Bayesian Posterior Probability Research Articles

Integrating Factor Models Using Bayesian Model Averaging: Evidence from Korea

This study applies the Bayesian model averaging approach to the Korean stock market data to yield an integrated factor model that can address model uncertainty. During the period from 2004 to 2022, we choose 14 factors and 10 macro predictors and generate a total of 10,485,760 candidate factor models by considering all possible combinations of each variable and whether to allow for model mispricing. The integrated model estimates the expected return and covariance matrix by combining the predictions of all the candidate models using Bayesian posterior probabilities as weights. In the Korean stock market, there is no clear winner model with dominant posterior probabilities, implying that model uncertainty is substantial. The optimal portfolio of the integrated model has a higher out-of-sample Sharpe ratio and lower downside risk than benchmark factor models. Model uncertainty has a significant impact on the estimation of the covariance matrix of the integrated model, and model disagreement about expected returns is particularly acute during periods of sharp market declines. In the presence of model uncertainty, Bayesian investors perceive equities to be riskier than historical volatility.

Prospective comparison of temporal myocardial function in men vs women after anterior ST-elevation myocardial infarction

Abstract Background Compared to men, women have been reported to have increased morbidity and mortality after ST-elevation myocardial infarction (STEMI), but sex differences in cardiac function in the acute and subacute phases of STEMI are incompletely understood. Objective To prospectively compare changes in cardiac function over the acute and subacute phases after anterior STEMI with timely reperfusion in women versus men. Methods The Stunning in Takotsubo versus Acute Myocardial Infarction (STAMI) study prospectively enrolled 94 men and 36 women with anterior STEMI. Echocardiography and blood sampling were performed within 4 hours of admission and at 1, 2, 3, 7, 14 and 30 days after admission. The primary outcome was akinesia recovery, defined as the difference in the per cent akinesia observed at baseline versus follow-up. Secondary outcomes included wall motion score index (WMSI), left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS). Mixed effects linear regression or zero-inflated tobit models with random intercepts were used to model echocardiographic parameters over time. Results Baseline patient characteristics were similar in both groups. The difference between women and men in akinesia recovery at 30 days was 8.4% (95% confidence interval [CI] 1.23-14.99). The covariate-adjusted Bayesian posterior probability that akinesia recovery and WMSI improvement at 30 days are more significant in women than men were 95% and 99%, respectively. Similar but less pronounced trends towards greater improvement in women than men were observed for LVEF and GLS. Conclusions After anterior STEMI with timely reperfusion, cardiac dysfunction recovered to a greater extent in women than in men.

Multiple Maternal Lineages of <i>Strauchbufo raddei</i> (Strauch, 1876) in Mongolia Revealed by Mitochondrial DNA

The Mongolian toad Strauchbufo raddei (Strauch, 1876) is one of widely distributed and dominated amphibian species in eastern Asian, including Mongolia. In this study, we amplified and sequenced a total of 50 samples of S. raddei, from three main regions in its Mongolian distribution range namely, Northern, Eastern, and Gobi regions. Our phylogenetic trees (Bayesian inference; BI and time-calibrated) and network analysis clearly support presence of multiple maternal mitochondrial DNA lineages for S. raddei in Mongolia. As expected, samples from these three regions were clustered separately in BI tree (Bayesian posterior probability (BPP 0.52). In addition, the population specific haplotypes, estimated genetic distances (e.g. uncorrelated p distance; ranged from 1% to 25%) and hierarchical AMOVA suggested relatively strong population genetic structure of S. raddei across Mongolia. Time-calibrated tree and ancestral range analysis showed that the first colonization of S. raddei may have occurred in Northern part of Mongolia approximately 9.63 mya, then dispersed over other parts of the country. Estimated approximate time for crossing event of S. raddei over dry steppe and semi-desert regions in Mongolia was 5.02 – 2.50 mya. Finally, high level of genetic diversity (overall; haplotype diversity, Hd = 0.93; nucleotide diversity, π = 0.011) of S. raddei were observed in Mongolia. Importantly, through this study, we contributed to closing sampling gaps in distribution range of S. raddei in Eastern Asia, which is key to better understanding species history, as well as describing cryptic lineages.

Leaf Rust Pathogens on Hypericum pseudohenryi: Describing Melampsora danbaensis sp. nov. and M. hyperici-pseudohenryi sp. nov. from China.

Based on morphological and phylogenetic evidence, two novel species of Melampsora were discovered on Hypericum pseudohenryi in China and have been thoroughly characterized. One of these species, designated as M. danbaensis, exhibits distinct features such as aecia of Uredo-type, typically appearing in gregarious or grouped arrangements, and presenting a shallowly pulvinate structure. Aeciospores exhibit tremendous variations in size, ranging in shape from globose to ellipsoidal and bearing pronounced verrucose texture. Telia resemble crusts one-spore deep, covering nearly the entire abaxial leaf surface, with sessile teliospores reaching sizes of up to 65.8 µm, and exhibiting a clavate to cylindrical shape. Another species, designated as M. hyperici-pseudohenryi, is distinguished by Uredo-type uredinia, which are hypophyllous, scattered or grouped, and interspersed with numerous paraphyses. Its urediniospores tend to be globose, ellipsoidal or obovoid, echinulate, and are accompanied by clavate to capitate paraphyses reaching lengths up to 77.6 µm. Phylogenetically, both species form a novel monophyletic clade within the Melampsora genus, with robust support demonstrated by a high Maximum likelihood bootstrap support (MLBS) value of 100% and a Bayesian posterior probability (BPP) of 1. This study enriches our understanding of the diversity and geographical distribution of Melampsora species that infect Hypericum plants in China.

Outcomes with revascularisation versus conservative management of participants with 3-vessel coronary artery disease in the ISCHEMIA trial.

Whether revascularisation (REV) improves outcomes in patients with three-vessel coronary artery disease (3V-CAD) is uncertain. Our objective was to evaluate outcomes with REV (percutaneous coronary intervention [PCI] or coronary artery bypass graft surgery [CABG]) versus medical therapy in patients with 3V-CAD. ISCHEMIA participants with 3V-CAD on coronary computed tomography angiography without prior CABG were included. Outcomes following initial invasive management (INV) with REV (PCI or CABG) versus initial conservative management (CON) with medical therapy alone were evaluated. Regression modelling was used to estimate the outcomes if all participants were to undergo prompt REV versus those assigned to CON. Outcomes were cardiovascular (CV) death/myocardial infarction (MI), death, CV death, and quality of life. Bayesian posterior probability for benefit (Pr [benefit]) for 1 percentage point lower 4-year rates with REV versus CON were evaluated. Among 1,236 participants with 3V-CAD (612 INV/624 CON), REV was associated with lower 4-year CV death/MI (adjusted 4-year difference: -4.4, 95% credible interval [CrI] -8.7 to -0.3 percentage points, Pr [benefit]=94.8%) when compared with CON, with similar results for PCI versus CON (-5.8, 95% CrI: -10.8 to -0.5 percentage points, Pr [benefit]=96.4%) and CABG versus CON (-3.7, 95% CrI: -8.8 to 1.5 percentage points, Pr [benefit]=84.7%). Adjusted 4-year REV versus CON differences were as follows: death -1.2 (95% CrI: -4.7 to 2.2) percentage points, CV death -2.3 (95% CrI: -5.5 to 0.8) percentage points, with similar results for PCI and for CABG. The Pr (benefit) for death with REV (PCI or CABG) versus CON was 49-63%. The adjusted 12-month Seattle Angina Questionnaire-7 summary score differences favoured REV: REV versus CON 4.6 (95% CrI: 2.7-6.4) percentage points; PCI versus CON 3.6 (95% CrI: 1.2-5.8) percentage points and CABG versus CON 4.3 (95% CrI: 1.5-6.9) percentage points with high Pr (benefit). In participants with 3V-CAD, REV (either PCI or CABG) was associated with a lower 4-year CV death/MI rate and improved quality of life, with similar results for PCI versus CON and CABG versus CON. The differences in all-cause mortality between REV and CON were small with wide confidence intervals. (ClinicalTrials.gov: NCT01471522).

Analysis of multiple gravitational influences on interregional population migration in South Korea

ABSTRACT Migration is the result of complex interactions between different socio-economic factors in different areas. This study analyses the multiple gravitational influences on interregional migration in South Korea. Spatial econometric models are employed to incorporate spatial interactions between multiple socio-economic gravitational influences into spatial weight matrices. Using Bayesian posterior probabilities to evaluate models incorporating different gravitational influences, this study finds that the primary driver of migration is the difference in human capital conditions between areas. Furthermore, it suggests that the simultaneous consideration of differences in both economic and human capital conditions across areas increases the attractiveness of certain areas for migration.

First report of leaf spot on Daphniphyllum macropodum caused by Neopestalotiopsis clavispora in China.

Daphniphyllum macropodum Miq., an evergreen arbor, is widely cultivated in southern China for its ornamental and medicinal value (Su et al. 2013). In October 2019, a severe leaf spot was observed on D. macropodum in Jinggangshan National Nature Reserve in Ji'an city, Jiangxi, China (114°06'23″E, 26°32'25″N). The plants were about 15 years old, and the disease incidence was estimated to be 15% (4/26 plants). The disease primarily appeared as small black spots on the leaves. At the late stage, the spots enlarged and coalesced into regular or irregular gray necrotic lesions with dark margins. We collected five samples per plant and total 20 samples were collected to isolated the pathogen strains. The margin of the diseased tissues was cut into 5 mm × 5 mm pieces; surface disinfected with 70% ethanol and 2% NaOCl for 30 s and 60 s, respectively; and rinsed thrice with sterile water. Tissues were placed on potato dextrose agar (PDA) and incubated at 25°C in the dark. Pure cultures were obtained by single-spore isolation method, and the representative isolates, JRM3, JRM6, and JRM8 were used for morphological studies and phylogenetic analyses. The colonies of three isolates grown on PDA were white, cottony, and flocculent, contained undulate edges with dense aerial mycelium on the surface at 25 °C. Conidiomata was black conidial masses on PDA. Conidia were 5-celled, clavate to fusiform, smooth, 19.3 to 24.4 long × 6.1 to 8.6 μm wide (n = 50). The 3 median cells were dark brown to olivaceous, the central cell was darker than the other 2 cells, and the basal and apical cells were hyaline. All conidia developed one basal appendage (3.4 to 8.3 μm long; n = 50), and 2 to 3 apical appendages (18 to 32 μm long; n = 50), filiform. The morphological characteristics of the isolates are comparable with those of the genus Neopestalotiopsis (Maharachchikumbura et al. 2014). The internal transcribed spacer (ITS) regions, β-tubulin 2 (TUB2) and translation elongation factor 1-alpha (TEF1-α) were amplified from genomic DNA for the three isolates using primers ITS1/ITS4, T1/Bt-2b, EF1-728F/EF-2 (Maharachchikumbura et al. 2014), respectively. The sequences of the isolates were submitted to GenBank (ITS, OQ372202 to OQ372204; TUB2, OQ390129 to OQ390131; TEF1-α, OQ390126 to OQ390128). A maximum likelihood and Bayesian posterior probability analyses using IQtree v. 1.6.8 and Mr. Bayes v. 3.2.6 with the concatenated sequences placed JRM3, JRM6, and JRM8 in the clade of N. clavispora. Based on the multi-locus phylogeny and morphology, three isolates were identified as N. clavispora. To confirm pathogenicity, eight healthy 10-year-old D. macropodum plants growing in the field were chosen, and 4 leaves per plant were wounded with a sterile needle and inoculated with 10 μL conidial suspension per leaf (106 conidia/ml). Eight plants inoculated with sterile water were used as control. All the inoculated leaves were covered with plastic bags to maintian a humidity environment for 2 days. The leaves inoculated with conidial suspension showed similar symptoms to those observed in the field, whereas control leaves were asymptomatic for 10 days. The same fungus were re-isolated from the lesions, whereas no fungus was isolated from control leaves. N. clavispora was determined as the pathogen of a variety of plant diseases, including Kadsura coccinea (Xie et al. 2018), Dendrobium officinale (Cao et al. 2022), Macadamia integrifolia (Santos et al. 2019). However, this is the first report of N. clavispora infecting D. macropodum in China. This work provided crucial information for epidemiologic studies and appropriate control strategies for this newly emerging disease.

Granulocyte-macrophage colony-stimulating factor neutralisation in patients with axial spondyloarthritis in the UK (NAMASTE): a randomised, double-blind, placebo-controlled, phase 2 trial

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a proinflammatory cytokine overproduced in several inflammatory and autoimmune diseases, including axial spondyloarthritis. Namilumab is a human IgG1 monoclonal anti-GM-CSF antibody that potently neutralises human GM-CSF. We aimed to assess the efficacy of namilumab in participants with moderate-to-severe active axial spondyloarthritis. This proof-of-concept, randomised, double-blind, placebo-controlled, phase 2, Bayesian (NAMASTE) trial was done at nine hospitals in the UK. Participants aged 18-75 years with axial spondyloarthritis, meeting the Assessment in SpondyloArthritis international Society (ASAS) criteria and the ASAS-defined MRI criteria, with active disease as defined by a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), were eligible. Those who had inadequately responded or had intolerance to previous treatment with an anti-TNF agent were included. Participants were randomly assigned (6:1) to receive subcutaneous namilumab 150 mg or placebo at weeks 0, 2, 6, and 10. Participants, site staff (except pharmacy staff), and central study staff were masked to treatment assignment. The primary endpoint was the proportion of participants who had an ASAS ≥20% improvement (ASAS20) clinical response at week 12 in the full analysis set (all randomly assigned participants). This trial is registered with ClinicalTrials.gov (NCT03622658). From Sept 6, 2018, to July 25, 2019, 60 patients with moderate-to-severe active axial spondyloarthritis were assessed for eligibility and 42 were randomly assigned to receive namilumab (n=36) or placebo (n=six). The mean age of participants was 39·5 years (SD 13·3), 17 were women, 25 were men, 39 were White, and seven had previously received anti-TNF therapy. The primary endpoint was not met. At week 12, the proportion of patients who had an ASAS20 clinical response was lower in the namilumab group (14 of 36) than in the placebo group (three of six; estimated between-group difference 6·8%). The Bayesian posterior probability η was 0·72 (>0·927 suggests high clinical significance). The rates of any treatment-emergent adverse events in the namilumab group were similar to those in the placebo group (31 vs five). Namilumab did not show efficacy compared with placebo in patients with active axial spondyloarthritis, but the treatment was generally well tolerated. Izana Bioscience, NIHR Oxford Biomedical Research Centre (BRC), NIHR Birmingham BRC, and Clinical Research Facility.

Ramipedicella gen. nov. (Ralfsiales, Phaeophyceae): a new crustose brown algal genus including two species, Ramipedicella miniloba sp. nov. and Ramipedicella longicellularis comb. nov.

The Ralfsiaceae family, part of the Ralfsiales order and consisting of crustose brown algae, includes five genera: Analipus, Endoplura, Fissipedicella, Heteroralfsia, and Ralfsia. In this study, a novel crustose genus named Ramipedicella gen. nov. is introduced within the Ralfsiaceae based on molecular and morphological analyses. Phylogenetic analyses using both concatenated dataset (rbcL + COI-5P genes) and rbcL indicate that the crustose brown algae that we collected from Korea and Russia form a unique grouping within the Ralfsiaceae. This grouping is strongly supported by both bootstrap analysis and Bayesian posterior probabilities. The genetic differences in the rbcL and COI-5P sequences between Ramipedicella and other genera within Ralfsiaceae range from 6.7 to 9.3% for rbcL and from 15.5 to 20.8% for COI-5P. Ramipedicella is characterized by crustose thalli having new crusts growing on top of old ones with a hypothallial basal layer and erect perithallial filaments, long cells with width-to-length ratio of 1 : 1–16, single chloroplast per cell, plurangia with one to several sterile cells, one to several unangia produced from unicellular stalks or from the lateral-basal region to the paraphyses, and unangia arising sequencially in irregularly branched specialized filaments. Ramipedicella, the recently identified genus, comprises two distinct species. Ramipedicella miniloba, the type species, is distinguished by crusts with small lobes, numerous hair tufts, plurangia terminated by 1–4 sterile cells, and large oblong unangia. Ramipedicella longicellularis is identified by generally smooth crusts, absence of phaeophycean hairs, plurangia terminated by 1–2 apical sterile cells, and smaller mostly oblanceolate unangia.

First Report of Tobacco Leaf Tip Blight Caused by Alternaria gossypina in China.

Tobacco (Nicotiana tabacum L.) belongs to the family Solanaceae, an economically significant crop (Zhou et al. 2023). Twelve samples with leaf spots were collected in Keti Village, Changshun County, Zunyi City, Guizhou province, China in 2022. Twenty-five percent of the samples had dry lesions near the leaf tip which resulted leaf tip blight after development. Fungi were isolated by a previous method (Wei et al. 2022). Six Alternaria strains were obtained and preserved in the Fungal Herbarium of Yangtze University (YZU), Jingzhou, Hubei, China. Among them, one strain YZU 221477 showed distinct cultural characteristics out of five A. alternata strains, which was again determined by growing on potato dextrose agar (PDA) at 25°C for 7 days in dark to evaluate. The colonies (60 mm in diameter) were white cottony in the center surrounded by vinaceous purple. To examine the morphology, mycelia were inoculated onto potato carrot agar (PCA) at 22°C, following an 8 h light/16 h dark photoperiod (Simmons 2007). Conidia were obclavate or ovoid, normally 3-5 conidial units per chain, 20-38 × 10-16.5 μm, 3 to 5 transverse septa, beakless or a short beak (4-30 μm). The observation results were consistent with those of A. gossypina (Zhang 2003). Total genomic DNA was extracted using the CTAB method and seven gene regions including internal transcribed spacer of rDNA (ITS), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), translation elongation factor 1 alpha (TEF1), RNA polymerase second largest subunit (RPB2), Alternaria major allergen gene (Alt a 1), endopolygalacturonase (EndoPG) and an anonymous gene region (OPA10-2) were amplified with ITS5/ITS4, gpd1/gpd2, EF1-728F/EF1-986R, RPB2-5F/RPB2-7cR, Alt-for/Alt-rev, PG3/PG2b and OPA10-2L/OPA10-2R primers, respectively. All sequences were deposited in GenBank (ITS: OR710806; GAPDH: PP057862; TEF1: PP158601; RPB2: PP057863; Alt a 1: PP057865; EndoPG: PP057861; OPA10-2: PP057864). Combining with relevant sequences retrieved from the NCBI database were used for the phylogenetic analysis. Maximum Likelihood (ML) tree was constructed with RAxML v.7.2.8 employing GTRCAT model using 1000 bootstrap (BS) replicates to assess statistical support. The results indicated that the present strain grouped with A. gossypina (type strain of CBS 104.32) supported with 73% bootstrap values, also having a support of 0.83 Bayesian posterior probabilities values. Based on morphology and molecular evidence, the strain YZU 221477 is identified as Alternaria gossypina. Pathogenicity was examined to fulfill Koch's postulates. Mycelial plugs (6 mm diameter) of the present strain and A. alternata cultivated on PDA were taken from the margin and inoculated onto viable tobacco leaves (Cultivar: Yunyan 87, n=3) growing forty days, while controls were inoculated with sterile PDA. The assay was conducted three times. The plants were maintained at 25°C with humidity levels over 85% in a greenhouse. Leaves were evaluated after 7 days, necrotic spots encircled by yellow halos were on both inoculums, except controls. Pathogen re-isolation confirmed that it was the same as inoculated fungus based on morphology. A. gossypina was firstly found on cotton (Hopkins 1931), late reported to induce disease on Minneola, Nopalea, Hibiscus, Citrus, Solanum and Ageratina. To our knowledge, this is the first report of A. gossypina causing tobacco leaf tip blight in China, and it also provides a basis for controlling of tobacco leaf tip blight.

Hysterium madraspatanum (Hysteriaceae), a new species from Tropical Dry Evergreen Forest of Tamil Nadu, India

A new species of Hysterium, is described from tropical dry evergreen forest region of Chennai, Tamil Nadu, India, based on both morphological characteristics and molecular phylogenetic analysis using the Internal Transcribed Spacers (ITS) region of nuclear ribosomal DNA. The key morphological characters of the ascomata include the presence of a longitudinal slit remaining closed even at maturity. The ascospores biseriate having three septa with all the cells evenly pigmented including the terminal cells. The ascus measuring 115–122 × 20–22 μm. Ascospores initially two celled and finally become four celled, hyaline first, later changing to yellow and then dark brown, oblong to ellipsoid, 28–39 × 7–12 μm. The nrITS-based phylogenetic tree inferred from the Bayesian posterior probabilities indicate that H. madraspatanum is closely related to Hysterium pulicare, H. angustatum and H. rhizophorae. However, H. madraspatanum is morphologically distinct from them by having relatively larger spore size, shallow groove in the ascomata, spores with concolorous terminal cells. Therefore, is a novel species under the genus Hysterium. Azadirachta indica is reported in the study as a new host for the genus Hysterium.

Clinical outcomes in patients with piperacillin/tazobactam-non-susceptible but ceftriaxone-susceptible E. coli or K. pneumoniae bloodstream infection.

A small proportion of Escherichia coli and Klebsiella pneumoniae demonstrate in vitro non-susceptibility to piperacillin/tazobactam but retain susceptibility to ceftriaxone. Uncertainty remains regarding how best to treat these isolates. We sought to compare clinical outcomes between patients with piperacillin/tazobactam-non-susceptible but ceftriaxone-susceptible E. coli or K. pneumoniae bloodstream infection receiving definitive therapy with ceftriaxone versus an alternative effective antibiotic. We retrospectively identified patients with a positive blood culture for piperacillin/tazobactam-non-susceptible but ceftriaxone-susceptible E. coli or K. pneumoniae between 1 January 2013 and 31 December 2022. Patients were divided into one of two definitive treatment groups: ceftriaxone or alternative effective antibiotic. Our primary outcome was a composite of 90 day all-cause mortality, hospital readmission, or recurrence of infection. We used Cox proportional hazards models to compare time with the composite outcome between groups. Sixty-two patients were included in our analysis. Overall, median age was 63 years (IQR 49.5-71.0), the most common source of infection was intra-abdominal (25/62; 40.3%) and the median total duration of therapy was 12.0 days (IQR 9.0-16.8). A total of 9/22 (40.9%) patients in the ceftriaxone treatment group and 18/40 (45.0%) patients in the alternative effective antibiotic group met the composite endpoint. In an adjusted time-to-event analysis, there was no difference in the composite endpoint between groups (HR 0.67, 95% CI 0.30-1.50). The adjusted Bayesian posterior probability that the HR was less than or equal to 1 (i.e. ceftriaxone is as good or better than alternative therapy) was 85%. These findings suggest that ceftriaxone can be used to effectively treat bloodstream infections with E. coli or K. pneumoniae that are non-susceptible to piperacillin/tazobactam but susceptible to ceftriaxone.

Abstract PS16-01: Comparison of an Atezolizumab monotherapy window followed by Atezolizumab and chemotherapy vs. Atezolizumab and chemotherapy alone in triple negative breast cancer (TNBC) – final analysis of the neoadjuvant neoMono trial

Abstract Background: Improvement of systemic therapy of TNBC still is a medical need. Exploratory data from the neoadjuvant GeparNuevo trial suggested a benefit from an immune checkpoint inhibitor (ICI) monotherapy window in TNBC. The neoMono trial prospectively analyzed whether the addition of a preceding Atezolizumab monotherapy window prior to Atezolizumab and chemotherapy (CTX) improves pCR rates among patients (pts) with early TNBC. In an interim analysis after 100 pCR events, patients with unselected TNBC did not show a significant benefit from an Atezolizumab monotherapy window, while an exploratory analysis suggested a highly clinically relevant benefit among pts with PD-L1 positive TNBC. Here we present the final primary endpoint analysis. Methods: NeoMono is a phase 2 randomized multicenter trial that was planned to recruit a maximum of 458 female and male pts with primary TNBC (defined as ER/PR < 10% and HER2 negative) with tumor stages cT1c – cT4d (cN0 and cN+). As the protocol mandated termination of trial recruitment based on the results of the interim analysis, the final ITT population was limited to 359 pts. PD-L1 status had to be identifiable by central pathology by means of the VENTANA PD-L1 (SP142) assay and was defined by PD-L1 expression on immune cells (IC). Neoadjuvant treatment in both study arms consisted of Atezolizumab 1200 mg every 3 weeks in addition to neoadjuvant CTX (12 x Carboplatin/Paclitaxel q1w followed by 4x Epirubicin/Cyclophosphamide q3w). Combination therapy in arm A was preceded by an Atezolizumab monotherapy window of 840 mg once two weeks prior to initiation of combination therapy, while patients in arm B received no immune monotherapy window. Study goals are to compare the efficacy of neoadjuvant CTX + Atezolizumab with versus without a two-week atezolizumab monotherapy window preceding CTX + ICI (primary endpoint: pCR) and to identify biomarkers for response and resistance through analysis of sequential tissue and liquid biopsies. The neoMono statistical design uses Bayesian posterior probabilities (uniform prior distribution) and logistic regression to analyze the primary endpoint. Results: 180 pts in arm A and 179 in arm B from 34 study sites were included in the final primary endpoint analysis. Demographics and baseline characteristics as well as drug exposure were well-balanced in both arms. Posterior mean pCR rates in the ITT population in study arms A and B were 65.7% (95% high posterior density interval (HPDI): 58.5%, 72.5%) and 69% (62.2%, 75.9%), respectively. In an exploratory analysis stratified by PD-L1 IC status (negative: < 1% versus positive: ≥ 1%), pCR rates in arm A were 91.5% in the PD-L1 IC-positive group and 56.1% in the PD-L1 IC-negative group, the corresponding pCR rates in arm B were 82.2% and 64.5%, respectively. In a multivariate analysis of the ITT population including tumor size, nodal status, tumor grade, age and PD-L1 status, the odds ratio for achieving a pCR was 4.77 (p < 0.001) for PD-L1-positive and 2.36 (p=0.023) for grade 3 tumors. In an exploratory analysis including HER2 status, odds for achieving a pCR were significantly higher for patients with HER2-negative (IHC 0) vs. HER2-low tumors (OR 1.73, p=0.036). No new safety signals were observed. Conclusion: The final primary endpoint analysis of the neoMono trial demonstrated the highest pCR rates ever reported in a phase II/III trial in TNBC. While a significant impact of an ICI monotherapy window on the pCR rate after combination of CTX + ICI in an unselected ITT population could not be demonstrated, neoMono indicates for the first time in a randomized prospective setting that patients with immune active TNBC might derive particular benefit from a preceding ICI monotherapy window. The results of the neoMono trial are mainly justifying the conduction of a confirmative trial in immune active TNBC. However, our results underscore the potential role of pre-therapeutic ICI monotherapy window as part of future therapeutic concepts in TNBC. Citation Format: Hans-Christian Kolberg, Johannes Schumacher, Ramona Erber, Michael Braun, Peter A. Fasching, Eva-Maria Grischke, Christian Schem, Michael P. Lux, Mustafa Deryal, Oliver Hoffmann, Bernhard Heinrich, Georg Kunz, Kristina Lübbe, Petra Krabisch, Arndt Hartmann, Philip Raeth, Sabine Kasimir-Bauer, Cornelia Kolberg-Liedtke. Comparison of an Atezolizumab monotherapy window followed by Atezolizumab and chemotherapy vs. Atezolizumab and chemotherapy alone in triple negative breast cancer (TNBC) – final analysis of the neoadjuvant neoMono trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS16-01.

Ketamine for acute pain after trauma: A pragmatic, randomized clinical trial.

Non-narcotic intravenous medications may be a beneficial adjunct to oral multimodal pain regimens (MMPRs) which reduce but do not eliminate opioid exposure and prescribing after trauma. We hypothesized that the addition of a subdissociative ketamine infusion (KI) to a standardized oral MMPR reduces inpatient opioid exposure. Eligible adult trauma patients admitted to the intermediate or intensive care unit were randomized upon admission to our institutional MMPR per usual care (UC) or UC plus subdissociative KI for 24 hours to 72 hours after arrival. The primary outcome was morphine milligram equivalents per day (MME/d) and secondary outcomes included total MME, discharge with an opioid prescription (OP%), and rates of ketamine side effects. Bayesian posterior probabilities (pp) were calculated using neutral priors. A total of 300 patients were included in the final analysis with 144 randomized to KI and 156 to UC. Baseline characteristics were similar between groups. The Injury Severity Scores for KI were 19 [14, 29] versus UC 22 [14, 29]. The KI group had a lower rate of long-bone fracture (37% vs. 49%) and laparotomy (16% vs. 24%). Patients receiving KI had an absolute reduction of 7 MME/day, 96 total MME, and 5% in OP%. In addition, KI had a relative risk (RR) reduction of 19% in MME/day (RR, 0.81 [0.69-0.95], pp = 99%), 20% in total MME (RR, 0.80 [0.64-0.99], pp = 98%), and 8% in OP% (RR, 0.92 [0.76-1.11], pp = 81%). The KI group had a higher rate of delirium (11% vs. 6%); however, rates of other side effects such as arrythmias and unplanned intubations were similar between groups. Addition of a subdissociative ketamine infusion to an oral MMPR resulted in a decrease in opioid exposure in severely injured patients. Subdissociative ketamine infusions can be used as a safe adjunct to decrease opioid exposure in monitored settings. Therapeutic/Care Management; Level I.

Abstract CT289: A phase II study of Tucatinib and Ado-trastuzumab Emtansine (T-DM1) in patients with HER2-positive metastatic solid tumors and metastases to brain (TUCATEMEB)

Abstract Background: HER2 overexpression or amplification is a validated prognostic and predictive biomarker for treatments in several tumor types. The development of brain metastases is an unfortunate and common complication in patients with metastatic cancer and the incidence of brain metastases continues to grow as advances in cancer treatment extend the survival. Unfortunately many of the clinical trials still exclude patients with brain metastases. Tucatinib is a selective small molecule HER2 inibitor that has shown intracranial activity and it is approved with trastuzumab and capecitabine for treatment of patients with breast cancer including with active brain metastases. Tucatinib showed significant preclinical and clinical antitumor activity in combination with other HER2-targeted therapies, including T-DM1 in breast and other cancers. We hypothesize that the combination of tucatinib and T-DM1 will be a safe and effective treatment in HER2-positive (+) metastatic solid tumors that have metastasized to the brain. To test this hypothesis, we are conducting a Phase II Study of Tucatinib and T-DM1 in Patients with HER2+ Metastatic Solid Tumors and Metastases to Brain (TUCATEMEB). Methods: Eligible adult patients with HER2-positive solid tumors and active brain metastases (with at least one untreated brain lesion ≥0.5 cm and <3.0 cm) will be enrolled in the study. HER2 positivity is defined as HER2 overexpression by immunohistochemistry 3+ or 2+ and fluorescence in situ hybridization positive and/or HER2 amplification by in situ hybridization or next-generation sequencing and/or activating ERBB2 mutation. Patients will receive the study treatment in 21-day cycles: Tucatinib 300 mg orally twice daily; T-DM1 3.6 mg/kg intravenously on Day 1. The primary objective is to determine the intracranial antitumor activity of the tucatinib and T-DM1 combination per the modified RECIST in patients with HER2+ metastatic solid tumors and brain metastases. The secondary objectives are to determine the intracranial antitumor activity per the RANO-BM criteria; to evaluate the safety and tolerability, the duration of intracranial response, the overall survival, the progression free survival, the systemic antitumor activity and clinical benefit rate in patients with HER2+ metastatic solid tumors and brain metastases. Exploratory objectives are to assess predictive and pharmacodynamic markers of response and to corelate them with clinical and molecular characteristics. The efficacy endpoint will be monitored using the Bayesian optimal phase 2 BOP2 design and safety and tolerability will be monitored based on Bayesian posterior probability. Restaging brain MRI and systemic scans will be performed every 6 weeks for the first 12 weeks, and every 9 weeks thereafter. The trial opened in May 2023 and is enrolling patients (NCT05673928). Citation Format: Ecaterina E. Dumbrava, Amber M. Kennon, Rashmi K. Murthy, Emma J. Montazari, Hussein Tawbi, Jing Li, Frederick F. Lang, Gisela Sanchez, Jianbo Wang, Isabella C. Glitza, Barbara J. O'Brien, Thomas Beckham, Todd Swanson, Martin C. Tom, Uyen M. Vu, Tanisha T. Darko, Tiantian Cai, Komal Shah, Funda Meric-Bernstam, Jordi Rodon. A phase II study of Tucatinib and Ado-trastuzumab Emtansine (T-DM1) in patients with HER2-positive metastatic solid tumors and metastases to brain (TUCATEMEB) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT289.

Effect of Early vs Late Inguinal Hernia Repair on Serious Adverse Event Rates in Preterm Infants

Inguinal hernia repair in preterm infants is common and is associated with considerable morbidity. Whether the inguinal hernia should be repaired prior to or after discharge from the neonatal intensive care unit is controversial. To evaluate the safety of early vs late surgical repair for preterm infants with an inguinal hernia. A multicenter randomized clinical trial including preterm infants with inguinal hernia diagnosed during initial hospitalization was conducted between September 2013 and April 2021 at 39 US hospitals. Follow-up was completed on January 3, 2023. In the early repair strategy, infants underwent inguinal hernia repair before neonatal intensive care unit discharge. In the late repair strategy, hernia repair was planned after discharge from the neonatal intensive care unit and when the infants were older than 55 weeks' postmenstrual age. The primary outcome was occurrence of any prespecified serious adverse event during the 10-month observation period (determined by a blinded adjudication committee). The secondary outcomes included the total number of days in the hospital during the 10-month observation period. Among the 338 randomized infants (172 in the early repair group and 166 in the late repair group), 320 underwent operative repair (86% were male; 2% were Asian, 30% were Black, 16% were Hispanic, 59% were White, and race and ethnicity were unknown in 9% and 4%, respectively; the mean gestational age at birth was 26.6 weeks [SD, 2.8 weeks]; the mean postnatal age at enrollment was 12 weeks [SD, 5 weeks]). Among 308 infants (91%) with complete data (159 in the early repair group and 149 in the late repair group), 44 (28%) in the early repair group vs 27 (18%) in the late repair group had at least 1 serious adverse event (risk difference, -7.9% [95% credible interval, -16.9% to 0%]; 97% bayesian posterior probability of benefit with late repair). The median number of days in the hospital during the 10-month observation period was 19.0 days (IQR, 9.8 to 35.0 days) in the early repair group vs 16.0 days (IQR, 7.0 to 38.0 days) in the late repair group (82% posterior probability of benefit with late repair). In the prespecified subgroup analyses, the probability that late repair reduced the number of infants with at least 1 serious adverse event was higher in infants with a gestational age younger than 28 weeks and in those with bronchopulmonary dysplasia (99% probability of benefit in each subgroup). Among preterm infants with inguinal hernia, the late repair strategy resulted in fewer infants having at least 1 serious adverse event. These findings support delaying inguinal hernia repair until after initial discharge from the neonatal intensive care unit. ClinicalTrials.gov Identifier: NCT01678638.

A Bayesian approach using spatiotemporal features for suitable next hop selection in opportunistic networks

SummaryOpportunistic network (OppNet) belongs to the category of Mobile Ad‐hoc Networks (MANETs), a kind of Delay Tolerant Network (DTN), where the wireless nodes are completely mobile and the data transmission routes are dynamic. The major challenge in developing a routing model for such a network is the unpredictable nature of the movement of the nodes. In this paper, a spatiotemporal prediction model based on human mobility pattern is proposed using Bayesian posterior probability (BPPR) where several clusters are identified within the network and the day and time duration of nodes visiting those clusters are recorded. The Bayesian posterior probability is then used to determine the probability of the neighbor node visiting the destination's cluster. If the calculated probability for that node is higher than a specified threshold, the packet will be forwarded. A comparison of the results obtained on simulation is made with benchmark models—Epidemic, Prophet, HBPR, EDR, NexT, and EBC, to name a few, where it is found that on average the proposed model outperforms the other models in terms of delivery probability, hop count and number of messages dropped by around 23.89%, 24.8%, 24.4%, 37%, 11%, and 42% respectively, with varying number of nodes, TTL, message generation interval, and buffer size. Similar improvements have been observed in terms of the other two metrics. In terms of overhead ratio, the proposed model outperforms Epidemic, Prophet, HBPR, NexT, and EBC. However, as the number of nodes and TTL are varied, BPPR performs better than NexT by around 9% and 12%, respectively, in terms of average latency.

First report of Colletotrichum siamense causing fruit anthracnose on Acer fabric in China.

Acer fabric Hance is an evergreen tree widely cultivated in China for its ornamental value (Liu et al. 2021). In August 2021, serious fruit anthracnose, with brown to black irregular sunken lesions, occurred on A. fabric plants at the campus of Jiangxi Agricultural University (28°45'56″N, 115°50'21″E) in Nanchang, Jiangxi province, China. On average, 25% of the fruit per individual tree was affected. Small spots initially formed along the edge of the fruit and gradually expanded into dark brown spots, and eventually the diseased fruit withered. Small pieces (4 × 4 mm) from the affected fruits were surface sterilized in 70% ethanol for 30 s, followed by 2% NaOCl for 1 min, and then rinsed three times with sterile water (Liao et al. 2023). Tissues were placed on potato dextrose agar (PDA) and incubated at 25°C. Pure cultures were obtained by monosporic isolation, and the representative isolates, AFG-3, AFG-7, and AFG-12, were used for morphological studies and phylogenetic analyses. Colonies on the PDA of the three isolates were white to gray with cottony mycelia and grayish-white on the undersides of the culture under incubation at 25°C in the dark for 7 days. Conidia were single-celled, hyaline, cylindrical, clavate, and measured 12.6-17.3 × 4.2-5.6 µm (14.2 ± 0.9 × 4.5 ± 0.3 µm, n = 100). Appressoria were brown to dark brown, ovoid to clavate, slightly irregular to irregular, and ranged from 5.5-9.2 × 4.5-6.7 µm (7.2 ± 0.2 × 5.4 ± 0.5 µm, n=100). Morphological features were similar to Colletotrichum gloeosporioides species complex (Weir et al. 2012). The internal transcribed spacer (ITS) regions, actin (ACT), calmodulin (CAL), beta-tubulin 2 (TUB2), chitin synthase (CHS-1), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) were amplified using primers ITS1/ITS4, ACT-512F/ACT-783R, CL1/CL2, T1/Bt2b, CHS-79F/CHS-354R and GDF/GDR (Weir et al. 2012), respectively. All sequences were deposited into GenBank (ITS, OQ184035 - OQ184037; ACT, OQ196109 - OQ196111; GAPDH, OQ196115 - OQ196117; TUB2, OQ196121 - OQ196123; CHS-1, OQ196112 - OQ196114; CAL, OQ196118 - OQ196120). A maximum likelihood and Bayesian posterior probability analysis using IQtree v. 1.6.8 and Mr. Bayes v. 3.2.6 with the concatenated sequences placed AFG-3, AFG-7, and AFG-12 in the clade of C. siamense. Based on the multi-locus phylogeny and morphology, three isolates were identified as C. siamense. Pathogenicity tests were conducted on six 9-year-old A. fabric plants. Healthy fruits were wounded with a sterile needle and inoculated by placing a drop on the surface of wounded tissue (106 conidia/mL; 20 µL) prepared from the three isolates. The conidial suspension of each isolate was inoculated onto three fruit per plant. Another nine fruit on three plants inoculated with sterile water served as the control (Wan et al. 2022). All the inoculated fruit were covered with plastic bags to keep the humidity for two days. All the inoculated fruit showed dark brown spots similar to those symptoms observed on naturally infected fruit on campus, whereas control fruit were asymptomatic. C. siamense was reisolated from the inoculated fruit. The pathogen was previously reported to cause fruit anthracnose on Carya illinoinensis (Zhuo et al. 2022), Chili Pepper (May et al. 2021), and Salix babylonica (Zhang et al. 2023). This study confirmed that C. siamense also causes anthracnose on fruit of A. fabric. This work contributes to a better understanding of the etiology of fruit anthracnose on A. fabric in south China and helps develop effective control strategies.

A Software Tool for Estimating Uncertainty of Bayesian Posterior Probability for Disease.

The role of medical diagnosis is essential in patient care and healthcare. Established diagnostic practices typically rely on predetermined clinical criteria and numerical thresholds. In contrast, Bayesian inference provides an advanced framework that supports diagnosis via in-depth probabilistic analysis. This study's aim is to introduce a software tool dedicated to the quantification of uncertainty in Bayesian diagnosis, a field that has seen minimal exploration to date. The presented tool, a freely available specialized software program, utilizes uncertainty propagation techniques to estimate the sampling, measurement, and combined uncertainty of the posterior probability for disease. It features two primary modules and fifteen submodules, all designed to facilitate the estimation and graphical representation of the standard uncertainty of the posterior probability estimates for diseased and non-diseased population samples, incorporating parameters such as the mean and standard deviation of the test measurand, the size of the samples, and the standard measurement uncertainty inherent in screening and diagnostic tests. Our study showcases the practical application of the program by examining the fasting plasma glucose data sourced from the National Health and Nutrition Examination Survey. Parametric distribution models are explored to assess the uncertainty of Bayesian posterior probability for diabetes mellitus, using the oral glucose tolerance test as the reference diagnostic method.

First Report of Apiospora arundinis Causing Leaf Spot on Polygonatum cyrtonema Hua in China.

Polygonatum cyrtonema Hua, which is a perennial herb of Liliaceae, can be used as clinical Chinese medicine for treating diabetes and asthma. It is widely cultivated in China, with 700 ha planted in Tonggu County, Jiangxi province (Chen et al. 2022). In June 2022, leaf spot symptoms were observed on P. cyrtonema in Tonggu county (28°71'42″N, 114°56'19″E), and the disease incidence was estimated to be above 35%. In the early stages of infection, small brown spots appear on the edge or tip of the leaves. As the lesion matures, the spots gradually expand to form wedge-shaped or elliptic to irregular lesions with brown edges and yellow halos. To identify the pathogen species, leaf pieces (5 × 5 mm) from the lesion borders were surface sterilized in 75% ethanol for 30 s, followed by 2% NaClO for 2 min, then rinsed with sterile distilled water for 3 times and dried with sterile filter paper. The tissues were placed on potato dextrose agar (PDA) and incubated at 25°C. Pure cultures were obtained by monosporic isolation, and the representative isolates, HJYB2-1, HJYB2-2 were used for morphological studies and phylogenetic analyses. Colonies on PDA of the two isolates were white with fluffy aerial mycelia. The hyphae were smooth, hyaline, and branched. The conidiophores were hyaline or pale brown and produced conidiogenous cells. The conidiogenous cells were pale brown, smooth, and ampulliform, 5.8-11.7 × 3.0-4.9 μm (n=50). The conidia were brown, smooth, and ellipsoidal to spherical, 4.7-7.3 × 2.3-4.5 μm (n=50). Morphological features were similar to Apiospora arundinis species complex (Crous et al. 2013, Pintos et al. 2021). For molecular identification, the ITS, TUB2 and TEF 1-α genes were amplified with the primer pairs ITS1/ITS4, T1/Bt-2b and EF1-728F/EF-2 (White et al. 1990), respectively. The generated sequences were deposited in GenBank with accession numbers OR229623, OR229624 (ITS), OR260104, OR260105 (TUB2), and OR290789, OR290790 (TEF1-α). Maximum likelihood and Bayesian posterior probability analyses using IQtree v. 1.6.8 and Mr. Bayes v. 3.2.6 with the concatenated sequences placed HJYB2-1 and HJYB2-2 in the clade of A. arundinis. The two isolates were identified as A. arundinis based on morphological and multilocus phylogenetic analyses. For pathogenicity testing, healthy leaves of six P. cyrtonema plants (five leaves each, n=30) in the field were pin-pricked with a sterile needle and inoculated with 100 µL spore suspension on the wound (1×106 conidia per mL). Healthy leaves of another three P. cyrtonema plants (five leaves each, n=15) in the field were pin-pricked with a sterile needle, inoculated with sterile distilled water and served as the control. All the inoculated leaves were covered with plastic bags to keep a high-humidity environment with a temperature of about 28℃. The test was repeated three times. More than 90% of inoculated leaves showed similar symptoms to those observed in the field, whereas control leaves were asymptomatic for 7 days. Apiospora arundinis was reisolated from the leaf lesions on the inoculated plants. No pathogenic fungus was isolated from the control leaves. A. arundinis has been reported causing disease on Camellia sinensis (Thangaraj et al. 2019), Prunus persica (Ji et al. 2020), Saccharum officinarum (Liao et al. 2022) but has not previously been reported causing disease on P. cyrtonema. To our knowledge, this is the first report that A. arundinis can cause leaf spot on P. cyrtonema in China. Our result should help with future monitoring and control of this disease.