learning architecture. The semi-global practical finite-time stability of the controlled system and the finite-time convergence of the tracking error are guaranteed.

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To resolve the congestion caused by imbalanced traffic at intersections, this paper establishes a model of the average delay deviation with the minimization of the average delay in the approach as the optimization objective. Then, the signal control scheme is further optimized based on the variable approach lanes setting. First, we investigate the threshold conditions for setting the VALs under different flows in a single approach direction. The results show that when the ratio of left-turn traffic exceeds the threshold range of 0.20~0.28, the function of the VALs needs to be changed from straight to left-turn. Then, based on the improved Webster's formula, an optimal timing method that aims at minimizing the average vehicle delay, minimizing the queue length, and maximizing the capacity, is proposed. Finally, taking the actual Huangke intersection in the Hefei demonstration area as an example, three schemes are compared and analyzed in the case of a VAL at the intersection. The results show that under the cooperative optimization scheme proposed in this paper, the travel time and the efficiency of the intersection could be reduced by 18.7% and 9.9%, respectively, when compared with the original and Webster's schemes.

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In this paper, we propose a new data-aided (DA) joint angle and delay (JADE) maximum likelihood (ML) estimator. The latter consists of a substantially modified and, hence, significantly improved gray wolf optimization (GWO) technique by fully integrating and embedding within it the powerful importance sampling (IS) concept. This new approach, referred to hereafter as GWOEIS (for "GWO embedding IS"), guarantees global optimality, and offers higher resolution capabilities over orthogonal frequency division multiplex (OFDM) (i.e., multi-carrier and multi-path) single-input multiple-output (SIMO) channels. The traditional GWO randomly initializes the wolfs' positions (angles and delays) and, hence, requires larger packs and longer hunting (iterations) to catch the prey, i.e., find the correct angles of arrival (AoAs) and time delays (TDs), thereby affecting its search efficiency, whereas GWOEIS ensures faster convergence by providing reliable initial estimates based on a simplified importance function. More importantly, and beyond simple initialization of GWO with IS (coined as IS-GWO hereafter), we modify and dynamically update the conventional simple expression for the convergence factor of the GWO algorithm that entirely drives its hunting and tracking mechanisms by accounting for new cumulative distribution functions (CDFs) derived from the IS technique. Simulations unequivocally confirm these significant benefits in terms of increased accuracy and speed Moreover, GWOEIS reaches the Cramér-Rao lower bound (CRLB), even at low SNR levels.

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Introduction: Activating Signal Cointegrator 1 Complex, Subunit 3 (ASCC3) has been implicated in the pathogenesis of neurodevelopmental disorders and neuromuscular diseases (MIM: 620700). This paper analyzes the clinical manifestations of three patients with developmental delay caused by ASCC3 genetic variation. Additionally, we discuss the previously reported clinical features of these patients along with our own findings, thereby enhancing our understanding of these genetic disorders and providing valuable insights into diagnosis, treatment, and potential interventions for affected individuals. Methods: In this study, we utilized trio-whole-exome sequencing (Trio-WES) and trio-copy number variations sequencing (Trio-CNV-seq) to analyze three unique families diagnosed with developmental delay caused by variation in ASCC3. Additionally, we retrospectively examined eleven previously reported ASCC3 genetic variations exhibiting similar clinical features. Results: Proband I (family 1) and Proband III (family 3) exhibited global developmental delays, characterized by intellectual disability, motor impairment, language retardation, lower muscle strength, and reduced muscle tone in their extremities. Proband II (family 2) presented poor response and dysphagia during feeding within 7 days after birth, clinical examination displayed short limbs, long trunk proportions, and clenched fists frequently observed alongside high muscle tone in his limbs -all indicative signs of developmental delay. Trio-WES revealed compound heterozygous variants in ASCC3 inherited from their parents. Proband I carried c. [489 dup]; [1897C>T], proband II carried c. [2314C>T]; [5002T>A], and proband III carried c. [5113G>T]; [718delG] variations, respectively. Conclusion: This study present the first report of Chinese children carrying compound heterozygous genetic variants in ASCC3 with LOF variants, elucidating the relationship between these variants and various aspects of intellectual disability. This novel finding expands the existing spectrum of ASCC3 variations.

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There is still more to learn about the etiology of extremely uncommon developmental disorders. A heterozygous or hemizygous pathogenic variation in male-specific lethal 3 (MSL3) causes the uncommon X-linked condition known as Basilicata-Akhtar syndrome, which is characterized by a global developmental delay that is evident from infancy, feeding difficulties, and muscle hypotonia. Thus far, over 40 cases have been documented. Here, we report the first case of Basilicata-Akhtar syndrome in India. A 3-year-old boy presented with global development delay. Physical examination revealed dysmorphism and hypotonia. After whole exome sequencing, exon 8 of the MSL3 gene on chromosome X showed evidence of a hemizygous single base pair deletion.

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Tropical cyclones become increasingly nonlinear and dynamically unstable in high-resolution models. The initial conditions are typically sub-optimal, leaving scope to improve the accuracy of forecasts with improved data assimilation. Simultaneously, the lack of real ground-based GNSS observations over the ocean poses significant challenges when evaluating the assimilation results in oceanic regions. In this study, an Observation System Simulation Experiment is carried out based on a tropical cyclone case. Assimilation experiments using the WRF-PDAF framework are conducted. Conventional and GNSS observation operators are implemented. A diverse array of synthetic observations, encompassing temperature (T), wind components (U and V), precipitable water (PW), and zenith total delay (ZTD), are assimilated utilizing the Local Error-Subspace Transform Kalman filter (LESTKF). The findings highlight the improvement in forecast accuracy achieved through the assimilation process over the ocean. Multiple observation types further improve the forecast accuracy. The study underscores the crucial role of GNSS data assimilation techniques. The assimilation of GNSS data presents potential for advancing weather forecasting capabilities. Thus, the construction of ground-based GNSS observation stations over the ocean is promising.

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Background/Objectives: We aimed to investigate the relationship between deformational plagiocephaly (DP) severity and anterior fontanelle size and to explore the connection between fontanelle size and developmental delay. Methods: We enrolled 189 (122 boys and 67 girls; mean corrected age, 119.79 days) of the 256 infants who visited our clinic for plagiocephaly between March 2022 and June 2023. This study analyzed the correlation between cranial vault asymmetry (CVA) and anterior fontanelle size as measured using skull anteroposterior (AP) radiography and ultrasonography. The severity of DP was graded from minimal to severe based on the Argenta classification. Infants were grouped according to CVA severity as follows: Group 1 (CVA ≤ 5 mm), Group 2 (5 mm < CVA < 10 mm), and Group 3 (CVA ≥ 10 mm). Additionally, 40 infants underwent the Denver Developmental Screening Test II (DDST-II) for neurodevelopmental delays and were divided into groups based on the presence or absence of developmental delays for fontanelle size comparison. Results: Age showed a significant negative correlation with fontanelle size (correlation coefficient -0.234, p < 0.05), indicating that fontanelle size decreases as infants age. No significant differences in fontanelle size were observed among the three CVA groups (p = 0.074) or between the developmentally delayed and non-delayed groups (p = 0.09). This study found no correlation between CVA and fontanelle size or between fontanelle size and developmental delay. Conclusions: The findings show that, while anterior fontanelle size decreased with age, there was no significant correlation between the fontanelle size and the severity of deformational plagiocephaly or developmental delays.

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BACKGROUND: Celiac disease (CD) is underdiagnosed and associated with diagnostic delays. This has long-term consequences for the health and well-being of people living with the condition. Little is known about the qualitative configurations of the assessment processes of people living with CD. METHODS: Using a thematic network analysis of 24 in-depth interviews, this study explored the experiences of people living with CD related to their assessment processes leading to being diagnosed. RESULTS: A significant diagnostic delay (up to 26 years) was evident in many interviews. Factors contributing to diagnostic delay included limited knowledge about CD among general practitioners (GP) and in the general population, categorisations of symptoms as 'typical' or 'atypical' and psychosomatic explanations of symptoms. Diagnostic delay resulted in (1) decreased psychological well-being due to severe symptoms, changes in self-perception and self-blame; (2) decreased physiological well-being due to comorbidities; and (3) mistrust in the healthcare system, leading to an increase in informants' responsibility for expediting their assessment processes. This suggested the presence of a neoliberal tendency because informants felt they were primarily responsible for their assessment processes. CONCLUSIONS: We encourage the implementation of initiatives to increase awareness of CD among GPs as well as more consistent and frequent use of the screening guideline due to variations in its clinical presentation. Increased awareness and consistency could reduce variations in assessment processes given GPs' varying knowledge about the condition.

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INTRODUCTION: Surgery is often delayed in patients with proximal femoral fractures who receive oral anticoagulants, to avoid complications related to perioperative bleeding. However, surgery delay may increase the risk of postoperative mortality. Our primary goal was to understand whether anticoagulated patients benefit from early surgery in terms of survival and perioperative complications. METHODS: This is a multicenter retrospective cohort study of 581,189 patients with proximal femoral fractures. About 2.0 % (n = 11,385) received direct oral anticoagulants (DOAC) and 1.5 % (n = 8,726) received warfarin. Surgery was performed within 48 h in 37.6 % of DOAC patients, 27.6 % of warfarin patients and in 41.9 % of nonanticoagulated patients. Survival analysis was applied to compare mortality rate, blood transfusions, systemic complications and surgical complications during hospitalization between the study groups. RESULTS: Patients receiving anticoagulation were older and had more comorbidities than patients without anticoagulation. There were overall similar rates of mortality (0.8 %, 1.1 % and 1.2 %) and surgical complications (2.1 %, 2.1 % and 2.2 %) in non-anticoagulated, DOAC and warfarin patients. Blood transfusions and systemic complications were higher in all anticoagulated patients regardless of surgery timing. There were comparable rates of early surgery (41.9 %, 37.6 % and 27.6 %, respectively). When operated early, DOAC patients had more surgical complications (OR=1.24, p = 0.04). Warfarin patients operated early had higher mortality (OR=1.48, p = 0.08) and higher risk of blood transfusions (OR=1.24, p < 0.001). DISCUSSION: Age and comorbidities could explain higher rates of postoperative systemic complications in anticoagulated patients. Nevertheless, overall short-term mortality was similar between the groups. Early surgery was associated with higher rates of surgical complications in DOAC patients. When operated early, patients receiving warfarin were at an increased risk of mortality (p = 0.08) and perioperative blood transfusions.

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The time delay (TD) in the levitation control system significantly affects the dynamic performance of the closed-loop system in electromagnetic suspension (EMS) maglev vehicles. Excessive TD can cause levitation instability, making it essential to explore effective mitigation methods. To address this issue, a Smith Predictor (SP) is integrated into the traditional PID levitation control system. The combination of theoretical analysis and numerical simulation is employed to assess the stability of the time-delay levitation control system after the integration of the Smith Predictor. Theoretical analysis reveals that when TD exceeds a critical threshold, the levitation system becomes unstable. The addition of SP alters the root trajectory of the system characteristic equation from positive to negative, and recovers the levitation system to stable status. Assuming complete knowledge of the dynamic system, the TD compensation value in the SP becomes a key parameter that determines its performance. A minimum effective value (MEV) for TD compensation is identified, correlating with the system's stability region. Under the influence of TD, more complex systems and higher running speeds of the maglev vehicle lead to a narrower stable region and a larger MEV for TD compensation. Given the simulation parameters in this paper, with a system TD of 15 ms and a maximum vehicle speed of 160 km/h, the MEV for TD compensation in the SP should be set at 12 ms.

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PURPOSE: Triple-negative breast cancer (TNBC) is an aggressive breast cancer histological type that is predictive of poor outcomes, shorter remission periods and reduced survival. TNBC is treated with surgery and neo/adjuvant chemotherapy, with evidence of association between longer periods from surgery to adjuvant chemotherapy (time to chemotherapy, TTC) and poorer survival outcomes. This study investigated regional differences in TTC period between regions and ethnic groups to evaluate equity of care in the English TNBC population. Time from neoadjuvant chemotherapy to surgery (time to surgery, TTS) was also compared between groups. METHODS: This retrospective cohort study compared TTC and TTS periods in TNBC patients in England over a two-year period. TTC and TTS were compared by English region and ethnicity, testing for significant differences in treatment pathway timing by these demographics. RESULTS: 1347 TNBC patients were included in the study. Significant regional differences in TTC were observed, with the longest median period of 50 days (IQR 36, 83) in the Midlands compared to 38 days (IQR 27, 55) in the North West (p < 0.001). No significant differences in TTS were observed between regions. Ethnicity was not significantly associated with timeliness of neo/adjuvant chemotherapy initiation (p > 0.05). CONCLUSION: These findings suggest regional differences in TTC for patients treated with surgery and chemotherapy for TNBC. Given evidence of increased mortality risk as the TTC period increases, the causes of regional disparities warrant further investigation. This study can inform targets for improvement in the delivery of adjuvant chemotherapy in cancer treatment centres in England.

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Protein phosphatase 2A (PP2A) is a family of multifunctional enzymatic complexes crucial for cellular signalling, playing a pivotal role in brain function and development. Mutations in specific genes encoding PP2A complexes have been associated with neurodevelopmental disorders with hypotonia and high risk of seizures. In the current work, we present an individual with specific learning problems, motor coordination disorders, hypotonia and behavioural issues. Although whole exome sequencing (WES) did not unveil pathogenic variants in known genes related to these symptoms, a de novo heterozygous variant Glu191Lys was identified within PPP2R5E, encoding the PP2A regulatory subunit B56ε. The novel variant was not observed in the four healthy brothers and was not detected as parental somatic mosaicism. The mutation predicted a change of charge of the mutated amino acid within a conserved LFDSEDPRER motif common to all PPP2R5 B-subunits. Biochemical assays demonstrated a decreased interaction with the PP2A A and C subunits, leading to disturbances in holoenzyme formation, and thus likely, function. For the first time, we report a potential causal link between the observed variant within the PPP2R5E gene and the symptoms manifested in the subject, spanning specific learning problems and motor coordination disorders potentially associated with myopathy.

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BACKGROUND: Post-endoscopic duodenal perforation is a severe adverse event with high morbidity and mortality rates. Managing this rare event is challenging owing to limited clear guidelines. This retrospective study aimed to examine the relationship between time-to-treatment and morbidity among patients with post-endoscopic duodenal perforations. METHODS: Over 20 years, 78 consecutive patients with post-endoscopic duodenal perforations were analyzed. Among these, most patients underwent endoscopic procedures at the Paoli-Calmettes Institute, whereas some were referred from other centers after a diagnosis of perforation. We described the characteristics of patients who underwent medical treatment alone or interventional procedures. Among patients who underwent interventional management, we compared the outcomes following early or delayed procedures (later than 24 h post-duodenal perforation diagnosis). RESULTS: Overall, 78 patients with post-endoscopic duodenal perforation were identified between September 2003 and September 2022. Of these, 17 (22%) patients underwent non-operative management, and 61 (78%) with peritonitis or adverse clinical features were treated with endoscopic or surgical procedures. Additionally, among these patients, 40 (65%) underwent immediate invasive procedures, surgically (n = 20) or endoscopically (n = 20). Patients with delayed procedures experienced more major Clavien-Dindo ≥ 3 complications and had an increase by 21 of the median comprehensive complication index. Overall, mortality occurred in 7 (8.9%) patients in the entire cohort and in 3 (14.3%) with delayed invasive procedures. CONCLUSIONS: Delayed decision-making is a key factor complicating post-endoscopic duodenal perforation. Therefore, invasive procedures should be performed promptly in cases of adverse conditions requiring additional procedures, ideally within the first 24 h of perforation diagnosis.

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The current study explored a free-operant analogue of discrete-trial procedures to study the effects of amount and delay of reinforcement on choice and response rate. Rats responded on a multiple variable-interval (VI) 45-s, 45-s schedule, with interspersed choice probe trials. Comparison of relative response rates and percentage of choice revealed some discrepancies between the free-operant analogue and discrete-trial procedures. Amount of reward controlled choice behavior when the ratios of delays were similar. When reward delays were more discrepant, delay length controlled choice behavior. Whereas the percentage of choice was larger for the larger magnitude reward, the relative rate of response for the larger magnitude was less than .50. In contrast, when the percentage of choice generally fell to below 50% (with large amount and large delay differences between alternatives), relative response rate indicated a preference for the larger amount alternative. This study shows the feasibility and utility of a free-operant analogue of discrete-choice studies that could be used to develop an analysis of preference.

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Background: α-mannosidosis (MAN) is a rare genetic condition that segregates in an autosomal recessive manner. Lack of lysosomal alpha-mannosidase is the underlying cause of the disease. Symptoms of the disease gradually worsen with the age. Newborns are usually asymptomatic, however, some cases are reported with either congenital ankle equinus or hydrocephalus during the first year. Primary symptoms are characterized by immune deficiency, hearing loss, skeletal abnormalities, progressive mental, motor and speech functions' impairment followed by facial asymmetry. Methods: We studied two Saudi families (A and B) with bilateral moderate hearing loss (family A) and clubfoot with glaucoma (family B). Clinical diagnosis was not reached based on phenotype of patients. Therefore, hypothesis-free whole exome sequencing (WES) was performed on DNA samples from affected individuals of both the families, followed by Sanger sequencing and segregation analysis to validate the segregation of the identified variant. Furthermore, 3D protein modelling was performed to determine the in silico effects of the identified variant on the protein structure and function. Results: Re-examination of clinical features revealed that the patients in family A have speech delay and hearing impairment along with craniostenosis, whereas the patients from family B have only clubfoot and glaucoma. WES identified a well known pathogenic homozygous frameshift variant (NM_000528.4: c.2402dupG; p.S802fs*129) in MAN2B1 in both the families. Sanger sequencing confirmed the segregation of the variant with the disease phenotype in both the families. 3D structural modeling of the MAN2B1 protein revealed significant changes in the tertiary structure of the mutant protein, which would affect enzyme function. This report presents a new case where partial and novel α-mannosidosis phenotypes are associated with a MAN2B1 gene pathogenic variant. Conclusion: Patients in both the families have manifested peculiar set of clinical symptoms associated with α-mannosidosis. Family A manifested partial clinical symptoms missing several characteristic features like intellectual disability, dysmorphic features, neurological and abdominal manifestations, whereas family B has no reported clinical symptoms related to α-mannosidosis except the novel symptoms including club foot and glaucoma which has never been reported earlier The current findings support the evidence that biallelic variants of MAN2B1 are associated with new clinical variants of α-mannosidosis.

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Capillary flow profile of liquid samples in porous media is closely related to the important properties of liquid samples, including the viscosity and the surface energy. Therefore, capillary flow profile can be used as an index to differentiate liquid samples with different properties. Fast and automatic characterization of capillary flow profile of liquid samples is necessary. In this work, we develop a portable and economical capacitance acquisition system (CASY) to easily obtain the capillary flow profile of liquid samples on microfluidic thread-based analytical devices (µTADs) by measuring the capacitance during the capillary flow. At first, we validate the accuracy of this method by comparing with the traditional method by video analysis in obtaining the capillary flow profiles in µTADs of cotton threads or glass fiber threads. Then we use it to differentiate liquid samples with different viscosity (mixture of water and glycerol). In addition, capillary flow profile on µTADs with chemical valves (chitosan or sucrose) can also be obtained on this device. Lastly, we show the potential of this device in measurement of hematocrit (HCT) of whole blood samples. This device can be used to catalog liquid biological samples with different properties in point-of-care diagnostics in the near future.

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Understanding cell state transitions and their governing regulatory mechanisms remains one of the fundamental questions in biology. We develop a computational method, state transition inference using cross-cell correlations (STICCC), for predicting reversible and irreversible cell state transitions at single-cell resolution by using gene expression data and a set of gene regulatory interactions. The method is inspired by the fact that the gene expression time delays between regulators and targets can be exploited to infer past and future gene expression states. From applications to both simulated and experimental single-cell gene expression data, we show that STICCC-inferred vector fields capture basins of attraction and irreversible fluxes. By connecting regulatory information with systems' dynamical behaviors, STICCC reveals how network interactions influence reversible and irreversible state transitions. Compared to existing methods that infer pseudotime and RNA velocity, STICCC provides complementary insights into the gene regulation of cell state transitions.

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Spiking Neural Networks (SNNs) hold great potential for mimicking the brain's efficient processing of information. Although biological evidence suggests that precise spike timing is crucial for effective information encoding, contemporary SNN research mainly concentrates on adjusting connection weights. In this work, we introduce Delay Learning based on Temporal Coding (DLTC), an innovative approach that integrates delay learning with a temporal coding strategy to optimize spike timing in SNNs. DLTC utilizes a learnable delay shift, which assigns varying levels of importance to different informational elements. This is complemented by an adjustable threshold that regulates firing times, allowing for earlier or later neuron activation as needed. We have tested DLTC's effectiveness in various contexts, including vision and auditory classification tasks, where it consistently outperformed traditional weight-only SNNs. The results indicate that DLTC achieves remarkable improvements in accuracy and computational efficiency, marking a step forward in advancing SNNs towards real-world applications. Our codes are accessible at https://github.com/sunpengfei1122/DLTC.