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We evaluated uterine contraction frequency in women receiving 17 alpha-hydroxyprogesterone caproate (17-OHP-C) for the prevention of preterm delivery. Women with singleton pregnancies and receiving weekly 17-OHP-C and outpatient tococardiography were identified from a database. The mean and maximum contraction frequencies per hour were compared from 3 days before to 3 days after 17-OHP-C dosing. McNemar chi(2), Mann-Whitney U, and Friedman test statistics were used for analysis. Data were obtained from 388 women. Median contraction frequency was greater for women with subsequent preterm birth versus those delivering at term (1.5 [range 0, 14.5] versus 1.2 [range 0, 21.0] contractions per hour, P < 0.001). No reduction in contraction frequency was observed after 17-OHP-C administration, and in fact, the converse was observed for the average contractions 3 days prior compared with 3 days posttreatment ( P < 0.001). In the subgroup of women with a subsequent spontaneous preterm, the proportion who had an average contraction frequency of more than five per hour 1 day preinjection versus 1 day postinjection was not significantly different (2.6% versus 3.0%, P = 1.0). Administration of 17-OHP-C was not associated with a reduction in contraction frequency. To be effective, this drug likely has effects by mechanisms other than tocolysis. Although a statistically significant increase in contractions was identified posttherapy versus pretherapy, the clinical importance of this observation is unknown. [ABSTRACT FROM AUTHOR]

Background: A significant number of coronavirus disease 2019 (COVID-19) survivors are experiencing long COVID, with symptoms lasting beyond three months. While diverse long COVID symptoms are established, there are gaps in understanding its long-term trends, intensity, and risk factors, requiring further investigation., Aims: This study aimed to investigate the long COVID characteristics and associated factors by following COVID-19 survivors for one year post-infection and comparing them with healthy counterparts., Main Methods: In this longitudinal, correlational study, COVID-19 survivors diagnosed between November 2021 and February 2023 were monitored every three months for a year. Participants aged ≥18 years who had reported a positive COVID-19 test were recruited via social media and healthcare provider referrals., Key Findings: Out of 182 survivors who initially agreed to participate, 176 completed the study. The mean age was 47.56 years (SD = 16.2), and 51.1 % were female. There was a clinically significant decline in cognitive function and health-related quality of life over time, with symptoms like shortness of breath, reduced physical fitness, and increased health concerns. Those with severe acute COVID-19 symptoms experienced greater cognitive and physical declines and more shortness of breath a year later. Lower financial status was linked to poorer health-related quality of life and increased health concerns., Significance: A year post-infection, COVID-19's impact on cognitive function and health-related quality of life remains significant, affecting individuals and communities. Survivors with severe initial symptoms and economic disadvantages need more attention. Future research should identify additional predictors of severe long COVID., Competing Interests: Declaration of competing interest None to declare., (Copyright © 2024. Published by Elsevier Inc.)

PCAB (prednisone, cyclophosphamide, doxorubicin, carmustine) is a single-day regimen previously used for induction and now in relapsed/refractory multiple myeloma (RRMM). We retrospectively analysed the outcomes of 85 patients from five Australian centres. These included 30 patients (35.3%) who received PCAB with one additional agent (bortezomib most frequently). Median age of the patients was 65 years (37-80), with a median of four (1-8) prior lines of therapy. ORR was 37% (CR 4.9%). Median progression free survival and overall survival were 4.4 months (95% CI 3.5-6.7) and 7.4 months (95% CI 6.4-10.2), respectively. Extramedullary disease (EMD) was associated with shorter survival. Grade 3 or 4 cytopenia and febrile neutropenia occurred in 76.2% and 39.1%, respectively, with six (7.1%) treatment-related mortalities. Median inpatient stay was 3.3 days/28-day cycle (IQR 0.6-13), and for patients who died, a median of 20.2% of days alive were spent inpatient (IQR 6.4-39.1%). Three patients were successfully bridged to CAR T-cell therapy using PCAB, despite being penta-exposed and having EMD. PCAB may be considered as a useful salvage therapy amongst other polychemotherapy regimens in late relapse. Further studies is warranted to investigate and define its role as a bridging therapy to novel therapeutics., (© 2024 The Author(s). European Journal of Haematology published by John Wiley & Sons Ltd.)

Background: Despite recent advances, optimal therapeutic approaches applicable to subpopulations with primary central nervous system (CNS) lymphoma outside of clinical trials remain to be determined., Methods: We performed a retrospective study of immunocompetent, adult patients with histologically confirmed diffuse large B-cell lymphoma of the CNS (PCNSL). 190/204 (93%) patients (median age: 65) received one of five high-dose methotrexate (HD-MTX) containing chemotherapy regimens: MPV/Ara-C (HD-MTX, procarbazine, and vincristine, followed by cytarabine [Ara-C]) ( n  = 94, 50%), MATRix (HD-MTX, Ara-C, thiotepa, and rituximab) ( n  = 19, 10%), HD-MTX/Ara-C ( n  = 31, 16%), HD-MTX monotherapy ( n  = 35, 18%) and MBVP (HD-MTX, carmustine, teniposide, prednisolone) ( n  = 11, 6%)., Results: Cumulative median HD-MTX and Ara-C doses were 17 g/m 2 (range: 1-64 g/m 2 ) and 12 g/m 2 (0-32 g/m 2 ) respectively. Using 14 g/m 2 as the reference dose, the median HD-MTX relative dose intensity (HD-MTX-RDI) was 1.25 (0.27-4.57) with 84% receiving > 0.75. The overall response rate (ORR) was 72% (complete response: 50%) after completing HD-MTX. At a median follow-up of 3.41 years (0.06-9.42), progression-free survival (PFS) and overall survival (OS) were different between chemotherapy cohorts, with the best outcomes achieved in the MPV/Ara-C cohort (2-year PFS 74%, 2-year OS 82%; p  = 0.0001 and p  = 0.0024 respectively). On multivariate analysis, MPV/Ara-C administration and HD-MTX-RDI > 0.75 were associated with longer PFS and OS., Conclusion: Sequential, response-adapted approaches can improve outcomes, even in older patients who are ineligible for a high-intensity concurrent chemotherapy approach and do not undergo traditional consolidative strategies., Competing Interests: Katharine Louise Lewis: Consultancy/Honoraria: Jansen Roche. Trial steering committee: Loxo/Lilly. Advisory: IQVIA and MSD; Pietro R. Di Ciaccio: Honoraria/travel funding: Janssen, Astra Zeneca, and Gilead/Kite; Chan Y. Cheah: Research funding: Beigene. Advisory: Janssen Cilag. Joel Wight: Honoraria: Janssen, MDI, Beigene, MSD, and Abbvie. Travel support: Kite/Gilead. Jake Shortt: Consultancy: BMS, Otsuka, Pfizer, and Astellas. Speaker's Bureau: Mundipharma and Novartis. Research funding: Astex. Dipti Talaulikar: Consultancy/Advisory/Honoraria: Roche, Janssen, Beigene, Novartis, Amgen, Antengene, CSL, EUSA, BMS, and Takeda. Research funding: Roche, Janssen, and Takeda. Tara Cochrane: Research funding: Beigene. Advisory: Janssen Cilag. Eliza A. Hawkes: Consultancy/Advisory: AstraZeneca, Janssen Oncology, Merck Sharpe & Dohme, Gilead Sciences, Bristol Myers Squibb, Novartis, Beigene, Link Healthcare, and Regeneron. Speaker's Bureau: Roche/Genentech, Regeneron, and Abbvie. Research funding: AstraZeneca, Celgene, Merck KGaA, Janssen‐Cilag, Gilead Sciences, Mundipharma, Bristol‐Myers Squibb, and Roche/Genentech. Travel: AstraZeneca., (© 2024 The Author(s). eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

VEGFR2 (Vascular endothelial growth factor receptor 2) is a central regulator of placental angiogenesis. The study of the VEGFR2 proteome of chorionic villi at term revealed its partners MDMX (Double minute 4 protein) and PICALM (Phosphatidylinositol-binding clathrin assembly protein). Subsequently, the oxytocin receptor (OT-R) and vasopressin V1aR receptor were detected in MDMX and PICALM immunoprecipitations. Immunogold electron microscopy showed VEGFR2 on endothelial cell (EC) nuclei, mitochondria, and Hofbauer cells (HC), tissue-resident macrophages of the placenta. MDMX, PICALM, and V1aR were located on EC plasma membranes, nuclei, and HC nuclei. Unexpectedly, PICALM and OT-R were detected on EC projections into the fetal lumen and OT-R on 20-150 nm clusters therein, prompting the hypothesis that placental exosomes transport OT-R to the fetus and across the blood-brain barrier. Insights on gestational complications were gained by univariable and multivariable regression analyses associating preeclampsia with lower MDMX protein levels in membrane extracts of chorionic villi, and lower MDMX, PICALM, OT-R, and V1aR with spontaneous vaginal deliveries compared to cesarean deliveries before the onset of labor. We found select associations between higher MDMX, PICALM, OT-R protein levels and either gravidity, diabetes, BMI, maternal age, or neonatal weight, and correlations only between PICALM-OT-R (p < 2.7 × 10 -8 ), PICALM-V1aR (p < 0.006), and OT-R-V1aR (p < 0.001). These results offer for exploration new partnerships in metabolic networks, tissue-resident immunity, and labor, notably for HC that predominantly express MDMX., (© 2024. The Author(s).)

The primary analysis of MAGNOLIA, an open-label, single-arm, multicenter, phase 2 study, demonstrated that the next-generation Bruton tyrosine kinase (BTK) inhibitor zanubrutinib provided a high overall response rate (ORR) in patients with relapsed/refractory marginal zone lymphoma (R/R MZL), with a favorable safety/tolerability profile. Presented here, is the final analysis of MAGNOLIA, performed to characterize the durability of response and longer-term safety and tolerability. Zanubrutinib (160 mg twice daily) was evaluated in 68 patients with R/R MZL who had received at least 1 anti-CD20-directed regimen. The primary end point was independent review committee (IRC)-assessed ORR. Secondary end points included investigator-assessed ORR, duration of response (DOR), progression-free survival (PFS), overall survival (OS), health-related quality of life, safety, and tolerability. With a median follow-up of 27.4 months, the IRC-assessed ORR was 68.2% (95% confidence interval [CI], 55.6-79.1), with a 24-month DOR event-free rate of 72.9% (95% CI, 54.4-84.9). PFS and OS at 24 months were 70.9% (95% CI, 57.2-81.0) and 85.9% (95% CI, 74.7-92.4), respectively. The zanubrutinib safety profile was consistent with the primary analysis, with no new safety signals observed. Atrial fibrillation/flutter (n = 2 [2.9%]) and hypertension (n = 3 [4.4%]) were uncommon. Neutropenia (n = 8 [11.8%]) was the most common grade ≥3 adverse event. In this final analysis of MAGNOLIA, zanubrutinib demonstrated sustained clinical responses beyond 2 years, with 73% of responders alive and progression free. Zanubrutinib continued to demonstrate a favorable safety/tolerability profile with the additional time on treatment. This trial was registered at www.clinicaltrials.gov as #NCT03846427., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Introduction: Hyperfibrinolysis diagnosed on Rotational Thromboelastography (ROTEM) is associated with increased transfusion requirements and mortality in trauma. The diagnosis and significance of hyperfibrinolysis in a mixed, non-cardiac, general surgical population has not been investigated. We aimed to measure agreement between four ROTEM algorithms for diagnosing hyperfibrinolysis and transfusion requirements and mortality in general surgical patients. These algorithms mostly incorporate measures of early or late clot amplitude reduction on the Extrinsic Clotting Pathway Test with Tissue Factor (EXTEM) channel., Method: Four hospital administrative data sets were linked from 2019 to 2022. Adults >18 years were included if a ROTEM was performed during their surgery (intraoperative period) or within 24-h of the surgery completion (postoperative period). The four hyperfibrinolysis criteria were applied to the ROTEM data and assessed for their agreement, intraoperative and postoperative transfusion requirements and in-patient mortality., Results: We linked 933 ROTEMs to 558 patient-procedures. One algorithm identified hyperfibrinolysis on only three patients so was excluded. Agreement between the remaining three was slight (Cohens Kappa 0.18 (p < 0.001)) with hyperfibrinolysis diagnosed between 22 and 69 % of the procedures. The association between hyperfibrinolysis diagnosis and intraoperative or postoperative transfusion requirement was inconsistent between the criteria. However, an algorithm put forward by Goerling et al. was more often associated with transfusion requirement and inpatient mortality., Discussion: The poor agreement between criteria suggests that some ROTEM criteria may not transfer directly to general surgical patients. Future research should focus on optimising hyperfibrinolysis cut-off values to update algorithms for bleeding general surgical patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2023. Published by Elsevier Ltd. All rights reserved.)

Objectives: Acute respiratory distress syndrome (ARDS) is a critical complication in severe COVID-19 patients. The intravenous infusion (IVF) of umbilical cord- (UC-) mesenchymal stem cells (MSCs), validated to substantially reduce the release of several inflammatory cytokines in vivo , was also shown to exhibit benefits in improving hypoxemia among severe COVID-19 patients. A single dose of IVF-UC-MSCs therapy for severe COVID-19 patients was shown to alleviate the initial ARDS severity, but have 50%-67% case-fatality rates. In Taiwan, few adult patients with severe COVID-19-induced ARDS receiving compassionate adjuvant treatment consisting of either a single dose (1-10 × 10 6  cells/kg body weight (kg BW)) or three doses (5 × 10 6  cells/kg BW in each dose) of IVF-UC-MSCs had good outcomes. However, the optimal dosage and rounds of IVF-UC-MSCs administration for the treatment of severe COVID-19 patients with ARDS are undetermined., Methods: We reviewed the 2020-2022 PubMed literature database concerning the clinical efficacy of IVF-UC-MSCs among severe COVID-19 patients., Results: The data of COVID-19 case series in the PubMed literature revealed a notable heterogeneity in the therapeutic dosage (a single dose: 1-10 × 10 6  cells/kg BW; and three doses: 50-200 × 10 6  cells/kg BW in each dose) and the post-ARDS days of IVF-UC-MSCs administration (a single dose: 1-12; and multiple doses: 5-14) for the treatment of severe COVID-19-associated ARDS. The survival rates among these severe COVID-19 patients ranged from 50% to 76%. However, an overall rate of 93.1% of significant improvement in hypoxemia was observed for the COVID-19 survivors receiving IVF-UC-MSCs at the initial ARDS stage., Conclusions: According to our analysis, the ideal treatment dosage of IVF-UC-MSCs for severe COVID-19-induced ARDS is likely 5 × 10 6  cells/kg BW for three cycles within 5 days of ARDS onset in severe COVID-19 patients., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2023 Po-Ren Hsueh et al.)

Using tissue whole exome sequencing (WES) and circulating tumor cell-free DNA (ctDNA), this Australasian Leukaemia & Lymphoma Group translational study sought to characterize primary and acquired molecular determinants of response and resistance of marginal zone lymphoma (MZL) to zanubrutinib for patients treated in the MAGNOLIA clinical trial. WES was performed on baseline tumor samples obtained from 18 patients. For 7 patients, ctDNA sequence was interrogated using a bespoke hybrid-capture next-generation sequencing assay for 48 targeted genes. Somatic mutations were correlated with objective response data and survival analysis using Fisher exact test and Kaplan-Meier (log-rank) method, respectively. Baseline WES identified mutations in 33 of 48 (69%) prioritized genes. NF-κB, NOTCH, or B-cell receptor (BCR) pathway genes were implicated in samples from 16 of 18 patients (89%). KMT2D mutations (n = 11) were most common, followed by FAT1 (n = 9), NOTCH1, NOTCH2, TNFAIP3 (n = 5), and MYD88 (n = 4) mutations. MYD88 or TNFAIP3 mutations correlated with improved progression-free survival (PFS). KMT2D mutations trended to worse PFS. Acquired resistance mutations PLCG2 (R665W/R742P) and BTK (C481Y/C481F) were detected in 2 patients whose disease progressed. A BTK E41K noncatalytic activating mutation was identified before treatment in 1 patient who was zanubrutinib-refractory. MYD88, TNFAIP3, and KMT2D mutations correlate with PFS in patients with relapsed/refractory MZL treated with zanubrutinib. Detection of acquired BTK and PLCG2 mutations in ctDNA while on therapy is feasible and may herald clinical disease progression. This trial was registered at https://anzctr.org.au/ as #ACTRN12619000024145., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Aim: To evaluate the accuracy of melphalan test dose pharmacokinetic (PK) predictions of the subsequent high dose (HDM) area under the concentration-versus-time curve (AUC) and to identify sources of prediction error (PE)., Methods: A prospective multicentre PK study was conducted in 40 myeloma patients of median age 60 (range:35-71) years using a 20 mg/m 2 test dose administered 1-3 days prior to HDM (predominantly 180 mg/m 2 ). PK data were collected post the test and high doses to compare predicted versus actual AUCs determined using the trapezoidal rule. Test and high dose infusion concentration, volume and duration and the time from preparation to infusion were compared using the paired Wilcoxin rank sign test. The impact of Melphalan administration parameters on PE was evaluated using the Mann-Whitney test. The predictive capacity of a previously published population PK (PopPK) model was also examined., Results: Predicted HDM AUC was within 15% of the observed values in only 63% of patients when analysed using the trapezoidal rule and 70% of patients using PopPK. Test dose infusion concentration, volume, duration and time from preparation to infusion were significantly lower than for HDM (p < 0.005). Test dose administration within 15 min of reconstitution (n = 5) was associated with significantly lower PE than administration times of 16-60 min (n = 22), p < 0.05. Test and HDM infusion concentrations were lower in patients with large PE (> ± 15%), but the differences were not significant (p = 0.078, 0.228, respectively)., Conclusion: Test dose PK has the potential to predict subsequent HDM exposure to achieve a target AUC once melphalan administration parameters are optimised to account for stability issues in the formulation., (© 2022. Crown.)

Background: Vaccine-induced thrombotic thrombocytopenia (VITT) is a rare complication of adenovirus-based vaccines aimed to prevent and minimize COVID-19 and related pathophysiology., Objectives: To describe patterns of testing for anti-platelet factor 4 (PF4) antibodies using various ELISA assays in a large Australian cohort and comparative functional platelet activation assays in a subset., Patients/methods: Asserachrom HPIA IgG ELISA was performed in 1284 patients over a period of 12 months, supplemented in select cohorts by comparative ELISA using three other methods (n = 78-179), three different functional assays (flow cytometry, serotonin release assay, and/or Multiplate; n = 476), and rapid immunological chemiluminescence anti-PF4 assay (n = 460), in a multicenter study., Results: For first episode presentations, 190/1284 (14.8%) ELISA tests were positive. Conversely, most (445/460; 96.7%) chemiluminescence anti-PF4 test results were negative. All functional assays showed associations of higher median ELISA optical density with functional positivity and with high rates of ELISA positivity (64.0% to 85.2%). Data also identified functional positivity in 14.8%-36.0% of ELISA negative samples, suggesting false negative VITT by HPIA IgG ELISA in upward of one third of assessable cases., Conclusion: To our knowledge, this is the largest multicenter evaluation of anti-PF4 testing for investigation of VITT. Discrepancies in test results (ELISA vs. ELISA or ELISA vs. functional assay) in some patients highlighted limitations in relying on single methods (ELISA and functional) for PF4 antibody detection in VITT, and also highlights the variability in phenotypic test presentation and pathomechanism of VITT., (© 2022 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Long-term outcomes after non-traumatic pediatric out-of-hospital cardiac arrest (OHCA) are not well understood. This systematic review aimed to summarize long-term outcomes (1 year and beyond), including overall survival, survival with favorable neurological outcomes, and health-related quality of life (HRQoL) outcomes) amongst pediatric OHCA patients who survived to discharge. Embase, Medline, and The Cochrane Library were searched from inception to October 6, 2021. Studies were included if they reported outcomes at 1 year or beyond after pediatric OHCA. Data abstraction and quality assessment was conducted by three authors independently. Qualitative outcomes were reported systematically. Seven studies were included, and amongst patients that survived to hospital discharge or to 30 days, longer-term survival was at least 95% at 24 months of follow up. A highly variable proportion (range 10-71%) of patients had favorable neurological outcomes at 24 months of follow up. With regard to health-related quality of life outcomes, at a time point distal to 1 year, at least 60% of pediatric non-traumatic OHCA patients were reported to have good outcomes. Our study found that at least 95% of pediatric OHCA patients, who survived to discharge, survived to a time point distal to 1 year. There is a general paucity of data surrounding the pediatric OHCA population.

We investigated the storage lower urinary tract symptoms (LUTS) before and after the first dose of coronavirus disease 2019 (COVID-19) vaccine and the association between pre-vaccinated overactive bladder (OAB) and the worsening of storage LUTS following COVID-19 vaccination. This cross-sectional study in a third-level hospital in Taiwan used the validated pre- and post-vaccinated Overactive Bladder Symptom Score (OABSS). Diagnosis of OAB was made using pre-vaccinated OABSS. The deterioration of storage LUTS was assessed as the increased score of OABSS following vaccination. Of 889 subjects, up to 13.4% experienced worsened storage LUTS after vaccination. OAB was significantly associated with an increased risk of worsening urinary urgency (p = 0.030), frequency (p = 0.027), and seeking medical assistance due to urinary adverse events (p < 0.001) after vaccination. The OAB group faced significantly greater changes in OABSS-urgency (p = 0.003), OABSS-frequency (p = 0.025), and total OABSS (p = 0.014) after vaccination compared to those observed in the non-OAB group. Multivariate regression revealed that pre-vaccinated OAB (p = 0.003) was a risk for the deterioration of storage LUTS. In conclusion, storage LUTS may deteriorate after vaccination. OAB was significantly associated with higher risk and greater changes in worsening storage LUTS. Storage LUTS should be closely monitored after COVID-19 vaccination, especially in those OAB patients.

We study how individuals' formation of inflation expectations are affected by the stringent containment and economic support measures put in place during the COVID-19 pandemic. Using the New York Fed Survey of Consumer Expectations (SCE) and the Oxford COVID-19 Government Response Tracker (OxCGRT), we find that policies aimed at containing the pandemic lead to an increase in individuals' inflation expectations and inflation uncertainty. We also find some heterogeneity in the impact across different demographic groups., (© 2022 The Authors. The Australian Economic Review published by John Wiley & Sons Australia, Ltd on behalf of The University of Melbourne, Melbourne Institute: Applied Economic & Social Research, Faculty of Business and Economics.)

Purpose: Marginal zone lymphoma (MZL) is an uncommon non-Hodgkin lymphoma with malignant cells that exhibit a consistent dependency on B-cell receptor signaling. We evaluated the efficacy and safety of zanubrutinib, a next-generation selective Bruton tyrosine kinase inhibitor, in patients with relapsed/refractory (R/R) MZL., Patients and Methods: Patients with R/R MZL were enrolled in the phase II MAGNOLIA (BGB-3111-214) study. The primary endpoint was overall response rate (ORR) as determined by an independent review committee (IRC) based on the Lugano 2014 classification., Results: Sixty-eight patients were enrolled. After a median follow-up of 15.7 months (range, 1.6 to 21.9 months), the IRC-assessed ORR was 68.2% and complete response (CR) was 25.8%. The ORR by investigator assessment was 74.2%, and the CR rate was 25.8%. The median duration of response (DOR) and median progression-free survival (PFS) by independent review was not reached. The IRC-assessed DOR rate at 12 months was 93.0%, and IRC-assessed PFS rate was 82.5% at both 12 and 15 months. Treatment was well tolerated with the majority of adverse events (AE) being grade 1 or 2. The most common AEs were diarrhea (22.1%), contusion (20.6%), and constipation (14.7%). Atrial fibrillation/flutter was reported in 2 patients; 1 patient had grade 3 hypertension. No patient experienced major hemorrhage. In total, 4 patients discontinued treatment due to AEs, none of which were considered treatment-related by the investigators., Conclusions: Zanubrutinib demonstrated high ORR and CR rate with durable disease control and a favorable safety profile in patients with R/R MZL., (©2021 The Authors; Published by the American Association for Cancer Research.)

Purpose: Venetoclax is an oral BCL-2 inhibitor with single-agent activity in patients with relapsed or refractory multiple myeloma (RRMM) with t(11;14) translocation. Venetoclax efficacy in RRMM may be potentiated through combination with agents including bortezomib, dexamethasone, and daratumumab., Methods: This phase I study (NCT03314181) evaluated venetoclax with daratumumab and dexamethasone (VenDd) in patients with t(11;14) RRMM and VenDd with bortezomib (VenDVd) in cytogenetically unselected patients with RRMM. Primary objectives included expansion-phase dosing, safety, and overall response rate. Secondary objectives included further safety analysis, progression-free survival, duration of response, time to progression, and minimal residual disease negativity., Results: Forty-eight patients were enrolled, 24 each in parts 1 (VenDd) and 2 (VenDVd). There was one dose-limiting toxicity in part 1 (grade 3 febrile neutropenia, 800 mg VenDd). Common adverse events with VenDd and VenDVd included diarrhea (63% and 54%) and nausea (50% and 50%); grade ≥ 3 adverse events were observed in 88% in the VenDd group and 71% in the VenDVd group. One treatment-emergent death occurred in part 2 (sepsis) in the context of progressive disease, with no other infection-related deaths on study with medians of 20.9 and 20.4 months of follow-up in parts 1 and 2, respectively. The overall response rate was 96% with VenDd (all very good partial response or better [≥ VGPR]) and 92% with VenDVd (79% ≥ VGPR). The 18-month progression-free survival rate was 90.5% (95% CI, 67.0 to 97.5) with VenDd and 66.7% (95% CI, 42.5 to 82.5) with VenDVd., Conclusion: VenDd and VenDVd produced a high rate of deep and durable responses in patients with RRMM. These results support continued evaluation of venetoclax with daratumumab regimens to treat RRMM, particularly in those with t(11;14)., Competing Interests: Nizar J. BahlisHonoraria: Celgene, Janssen, AbbVie, Amgen, Sanofi, Takeda, Karyopharm Therapeutics, GlaxoSmithKline, Genentech/RocheConsulting or Advisory Role: Janssen, Celgene, Amgen, Sanofi, Takeda, Pfizer, Karyopharm TherapeuticsResearch Funding: Janssen, Celgene Rachid BazConsulting or Advisory Role: Karyopharm Therapeutics, BMS, AbbVie, Oncopeptides, Shattuck Labs, SanofiResearch Funding: Karyopharm Therapeutics, Celgene, Merck Sharp & Dohme, Takeda, Signal Genetics, AbbVie, Sanofi, Janssen, BMS Simon J. HarrisonHonoraria: AbbVie, Amgen, Celgene/Bristol Myers Squibb, GlaxoSmithKline, Janssen Cilag, Novartis, Roche/Genentech, Takeda, Haemalogix, SanofiConsulting or Advisory Role: AbbVie, Amgen, Celgene/Bristol Myers Squibb, GlaxoSmithKline, Janssen Cilag, Novartis, Roche/Genentech, Takeda, Haemalogix, SanofiSpeakers' Bureau: AbbVie, Amgen, Celgene/Bristol Myers Squibb, GlaxoSmithKline, Janssen Cilag, Novartis, Roche/Genentech, Takeda, TerumoResearch Funding: Haemalogix, Janssen CilagExpert Testimony: EUSA Pharma, Terumo Hang QuachConsulting or Advisory Role: GlaxoSmithKline, Celgene, Karyopharm Therapeutics, Janssen-Cilag, CSL Behring, Amgen, SanofiResearch Funding: Celgene, Amgen, Karopharm, GlaxoSmithKline, Sanofi Torben PlesnerConsulting or Advisory Role: Janssen, Celgene, Takeda, AbbVie, Genmab, Oncopeptides, GenentechSpeakers' Bureau: Janssen, TakedaResearch Funding: Janssen, Genmab, Celgene, Takeda, Oncopeptides, Genentech, AbbVie, Roche Philippe MoreauHonoraria: Celgene, Janssen-Cilag, Amgen, GlaxoSmithKline, AbbVie, SanofiConsulting or Advisory Role: Celgene, Janssen, Amgen, GlaxoSmithKline, Sanofi, AbbVie Simon D. GibbsHonoraria: Janssen Oncology, Pfizer, AbbVie, Celgene/Bristol Myers Squibb, AmgenConsulting or Advisory Role: AbbVie Abdullah Al MasudEmployment: AbbVieStock and Other Ownership Interests: AbbVie Jeremy A. RossEmployment: AbbVieStock and Other Ownership Interests: AbbVie Orlando BuenoEmployment: AbbVieStock and Other Ownership Interests: AbbVieResearch Funding: AbbVieTravel, Accommodations, Expenses: AbbVie Jonathan L. KaufmanHonoraria: TecnofarmaConsulting or Advisory Role: Janssen, Celgene, TG Therapeutics, Sanofi, Tecnofarma, GenentechResearch Funding: Merck, Celgene, Janssen, Sutro Biopharma, Fortis, Amgen, AbbVie/Genentech, Bristol Myers SquibbTravel, Accommodations, Expenses: Janssen, Celgene, Bristol Myers Squibb, Sanofi, Amgen, TakedaNo other potential conflicts of interest were reported.

Primary and secondary central nervous system lymphomas (PCNSL/SCNSL) are aggressive rare malignancies with dismal outcomes. Encouraging data have emerged from Phase I/II clinical trials treating relapsed/refractory PCNSL/SCNSL with ibrutinib. We analysed 33 patients who received ibrutinib, alone or with other therapies, for PCNSL (n = 9) or SCNSL (n = 24). The objective response rate was 58% (complete response 55%). The median progression-free survival and overall survival for patients with PCNSL were both 3·1 months; for SCNSL, 10·2 and 11·5 months respectively. Only one invasive fungal infection was observed, despite concurrent or recent use of dexamethasone 8-16 mg daily in 14 patients (42%). Ibrutinib has encouraging activity in these aggressive malignancies., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

This research explored the effects of the coronavirus disease (COVID-19) outbreak on stock price movements of China's tourism industry by using an event study method. The results showed that the crisis negatively impacted tourism sector stocks. Further quantile regression analyses supported the non-linear relationship between the government's responses and stock returns. The results present that the resurgence of the virus in Beijing did bring about a short-term negative impact on the tourism industry. The empirical results can be used for future researchers to conduct a comparative study of cultural differences concerning government responses to the COVID-19., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2021.)

Using a monthly panel data of 13 Chinese provinces (cities) over the period from December 2019 to August 2020, this research investigates the impact of COVID-19 on the freight transport. We find that COVID-19 has a positive impact on the road freight transport turnover. This effect is pronounced under the higher numbers of COVID-19 confirmed cases and the lower level of gasoline production, and vice versa. In brief,•This study finds that COVID-19 has a positive impact on the road freight transport turnover.•This effect is pronounced under the higher numbers of COVID-19 confirmed cases and the lower level of gasoline production, and vice versa., (© 2020 The Authors. Published by Elsevier B.V.)

Innovation can include creativity, innovation mechanisms, and entrepreneurship. The ability to innovate is an important indicator of economic and social development, and creativity is an educational indicator of learning effectiveness. This article explores creativity and innovation from an educational perspective and proposes a sustainability-oriented creativity, innovation, and entrepreneurship education framework that uses creative problem solving. This framework contains four layers and three dimensions. The first layer concerns the thinker and basic structure, and the second layer contains the catalyst of sustainable development goals (SDGs). The third layer is the advanced structure of cultivating SDG thinkers. The final layer is the generation of students who will attempt to start up social enterprises. The three aspects apply the creative nature of diffuse thinking to social innovation; apply demand expansion to extend individual needs to societal needs; and apply educational goal development to encourage sustainability. We expect this framework, which can turn thinkers into doers through creativity and social innovation, to apply to different disciplines. This article provides suggestions for (1) designing curriculum in creativity, innovation, and entrepreneurship education (CIE) for different education level and (2) transitioning technical and vocational education in developing economies on the road to sustainable development., (Copyright © 2020 Shu, Ho and Huang.)

A promising method has been demonstrated to fabricate quantum dot (QD)-converted full-color micro-light emitting diodes (LEDs) by inkjet printing (IJP) instead of the mass transfer of three red-green-blue (RGB) color chips. By introducing an additional medium, that is, NaCl into a formulated ink, QD deposition is manipulated by the NaCl-QD adhesive force and the capillary flow inside the liquid drop via varying the substrate hydrophobicity, which enabled spontaneous self-encapsulation of QDs in a single NaCl crystal. An RGB QD@NaCl array with a small pixel size and uniform size distribution (diameter = 3.74 ± 0.5 μm) is obtained in the IJP process, which demonstrated a full-color micro-LED display with a color gamut of approximately 110% of the National Television System Committee (NTSC) standard.

Motivation: Non-linear ordinary differential equation (ODE) models that contain numerous parameters are suitable for inferring an emulated gene regulatory network (eGRN). However, the number of experimental measurements is usually far smaller than the number of parameters of the eGRN model that leads to an underdetermined problem. There is no unique solution to the inference problem for an eGRN using insufficient measurements., Results: This work proposes an evolutionary modelling algorithm (EMA) that is based on evolutionary intelligence to cope with the underdetermined problem. EMA uses an intelligent genetic algorithm to solve the large-scale parameter optimization problem. An EMA-based method, GREMA, infers a novel type of gene regulatory network with confidence levels for every inferred regulation. The higher the confidence level is, the more accurate the inferred regulation is. GREMA gradually determines the regulations of an eGRN with confidence levels in descending order using either an S-system or a Hill function-based ODE model. The experimental results showed that the regulations with high-confidence levels are more accurate and robust than regulations with low-confidence levels. Evolutionary intelligence enhanced the mean accuracy of GREMA by 19.2% when using the S-system model with benchmark datasets. An increase in the number of experimental measurements may increase the mean confidence level of the inferred regulations. GREMA performed well compared with existing methods that have been previously applied to the same S-system, DREAM4 challenge and SOS DNA repair benchmark datasets., Availability and Implementation: All of the datasets that were used and the GREMA-based tool are freely available at https://nctuiclab.github.io/GREMA., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

In the treatment of diffuse large B-cell lymphoma, a persistently positive [ 18 F]fluorodeoxyglucose positron emission tomography (PET) scan typically carries a poor prognosis. In this prospective multi-center phase II study, we sought to establish whether treatment intensification with R-ICE (rituximab, ifosfamide, carboplatin, and etoposide) chemotherapy followed by 90Y-ibritumomab tiuxetan-BEAM (BCNU, etoposide, cytarabine, and melphalan) for high-risk diffuse large B-cell lymphoma patients who are positive on interim PET scan after 4 cycles of R-CHOP-14 (rituximab, cyclophosphamide, doxorubicin, and prednisone) can improve 2-year progression-free survival from a historically unfavorable rate of 40% to a rate of 65%. Patients received 4 cycles of R-CHOP-14, followed by a centrally-reviewed PET performed at day 17-20 of cycle 4 and assessed according to International Harmonisation Project criteria. Median age of the 151 evaluable patients was 57 years, with 79% stages 3-4, 54% bulk, and 54% International Prognostic Index 3-5. Among the 143 patients undergoing interim PET, 101 (71%) were PET-negative (96 of whom completed R-CHOP), 42 (29%) were PET-positive (32 of whom completed R-ICE and 90Y-ibritumomab tiuxetan-BEAM). At a median follow up of 35 months, the 2-year progression-free survival for PET-positive patients was 67%, a rate similar to that for PET-negative patients treated with R-CHOP-14 (74%, P=0.11); overall survival was 78% and 88% (P=0.11), respectively. In an exploratory analysis, progression-free and overall survival were markedly superior for PET-positive Deauville score 4 versus score 5 (P=0.0002 and P=0.001, respectively). Therefore, diffuse large B-cell lymphoma patients who are PET-positive after 4 cycles of R-CHOP-14 and who switched to R-ICE and 90Y-ibritumomab tiuxetan-BEAM achieved favorable survival outcomes similar to those for PET-negative R-CHOP-14-treated patients. Further studies are warranted to confirm these promising results. (Registered at: ACTRN12609001077257)., (Copyright© Ferrata Storti Foundation.)

Single agent azacitidine or immunomodulatory drugs are effective in myelodysplastic syndrome (MDS), with differing target mechanisms and toxicities. Objectives of this ALLG MDS3 study in clinically advanced MDS, AMML and low blast AML were to establish safety, response and quality of life of azacitidine and thalidomide. Patients received azacitidine (75mg/m 2 /d sc 7days every 28 days), and oral thalidomide up to 100mg/d for maximum 12months. Eighty patients registered; median age 68 years (range 42-82), 49% IPSS int2-high. With 36.5 months follow up, patients received median 9 cycles azacitidine, 6.1mths thalidomide. Nonhematologic toxicity grade 3+ in 85%, commonly infections. Overall response rate was 63%; 26% CR were unaffected by IPSS. Median response duration 26.3months; overall survival was 28.1months. This combination azacitidine and thalidomide in clinically advanced MDS, CMML and low-blast AML was tolerable without unexpected toxicity and encouraging responses support further investigation of combination approaches with hypomethylating agent and immunomodulatory drug.

Wide gamut light emitting diodes using quantum dot-silicone film protected by atomic layer deposited TiO2 film were demonstrated. The core/shell QDs with multi-emission peaks were synthesised by a one-pot approach, in which the emission wavelength and colour composition were in situ adjusted during the synthetic process.

Promising reports of combination immunosuppression with high-dose dexamethasone and rituximab for the treatment of primary immune thrombocytopenia (ITP) have recently emerged. They suggest a potential to further optimize the efficacy of therapy. We investigate the use of a novel combination of conventional therapies in ITP given over 4 weeks. From 2011 to 2014, 20 patients were prospectively enrolled onto a single-arm phase 2b study to describe the safety, efficacy, and tolerability of oral dexamethasone 40 mg for days 1 to 4, oral cyclosporine 2.5 to 3 mg/kg daily for day 1 to 28, and intravenous low-dose rituximab 100 mg for days 7, 14, 21, and 28. There were no therapy-related serious adverse side effects, 6-month response rate was 60%, and treatment was well tolerated. Responders enjoyed relapse-free survivals of 92% and 76%, respectively, at 12 and 24 months. This study highlights the possibility of achieving an enduring remission from 4 weeks of therapy. This study is registered at www.anzctr.org.au (#ANZCTRN12611000015943)., (© 2015 by The American Society of Hematology.)

In order to compare the effects of weathering on two types of mixed oil, simulated weathering experiments were performed. The first sample was a mixture of two fresh oils and the second sample was a mixture of one fresh oil and another oil sample that had undergone a serious weathering process. Comparative studies evaluated decay rates and changes in diagnostic ratios of some fingerprinting biomarkers. Results showed that the mixing process affected the weathering rate of some compounds in the oils and also that certain diagnostic ratios are more suitable for estimating mixing proportions. A Pr/n-C17 versus Ph/n-C18 plot can be used to identify the end-numbers of mixed oils and the (C13+C14)/(C25+C26) ratio is a useful diagnostic ratio to detect the degree of weathering. Finally, hopane, sterane, and alkylated PAH fingerprints were found to give useful insights about the sources of the mixed oils., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

An optical filter with tunable wavelength and bandwidth is demonstrated using two phototunable cholesteric liquid crystals (CLCs) configured in a reflection mode. In this mode, incident light is first reflected by one Azo-chiral-doped CLC and then by another one. The tuning mechanism, which is based on the pitch modulation of the CLCs that contain an Azo-chiral dopant, can be controlled by two pumping laser beams. The central wavelength can be tuned from 510 to 628 nm, and the bandwidth can be changed from 13 to 79 nm.

In this study, a population of evolutionary biological networks is described by a stochastic dynamic system with intrinsic random parameter fluctuations due to genetic variations and external disturbances caused by environmental changes in the evolutionary process. Since information on environmental changes is unavailable and their occurrence is unpredictable, they can be considered as a game player with the potential to destroy phenotypic stability. The biological network needs to develop an evolutionary strategy to improve phenotypic stability as much as possible, so it can be considered as another game player in the evolutionary process, ie, a stochastic Nash game of minimizing the maximum network evolution level caused by the worst environmental disturbances. Based on the nonlinear stochastic evolutionary game strategy, we find that some genetic variations can be used in natural selection to construct negative feedback loops, efficiently improving network robustness. This provides larger genetic robustness as a buffer against neutral genetic variations, as well as larger environmental robustness to resist environmental disturbances and maintain a network phenotypic traits in the evolutionary process. In this situation, the robust phenotypic traits of stochastic biological networks can be more frequently selected by natural selection in evolution. However, if the harbored neutral genetic variations are accumulated to a sufficiently large degree, and environmental disturbances are strong enough that the network robustness can no longer confer enough genetic robustness and environmental robustness, then the phenotype robustness might break down. In this case, a network phenotypic trait may be pushed from one equilibrium point to another, changing the phenotypic trait and starting a new phase of network evolution through the hidden neutral genetic variations harbored in network robustness by adaptive evolution. Further, the proposed evolutionary game is extended to an n-tuple evolutionary game of stochastic biological networks with m players (competitive populations) and k environmental dynamics.

Angiogenesis occurs during tissue growth, development and wound healing. It is also required for tumor progression and represents a rational target for therapeutic intervention. NBM-T-BMX-OS01 (BMX), derived from the semisynthesis of osthole, an active ingredient isolated from Chinese herb Cnidium monnieri (L.) Cuss., was recently shown to enhance learning and memory in rats. In this study, we characterized the anti-angiogenic activities of NBM-T-BMX-OS01 (BMX) in an effort to develop novel inhibitors to suppress angiogenesis and tumor growth. BMX inhibited vascular endothelial growth factor (VEGF)-induced proliferation, migration and endothelial tube formation in human umbilical endothelial cells (HUVECs). BMX also attenuated VEGF-induced microvessel sprouting from aortic rings ex vivo and reduced HCT116 colorectal cancer cells-induced angiogenesis in vivo. Moreover, BMX inhibited the phosphorylation of VEGFR2, FAK, Akt and ERK in HUVECs exposed to VEGF. BMX was also shown to inhibit HCT116 cell proliferation and to suppress the growth of subcutaneous xenografts of HCT116 cells in vivo. Taken together, this study provides evidence that BMX modulates vascular endothelial cell remodeling and leads to the inhibition of tumor angiogenesis. These results also support the role of BMX as a potential drug candidate and warrant the clinical development in the treatment of cancer.

Numerous prediction methods of DNA-binding domains/proteins were proposed by identifying informative features and designing effective classifiers. These researches reveal that the DNA-protein binding mechanism is complicated and existing accurate predictors such as support vector machine (SVM) with position specific scoring matrices (PSSMs) are regarded as black-box methods which are not easily interpretable for biologists. In this study, we propose an ensemble fuzzy rule base classifier consisting of a set of interpretable fuzzy rule classifiers (iFRCs) using informative physicochemical properties as features. In designing iFRCs, feature selection, membership function design, and fuzzy rule base generation are all simultaneously optimized using an intelligent genetic algorithm (IGA). IGA maximizes prediction accuracy, minimizes the number of features selected, and minimizes the number of fuzzy rules to generate an accurate and concise fuzzy rule base. Benchmark datasets of DNA-binding domains are used to evaluate the proposed ensemble classifier of 30 iFRCs. Each iFRC has a mean test accuracy of 77.46%, and the ensemble classifier has a test accuracy of 83.33%, where the method of SVM with PSSMs has the accuracy of 82.81%. The physicochemical properties of the first two ranks according to their contribution are positive charge and Van Der Waals volume. Charge complementarity between protein and DNA is thought to be important in the first step of recognition between protein and DNA. The amino acid residues of binding peptides have larger Van Der Waals volumes and positive charges than those of non-binding ones. The proposed knowledge acquisition method by establishing a fuzzy rule-based classifier can also be applicable to predict and analyze other protein functions from sequences.

A patient with a suspected malignancy and pancytopenia warrants much consideration. Most clinicians would consider bone marrow infiltrative process, heralding a grave prognosis. However, rare occurrence of hemophagocytic lymphohistiocytosis is another diagnostic possibility we should keep in mind. The treatment choices and overall prognosis may differ from patients without hemophagocytosis. We present a case of incidentally found advanced renal cell carcinoma (RCC) concurrent with hemophagocytosis process in the bone marrow. We also discuss the importance of this finding.

Background: Existing methods for predicting protein solubility on overexpression in Escherichia coli advance performance by using ensemble classifiers such as two-stage support vector machine (SVM) based classifiers and a number of feature types such as physicochemical properties, amino acid and dipeptide composition, accompanied with feature selection. It is desirable to develop a simple and easily interpretable method for predicting protein solubility, compared to existing complex SVM-based methods., Results: This study proposes a novel scoring card method (SCM) by using dipeptide composition only to estimate solubility scores of sequences for predicting protein solubility. SCM calculates the propensities of 400 individual dipeptides to be soluble using statistic discrimination between soluble and insoluble proteins of a training data set. Consequently, the propensity scores of all dipeptides are further optimized using an intelligent genetic algorithm. The solubility score of a sequence is determined by the weighted sum of all propensity scores and dipeptide composition. To evaluate SCM by performance comparisons, four data sets with different sizes and variation degrees of experimental conditions were used. The results show that the simple method SCM with interpretable propensities of dipeptides has promising performance, compared with existing SVM-based ensemble methods with a number of feature types. Furthermore, the propensities of dipeptides and solubility scores of sequences can provide insights to protein solubility. For example, the analysis of dipeptide scores shows high propensity of α-helix structure and thermophilic proteins to be soluble., Conclusions: The propensities of individual dipeptides to be soluble are varied for proteins under altered experimental conditions. For accurately predicting protein solubility using SCM, it is better to customize the score card of dipeptide propensities by using a training data set under the same specified experimental conditions. The proposed method SCM with solubility scores and dipeptide propensities can be easily applied to the protein function prediction problems that dipeptide composition features play an important role., Availability: The used datasets, source codes of SCM, and supplementary files are available at http://iclab.life.nctu.edu.tw/SCM/.

Background/aims: Fluid overload is an important factor causing cardiovascular complications in dialysis patients. We compared fluid status, blood pressure (BP) and heart function between peritoneal dialysis (PD) patients and hemodialysis (HD) patients., Methods: We recruited 94 PD and 75 HD patients in our hospital. Fluid status was assessed by bioimpedance spectroscopy. Home BP was recorded. Use of antihypertensives was retrieved by chart review. In each group, 39 patients received echocardiographic examinations., Results: PD patients' fluid status was similar to that of predialysis HD patients. PD patients had lower systolic BP. E/E' and left ventricular mass index (LVMI) showed no significant intergroup difference. In multiple linear regression analyses, overhydration (OH)/extracellular water ratio >0.15 was associated with higher systolic BP, E/E' and LVMI., Conclusions: While PD was associated with higher OH but non-inferior BP control and heart function, OH was indeed related to poor BP control, diastolic dysfunction and left ventricular hypertrophy., (Copyright © 2012 S. Karger AG, Basel.)

Background: Admission for an acute heart failure (HF) confers an extremely poor prognosis. We aimed at finding out whether simultaneous assessment of multiple plasma-based biomarkers and Doppler echocardiography could provide complementary information and thus enable clinicians to stratify risk more effectively among patients hospitalized with acute HF; hence, untoward events after discharge avoided., Methods: A comprehensive echocardiographic study and measurements of cardiac troponin I (cTnI), N-terminal pro-B-type natriuretic protein (NT-proBNP), and high-sensitivity C-reactive protein (hsCRP) were conducted in 87 patients with symptomatic de novo acute HF or decompensation of chronic HF. Major adverse cardiac events (MACE) regarding cardiac death or hospitalization with worsening HF during a median follow-up period of 191 days were determined., Results: According to the univariate analysis, echocardiographic variables left atrial volume, left atrial volume index, pulmonary artery systolic pressure, E/E' ratio, and the concentrations of NT-proBNP were significantly related to clinical outcomes (all P-values < 0.05). Cox proportional hazard analysis identified two independent prognostic predictors of MACE: E/E' ratio and NT-proBNP. Moreover, the combining of plasma level of NT-proBNP with E/E' ratio provided independent and additional prognostic value in identifying high-risk acute HF patients., Conclusions: These findings reinforce the necessity of combining the heart hemodynamic variable E/E' ratio and plasma-based neurohormonal biomarker NT-proBNP when clinicians attempt to define the individual risk of patients hospitalized with acute HF., (© 2011, Wiley Periodicals, Inc.)

Background: Existing methods of predicting DNA-binding proteins used valuable features of physicochemical properties to design support vector machine (SVM) based classifiers. Generally, selection of physicochemical properties and determination of their corresponding feature vectors rely mainly on known properties of binding mechanism and experience of designers. However, there exists a troublesome problem for designers that some different physicochemical properties have similar vectors of representing 20 amino acids and some closely related physicochemical properties have dissimilar vectors., Results: This study proposes a systematic approach (named Auto-IDPCPs) to automatically identify a set of physicochemical and biochemical properties in the AAindex database to design SVM-based classifiers for predicting and analyzing DNA-binding domains/proteins. Auto-IDPCPs consists of 1) clustering 531 amino acid indices in AAindex into 20 clusters using a fuzzy c-means algorithm, 2) utilizing an efficient genetic algorithm based optimization method IBCGA to select an informative feature set of size m to represent sequences, and 3) analyzing the selected features to identify related physicochemical properties which may affect the binding mechanism of DNA-binding domains/proteins. The proposed Auto-IDPCPs identified m = 22 features of properties belonging to five clusters for predicting DNA-binding domains with a five-fold cross-validation accuracy of 87.12%, which is promising compared with the accuracy of 86.62% of the existing method PSSM-400. For predicting DNA-binding sequences, the accuracy of 75.50% was obtained using m = 28 features, where PSSM-400 has an accuracy of 74.22%. Auto-IDPCPs and PSSM-400 have accuracies of 80.73% and 82.81%, respectively, applied to an independent test data set of DNA-binding domains. Some typical physicochemical properties discovered are hydrophobicity, secondary structure, charge, solvent accessibility, polarity, flexibility, normalized Van Der Waals volume, pK (pK-C, pK-N, pK-COOH and pK-a(RCOOH)), etc., Conclusions: The proposed approach Auto-IDPCPs would help designers to investigate informative physicochemical and biochemical properties by considering both prediction accuracy and analysis of binding mechanism simultaneously. The approach Auto-IDPCPs can be also applicable to predict and analyze other protein functions from sequences.

The prediction of non-classical secreted proteins is a significant problem for drug discovery and development of disease diagnosis. The characteristic of non-classical secreted proteins is they are leaderless proteins without signal peptides in N-terminal. This characteristic makes the prediction of non-classical proteins more difficult and complicated than the classical secreted proteins. We identify a set of informative physicochemical properties of amino acid indices cooperated with support vector machine (SVM) to find discrimination between secreted and non-secreted proteins and to predict non-classical secreted proteins. When the sequence identity of dataset was reduced to 25%, the prediction accuracy on training dataset is 85% which is much better than the traditional sequence similarity-based BLAST or PSI-BLAST tool. The accuracy of independent test is 82%. The most effective features of prediction revealed the fundamental differences of physicochemical properties between secreted and non-secreted proteins. The interpretable and valuable information could be beneficial for drug discovery or the development of new blood biochemical examinations.

Background/purpose: The yeast Kodamaea ohmeri rarely causes life-threatening human infections. However, risk factors, laboratory diagnoses, and treatments for K. ohmeri infection have been limited, and the optimal therapy for K. ohmeri infection has not been identified., Methods: Twenty cases of K. ohmeri infection have been reported in the English medical literature. We present two new cases of K. ohmeri fungemia. We investigated the nature and treatment of K. ohmeri infections using minimum inhibitory concentrations of antifungal agents and by comparing the two cases with those described in the literature., Results: From March 1998 to December 2008, a total of 22 patients with K. ohmeri infections were studied. Hematological malignancies and diabetes were the most common co-morbidities for K. ohmeri infections, with crude prevalence rates of 27.3% and 18.2%, respectively. The K. ohmeri isolates showed less susceptibility to fluconazole but greater susceptibility to amphotericin B [15/25 isolates (60%) vs. 25/25 isolates (100%), respectively]. Good outcomes (8/9 cases; 88.9%) were found following removal of indwelling catheters and implants. In addition, voriconazole and echinocandins, such as caspofungin and micafungin, also showed excellent minimum inhibitory concentrations against K. ohmeri., Conclusion: K. ohmeri should not be regarded as a contaminant of blood cultures. Favorable outcomes for this potentially life-threatening infection are promoted by the removal of indwelling catheters; furthermore, outcomes are associated with optimal antifungal regimens, especially voriconazole and echinocandins., (Copyright © 2010 Taiwan Society of Microbiology. Published by Elsevier B.V. All rights reserved.)

Background: Obstructive sleep apnea (OSA) is a common disorder in modern society and closely associated with obesity. Because OSA increases the likelihood of complications in the perioperative period, preoperative recognition is very important for bariatric patients. Polysomnography (PSG) remains the gold standard for diagnosis, but it is a time-consuming and expensive examination. Our study is aimed at identifying practical clinical predictors of OSA for bariatric patients., Methods: From April 2006 to December 2007, 101 morbid obese patients [41 men and 60 women, mean age 30.3 +/- 8.5, mean body mass index (BMI) 43.3 +/- 6.9] who underwent PSG before bariatric surgery were retrospectively studied. The severity of OSA was categorized by the apnea-hypopnea index (AHI) as follows: normal, 0 to 4.9; mild, 5 to 14.9; moderate, 15 to 29.9; and severe, >/=30. Chi-squared tests and linear regression models were used to assess associations between clinical parameters and AHI; P < 0.05 was considered statistically significant., Results: The mean Epworth sleepiness scale (ESS) score was 8.2 +/- 4.7, and the mean AHI was 28.9 +/- 33.8 per hour. Of 101 patients, 83 patients had OSA; including severe (32.7%), moderate (17.8%), and mild (31.7%) OSA; 18.5% had no OSA. Patients with severe OSA are significantly male predominant and had higher BMI, systolic blood pressure, hemoglobin, neck and waist circumference, and ESS scores. In linear regression model analysis, the parameters which positively correlated with AHI were body weight, BMI, systolic blood pressure, diastolic blood pressure, hemoglobin, waist and neck circumferences, and the scores of ESS. Multivariate analysis confirmed that BMI, neck circumference, and scores of ESS are independent predictors of the increasing of AHI., Conclusions: OSA is highly prevalent (82.2%) in Asian bariatric patients. BMI, neck circumference, and scores of ESS are independent predictors of OSA in these patients.