Corrigendum to "Polysaccharide and ethanol extracts of Anoectochilus formosanus Hayata: Antioxidant, wound-healing, antibacterial, and cytotoxic activities".

[This corrects the article DOI: 10.1016/j.heliyon.2023.e13559.].

Excision of a Protein-Derived Amine for p-Aminobenzoate Assembly by the Self-Sacrificial Heterobimetallic Protein CADD.

Chlamydia protein associating with death domains (CADD), the founding member of a recently discovered class of nonheme dimetal enzymes termed hemeoxygenase-like dimetaloxidases (HDOs), plays an indispensable role in pathogen survival. CADD orchestrates the biosynthesis of p-aminobenzoic acid (pABA) for integration into folate via the self-sacrificial excision of a protein-derived tyrosine (Tyr27) and several additional processing steps, the nature and timing of which have yet to be fully clarified. Nuclear magnetic resonance (NMR) and proteomics approaches reveal the source and probable timing of amine installation by a neighboring lysine (Lys152). Turnover studies using limiting O2 have identified a para-aminobenzaldehyde (pABCHO) metabolic intermediate that is formed on the path to pABA formation. The use of pABCHO and other probe substrates shows that the heterobimetallic Fe/Mn form of the enzyme is capable of oxygen insertion to generate the pABA-carboxylate.

[Analysis of therapeutic mechanism of Liushen Wan against colitis-associated colorectal cancer based on network pharmacology and validation in mice].

OBJECTIVE: To explore the therapeutic mechanism of Liushen Wan (LSW) against colitis-associated colorectal cancer (CAC) by network pharmacology. METHODS: TCMSP, BATMAN-TCM, CNKI, PubMed, Genecards, OMIM, and TTD databases were used to obtain the related targets of LSW and CAC. The common targets of LSW and CAC were obtained using Venny online website. The PPI network was constructed using Cytoscape 3.8.2 to screen the core targets of LSW in the treatment of CAC. GO and KEGG enrichment analysis were conducted using DAVID database. The therapeutic effect of LSW on CAC was evaluated in a C57BL/6J mouse model of AOM/DSS-induced CAC by observing the changes in body weight, disease activity index, colon length, and size and number of the tumor. HE staining and RT-qPCR were used to analyze the effect of LSW on inflammatory mediators. Immunohistochemistry and TUNEL staining were used to evaluate the effect of LSW on the proliferation and apoptosis of AOM/DSS-treated colon tumor cells. Immunohistochemistry and Western blotting were used to detect the effects of LSW on the expression of TLR4 proteins in CAC mice. RESULTS: Network pharmacology analysis identified 69 common targets of LSW and CAC, and 33 hub targets were screened in the PPI network. KEGG pathway enrichment analysis suggested that the effect of LSW on CAC was mediated by the Toll-like receptor signaling pathway. In the mouse model of AOM/DSS-induced CAC, LSW significantly inhibited colitis-associated tumorigenesis, reduced tumor number and tumor load (P < 0.05), obviously improved histopathological changes in the colon, downregulated the mRNA levels of proinflammatory cytokines, and inhibited the proliferation (P < 0.01) and promoted apoptosis of colon tumor cells (P < 0.001). LSW also significantly decreased TLR4 protein expression in the colon tissue (P < 0.05). CONCLUSION: LSW can inhibit CAC in mice possibly by regulating the expression of TLR4 to reduce intestinal inflammation, inhibit colon tumor cell proliferation and promote their apoptosis.

Appraising features and outlook of women and men discharged after an acute coronary syndrome: evidence from the 23,700-patient PRAISE International Registry.

BACKGROUND: Acute coronary syndromes (ACS) are a common cause of morbidity and mortality. Several studies have focused on ACS at admission, but limited evidence is available on sex-based comparison of patients discharged after ACS. We appraised the outlook of women and men discharged after ACS. METHODS: Details on women enrolled in the PRAISE registry, an international cohort study spanning 23,700 patients included between 2003 and 2019, were systematically collected. We focused on patient and procedural features, medications at discharge, and 1-year outcomes. The primary endpoint was the composite of death, myocardial infarction, or major bleeding after discharge. RESULTS: A total of 17,804 (76.5%) men and 5466 (23.5%) women were included. Several baseline differences were found, including risk factors and prior revascularization (all P<0.05). Men underwent more frequently radial access, and at discharge they received more commonly dual antiplatelet therapy and guideline-directed medical therapy (P<0.001). At 1-year follow-up, risks of death, reinfarction, major bleeding, and non-fatal major bleeding, jointly or individually, were all significantly higher in women (all P≤0.01). All such differences however did not hold true at multivariable analysis, with the exception of major bleeding, which appeared surprisingly less common in females at fully adjusted analysis (P=0.017). CONCLUSIONS: Women, albeit only apparently, had worse outcomes 1 year after discharge for ACS, but adjusted analysis suggested instead that they faced a lower risk of major bleeding after discharge. These findings support the call for more aggressive management of women after ACS.

Polysaccharide and ethanol extracts of Anoectochilus formosanus Hayata: Antioxidant, wound-healing, antibacterial, and cytotoxic activities.

Introduction: Polysaccharide and alcohol extracts of Anoectochilus formosanus Hayata have attracted great attention as they exhibit noteworthy properties such as prebiotic and anti-hyperglycemic effects. However, the antioxidant and wound-healing activities of the polysaccharide extract as well as the antibacterial and cytotoxic effects of the ethanol extracts have not been thoroughly uncovered. Therefore, our study investigated these bioactivities of the two extracts prepared from Anoectochilus formosanus to broaden understandings of medical benefits of the plant. Methods: The monosaccharide composition was analyzed by HPAEC-PAD. The antioxidant and wound-healing activities of the polysaccharide extract were evaluated by ABTS and scratch assays, respectively. The broth dilution method was used to determine the antibacterial ability of the ethanol extract. Additionally, the cytotoxic and mechanistic effects of this extract against hepatocellular carcinoma HUH-7 cells was assessed by MTT assay, qRT-PCR and Western blotting methods. Results: The polysaccharide extract possessed an effective free radical scavenging ability in an ABTS assay (IC50 = 44.92 µg/ml). The extract also ameliorated wound recovery in a fibroblast scratch assay. Meanwhile, the ethanol extract was able to inhibit the growth of Staphylococcus aureus (MIC = 2500 µg/ml), Bacillus cereus (MIC = 2500 µg/ml), Escherichia coli (MIC = 2500 µg/ml), and Pseudomonas aeruginosa (MIC = 1250 µg/ml). Additionally, it repressed the viability of HUH-7 cells (IC50 = 53.44 µg/ml), possibly through upregulating the expression of caspase 3 (CASP3), CASP8, and CASP9 at both mRNA and protein levels. Conclusion: The polysaccharide extract of A. formosanus exhibited the antioxidant and wound-healing properties whereas the ethanol extract showed the antibacterial activity and cytotoxicity against HUH-7 cells. These findings specify notable biological effects of the two extracts which could be of potential use in human healthcare.

MRI features and whole-lesion apparent diffusion coefficient histogram analysis of brain metastasis from non-small cell lung cancer for differentiating epidermal growth factor receptor mutation status.

AIM: To explore the utility of magnetic resonance imaging (MRI) characteristics and whole-lesion apparent diffusion coefficient histogram analysis of brain metastasis from non-small cell lung cancer (NSCLC) in the differentiation of epidermal growth factor receptor (EGFR) mutation status. MATERIALS AND METHODS: Forty-eight patients with brain metastases from NSCLC were enrolled in this retrospective study. Patients were subtyped into EGFR mutation (23 cases) and wild-type (25 cases) groups. Whole-lesion histogram metrics were derived from the apparent diffusion coefficient (ADC) maps, and imaging features were evaluated according to conventional MRI. Student's t-test or Mann-Whitney U-test, chi-squared test, and receiver operating characteristic (ROC) curve analysis were performed to discriminate the two groups and to determine the diagnostic efficacy of ADC histogram parameters. RESULTS: EGFR mutation group had more multiple brain metastases, less peritumoural brain oedema (PTBO), and lower peritumoural brain oedema index (PTBO-I) than EGFR wild-type group (all p<0.05). In addition, 90th and 75th percentiles of ADC and maximum ADC in the EGFR mutation group were significantly higher than in the EGFR wild-type group (all p<0.05). Ninetieth percentile of ADC had the highest area under the curve (AUC; 0.711), and it was found to outperform 75th percentile of ADC (AUC, 0.662; p=0.039) and maximum ADC (AUC, 0.681). CONCLUSIONS: Whole-lesion ADC histogram analysis and MRI features of brain metastasis from NSCLC are expected to be potential biomarkers to non-invasively differentiate the EGFR mutation status.

Distal Hydrophobic Loop Modulates the Copper Active Site and Reaction of AA13 Polysaccharide Monooxygenases.

Polysaccharide monooxygenases (PMOs) use a type-2 copper center to activate O2 for the selective hydroxylation of one of the two C-H bonds of glycosidic linkages. Our electron paramagnetic resonance (EPR) analysis and molecular dynamics (MD) simulations suggest the unprecedented dynamic roles of the loop containing the residue G89 (G89 loop) on the active site structure and reaction cycle of starch-active PMOs (AA13 PMOs). In the Cu(II) state, the G89 loop could switch between an "open" and "closed" conformation, which is associated with the binding and dissociation of an aqueous ligand in the distal site, respectively. The conformation of the G89 loop influences the positioning of the copper center on the preferred substrate of AA13 PMOs. The dissociation of the distal ligand results in the bending of the T-shaped core of the Cu(II) active site, which could help facilitate its reduction to the active Cu(I) state. In the Cu(I) state, the G89 loop is in the "closed" conformation with a confined copper center, which could allow for efficient O2 binding. In addition, the G89 loop remains in the "closed" conformation in the Cu(II)-superoxo intermediate, which could prevent off-pathway superoxide release via exchange with the distal aqueous ligand. Finally, at the end of the reaction cycle, aqueous ligand binding to the distal site could switch the G89 loop to the "open" conformation and facilitate product release.

Self-sacrificial tyrosine cleavage by an Fe:Mn oxygenase for the biosynthesis of para-aminobenzoate in Chlamydia trachomatis.

Chlamydia protein associating with death domains (CADD) is involved in the biosynthesis of para-aminobenzoate (pABA), an essential component of the folate cofactor that is required for the survival and proliferation of the human pathogen Chlamydia trachomatis. The pathway used by Chlamydiae for pABA synthesis differs from the canonical multi-enzyme pathway used by most bacteria that relies on chorismate as a metabolic precursor. Rather, recent work showed pABA formation by CADD derives from l-tyrosine. As a member of the emerging superfamily of heme oxygenase-like diiron oxidases (HDOs), CADD was proposed to use a diiron cofactor for catalysis. However, we report maximal pABA formation by CADD occurs upon the addition of both iron and manganese, which implicates a heterobimetallic Fe:Mn cluster is the catalytically active form. Isotopic labeling experiments and proteomics studies show that CADD generates pABA from a protein-derived tyrosine (Tyr27), a residue that is ∼14 Šfrom the dimetal site. We propose that this self-sacrificial reaction occurs through O2 activation by a probable Fe:Mn cluster through a radical relay mechanism that connects to the "substrate" Tyr, followed by amination and direct oxygen insertion. These results provide the molecular basis for pABA formation in C. trachomatis, which will inform the design of novel therapeutics.

A case report of rare granular cell tumor of the urinary bladder.

Granular cell tumors (GCT) are uncommon tumors that originate in any part of the body. They have been mainly observed in the skin and soft tissue of the head and neck, and are mostly benign tumors. Urinary bladder GCT are extremely rare tumors. The diagnosis of urinary bladder GCT needs high clinical suspicion by the urologist and the pathologist. We herein report a case of rare granular cell tumor of the urinary bladder in a young woman.

Generation of double Holliday junction DNAs and their dissolution/resolution within a chromatin context.

Four-way DNA intermediates, also known as Holliday junctions (HJs), are formed during homologous recombination and DNA repair, and their resolution is necessary for proper chromosome segregation. To facilitate the biochemical analysis of HJ processing, we developed a method involving DNAzyme self-cleavage to generate 1.8-kb DNA molecules containing either single (sHJ) or double Holliday junctions (dHJs). We show that dHJ DNAs (referred to as HoJo DNAs) are dissolved by the human BLM­TopIIIα­RMI1­RMI2 complex to form two noncrossover products. However, structure-selective endonucleases (human GEN1 and SMX complex) resolve DNA containing single or double HJs to yield a mixture of crossover and noncrossover products. Finally, we demonstrate that chromatin inhibits the resolution of the double HJ by GEN or SMX while allowing BTRR-mediated dissolution.

[Transcription factor EB related autophagy in the treatment of multiple myeloma and its mechanism].

Objective: To clarify the effects of bortezomib combined with or without siramesine on the proliferation of multiple myeloma cell lines, the expression changes of transcription factor EBC (TFEB) nuclear translocation and the level of autophagy, and to provide basis for further exploring the regulation mechanism of transcription factor TFEB on autophagy. Methods: The multiple myeloma cell lines RPMI8226 and U266 were cultured in vitro, and the multiple myeloma cells were treated with a certain concentration of bortezomib and siramesine. The changes of cell proliferation inhibition were detected by CCK-8 method. Real time PCR and Western blot were used to detect the relative expression of TFEB, autophagy-related factor LC3B, Beclin1, p62, LAMP1 mRNA and protein. Results: As the concentration of bortezomib increased and the duration of action increased, the proliferation inhibition rates of the two cell lines gradually increased (P<0.05) . The combination of the two drugs has a synergistic inhibitory effect on the proliferation of the above-mentioned multiple myeloma cell lines (P<0.05) . In the blank control group, single drug group, and combination drug group, the relative expression of TFEB mRNA and protein in the cytoplasm decreased sequentially (P<0.05) , and the relative expression of TFEB mRNA and protein in the nucleus increased sequentially (P<0.05) . The relative expression of autophagy-related factors LC3B, Beclin1, LAMP1 mRNA and protein increased sequentially, and the relative expression of p62 mRNA and protein decreased sequentially (P<0.05) . Conclusion: Bortezomib and siramesine can synergistically inhibit the growth of multiple myeloma cells, which is related to the increased autophagy expression in multiple myeloma cell lines and the expression of TFEB with nuclear translocation is also enhanced.

[Role of the liver-enriched transcription factor binding site mutation in the C promoter region of hepatitis B virus genome for HBx-enhanced hepatitis B virus replication].

Objective: To construct a recombinant HBV replication-type plasmid with liver-enriched transcription factor binding site mutation at proximal of HBV C promoter in order to elucidate the role of HBx-enhanced HBV replication. Methods: Site-directed mutagenesis technology was used to construct a recombinant plasmid with liver-enriched transcription factor binding site mutation at proximal of HBV C promoter on the basis of wild-type HBV replicating plasmid and HBV replicating plasmid lacking HBx expression. Subsequently, plasmid transfection was carried out in HBV liver cancer cell replication model and mouse replication model, and HBV replication intermediates of cells and mouse liver tissue were extracted for detection. Results: Based on the HBV replicating plasmid, the HBV replicating plasmid with liver-enriched transcription factor binding site mutation at proximal of HBV C promoter was successfully constructed. HBx-enhanced HBV replication were detected in both the HBV liver cancer replication model and the mouse replication model. After mutating liver-enriched transcription factor binding site mutation at proximal of HBV C promoter, the effect of HBx on the enhancement of HBV replication was not significantly affected. Conclusion: HBx may not enhance HBV replication through liver-enriched transcription factor binding site mutation at proximal of HBV C promoter. The role of other liver-enriched transcription factor binding sites in HBx-enhanced HBV replication needs further study.

A survey of public awareness of dysphagia.

OBJECTIVES: Purpose: Dysphagia affects a wide cross-section of society. Reports of stigma and missed diagnoses suggest limited public awareness of this prevalent condition, exacerbating the hidden disability stemming from this impairment. This study explored the public awareness of dysphagia among people both with and without occupational ties to healthcare to assess the level of awareness and identify topics where public knowledge may be deficient. METHODS: Method: An online purpose-built survey was administered to determine self-assessed awareness of dysphagia, and researcher-assessed understanding of the causes, symptoms, assessment and treatment of swallowing disorders. Survey answers (n = 374) were grouped by healthcare (n = 105) and non-healthcare (n = 269) respondents. Responses were analysed using both qualitative and quantitative methods. RESULTS: Result: Self-assessed respondent awareness was low among 71% of non-healthcare and 29% of healthcare respondents, corroborating the limited demonstrated knowledge of the causes, symptoms, assessment and treatment of dysphagia. Self-assessed and researcher-assessed awareness was more limited among non-healthcare respondents. CONCLUSIONS: Conclusion: Survey results confirm limited public knowledge of dysphagia and demonstrate the need for greater public awareness of this largely invisible disorder.

Isothermal Titration Calorimetry of Membrane Proteins.

The ability to quantify protein-protein interactions without adding labels to protein has made isothermal titration calorimetry (ITC) a preferred technique to study proteins in aqueous solution. Here, we describe the application of ITC to the study of protein-protein interactions in membrane mimics using the association of integrin αIIb and ß3 transmembrane domains in phospholipid bicelles as an example. A higher conceptual and experimental effort compared to water-soluble proteins is required for membrane proteins and rewarded with rare thermodynamic insight into this central class of proteins.

Dynamic interactions of lactic acid bacteria in Korean sourdough during back-slopping process.

AIMS: This study aimed to clarify the cause of quality reduction in Korean sourdough after successive back-slopping. METHODS AND RESULTS: We investigated the dynamic changes in lactic acid bacteria during the back-slopping process using genetic fingerprinting techniques. During the initial propagation phases, the dominant lactic acid bacteria were Fructilactobacillus sanfranciscensis (<5 log CFU per g sourdough), Latilactobacillus curvatus (9·5 log CFU per g sourdough) and Levilactobacillus brevis (6·5 log CFU per g sourdough). However, after the 11th propagation, F. sanfranciscensis became more prominent (>9·0 log CFU per g sourdough), whereas L. curvatus and L. brevis rapidly decreased. Monitoring these bacteria in the co-culture system revealed that acid-tolerant F. sanfranciscensis rapidly utilized maltose (1·65 g l-1  h-1 ) and produced large amounts of lactic acid, whereas L. brevis and L. curvatus consumed maltose slowly and L. curvatus was poorly tolerant to lactic acid. CONCLUSION: The results indicate that competition exists between the lactic acid bacteria in sourdough during the back-slopping process, and microbial succession by acid-tolerant species results in quality reduction of sourdough. SIGNIFICANCE AND IMPACT OF THE STUDY: This study uncovered the cause of microbial changes during the propagation of Korean sourdough and proposed a strategy to develop starters to produce high-quality bakery products.

The genus Rhoenanthus Eaton, 1881 in China with the redescription of R. hunanensis You amp; Gui, 1995 (Ephemeroptera: Potamanthidae).

The potamanthid mayfly genus Rhoenanthus Eaton, which was not investigated systematically before in China, is revised herein. Six species in the subgenus Potamanthindus are recognized. Among them, R. sapa, R. obscurus and R. coreanus are new records for this country, and the presence in China of the species R. magnificus and R. hunanensis is confirmed, the nymphal stage of the latter species being described for the first time. Phylogenetically and evolutionarily, R. sapa, which has shorter maxillary and labial palpi, foretibiae and less setaceous mouthparts and forelegs, is close to the plesiomorphic genus Potamanthus. At the same time, R. youi, R. obscurus and R. coreanus, which have larger tusks and spines, longer and more setaceous foretibiae, maxillary and labial palpi, are somewhat similar to the other subgenus Rhoenanthus (Rhoenanthus). The Chinese Rhoenanthus (Potamanthindus) species indicate that the genus Rhoenanthus is closer to Anthopotamus rather than Potamanthus, both of them bearing elongated mandibular tusks.

[Clinical significance and management strategies of low-level viremia during the treatment of chronic hepatitis B].

Chronic hepatitis B and its related complications seriously endanger the lives and health of our country people. Although the first-line nucleos(t)ide analogs such as entecavir, tenofovir disoproxil fumarate and tenofovir alafenamide fumarate can inhibit virus replication to a certain extent, delay or prevent disease progression, and reduce the incidence of hepatitis B-related liver cancer, but in clinical practice, HBV DNA positivity is still detected continuously or intermittently in the serum of some patients. Therefore, low-level viremia has received widespread attention and triggered discussion, and has become the difficulties and hotspot of antiviral treatment of chronic hepatitis B. This article summarizes and discusses the definition and incidence in line with the main guidelines and studies, impact of disease control and clinical prognosis, and the current treatment options in order to provide definite reference for the management of low-level viremia during antiviral therapy in patients with chronic hepatitis B.

Can the Behavioral Model of Health Care Utilization Be Used to Predict Completion of a Mental Health Assessment Following Intimate Partner Violence?

Survivors of intimate partner violence (IPV) may experience mental health problems. Although some survivors access mental health resources to address these concerns, many discontinue prematurely. One model of health care utilization that has recently gained attention in the trauma literature is the behavioral model of health care utilization (BMHU). This model considers three groups of variables in predicting health care utilization: immutable predisposing variables (e.g., age), enabling resources (e.g., income), and measures of need (e.g., symptom severity). The current study tested the BMHU's ability to predict completion of a free, multisession mental health evaluation for female survivors of IPV (N = 214). Two models were tested, each assessing a separate need-based predictor: The first model assessed symptoms of depression and the second model assessed symptoms of posttraumatic stress disorder (PTSD). Results were consistent across both models and suggested that younger age and receiving public assistance were both associated with a lower likelihood of completing the evaluation. Contrary to the BMHU's assumed positive relation between symptom severity and health care utilization, greater severity of depression and PTSD symptoms were both associated with a lower likelihood of completing the evaluation. It is possible that following IPV, experiencing psychological distress may engender help-seeking but too much distress may serve as a barrier to continued utilization. Future research should seek to better understand the complex relation between need and access, in the context of mental health care, and develop strategies for retaining IPV survivors who access mental health resources.

Factor Structure of the Communication Patterns Questionnaire in Violence-Exposed Women.

Understanding and addressing violence among intimate partners requires sound assessment of their communication patterns. In prior research, the 35-item, self-report Communication Patterns Questionnaire (CPQ) has been used to assess communication patterns in violent relationships. To date, psychometric analysis of the CPQ has been examined only among nonviolent couples; no studies have examined the psychometric properties of this measure in a sample of survivors of intimate partner violence (IPV). Using confirmatory factor analysis, the present study evaluated the factor structure of the CPQ in a sample of women survivors of IPV who sought mental health assessments at a university research clinic. Analyses suggested that a modified three-factor solution (constructive communication [CC], self-demand/partner withdraw [SDPW], partner demand/self-withdraw [PDSW]) provided good fit in our sample. Internal consistency estimates for each of the modified scales were acceptable and exceeded reported coefficients in prior IPV studies. Significant bivariate correlations among modified scales, and between communication patterns and aggressive behaviors, provided initial validity evidence for the CPQ scales in our sample. We found CC to be negatively associated with partner psychological aggression, PDSW to be positively associated with all forms of partner aggression and respondent psychological aggression, and SDPW to be positively associated with respondent physical and psychological aggression. The results of this study indicate that the CPQ may be an appropriate measure for assessing communication patterns in violent relationships; however, modified scoring procedures should be used. We contextualize our results within existing models of IPV and address clinical, cultural, and contextual issues in communication patterns assessment.

Prediction of breakthrough pain during labour neuraxial analgesia: comparison of machine learning and multivariable regression approaches.

INTRODUCTION: Risk-prediction models for breakthrough pain facilitate interventions to forestall inadequate labour analgesia, but limited work has used machine learning to identify predictive factors. We compared the performance of machine learning and regression techniques in identifying parturients at increased risk of breakthrough pain during labour epidural analgesia. METHODS: A single-centre retrospective study involved parturients receiving patient-controlled epidural analgesia. The primary outcome was breakthrough pain. We randomly selected 80% of the cohort (training cohort) to develop three prediction models using random forest, XGBoost, and logistic regression, followed by validation against the remaining 20% of the cohort (validation cohort). Area-under-the-receiver operating characteristic curve (AUC), sensitivity, specificity, and positive and negative predictive values (PPV and NPV) were used to assess model performance. RESULTS: Data from 20 716 parturients were analysed. The incidence of breakthrough pain was 14.2%. Of 31 candidate variables, random forest, XGBoost and logistic regression models included 30, 23, and 15 variables, respectively. Unintended venous puncture, post-neuraxial analgesia highest pain score, number of dinoprostone suppositories, neuraxial technique, number of neuraxial attempts, depth to epidural space, body mass index, pre-neuraxial analgesia oxytocin infusion rate, maternal age, pre-neuraxial analgesia cervical dilation, anaesthesiologist rank, and multiparity, were identified in all three models. All three models performed similarly, with AUC 0.763-0.772, sensitivity 67.0-69.4%, specificity 70.9-76.2%, PPV 28.3-31.8%, and NPV 93.3-93.5%. CONCLUSIONS: Machine learning did not improve the prediction of breakthrough pain compared with multivariable regression. Larger population-wide studies are needed to improve predictive ability.