Rapid groundwater decline and some cases of recovery in aquifers globally.

Groundwater resources are vital to ecosystems and livelihoods. Excessive groundwater withdrawals can cause groundwater levels to decline1-10, resulting in seawater intrusion11, land subsidence12,13, streamflow depletion14-16 and wells running dry17. However, the global pace and prevalence of local groundwater declines are poorly constrained, because in situ groundwater levels have not been synthesized at the global scale. Here we analyse in situ groundwater-level trends for 170,000 monitoring wells and 1,693 aquifer systems in countries that encompass approximately 75% of global groundwater withdrawals18. We show that rapid groundwater-level declines (>0.5 m year-1) are widespread in the twenty-first century, especially in dry regions with extensive croplands. Critically, we also show that groundwater-level declines have accelerated over the past four decades in 30% of the world's regional aquifers. This widespread acceleration in groundwater-level deepening highlights an urgent need for more effective measures to address groundwater depletion. Our analysis also reveals specific cases in which depletion trends have reversed following policy changes, managed aquifer recharge and surface-water diversions, demonstrating the potential for depleted aquifer systems to recover.

Benralizumab versus Mepolizumab for Eosinophilic Granulomatosis with Polyangiitis.

BACKGROUND: Eosinophilic granulomatosis with polyangiitis (EGPA) is a vasculitis characterized by eosinophilic inflammation. Benralizumab, a monoclonal antibody against the interleukin-5α receptor expressed on eosinophils, may be an option for treating EGPA. METHODS: We conducted a multicenter, double-blind, phase 3, randomized, active-controlled noninferiority trial to evaluate the efficacy and safety of benralizumab as compared with mepolizumab. Adults with relapsing or refractory EGPA who were receiving standard care were randomly assigned in a 1:1 ratio to receive benralizumab (30 mg) or mepolizumab (300 mg) subcutaneously every 4 weeks for 52 weeks. The primary end point was remission at weeks 36 and 48 (prespecified noninferiority margin, -25 percentage points). Secondary end points included the accrued duration of remission, time to first relapse, oral glucocorticoid use, eosinophil count, and safety. RESULTS: A total of 140 patients underwent randomization (70 assigned to each group). The adjusted percentage of patients with remission at weeks 36 and 48 was 59% in the benralizumab group and 56% in the mepolizumab group (difference, 3 percentage points; 95% confidence interval [CI], -13 to 18; P = 0.73 for superiority), showing noninferiority but not superiority of benralizumab to mepolizumab. The accrued duration of remission and the time to first relapse were similar in the two groups. Complete withdrawal of oral glucocorticoids during weeks 48 through 52 was achieved in 41% of the patients who received benralizumab and 26% of those who received mepolizumab. The mean (±SD) blood eosinophil count at baseline was 306.0±225.0 per microliter in the benralizumab group and 384.9±563.6 per microliter in the mepolizumab group, decreasing to 32.4±40.8 and 71.8±54.4 per microliter, respectively, at week 52. Adverse events were reported in 90% of the patients in the benralizumab group and 96% of those in the mepolizumab group; serious adverse events were reported in 6% and 13%, respectively. CONCLUSIONS: Benralizumab was noninferior to mepolizumab for the induction of remission in patients with relapsing or refractory EGPA. (Funded by AstraZeneca; MANDARA ClinicalTrials.gov number, NCT04157348.).

Spatiotemporal origin of soil water taken up by vegetation.

Vegetation modulates Earth's water, energy and carbon cycles. How its functions might change in the future largely depends on how it copes with droughts1-4. There is evidence that, in places and times of drought, vegetation shifts water uptake to deeper soil5-7 and rock8,9 moisture as well as groundwater10-12. Here we differentiate and assess plant use of four types of water sources: precipitation in the current month (source 1), past precipitation stored in deeper unsaturated soils and/or rocks (source 2), past precipitation stored in groundwater (source 3, locally recharged) and groundwater from precipitation fallen on uplands via river-groundwater convergence toward lowlands (source 4, remotely recharged). We examine global and seasonal patterns and drivers in plant uptake of the four sources using inverse modelling and isotope-based estimates. We find that (1), globally and annually, 70% of plant transpiration relies on source 1, 18% relies on source 2, only 1% relies on source 3 and 10% relies on source 4; (2) regionally and seasonally, source 1 is only 19% in semi-arid, 32% in Mediterranean and 17% in winter-dry tropics in the driest months; and (3) at landscape scales, source 2, taken up by deep roots in the deep vadose zone, is critical in uplands in dry months, but source 4 is up to 47% in valleys where riparian forests and desert oases are found. Because the four sources originate from different places and times, move at different spatiotemporal scales and respond with different sensitivity to climate and anthropogenic forces, understanding the space and time origins of plant water sources can inform ecosystem management and Earth system models on the critical hydrological pathways linking precipitation to vegetation.

Widespread potential loss of streamflow into underlying aquifers across the USA.

Most rivers exchange water with surrounding aquifers1,2. Where groundwater levels lie below nearby streams, streamwater can infiltrate through the streambed, reducing streamflow and recharging the aquifer3. These 'losing' streams have important implications for water availability, riparian ecosystems and environmental flows4-10, but the prevalence of losing streams remains poorly constrained by continent-wide in situ observations. Here we analyse water levels in 4.2 million wells across the contiguous USA and show that nearly two-thirds (64 per cent) of them lie below nearby stream surfaces, implying that these streamwaters will seep into the subsurface if it is sufficiently permeable. A lack of adequate permeability data prevents us from quantifying the magnitudes of these subsurface flows, but our analysis nonetheless demonstrates widespread potential for streamwater losses into underlying aquifers. These potentially losing rivers are more common in drier climates, flatter landscapes and regions with extensive groundwater pumping. Our results thus imply that climatic factors, geological conditions and historic groundwater pumping jointly contribute to the widespread risk of streams losing flow into surrounding aquifers instead of gaining flow from them. Recent modelling studies10 have suggested that losing streams could become common in future decades, but our direct observations show that many rivers across the USA are already potentially losing flow, highlighting the importance of coordinating groundwater and surface water policy.

Double stress of waterlogging and drought drives forest-savanna coexistence.

Forest-savanna boundaries are ecotones that support complex ecosystem functions and are sensitive to biotic/abiotic perturbations. What drives their distribution today and how it may shift in the future are open questions. Feedbacks among climate, fire, herbivory, and land use are known drivers. Here, we show that alternating seasonal drought and waterlogging stress favors the dominance of savanna-like ecosystems over forests. We track the seasonal water-table depth as an indicator of water stress when too deep and oxygen stress when too shallow and map forest/savanna occurrence within this double-stress space in the neotropics. We find that under a given annual precipitation, savannas are favored in landscape positions experiencing double stress, which is more common as the dry season strengthens (climate driver) but only found in waterlogged lowlands (terrain driver). We further show that hydrological changes at the end of the century may expose some flooded forests to savanna expansion, affecting biodiversity and soil carbon storage. Our results highlight the importance of land hydrology in understanding/predicting forest-savanna transitions in a changing world.

Impactful scientists have higher tendency to involve collaborators in new topics.

In scientific research, collaboration is one of the most effective ways to take advantage of new ideas, skills, and resources and for performing interdisciplinary research. Although collaboration networks have been intensively studied, the question of how individual scientists choose collaborators to study a new research topic remains almost unexplored. Here, we investigate the statistics and mechanisms of collaborations of individual scientists along their careers, revealing that, in general, collaborators are involved in significantly fewer topics than expected from a controlled surrogate. In particular, we find that highly productive scientists tend to have a higher fraction of single-topic collaborators, while highly cited-i.e., impactful-scientists have a higher fraction of multitopic collaborators. We also suggest a plausible mechanism for this distinction. Moreover, we investigate the cases where scientists involve existing collaborators in a new topic. We find that, compared to productive scientists, impactful scientists show strong preference of collaboration with high-impact scientists on a new topic. Finally, we validate our findings by investigating active scientists in different years and across different disciplines.

Ca2+-dependent protein acyltransferase DHHC21 controls activation of CD4+ T cells.

Despite the recognized significance of reversible protein lipidation (S-acylation) for T cell receptor signal transduction, the enzymatic control of this post-translational modification in T cells remains poorly understood. Here, we demonstrate that DHHC21 (also known as ZDHHC21), a member of the DHHC family of mammalian protein acyltransferases, mediates T cell receptor-induced S-acylation of proximal T cell signaling proteins. Using Zdhhc21dep mice, which express a functionally deficient version of DHHC21, we show that DHHC21 is a Ca2+/calmodulin-dependent enzyme critical for activation of naïve CD4+ T cells in response to T cell receptor stimulation. We find that disruption of the Ca2+/calmodulin-binding domain of DHHC21 does not affect thymic T cell development but prevents differentiation of peripheral CD4+ T cells into Th1, Th2 and Th17 effector T helper lineages. Our findings identify DHHC21 as an essential component of the T cell receptor signaling machinery and define a new role for protein acyltransferases in regulation of T cell-mediated immunity.

Adjuvant treatment strategy evolution and risk stratification for hormone receptor-positive, human epidermal growth factor receptor-2 negative early breast cancer in China.

BACKGROUND: Patients with hormone receptor-positive (HR+), human epidermal growth factor receptor-2 negative (HER2-) early breast cancer (EBC) with high-risk clinicopathological features face an increased risk of recurrence. This study explored the evolving treatment landscape and clinical outcomes in patients with EBC using a nationwide database. PATIENTS AND METHODS: The study cohort comprised HR+/HER2-, stages 1-3, patients with EBC who underwent surgery and received adjuvant endocrine therapy (AET) from January 2013 to March 2021. High-risk patients were defined by ≥4 positive axillary lymph nodes, or 1-3 positive lymph node(s) with at least one high-risk feature (histologic grade 3, tumor size ≥5 cm, or Ki-67 ≥20%). A low-risk cohort included patients not meeting the criteria. Survival analysis was conducted with a cutoff of September 2021. RESULTS: The study included 4088 eligible patients (1310 high-risk patients and 2778 low-risk patients). High-risk patients were more likely to receive adjuvant chemotherapy and radiotherapy compared to low-risk patients. From 2013 to 2021, an increasing proportion of patients received aromatase inhibitors and ovarian function suppression as part of their AET. The 2-, 5-, and 7-year invasive disease-free survival for high-risk cohort were 90.67%, 75.26%, and 57.10%, respectively, these rates were notably higher for low-risk cohort at 97.14%, 89.85%, and 84.83%. High-risk patients demonstrated a higher risk of recurrence or death compared with low-risk patients (hazard ratio, 2.38; 95% CI, 1.82-3.12). CONCLUSION: In the setting of standard or even intensive AET, patients with EBC with high-risk features still present high recurrence risk, highlighting the urgent need for innovative adjuvant treatment strategies.

First-In-Human Phase I Study of Tinengotinib (TT-00420), a Multiple Kinase Inhibitor, as a Single Agent in Patients With Advanced Solid Tumors.

PURPOSE: This first-in-human phase I dose-escalation study evaluated the safety, pharmacokinetics, and efficacy of tinengotinib (TT-00420), a multi-kinase inhibitor targeting fibroblast growth factor receptors 1-3 (FGFRs 1-3), Janus kinase 1/2, vascular endothelial growth factor receptors, and Aurora A/B, in patients with advanced solid tumors. PATIENTS AND METHODS: Patients received tinengotinib orally daily in 28-day cycles. Dose escalation was guided by Bayesian modeling using escalation with overdose control. The primary objective was to assess dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and dose recommended for dose expansion (DRDE). Secondary objectives included pharmacokinetics and efficacy. RESULTS: Forty-eight patients were enrolled (dose escalation, n = 40; dose expansion, n = 8). MTD was not reached; DRDE was 12 mg daily. DLTs were palmar-plantar erythrodysesthesia syndrome (8 mg, n = 1) and hypertension (15 mg, n = 2). The most common treatment-related adverse event was hypertension (50.0%). In 43 response-evaluable patients, 13 (30.2%) achieved partial response (PR; n = 7) or stable disease (SD) ≥ 24 weeks (n = 6), including 4/11 (36.4%) with FGFR2 mutations/fusions and cholangiocarcinoma (PR n = 3; SD ≥ 24 weeks n = 1), 3/3 (100.0%) with hormone receptor (HR)-positive/HER2-negative breast cancer (PR n = 2; SD ≥ 24 weeks n = 1), 2/5 (40.0%) with triple-negative breast cancer (TNBC; PR n = 1; SD ≥ 24 weeks n = 1), and 1/1 (100.0%) with castrate-resistant prostate cancer (CRPC; PR). Four of 12 patients (33.3%; HR-positive/HER2-negative breast cancer, TNBC, prostate cancer, and cholangiocarcinoma) treated at DRDE had PRs. Tinengotinib's half-life was 28-34 hours. CONCLUSIONS: Tinengotinib was well tolerated with favorable pharmacokinetic characteristics. Preliminary findings indicated potential clinical benefit in FGFR inhibitor-refractory cholangiocarcinoma, HER2-negative breast cancer (including TNBC), and CRPC. Continued evaluation of tinengotinib is warranted in phase II trials.

Cancer immunotherapy of Wilms tumor: a narrative review.

Wilms tumor (WT) is the most common malignant tumor of the urinary system in children. Though the traditional treatment of surgery plus radiotherapy and chemotherapy achieves exciting clinical efficacy, in relapsed and refractory cases, the long-term overall survival rates are poor. Besides, chemotherapy and radiation have serious long-term toxic side effects on children. Cancer immunotherapy is a new tumor therapy that works by activating the body's immune system to allow immune cells to kill tumor cells more efficiently. Currently, cancer immunotherapy has been tested in clinical trials or basic studies in WT. This article reviews the current status of clinical trials and basic research of cancer immunotherapy in WT to promote the application of cancer immunotherapy in WT patients.

[Box: see text].

Reactivating ordinal position information from auditory sequence memory in human brains.

Retaining a sequence of events in their order is a core ability of many cognitive functions, such as speech recognition, movement control, and episodic memory. Although content representations have been widely studied in working memory (WM), little is known about how ordinal position information of an auditory sequence is retained in the human brain as well as its coding characteristics. In fact, there is still a lack of an efficient approach to directly accessing the stored ordinal position code during WM retention. Here, 31 participants performed an auditory sequence WM task with their brain activities recorded using electroencephalography (EEG). We developed new triggering events that could successfully reactivate neural representations of ordinal position during the delay period. Importantly, the ordinal position reactivation is further related to recognition behavior, confirming its indexing of WM storage. Furthermore, the ordinal position code displays an intriguing "stable-dynamic" format, i.e. undergoing the same dynamic neutral trajectory in the multivariate neural space during both encoding and retention (whenever reactivated). Overall, our results provide an effective approach to accessing the behaviorally-relevant ordinal position information in auditory sequence WM and reveal its new temporal characteristics.

Spatiotemporal variations in soil pollution by polycyclic aromatic hydrocarbons over a 20-year economic boom in different districts of a heavy industrial city in North China.

Urbanization-related human activities, such as population aggregation, rapid industrial expansion, and intensified traffic, are key factors that impact local polycyclic aromatic hydrocarbon emissions and their associated health risks. Consequently, regions with varying degrees of urbanization within a megacity may exhibit diverse spatiotemporal patterns in the presence and distribution of soil polycyclic aromatic hydrocarbons, resulting in different levels of ecological risks for local inhabitants following the same period of development. In this study, we measured the concentrations of 16 polycyclic aromatic hydrocarbons in soil samples collected from industrial district and rural district in Tianjin (China) in 2018, and compared with polycyclic aromatic hydrocarbon data in 2001 from a previous study to characterize these regional variations in occurrence, source, and human risk of polycyclic aromatic hydrocarbons induced by urbanization with time and space. The results indicate the 20-year rapid urbanization and industrialization has differentially affected the composition, distribution and sources of polycyclic aromatic hydrocarbons in soils from different economic functional zones in Tianjin. Additionally, its impact on health risks in rural district appeared to be more significant than that in industrial district.

Walking pace and microvascular complications among individuals with type 2 diabetes: A cohort study from the UK Biobank.

INTRODUCTION: Walking pace is associated with various health-related outcomes. The aim of this study was to investigate the association between self-reported walking pace and the incidences of diabetic microvascular complications among participants with type 2 diabetes (T2D). METHODS: Self-reported walking pace was classified as brisk, average, or slow. The outcomes were the incidences of diabetic retinopathy, diabetic neuropathy, and diabetic nephropathy. COX proportional hazards models adjusted for sociodemographic, lifestyle, and health-related factors were used to estimate hazard ratios (HRs) and 95% CIs. RESULTS: A total of 14 518 participants with T2D in the UK Biobank (mean age 59.7 ± 7.0 years, 5028 [34.6%] women) were included. During a median follow-up of 12.5 (interquartile range: 11.6-13.4) years, 2980 participants developed diabetic microvascular complications. After adjusting for confounding factors, and compared with brisk walkers, slow walkers had a multivariable-adjusted HR of 1.98 (95% CI 1.58, 2.47) for composite diabetic microvascular complications, 1.54 (95% CI 1.11, 2.14) for diabetic retinopathy, 3.26 (95% CI 2.08, 5.11) for diabetic neuropathy, and 2.32 (95% CI 1.91, 2.82) for diabetic nephropathy. Average walking pace was associated with a higher risk for diabetic nephropathy (HR 1.51, 95 CI% 1.27-1.79) compared with brisk walking. Additionally, ≥1 diabetic microvascular complication occurred in 447 (14.7%) of participants with brisk walking pace, 1702 (19.5%) with average walking pace, and 831 (30.4%) with slow walking pace. Time from study recruitment to first diagnosis was shorter in participants who reported a slow walking pace, compared with brisk or average walkers. Among participants who had diabetic nephropathy as their first diagnosis, slow walking pace was associated with subsequent risk of a second diabetic microvascular complication (HR 3.88, 95 CI% 2.27-6.60). CONCLUSIONS: Self-reported slow walking pace is associated with a higher risk of diabetic microvascular complications among participants with T2D in this population-based cohort study.

Modifiable lifestyle, mental health status and diabetic retinopathy in U.S. adults aged 18-64 years with diabetes: a population-based cross-sectional study from NHANES 1999-2018.

BACKGROUND: The relationship between integrated lifestyles, mental status and their impact on overall well-being has attracted considerable attention. This study aimed to evaluate the association between lifestyle factors, depression and diabetic retinopathy (DR) in adults aged 18-64 years. METHODS: A cohort of 3482 participants diagnosed with diabetes was drawn from the National Health and Nutrition Examination Survey (NHANES) spanning the years 1999-2018. DR was defined based on self-reported diabetic retinopathy diagnoses by professional physicians, relying on Diabetes Interview Questionnaires. Subgroup analysis was employed to assess lifestyle and psychological factors between participants with DR and those without, both overall and stratified by diabetic duration. Continuous variables were analyzed using the student's t test, while weighted Rao-Scott χ2 test were employed for categorical variables to compare characteristics among the groups. RESULTS: Of the 3482 participants, 767 were diagnosed with diabetic retinopathy, yielding a weighted DR prevalence of 20.8%. Patients with DR exhibited a higher prevalence of heavy drinking, depression, sleep deprivation, and insufficient physical activity compared to those without DR. Furthermore, multivariable logistic regression analysis revealed that sleeping less than 5 h (OR = 3.18, 95%CI: 2.04-4.95, p < 0.001) and depression (OR = 1.35, 95%CI:1.06-1.64, p = 0.025) were associated with a higher risk of DR, while moderate drinking (OR = 0.49, 95%CI: 0.32-0.75, p = 0.001) and greater physical activity (OR = 0.64, 95%CI: 0.35-0.92, p = 0.044) were identified as protective factors. CONCLUSIONS: Adults aged 18-64 years with DR exhibited a higher prevalence of lifestyle-related risk factors and poorer mental health. These findings underscore the need for concerted efforts to promote healthy lifestyles and positive emotional well-being in this population.

Analysis of Factors Influencing the Stigma Associated with Postoperative Cervical Cancer Patients and the Impact of Integrated Nursing Interventions on Stigma.

Objective: To investigate the influencing factors related to stigma and nursing interventions for patients after cervical cancer surgery. Methods: The clinical data of 158 patients with cervical cancer treated with radical cervical cancer in Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology from November 2016 to December 2021 were retrospectively analyzed. The patients were divided into a research group (79 cases) and a control group (79 cases) based on the random number method. In the control group, patients were given general nursing instructions during the post-operative visit. In contrast, the research group provided comprehensive nursing interventions to patients and their families based on the observation group. The Social Impact Scale (SIS) was used to assess the patients' stigma; the Self-Rating Anxiety Scale (SAS), Trait Coping Style Questionnaire (TCSQ), and Quality of Life Questionnaire for Cancer Patients (QLQ-C30) were also used to assess the patients' pre- and post-care interventions. The patients' status was assessed before and after the intervention. Results: The SIS score (49.68±8.41) and TCSQ negative coping score (30.14±7.06) of the patients in the research group after the nursing intervention were much smaller than those in the control group, and the TCSQ positive coping score (40.36±6.51) was much larger than that of the control group (P < .05). The SAS anxiety score (31.65±7.36) was much smaller, and the QLQ-C30 score (78.65±16.59) was much larger in the research group than in the control group after the nursing intervention (P < .05). Conclusion: Risk factors affecting postoperative cervical cancer patients' sense of stigma include age 18-35 years, high school and above, employed, monthly income >3000 RMB, family history of the disease, disease duration >5 years, and postoperative chemotherapy, etc. Comprehensive clinical interventions can be given to patients with these conditions to reduce the sense of stigma.

Digital Serious Games to Promote Behavior Change in Children With Chronic Diseases: Scoping Review and Development of a Self-Management Learning Framework.

BACKGROUND: Digital serious games (SGs) have rapidly become a promising strategy for entertainment-based health education; however, developing SGs for children with chronic diseases remains a challenge. OBJECTIVE: In this study, we attempted to provide an updated scope of understanding of the development and evaluation of SG educational tools and develop a framework for SG education development to promote self-management activities and behavior change in children with chronic diseases. METHODS: This study consists of a knowledge base and an analytical base. This study followed the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) guidelines. To build the knowledge base, 5 stages of research were developed, including refining the review question (stage 1), searching for studies (stage 2), selecting relevant studies (stage 3), charting the information (stage 4), and collating the results (stage 5). Eligible studies that developed SG prototypes and evaluated SG education for children with chronic diseases were searched for in PubMed, Embase, Google Scholar, and peer-reviewed journals. In the analytical base, the context-mechanism-output approach and game taxonomy were used to analyze relevant behavioral theories and essential game elements. Game taxonomy included social features, presentation, narrative and identity, rewards and punishment, and manipulation and control. A total of 2 researchers selected the domains for the included behavioral theories and game elements. The intended SG framework was finalized by assembling SG fragments. Those SG fragments were appropriately reintegrated to visualize a new SG framework. RESULTS: This scoping review summarized data from 16 randomized controlled trials that evaluated SG education for children with chronic diseases and 14 studies on SG frameworks. It showed that self-determination theory was the most commonly used behavioral theory (9/30, 30%). Game elements included feedback, visual and audio designs, characters, narratives, rewards, challenges, competitions, goals, levels, rules, and tasks. In total, 3 phases of a digital SG framework are proposed in this review: requirements (phase 1), design and development (phase 2), and evaluation (phase 3). A total of 6 steps are described: exploring SG requirements (step 1), identifying target users (step 2), designing an SG prototype (step 3), building the SG prototype (step 4), evaluating the SG prototype (step 5), and marketing and monitoring the use of the SG prototype (step 6). Safety recommendations to use digital SG-based education for children in the post-COVID-19 era were also made. CONCLUSIONS: This review summarizes the fundamental behavioral theories and game elements of the available literature to establish a new theory-driven step-by-step framework. It can support game designers, clinicians, and educators in designing, developing, and evaluating digital, SG-based educational tools to increase self-management activities and promote behavior change in children with chronic diseases.

Characterization of AST-001 non-clinical pharmacokinetics: A novel selective AKR1C3-activated prodrug in mice, rats, and cynomolgus monkeys.

AST-001 is a chemically synthesized inactive nitrogen mustard prodrug that is selectively cleaved to a cytotoxic aziridine (AST-2660) via aldo-keto reductase family 1 member C3 (AKR1C3). The purpose of this study was to investigate the pharmacokinetics and tissue distribution of the prodrug, AST-001, and its active metabolite, AST-2660, in mice, rats, and monkeys. After single and once daily intravenous bolus doses of 1.5, 4.5, and 13.5 mg/kg AST-001 to Sprague-Dawley rats and once daily 1 h intravenous infusions of 0.5, 1.5, and 4.5 mg/kg AST-001 to cynomolgus monkeys, AST-001 exhibited dose-dependent pharmacokinetics and reached peak plasma levels at the end of the infusion. No significant accumulation and gender differences were observed after 7 days of repeated dosing. In rats, the half-life of AST-001 was dose independent and ranged from 4.89 to 5.75 h. In cynomolgus monkeys, the half-life of AST-001 was from 1.66 to 5.56 h and increased with dose. In tissue distribution studies conducted in Sprague-Dawley rats and in liver cancer PDX models in female athymic nude mice implanted with LI6643 or LI6280 HepG2-GFP tumor fragments, AST-001 was extensively distributed to selected tissues. Following a single intravenous dose, AST-001 was not excreted primarily as the prodrug, AST-001 or the metabolite AST-2660 in the urine, feces, and bile. A comprehensive analysis of the preclinical data and inter-species allometric scaling were used to estimate the pharmacokinetic parameters of AST-001 in humans and led to the recommendation of a starting dose of 5 mg/m2 in the first-in-human dose escalation study.

Motifs-based link prediction for heterogeneous multilayer networks.

Link prediction has a wide range of applications in the study of complex networks, and the current research on link prediction based on single-layer networks has achieved fruitful results, while link prediction methods for multilayer networks have to be further developed. Existing research on link prediction for multilayer networks mainly focuses on multiplexed networks with homogeneous nodes and heterogeneous edges, while there are relatively few studies on general multilayer networks with heterogeneous nodes and edges. In this context, this paper proposes a method for heterogeneous multilayer networks based on motifs for link prediction. The method considers not only the effect of heterogeneity of edges on network links but also the effect of heterogeneous and homogeneous nodes on the existence of links between nodes. In addition, we use the role function of nodes to measure the contribution of nodes to form the motifs with links in different layers of the network, thus enabling the prediction of intra- and inter-layer links on heterogeneous multilayer networks. Finally, we apply the method to several empirical networks and find that our method has better link prediction performance than several other link prediction methods on multilayer networks.

A nomogram-based prediction model for dysphagia in patients with chronic obstructive pulmonary disease: A cross-sectional study.

AIM AND OBJECTIVES: To investigate the prevalence of dysphagia in patients with COPD, identify the risk factors for dysphagia, develop a visual clinical prediction model and quantitatively predict the probability of developing dysphagia. BACKGROUND: Patients with COPD are at high risk of dysphagia, which is strongly linked to the acute exacerbation of their condition. The use of effective tools to predict its risk may contribute to the early identification and treatment of dysphagia in patients with COPD. DESIGN: A cross-sectional design. METHODS: From July 2021 to April 2023, we enrolled 405 patients with COPD for this study. The clinical prediction model was constructed according to the results of a univariate analysis and a logistic regression analysis, evaluated by discrimination, calibration and decision curve analysis and visualized by a nomogram. This study was reported using the TRIPOD checklist. RESULTS: In total, 405 patients with COPD experienced dysphagia with a prevalence of 59.01%. A visual prediction model was constructed based on age, whether combined with cerebrovascular disease, chronic pulmonary heart disease, acute exacerbation of COPD, home noninvasive positive pressure ventilation, dyspnoea level and xerostomia level. The model exhibited excellent discrimination at an AUC of .879. Calibration curve analysis indicated a good agreement between experimental and predicted values, and the decision curve analysis showed a high clinical utility. CONCLUSION: The model we devised may be used in clinical settings to predict the occurrence of dysphagia in patients with COPD at an early stage. RELEVANCE TO CLINICAL PRACTICE: The model can help nursing staff to calculate the risk probability of dysphagia in patients with COPD, formulate personalized preventive care measures for high-risk groups as soon as possible to achieve early prevention or delay of dysphagia and its related complications and improve the prognosis. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution.

Seasonal patterns, fate and ecological risk assessment of pharmaceutical compounds in a wastewater treatment plant with Bacillus bio-reactor treatment.

Pharmaceutical compounds (PhCs) pose a growing concern with potential environmental impacts, commonly introduced into the environment via wastewater treatment plants (WWTPs). The occurrence, removal, and season variations of 60 different classes of PhCs were investigated in the baffled bioreactor (BBR) wastewater treatment process during summer and winter. The concentrations of 60 PhCs were 3400 ± 1600 ng/L in the influent, 2700 ± 930 ng/L in the effluent, and 2400 ± 120 ng/g dw in sludge. Valsartan (Val, 1800 ng/L) was the main contaminant found in the influent, declining to 520 ng/L in the effluent. The grit chamber and BBR tank were substantially conducive to the removal of VAL. Nonetheless, the BBR process showcased variable removal efficiencies across different PhC classes. Sulfadimidine had the highest removal efficiency of 87 ± 17% in the final effluent (water plus solid phase). Contrasting seasonal patterns were observed among PhC classes within BBR process units. The concentrations of many PhCs were higher in summer than in winter, while some macrolide antibiotics exhibited opposing seasonal fluctuations. A thorough mass balance analysis revealed quinolone and sulfonamide antibiotics were primarily eliminated through degradation and transformation in the BBR process. Conversely, 40.2 g/d of macrolide antibiotics was released to the natural aquatic environment via effluent discharge. Gastric acid and anticoagulants, as well as cardiovascular PhCs, primarily experienced removal through sludge adsorption. This study provides valuable insights into the intricate dynamics of PhCs in wastewater treatment, emphasizing the need for tailored strategies to effectively mitigate their release and potential environmental risks.