A fractional-order model for optimizing combination therapy in heterogeneous lung cancer: integrating immunotherapy and targeted therapy to minimize side effects.

This research presents a novel approach to address the complexities of heterogeneous lung cancer dynamics through the development of a Fractional-Order Model. Focusing on the optimization of combination therapy, the model integrates immunotherapy and targeted therapy with the specific aim of minimizing side effects. Notably, our approach incorporates a clever fusion of Proportional-Integral-Derivative (PID) feedback controls alongside the optimization process. Unlike previous studies, our model incorporates essential equations accounting for the interaction between regular and mutated cancer cells, delineates the dynamics between immune cells and mutated cancer cells, enhances immune cell cytotoxic activity, and elucidates the influence of genetic mutations on the spread of cancer cells. This refined model offers a comprehensive understanding of lung cancer progression, providing a valuable tool for the development of personalized and effective treatment strategies. the findings underscore the potential of the optimized treatment strategy in achieving key therapeutic goals, including primary tumor control, metastasis limitation, immune response enhancement, and controlled genetic mutations. The dynamic and adaptive nature of the treatment approach, coupled with economic considerations and memory effects, positions the research at the forefront of advancing precision and personalized cancer therapeutics.

The Association of Obstructive Sleep Apnea with Urological Cancer Incidence and Mortality-A Systematic Review and Meta-analysis.

BACKGROUND AND OBJECTIVE: While obstructive sleep apnea (OSA) and urological cancer are both strongly associated with hypoxia, controversy exists regarding their association with each other. This study aims to summarize and synthesize evidence to clarify the association between OSA and urological cancer incidence and mortality. METHODS: According to a prespecified protocol, PubMed, Embase, Cochrane Library, and Scopus were searched from inception to November 16, 2023, for observational and randomized studies reporting the association of OSA with urological cancer incidence or mortality. We pooled maximally covariate-adjusted hazard ratios (HRs) using a random-effects inverse variance-weighted model. Two reviewers independently assessed the quality of evidence using the Newcastle-Ottawa Scale and the Grading of Recommendations, Assessment, Development and Evaluation framework. KEY FINDINGS AND LIMITATIONS: From 1814 records, we included 12 studies comprising 9 290 818 participants in total, of which nine studies were analyzed quantitatively. OSA patients had an increased risk of kidney (HR: 1.75, 95% confidence interval [CI]: 1.21-2.53) and bladder (HR: 1.76, 95% CI: 1.05-2.96) cancer. However, OSA was not associated with prostate cancer incidence (HR: 1.29, 95% CI: 0.82-2.04). We systematically reviewed evidence surrounding OSA and testicular cancer incidence and urological cancer mortality. CONCLUSIONS AND CLINICAL IMPLICATIONS: OSA may be associated with a higher risk of kidney and bladder cancer, but not prostate cancer. Future work may help clarify the possibility of a dose-response relationship between OSA and urological cancer, and the effect of OSA treatment on urological cancer incidence or progression. PATIENT SUMMARY: This research highlights a potential longitudinal association between OSA and kidney and bladder cancer, but not prostate cancer.

Protective effect of 8-Gingerol, a potent constituent of ginger, on acute lung injury following hemorrhagic shock in rats.

Acute lung injury (ALI) is a common complication after hemorrhagic shock (HS), which is associated with HS-induced inflammatory response, oxidative stress, and cell apoptosis. This study aimed to investigate the therapeutic efficacy of 8-Gingerol, a constituent extracted from ginger, on ALI after HS in rats. We established a fixed press hemorrhage model in SD rats, in which the HS rats were administered 15 or 30 mg/kg of 8-Gingerol by intraperitoneal injection before fluid resuscitation. H&E staining and TUNEL staining were performed to evaluate histopathological changes and cell apoptosis in lung tissues, respectively. Quantitative reverse transcription PCR and Western blot were used to measure gene and protein expression. Pro-inflammatory cytokines were detected by ELISA kits. Immunofluorescence of myeloperoxidase was used to evaluate neutrophil infiltration. 8-Gingerol reduced pulmonary edema, alveolar wall thickness, and cell apoptosis in lung tissues of HS rats. Regarding inflammatory responses, 8-Gingerol attenuated neutrophil infiltration in lung tissues, reduced pro-inflammatory cytokines in lung tissues and bronchoalveolar lavage fluid, and decreased the levels of NLRP3, ASC, and cleaved caspase 1 in lung tissues. Additionally, 8-Gingerol ameliorated oxidative stress in lung tissues as evidenced by increased antioxidant indicators (SOD and GSH) and decreased production of MDA and ROS. The therapeutic effects of 8-Gingerol were associated with the regulation of MAPK and Nrf2/HO-1 pathways. These results support 8-Gingerol as a promising drug for the treatment of HS-induced ALI.

A prognostic model for anoikis-related genes in pancreatic cancer.

Anoikis, a distinct form of programmed cell death, is crucial for both organismal development and maintaining tissue equilibrium. Its role extends to the proliferation and progression of cancer cells. This study aimed to establish an anoikis-related prognostic model to predict the prognosis of pancreatic cancer (PC) patients. Gene expression data and patient clinical profiles were sourced from The Cancer Genome Atlas (TCGA-PAAD: Pancreatic Adenocarcinoma) and the International Cancer Genome Consortium (ICGC-PACA: Pancreatic Ductal Adenocarcinoma). Non-cancerous pancreatic tissue gene expression data were obtained from the Genotype-Tissue Expression (GTEx) project. The R package was used to construct anoikis-related PC prognostic models, which were later validated with the ICGC-PACA database. Survival analyses demonstrated a poorer prognosis for patients in the high-risk group, consistent across both TCGA-PAAD and ICGC-PACA datasets. A nomogram was designed as a predictive tool to estimate patient mortality. The study also analyzed tumor mutations and immune infiltration across various risk groups, uncovering notable differences in tumor mutation patterns and immune landscapes between high- and low-risk groups. In conclusion, this research successfully developed a prognostic model centered on anoikis-related genes, offering a novel tool for predicting the clinical trajectory of PC patients.

Natural history of initially asymptomatic severe aortic stenosis: a one-stage meta-analysis.

BACKGROUND: Current guidelines on the management strategy for patients with asymptomatic severe aortic stenosis (AS) remain unclear. This uncertainty stems from the lack of data regarding the natural history of these patients. To address this gap, we performed a systematic review and meta-analysis examining the natural history of asymptomatic severe AS patients receiving conservative treatment. METHODS: The PubMed, Cochrane, and Embase databases were searched from inception to 24 January 2024 using the keywords "asymptomatic" AND "aortic" AND "stenosis". We included studies examining patients with asymptomatic severe AS. In interventional trials, only data from conservatively managed arms were collected. A one-stage meta-analysis was conducted using individual patient data reconstructed from published Kaplan-Meier curves. Sensitivity analysis was performed for major adverse cardiovascular outcomes in patients who remained asymptomatic throughout follow-up. RESULTS: A total of 46 studies were included (n = 9545). The median time to the development of symptoms was 1.11 years (95% CI 0.90-1.53). 49.36% (40.85-58.59) of patients who were asymptomatic had suffered a major adverse cardiovascular event by 5 years. The median event-free time for heart failure hospitalization (HFH) was 5.50 years (95% CI 5.14-5.91) with 36.34% (95% CI 33.34-39.41) of patients experiencing an HFH by year 5. By 5 years, 79.81% (95% CI 69.26-88.58) of patients developed symptoms (angina, dyspnoea, syncope and others) and 12.36% (95% CI 10.01-15.22) of patients died of cardiovascular causes. For all-cause mortality, the median survival time was 9.15 years (95% CI 8.50-9.96) with 39.43% (CI 33.41-36.40) of patients dying by 5 years. The median time to AVR was 4.77 years (95% CI 4.39-5.17), with 52.64% (95% CI 49.85-55.48) of patients requiring an AVR by 5 years. CONCLUSION: Our results reveal poor cardiovascular outcomes for patients with asymptomatic severe AS on conservative treatment. A significant proportion eventually requires an AVR. Further research is needed to determine if early intervention with AVR is more effective than conservative treatment.

ADSC-derived exosomes provide neuroprotection in sepsis-associated encephalopathy by regulating hippocampal pyroptosis.

AIMS: Adipose-derived stem cell (ADSC)-derived exosomes have been recognized for their neuroprotective effects in various neurological diseases. This study investigates the potential neuroprotective effects of ADSC-derived exosomes in sepsis-associated encephalopathy (SAE). METHODS: Behavioral cognitive functions were evaluated using the open field test, Y-maze test, and novel object recognition test. Brain activity was assessed through functional magnetic resonance imaging (fMRI). Pyroptosis was measured using immunofluorescence staining and western blotting. RESULTS: Our findings indicate that ADSC-derived exosomes mitigate cognitive impairment, improve survival rates, and prevent weight loss in SAE mice. Additionally, exosomes protect hippocampal function in SAE mice, as demonstrated by fMRI evaluations. Furthermore, SAE mice exhibit neuronal damage and infiltration of inflammatory cells in the hippocampus, conditions which are reversed by exosome treatment. Moreover, our study highlights the downstream regulatory role of the NLRP3/caspase-1/GSDMD signaling pathway as a crucial mechanism in alleviating hippocampal inflammation. CONCLUSION: ADSC-derived exosomes confer neuroprotection in SAE models by mediating the NLRP3/caspase-1/GSDMD pathway, thereby ameliorating cognitive impairment.

Contemporary Incidence of Cognitive Impairment or Dementia in Patients undergoing Coronary Artery Bypass Grafting: A Systematic Review and Meta-analysis.

INTRODUCTION: Despite the high prevalence of cognitive impairment or dementia post coronary artery bypass grafting (CABG), the incidence of cognitive impairment or dementia post-CABG in contemporary practice is currently unclear. Therefore, this paper aims to investigate the incidence and associated risk factors of cognitive impairment or dementia in patients post-CABG. METHODS: A systematic search across three databases (PubMed, SCOPUS and Embase) was conducted for studies published in or after 2013 that reported cognitive impairment or dementia post-CABG. Subgroup analyses and meta-regression by risk factors were performed to determine their influence on the results. RESULTS: This analysis included 23 studies with a total of 2620 patients. The incidence of cognitive impairment or dementia less than one month, two to six months, and more than twelve months post-CABG was 35.96% (95%CI: 28.22-44.51, I2=87%), 21.33% (95%CI: 13.44-32.15, I2=88%) and 39.13% (95%CI: 21.72-58.84, I2=84%), respectively. Meta-regression revealed that studies with more than 80% of the cohort diagnosed with hypertension were significantly associated with incidence of cognitive impairment or dementia less than one-month post-CABG. CONCLUSION: This meta-analysis demonstrates a high incidence of cognitive impairment or dementia in patients post-CABG in contemporary practice, particularly less than one month post-CABG. We found that hypertension was a significant risk factor in the short term (less than one month) follow-up period for cognitive impairment or dementia post-CABG. Future research should be done to assess strategies to reduce cognitive impairment post-CABG. .

P-doped spherical hard carbon with high initial coulombic efficiency and enhanced capacity for sodium ion batteries.

Hard carbon (HC) is one of the most promising anode materials for sodium-ion batteries (SIBs) due to its cost-effectiveness and low-voltage plateau capacity. Heteroatom doping is considered as an effective strategy to improve the sodium storage capacity of HC. However, most of the previous heteroatom doping strategies are performed at a relatively low temperature, which could not be utilized to raise the low-voltage plateau capacity. Moreover, extra doping of heteroatoms could create new defects, leading to a low initial coulombic efficiency (ICE). Herein, we propose a repair strategy based on doping a trace amount of P to achieve a high capacity along with a high ICE. By employing the cross-linked interaction between glucose and phytic acid to achieve the in situ P doped spherical hard carbon, the obtained PHC-0.2 possesses a large interlayer space that facilitates Na+ storage and transportation. In addition, doping a suitable amount of P could repair some defects in carbon layers. When used as an anode material for SIBs, the PHC-0.2 exhibits an enhanced reversible capacity of 343 mA h g-1 at 20 mA g-1 with a high ICE of 92%. Full cells consisting of a PHC-0.2 anode and a Na2Fe0.5Mn0.5[Fe(CN)6] cathode exhibited an average potential of 3.1 V with an initial discharge capacity of 255 mA h g-1 and an ICE of 85%. The full cell displays excellent cycling stability with a capacity retention of 80.3% after 170 cycles. This method is simple and low-cost, which can be extended to other energy storage materials.

Durable Effect of Acupuncture for Chronic Neck Pain: A Systematic Review and Meta-Analysis.

OBJECTIVE: Chronic neck pain, a prevalent health concern characterized by frequent recurrence, requires exploration of treatment modalities that provide sustained relief. This systematic review and meta-analysis aimed to evaluate the durable effects of acupuncture on chronic neck pain. METHODS: We conducted a literature search up to March 2024 in six databases, including PubMed, Embase, and the Cochrane Library, encompassing both English and Chinese language publications. The main focus of evaluation included pain severity, functional disability, and quality of life, assessed at least 3 months post-acupuncture treatment. The risk of bias assessment was conducted using the Cochrane Risk of Bias 2.0 tool, and meta-analyses were performed where applicable. RESULTS: Eighteen randomized controlled trials were included in the analysis. Acupuncture as an adjunct therapy could provide sustained pain relief at three (SMD: - 0.79; 95% CI - 1.13 to - 0.46; p < 0.01) and six (MD: - 18.13; 95% CI - 30.18 to - 6.07; p < 0.01) months post-treatment. Compared to sham acupuncture, acupuncture did not show a statistically significant difference in pain alleviation (MD: - 0.12; 95% CI - 0.06 to 0.36; p = 0.63). However, it significantly improved functional outcomes as evidenced by Northwick Park Neck Pain Questionnaire scores 3 months post-treatment (MD: - 6.06; 95% CI - 8.20 to - 3.92; p < 0.01). Although nine studies reported an 8.5%-13.8% probability of adverse events, these were mild and transitory adverse events. CONCLUSION: Acupuncture as an adjunct therapy may provide post-treatment pain relief lasting at least 3 months for patients with chronic neck pain, although it is not superior to sham acupuncture, shows sustained efficacy in improving functional impairment for over 3 months, with a good safety profile.

Intra-articular sustained-release of pirfenidone as a disease-modifying treatment for early osteoarthritis.

Osteoarthritis (OA) is a major clinical challenge, and effective disease-modifying drugs for OA are still lacking due to the complicated pathology and scattered treatment targets. Effective early treatments are urgently needed to prevent OA progression. The excessive amount of transforming growth factor ß (TGFß) is one of the major causes of synovial fibrosis and subchondral bone sclerosis, and such pathogenic changes in early OA precede cartilage damage. Herein we report a novel strategy of intra-articular sustained-release of pirfenidone (PFD), a clinically-approved TGFß inhibitor, to achieve disease-modifying effects on early OA joints. We found that PFD effectively restored the mineralization in the presence of excessive amount of TGFß1 (as those levels found in patients' synovial fluid). A monthly injection strategy was then designed of using poly lactic-co-glycolic acid (PLGA) microparticles and hyaluronic acid (HA) solution to enable a sustained release of PFD (the "PLGA-PFD + HA" strategy). This strategy effectively regulated OA progression in destabilization of the medial meniscus (DMM)- induced OA mice model, including preventing subchondral bone loss in early OA and subchondral bone sclerosis in late OA, and reduced synovitis and pain with cartilage preservation effects. This finding suggests the promising clinical application of PFD as a novel disease-modifying OA drug.

ERß activation improves nonylphenol-induced depression and neurotransmitter secretion disruption via the TPH2/5-HT pathway.

The aim of this study is to investigate the role of estrogen receptor ß (ERß) in nonylphenol (NP) - induced depression - like behavior in rats and its impact on the regulation of the TPH2/5-HT pathway. In the in vitro experiment, rat basophilic leukaemia cells (RBL-2H3) cells were divided into the four groups: blank group, NP group (20 µM), ERß agonist group (0.01 µM), and NP＋ERß agonist group (20 µM＋0.01 µM). For the in vivo experiment, 72 adult male Sprague-Dawley rats were randomly divided into following six groups: the Control, NP (40 mg/kg) group, ERß agonist (2 mg/kg, Diarylpropionitrile (DPN)) group, ERß inhibitor (0.1 mg/kg, 4-(2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl) phenol (PHTPP)) group, NP+ERß agonist (40 mg/kg NP ＋ 2 mg/kg DPN) group, and NP+ERß inhibitor (40 mg/kg NP + 0.1 mg/kg PHTPP) group, with 12 rats in each group. Each rat in drug group were given NP by gavage and/or received a single intraperitoneal injection of DPN 2 mg/kg or PHTPP 0.1 mg/kg. Both in vivo and in vitro, NP group showed a decrease in the expression levels of ERß, tryptophan hydroxylase (TPH1), and tryptophan hydroxylase-2 (TPH2) genes and proteins, and reduced levels of DA, NE, and 5-hydroxytryptophan (5-HT) neurotransmitters. RBL-2H3 cells showed signs of cell shrinkage, with rounded cells, increased suspension and more loosely arranged cells. The effectiveness of the ERß agonist stimulation exhibited an increase exceeding 60% in RBL-2H3 cells. The application of ERß agonist resulted in an alleviation the aforementioned alterations. ERß agonist activated the TPH2/5-HT signaling pathways. Compared to the control group, the NP content in the brain tissue of the NP group was significantly increased. The latency to eat for the rats was longer and the amount of food consumed was lower, and the rats had prolonged immobility time in the behavioral experiment of rats. The expression levels of ERß, TPH1, TPH2, 5-HT and 5-HITT proteins were decreased in the NP group, suggesting NP-induced depression-like behaviours as well as disturbances in the secretion of serum hormones and monoamine neurotransmitters. In the NP group, the midline raphe nucleus showed an elongated nucleus with a dark purplish-blue colour, nuclear atrophy, displacement and pale cytoplasm. ERß might ameliorate NP-induced depression-like behaviors, and secretion disorders of serum hormones and monoamine neurotransmitters via activating TPH2/5-HT signaling pathways.

NECA alleviates inflammatory responses in diabetic retinopathy through dendritic cell toll-like receptor signaling pathway.

Introduction: This study examined the impact of 5'-(N- ethylcarboxamido)adenosine (NECA) in the peripheral blood of healthy individuals, those with diabetes mellitus, diabetic retinopathy (DR), and C57BL/6 mice, both in vivo and in vitro. Methods: Enzyme-linked immunosorbent assay (ELISA) and flow cytometry (FCM) were used to evaluate the effects of NECA on dendritic cells (DCs) and mouse bone marrow-derived dendritic cells (BMDCs) and the effects of NECA-treated DCs on Treg and Th17 cells. The effect of NECA on the Toll-like receptor (TLR) pathway in DCs was evaluated using polymerase chain reaction (PCR) and western blotting (WB). Results: FCM and ELISA showed that NECA inhibited the expression of surface markers of DCs and BMDCs, increased anti-inflammatory cytokines and decreased proinflammatory cytokines. PCR and WB showed that NCEA decreased mRNA transcription and protein expression in the TLR-4-MyD88-NF-kß pathway in DCs and BMDCs. The DR severity in streptozocin (STZ) induced diabetic mice was alleviated. NECA-treated DCs and BMDCs were co-cultivated with CD4+T cells, resulting in modulation of Treg and Th17 differentiation, along with cytokine secretion alterations. Conclusion: NECA could impair DCs' ability to present antigens and mitigate the inflammatory response, thereby alleviating the severity of DR.

Propionic acid ameliorates cognitive function through immunomodulatory effects on Th17 cells in perioperative neurocognitive disorders.

Background: Elderly patients undergoing surgery are prone to cognitive decline known as perioperative neurocognitive disorders (PND). Several studies have shown that the microglial activation and the decrease of short-chain fatty acids (SCFAs) in gut induced by surgery may be related to the pathogenesis of PND. The purpose of this study was to determine whether microglia and short-chain fatty acids were involved in cognitive dysfunction in aged rats. Methods: Male wild-type Wistar rats aged 11-12 months were randomly divided into control group (Ctrl: Veh group), propionic acid group (Ctrl: PA group), exploratory laparotomy group (LP: Veh group) and propionic acid + exploratory laparotomy group (LP: PA group) according to whether exploratory laparotomy (LP) or PA pretreatment for 21 days was performed. The motor ability of the rats was evaluated by open field test on postoperative day 3 (POD3), and then the cognitive function was evaluated by Y-maze test and fear conditioning test. The expression of IL-1ß, IL-6, RORγt and IL-17A mRNA in hippocampus was detected by RT-qPCR, the expression of IL-17A and IL-17RA in hippocampus was detected by Western blot, and the activation of microglia was detected by immunofluorescence. Results: The PND rat model was successfully established by laparotomy. Compared with Ctrl: Veh group, the body weight of LP: Veh group decreased, the percentage of spontaneous alternations in Y maze decreased (P < 0.001), and the percentage of freezing time in contextual fear test decreased (P < 0.001). Surgery triggers neuroinflammation, manifested as the elevated levels of the inflammatory cytokines IL-1ß (P < 0.001) and IL-6 (P < 0.001), the increased expression of the transcription factor RORγt (P = 0.0181, POD1; P = 0.0073, POD5)and major inflammatory cytokines IL-17A (P = 0.0215, POD1; P = 0.0071, POD5), and the increased average fluorescence intensity of Iba1 (P < 0.001, POD1; P < 0.001, POD5). After PA preconditioning, the recovery of rats in LP: PA group was faster than that in LP: Veh group as the body weight lost on POD1 (P = 0.0148) was close to the baseline level on POD5 (P = 0.1846), and they performed better in behavioral tests. The levels of IL-1ß (P < 0.001) and IL-6 (P = 0.0035) inflammatory factors in hippocampus decreased on POD1 and the average fluorescence intensity of Iba1 decreased (P = 0.0024, POD1; P < 0.001, POD5), representing the neuroinflammation was significantly improved. Besides, the levels of RORγt mRNA (P = 0.0231, POD1; P = 0.0251, POD5) and IL-17A mRNA (P = 0.0208, POD1; P = 0.0071, POD5) in hippocampus as well as the expression of IL-17A (P = 0.0057, POD1; P < 0.001, POD5) and IL-17RA (P = 0.0388) decreased. Conclusion: PA pretreatment results in reduced postoperative neuroinflammation and improved cognitive function, potentially attributed to the regulatory effects of PA on Th17-mediated immune responses.

Ca(H2PO4)2 and MgSO4 activated nitrogen-related bacteria and genes in thermophilic stage of compost.

This study was conducted to investigate the effects of Ca(H2PO4)2 and MgSO4 on the bacterial community and nitrogen metabolism genes in the aerobic composting of pig manure. The experimental treatments were set up as control (C), 1% Ca(H2PO4)2 + 2% MgSO4 (CaPM1), and 1.5% Ca(H2PO4)2 + 3% MgSO4 (CaPM2), which were used at the end of composting for potting trials. The results showed that Ca(H2PO4)2 and MgSO4 played an excellent role in retaining nitrogen and increasing the alkali-hydrolyzed nitrogen (AN), available phosphorus (AP), and available potassium (AK) contents of the composts. Adding Ca(H2PO4)2 and MgSO4 changed the microbial community structure of the compost. The microorganisms associated with nitrogen retention were activated. The complexity of the microbial network was enhanced. Genetic prediction analysis showed that the addition of Ca(H2PO4)2 and MgSO4 reduced the accumulation of nitroso-nitrogen and the process of denitrification. At the same time, despite the reduction of genes related to nitrogen fixation, the conversion of ammonia to nitrogenous organic compounds was promoted and the stability of nitrogen was increased. Mantel test analysis showed that Ca(H2PO4)2 and MgSO4 can affect nitrogen transformation-related bacteria and thus indirectly affect nitrogen metabolism genes by influencing the temperature, pH, and organic matter (OM) of the compost and also directly affected nitrogen metabolism genes through PO43- and Mg2+. The pot experiment showed that composting with 1.5% Ca(H2PO4)2 + 3% MgSO4 produced the compost product that improved the growth yield and nutrient content of cilantro and increased the fertility of the soil. In conclusion, Ca(H2PO4)2 and MgSO4 reduces the loss of nitrogen from compost, activates nitrogen-related bacteria and genes in the thermophilic phase of composting, and improves the fertilizer efficiency of compost products. KEY POINTS: • Ca(H2PO4)2 and MgSO4 reduced the nitrogen loss and improved the compost effect • Activated nitrogen-related bacteria and altered nitrogen metabolism genes • Improved the yield and quality of cilantro and fertility of soil.

Case report: Donor-derived CLL-1 chimeric antigen receptor T-cell therapy for relapsed/refractory acute myeloid leukemia bridging to allogeneic hematopoietic stem cell transplantation after remission.

Background: Explore the efficacy and safety of donor-derived CLL-1 chimeric antigen receptor T-cell therapy (CAR-T) for relapsed/refractory acute myeloid leukemia (R/R AML) bridging to allogeneic hematopoietic stem cell transplantation (allo-HSCT) after remission. Case presentation: An adult R/R AML patient received an infusion of donor-derived CLL-1 CAR-T cells, and the conditioning regimen bridging to allo-HSCT was started immediately after remission on day 11 after CAR-T therapy upon transplantation. Then, routine post-HSCT monitoring of blood counts, bone marrow (BM) morphology, flow cytometry, graft-versus-host disease (GVHD) manifestations, and chimerism status were performed. Result: After CAR-T therapy, cytokine release syndrome was grade 1. On day 11 after CAR-T therapy, the BM morphology reached complete remission (CR), and the conditioning regimen bridging to allo-HSCT started. Leukocyte engraftment, complete donor chimerism, and platelet engraftment were observed on days +18, +23, and +26 post-allo-HSCT, respectively. The BM morphology showed CR and flow cytometry turned negative on day +23. The patient is currently at 4 months post-allo-HSCT with BM morphology CR, negative flow cytometry, complete donor chimerism, and no extramedullary relapse/GVHD. Conclusion: Donor-derived CLL-1 CAR-T is an effective and safe therapy for R/R AML, and immediate bridging to allo-HSCT after remission may better improve the long-term prognosis of R/R AML.

Machine Learning Modeling to Predict Atrial Fibrillation Detection in Embolic Stroke of Undetermined Source Patients.

BACKGROUND: In patients with embolic stroke of undetermined source (ESUS), occult atrial fibrillation (AF) has been implicated as a key source of cardioembolism. However, only a minority acquire implantable cardiac loop recorders (ILRs) to detect occult paroxysmal AF, partly due to financial cost and procedural inconvenience. Without the initiation of appropriate anticoagulation, these patients are at risk of increased ischemic stroke recurrence. Hence, cost-effective and accurate methods of predicting AF in ESUS patients are highly sought after. OBJECTIVE: We aimed to incorporate clinical and echocardiography data into machine learning (ML) algorithms for AF prediction on ILRs in ESUS. METHODS: This was a single-center cohort study that included 157 consecutive patients diagnosed with ESUS from October 2014 to October 2017 who had ILR evaluation. We developed four ML models, with hyperparameters tuned, to predict AF detection on an ILR. RESULTS: The median age of the cohort was 67 (IQR 59-74) years old and the median monitoring duration was 1051 (IQR 478-1287) days. Of the 157 patients, 32 (20.4%) had occult AF detected on the ILR. Support vector machine predicted for AF with a 95% confidence interval area under the receiver operating characteristic curve (AUC) of 0.736-0.737, multilayer perceptron with an AUC of 0.697-0.708, XGBoost with an AUC of 0.697-0.697, and random forest with an AUC of 0.663-0.674. ML feature importance found that age, HDL-C, and admitting heart rate were important non-echocardiography variables, while peak mitral A-wave velocity and left atrial volume were important echocardiography parameters aiding this prediction. CONCLUSION: Machine learning modeling incorporating clinical and echocardiographic variables predicted AF in ESUS patients with moderate accuracy.

Effects of crayfish shell powder and bamboo-derived biochar on nitrogen conversion, bacterial community and nitrogen functional genes during pig manure composting.

This study investigated the effects of crayfish shell powder (CSP) and bamboo-derived biochar (BDB) on nitrogen metabolism, bacterial community and nitrogen functional genes during pig manure composting. Four treatments were established: CP (with no additives), TP1 (5 % BDB), TP2 (5 % CSP) and TP3 (2.5 % BDB + 2.5 % CSP). Compared to CP, the germination index (GI) of TP reached > 85 % 10 days earlier. Meanwhile, TP3 reduced NH3 and N2O emissions by 42.90 % and 65.9 %, respectively, while increased TN (total nitrogen) concentration by 5.43 g/kg. Furthermore, additives changed the bacterial structure and formed a beneficial symbiotic relationship with essential N-preserving bacteria, thereby enhancing nitrogen retention throughout the composting process. Metagenomic analysis revealed that additives upregulated nitrification genes and downregulated denitrification and nitrate reduction genes, ultimately improving nitrogen cycling and mitigating NH3 and N2O emissions. In conclusion, the results confirmed that TP3 was the most effective treatment in reducing nitrogen loss.

Application value of metagenomic next-generation sequencing in hematological patients with high-risk febrile neutropenia.

Background: Metagenomic next-generation sequencing (mNGS) is a novel non-invasive and comprehensive technique for etiological diagnosis of infectious diseases. However, its practical significance has been seldom reported in the context of hematological patients with high-risk febrile neutropenia, a unique patient group characterized by neutropenia and compromised immune responses. Methods: This retrospective study evaluated the results of plasma cfDNA sequencing in 164 hematological patients with high-risk febrile neutropenia. We assessed the diagnostic efficacy and clinical impact of mNGS, comparing it with conventional microbiological tests. Results: mNGS identified 68 different pathogens in 111 patients, whereas conventional methods detected only 17 pathogen types in 36 patients. mNGS exhibited a significantly higher positive detection rate than conventional methods (67.7% vs. 22.0%, P < 0.001). This improvement was consistent across bacterial (30.5% vs. 9.1%), fungal (19.5% vs. 4.3%), and viral (37.2% vs. 9.1%) infections (P < 0.001 for all comparisons). The anti-infective treatment strategies were adjusted for 51.2% (84/164) of the patients based on the mNGS results. Conclusions: mNGS of plasma cfDNA offers substantial promise for the early detection of pathogens and the timely optimization of anti-infective therapies in hematological patients with high-risk febrile neutropenia.

Gradient-flow adaptive importance sampling for Bayesian leave one out cross-validation for sigmoidal classification models.

We introduce a set of gradient-flow-guided adaptive importance sampling (IS) transformations to stabilize Monte-Carlo approximations of point-wise leave one out cross-validated (LOO) predictions for Bayesian classification models. One can leverage this methodology for assessing model generalizability by for instance computing a LOO analogue to the AIC or computing LOO ROC/PRC curves and derived metrics like the AUROC and AUPRC. By the calculus of variations and gradient flow, we derive two simple nonlinear single-step transformations that utilize gradient information to shift a model's pre-trained full-data posterior closer to the target LOO posterior predictive distributions. In doing so, the transformations stabilize importance weights. Because the transformations involve the gradient of the likelihood function, the resulting Monte Carlo integral depends on Jacobian determinants with respect to the model Hessian. We derive closed-form exact formulae for these Jacobian determinants in the cases of logistic regression and shallow ReLU-activated artificial neural networks, and provide a simple approximation that sidesteps the need to compute full Hessian matrices and their spectra. We test the methodology on an n≪p dataset that is known to produce unstable LOO IS weights.

High-altitude-induced alterations in intestinal microbiota.

In high-altitude environments characterized by low pressure and oxygen levels, the intestinal microbiota undergoes significant alterations. Whether individuals are subjected to prolonged exposure or acute altitude changes, these conditions lead to shifts in both the diversity and abundance of intestinal microbiota and changes in their composition. While these alterations represent adaptations to high-altitude conditions, they may also pose health risks through certain mechanisms. Changes in the intestinal microbiota induced by high altitudes can compromise the integrity of the intestinal mucosal barrier, resulting in gastrointestinal dysfunction and an increased susceptibility to acute mountain sickness (AMS). Moreover, alterations in the intestinal microbiota have been implicated in the induction or exacerbation of chronic heart failure. Targeted modulation of the intestinal microbiota holds promise in mitigating high-altitude-related cardiac damage. Dietary interventions, such as adopting a high-carbohydrate, high-fiber, low-protein, and low-fat diet, can help regulate the effects of intestinal microbiota and their metabolic byproducts on intestinal health. Additionally, supplementation with probiotics, either through dietary sources or medications, offers a means of modulating the composition of the intestinal microbiota. These interventions may offer beneficial effects in preventing and alleviating AMS following acute exposure to high altitudes.