Comparative Assessment of the Addictive Potential of Synthetic Cathinones by Zebrafish Conditioned Place Preference (CPP) Paradigm.

Synthetic cathinones have gained increasing popularity in the illicit drug market, yet their abuse potential remains poorly understood. In this study, zebrafish were used to compare the addictive potential of three cathinone analogs, namely pentylone, eutylone, and N-ethylpentylone (NEP). The zebrafish received various doses (0 to 60 mg/kg) of the cathinone analogs by oral gavage over two sessions per day for two consecutive days to induce conditioned place preference (CPP). Pentylone, eutylone, and NEP dose-dependently induced CPP, with NEP showing significantly higher CPP than pentylone and eutylone at the dose of 20 mg/kg. The fish that received 60 mg/kg of cathinones underwent extinction, followed by reinstatement triggered by drug priming. NEP required six sessions to meet the criteria of extinction, followed by eutylone, which required four sessions, and pentylone, which required three sessions. Furthermore, NEP and eutylone at a dose of 40 mg/kg could reinstate the extinguished CPP, while 60 mg/kg of pentylone was necessary for CPP reinstatement. The persistence of susceptibility to reinstatement was also assessed at 7 and 14 days after the initial reinstatement. The CPP induced by all three cathinone analogs could be reinstated 7 days after the initial reinstatement, whereas only CPP induced by NEP, but not pentylone and eutylone, could be reinstated again after 14 days. Considering the potency to induce CPP, resistance to extinction, and the propensity for reinstatement, the abuse liability rank order of the cathinone analogs might be as follows: NEP > eutylone > pentylone. These findings suggest that the zebrafish CPP paradigm can serve as a viable model for assessing the relative abuse liability of substances.

A Single Lung Abscess Caused by Panton-Valentine Leukocidin-Producing Methicillin-Resistant Staphylococcus aureus.

This case report presents a rare occurrence of a single lung abscess caused by Panton-Valentine leukocidin (PVL)-producing methicillin-resistant Staphylococcus aureus (MRSA) in a 38-year-old immunocompetent man. The patient, of Southeast Asian origin, presented with symptoms of fever, chest pain, cough, and shortness of breath following a recent flu-like illness. Imaging indicated a cavitary lung lesion in the left lower lobe, suggestive of a lung abscess. Initial antibiotic treatment failed, and drainage of the abscess confirmed MRSA with the PVL gene, indicating a community-acquired MRSA infection. The patient received intravenous vancomycin followed by oral linezolid, leading to the resolution of the abscess. Contact tracing and decolonization measures were implemented. This case highlights the importance of considering PVL-producing S. aureus as a potential pathogen in severe necrotizing pneumonia or sepsis and underscores the need for prompt diagnosis, appropriate antibiotic therapy, and infection control measures in managing such infections.

Clinical outcomes of carbapenem-resistant gram-negative bacterial bloodstream infection in patients with end-stage renal disease in intensive care units: a multicenter retrospective observational study.

BACKGROUND: Carbapenem-resistant gram-negative bacteria (CRGNB) present a considerable global threat due to their challenging treatment and increased mortality rates, with bloodstream infection (BSI) having the highest mortality rate. Patients with end-stage renal disease (ESRD) undergoing renal replacement therapy (RRT) face an increased risk of BSI. Limited data are available regarding the prognosis and treatment outcomes of CRGNB-BSI in patients with ESRD in intensive care units (ICUs). METHODS: This multi-center retrospective observational study included a total of 149 ICU patients with ESRD and CRGNB-BSI in Taiwan from January 2015 to December 2019. Clinical and microbiological outcomes were assessed, and multivariable regression analysis was used to evaluate the independent risk factors for day-28 mortality and the impact of antimicrobial therapy regimen on treatment outcomes. RESULTS: Among the 149 patients, a total of 127 patients (85.2%) acquired BSI in the ICU, with catheter-related infections (47.7%) and pneumonia (32.2%) being the most common etiologies. Acinetobacter baumannii (49.0%) and Klebsiella pneumoniae (31.5%) were the most frequently isolated pathogens. The day-28 mortality rate from BSI onset was 52.3%, and in-hospital mortality was 73.2%, with survivors experiencing prolonged hospital stays. A higher Sequential Organ Failure Assessment (SOFA) score (adjusted hazards ratio [aHR], 1.25; 95% confidence interval [CI] 1.17-1.35) and shock status (aHR, 2.12; 95% CI 1.14-3.94) independently predicted day-28 mortality. Colistin-based therapy reduced day-28 mortality in patients with shock, a SOFA score of ≥ 13, and Acinetobacter baumannii-related BSI. CONCLUSIONS: CRGNB-BSI led to high mortality in critically ill patients with ESRD. Day-28 mortality was independently predicted by a higher SOFA score and shock status. In patients with higher disease severity and Acinetobacter baumannii-related BSI, colistin-based therapy improved treatment outcomes.

Multisystem inflammatory syndrome in neonates (MIS-N): an updated systematic review.

Introduction: The aim of the study was to summarize and update clinical features and outcomes of multisystem inflammatory syndrome in neonates (MIS-N). Methods: A systematic literature search was conducted of studies on MIS-N published in PubMed, MEDLINE, EMBASE, CNKI, and WHO COVID-19 databases between 1 December 2019 and 30 June 2023. Reference lists of selected articles, Google Scholar, and pre-print servers were searched for additional studies. The methodological quality of included studies was assessed. Results: Of 1,572 records screened after the initial search, 35 studies involving a total of 201 neonates with MIS-N were included. One study was retrieved from a pre-print server. For those with available data, 34/47 (78.7%) mothers were infected in the third trimester. Of the 199 mothers (two with twin pregnancies), 183 (92.0%) were from India. The median age of neonates at presentation was 2.0 days (interquartile range 1.0-9.5). Over two-thirds (144/201, 71.6%) presented with respiratory distress, while 112 (55.7%) had cardiac involvement, such as ventricular dysfunctions, involvement of coronary arteries, and atrioventricular blocks. Arrhythmias and thrombosis were reported in 15/201 (7.5%) and 2/201 (3.0%) neonates, respectively. All neonates, except one, required critical care; 64/160 (40.0%) required inotropic support and 105/187 (56.1%) required respiratory support, of whom 59/105 (56.2%) were specified to require intubation. The mortality rate was 5.0% (10/201). Discussion/Conclusion: MIS-N should be considered in ill neonates presenting with involvement of two or more organ systems, especially among those neonates with cardiorespiratory dysfunctions, in the presence of proven or suspected maternal COVID-19 infection during pregnancy. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021278717, PROSPERO, identifier CRD42021278717.

Kikuchi-Fujimoto disease following SARS-CoV-2 infection: A rare disease with increased incidence during the COVID-19 pandemic?

Kikuchi-Fujimoto Disease (KFD), also known as Kikuchi disease or Kikuchi histiocytic necrotizing lymphadenitis, is a rare and self-limiting condition characterized by cervical lymphadenopathy and fever, primarily affecting young Asian adults. The aetiology of KFD remains unknown, although various infectious agents have been suggested as potential triggers. With the emergence of the COVID-19 pandemic, cases of post-COVID-19 KFD and post-COVID-19 vaccine KFD have been reported. In this article, we present the first case of post-COVID-19 KFD in Hong Kong. A 24-year-old man developed fever and painful neck swelling 1 month after recovering from COVID-19. Diagnostic evaluation, including ultrasound-guided fine needle aspiration cytology (FNAC), confirmed the diagnosis of KFD. The patient's symptoms resolved spontaneously with supportive care. This case underscores the importance of considering KFD as a potential differential diagnosis in patients presenting with cervical lymphadenopathy and fever following COVID-19 recovery or vaccination.

RAB31 drives extracellular vesicle fusion and cancer-associated fibroblast formation leading to oxaliplatin resistance in colorectal cancer.

Epithelial-mesenchymal transition (EMT) is associated with tumorigenesis and drug resistance. The Rab superfamily of small G-proteins plays a role in regulating cell cytoskeleton and vesicle transport. However, it is not yet clear how the Rab family contributes to cancer progression by participating in EMT. By analysing various in silico datasets, we identified a statistically significant increase in RAB31 expression in the oxaliplatin-resistant group compared to that in the parental or other chemotherapy drug groups. Our findings highlight RAB31's powerful effect on colorectal cancer cell lines when compared with other family members. In a study that analysed multiple online meta-databases, RAB31 RNA levels were continually detected in colorectal tissue arrays. Additionally, RAB31 protein levels were correlated with various clinical parameters in clinical databases and were associated with negative prognoses for patients. RAB31 expression levels in all three probes were calculated using a computer algorithm and were found to be positively correlated with EMT scores. The expression of the epithelial-type marker CDH1 was suppressed in RAB31 overexpression models, whereas the expression of the mesenchymal-type markers SNAI1 and SNAI2 increased. Notably, RAB31-induced EMT and drug resistance are dependent on extracellular vesicle (EV) secretion. Interactome analysis confirmed that RAB31/AGR2 axis-mediated exocytosis was responsible for maintaining colorectal cell resistance to oxaliplatin. Our study concluded that RAB31 alters the sensitivity of oxaliplatin, a supplementary chemotherapy approach, and is an independent prognostic factor that can be used in the treatment of colorectal cancer.

Acute Kidney Injury and Subsequent Cardiovascular Disease: Epidemiology, Pathophysiology, and Treatment.

Cardiovascular disease poses a significant threat to individuals with kidney disease, including those affected by acute kidney injury (AKI). In the short term, AKI has several physiological consequences that can impact the cardiovascular system. These include fluid and sodium overload, activation of the renin-angiotensin-aldosterone system and sympathetic nervous system, and inflammation along with metabolic complications of AKI (acidosis, electrolyte imbalance, buildup of uremic toxins). Recent studies highlight the role of AKI in elevating long-term risks of hypertension, thromboembolism, stroke, and major adverse cardiovascular events, though some of this increased risk may be due to the impact of AKI on the course of chronic kidney disease. Current management strategies involve avoiding nephrotoxic agents, optimizing hemodynamics and fluid balance, and considering renin-angiotensin-aldosterone system inhibition or sodium-glucose cotransporter 2 inhibitors. However, future research is imperative to advance preventive and therapeutic strategies for cardiovascular complications in AKI. This review explores the existing knowledge on the cardiovascular consequences of AKI, delving into epidemiology, pathophysiology, and treatment of various cardiovascular complications following AKI.

The impact and risk factors for developing pneumogenic bacteremia in carbapenem-resistant Acinetobacter baumannii nosocomial pneumonia in the intensive care unit: A multicenter retrospective study.

OBJECTIVES: This study analyzed the risk and impact of developing pneumogenic bacteremia in patients with CRAB nosocomial pneumonia in ICU. METHODS: This is multicenter retrospective study. Clinical outcomes were compared between bacteremia and non-bacteremia group, and the risk factors for mortality and developing pneumogenic CRAB bacteremia were analyzed. RESULTS: After patient recruitment, 164 cases were in the bacteremia group, and 519 cases were in the non-bacteremia group. The bacteremia group had 22.4 percentage of increase in-hospital mortality than the non-bacteremia group (68.3% vs 45.9%, P < 0.001). Multivariate analysis showed bacteremia was an independent risk factor for in-hospital mortality (aHR = 2.399, P < 0.001). A long time-interval between ICU admission and pneumonia onset was an independent risk factor for developing bacteremia (aOR = 1.040, P = < 0.001). Spearman's rank correlation analysis indicated a high correlation between the days from ICU admission to pneumonia onset and the days of ventilator use before pneumonia onset (correlation coefficient (ρ) = 0.777). CONCLUSIONS: In patients with CRAB nosocomial pneumonia, bacteremia increased the in-hospital mortality, and a longer interval from ICU admission to pneumonia onset was an independent risk factor for developing bacteremia, which was highly associated with the use of mechanical ventilation.

Early absolute lymphocyte count was associated with one-year mortality in critically ill surgical patients: A propensity score-matching and weighting study.

BACKGROUND: Absolute lymphocyte count (ALC) is a crucial indicator of immunity in critical illness, but studies focusing on long-term outcomes in critically ill patients, particularly surgical patients, are still lacking. We sought to explore the association between week-one ALC and long-term mortality in critically ill surgical patients. METHODS: We used the 2015-2020 critical care database of Taichung Veterans General Hospital (TCVGH), a referral hospital in central Taiwan, and the primary outcome was one-year all-cause mortality. We assessed the association between ALC and long-term mortality by measuring hazard ratios (HRs) with 95% confidence intervals (CIs). Furthermore, we used propensity score-matching and -weighting analyses, consisting of propensity score matching (PSM), inverse probability of treatment weighting (IPTW), and covariate balancing propensity score (CBPS), to validate the association. RESULTS: A total of 8052 patients were enrolled, with their one-year mortality being 24.2%. Cox regression showed that low ALC was independently associated with mortality (adjHR 1.140, 95% CI 1.091-1.192). Moreover, this association tended to be stronger among younger patients, patients with fewer comorbidities and lower severity. The association between low ALC and mortality in original, PSM, IPTW, and CBPS populations were 1.497 (95% CI 1.320-1.697), 1.391 (95% CI 1.169-1.654), 1.512 (95% CI 1.310-1.744), and 1.511 (95% CI 1.310-1.744), respectively. Additionally, the association appears to be consistent, using distinct cutoff levels to define the low ALC. CONCLUSIONS: We identified that early low ALC was associated with increased one-year mortality in critically ill surgical patients, and prospective studies are warranted to confirm the finding.

Long-Term Clinical Outcomes of Acute Kidney Disease in Patients Receiving Extracorporeal Membrane Oxygenation.

INTRODUCTION: Extracorporeal membrane oxygenation (ECMO) is widely used; however, studies on the long-term outcomes of ECMO are scarce. We investigated the long-term clinical outcomes of acute kidney disease (AKD) in patients receiving ECMO. METHODS: Electronic data (2009-2018) were retrospectively collected from a multicenter database. Patients were divided into two groups (AKD and non-AKD) according to their AKD status 8-90 days after the initiation of ECMO. Inverse probability of treatment weighting was used to balance baseline covariates between the two groups. The primary outcomes were major adverse kidney events (MAKEs) and major adverse cardiovascular events (MACEs), and the secondary outcomes were all-cause readmission, sepsis-related readmission, infection-related readmission, and dementia. RESULTS: Totally, 395 patients were eligible for analysis; of them, 160 patients (40.5%) developed AKD. The AKD group had a higher risk of MAKEs (hazard ratio [HR]: 2.06; 95% confidence interval [CI]: 1.68-2.53) than did the non-AKD group. Subgroup analysis revealed that the observed unfavorable effect of AKD on the risk of MAKEs was more pronounced in patients receiving venovenous ECMO than in those receiving venoarterial ECMO (HR: 5.69 vs. 1.85, respectively; p for interaction = 0.004). AKD group had a higher risk of MACE during the initial 3-year post-ECMO in comparison to those without (HR: 1.68; 95% CI: 1.22-2.30). Moreover, the risks of all-cause, sepsis-related, and infection-related readmissions were high in AKD survivors. CONCLUSIONS: AKD is associated with an increased risk of long-term MAKEs and initial 3-year MACE in ECMO recipients. In addition, AKD is associated with increased risks of all-cause, infection-related, and sepsis-related readmissions.

D-optimal Design Optimization of Solvent Mixture for Flavonoid Extraction from Phalaenopsis Leaves with Antioxidant Activity.

Aims: This study aimed to optimize the extraction of flavonoids and antioxidants from Phalaenopsis leaves by using solvent mixtures. Method: The total flavonoid content (TFC) and antioxidant activity were evaluated using the colorimetric method and ferric-reducing antioxidant power (FRAP), respectively. Maceration extracts from fresh leaves were used for the analysis. The study used the Design Expert 13.0 program to optimize the solvents (water, acetone, and methanol) and their combined ratio. Result: The results showed that 100% acetone was the best solvent for both responses, with a desirability value of 0.884, TFC of 0.434 mg QE/g fresh weight (FW) and FRAP of 713.53 µmol TE/g FW. Screening of the most potent Phalaenopsis genotypes for obtaining the most active leaf extract showed that P. amboinensis and P. pantherina were the best genotypes for TFC (0.786-0.797 mg QE/g FW) and FRAP activity (862.25-891.48 µmol TE/g FW). Conclusion: This study demonstrates an easy and useful way to obtain flavonoids and antioxidants from Phalaenopsis materials that can be used in the flower-based industry to make new functional ingredients.

PPAR-γ agonists reactivate the ALDOC-NR2F1 axis to enhance sensitivity to temozolomide and suppress glioblastoma progression.

Glioblastoma (GBM) is a type of brain cancer categorized as a high-grade glioma. GBM is characterized by limited treatment options, low patient survival rates, and abnormal serotonin metabolism. Previous studies have investigated the tumor suppressor function of aldolase C (ALDOC), a glycolytic enzyme in GBM. However, it is unclear how ALDOC regulates production of serotonin and its associated receptors, HTRs. In this study, we analyzed ALDOC mRNA levels and methylation status using sequencing data and in silico datasets. Furthermore, we investigated pathways, phenotypes, and drug effects using cell and mouse models. Our results suggest that loss of ALDOC function in GBM promotes tumor cell invasion and migration. We observed that hypermethylation, which results in loss of ALDOC expression, is associated with serotonin hypersecretion and the inhibition of PPAR-γ signaling. Using several omics datasets, we present evidence that ALDOC regulates serotonin levels and safeguards PPAR-γ against serotonin metabolism mediated by 5-HT, which leads to a reduction in PPAR-γ expression. PPAR-γ activation inhibits serotonin release by HTR and diminishes GBM tumor growth in our cellular and animal models. Importantly, research has demonstrated that PPAR-γ agonists prolong animal survival rates and increase the efficacy of temozolomide in an orthotopic brain model of GBM. The relationship and function of the ALDOC-PPAR-γ axis could serve as a potential prognostic indicator. Furthermore, PPAR-γ agonists offer a new treatment alternative for glioblastoma multiforme (GBM).

Correlating Reiff scores with clinical, functional, and prognostic factors: characterizing noncystic fibrosis bronchiectasis severity: validation from a nationwide multicenter study in Taiwan.

BACKGROUND: Our study aimed to confirm a simplified radiological scoring system, derived from a modified Reiff score, to evaluate its relationship with clinical symptoms and predictive outcomes in Taiwanese patients with noncystic fibrosis bronchiectasis (NCFB). METHODS: This extensive multicenter retrospective study, performed in Taiwan, concentrated on patients diagnosed with NCFB verified through high-resolution computed tomography (HRCT) scans. We not only compared the clinical features of various types of bronchiectasis (cylindrical, varicose, and cystic). Furthermore, we established relationships between the severity of clinical factors, including symptom scores, pulmonary function, pseudomonas aeruginosa colonization, exacerbation and admission rates, and HRCT parameters using modified Reiff scores. RESULTS: Data from 2,753 patients were classified based on HRCT patterns (cylindrical, varicose, and cystic) and severity, assessed by modified Reiff scores (mild, moderate, and severe). With increasing HRCT severity, a significant correlation was found with decreased forced expiratory volume in the first second (FEV1) (p < 0.001), heightened clinical symptoms (p < 0.001), elevated pathogen colonization (pseudomonas aeruginosa) (p < 0.001), and an increased annual hospitalization rate (p < 0.001). In the following multivariate analysis, elderly age, pseudomonas aeruginosa pneumonia, and hospitalizations per year emerged as the only independent predictors of mortality. CONCLUSION: Based on our large cohort study, the simplified CT scoring system (Reiff score) can serve as a useful adjunct to clinical factors in predicting disease severity and prognosis among Taiwanese patients with NCFB.

Recent advances in near-infrared I/II persistent luminescent nanoparticles for biosensing and bioimaging in cancer analysis.

Photoluminescent materials (PLNs) are photoluminescent materials that can absorb external excitation light, store it, and slowly release it in the form of light in the dark to achieve long-term luminescence. Developing near-infrared (NIR) PLNs is critical to improving long-afterglow luminescent materials. Because they excite in vitro, NIR-PLNs have the potential to avoid interference from in vivo autofluorescence in biomedical applications. These materials are promising for biosensing and bioimaging applications by exploiting the near-infrared biological window. First, we discuss the biomedical applications of PLNs in the first near-infrared window (NIR-I, 700-900 nm), which have been widely developed and specifically introduce biosensors and imaging reagents. However, the light in this area still suffers from significant light scattering and tissue autofluorescence, which will affect the imaging quality. Over time, fluorescence imaging technology in the second near-infrared window (NIR-II, 1000-1700 nm) has also begun to develop rapidly. NIR-II fluorescence imaging has the advantages of low light scattering loss, high tissue penetration depth, high imaging resolution, and high signal-to-noise ratio, and it shows broad application prospects in biological analysis and medical diagnosis. This critical review collected and sorted articles from the past 5 years and introduced their respective fluorescence imaging technologies and backgrounds based on the definitions of NIR-I and NIR-II. We also analyzed the current advantages and dilemmas that remain to be solved. Herein, we also suggested specific approaches NIR-PLNs can use to improve the quality and be more applicable in cancer research.

Development of a Weight-Band Dosing Approach for Vosoritide in Children with Achondroplasia Using a Population Pharmacokinetic Model.

BACKGROUND AND OBJECTIVE: Vosoritide is a recently approved therapy for achondroplasia, the most common form of disproportionate short stature, that has been shown to be well tolerated and effective in increasing linear growth. This study aimed to develop a population pharmacokinetic (PPK) model to characterize pharmacokinetics (PK) of vosoritide and establish a weight-band dosing regimen. METHODS: A PPK model was developed using data from five clinical trials in children with achondroplasia (aged 0.95-15 years) who received daily per-kg doses of vosoritide. The model was used to simulate expected exposures in children with a refined weight-band dosing regimen. Simulated exposure was compared with the observed exposure from the pivotal clinical trial to evaluate appropriateness of the weight-band dosing regimen. RESULTS: A one-compartment model with a change-point first-order absorption and first-order elimination accurately described PK of vosoritide in children with achondroplasia. Body weight was found to be a predictor of vosoritide's clearance and volume of distribution. Additionally, it was observed that dosing solution concentration and duration of treatment influenced bioavailability. The weight-band dosing regimen resulted in simulated exposures that were within the range demonstrated to be well tolerated and effective in the pivotal clinical trial and showed improved consistency in drug exposure across the achondroplasia population. CONCLUSIONS: The weight-band dosing regimen reduced the number of recommended dose levels by body weight and is expected to simplify dosing for children with achondroplasia and their caregivers. CLINICAL TRIAL REGISTRATION: NCT02055157, NCT02724228, NCT03197766, NCT03424018, and NCT03583697.

Calcium channel inhibitor and extracellular calcium improve aminoglycoside-induced hair cell loss in zebrafish.

Aminoglycosides are commonly used antibiotics for treatment of gram-negative bacterial infections, however, they might act on inner ear, leading to hair-cell death and hearing loss. Currently, there is no targeted therapy for aminoglycoside ototoxicity, since the underlying mechanisms of aminoglycoside-induced hearing impairments are not fully defined. This study aimed to investigate whether the calcium channel blocker verapamil and changes in intracellular & extracellular calcium could ameliorate aminoglycoside-induced ototoxicity in zebrafish. The present findings showed that a significant decreased number of neuromasts in the lateral lines of zebrafish larvae at 5 days' post fertilization after neomycin (20 µM) and gentamicin (20 mg/mL) exposure, which was prevented by verapamil. Moreover, verapamil (10-100 µM) attenuated aminoglycoside-induced toxic response in different external calcium concentrations (33-3300 µM). The increasing extracellular calcium reduced hair cell loss from aminoglycoside exposure, while lower calcium facilitated hair cell death. In contrast, calcium channel activator Bay K8644 (20 µM) enhanced aminoglycoside-induced ototoxicity and reversed the protective action of higher external calcium on hair cell loss. However, neomycin-elicited hair cell death was not altered by caffeine, ryanodine receptor (RyR) agonist, and RyR antagonists, including thapsigargin, ryanodine, and ruthenium red. The uptake of neomycin into hair cells was attenuated by verapamil and under high external calcium concentration. Consistently, the production of reactive oxygen species (ROS) in neuromasts exposed to neomycin was also reduced by verapamil and high external calcium. Significantly, zebrafish larvae when exposed to neomycin exhibited decreased swimming distances in reaction to droplet stimulus when compared to the control group. Verapamil and elevated external calcium effectively protected the impaired swimming ability of zebrafish larvae induced by neomycin. These data imply that prevention of hair cell damage correlated with swimming behavior against aminoglycoside ototoxicity by verapamil and higher external calcium might be associated with inhibition of excessive ROS production and aminoglycoside uptake through cation channels. These findings indicate that calcium channel blocker and higher external calcium could be applied to protect aminoglycoside-induced listening impairments.

Lower body mass index is an independent predictor of mortality in older patients with acute respiratory distress syndrome.

Background: Acute respiratory distress syndrome (ARDS) is associated with high mortality. The impacts of body mass index (BMI) on the morality of older patients with ARDS remain unclear. Methods: This is a single-center cohort study which was conducted at Taichung Veterans General Hospital, Taiwan. Adult patients admitted to the ICU needing mechanical ventilation with ARDS were included for analysis. We compared the data of older patients (age ≥65 years) with those of younger patients (Age <65 years). The factors associated with in-hospital mortality of older patients were investigated. Results: This study included a total of 728 (mean age: 66 years; men: 63%) patients, and 425 (58.4%) of them aged ≥65 years. Older patients exhibited lower body mass index (BMI) (23.8 vs 25.2), higher Acute Physiology and Chronic Health Evaluation (APACHE) II scores (28.9 vs 26.3), higher Charlson Comorbidity Index (CCI) (4.0 vs 3.4), and lower Sequential Organ Failure Assessment (SOFA) scores (10.0 vs 11.1) than younger patients. Furthermore, older patients had mortality rates similar to younger patients (40.5% vs 42.9%, P = 0.542), but had longer length of stay in the ICU (17.6 vs 15.6 days, P = 0.047). For older patients, BMI <18.5 (odds ratio [OR], 2.78; 95% confidence interval [CI], 1.45-5.34), high SOFA score (OR, 1.20; 95% CI, 1.12-1.28), and moderate (OR, 1.95; 95% CI 1.20-3.14) or severe ARDS (OR, 2.30; 95% CI 1.26-4.22) were independent risk factors for mortality. Conclusions: In this cohort, critical ill older patients with ARDS had lower BMI, more comorbidities, and higher APACHE II scores than younger patients. Mortality rate was similar between older and younger patients. Low BMI, high SOFA score, and moderate or severe ARDS were independently associated with mortality in older patients with ARDS.

Discovery and Preclinical Pharmacology of NX-2127, an Orally Bioavailable Degrader of Bruton's Tyrosine Kinase with Immunomodulatory Activity for the Treatment of Patients with B Cell Malignancies.

Bruton's tyrosine kinase (BTK), a member of the TEC family of kinases, is an essential effector of B-cell receptor (BCR) signaling. Chronic activation of BTK-mediated BCR signaling is a hallmark of many hematological malignancies, which makes it an attractive therapeutic target. Pharmacological inhibition of BTK enzymatic function is now a well-proven strategy for the treatment of patients with these malignancies. We report the discovery and characterization of NX-2127, a BTK degrader with concomitant immunomodulatory activity. By design, NX-2127 mediates the degradation of transcription factors IKZF1 and IKZF3 through molecular glue interactions with the cereblon E3 ubiquitin ligase complex. NX-2127 degrades common BTK resistance mutants, including BTKC481S. NX-2127 is orally bioavailable, exhibits in vivo degradation across species, and demonstrates efficacy in preclinical oncology models. NX-2127 has advanced into first-in-human clinical trials and achieves deep and sustained degradation of BTK following daily oral dosing at 100 mg.

TALE-based organellar genome editing and gene expression in plants.

KEY MESSAGE: TALE-based editors provide an alternative way to engineer the organellar genomes in plants. We update and discuss the most recent developments of TALE-based organellar genome editing in plants. Gene editing tools have been widely used to modify the nuclear genomes of plants for various basic research and biotechnological applications. The clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 editing platform is the most commonly used technique because of its ease of use, fast speed, and low cost; however, it encounters difficulty when being delivered to plant organelles for gene editing. In contrast, protein-based editing technologies, such as transcription activator-like effector (TALE)-based tools, could be easily delivered, expressed, and targeted to organelles in plants via Agrobacteria-mediated nuclear transformation. Therefore, TALE-based editors provide an alternative way to engineer the organellar genomes in plants since the conventional chloroplast transformation method encounters technical challenges and is limited to certain species, and the direct transformation of mitochondria in higher plants is not yet possible. In this review, we update and discuss the most recent developments of TALE-based organellar genome editing in plants.

Advancing anti-oppression and social justice in healthcare through competency-based medical education (CBME).

Competency-based medical education (CBME) focuses on preparing physicians to improve the health of patients and populations. In the context of ongoing health disparities worldwide, medical educators must implement CBME in ways that advance social justice and anti-oppression. In this article, authors describe how CBME can be implemented to promote equity pedagogy, an approach to education in which curricular design, teaching, assessment strategies, and learning environments support learners from diverse groups to be successful. The five core components of CBME programs - outcomes competency framework, progressive sequencing of competencies, learning experiences tailored to learners' needs, teaching focused on competencies, and programmatic assessment - enable individualization of learning experiences and teaching and encourage learners to partner with their teachers in driving their learning. These educational approaches appreciate each learner's background, experiences, and strengths. Using an exemplar case study, the authors illustrate how CBME can afford opportunities to enhance anti-oppression and social justice in medical education and promote each learner's success in meeting the expected outcomes of training. The authors provide recommendations for individuals and institutions implementing CBME to enact equity pedagogy.