Relationship between syncopal symptoms and head-up tilt test modes.

OBJECTIVE: Head-up tilt test (HUTT) is an important tool in the diagnosis of pediatric vasovagal syncope. This research will explore the relationship between syncopal symptoms and HUTT modes in pediatric vasovagal syncope. METHODS: A retrospective analysis was performed on the clinical data of 2513 children aged 3-18 years, who were diagnosed with vasovagal syncope, from Jan. 2001 to Dec. 2021 due to unexplained syncope or pre-syncope. The average age was 11.76 ± 2.83 years, including 1124 males and 1389 females. The patients were divided into the basic head-up tilt test (BHUT) group (596 patients) and the sublingual nitroglycerine head-up tilt test (SNHUT) group (1917 patients) according to the mode of positive HUTT at the time of confirmed pediatric vasovagal syncope. RESULTS: (1) Baseline characteristics: Age, height, weight, heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), and composition ratio of syncope at baseline status were higher in the BHUT group than in the SNHUT group (all P < 0.05). (2) Univariate analysis: Age, height, weight, HR, SBP, DBP, and syncope were potential risk factors for BHUT positive (all P < 0.05). (3) Multivariate analysis: syncope was an independent risk factor for BHUT positive, with a probability increase of 121% compared to pre-syncope (P<0.001). CONCLUSION: The probability of BHUT positivity was significantly higher than SNHUT in pediatric vasovagal syncope with previous syncopal episodes.

Relationships between high-concentration toxic metals in sediment and evolution of microbial community structure and carbon-nitrogen metabolism functions under long-term stress perspective.

Microorganisms are highly sensitive to toxic metal pollution and play an important role in the material cycling and energy flow of the water ecosystem. Herein, 13 sediment samples from Junchong Reservoir (Guangxi Province, China) were collected in December 2021. The spatial distribution of pollution levels for toxic metals and the effects of toxic metals on the composition, functional characteristics, and metabolism of microorganisms were investigated. The results demonstrated that the area is a proximate area to industrial zones with severity of toxic metal pollution. Their mean concentrations of As, Cu, Zn, and Pb were up to 128.79 mg/kg, 57.62 mg/kg, 594.77 mg/kg, and 97.12 mg/kg respectively. There was a strong correlation between As, Cu, Zn, and Pb, with the highest correlation coefficient reaching 0.94. As the level of toxic metal pollution increases, the diversity and abundance of microorganisms gradually decrease. Compared to those with lower pollution levels, the Shannon index in regions with higher pollution levels decreases by up to 0.373, and the Chao index decreases by up to 143.507. However, the relative abundance of Bacteroidota, Patescibacteria, and Chloroflexi increased by 23%, 20%, and 5%, respectively, indicating their higher adaptability to toxic metals. Furthermore, microbial carbon and nitrogen metabolism were also affected by the presence of toxic metals. FAPROTAX analysis demonstrated an abundant reduction of ecologically functional groups associated with carbon and nitrogen transformations under high toxic metal pollution levels. KEGG pathway analysis indicated that carbon fixation and nitrogen metabolism pathways were inhibited with increasing toxic metal concentrations. These findings would contribute to a better understanding of the effects of toxic metal pollution on sediment microbial communities and function, shedding light on the ecological consequences of toxic metal contamination.

Delayed treatment initiation of oral anticoagulants among Medicare patients with atrial fibrillation.

Study objective: This study aimed to identify factors associated with delayed oral anticoagulant (OAC) treatment initiation among atrial fibrillation (AF) patients in United States (US) clinical practice. Participants: Medicare beneficiaries newly diagnosed with AF without moderate-to-severe mitral stenosis or a mechanical heart valve, were aged ≥65 years and prescribed OAC on or after 10/1/2015 through 2019 were included. Delayed and early OAC initiation were defined as >3 months and 0-3 months initiation from first AF diagnosis, respectively. Main outcome measures: Association between delayed OAC initiation and patient demographics, clinical and index OAC coverage and formulary characteristics was examined using multivariable logistic regression. Results: A total of 446,441 patients met the inclusion criteria; 30.0 % (N = 131,969) were identified as delayed and 70.0 % (N = 314,472) as early OAC initiation. Median age for both cohorts was 78 years. In the early and delayed OAC cohorts, 47.1 % and 47.6 % were male and 88.8 % and 86.6 %, were White, respectively. Factors associated with delayed OAC initiation (odds ratio; 95 % confidence interval) included Black race (1.29; 1.25 to 1.33), west region (1.29; 1.26 to 1.32), comorbidities such as dementia (1.27; 1.23 to 1.30), recent bleeding hospitalization (1.22; 1.18 to 1.27), prior authorization (1.69; 1.66 to 1.71), tier 4 formulary for index OAC at AF diagnosis (1.26; 1.22 to 1.30). Conclusion: Our study revealed that nearly one-third of Medicare patients with AF experienced delayed OAC initiation. Key patient characteristics found to be associated with delayed OAC initiation included race and ethnicity, comorbidities, and formulary restrictions.

PRMT5 is an actionable therapeutic target in CDK4/6 inhibitor-resistant ER+/RB-deficient breast cancer.

CDK4/6 inhibitors (CDK4/6i) have improved survival of patients with estrogen receptor-positive (ER+) breast cancer. However, patients treated with CDK4/6i eventually develop drug resistance and progress. RB1 loss-of-function alterations confer resistance to CDK4/6i, but the optimal therapy for these patients is unclear. Through a genome-wide CRISPR screen, we identify protein arginine methyltransferase 5 (PRMT5) as a molecular vulnerability in ER+/RB1-knockout breast cancer cells. Inhibition of PRMT5 blocks the G1-to-S transition in the cell cycle independent of RB, leading to growth arrest in RB1-knockout cells. Proteomics analysis uncovers fused in sarcoma (FUS) as a downstream effector of PRMT5. Inhibition of PRMT5 results in dissociation of FUS from RNA polymerase II, leading to hyperphosphorylation of serine 2 in RNA polymerase II, intron retention, and subsequent downregulation of proteins involved in DNA synthesis. Furthermore, treatment with the PRMT5 inhibitor pemrametostat and a selective ER degrader fulvestrant synergistically inhibits growth of ER+/RB-deficient cell-derived and patient-derived xenografts. These findings highlight dual ER and PRMT5 blockade as a potential therapeutic strategy to overcome resistance to CDK4/6i in ER+/RB-deficient breast cancer.

Clinical Impact of Switching or Continuation of Apixaban or Rivaroxaban among Patients with Non-Valvular Atrial Fibrillation.

BACKGROUND: Real-world evidence on direct oral anticoagulant outcomes among Non-Valvular Atrial Fibrillation (NVAF) patients is limited. We aimed to evaluate stroke/systemic embolism (SE) and major bleeding (MB) risks among NVAF patients continuing or switching to different oral anticoagulants. METHODS: Using Optum's de-identified Clinformatics® Data Mart Database, we identified NVAF patients initiating apixaban or rivaroxaban between 1 January 2013 and 31 December 2021. Patients switching therapies within 30 days before or 90 days after discontinuing their initial DOAC and those who continued initial therapy were included. The index date was the switch date for switchers, while continuers were assigned a hypothetic index date. Switchers and continuers were propensity score matched based on pre-index characteristics. RESULTS: Among 167,868 apixaban and 65,888 rivaroxaban initiators, 2900 apixaban-to-rivaroxaban switchers were matched with 14,500 apixaban continuers, and 2873 rivaroxaban-to-apixaban switchers were matched with 14,365 rivaroxaban continuers. Apixaban-to-rivaroxaban switching was associated with higher stroke/SE risk (HR: 1.99, 95% CI: 1.38-2.88) and MB risk (HR:1.80, 95% CI: 1.46-2.23) than continuing apixaban. Rivaroxaban-to-apixaban switching had similar stroke/SE risk (HR: 0.74, 95% CI: 0.45-1.22) but lower MB risk (HR: 0.49, 95% CI: 0.38-0.65) than continuing rivaroxaban. CONCLUSIONS: These findings may aid physicians and patients in making informed decisions when considering a switch between apixaban and rivaroxaban.

Effectiveness and safety of anticoagulants among patients with venous thromboembolism and active cancer who also had prior bleed or prior renal disease.

OBJECTIVE: Patients with active cancer and venous thromboembolism (VTE) have elevated risk of recurrent VTE (rVTE) and major bleeding (MB). The risk is even higher within those with a prior bleeding event or renal disease. There is a need to understand the risk of rVTE and MB of commonly used anticoagulants among these high-risk patients. METHODS: VTE patients with active cancer and treated with apixaban, warfarin, or low molecular weight heparin (LMWH) within 30 days of VTE were identified from five claims databases in the United States. Inverse probability of treatment weighting (IPTW) was used to balance patient characteristics. The post-IPTW population was stratified by prior bleed or renal disease status. Cox proportional hazards models were used to evaluate interactions between treatment and prior bleed or renal disease on risk of rVTE and MB, with p value <.1 considered significant. RESULTS: Study criteria were met by 30,586 VTE cancer patients: 35.0% had prior bleed and 29.0% had renal disease. For apixaban, LMWH, and warfarin cohorts, the incidence (events per 100 person-years) of MB was higher in patients with prior bleed (17.48 vs 7.58, 25.61 vs 13.11, and 20.38 vs 8.97) or renal disease (15.79 vs 8.71, 22.11 vs 15.90, and 18.49 vs 10.39) vs those without the conditions. Generally, there were no significant interactions between anticoagulant use and prior bleed or renal disease on rVTE and MB (p for interaction >.1). CONCLUSION: The incidence of MB was higher among those with prior bleed or renal disease. Effects of apixaban, warfarin, or LMWH were generally consistent regardless of prior bleed or renal disease status.

The pharmacokinetics/pharmacodynamics of ceftazidime/avibactam for central nervous system infections caused by carbapenem-resistant Gram-negatives: a prospective study.

OBJECTIVES: To describe the pharmacokinetics/pharmacodynamics (PK/PD) of ceftazidime/avibactam in critically ill patients with CNS infections. METHODS: A prospective study of critically ill patients with CNS infections who were treated with ceftazidime/avibactam and the steady-state concentration (Css) of ceftazidime/avibactam in serum and/or CSF was conducted between August 2020 and May 2023. The relationship between PK/PD goal achievement, microbial eradication and the clinical efficacy of ceftazidime/avibactam was evaluated. RESULTS: Seven patients were finally included. The ceftazidime/avibactam target attainment in plasma was optimal for three, quasi-optimal for one and suboptimal for three. In three patients with CSF drug concentrations measured, ceftazidime/avibactam target attainment in CSF was 100% (3/3), which was optimal. The AUCCSF/serum values were 0.59, 0.44 and 0.35 for ceftazidime and 0.57, 0.53 and 0.51 for avibactam. Of the seven patients, 100% (7/7) were treated effectively, 71.4% (5/7) achieved microbiological eradication, 85.7% (6/7) survived and 14.3% (1/7) did not survive. CONCLUSIONS: The limited clinical data suggest that ceftazidime/avibactam is effective in the treatment of CNS infections caused by MDR Gram-negative bacilli (MDR-GNB), can achieve the ideal drug concentration of CSF, and has good blood-brain barrier penetration.

Effectiveness and safety of anticoagulants among patients with venous thromboembolism and common cancers or cancers with high venous thromboembolism risk.

Aim: Treatment effects among anticoagulant-treated patients with venous thromboembolism (VTE) and cancer across tumor types were evaluated. Methods: Patients initiating an anticoagulant within 30 days after VTE were identified. After inverse probability treatment weighting, patients were stratified by tumor type. Interactions between treatment and tumor type on recurrent VTE, major bleeding and clinically relevant non-major bleeding were assessed using Cox proportional hazard models. Results: Treatment effects were generally not significantly different among patients with or without the following cancer types: prostate, breast, lung, pancreatic or multiple myeloma. Few significant interactions were observed for lung and pancreatic cancer. Conclusion: Anticoagulant treatment effects were generally consistent across tumor types. The significant interactions may indicate tumor-specific effects of anticoagulants, but further research is needed.

A descriptive pharmacokinetic/pharmacodynamic analysis of ceftazidime-avibactam in a case series of critically ill patients with augmented renal clearance.

To describe the pharmacokinetics/pharmacodynamics (PK/PD) of a 2 h infusion of ceftazidime-avibactam (CAZ-AVI) in critically ill patients with augmented renal clearance (ARC). A retrospective review of all critically ill patients with ARC who were treated with CAZ-AVI between August 2020 and May 2023 was conducted. Patients whose 12-h creatinine clearance prior to CAZ-AVI treatment and steady-state concentration (Css) of CAZ-AVI were both monitored were enrolled. The free fraction (fCss) of CAZ-AVI was calculated from Css. The joint PK/PD targets of CAZ-AVI were considered optimal when a Css/minimum inhibitory concentration (MIC) ratio for CAZ ≥4 (equivalent to 100% fT > 4 MIC) and a Css/CT ratio of AVI >1 (equivalent to 100% fT > CT 4.0 mg/L) were reached simultaneously, quasioptimal when only one of the two targets was reached, and suboptimal when neither target was reached. The relationship between PK/PD goal achievement, microbial eradication and the clinical efficacy of CAZ-AVI was evaluated. Four patients were included. Only one patient achieved optimal joint PK/PD targets, while the other three reached suboptimal targets. The patient with optimal PK/PD targets achieved microbiological eradication, while the other three patients did not, but all four patients achieved good clinical efficacy. Standard dosages may not enable most critically ill patients with ARC to reach the optimal joint PK/PD targets of CAZ-AVI. Optimal drug dose adjustment of CAZ-AVI in ARC patients requires dynamic drug concentration monitoring.

The relationship between demographic factors and syncopal symptom in pediatric vasovagal syncope.

This research proposed to retrospectively analyze 20 years of clinical data and investigate the relationship between demographic factors and syncopal symptom in pediatric vasovagal syncope. A total of 2513 children, 1124 males and 1389 females, age range 3-18 years, who presented to Department of Pediatric Cardiovasology, Children's Medical Center, The Second Xiangya Hospital, Central South University with unexplained syncope or pre-syncope and were diagnosed with vasovagal syncope were retrospectively collected and divided into syncope group (n = 1262) and pre-syncope group (n = 1251). (1) Females had a 36% increased risk of syncope compared to males, a 27% increased risk of syncope for every 1-year increase in age, and a 2% decreased risk of syncope for every 1 cm increase in height. (2) A non-linear relationship between age, height, weight and syncope was observed. When age > 10.67 years, the risk of syncope increases by 45% for each 1-year increase in age; when height < 146 cm, the risk of syncope decreases by 4% for each 1 cm increase in height; when weight < 28.5 kg, the risk of syncope decreases by 10% for each 1 kg increase in weight. Demographic factors are strongly associated with syncopal symptom in pediatric vasovagal syncope and can help to predict the risk.

Regulation of fungal raw-starch-degrading enzyme production depends on transcription factor phosphorylation and recruitment of the Mediator complex.

Filamentous fungus can produce raw-starch-degrading enzyme (RSDE) that efficiently degrades raw starch below starch gelatinization temperature. Employment of RSDE in starch processing can save energy. A key putative transcription factor PoxRsrA (production of raw-starch-degrading enzyme regulation in Penicillium oxalicum) was identified to regulate RSDE production in P. oxalicum; however, its regulatory mechanism remains unclear. Here we show that PoxRsrA1434-1730 was the transcriptional activation domain, with essential residues, D1508, W1509 and M1510. SANT (SWI3, ADA2, N-CoR and TFIIIB)-like domain 1 (SANT1) bound to DNA at the sequence 5'-RHCDDGGD-3' in the promoter regions of genes encoding major amylases, with an essential residue, R866. SANT2 interacted with a putative 3-hydroxyisobutyryl-CoA hydrolase, which suppressed phosphorylation at tyrosines Y1127 and Y1170 of PoxRsrA901-1360, thereby inhibiting RSDE biosynthesis. PoxRsrA1135-1439 regulated mycelial sporulation by interacting with Mediator subunit Med6, whereas PoxRsrA1440-1794 regulated RSDE biosynthesis by binding to Med31. Overexpression of PoxRsrA increased sporulation and RSDE production. These findings provide insights into the regulatory mechanisms of fungal RSDE biosynthesis.

Characteristics of hearing loss-associated gene mutations: A multi-center study of 119,606 neonates in Gannan.

BACKGROUND: HL is the second most common congenital disability in China, and its high incidence brings a serious burden of medical and educational sequelae. HL genetic screening enables the identification of individuals with inherited HL and carriers in a large scale. OBJECTIVE: This study aimed to measure the detection rates of hearing loss (HL)-associated gene mutations in the Gannan population. The molecular etiology and risk factors of hereditary HL were also analyzed. METHODS: In total, 119,606 newborns from 18 districts of Gannan were enrolled in this multi-center study conducted between April 2019 and April 2021. Otoacoustic Emission (OAE) was used for primary hearing screening 3 days after birth in quiet conditions, and OAE combined with automated auditory brainstem response (AABR) was applied 29-42 days after birth for those who failed or missed the initial screening. Meanwhile, high-throughput sequencing of hotspot HL-associated mutations in GJB2, GJB3, MTRNR1, and SLC26A4 were performed. RESULTS: Among the 119,606 newborns, 7796 (6.52%) failed the hearing screening. Genetic screening revealed that 5092 neonates (4.26%) carried HL-associated mutations. The detection rate of GJB2, SLC26A4, MTRNR1 and GJB3 mutations were 2.09%, 1.51%, 0.42% and 0.24%, respectively. The most prevalent variant was GJB2 c.235delC (1.74%). The second most prevalent variant was SLC26A4 c.919-2A > G (0.93%). The population who failed the hearing screening had a lower proportion (24.64%) of SLC26A4 gene variants compared to the population who passed (37.46%). Genetic screening identified 4612 (3.86%) carriers who were normal in hearing screenings. The concurrent hearing and genetic screening identified 480 (0.40%) neonates at high risk for hereditary HL. CONCLUSIONS: The results of this study suggest that the concurrent hearing screening and high-throughput genetic screening would greatly improve the effectiveness of newborn HL programs. This integration also facilitates the management of congenital HL, and aids in the prevention of aminoglycoside antibiotics-induced HL.

Improvement of triterpenoid production in mycelia of Antrodia camphorata through mutagenesis breeding and amelioration of CCl4-induced liver injury in mice.

Due to the scarcity of wild fruiting bodies, submerged fermentation of the medicinal fungus Antrodia camphorata is attracting much attention, but the production of bioactive triterpenoids is low. Therefore, there is an urgent need to improve the triterpenoid yield of submerged fermentation. Here, the A. camphorata mutant E3-64 was generated from strain AC16101 through random mutagenesis breeding, producing 172.8 mg triterpenoid per gram of dry mycelia. Further optimization of culture parameters resulted in a yield of 255.5 mg/g dry mycelia (i.e., an additional >1.4-fold increase), which is the highest reported yield thus far. Notably, mutant E3-64 produced 94% and 178% more of the triterpenoid components antcin A and antcamphin A, respectively, while it produced 52% and 15% less antcin B and G, respectively. Mutant E3-64 showed increased expression of key genes involved in triterpenoid biosynthesis, as well as different genome-wide single-nucleotide polymorphisms as compared with AC16101. Triterpenoids of the E3-64 mycelia exhibited remarkably protective activity against acute CCl4-induced liver injury in mice. This study shows the potential of A. camphorata for scientific research and commercial application.

Mid-dosing interval concentration is important for polymyxin B exposure and acute kidney injury in critically ill patients.

This study aimed to evaluate the association between polymyxin B (PMB) exposure and acute kidney injury (AKI) and analyze the risk factors for PMB-induced AKI in critically ill patients. Plasma concentrations of PMB were determined using an ultraperformance liquid chromatography-tandem mass spectrometer in intensive care unit patients who were administered PMB. Univariate and multivariate analyses were conducted to identify risk factors. A receiver operating characteristic curve was constructed to assess the discriminant power of the factors and to identify the cutoff value for AKI. The white blood cell count and estimated area under the concentration-time curve (AUC) of patients administered PMB were independent risk factors for PMB-induced AKI, where AUC were calculated using a first-order pharmacokinetic equation based on the mid-dosing interval concentration (C1/2t ) and peak concentration. The area under the receiver operating characteristic curve of the final model was 0.805 (95% confidence interval, 0.690-0.921). The cutoff value for the combined predictor was 0.57. Alternatively, when using C1/2t , which was strongly correlated with AUC, as the only independent risk factor, the analysis showed that the 3.47 µg/ml threshold provides favorable differentiation between the AKI and non-AKI groups. These results provide insightful information for therapeutic drug monitoring-guiding PMB dosing in clinical practice.

Analysis of Factors Influencing Whole Blood Hydroxychloroquine Concentration in Patients with Systemic Lupus Erythematosus in China.

INTRODUCTION: The aim of this study was to determine the factors associated with the concentrations of hydroxychloroquine (HCQ) and its major metabolite, desethylhydroxychloroquine (DHCQ), in patients with systemic lupus erythematosus (SLE). METHODS: Patients with SLE taking oral HCQ for at least 3 months were recruited from the Department of Rheumatology and Immunology of Nanjing Drum Tower Hospital. Clinical characteristics and laboratory values were examined. The concentrations of HCQ and DHCQ were measured by high-performance liquid chromatography, and the effects of various factors on the concentrations were investigated. RESULTS: A total of 272 patients were included in this study. The average concentration of HCQ was 690.90 ng/ml and the average concentration of DHCQ was 431.84 ng/ml. Multivariate analysis indicated that gender (P = 0.015), age (year) (P < 0.001), weight (kg) (P = 0.013), duration of HCQ use (month) (P < 0.001), systemic lupus erythematosus disease activity index (SLEDAI) (P < 0.001), platelet count (× 109/l) (P < 0.001), immunoglobulin G levels (g/l) (P = 0.014) were associated with low HCQ concentrations. Gender (P = 0.006), duration of HCQ use (month) (P < 0.001), SLEDAI (P = 0.007), and platelet count (× 109/l) (P < 0.001) were associated with low DHCQ concentrations. CONCLUSIONS: Patients with SLE require long-term administration of HCQ, but blood levels vary widely between individuals. Studying the factors influencing the blood HCQ and DHCQ concentrations and optimizing the dose according to individual characteristics might help to improve the efficacy of HCQ. TRIAL REGISTRATION: ChiCTR2300070628.

Next-generation sequencing analysis of the molecular spectrum of thalassemia in Southern Jiangxi, China.

BACKGROUND: Thalassemia is an extremely prevalent monogenic inherited blood disorder in southern China. It is important to comprehensively understand the molecular spectrum of thalassemia in an area with such a high prevalence of thalassemia before taking appropriate actions for the prevention and treatment of this disorder. Herein, we explored the clinical feasibility of using next-generation sequencing (NGS) for large-scale population screening to illustrate the prevalence and spectrum of thalassemia in Southern Jiangxi. METHODS: Blood samples collected from 136,312 residents of reproductive age in Southern Jiangxi were characterized for thalassemia by NGS. A retrospective analysis was then conducted on blood samples determined to be positive for thalassemia. RESULTS: In total, 19,827 (14.545%) subjects were diagnosed as thalassemia carriers, and the thalassemia prevalence rate significantly varied by geographical region (p < 0.001). A total of 40 α-thalassemia genotypes including 21 rare genotypes were identified, with -@-SEA/αα being the most prevalent genotype. 42 ß-thalassemia genotypes including 27 rare genotypes were identified, with the most common mutation IVS II-654 C > T accounting for 35.257% of these ß-thalassemia genotypes. Furthermore, 74 genotypes were identified among 608 individuals with combined α- and ß-thalassemia. Notably, most individuals with rare thalassemia mutations had mildly abnormal hematologic parameters including microcytic hypochromia. CONCLUSIONS: Our findings demonstrate the great heterogeneity and diverse spectrum of thalassemia in Southern Jiangxi, emphasizing the importance and necessity of persistent prevention and control of thalassemia in this region. Additionally, our findings further suggest that NGS can effectively identify rare mutations and reduce the misdiagnosis rate of thalassemia.

Payer formulary tier increases of apixaban: how patients respond and potential implications.

OBJECTIVE: To assess potential impacts of formulary tier increases of apixaban-an efficacious oral anticoagulant (OAC) for preventing stroke in patients with atrial fibrillation (AF)-on patients' prescription drug plan (PDP) switching and OAC treatment patterns. METHODS: Nationwide claims data for Medicare beneficiaries with Parts A, B, and D (100% sample) were used to assess apixaban-treated AF patients who faced a formulary tier increase for apixaban in 2017 by their Part D PDP. Patients' out-of-pocket (OOP) costs for apixaban were described, along with PDP switching and OAC treatment patterns. RESULTS: Among 1845 included patients, 97.7% had apixaban on tier 3 of their plan's formulary in 2016 and faced its increase to tier 4 for 2017. Approximately 4% (N = 81) of patients pre-emptively switched to a different PDP for 2017 with almost all switching to plans with apixaban on a lower formulary tier and 85.2% continuing apixaban treatment. Among the 96% (N = 1764) of patients who remained on the same PDP for 2017, over half (57.5%) continued apixaban treatment, despite increased OOP costs ($54 vs. $135 for a 30-day supply in 2016 vs. 2017). Only 12.4% of those who remained on the same plan for 2017 switched to another OAC, while as much as 30.1% discontinued OACs. These discontinuers exhibited higher comorbidity burdens than patients continuing on any OAC. CONCLUSION: The majority of patients continued on apixaban despite higher OOP cost, suggesting patients' reluctance to change treatment for non-medical reasons; however, 30% of patients discontinued OAC treatment after higher apixaban tier placement.

Arginine methyltransferases PRMT2 and PRMT3 are essential for biosynthesis of plant-polysaccharide-degrading enzymes in Penicillium oxalicum.

Many filamentous fungi produce plant-polysaccharide-degrading enzymes (PPDE); however, the regulatory mechanism of this process is poorly understood. A Gal4-like transcription factor, CxrA, is essential for mycelial growth and PPDE production in Penicillium oxalicum. Its N-terminal region, CxrAΔ207-733 is required for the regulatory functions of whole CxrA, and contains a DNA-binding domain (CxrAΔ1-16&Δ59-733) and a methylated arginine (R) 94. Methylation of R94 is mediated by an arginine N-methyltransferase, PRMT2 and appears to induce dimerization of CxrAΔ1-60. Overexpression of prmt2 in P. oxalicum increases PPDE production by 41.4-95.1% during growth on Avicel, compared with the background strain Δku70;hphR+. Another arginine N-methyltransferase, PRMT3, appears to assist entry of CxrA into the nucleus, and interacts with CxrAΔ1-60 in vitro under Avicel induction. Deletion of prmt3 resulted in 67.0-149.7% enhanced PPDE production by P. oxalicum. These findings provide novel insights into the regulatory mechanism of fungal PPDE production.

Protein arginine methyltransferase 5 (PRMT5) is an actionable therapeutic target in CDK4/6 inhibitor-resistant ER+/RB-deficient breast cancer.

CDK4/6 inhibitors (CDK4/6i) have improved survival of patients with estrogen receptor-positive (ER+) breast cancer. However, patients treated with CDK4/6i eventually develop drug resistance and progress. RB1 loss-of-function alterations confer acquired resistance to CDK4/6i, but the optimal therapy for these patients is unclear. Using a genome-wide CRISPR screen, we identified protein arginine methyltransferase 5 (PRMT5) as a molecular vulnerability in ER+/RB1-knockout (RBKO) breast cancer cells. PRMT5 inhibition blocked cell cycle G1-to-S transition independent of RB, thus arresting growth of RBKO cells. Proteomics analysis uncovered fused in sarcoma (FUS) as a downstream effector of PRMT5. Pharmacological inhibition of PRMT5 resulted in dissociation of FUS from RNA polymerase II (Pol II), Ser2 Pol II hyperphosphorylation, and intron retention in genes that promote DNA synthesis. Treatment with the PRMT5i inhibitor pemrametostat and fulvestrant synergistically inhibited growth of ER+/RB-deficient patient-derived xenografts, suggesting dual ER and PRMT5 blockade as a novel therapeutic strategy to treat ER+/RB-deficient breast cancer.

Finger vein recognition method based on ant colony optimization and improved EfficientNetV2.

Deep learning is an important technology in the field of image recognition. Finger vein recognition based on deep learning is one of the research hotspots in the field of image recognition and has attracted a lot of attention. Among them, CNN is the most core part, which can be trained to get a model that can extract finger vein image features. In the existing research, some studies have used methods such as combination of multiple CNN models and joint loss function to improve the accuracy and robustness of finger vein recognition. However, in practical applications, finger vein recognition still faces some challenges, such as how to solve the interference and noise in finger vein images, how to improve the robustness of the model, and how to solve the cross-domain problem. In this paper, we propose a finger vein recognition method based on ant colony optimization and improved EfficientNetV2, using ACO to participate in ROI extraction, fusing dual attention fusion network (DANet) with EfficientNetV2, and conducting experiments on two publicly available databases, and the results show that the recognition rate using the proposed method on the FV-USM dataset reaches The results show that the proposed method achieves a recognition rate of 98.96% on the FV-USM dataset, which is better than other algorithmic models, proving that the method has good recognition rate and application prospects for finger vein recognition.