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Background: Extreme floods are known to severely reorganise inhabited landscapes by inundation, clogging, scouring and damaging infrastructure and lives. However, their post-event impacts are poorly understood, especially concerning coupled hillslope channel feedbacks such as the reactivation of slope instabilities connected to the river and that may be able to block it upon sudden failure. The July 2021 Ahr valley flood exemplified this ability of concurrent and sustained landscape reorganisation. Here, we study a retrogressive slope instability near the town of Müsch, in the upper Ahr valley using field mapping, repeat airborne laser scanning, electrical resistivity tomography and passive seismic monitoring to reveal the failure geometry, its mechanisms and transient activity. Results: The old landslide developed in lower Devonian rocks. It is 100 m wide, 200 m long and approximately 15–20 m deep, which leads to a total volume of about 430,000 m3. This landslide was severely undercut by the 2021 flood with 7000 m3 of material eroded at the landslide toe. The landslide has started to react. Given the narrow section of the river at this location, there is a potential landslide dam hazard. We modelled the inundation volumes and back fill times for different failure scenarios, ranging between 20,000 m3 and 330,000 m3 accumulating within 5 min and 20 h. Conclusions: Our results imply a need to systematically screen flood impacted landscapes for sustained post-event hillslope activity that governs hillslope-channel coupling, driving both persistent sediment injection into the stream and sudden river blocking and subsequent damming. [ABSTRACT FROM AUTHOR]

Abstract Background Extreme floods are known to severely reorganise inhabited landscapes by inundation, clogging, scouring and damaging infrastructure and lives. However, their post-event impacts are poorly understood, especially concerning coupled hillslope channel feedbacks such as the reactivation of slope instabilities connected to the river and that may be able to block it upon sudden failure. The July 2021 Ahr valley flood exemplified this ability of concurrent and sustained landscape reorganisation. Here, we study a retrogressive slope instability near the town of Müsch, in the upper Ahr valley using field mapping, repeat airborne laser scanning, electrical resistivity tomography and passive seismic monitoring to reveal the failure geometry, its mechanisms and transient activity. Results The old landslide developed in lower Devonian rocks. It is 100 m wide, 200 m long and approximately 15–20 m deep, which leads to a total volume of about 430,000 m3. This landslide was severely undercut by the 2021 flood with 7000 m3 of material eroded at the landslide toe. The landslide has started to react. Given the narrow section of the river at this location, there is a potential landslide dam hazard. We modelled the inundation volumes and back fill times for different failure scenarios, ranging between 20,000 m3 and 330,000 m3 accumulating within 5 min and 20 h. Conclusions Our results imply a need to systematically screen flood impacted landscapes for sustained post-event hillslope activity that governs hillslope-channel coupling, driving both persistent sediment injection into the stream and sudden river blocking and subsequent damming.

Common statistical theory applicable to confirmatory phase III trial designs usually assumes that patients are enrolled simultaneously and there is no time gap between enrollment and outcome observation. However, in practice, patients are enrolled successively and there is a lag between the enrollment of a patient and the measurement of the primary outcome. For single‐stage designs, the difference between theory and practice only impacts on the trial duration but not on the statistical analysis and its interpretation. For designs with interim analyses, however, the number of patients already enrolled into the trial and the number of patients with available outcome measurements differ, which can cause issues regarding the statistical analyses of the data. The main issue is that current methodologies either imply that at the time of the interim analysis there are so‐called pipeline patients whose data are not used to make a statistical decision (like stopping early for efficacy) or the enrollment into the trial needs to be at least paused for interim analysis to avoid pipeline patients. There are methods for delayed responses available that introduced error‐spending stopping boundaries for the enrollment of patients followed by critical values to reject the null hypothesis in case the stopping boundaries have been crossed beforehand. Here, we will discuss other solutions, considering different boundary determination algorithms using conditional power and introducing a design allowing for recruitment restart while keeping the type I error rate controlled. [ABSTRACT FROM AUTHOR]

Background: Microvascular decompression (MVD) is an effective method for directly treating hemifacial spasms (HFS). The timing for the consideration of failed MVD and reoperation has been paradoxical. Objective: This study aimed to investigate the delayed complete remission of HFS in terms of prevalence rate, duration between surgery and delayed complete remission, and predictive factors. Methods: A hundred patients with HFS who underwent MVD from 2012–2021 were enrolled in the study. All HFS occurred as a result of compression of the facial nerve by adjacent blood vessels. Clinical information, intraoperative findings, and surgical outcomes were incorporated for data analysis. Results: In the first week after MVD, 67 of 100 patients achieved complete remission of HFS, while the remaining 33 had incomplete remission. In long-term follow-up, 26 individuals gradually developed delayed complete remission with a median duration of 9.1 months. Finally, 86 of 100 patients achieved complete long-term remission. Recurrent HFS and incomplete remission were found in 7 and 7 patients, respectively. Factors associated with postoperative complete remission in the first week were a severe degree of facial nerve compression (p = 0.047, OR 2.75, 95% CI 1.01–7.40), with long-term complete remission was left-sided HFS (p = 0.012, OR 5.73, 95% CI 1.47–22.36), and with the appearance of delayed complete remission was the prolonged duration of HFS at least 3 years before MVD (p = 0.046, OR 3.75, 95% CI 1.03–13.76). Transient facial paresis was found in 11% of the patients. Of them, facial nerve function recovered completely in all cases. Conclusions: A delayed complete remission of HFS could be expected in long-term follow-up after MVD and is probably related to a longer duration of HFS before surgery. Unnecessary reoperation should be avoided in the early years following the first surgery. [ABSTRACT FROM AUTHOR]

Introduction: The clinical outcomes and mechanisms of delayed responses to cardiac resynchronization therapy (CRT) remain unclear. We aimed to investigate the differences in outcomes and gain insight into the mechanisms of early and delayed responses to CRT. Methods: This retrospective study included 110 patients who underwent CRT implantation. Positive response to CRT was defined as ≥15% reduction of left ventricular (LV) end‐systolic volume on echocardiography at 1 year (early phase) and 3 years (delayed phase) after implantation. The latest mechanical activation site (LMAS) of the LV was identified using two‐dimensional speckle‐tracking radial strain analysis. Results: Seventy‐eight (71%) patients exhibited an early response 1 year after CRT implantation. Of 32 non‐responders in the early phase, 12 (38%) demonstrated a delayed response, and 20 (62%) were classified as non‐responders after 3 years. During the follow‐up time of 10.3 ± 0.5 years, the delayed and early responders had a similar prognosis of mortality and heart failure (HF) hospitalization. In contrast, non‐responders had a worse prognosis. Multivariate analysis revealed that a longer duration (months) between initial HF hospitalization and CRT (odds ratio [OR]: 1.126; 95% confidence interval [CI]: 1.036–1.222; p =.005), non‐exact concordance of LV lead location with LMAS (OR: 32.744; 95% CI: 1.101–973.518; p =.044), and pre‐QRS duration (OR: 0.901; 95% CI: 0.827–0.981; p =.016) were independent predictors of delayed response to CRT compared with early response. Conclusion: The prognoses were similar regardless of the response time after CRT. A longer history of HF, suboptimal LV lead position, and shorter pre‐QRS duration were related to delayed response than early response. [ABSTRACT FROM AUTHOR]

The characteristics of dynamic and delayed channel geomorphic responses to changing hydrological processes are still insufficiently understood, especially in large dammed rivers and segments farther downstream from the dam. Geomorphic effects farther downstream from the dam could be easily underestimated. This study investigated the hydrological changes and channel adjustments in the Chenglingji–Jiujiang Reach (CJR), ~450 km downstream from the Three Gorges Dam. The post‐dam evolution developed from early low‐intensity alternating erosion/deposition to later intense erosion. This is because the increasing sediment starvation caused by the dam and attenuated upstream sediment replenishment produced streams with excess transport capacity for the farther downstream channel, where the early mild evolution and fine‐sandy riverbed guaranteed adequate sediment availability. Additionally, the increasing geomorphic contribution of low‐to‐medium flows, coupled with revetment resistance to lateral adjustments, promoted migration of the major adjustment area from above the bankfull channel to below the medium‐flow channel and characterized erosion by one‐way incision with no evident channel narrowing/widening. The net increase in reach‐averaged thalweg incision depth during a later period (2.85 m) was 35 times larger than that during an earlier period (0.08 m). Channel morphogenetic intra‐annual hydrological processes were identified to contain all discharges smaller than 39 000 m3/s, and discharges of 30 000–39 000 m3/s exerted maximum geomorphic effects. On this basis, a method for estimating the cumulative erosion volume at equilibrium was proposed and integrated into the Delayed Response Model. The encouraging simulation and prediction results indicate that geomorphological adjustments within the CJR were greatly influenced by the hydrological conditions of current year and previous 4 years, while the impacts of extreme and rare events depended more on the consistency of their hydrological behaviours with channel evolutionary trends than on their temporal distances. This work facilitates the understanding and prediction of channel self‐adjustments farther downstream from the dam. [ABSTRACT FROM AUTHOR]

Reinfections of infected individuals during a viral epidemic contribute to the continuation of the infection for longer periods of time. In an epidemic, contagion starts with an infection wave, initially growing exponentially fast until it reaches a maximum number of infections, following which it wanes towards an equilibrium state of zero infections, assuming that no new variants have emerged. If reinfections are allowed, multiple such infection waves might occur, and the asymptotic equilibrium state is one in which infection rates are not negligible. This paper analyzes such situations by expanding the traditional SIR model to include two new dimensionless parameters, ε and θ, characterizing, respectively, the kinetics of reinfection and a delay time, after which reinfection commences. We find that depending on these parameter values, three different asymptotic regimes develop. For relatively small θ, two of the regimes are asymptotically stable steady states, approached either monotonically, at larger ε (corresponding to a stable node), or as waves of exponentially decaying amplitude and constant frequency, at smaller ε (corresponding to a spiral). For θ values larger than a critical, the asymptotic state is a periodic pattern of constant frequency. However, when ε is sufficiently small, the asymptotic state is a wave. We delineate these regimes and analyze the dependence of the corresponding population fractions (susceptible, infected and recovered) on the two parameters ε and θ and on the reproduction number R0. The results provide insights into the evolution of contagion when reinfection and the waning of immunity are taken into consideration. A related byproduct is the finding that the conventional SIR model is singular at large times, hence the specific quantitative estimate for herd immunity it predicts will likely not materialize. [ABSTRACT FROM AUTHOR]

A viable strategy for enhancing photovoltaic performance is to comprehend the underlying quantum physical regime of charge transfer in a double quantum dots (DQD) photocell. This work explored the photovoltaic performance dependent spatially correlated fluctuation in a DQD photocell. The effects of spatially correlated fluctuation on charge transfer and output photovoltaic efficiency were explored in a proposed DQD photocell model. The results revealed that the charge transport process and the time to peak photovoltaic efficiency were both significantly delayed by the spatially correlated fluctuation, while the anti-spatially correlated fluctuation reduced the output peak photovoltaic efficiency. Further results revealed that the delayed response could be suppressed by gap difference and tunneling coefficient within two dots. Subsequent investigation demonstrated that the delayed response was caused by the spatial correlation fluctuation slowing the generative process of noise-induced coherence, which had previously been proven to improve the quantum photovoltaic performance in quantum photocells. And the reduced photovoltaic properties were verified by the damaged noise-induced coherence owing to the anti-spatial correlation fluctuation and a hotter thermal ambient environment. The discovery of delayed response generated by the spatially correlated fluctuations will deepen the understanding of quantum features of electron transfer, as well as promises to take our understanding even further concerning quantum techniques for high efficiency DQD solar cells. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study was to determine risk factors for delayed response in patients with neurogenic and idiopathic overactive bladder (OAB) after intradetrusor onabotulinumtoxin A injection. Subjects and Methods: This is a retrospective study that included 87 patients who underwent onabotulinumtoxin A intradetrusor injection from October 2011 to November 2019. Patients were followed up at 2, 4, and 12 weeks post intervention in the outpatient clinic and over the phone. The data of patients with early response were compared with those with late response using univariate and multivariate analyses. Results: The study included 87 patients. The mean age was 41 ± 15.3 standard deviation, and 69% of the participants were female. Fifty-one percent were diagnosed with neurogenic OAB. A median response time to onabotulinumtoxin A injection of 7 days was demonstrated, and patients who responded during the first 7 days post procedure were considered early responders. Independent predictors for late response include diabetes (Relative risk: 3.89, P = 0.018, and 95% confidence interval [CI]: 1.26–11.98), >1 BTX-A session (Relative risk: 4, P = 0.011, and 95% CI: 1.38–11.6), and wet OAB (RR: 9.94, P = 0.002, and 95% CI: 2.31–42.17). Conclusions: The median time of onset post intradetrusor injection of onabotulinumtoxin A was found to be 7 days. Diabetes mellitus, wet OAB, and

Objective: The objective of this study was to determine risk factors for delayed response in patients with neurogenic and idiopathic overactive bladder (OAB) after intradetrusor onabotulinumtoxin A injection. Subjects and Methods: This is a retrospective study that included 87 patients who underwent onabotulinumtoxin A intradetrusor injection from October 2011 to November 2019. Patients were followed up at 2, 4, and 12 weeks post intervention in the outpatient clinic and over the phone. The data of patients with early response were compared with those with late response using univariate and multivariate analyses. Results: The study included 87 patients. The mean age was 41 ± 15.3 standard deviation, and 69% of the participants were female. Fifty-one percent were diagnosed with neurogenic OAB. A median response time to onabotulinumtoxin A injection of 7 days was demonstrated, and patients who responded during the first 7 days post procedure were considered early responders. Independent predictors for late response include diabetes (Relative risk: 3.89, P = 0.018, and 95% confidence interval [CI]: 1.26-11.98), >1 BTX-A session (Relative risk: 4, P = 0.011, and 95% CI: 1.38-11.6), and wet OAB (RR: 9.94, P = 0.002, and 95% CI: 2.31-42.17). Conclusions: The median time of onset post intradetrusor injection of onabotulinumtoxin A was found to be 7 days. Diabetes mellitus, wet OAB, and <1 Botox sessions were independent risk factors for late onset of response. [ABSTRACT FROM AUTHOR]

Identification of the optimal dose presents a major challenge in drug development with molecularly targeted agents, immunotherapy, as well as chimeric antigen receptor T-cell treatments. By casting dose finding as a Bayesian model selection problem, we propose an adaptive design by simultaneously incorporating the toxicity and efficacy outcomes to select the optimal biological dose (OBD) in phase I/II clinical trials. Without imposing any parametric assumption or shape constraint on the underlying dose–response curves, we specify curve-free models for both the toxicity and efficacy endpoints to determine the OBD. By integrating the observed data across all dose levels, the proposed design is coherent in dose assignment and thus greatly enhances efficiency and accuracy in pinning down the right dose. Not only does our design possess a completely new yet flexible dose-finding framework, but it also has satisfactory and robust performance as demonstrated by extensive simulation studies. In addition, we show that our design enjoys desirable coherence properties, while most of existing phase I/II designs do not. We further extend the design to accommodate late-onset outcomes which are common in immunotherapy. The proposed design is exemplified with a phase I/II clinical trial in chronic lymphocytic leukemia. [ABSTRACT FROM AUTHOR]

To enable an accurate recognition of neuronal excitability in an epileptic brain for modeling or localization of epileptic zone, here the brain response to single-pulse electrical stimulation (SPES) has been decomposed into its constituent components using adaptive singular spectrum analysis (SSA). Given the response at neuronal level, these components are expected to be the inhibitory and excitatory components. The prime objective is to thoroughly investigate the nature of delayed responses (elicited between 100 ms–1 s after SPES) for localization of the epileptic zone. SSA is a powerful subspace signal analysis method for separation of single channel signals into their constituent uncorrelated components. The consistency in the results for both early and delayed brain responses verifies the usability of the approach. [ABSTRACT FROM AUTHOR]

Climate change has caused inland wetlands shrinkage and exacerbated problems, such as sustainable development and ecological security, for years. These issues are mainly pronounced in the inland arid area. The ecological environment’s deterioration is especially severe in the drylands of the interior. However, dryland wetland changes and their response to climate are poorly understood. This study uses the K-means algorithm in Google Earth Engine (GEE) to classify two typical dryland wetlands (Ebinur and Bosten Lakes) for rapidly and accurately detecting dryland wetland changes. Moreover, it explores the long-term spatial–temporal variation in wetland distribution. In addition, it investigates the response of various lakes to climate change in northern and southern Xinjiang using wavelet analysis. The study’s results showed that K-means clustering in the GEE platform has a high classification accuracy (Kappa > 0.8) in wetland classification, making it a feasible approach. The terminal lake wetland types, represented by the Ebinur Lake, changed significantly between 2001 and 2021. In contrast, the inflow-outflow lake wetland types, represented by the Bosten Lake, perform more consistently. Significant spatial–temporal variation is observed at Ebinur Lake, with the lake gradually shrinking and transforming into a marsh, where the largest marsh proportion degrades into non-wetland during the year. Bosten Lake experienced frequent conversions between marsh and non-wetland throughout the year. Furthermore, the responses of various dryland lakes to climate change are consistent, and a low precedes precipitation and follows evapotranspiration. However, their sensitivity to climate response varies, with the terminal lake being most affected by climate change. Mastering the dynamic changes and climate response of dryland wetlands achieves the sustainable development goals of drylands, including carbon neutrality and peak carbon dioxide emissions.

Female rhesus monkeys and women are subject to age- and menopause-related deficits in working memory, an executive function mediated by the dorsolateral prefrontal cortex (dlPFC). Long-term cyclic administration of 17β-estradiol improves working memory, and restores highly plastic axospinous synapses within layer III dlPFC of aged ovariectomized monkeys. In this study, we tested the hypothesis that synaptic distributions of tau protein phosphorylated at serine 214 (pS214-tau) are altered with age or estradiol treatment, and couple to working memory performance. First, ovariectormized young and aged monkeys received vehicle or estradiol treatment, and were tested on the delayed response (DR) test of working memory. Serial section electron microscopic immunocytochemistry was then performed to quantitatively assess the subcellular synaptic distributions of pS214-tau. Overall, the majority of synapses contained pS214-tau immunogold particles, which were predominantly localized to the cytoplasm of axon terminals. pS214-tau was also abundant within synaptic and cytoplasmic domains of dendritic spines. The density of pS214-tau immunogold within the active zone, cytoplasmic, and plasmalemmal domains of axon terminals, and subjacent to the postsynaptic density within the subsynaptic domains of dendritic spines, were each reduced with age. None of the variables examined were directly linked to cognitive status, but a high density of pS214-tau immunogold particles within presynaptic cytoplasmic and plasmalemmal domains, and within postsynaptic subsynaptic and plasmalemmal domains, accompanied high synapse density. Together, these data support a possible physiological, rather than pathological, role for pS214-tau in the modulation of synaptic morphology in monkey dlPFC.

Age- and menopause-related deficits in working memory can be partially restored with estradiol replacement in women and female nonhuman primates. Working memory is a cognitive function reliant on persistent firing of dorsolateral prefrontal cortex (dlPFC) neurons that requires the activation of GluN2B-containing glutamate NMDA receptors. We tested the hypothesis that the distribution of phospho-Tyr1472-GluN2B (pGluN2B), a predominant form of GluN2B seen at the synapse, is sensitive to aging or estradiol treatment and coupled to working memory performance. First, ovariectomized young and aged rhesus monkeys (Macaca mulatta) received long-term cyclic vehicle (V) or estradiol (E) treatment and were tested on the delayed response (DR) test of working memory. Then, serial section electron microscopic immunocytochemistry was performed to quantitatively assess the subcellular distribution of pGluN2B. While the densities of pGluN2B immunogold particles in dlPFC dendritic spines were not different across age or treatment groups, the percentage of gold particles located within the synaptic compartment was significantly lower in aged-E monkeys compared to young-E and aged-V monkeys. On the other hand, the percentage of pGluN2B gold particles in the spine cytoplasm was decreased with E treatment in young, but increased with E in aged monkeys. In aged monkeys, DR average accuracy inversely correlated with the percentage of synaptic pGluN2B, while it positively correlated with the percentage of cytoplasmic pGluN2B. Together, E replacement may promote cognitive health in aged monkeys, in part, by decreasing the relative representation of synaptic pGluN2B and potentially protecting the dlPFC from calcium toxicity.

IntroductionSevere aplastic anemia(SAA)is a severe disease characterized by immune-mediated bone marrow failure and pancytopenia. Immunosuppressive therapy (ATG plus CsA, IST) is the standard treatment for patients who are not suitable for allogeneic hematopoietic stem cell transplantation (allo-HSCT). Some patients have a delayed response after 6 months of ATG, and unnecessary to be given secondary ATG or allo-HSCT. We attempted to distinguish patients who may get potential delayed response from those who were really not responsive to IST.MethodsWe collected data from 45 SAA patients who were assessed no-response to IST at 6 months after rATG and failed to receive secondary ATG or allo-HSCT.ResultsCsA plus eltrombopag (EPAG) group has an extra 75% response rate while CsA maintenance group has an extra 44% response rate at 12 months. ATG was applied within 30 days after diagnosis, ATG dosage was suffificient (ATG/lymphocyte ≥2), and absolute reticulocyte count (ARC) was ≥30×109 /L at 6 months, indicated patients could get delayed response and benefifit from CsA maintenance. Addition of EPAG could give an even better response. Otherwise, secondary ATG or allo-HSCT treatment were recommended to be given immediately.Clinical Trial Registrationhttps://www.chictr.org.cn/searchproj.aspx, identifier ChiCTR2300067615.

Background: In group-sequential designs, it is typically assumed that there is no time gap between patient enrollment and outcome measurement in clinical trials. However, in practice, there is usually a lag between the two time points. This can affect the statistical analysis of the data, especially in trials with interim analyses. One approach to address delayed responses has been introduced by Hampson and Jennison (J R Stat Soc Ser B Stat Methodol 75:3-54, 2013), who proposed the use of error-spending stopping boundaries for patient enrollment, followed by critical values to reject the null hypothesis if the stopping boundaries are crossed beforehand. Regarding the choice of a trial design, it is important to consider the efficiency of trial designs, e.g. in terms of the probability of trial success (power) and required resources (sample size and time)., Methods: This article aims to shed more light on the performance comparison of group sequential clinical trial designs that account for delayed responses and designs that do not. Suitable performance measures are described and designs are evaluated using the R package rpact. By doing so, we provide insight into global performance measures, discuss the applicability of conditional performance characteristics, and finally whether performance gain justifies the use of complex trial designs that incorporate delayed responses., Results: We investigated how the delayed response group sequential test (DR-GSD) design proposed by Hampson and Jennison (J R Stat Soc Ser B Stat Methodol 75:3-54, 2013) can be extended to include nonbinding lower recruitment stopping boundaries, illustrating that their original design framework can accommodate both binding and nonbinding rules when additional constraints are imposed. Our findings indicate that the performance enhancements from methods incorporating delayed responses heavily rely on the sample size at interim and the volume of data in the pipeline, with overall performance gains being limited., Conclusion: This research extends existing literature on group-sequential designs by offering insights into differences in performance. We conclude that, given the overall marginal differences, discussions regarding appropriate trial designs can pivot towards practical considerations of operational feasibility., (© 2024. The Author(s).)

Reinfections of infected individuals during a viral epidemic contribute to the continuation of the infection for longer periods of time. In an epidemic, contagion starts with an infection wave, initially growing exponentially fast until it reaches a maximum number of infections, following which it wanes towards an equilibrium state of zero infections, assuming that no new variants have emerged. If reinfections are allowed, multiple such infection waves might occur, and the asymptotic equilibrium state is one in which infection rates are not negligible. This paper analyzes such situations by expanding the traditional SIR model to include two new dimensionless parameters, ε and θ, characterizing, respectively, the kinetics of reinfection and a delay time, after which reinfection commences. We find that depending on these parameter values, three different asymptotic regimes develop. For relatively small θ, two of the regimes are asymptotically stable steady states, approached either monotonically, at larger ε (corresponding to a stable node), or as waves of exponentially decaying amplitude and constant frequency, at smaller ε (corresponding to a spiral). For θ values larger than a critical, the asymptotic state is a periodic pattern of constant frequency. However, when ε is sufficiently small, the asymptotic state is a wave. We delineate these regimes and analyze the dependence of the corresponding population fractions (susceptible, infected and recovered) on the two parameters ε and θ and on the reproduction number R0. The results provide insights into the evolution of contagion when reinfection and the waning of immunity are taken into consideration. A related byproduct is the finding that the conventional SIR model is singular at large times, hence the specific quantitative estimate for herd immunity it predicts will likely not materialize.

Age- and menopause-related impairment in working memory mediated by the dorsolateral prefrontal cortex (dlPFC) occurs in humans and nonhuman primates. Long-term cyclic 17β-estradiol treatment rescues cognitive deficits in aged ovariectomized rhesus monkeys while restoring highly plastic synapses. Here we tested whether distributions of G protein-coupled estrogen receptor 1 (GPER1) within monkey layer III dlPFC synapses are sensitive to age and estradiol, and coupled to cognitive function. Ovariectomized young and aged monkeys administered vehicle or estradiol were first tested on a delayed response test of working memory. Then, quantitative serial section immunoelectron microscopy was used to determine the distributions of synaptic GPER1. GPER1-containing nonperforated axospinous synapse density was reduced with age, and partially restored with estrogen treatment. The majority of synapses expressed GPER1, which was predominately localized to presynaptic cytoplasm and mitochondria. GPER1 was also abundant at plasmalemmas, and within cytoplasmic and postsynaptic density (PSD) domains of dendritic spines. GPER1 levels did not differ with age or treatment, and none of the variables examined were tightly associated with cognitive function. However, greater representation of GPER1 subjacent to the PSD accompanied higher synapse density. These data suggest that GPER1 is positioned to support diverse functions key to synaptic plasticity in monkey dlPFC.

Two‐stage single arm designs are widely used in phase II clinical trials with binary endpoints. The trial may be stopped early due to insufficient positive responses in the first stage. There may be some enrolled subjects who have yet to respond by the end of the first stage, and their data are ignored if the first stage results in rejection of the trial. It is possible that the result after the first stage is rejection by a slim margin, while the results of pipeline subjects are quite positive. In this case, combining the data from the two sources may provide a valuable opportunity to rescue a promising treatment that was mistakenly rejected. We propose a novel double‐check design to take advantage of the pipeline subjects' data to establish a rescue criterion based on two‐stage design. When the rescue criterion is met, the decision to reject the trial at the end of the first stage can be reversed, allowing the trial to continue. A derivation based on a binomial distribution shows that the double‐check strategy can strictly preserve the type I error rate. Further examination shows that the strategy can provide a slight increase in overall power and a substantial increase in conditional power when the proportion of positive response at the end of the first stage is at the margin. The extra rescue opportunity's cost is pretty low, only a slight increasing in the expected sample size. [ABSTRACT FROM AUTHOR]

Randomized clinical trials in oncology typically utilize time‐to‐event endpoints such as progression‐free survival or overall survival as their primary efficacy endpoints, and the most commonly used statistical test to analyze these endpoints is the log‐rank test. The power of the log‐rank test depends on the behavior of the hazard ratio of the treatment arm to the control arm. Under the assumption of proportional hazards, the log‐rank test is asymptotically fully efficient. However, this proportionality assumption does not hold true if there is a delayed treatment effect. Cancer immunology has evolved over time and several cancer vaccines are available in the market for treating existing cancers. This includes sipuleucel‐T for metastatic hormone‐refractory prostate cancer, nivolumab for metastatic melanoma, and pembrolizumab for advanced nonsmall‐cell lung cancer. As cancer vaccines require some time to elicit an immune response, a delayed treatment effect is observed, resulting in a violation of the proportional hazards assumption. Thus, the traditional log‐rank test may not be optimal for testing immuno‐oncology drugs in randomized clinical trials. Moreover, the new immuno‐oncology compounds have been shown to be very effective in prolonging overall survival. Therefore, it is desirable to implement a group sequential design with the possibility of early stopping for overwhelming efficacy. In this paper, we investigate the max‐combo test, which utilizes the maximum of two weighted log‐rank statistics, as a robust alternative to the log‐rank test. The new test is implemented for two‐stage designs with possible early stopping at the interim analysis time point. Two classes of weights are investigated for the max‐combo test: the Fleming and Harrington (1981) Gρ,γ$G^{\rho , \gamma }$weights and the Magirr and Burman (2019) modest (τ∗)$ (\tau ^{*})$ weights. [ABSTRACT FROM AUTHOR]

Abstract Background Major depressive disorder and associated mood syndromes are amongst the most common psychiatric disorders. To date, electroconvulsive therapy (ECT) is considered the most effective short-term treatment for patients with severe or treatment-resistant depression. In clinical practice, there is considerable variation in the ECT dosing schedule, with the number of sessions typically ranging from 6 to 12, with early antidepressant effects being predictive of increased positive outcomes. We describe here an unusual case of a female patient with severe depression who did not respond to ECT until the 11th session, after which she had shown a drastic improvement in her mental state. Case presentation A 75-year-old female presented to the old age psychiatry inpatient unit with new onset dysphoric mood, anhedonia, and severe negativity. She scored 23 on the 17-item Hamilton Rating Scale for Depression (HAM-D), and was rated 6 on Clinical Global Impression severity (CGIS) by the responsible clinician. She suffered from post-natal depression fifty years ago and was successfully treated with ECT. She was therefore initiated on a course of ECT treatment. Her condition initially deteriorated, displaying features of catatonia and psychosis, unresponsive to ECT treatment or concurrent psychotropic medications. After 11th ECT session, she started to show signs of clinical improvement and returned close to her baseline mental state after a total of 17 ECT sessions. She remained well 3 months post-treatment, scoring 4 on HAM-D, Clinical Global Improvement or change (CGI-C) rated as 1 (very much improved). The diagnosis was ICD-10 F32.3 severe depressive episode with psychotic symptoms. Conclusions we describe here an unusual case of delayed response to electroconvulsive therapy in the treatment of severe depressive disorder. Studies have shown the number of acute ECT treatments to be highly variable, affected by a number of factors including treatment frequency, condition treated and its severity, the ECT technical parameters, as well as concurrent use of pharmacological treatment. This may call for re-consideration of the current ECT treatment guidelines, requiring more research to help stratify and standardize the treatment regime.

Humans and nonhuman primates are vulnerable to age- and menopause- related decline in working memory, a cognitive function reliant on area 46 of the dorsolateral prefrontal cortex (dlPFC). We showed previously that presynaptic mitochondrial number and morphology in monkey dlPFC neurons correlate with working memory performance. The current study tested the hypothesis that the types of synaptic connections these boutons form are altered with aging and menopause in rhesus monkeys and that these metrics may be coupled with mitochondrial measures and working memory. Using serial section electron microscopy, we examined the frequencies and characteristics of nonsynaptic, single-synaptic, and multisynaptic boutons (MSBs) in the dlPFC. In contrast to our previous observations in the monkey hippocampal dentate gyrus, where MSBs comprised ∼40% of boutons, the vast majority of dlPFC boutons were single-synaptic, whereas MSBs constituted a mere 10%. The frequency of MSBs was not altered by normal aging, but decreased by over 50% with surgical menopause induced by ovariectomy in aged monkeys. Cyclic estradiol treatment in aged ovariectomized animals restored MSB frequencies to levels comparable to young and aged premenopausal monkeys. Notably, the frequency of MSBs positively correlated with working memory scores, as measured by the average accuracy on the delayed response (DR) test. Furthermore, MSB incidence positively correlated with the number of healthy straight mitochondria in dlPFC boutons and inversely correlated with the number of pathological donut-shaped mitochondria. Together, our data suggest that MSBs are coupled to cognitive function and mitochondrial health and are sensitive to estrogen. Significance statement: Many aged menopausal individuals experience deficits in working memory, an executive function reliant on recurrent firing of prefrontal cortex (PFC) neurons. However, little is known about the organization of presynaptic inputs to these neurons and how they may be altered with aging and menopause. Multisynaptic boutons (MSBs) were of particular interest, because they form multiple synapses and can enhance coupling between presynaptic and postsynaptic neurons. We found that higher MSB frequency correlated with better working memory performance in rhesus monkeys. Additionally, aged surgically menopausal monkeys experienced a 50% loss of MSBs that was restored with cyclic estradiol treatment. Together, our findings suggest that hormone replacement therapy benefits cognitive aging, in part by retaining complex synaptic organizations in the PFC.

We provide evidence of delayed attention and inaction in response to COVID-19 in countries that did not experience SARS in 2003. Using cross-country data, we find that individuals in countries that had SARS infections in 2003 searched more intensively for COVID-19-related information on Google in late January 2020, the time of the first known outbreak in Wuhan, China. Early attention to the novel virus, as measured by Google searches, is associated with deeper stock market drops in countries with SARS experience. In contrast, people in countries without SARS experience started to pay more attention much later, in March. Moreover, governments in these countries responded significantly more slowly in implementing social distancing policies to combat domestic COVID-19 outbreaks than governments in countries with SARS experience. Moreover, such early responses of individuals and governments in countries with SARS experience are prevalent within continent, even in non-Asian countries. Furthermore, people in countries with SARS experience are more compliant with social distancing rules. These timely attention and proactive responses of individuals and governments are more pronounced in countries that reported deaths caused by SARS, which left deeper imprints. Our findings suggest that the imprint of similar viruses' experience is a fundamental mechanism underlying timely responses to COVID-19. This paper was accepted by Haoxiang Zhu, finance. [ABSTRACT FROM AUTHOR]

Background: Major depressive disorder and associated mood syndromes are amongst the most common psychiatric disorders. To date, electroconvulsive therapy (ECT) is considered the most effective short-term treatment for patients with severe or treatment-resistant depression. In clinical practice, there is considerable variation in the ECT dosing schedule, with the number of sessions typically ranging from 6 to 12, with early antidepressant effects being predictive of increased positive outcomes. We describe here an unusual case of a female patient with severe depression who did not respond to ECT until the 11th session, after which she had shown a drastic improvement in her mental state. Case presentation: A 75-year-old female presented to the old age psychiatry inpatient unit with new onset dysphoric mood, anhedonia, and severe negativity. She scored 23 on the 17-item Hamilton Rating Scale for Depression (HAM-D), and was rated 6 on Clinical Global Impression severity (CGIS) by the responsible clinician. She suffered from post-natal depression fifty years ago and was successfully treated with ECT. She was therefore initiated on a course of ECT treatment. Her condition initially deteriorated, displaying features of catatonia and psychosis, unresponsive to ECT treatment or concurrent psychotropic medications. After 11th ECT session, she started to show signs of clinical improvement and returned close to her baseline mental state after a total of 17 ECT sessions. She remained well 3 months post-treatment, scoring 4 on HAM-D, Clinical Global Improvement or change (CGI-C) rated as 1 (very much improved). The diagnosis was ICD-10 F32.3 severe depressive episode with psychotic symptoms. Conclusions: we describe here an unusual case of delayed response to electroconvulsive therapy in the treatment of severe depressive disorder. Studies have shown the number of acute ECT treatments to be highly variable, affected by a number of factors including treatment frequency, condition treated and its severity, the ECT technical parameters, as well as concurrent use of pharmacological treatment. This may call for re-consideration of the current ECT treatment guidelines, requiring more research to help stratify and standardize the treatment regime. [ABSTRACT FROM AUTHOR]

This paper documents a strong delayed response to COVID-19, which is caused by the SARS-CoV- 2 virus in countries that did not encounter the SARS disease in 2003. The SARS outbreak was caused by a similar virus, SARS-CoV-1. Individuals in countries that developed SARS infections in 2003 search more intensively for COVID-19-related information on Google during the first outbreak of COVID-19 in Wuhan, China, in late January 2020. Governments in countries that have not experienced SARS respond significantly slower in implementing containment measures to combat COVID-19 than countries that have experienced SARS. Furthermore, the timely responses of individuals and governments are more pronounced in countries that reported deaths caused by SARS, which left deeper imprints. Consequently, COVID-19 case numbers and mortalities have been substantially higher in countries that did not experience SARS deaths. Our findings suggest that the imprint of the early experience of similar viruses is a fundamental mechanism underlying timely responses to COVID-19. [ABSTRACT FROM AUTHOR]

The delayed response of sedimentation is a phenomenon commonly encountered in the fluvial processes of rivers,while previous studies on the sedimentation of the Three Gorges Reservoir (TGR) give little consideration. A delayed response model of sedimentation is established considering sediment inflow and pool level to investigate the recent sedimentation characteristics at the TGR. Based on the measured data during 2003-2017 and the delayed response model,characteristics of water and sediment inflows,as well as characteristics and delayed laws of sedimentation in the flood seasons are comprehensively analyzed. The results indicate that the TGR exhibits the characteristics of large (low) water inflow and large (low) sediment inflow,and sedimentation in the flood seasons tended to increase in conjunction with the rise in pool levels during 2003-2012. There was a consistent relationship between the water and sediment change,and sedimentation in the flood seasons decreased owing to the operation of cascade reservoirs during 2013-2017. Accumulated sedimentation in the TGR during the flood seasons are closely related to the 5 years' linearly superimposed pool level. This indicates that sedimentation in the flood season is affected not only by the current year's sediment inflow and pool level but also by the sediment inflows and pool levels of the previous 4 years. [ABSTRACT FROM AUTHOR]

Objectives in Phase II drug combination studies are to estimate the efficacy response surface for the combination of doses of different drugs and to select the most efficient combination for the final Phase III clinical trial. One problem is to find an optimal design that allocates subjects to the dose-combinations which will maximize the information obtained in the trial. Adaptive designs help in these situations to ensure high efficiency of the study design. We are using a binary efficacy endpoint and consider the practical situation when the timing of the endpoint assessment period on the subject level is considerably longer relative to the inter-arrival time of subjects. This poses implementation challenges for the adaptive design. A solution to the adaptive design problem by using time-to-event models as longitudinal model will be presented. [ABSTRACT FROM AUTHOR]

Abstract To investigate the evolution characteristics of the Yichang–Chenglingji Reach (YCR) of the Middle Yangtze River and develop simulation methods, the temporal and spatial morphodynamic adjustments of the YCR were analysed comprehensively on the basis of runoff, sediment load, and cross-sectional profiles data at 220 cross sections from 2002 to 2016. Results showed that significant channel degradation has occurred in the YCR, especially in the low-flow channels, due to a drastic reduction in sediment yield since the operation of the Three Gorges Project (TGP). The variations of upstream flow and sediment regimes would drive equilibrium channels to become increasingly narrow and deep, and the current bankfull width and depth were less than their equilibrium counterparts in the recent period. However, the recent channel evolution was mainly characterized by the prominent channel deepening via a one-way deformation due to the large-scale bank revetments within the YCR, where the reach-scale bankfull depth increased by 1.6 m in the span of 15 years. A semi-empirical method for determining the equilibrium values of channel degradation and aggradation volume at the YCR was proposed on the basis of a comprehensive analysis of the effects of flow, sediment concentration, sediment gradation, and water depth. Moreover, the equilibrium values of the channel width and depth were estimated with the Least Action Principle method. The calculation methods for the equilibrium width, depth, width/depth ratio, and aggradation/degradation volume were combined with the Delayed Response Model (DRM). Then, the methods for calculating the variations in channel geometry and aggradation/degradation volume were derived. Results showed that the proposed methods effectively simulated the channel geometry and cumulative erosion volume in the YCR from 2002 to 2016. In addition, the response of the channel evolution in the YCR was closely related to the previous four-year hydrological conditions, implying that channel evolution may lag behind the variations of flow and sediment discharges. Highlights • Significant channel degradation has occurred in the low-flow channels. • The recent channel evolution was mainly characterized by the prominent deepening of the channel. • A semi-empirical method for determining the equilibrium values of channel degradation volume was proposed. • The proposed methods effectively simulated the dynamic adjustments of channel geometry. • The response of the channel evolution was closely related to the previous four-year hydrological conditions. [ABSTRACT FROM AUTHOR]

Most vertical wells pass through a mudstone interface at large angles (70-90∘), whereas the contact angle between a horizontal well and a lithologic interface is generally relatively small (20-50∘). Therefore, in the vicinity of this contact point, certain interfaces can be detected through a gamma curve (less than 45 cm), and these will cause a delayed response in the curve. Using the information obtained from the delayed response, the fluctuation characteristics of the lithologic contact interface can be characterized. This study examines gamma ray curves for 122 horizontal wells in the Songliao basin. A detailed analysis of the characteristics of the delayed response when the well passes through the interface between sand and mudstone is conducted, and the lengths of the delay intervals are determined for all wells. An equation for calculating the stratigraphic dip angle of the horizontal well is derived based on the drilling inclination angle in the logging process, and the true dip angle of the contact point is obtained. From these results, a plane distribution map of the dip angles in the study area is drawn and compared with the log interpretation results. Only slight differences are found, which demonstrates that the proposed method has a high reliability. Based on these results, a microstructural map of the fine sand top surface of the HDM reservoir in the Songliao basin is drawn (contour distance: 2 m), which can guide the deep development of the oilfield. [ABSTRACT FROM AUTHOR]

• Firms' delayed responses to M&A comment letters signify agency problems and adversely influence investor confidence. • The adverse effect of delayed response on investor confidence is more pronounced in firms with lower information transparency. • Firms with delayed responses experience significantly lower cumulative abnormal returns after the stock trading resumption date. This study examines the impact of firms' delayed responses to M&A comment letters on investor confidence. Using data from Internet stock message boards between 2015 and 2019 in China, we find that delayed responses by listed companies have a significant adverse effect on investor confidence, and this effect is more pronounced in firms with lower information transparency. Further, we examine firms' stock market performance after the stock trading resumption date and find that companies with delayed responses experience significantly lower cumulative abnormal returns. [ABSTRACT FROM AUTHOR]

Abstract: Defenses induced by herbivore feeding or phytohormones such as methyl jasmonate (MeJA) can affect growth, reproduction, and herbivory, not only on the affected individual but also in its neighboring plants. Here, we report multiannual defense, growth, and reproductive responses of MeJA‐treated bilberry (Vaccinium myrtillus) and neighboring ramets. In a boreal forest in western Norway, we treated bilberry ramets with MeJA and water (control) and measured responses over three consecutive years. We observed the treatment effects on variables associated with herbivory, growth, and reproduction in the MeJA‐treated and untreated ramet and neighboring ramets distanced from 10 to 500 cm. MeJA‐treated ramets had fewer grazed leaves and browsed shoots compared to control, with higher effects in 2014 and 2015, respectively. In 2013, growth of control ramets was greater than MeJA‐treated ramets. However, MeJA‐treated ramets had more flowers and berries than control ramets 2 years after the treatment. The level of insect and mammalian herbivory was also lower in untreated neighboring ramets distanced 10–150 cm and, consistent with responses of MeJA‐treated ramets, the stronger effect was also one and 2 years delayed, respectively. The same neighboring ramets had fewer flowers and berries than untreated ramets, indicating a trade‐off between defense and reproduction. Although plant–plant effects were observed across all years, the strength varied by the distance between the MeJA‐treated ramets and its untreated neighbors. We document that induced defense in bilberry reduces both insect and mammalian herbivory, as well as growth, over multiple seasons. The defense responses occurred in a delayed manner with strongest effects one and 2 years after the induction. Additionally, our results indicate defense signaling between MeJA‐treated ramets and untreated neighbors. In summary, this study shows that induced defenses are important ecological strategies not only for the induced individual plant but also for neighboring plants across multiple years in boreal forests. [ABSTRACT FROM AUTHOR]

The spatial and temporal evolution characteristics of the Qingshuigou channel during 1976-2015 were comprehensively analyzed to investigate the long-term evolution process of the channel. A calculation method for the erosion and aggradation volumes at the Qingshuigou channel was proposed on the basis of Delayed Response Model and by considering the effects of water and sediment conditions and channel extension and retreat. Results showed that the channel reaches at the upstream of the avulsion point were eroded and then aggraded during 1976-1980. Meanwhile, the sediment deposited at the downstream channel reaches and the deposition volume increased in the downstream direction as the channel and floodplain widened. The evolution of the upstream and downstream channel reaches became in-phase after 1980. Influenced by the water and sediment conditions and other factors, the channel was eroded during 1980-1986 and aggraded during 1986-1995. Erosion occurred again due to the artificial water diversion in 1996 and the implementation of water and sediment regulation scheme. The erosion rates decayed exponentially with time after 2002. The proposed method could accurately calculate the erosion/aggradation volume of the channel for a long time period, and it might be used to predict channel evolution in the near future. [ABSTRACT FROM AUTHOR]

Abstract: Background: The incidence and clinical outcomes of delayed response to cardiac resynchronization therapy (CRT) have not been well clarified. We aimed to observe the incidence and prognosis of delayed response and to identify its possible mechanisms. Methods: A total of 115 CRT patients were retrospectively analyzed in our study. Patients who met the enrollment criteria were divided into two groups: group A, conventional responders who showed response at 1‐year follow‐up, and group B, delayed responders who showed response after 1‐year follow‐up. CRT response was defined as an absolute increase of ≥10% in left ventricular ejection fraction. Results: Fifty‐two patients (61 ± 12 years, 37 male) experienced conventional response to CRT and 17 patients (63 ± 11 years, 10 male) experienced delayed response. The mean follow‐up time was 5.2 ± 2.4 years. The incidence of delayed response was 14.8% (17/115). All‐cause mortality and hospitalization rates for heart failure were similar for delayed and conventional responders. Multivariate logistic regression analysis revealed that scar burden > 35% was an independent predictor of CRT delayed response (odds ratio 8.794, P  =  0.038). Conclusions: A significant proportion of patients demonstrated delayed response to CRT. The delayed responders had a good prognosis that was similar to that of conventional responders. More scar burden might be related to the incidence of delayed response. [ABSTRACT FROM AUTHOR]

• The potential of Google Earth Engine (GEE) to detect long-term wetland change series is explored. • Comparing the response of different types of lake wetlands in the arid area to climate. • Evapotranspiration is the primary factor influencing wetland shrinkage in drylands. Climate change has caused inland wetlands shrinkage and exacerbated problems, such as sustainable development and ecological security, for years. These issues are mainly pronounced in the inland arid area. The ecological environment's deterioration is especially severe in the drylands of the interior. However, dryland wetland changes and their response to climate are poorly understood. This study uses the K-means algorithm in Google Earth Engine (GEE) to classify two typical dryland wetlands (Ebinur and Bosten Lakes) for rapidly and accurately detecting dryland wetland changes. Moreover, it explores the long-term spatial–temporal variation in wetland distribution. In addition, it investigates the response of various lakes to climate change in northern and southern Xinjiang using wavelet analysis. The study's results showed that K-means clustering in the GEE platform has a high classification accuracy (Kappa > 0.8) in wetland classification, making it a feasible approach. The terminal lake wetland types, represented by the Ebinur Lake, changed significantly between 2001 and 2021. In contrast, the inflow-outflow lake wetland types, represented by the Bosten Lake, perform more consistently. Significant spatial–temporal variation is observed at Ebinur Lake, with the lake gradually shrinking and transforming into a marsh, where the largest marsh proportion degrades into non-wetland during the year. Bosten Lake experienced frequent conversions between marsh and non-wetland throughout the year. Furthermore, the responses of various dryland lakes to climate change are consistent, and a low precedes precipitation and follows evapotranspiration. However, their sensitivity to climate response varies, with the terminal lake being most affected by climate change. Mastering the dynamic changes and climate response of dryland wetlands achieves the sustainable development goals of drylands, including carbon neutrality and peak carbon dioxide emissions. [ABSTRACT FROM AUTHOR]

We report the case of a 60-year-old woman with metastatic high-grade uterine leiomyosarcoma who achieved a delayed response to second-line therapy with the marine-derived drug trabectedin (Yondelis®, PharmaMar). We used 2-deoxy-2-[18F] fluorodeoxyglucose (FDG)-positron emission tomography (PET-CT) imaging as a tool for response monitoring in parallel with conventional re-staging according to Response Evaluation Criteria in Solid Tumours (RECIST) using computed tomography (CT). We illustrate the role of serial 18FDG-PET-CT imaging in the functional assessment of tumour response. Three cycles after commencement of trabectedin treatment, a reduction of the maximum standardized uptake value (SUVmax) of the solid component of the pelvic mass was observed, indicating a cystic or necrotic response in the tumour to trabectedin. After 7 cycles of treatment, on 18FDG-PET-CT there was clear evidence of ongoing disease improvement: the solid pelvic components were at worst stable, with an unchanged SUVmax, and possibly marginally reduced in size, while the pulmonary metastases had further reduced in size and become FDG negative; the bony metastases were stable. After a total of 13 cycles of treatment, administered over 13 months, the patient showed signs of progression on an 18FDG-PET-CT scan. The safety profile of trabectedin remained manageable, showing no evidence of cumulative toxicity and being associated with a preserved quality of life. This report illustrates potential limitations of RECIST in response assessments and the critical role of serial 18FDG-PET-CT imaging in assessing response to trabectedin treatment. Therefore, we propose that 18FDG-PET-CT may improve the assessment of response to trabectedin in selected patients.