Selective Mono-Defluorinative Cross-Coupling of Trifluoromethyl arenes via Multiphoton Photoredox Catalysis.

A new cross-coupling of trifluoromethyl arenes has been realized via multiphoton photoredox catalysis. Trifluoromethyl arenes were demonstrated to undergo selective mono-defluorinative alkylation under mild reaction conditions providing access to a series of valuable α,α-difluorobenzylic compounds. The reaction shows broad substrate scope and general functional group tolerance. In addition to the electron-deficient trifluoromethyl arenes that are easily reduced to the corresponding radical anion, more challenging electron-rich substrates were also successfully applied. Steady-State Stern-Volmer quenching studies indicated that the trifluoromethyl arenes were reduced by the multiphoton excited Ir-based photocatalyst.

Nickel-catalyzed C(sp2)-C(sp3) coupling via photoactive electron donor-acceptor complexes.

We have developed a novel Ni-catalyzed reductive cross-coupling reaction of aryl bromides and alkyl iodides via a photoactive electron donor-acceptor (EDA) complex. This photo-induced process enables the efficient construction of C(sp2)-C(sp3) bonds in the absence of an external photocatalyst. Electronically and structurally diverse aryl bromides, as well as secondary and primary alkyl iodides could undergo this transformation smoothly. Natural product derivatives were employed successfully, and UV-vis spectroscopy was utilized to gain mechanistic insight.

Tacrolimus alleviates pulmonary fibrosis progression through inhibiting the activation and interaction of ILC2 and monocytes.

Idiopathic pulmonary fibrosis (IPF) is a heterogeneous group of lung diseases with different etiologies and characterized by progressive fibrosis. This disease usually causes pulmonary structural remodeling and decreased pulmonary function. The median survival of IPF patients is 2-5 years. Predominantly accumulation of type II innate immune cells accelerates fibrosis progression by secreting multiple pro-fibrotic cytokines. Group 2 innate lymphoid cells (ILC2) and monocytes/macrophages play key roles in innate immunity and aggravate the formation of pro-fibrotic environment. As a potent immunosuppressant, tacrolimus has shown efficacy in alleviating the progression of pulmonary fibrosis. In this study, we found that tacrolimus is capable of suppressing ILC2 activation, monocyte differentiation and the interaction of these two cells. This effect further reduced activation of monocyte-derived macrophages (Mo-M), thus resulting in a decline of myofibroblast activation and collagen deposition. The combination of tacrolimus and nintedanib was more effective than either drug alone. This study will reveal the specific process of tacrolimus alleviating pulmonary fibrosis by regulating type II immunity, and explore the potential feasibility of tacrolimus combined with nintedanib in the treatment of pulmonary fibrosis. This project will provide new ideas for clinical optimization of anti-pulmonary fibrosis drug strategies.

Accelerating Antimicrobial Peptide Discovery for WHO Priority Pathogens through Predictive and Interpretable Machine Learning Models.

The escalating menace of multidrug-resistant (MDR) pathogens necessitates a paradigm shift from conventional antibiotics to innovative alternatives. Antimicrobial peptides (AMPs) emerge as a compelling contender in this arena. Employing in silico methodologies, we can usher in a new era of AMP discovery, streamlining the identification process from vast candidate sequences, thereby optimizing laboratory screening expenditures. Here, we unveil cutting-edge machine learning (ML) models that are both predictive and interpretable, tailored for the identification of potent AMPs targeting World Health Organization's (WHO) high-priority pathogens. Furthermore, we have developed ML models that consider the hemolysis of human erythrocytes, emphasizing their therapeutic potential. Anchored in the nuanced physical-chemical attributes gleaned from the three-dimensional (3D) helical conformations of AMPs, our optimized models have demonstrated commendable performance-boasting an accuracy exceeding 75% when evaluated against both low-sequence-identified peptides and recently unveiled AMPs. As a testament to their efficacy, we deployed these models to prioritize peptide sequences stemming from PEM-2 and subsequently probed the bioactivity of our algorithm-predicted peptides vis-à-vis WHO's priority pathogens. Intriguingly, several of these new AMPs outperformed the native PEM-2 in their antimicrobial prowess, thereby underscoring the robustness of our modeling approach. To elucidate ML model outcomes, we probe via Shapley Additive exPlanations (SHAP) values, uncovering intricate mechanisms guiding diverse actions against bacteria. Our state-of-the-art predictive models expedite the design of new AMPs, offering a robust countermeasure to antibiotic resistance. Our prediction tool is available to the public at https://ai-meta.chem.ncu.edu.tw/amp-meta.

FluoroFusion: NHC-Catalyzed Nucleophilic Aromatic Substitution Reaction Unveils Functional Perfluorinated Diarylmethanones.

A mild, facile, and metal-free approach via the N-heterocyclic carbene-catalyzed SNAr reaction between aryl aldehydes with perfluoroarenes to obtain the coveted functional perfluorinated diarylmethanones is disclosed. This method accommodates a diverse substrate range and exhibits notable tolerance toward various functional groups. Our success in modifying biologically relevant molecules, crafting a fully fluorinated bioisosteric analogue of drug candidate D1, and highlighting the potential of these ketones as valuable electrolyte additives for lithium-ion batteries (LIBs) underscores the versatility of our methodology.

The Clinical Analysis of Checkpoint Inhibitor Pneumonitis with Different Severities in Lung Cancer Patients: A Retrospective Study.

Immune-related adverse events (irAEs) of immunotherapy would lead to the temporary or permanent discontinuation of immune checkpoint inhibitors (ICIs). Among them, checkpoint inhibitor pneumonitis (CIP) is a potentially life-threatening irAE. This study aimed to identify the differences between patients with low-grade CIPs (grades 1-2) and high-grade CIPs (grades 3-5) and to explore the prognostic factors. We retrospectively reviewed the medical records of 916 lung cancer patients who were treated with ICIs. Patients with CIPs were identified after multidisciplinary discussion, and their clinical, laboratory, radiological, and follow-up data were analyzed. Among the 74 enrolled CIP patients, there were 31 low-grade CIPs and 43 high-grade CIPs. Compared with low-grade CIP patients, patients with high-grade CIPs were older (65.8 years vs. 61.5 years) and had lower serum albumin (35.2 g/L vs. 37.9 g/L), higher D-dimer (5.1 mg/L vs. 1.7 mg/L), and more pulmonary infectious diseases (32.6% vs. 6.5%) during follow-up. In addition, complication with pulmonary infectious diseases, management with intravenous immunoglobulin, tocilizumab, and longer duration of large dosage corticosteroids might be associated with worse outcomes for patients with CIPs. This study highlights potential risk factors for high-grade CIP and poor prognosis among lung cancer patients who were treated with anti-cancer ICIs.

Immunotherapy of microsatellite stable colorectal cancer: resistance mechanisms and treatment strategies.

In recent years, immunotherapy strategies based on immune checkpoint inhibitors have yielded good efficacy in colorectal cancer (CRC)especially in colorectal cancer with microsatellite instability-high. However, microsatellite-stable (MSS) CRCs account for about 85% of CRCs and are resistant to immunotherapy. Previous studies have shown that compared with MSS CRC, high microsatellite instability CRC possesses a higher frequency of mutations and can generate more neoantigens. Therefore, improving the sensitivity of immunotherapy to MSS CRC is a hot topic which is crucial for the treatment of MSS CRC. This review aims to discuss the factors contributing to MSS CRC insensitivity to immunotherapy and explored potential solutions to overcome immunotherapy resistance.

Probabilistic risk assessment for determining nonessential metals in commercial infant formula products in Taiwan.

During the early months of life, infant formula plays a crucial role as a primary source of both food and essential nutrients for infants, serving as a replacement for or supplement to breast milk. However, nonessential metals in infant formulas are a concern because infants are highly vulnerable to chemical exposure. The aim of this study was to investigate infant exposure to nonessential metals in infant formula products in Taiwan and assess the associated health risks. In this study, concentrations of arsenic (As), barium (Ba), cadmium (Cd), manganese (Mn), lead (Pb), and vanadium (V) in 45 formula products for 0-1-year-old infants were determined by inductively coupled plasma mass spectrometry. The mean As, Ba, Cd, Mn, Pb, and V concentrations were 6.42, 280, 3.72, 1425, 20.4, and 21.9 µg/kg, respectively. According to our probabilistic simulation of the estimated daily intake of metals, the proportion of hazard quotients exceeding one was 7.69% for As and 3.29% for Mn, and that of hazard index (HI) values exceeding 1 was >17% for metals. Arsenic had the largest HI contribution (46.9%), followed by Mn (22.3%) and Pb (12.7%). The nonessential metals content in infant formula raises potential noncarcinogenic health concerns for infants in Taiwan. Therefore, regulations for nonessential metals must be imposed on related food products in Taiwan, with a particular focus on As and Mn.

Mutations in CFAP47, a previously reported MMAF causative gene, also contribute to the respiratory defects in patients with PCD.

BACKGROUND: Primary ciliary dyskinesia (PCD) is a genetic ciliopathy characterized by dysfunction of motile cilia. Currently, approximately 50 causative genes accounting for 60%-70% of all PCD cases have been identified in PCD-affected individuals, but the etiology in approximately 30%-40% of PCD cases remains unknown. METHODS: We analyzed the clinical and genetic data of two PCD individuals who were suspected of having PCD. Whole-exome sequencing and Sanger sequencing were performed to identify and verify the variants in CFAP47. We also evaluated the expression of CFAP47 by real-time quantitative PCR and immunofluorescence. Transmission electron microscopy in respiratory epithelial cells was also conducted to analyze ciliary function. RESULTS: Two hemizygous missense variants of X-linked CFAP47 in two unrelated PCD individuals were identified. The expression of CFAP47 in two PCD individuals was significantly reduced in vivo and in vitro assays. A reduction in the amount of epithelial ciliary cells and basal bodies from PCD individuals was also observed. CONCLUSIONS: We describe two hemizygous missense variants of X-linked CFAP47 in two unrelated PCD individuals and prove CFAP47 variants are related to a reduced number of epithelial ciliary cells. Therefore, we suggest that CFAP47 should be known as a novel pathogenic gene of human PCD.

A randomized controlled trial of a proactive analgesic protocol demonstrates reduced opioid use among hospitalized adults with inflammatory bowel disease.

Most hospitalized patients with inflammatory bowel disease (IBD) experience pain. Despite the known risks associated with opioids in IBD including risk for misuse, overdose, infection, readmission, and even death, opioid use is more prevalent in IBD than any other chronic gastrointestinal condition. Most hospitalized IBD patients receive opioids; however, opioids have not been shown to improve pain during hospitalization. We conducted a randomized controlled trial in hospitalized patients with IBD to evaluate the impact of a proactive opioid-sparing analgesic protocol. Wearable devices measured activity and sleep throughout their hospitalization. Chronic opioid users, post-operative, and pregnant patients were excluded. The primary endpoint was a change in pain scores from admission to discharge. Secondary endpoints included opioid use, functional activity, sleep duration and quality, and length of stay. Of 329 adults with IBD evaluated for eligibility, 33 were enrolled and randomized to the intervention or usual care. Both the intervention and control group demonstrated significant decreases in pain scores from admission to discharge (- 2.6 ± 2.6 vs. - 3.0 ± 3.2). Those randomized to the intervention tended to have lower pain scores than the control group regardless of hospital day (3.02 ± 0.90 vs. 4.29 ± 0.81, p = 0.059), used significantly fewer opioids (daily MME 11.8 ± 15.3 vs. 30.9 ± 42.2, p = 0.027), and had a significantly higher step count by Day 4 (2330 ± 1709 vs. 1050 ± 1214; p = 0.014). There were no differences in sleep duration, sleep quality, readmission, or length-of-stay between the two groups. A proactive analgesic protocol does not result in worsening pain but does significantly reduce opioid-use in hospitalized IBD patients.Clinical trial registration number: NCT03798405 (Registered 10/01/2019).

Delayed Collagen Production without Myofibroblast Formation Contributes to Reduced Scarring in Adult Skin Microwounds.

In adult mammals, wound healing predominantly follows a fibrotic pathway, culminating in scar formation. However, cutaneous microwounds generated through fractional photothermolysis, a modality that produces a constellation of microthermal zones, exhibit a markedly different healing trajectory. Our study delineates the cellular attributes of these microthermal zones, underscoring a temporally limited, subclinical inflammatory milieu concomitant with rapid re-epithelialization within 24 hours. This wound closure is facilitated by the activation of genes associated with keratinocyte migration and differentiation. In contrast to macrothermal wounds, which predominantly heal through a robust myofibroblast-mediated collagen deposition, microthermal zones are characterized by absence of wound contraction and feature delayed collagen remodeling, initiating 5-6 weeks after injury. This distinct wound healing is characterized by a rapid re-epithelialization process and a muted inflammatory response, which collectively serve to mitigate excessive myofibroblast activation. Furthermore, we identify an initial reparative phase characterized by a heterogeneous extracellular matrix protein composition, which precedes the delayed collagen remodeling. These findings extend our understanding of cutaneous wound healing and may have significant implications for the optimization of therapeutic strategies aimed at mitigating scar formation.

Estrogen/Progesterone Receptor Expression and Cancer Antigen 125 Level as Preoperative Predictors to Estimate Lymph Node Metastasis in Endometrioid Endometrial Cancer.

Loss of estrogen receptor/progesterone receptor (ER/PR) in endometrial cancer (EC) is associated with tumor progression and poor outcomes. Elevated pretreatment cancer antigen 125 (CA 125) level is a risk factor for lymph node metastasis (LNM). We evaluated whether the combination of ER/PR expression and CA 125 level could be used as a biomarker to predict LNM. We retrospectively investigated patients with endometrioid EC who underwent complete staging surgery during January 2015 to December 2020. We analyzed ER/PR status using immunohistochemical staining, and quantified its expression using the sum of both ER/PR H-scores. Receiver operating characteristic curves were used to identify optimal cutoff values of H-score and CA 125 levels for predicting LNM. A nomogram for predicting LNM was constructed and validated by bootstrap resampling. In 396 patients, the optimal cutoff values of the ER/PR H-score and CA 125 were 407 (area under the receiver operating characteristic curve: 0.645, P=0.001) and 40 U/mL (area under the receiver operating characteristic curve: 0.762, P<0.001), respectively. Multivariate analysis showed that CA 125 ≥40 UmL (odds ratio: 10.02; 95% CI: 4.74-21.18) and ER/PR H-score <407 (odds ratio: 4.20; 95% CI: 1.55-11.32) were independent predictors. An LNM predictive nomogram was constructed using these 2 variables and our model yielded a negative predictive value and negative likelihood ratio of 98.3% and 0.14, respectively. ER/PR expression with pretreatment CA 125 levels can help estimate LNM risk and aid in decision-making regarding the need for lymphadenectomy in patients with endometrioid EC.

Risk factors associated with COVID-19 pneumonia in Chinese patients with pre-existing interstitial lung disease during the SARS-CoV-2 pandemic.

In China, the emergence of a nationally widespread epidemic infection of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) has appeared within a month since December 7, 2022. To evaluate the risk factors for suffering from coronavirus disease 2019 (COVID-19) pneumonia due to infection with SARS-CoV-2 in different kinds of interstitial lung disease (ILD) patients with diverse immunizations, we conducted this retrospective study on 525 patients with ILDs who underwent regular follow-up in our ILD clinic. Among them, 128 ILD patients (24.4%) suffered from COVID-19 pneumonia after SARS-CoV-2 infection. Patients were older with a male predominance in the pneumonia group than in the nonpneumonia group (65.0 ± 10.0 years vs. 56.4 ± 11.7 years, p < 0.001, 55.5% vs. 39.5%, p = 0.002, respectively). Connective tissue disease-associated ILD (CTD-ILD) (25%), idiopathic pulmonary fibrosis (23.4%), and interstitial pneumonia with autoimmune features (21.1%) were the main pre-existing ILDs in the pneumonia group. In Cox multivariable analysis, only male sex and corticosteroid use were risk factors for COVID-19 pneumonia after infection. Two or three doses of vaccination were a protective factor for pre-existing ILD patients suffering from COVID-19 pneumonia. More than two doses of vaccination were strongly recommended for pre-existing ILD patients, particularly for males who were administered corticosteroids.

Building-Block Size Mediates Microporous Annealed Particle Hydrogel Tube Microenvironment Following Spinal Cord Injury.

Spinal cord injury (SCI) is a life-altering event, which often results in loss of sensory and motor function below the level of trauma. Biomaterial therapies have been widely investigated in SCI to promote directional regeneration but are often limited by their pre-constructed size and shape. Herein, the design parameters of microporous annealed particles (MAPs) are investigated with tubular geometries that conform to the injury and direct axons across the defect to support functional recovery. MAP tubes prepared from 20-, 40-, and 60-micron polyethylene glycol (PEG) beads are generated and implanted in a T9-10 murine hemisection model of SCI. Tubes attenuate glial and fibrotic scarring, increase innate immune cell density, and reduce inflammatory phenotypes in a bead size-dependent manner. Tubes composed of 60-micron beads increase the cell density of the chronic macrophage response, while neutrophil infiltration and phenotypes do not deviate from those seen in controls. At 8 weeks postinjury, implantation of tubes composed of 60-micron beads results in enhanced locomotor function, robust axonal ingrowth, and remyelination through both lumens and the inter-tube space. Collectively, these studies demonstrate the importance of bead size in MAP construction and highlight PEG tubes as a biomaterial therapy to promote regeneration and functional recovery in SCI.

Apoptotic Cell-Derived CD14(+) Microparticles Promote the Phagocytic Activity of Neutrophilic Precursor Cells in the Phagocytosis of Apoptotic Cells.

Membranous CD14 is crucial in the phagocytic activity of neutrophils. However, the role of CD14(+) microparticles (MPs) derived from apoptotic neutrophils (apo-MP) during the phagocytic process is not clear. All trans-retinoic acid (ATRA) induces acute promyelocytic leukemic NB4 cells along granulocytic differentiation. In this study, we investigated the role of CD14(+)apo-MP in the cell-cell interaction during the phagocytic process of apoptotic cells by viable ATRA-NB4 cells. We firstly demonstrate that CD14 expression and phagocytic activity of NB4 cells were upregulated simultaneously after ATRA treatment in a time-dependent manner, and both were significantly enhanced via concurrent lipopolysaccharide treatment. The phagocytic activity of ATRA-NB4 cells and lipopolysaccharide-treated ATRA-NB4 cells were both significantly attenuated by pre-treating cells with an antibody specific to either CD14 or TLR4. Further flow cytometric analysis demonstrates that apoptotic ATRA-NB4 cells release CD14(+)apo-MP in an idarubicin dosage-dependent manner. Both CD14 expression and the phagocytic activity of viable ATRA-NB4 cells were significantly enhanced after incubation with apo-MP harvested from apoptotic ATRA-NB4 cells, and the apo-MP-enhanced phagocytic activity was significantly attenuated by pre-treating apo-MP with an anti-CD14 antibody before incubation with viable cells. We conclude that CD14(+)apo-MP derived from apoptotic ATRA-NB4 cells promotes the phagocytic activity of viable ATRA-NB4 cells in engulfing apoptotic cells.

Acupuncture Improves Sleep Disorders and Depression among Patients with Parkinson's Disease: A Meta-Analysis.

Parkinson's disease (PD) is associated with a range of non-motor symptoms that lack effective treatments. Acupuncture is a popular alternative therapy for PD patients that has been shown to improve motor symptoms. However, the efficacy of acupuncture in treating non-motor symptoms has remained controversial. The goal of our study was to systematically assess the existing evidence for acupuncture's efficacy in treating PD non-motor symptoms of sleep disorders, depression, anxiety, and fatigue. We conducted a meta-analysis of clinical trials by searching Pubmed, Embase, CINAHL, and Web of Science as electronic databases to evaluate acupuncture treatment for PD non-motor symptoms. Thirteen clinical trials met our inclusion criteria, and their methodological quality was assessed using the modified Jadad scale, indicating a moderate overall quality. Our results showed that acupuncture improved PD-related sleep disorders and depression but had no effect on anxiety and fatigue. Our meta-analysis suggests that acupuncture can be used as a complementary treatment for sleep disturbances and depression in PD patients and may exhibit a dual therapeutic effect on motor and non-motor symptoms. However, further well-designed clinical trials with larger sample sizes are needed to confirm these findings. Overall, our study highlights the potential of acupuncture as a viable complementary therapy for the treatment of PD non-motor symptoms of sleep disorders and depression, which can improve the quality of life of PD patients.

Discovery of HDAC6, HDAC8, and 6/8 Inhibitors and Development of Cell-Based Drug Screening Models for the Treatment of TGF-ß-Induced Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis is incurable, and its progression is difficult to control and thus can lead to pulmonary deterioration. Pan-histone deacetylase inhibitors such as SAHA have shown potential for modulating pulmonary fibrosis yet with off-target effects. Therefore, selective HDAC inhibitors would be beneficial for reducing side effects. Toward this goal, we designed and synthesized 24 novel HDAC6, HDAC8, or dual HDAC6/8 inhibitors and established a two-stage screening platform to rapidly screen for HDAC inhibitors that effectively mitigate TGF-ß-induced pulmonary fibrosis. The first stage consisted of a mouse NIH-3T3 fibroblast prescreen and yielded five hits. In the second stage, human pulmonary fibroblasts (HPFs) were used, and four out of the five hits were tested for caco-2 permeability and liver microsome stability to give two potential leads: J27644 (15) and 20. This novel two-stage screen platform will accelerate the discovery and reduce the cost of developing HDAC inhibitors to mitigate TGF-ß-induced pulmonary fibrosis.

Pretreatment carcinoembryonic antigen combined with cancer antigen-125 for predicting lymph node metastasis in endometrial carcinoma: a retrospective cohort study.

PURPOSE: To investigate whether the cost-effective, pretreatment tumor markers carcinoembryonic antigen (CEA) and carbohydrate antigen-125 (CA-125) can be used to predict lymph node metastasis (LNM) in endometrioid-type endometrial cancer (EC) and to develop a predictive model. METHODS: This was a single-center retrospective study of patients with endometrioid-type EC who underwent complete staging surgery between January 2015 and June 2022. We identified the optimal cut-off values of CEA and CA-125 for predicting LNM using receiver operating characteristic (ROC) curves. Stepwise multivariate logistic regression analysis was used to identify independent predictors. A nomogram for predicting LNM was constructed and validated by bootstrap resampling. RESULTS: The optimal cut-off values of CEA and CA-125 were 1.4 ng/mL (area under the ROC curve (AUC) 0.62) and 40 U/mL (AUC 0.75), respectively. Multivariate analysis showed that CEA (odds ratio (OR) 1.94; 95% confidence interval (CI) 1.01-3.74) and CA-125 (OR 8.75; 95% CI 4.42-17.31) were independent predictors of LNM. Our nomogram showed adequate discrimination with a concordance index of 0.78. Calibration curves for the probability of LNM showed optimal agreement between the predicted and actual probabilities. The risk of LNM for markers below the cut-offs was 3.6%. The negative predictive value and negative likelihood ratio were 96.6% and 0.26, respectively, with moderate ability to rule out the possibility of LNM. CONCLUSION: We report a cost-effective method of using pretreatment CEA and CA-125 levels to identify patients with endometrioid-type EC who are at a low risk for LNM, which may guide decision-making regarding aborting lymphadenectomy.

Microscopic polyangiitis initially presenting with idiopathic pulmonary fibrosis: a case report.

Usual interstitial pneumonia is the most common type of microscopic polyangiitis (MPA)-associated interstitial lung disease, and patients may initially present with isolated pulmonary fibrosis, which often leads to a misdiagnosis of idiopathic pulmonary fibrosis (IPF). Here, we describe a patient who developed fever of unknown origin, microscopic hematuria and renal insufficiency, who then tested positive for antineutrophil cytoplasmic antibody (ANCA) and was diagnosed with MPA after receiving antifibrotic medication for IPF (original diagnosis) for almost 10 years. The patient's symptoms were ameliorated after administration of additional glucocorticoids and immunosuppressants.

Combined Programmed Intermittent Bolus and Patient-Controlled Bolus Is a More Favorable Setting for Epidural Pain Relief Than Continuous Infusion.

Epidural analgesia is a suitable and effective treatment for labor pain. However, the preferable modality setting for delivery remains debatable. This study adopted a programmed intermittent epidural bolus (PIEB) setting in conjunction with a patient-controlled epidural analgesia (PCEA) setting to improve the quality of labor analgesia and reduce the number of medical staff. We conducted a prospective observational analysis of primigravida parturients scheduled for spontaneous labor, which required epidural analgesia for painless labor. A total of 483 healthy primigravida parturients with singleton pregnancies were included in this cohort; 135 nulliparous patients were assigned to the continuous infusion setting (CEI) group and 348 to the PIEB + PCEA group. Compared to the CEI setting, the PIEB + PCEA setting significantly reduced the manual rescue by the clinician, extended the time required for the first manual rescue dose, and acclaimed good maternal satisfaction. The use of the CEI mode increased for poor performance requiring more than two rescues with an odds ratio of 2.635 by a binary logistic regression analysis. Using the PIEB + PCEA setting as the maintenance infusion had a longer duration for the first requested manual rescue, fewer manual rescue boluses, excellent satisfaction, and no significant increase in adverse events compared to the CEI setting.