Artificial aeration has been considered to be the most effective method to enhance the nitrogen removal efficiency of constructed wetlands (CWs) under low carbon-nitrogen (C/N) ratio conditions. However, it is worth noting that enhancing nitrogen removal in intermittently aerated CWs often exacerbates greenhouse gas (GHG) emissions making the wetlands become a carbon source. The synergistic effect of using a biodegradable polymer, poly (butylene succinate) (PBS), as a solid carbon source to address this challenge remains obscure. This study established three vertical flow CWs: a non-aerated control (CWB), an intermittently aerated system (CWA), and an intermittently aerated system amended with PBS (CWP). Results demonstrated that CWP achieved superior total nitrogen removal efficiency (94.28 ± 4.14%) without secondary COD pollution. Concurrently, CWP drastically mitigated GHG emissions, reducing the total global warming potential by 64.9% and 70.8% compared to CWA and CWB, respectively, primarily by substantially reducing nitrous oxide emissions. Mechanistically, PBS addition significantly enriched key denitrification genes, elevating the nosZ/nirS + nirK ratio by over 38%. This fostered a beneficial microbial community distinct from the controls, enriching for efficient heterotrophic nitrification-aerobic denitrification genera such as Acidovorax and Propionivibrio. Furthermore, metabolic pathway analysis revealed that CWP not only promoted complete denitrification but also coordinately upregulated the entire aerobic methane oxidation pathway, enhancing the processing of formaldehyde. This study demonstrates that integrating PBS into intermittently aerated CWs is an effective strategy to simultaneously achieve high-efficiency nutrient removal and profound GHG mitigation for low C/N wastewater.
Renal dysfunction is a major postoperative complication of thoracoabdominal aortic aneurysm repair and is closely associated with increased mortality. We adopted a simple method involving intermittent cold crystalloid perfusion into the renal arteries using gravity infusion during thoracoabdominal aortic aneurysm repair and evaluated its effectiveness. Between April 2011 and January 2024, 63 patients underwent open thoracoabdominal aortic aneurysm repair at Fukuoka University Hospital. After excluding 11 cases, 52 cases were retrospectively analyzed. Intermittent renal perfusion was performed using 4 °C lactated Ringer solution containing mannitol and methylprednisolone. Patients were classified into chronic kidney disease (< 45 mL/min) and non-chronic kidney disease groups (≥ 45 mL/min) based on the preoperative estimated glomerular filtration rate, and renal function was assessed. There were no significant differences in operative or ischemic parameters between the groups. Postoperative acute kidney injury (Kidney Disease: Improving Global Outcomes stage ≥ 2) occurred in 21% of all patients, with no significant difference between the groups. Serum creatinine levels increased transiently postoperatively in both groups but returned to baseline or improved at discharge. No patient required long-term dialysis. Urine output tended to be higher in the chronic kidney disease group than in the non-chronic kidney disease group, particularly during the early postoperative period. Intermittent cold crystalloid perfusion is a simple and effective method for renal protection in thoracoabdominal aortic aneurysm repair with favorable clinical outcomes regardless of preoperative renal function. The absence of permanent dialysis cases suggests that this approach is safe and feasible, particularly in emergencies and resource-limited settings.
Organochlorine pesticides (OCPs) remain a persistent environmental threat because of their chemical stability, strong lipophilicity, and bioaccumulation in adipose tissue, where they disrupt metabolic regulation. In this study, we examined how dietary context modulates the metabolic toxicity of an organochlorine pesticide mixture (OCPM; chlordane, heptachlor, p,p'-DDT, β-HCH, and hexachlorobenzene in a 1:1:1:1:1 ratio) using a murine model chronically exposed to environmentally relevant doses (0.05-2 mg/kg body weight). Mice were maintained either on a high-fat diet (HFD, 60 kcal%) or under an intermittent calorie restriction (ICR) regimen consisting of alternating two-week cycles of HFD and low-fat diet (LFD, 10 kcal%) for 12 weeks. Under HFD conditions, OCPM exposure induced hyperglycemia, elevated triglycerides and TNF-α, reduced adiponectin, and suppressed insulin signaling (IRβ, p-PI3K, p-AKT, and GLUT4 expression), accompanied by hepatic lipid accumulation and pancreatic β-cell disorganization. In contrast, ICR markedly attenuated these abnormalities by restoring lipid and inflammatory profiles, improving insulin sensitivity (lower HOMA-IR and higher QUICKI), and preserving hepatic mitochondrial content, glycogen stores, and islet morphology. Notably, the lowest dose of OCPM (0.05 mg/kg) produced the greatest metabolic impairment, consistent with a non-monotonic endocrine-disrupting response. Collectively, these findings demonstrate that dietary context critically shapes the metabolic consequences of chronic OCP exposure and suggest that intermittent nutritional modulation enhances metabolic resilience and may represent a practical strategy to mitigate pollutant-induced metabolic dysfunction.
To report a case of canaliculops, a rare, non-inflammatory cystic dilatation of the lacrimal canaliculus, presenting with an unusual intermittent clinical course. A 68-year-old woman presented with recurrent medial canthal swelling and episodic epiphora caused by a cystic lesion of the superior canaliculus. The lesion was successfully managed with marsupialization and bicanalicular intubation under endoscopic guidance. Histopathological examination revealed multilayered, non-keratinized stratified squamous epithelium without goblet cells, inflammatory infiltrates, or evidence of malignancy. Immunohistochemical analysis demonstrated positivity for CK14, supporting the diagnosis of canaliculops. Most cases of canaliculops are idiopathic and exhibit a stable or slowly progressive course; however, some may present with intermittent symptoms. Increased awareness of this underrecognized entity may facilitate earlier diagnosis and appropriate management.
The objective of this study was to evaluate whether an extended-infusion strategy for meropenem is associated with a reduced incidence and severity of acute kidney injury in critically ill patients receiving combination therapy with colistimethate sodium for carbapenem-resistant gram-negative infections. While extended infusion is known to optimize pharmacokinetic/pharmacodynamic targets, its potential as a kidney-sparing intervention remains to be elucidated. A single-center, retrospective cohort study was conducted in the intensive care unit between January 2021 and October 2025. Critically ill adults receiving combination therapy with colistimethate sodium and meropenem for at least 72 hours were included. Patients were stratified into prolonged infusion (at least 3 hours per dose) and intermittent infusion (less than 1 hour per dose) groups. Propensity score matching (1:1) was performed to balance baseline characteristics. To account for the variable duration of therapy and the competing risk of mortality, data were analyzed using the Fine-Gray proportional subdistribution hazards model. The primary outcome was the incidence of acute kidney injury according to the Kidney Disease: Improving Global Outcomes criteria. Secondary outcomes included severity of injury, requirement for renal replacement therapy, and in-hospital mortality. After matching, 146 pairs (292 patients) were analyzed. The prolonged infusion group exhibited a significantly lower incidence of acute kidney injury than the intermittent infusion group (24.7% versus 39.7%, p=0.006). Severe acute kidney injury (stage 2 or 3) was also less frequent in the prolonged infusion group (9.6% versus 19.2%, p=0.019). In-hospital mortality (19.2% versus 28.1%, p=0.021) and renal replacement therapy requirements (5.5% versus 12.3%, p=0.034) were significantly lower with prolonged infusion. Multivariate Fine-Gray analysis confirmed that prolonged infusion was an independent protective factor against acute kidney injury (adjusted subdistribution hazard ratio 0.55, 95% confidence interval 0.35-0.86, p=0.009). Extended infusion of meropenem is independently associated with a reduced incidence and severity of acute kidney injury in critically ill patients receiving colistimethate sodium. This dosing strategy may also lower mortality and the need for renal replacement therapy. While these observational findings require validation in prospective trials, they support the consideration of extended infusion as a potential kidney-sparing intervention in this high-risk population. Why was the study done? Critically ill patients in the intensive care unit often receive a combination of two powerful antibiotics, colistimethate sodium and meropenem, to treat severe infections. While effective, colistimethate sodium frequently causes acute kidney injury, which is a sudden and serious form of kidney damage. We conducted this study to determine whether changing the way doctors administer meropenem—using a slow, three-hour “extended infusion” instead of a standard quick drip—could reduce the risk of kidney damage in these patients. What did the researchers do and find? We analyzed 292 patients who received both antibiotics for at least three days between 2021 and 2025. We compared those who received slow infusions of meropenem to those who received quick infusions, ensuring that both groups had similar health characteristics to make the comparison fair. We found that patients in the slow-infusion group had a significantly lower rate of kidney injury (24.7% compared to 39.7% in the quick-infusion group). Furthermore, patients receiving the slow infusion were less likely to die during their hospital stay or require dialysis. What do these results mean? Administering meropenem as a slow drip appears to be a simple, no-cost change that may help improve the safety profile of this antibiotic combination for critically ill patients. Our observational data showed that this approach is associated with a significantly lower chance of severe kidney damage and potentially better overall survival. We suggest that hospitals could consider slow infusion as a potential protective strategy when treating high-risk patients with these two drugs, although further prospective research is needed to definitively confirm these benefits.
Periods of elevated ambient temperature challenge the body's ability to maintain internal homeostasis, and heat stress poses particular risks during pregnancy. Epidemiological studies associate gestational heat exposure with higher rates of congenital anomalies such as hypospadias, yet the direct link between gestational heat exposure and reproductive anomalies remains unknown. In this study, we examined the effects of intermittent heat exposure on reproductive development in male mouse offspring. Pregnant dams either remained at constant temperature of 22°C (control) or were exposed to 38°C for 2 hours daily (experimental) from embryonic day (E)10 to E18, modeling intermittent heat exposure during mid-to-late gestation. Embryos were collected at E18 for analysis. While heat exposure did not affect pregnancy outcomes, including placental development, litter size, sex ratio, or fetal growth, male embryos exhibited significantly reduced anogenital distance and increased hypospadias scores, which are both markers of disrupted androgen signaling. Despite these phenotypic changes, expression of genes involved in androgen synthesis in the fetal testis, as well as gene expression in external genitalia, remained unchanged. Instead, transcriptomic analysis revealed significant alterations in testicular pathways related to RNA splicing and mRNA processing. Together, these findings reveal that maternal heat stress disrupts reproductive development of male offspring, with altered gene regulatory processes being a potential driver.
Mediastinal tumors pose significant surgical and anesthetic challenges. In this paper, we discuss the management of a large mediastinal tumor complicated by sudden aortic injury. With the strategic application of an intermittent ascending aorta clamping technique combined with timely extracorporeal support, the aortic injury could be successfully managed. Additionally, complete tumor resection was possible without any deterioration of vital organ functions, which resulted in a successful outcome. Our experience with this case offers valuable insights for managing similar challenging surgical scenarios.
This study aimed to evaluate the effects of intermittent fasting (IF) on glycated hemoglobin (HbA1c), fasting blood glucose (FBG), body weight (BW), and body mass index (BMI) in pa-tients with type 2 diabetes mellitus (T2DM) and prediabetes. A systematic search of PubMed, Cochrane Library, Embase, Scopus, and Web of Science was conducted for randomized controlled trials on IF in T2DM and prediabetes published before September 30, 2025. Meta-analysis was performed using RevMan 5.3 and Stata 17.0. Fourteen studies (sixteen arms), involving 899 patients, were included. Four studies (five arms) compared IF with ad libitum diet (316 patients), and ten studies (eleven arms) compared IF with continuous energy restriction diets (CERD) (583 patients). Meta-analysis showed that IF was more effective than the ad libitum diet in reducing HbA1c, BW, BMI and FBG (Standard-ized Mean Difference (SMD) (Hedges's g) -0.64, 95% Confidence Interval (CI) -1.04, -0.24; p <0.05), (SMD (Hedges's g) -0.30, 95% CI -0.55, -0.05; p <0.05), (SMD (Hedges's g) -0.26, 95% CI -0.51, 0.00; p = 0.05), (SMD (Hedges's g) -0.39, 95% CI -0.64 to -0.15; p <0.05). IF demonstrated effects similar to CERD (p <0.05) in terms of HbA1c, BW, BMI, and FBG. Among 14 studies, dropout rates were 21.5% (IF), 26.2% (CERD), and 15.9% (ad libitum). CERD showed a significantly higher dropout rate than ad libitum, whereas no significant differences were observed between IF and CERD or between IF and ad libitum. Intermit-tent fasting is a effective dietary approach for patients with T2DM and prediabetes.
Novel therapies are needed to improve smoking cessation outcomes in people with opioid use disorder (OUD), as they are far more likely to smoke cigarettes (70-90%) compared to the general population (11.6%) and demonstrate a poorer response to smoking cessation interventions. This pilot study, intended to be a hypothesis-generating mechanistic investigation, is the first to explore the impact of a single day (four sessions) of accelerated intermittent theta burst stimulation (iTBS) (1800 pulses/session) versus sham iTBS applied to the left dorsolateral prefrontal cortex (L-dlPFC) in people with OUD who smoke tobacco cigarettes (n = 8 received iTBS, n = 7 received sham iTBS). Resting-state functional connectivity was acquired at baseline and after the fourth session. Attentional bias for cigarette and opioid cues, and craving assessments, were completed at baseline, and after the first and fourth sessions. Connectivity between the L-dlPFC seed and a cluster comprising the left anterior supramarginal gyrus showed a significant group × time interaction, with planned comparisons showing a greater increase at follow-up in the iTBS compared with sham iTBS group (t12 = 6.37, β = 0.40, p < 0.001). Cigarette cue attentional bias showed a significant group × session interaction (t80 = 2.34, p = 0.02), with planned comparisons showing a decrease after iTBS and an increase following sham iTBS. No effect of iTBS was observed for opioid cue attentional bias. Cigarette craving decreased in both iTBS and sham groups but did not show a significant group × session interaction. These results are promising but should be interpreted with caution, given the limited sample size, which precluded analyses adjusting for sex or medications for OUD. This pilot study aims to identify neural and behavioral targets for future studies of accelerated iTBS in people with OUD who smoke cigarettes. Future trials could examine the effects of increased doses of iTBS (e.g., more days of accelerated iTBS) to identify dosing to promote smoking cessation among individuals with OUD effectively.
This study aimed to identify clinical factors associated with early motor recurrence after unilateral lateral rectus recession with medial rectus plication (RP) in children with basic-type intermittent exotropia (IXT). This retrospective cohort study enrolled children with basic-type IXT who underwent unilateral RP between January 2022 and December 2023. The primary outcome was early motor recurrence, defined as an exodeviation greater than 10 prism diopters (PD) at near at 6 months postoperatively. Early motor success was defined as horizontal exodeviation or esodeviation of 10 PD or less. Deviation at distance and near, fusion, and stereopsis were evaluated at predefined postoperative time points. Multivariable logistic regression and receiver operating characteristic (ROC) analyses were used to assess factors associated with early recurrence and final motor outcomes. Ninety-one patients were included (mean age, 8.10 ± 3.06 years; mean follow-up, 16.81 months). Thirty-one patients met criteria for early motor recurrence, and 60 achieved early motor success. The early recurrence group had significantly larger residual exodeviation at distance and near during the first postoperative week (P < 0.05). In adjusted logistic regression analyses, both near and distance deviations within the first postoperative week were independently associated with early motor recurrence at 6 months (near: OR = 0.738, 95% CI 0.609-0.895, P = 0.002; distance: OR = 0.736, 95% CI 0.606-0.893, P = 0.002) and with final motor failure (near: OR = 0.798, 95% CI 0.683-0.932, P = 0.004; distance: OR = 0.796, 95% CI 0.681-0.930, P = 0.004). Alignment at 6 months showed stronger adjusted associations with final motor outcome at both near and distance. ROC analysis showed moderate discriminative performance for near deviation within 1 week in identifying early recurrence (AUC = 0.7315) and stronger discrimination for near deviation at 6 months in identifying final motor outcome (AUC = 0.8461); these thresholds require external validation. At final follow-up, fusion was more frequent in the early motor success group (P = 0.011). Among children with basic-type IXT undergoing unilateral RP, early postoperative alignment at near and distance was associated with early motor recurrence and final motor failure. Alignment at 6 months showed stronger associations with final motor outcome and should be interpreted as a mid-term prognostic marker rather than an independent early predictor. These findings support careful monitoring of near and distance alignment during the first 6 postoperative months, while acknowledging that the proposed cutoff values require validation in larger, independent cohorts.
Betrixaban is an oral factor Xa inhibitor that is indicated for venous thromboembolism (VTE) prophylaxis in hospitalized patients. It has minimal renal excretion, but it is not well studied in patients with severe renal dysfunction or patients with end-stage renal disease (ESRD). In this evaluation, we discuss betrixaban use in a patient with ESRD on intermittent hemodialysis (HD) and a history of heparin-induced thrombocytopenia (HIT) and contraindication to heparin therapy due to a positive platelet factor 4 IgG antibody. The patient was started on betrixaban for VTE prophylaxis, dosed as 80 mg once followed by 40 mg daily for a total of 15 days of therapy before they were discharged. The patient was continued on their home dialysis schedule of three times weekly and received a total of seven sessions of HD while admitted. Several anti-Xa levels collected after the second dose of betrixaban ranged between 0.12 and 0.32 IU/mL, which were within the predicted therapeutic range for betrixaban based on previous pre-clinical studies. A trough level drawn on day 7 of 0.15 IU/mL indicated the absence of accumulation. Betrixaban was well tolerated with no reported bleeding or VTE events. This case report demonstrates the successful use of betrixaban without accumulation for a patient with ESRD on HD. Betrixaban may be a potential choice when standard options are unsuitable for VTE prophylaxis or in patients with contraindications to other treatments.
暂无摘要（点击查看详情）
This focused update to the European Society for Vascular Surgery (ESVS) clinical practice guidelines (CPGs) on asymptomatic peripheral arterial disease and intermittent claudication (IC) provide revised recommendations on paclitaxel coated devices for endovascular infrainguinal interventions. Recent evidence, particularly from the SWEDEPAD 2 trial, prompted re-evaluation of their efficacy and potential long term risks. As the previously published guidelines were directed towards patients with Rutherford categories 0 - 3, the present update maintains the same scope. A narrative systematic review assessed the benefits and risks of paclitaxel coated balloons and stents in infrainguinal revascularisation for IC. The ESVS Guidelines Writing Committee incorporated new randomised trial data into updated recommendations, graded according to the ESVS CPGs recommendation grading system. The updated evidence suggested limited clinical benefit and possible long term harm from paclitaxel coated devices in this population. SWEDEPAD 2 reported no improvement in quality of life (difference in six item Vascular Quality of Life Questionnaire [VascuQoL-6] score at 12 months was -0.02 [95% confidence interval -0.66 - 0.62], indicating no clinically relevant effect) or in reduced re-intervention at 12 months compared with uncoated devices, and indicated a potential excess in the long term all cause mortality rate. These findings corroborate earlier safety concerns raised in a 2018 meta-analysis and in subsequent pooled analyses. Recently published long term efficacy and safety data from some additional pivotal drug coated balloon trials were also considered but reported no or marginal clinical benefits. The update consistently emphasises supervised exercise therapy and best medical therapies as first line treatment. Endovascular revascularisation is recommended only for persistent lifestyle limiting symptoms despite conservative therapy. Paclitaxel coated devices may be considered only for selected cases with re-stenosis following transparent discussion of uncertain long term safety and, at best, modest symptomatic benefit. This ESVS focused update integrates emerging evidence to guide contemporary management of IC. Clinicians should carefully balance the limited short term procedural benefits of paclitaxel coated devices against the lack of proven quality of life improvement and the persisting uncertainty regarding long term mortality risk. Management of IC should follow a stepwise approach, prioritising lifestyle modification, exercise therapy, and optimal secondary preventive pharmacotherapy, with revascularisation reserved for compliant patients who remain significantly limited. Emphasis should be placed on conservative management, shared decision making, and continued research to further define the long term safety profile of paclitaxel coated endovascular devices.
How systemic hormonal signals coordinate stem cell fate decisions in adult tissues remains incompletely understood. In bone marrow, Cxcl12-abundant reticular (CAR) cells, marked by Early B-cell Factor 3 (Ebf3) expression, are multipotent mesenchymal progenitors that maintain the hematopoietic stem cell niche and serves as a major osteoblast progenitor source during adult bone remodeling. Using inducible lineage tracing coupled with single-cell transcriptomics and conditional genetics in mice, we show that intermittent parathyroid hormone (iPTH; teriparatide) drives osteogenesis from CAR cells by simultaneously engaging cell-intrinsic and cell-extrinsic mechanisms. Directly, iPTH suppresses lineage-enforcing transcription factors Ebf3, Ebf1, and Foxc1, thereby destabilizing progenitor identity and priming CAR cells for osteogenic commitment. Simultaneously, iPTH stimulates osteoclastic bone resorption, releasing TGFß which recruits these primed progenitors to bone surfaces, a process abolished by osteoclast depletion. Preventing CAR cell maturation via Sp7 deletion abrogates iPTH-induced bone gain, establishing these progenitors as essential mediators of bone anabolism. This coupled mechanism, in which intrinsic transcriptional priming converges with extrinsic niche remodeling, is conserved in human CAR cells from teriparatide-treated postmenopausal women, which show concordant suppression of EBF3 and FOXC1 and elevated TGFß-responsive gene signatures. These findings reveal a general principle by which a systemic hormone orchestrates tissue remodeling through simultaneous reprogramming of progenitor identity and remodeling of the niche microenvironment.
Individuals with body dysmorphic disorder misperceive defects of their physical appearance. Current evidence suggests that visual processing abnormalities may underlie this core symptom. Separate pre-clinical studies testing perceptual and attentional interventions and non-invasive neuromodulation suggest that these visual processing abnormalities may be modifiable, but their combined effects on neural connectivity and perceptual processing remain unclear. Thirty-nine unmedicated men and women with body dysmorphic disorder or subclinical body dysmorphic disorder received intermittent theta burst stimulation and continuous theta burst stimulation targeting the lateral parietal cortex combined with a visual attention modification paradigm during functional magnetic resonance imaging, in a crossover design. Dynamic effective connectivity within dorsal and ventral visual stream pathways was calculated, and global visual processing biases were assessed using the face inversion effect before and after stimulation plus attention modification. Intermittent theta burst stimulation resulted in increased connectivity in higher-level dorsal visual stream pathways during naturalistic viewing following attention modification, whereas continuous theta burst stimulation was associated with reduced connectivity in lower-level dorsal pathways and increased connectivity in ventral stream pathways. These changes were accompanied by differential effects on global visual processing, with stimulation type modulating the magnitude of the face inversion effect. Combined neuromodulation and visual attention modification modulate visual system connectivity and perceptual processing in individuals with body dysmorphic disorder symptoms. These findings support a mechanistic link between dorsal-ventral stream dynamics and perceptual biases. Integrating neuromodulation with perceptual retraining may represent a viable approach for targeting core symptoms of distorted appearance perception. ClinicalTrials.gov : NCT05607121.
There is a need for a comprehensive understanding of alveolar bone biology, given its unique characteristics compared to other skeletal sites. To this end, we established novel female murine alveolar osteoblastic cell lines and analyzed their responses to hormones and mechanical cues. Cell lines were obtained by conditionally immortalizing primary alveolar osteoblasts isolated from the jaws of wild-type female mice and screened for high expression of alkaline phosphatase. Three clones were selected for further characterization. All clones differentiate into mature osteoblasts and mineralize the matrix. Two clones, ObB5-2 and ObC4-2, were further analyzed for their responsiveness to hormones and mechanical forces. Both responded to parathyroid hormone (PTH), 1,25OH2D3, and mechanical stimulations. Continuous treatment with PTH or 1,25OH2D3, inhibited mineralization and significantly suppressed Dmp1 expression. Intermittent PTH (iPTH) also inhibited mineralization in both clones. In ObB5-2, iPTH suppressed Dmp1, Sost, and Opg expression at doses as low as 1 nM PTH. Next, we assessed whether these cells support osteoclastogenesis. Both clones promoted the formation of TRAP-positive osteoclasts when cultured with bone marrow macrophages. Lastly, cells were subjected to fluid flow shear stress and simulated microgravity prior to gene expression analysis. ObC4-2 was highly sensitive to mechanical loads whereas ObB5-2 responded more to simulated microgravity. In summary, these findings describe novel female murine alveolar osteoblastic cell lines that provide a valuable model for studying the cellular and molecular mechanisms of alveolar bone remodeling. Unlike long bone derived cells and primary osteoblasts, these cells did not increase mineralization upon intermittent PTH, highlighting site specific differences in osteoblast function.
Blocking the programmed cell death 1 (PD-1) pathway using monoclonal antibodies reinvigorates exhausted T cells (Tex), enhancing control of chronic viral infections and cancer. Considerable effort has focused on evaluating different PD-1 blockade agents in preclinical and clinical cancer settings, but relatively little information exists on how to optimize the pharmacodynamic effects of PD-1 pathway blockade on reinvigorating Tex. To address this question, we performed longitudinal tracking of Tex reinvigoration during chronic infection with lymphocytic choriomeningitis virus (LCMV) following different regimens of PD-1 blockade. We compared single-cycle (2 weeks of treatment), long-term continuous PD-1 pathway blockade (i.e. 3 months), or blockade followed by a drug holiday and then re-blockade (intermittent treatment). These studies revealed little benefit of continuous versus single-cycle PD-1 blockade, with both resulting in a single peak of Tex reinvigoration and similar effects on viral replication. In contrast, intermittent blockade resulted in a new cycle of secondary Tex reinvigoration upon redosing after a washout and this secondary Tex reinvigoration improved disease control. Mechanistically, long-term blockade eroded the ability of Tex progenitor cells (Tpex) to give rise to downstream, more functional Tex intermediate (Tex-Int) progeny, whereas the drug holiday restored this Tpex proliferative and differentiation capacity. Tpex from long-term treated mice showed evidence of adaptive resistance and additional layers of negative regulation, including sustained expression of the inhibitory receptor CD22. Indeed, co-blockade of PD-1 and CD22 using combination antibodies or bispecific antibody approaches improved disease control and reinvigoration of Tex. These data have implications for clinical immune pharmacodynamics of PD-1 blockade and provide insights into the biology of Tex reinvigoration. Modifying the immunopharmacology of PD-1 blockade reveals a benefit of a drug holiday and identifies mechanisms of Tex progenitor deficiency provoked by prolonged loss of PD-1 signals including the inhibitory receptor CD22.
To determine the demographic and clinical characteristics, potential specific antidote treatments, clinical outcomes, and organ failure (morbidity) rates of patients with mushroom poisoning admitted to our center. We included 425 patients admitted to the emergency department of Kayseri City Hospital complaining of mushroom poisoning, between May 2018 and December 2023, who met the study criteria. The median age of the 425 patients admitted was 51 years (34-63); 49.5% were female (n = 211), and 75% (n = 319) were admitted by ambulance. According to the Poisoning Severity Score, 70.3% (n = 299) of cases were mild, 21.9% (n = 93) moderate, 7.3% (n = 31) severe, and 0.5% (n = 2) fatal. Patients who received specific antidote treatment had a statistically significantly higher morbidity rate than those who did not (48.6% vs. 22.9%, p < 0.01). In the subgroup analysis, hepatotoxicity was more common (35.8% vs. 8.8%, p < 0.01), whereas there was no significant difference in other organ failure. Mushroom poisoning is an uncommon type of poisoning that varies seasonally. The integrity of treatment may have been lost because of intermittent visits. We recommend careful evaluation of the patients and rapid initiation of specific possible antidote therapies, in addition to basic supportive treatment (fluid resuscitation, activated charcoal, and so on).
While tree pollen is a major trigger of allergic respiratory conditions and different taxa exhibit varying allergenic potentials, the lack of high-resolution, taxon-specific exposure metrics have limited our ability to identify which local pollen taxa are primarily responsible for respiratory illness. Traditional pollen monitoring networks, which have an intermittent sampling schedule, are not ideal for examining the delayed effects of pollen exposure due to the missing days. In this study, we developed a modeling framework integrating atmospheric dispersion effects, taxa-specific phenology, and machine learning to predict daily counts of 13 tree taxa in the five-county Metro Atlanta area, Georgia at a 1-km resolution from 2020 to 2024. Machine learning model performance was validated with daily pollen counts collected by a multi-site monitoring network equipped with automated pollen sensors. Findings showed that Betula and Quercus pollens exhibited higher predictive performance than other taxa, with R 2 values ranging from 0.69 to 0.92 and from 0.71 to 0.89, respectively. Our 1-kilometer prediction data provides gapless exposure metrics to understand the spatial and temporal variability in pollen exposure, can facilitate investigation of urban pollen hotspots and support epidemiologic studies of pollen-related respiratory outcomes.
The integration of renewable energy sources (RESs) into energy systems poses considerable operational challenges, due to their intermittent and stochastic nature. Grid-connected energy storage systems (ESSs) present a compelling alternative for reliably accommodating various RESs. This paper presents an optimal scheduling for allocating wind-storage system capacity in high mountain regions with abundant wind resources and irrigation pumping demand. To capture uncertainty in wind and solar generation, a scenario-free stochastic formulation is adopted, enabling tractable and scalable uncertainty modelling. To reduce the overall lifecycle comprehensive cost (COC), a synergistic optimization model is developed by integrating features of wind energy, pumping unit parameters, and storage configurations. The model considers startup/shutdown losses, optimal flow distribution, and operating expenses of the pumping station while optimizing energy storage capacity. A single-battery system is compared with a hybrid battery-hydrogen storage strategy. Results show the hybrid solution reduces COC by 5.4%, alleviates battery operational stress, and maintains pumping station efficiency. The framework incorporates a reliability model for wind power generation, ensuring robust lifecycle cost optimization. This approach demonstrates the financial and technological benefits of hybrid storage in renewable energy-driven irrigation systems. Simulations in the case study validate the flexibility and effectiveness of the proposed approach across various practical settings.