Development of IL-17A inhibitor-induced atopic dermatitis-like rash in psoriasis patients: Insights into immune shift.

Cases of atopic dermatitis (AD)-like rash induced by IL-17A inhibitor secukinumab treatment (SI-AD) have been recently reported in psoriasis patients. To identify immune and inflammatory factors expression in SI-AD. A panel of 15 immune and inflammatory factors in peripheral blood samples from various groups, including patients with patients with SI-AD, psoriasis with secukinumab (S-stable), advanced psoriasis patients (Advanced) and healthy controls (HC). Interleukin-10 (IL-10), IL-4 and IL-17A were detected in skin tissue biopsy samples by immunohistochemistry and real-time quantitative polymerase chain reaction. The immunoglobulin E levels in the SI-AD patients exceeded normal values. The IL-10 levels in SI-AD patients were higher than those in S-stable patients, advanced patients and HC. The IL-4 levels in SI-AD patients were higher than that in S-stable patients and HC. The IL-17A levels in SI-AD patients were higher than those in advanced psoriasis patients and HC, but no significant differences were observed between SI-AD patients and S-stable patients. IL-10 and IL-4 levels were higher in AD-like rashes than in healthy skin, while IL-17A did not differ significantly between the two. Upon discontinuing secukinumab, and switching to oral cyclosporine, antihistamines, Janus kinase 1 inhibitor and topical glucocorticoids, SI-AD patients experienced significant improvement in their skin lesions. Upon reexamination, all 15 immune and inflammatory factors returned to normal levels. Immune shift from Th17 towards Th2 may occur in SI-AD, as indicated by abnormal expression of multiple immune and inflammatory factors observed in peripheral blood and skin tissues.

Biologics initiation in moderate versus severe rheumatoid arthritis: real-world experience from a Canadian registry.

OBJECTIVES: To evaluate the treat-to-target experience, and quality of life measures of moderate and severe rheumatoid arthritis (RA) patients initiating a biologic in a real-world setting of a publicly funded payer system. METHODS: Biologic naive RA patients who had initiated their first biologic while enrolled in the Ontario Best Practices Research Initiative registry from 2008 to 2020 were selected if they had moderate (DAS28 >3.2 to ≤5.1) or severe (DAS28 >5.1) RA. Remission, LDA, DAS28, HAQ-DI, fatigue, sleep, drug persistence and characteristics associated with remission were assessed at 12 months post biologic initiation. RESULTS: Overall, 838 patients initiated their first biologic, 264 had moderate RA and 219 had severe RA. After 12 months, 44% moderate RA vs. 21% severe RA achieved remission (p<0.0001), and 59% moderate RA vs. 35% severe RA reached LDA (p<0.0001). Mean change (SD) from baseline in DAS28 was 2.2 (1.5) in severe RA vs. 1.4 (1.3) in moderate RA (p<0.0001), in fatigue score was 1.11 (3.2) in severe RA vs. 0.98 (3.2) in moderate RA (p<0.0001). Moderate disease at a biologic initiation was positively associated with remission (p=0.0016). Female gender (p=0.0170), and a higher HAQ-DI score at baseline (p=0.0042) were negatively associated with remission. Biologic persistence was 77% for moderate, and 73% for severe (p=0.2444). CONCLUSIONS: Severe RA patients had higher mean score improvements in DAS28, sleep and fatigue. Moderate RA was more likely to reach remission or LDA. Both groups had similar biologic persistence at 12 months. These findings highlight the importance of the treat-to-target approach and its potential underutilisation in the real-world setting.

Impact of early rehabilitation therapy on functional outcomes in patients post distal radius fracture surgery: a systematic review and meta-analysis.

BACKGROUND: This meta-analysis aims to investigate the efficacy of early rehabilitation on patients who have undergone surgery for distal radius fractures (DRFs) with palmar plating, focusing on multiple outcome measures including upper limb function, wrist function, back extension mobility, pain levels, and complications. METHODS: A rigorous search strategy adhering to the PRISMA guidelines was employed across four major databases, including PubMed, Embase, Web of Science, and the Cochrane Library. Studies were included based on stringent criteria, and data extraction was performed independently by two reviewers. Meta-analysis was conducted employing both fixed-effect and random-effects models as dictated by heterogeneity, assessed by the I2 statistic and chi-square tests. A total of 7 studies, encompassing diverse demographic groups and timelines, were included for the final analysis. RESULTS: The meta-analysis disclosed that early rehabilitation yielded a statistically significant improvement in upper limb function (SMD -0.27; 95% CI -0.48 to -0.07; P < 0.0001) and back extension mobility (SMD 0.26; 95% CI 0.04 to 0.48; P = 0.021). A notable reduction in pain levels was observed in the early rehabilitation group (SMD -0.28; 95% CI -0.53 to -0.02; P = 0.03). However, there were no significant differences in wrist function (SMD -0.13; 95% CI -0.38 to 0.12; P = 0.36) and complications (OR 0.99; 95% CI 0.61 to 1.61; P = 0.96). CONCLUSIONS: Early rehabilitation post-DRF surgery with palmar plating has been found to be beneficial in enhancing upper limb functionality and back extension mobility, and in reducing pain levels. Nevertheless, no significant impact was observed regarding wrist function and complications.

Metagenomic Next-Generation Sequencing as an Effective Diagnostic Tool for Talaromycosis in HIV-Negative Patients.

The diagnosis of Talaromyces marneffei infection in HIV-negative patients remains challenging. There is an urgent need for rapid and convenient methods to diagnose this complicated disease. The aim of this study was to evaluate the diagnostic efficiency of metagenomic next-generation sequencing (mNGS) for talaromycosis in non-HIV-infected patients by comparing mNGS with traditional microbial culture. In total, 66 samples from 57 patients were analyzed via both mNGS and microbial culture. The ROC curve showed a sensitivity for mNGS of 97.22%, which was greater than that of microbial culture (61.11%). Samples from the respiratory tract, infectious skin lesions, and lymph nodes are recommended as routine samples for talaromycosis detection via mNGS. Furthermore, mNGS significantly reduced the diagnostic time compared to microbial culture. Overall, our study demonstrated that mNGS is a promising tool for rapid and accurate pathogenic detection in HIV-negative patients with talaromycosis.

FBXL19 Targeted STK11 Degradation Enhances Cigarette Smoke-Induced Airway Epithelial Cell Cytotoxicity.

Objective: To investigate the effects of cigarette smoke (CS) on Serine/Threonine Kinase 11 (STK11) and to determine STK11's role in CS-induced airway epithelial cell cytotoxicity.Methods: STK11 expression levels in the lung tissues of smokers with or without COPD and mice exposed to CS or room air (RA) were determined by immunoblotting and RT-PCR. BEAS-2Bs-human bronchial airway epithelial cells were exposed to CS extract (CSE), and the changes in STK11 expression levels were determined by immunoblotting and RT-PCR. BEAS-2B cells were transfected with STK11-specific siRNA or STK11 expression plasmid, and the effects of CSE on airway epithelial cell cytotoxicity were measured. To determine the specific STK11 degradation-proteolytic pathway, BEAS-2Bs were treated with cycloheximide alone or combined with MG132 or leupeptin. Finally, to identify the F-box protein mediating the STK11 degradation, a screening assay was performed using transfection with a panel of FBXL E3 ligase subunits.Results: STK11 protein levels were significantly decreased in the lung tissues of smokers with COPD relative to smokers without COPD. STK11 protein levels were also significantly decreased in mouse lung tissues exposed to CS compared to RA. Exposure to CSE shortened the STK11 mRNA and protein half-life to 4 h in BEAS-2B cells. STK11 protein overexpression attenuated the CSE-induced cytotoxicity; in contrast, its knockdown augmented CSE-induced cytotoxicity. FBXL19 mediates CSE-induced STK11 protein degradation via the ubiquitin-proteasome pathway in cultured BEAS-2B cells. FBXL19 overexpression led to accelerated STK11 ubiquitination and degradation in a dose-dependent manner.Conclusions: Our results suggest that CSE enhances the degradation of STK11 protein in airway epithelial cells via the FBXL19-mediated ubiquitin-proteasomal pathway, leading to augmented cell death.HIGHLIGHTSLung tissues of COPD-smokers exhibited a decreased STK11 RNA and protein expression.STK11 overexpression attenuates CS-induced airway epithelial cell cytotoxicity.STK11 depletion augments CS-induced airway epithelial cell cytotoxicity.CS diminishes STK11 via FBXL19-mediated ubiquitin-proteasome degradation.

Cigarette smoking is a secondary cause of folliculin loss.

BACKGROUND: Birt-Hogg-Dubé syndrome (BHD) is a clinical syndrome manifesting with cystic lung disease and pneumothorax. Features of BHD result from the loss-of-function mutations of the folliculin (FLCN) gene. Chronic obstructive pulmonary disease (COPD), characterised by an irreversible airflow limitation, is primarily caused by cigarette smoking. OBJECTIVE: Given that COPD often shares structural features with BHD, we investigated the link between COPD, cigarette smoke (CS) exposure and FLCN expression. METHODS: We measured the expression of FLCN in human COPD lungs and CS-exposed mouse lungs, as well as in CS extract (CSE)-exposed immortalised human airway epithelial cells by immunoblotting. RESULTS: We found that the lung FLCN protein levels in smokers with COPD and CS exposure mice exhibit a marked decrease compared with smokers without COPD and room air exposure mice, respectively. We confirmed CS induced degradation of FLCN in immortalised human bronchial epithelial Beas-2B cells via ubiquitin proteasome system. Further, siRNA targeting FLCN enhanced CSE-induced cytotoxicity. By contrast, FLCN overexpression protected cells from CSE-induced cytotoxicity. We found that FBXO23, the ubiquitin E3 ligase subunit, specifically binds to and targets FLCN for degradation. Inhibition of ATM (ataxia-telangiectasia mutated) attenuated CSE induced FLCN degradation, suggesting a role of ATM in FLCN proteolysis. We further confirmed that the mutant of major FLCN phosphorylation site serine 62A is resistant to CSE-induced degradation and cytotoxicity. CONCLUSIONS: Our study demonstrates that CS exposure is a secondary cause of FLCN deficiency due to the enhanced proteolysis, which promoted airway epithelial cell death.

Protein arginine N-methyltransferase 4 (PRMT4) contributes to lymphopenia in experimental sepsis.

BACKGROUND: One hallmark of sepsis is the reduced number of lymphocytes, termed lymphopenia, that occurs from decreased lymphocyte proliferation or increased cell death contributing to immune suppression. Histone modification enzymes regulate immunity by their epigenetic and non-epigenetic functions; however, the role of these enzymes in lymphopenia remains elusive. METHODS: We used molecular biological approaches to investigate the high expression and function of a chromatin modulator protein arginine N-methyltransferase 4 (PRMT4)/coactivator-associated arginine methyltransferase 1 in human samples from septic patients and cellular and animal septic models. RESULTS: We identified that PRMT4 is elevated systemically in septic patients and experimental sepsis. Gram-negative bacteria and their derived endotoxin lipopolysaccharide (LPS) increased PRMT4 in B and T lymphocytes and THP-1 monocytes. Single-cell RNA sequencing results indicate an increase of PRMT4 gene expression in activated T lymphocytes. Augmented PRMT4 is crucial for inducing lymphocyte apoptosis but not monocyte THP-1 cells. Ectopic expression of PRMT4 protein caused substantial lymphocyte death via caspase 3-mediated cell death signalling, and knockout of PRMT4 abolished LPS-mediated lymphocyte death. PRMT4 inhibition with a small molecule compound attenuated lymphocyte death in complementary models of sepsis. CONCLUSIONS: These findings demonstrate a previously uncharacterised role of a key chromatin modulator in lymphocyte survival that may shed light on devising therapeutic modalities to lessen the severity of septic immunosuppression.

Dehalogenimonas etheniformans sp. nov., a formate-oxidizing, organohalide-respiring bacterium isolated from grape pomace.

A strictly anaerobic, organohalide-respiring bacterium, designated strain GPT, was characterized using a polyphasic approach. GPT is Gram-stain-negative, non-spore-forming and non-motile. Cells are irregular cocci ranging between 0.6 and 0.9 µm in diameter. GPT couples growth with the reductive dechlorination of 1,2-dichloroethane, vinyl chloride and all polychlorinated ethenes, except tetrachloroethene, yielding ethene and inorganic chloride as dechlorination end products. H2 and formate serve as electron donors for organohalide respiration in the presence of acetate as carbon source. Major cellular fatty acids include C16 : 0, C18 : 1ω9c, C16 : 1, C14 : 0 and C18 : 0. On the basis of 16S rRNA gene phylogeny, GPT is most closely related to Dehalogenimonas formicexedens NSZ-14T and Dehalogenimonas alkenigignens IP3-3T with 99.8 and 97.4 % sequence identities, respectively. Genome-wide pairwise comparisons based on average nucleotide identity, average amino acid identity and digital DNA-DNA hybridization do not support the inclusion of GPT in previously described species of the genus Dehalogenimonas with validly published names. On the basis of phylogenetic, physiological and phenotypic traits, GPT represents a novel species within the genus Dehalogenimonas, for which the name Dehalogenimonas etheniformans sp. nov. is proposed. The type strain is GPT (= JCM 39172T = CGMCC 1.17861T).

Meta-analysis of the prognostic value of soluble programmed death ligand-1 (sPD-L1) in cancers.

BACKGROUND: The soluble programmed death ligand-1 (sPD-L1) and its prognostic role in cancers have been investigated in numerous studies. However, due to the inconsistency on some findings, this meta-analysis was performed to assess the prognostic value of sPD-L1 in patients with cancer. METHODS: We searched the PubMed, Web of Science, MEDLINE, Wiley Online Library and ScienceDirect, and screened the studies for eligibility. Recurrence-free survival (RFS), progression-free survival (PFS) and disease-free survival (DFS) were for short term survival. The overall survival (OS) was for long term survival. RESULTS: Forty studies with 4441 patients were included in this meta-analysis. Elevated sPD-L1 was associated with short OS [HR = 2.44 (2.03-2.94), p = 0.000]. Moreover, a high sPD-L1 was predictive of worse DFS/RFS/PFS [HR = 2.52 (1.83-3.44), p = 0.000]. In addition, high sPD-L1 was consistently correlated with poor OS in irrespective of study type, univariate and multivariate analysis, ethnicity, cut-off value of sPD-L1, sample and treatment. In the subgroup analysis, high sPD-L1 was correlated with poor OS in gastrointestinal cancer, lung cancer, hepatic cancer, oesophageal cancer and clear cell renal cell carcinoma. CONCLUSIONS: The present meta-analysis showed that a high level of sPD-L1 was associated with worse prognosis in some types of cancer.

Medical cannabis use by rheumatology patients in routine clinical care: results from The Ontario Best Practices Research Initiative.

OBJECTIVES: Medical cannabis is often used to alleviate common symptoms in patients with chronic conditions. With cannabis legalisation in Canada and easier access, it is important that rheumatologists understand its potential impact on their practice. Among patients attending rheumatology clinics in Ontario we assessed: the prevalence of medical cannabis use; symptoms treated; rheumatologists' perceptions. METHODS: Eight rheumatology clinics recruited consecutive adult patients in a 3-part medical cannabis survey: the first completed by rheumatologists; the second by all patients; the third by medical cannabis users. Student's t-test and Chi-square test were used to compare medical cannabis users to never users. RESULTS: 799 patients participated, 163 (20.4%) currently using medical cannabis or within <2 years and 636 never users; most had rheumatoid arthritis (37.8%) or osteoarthritis (34.0%). Compared to never users, current/past-users were younger; more likely to be taking opioids/anti-depressants, have psychiatric/gastrointestinal disorders, and have used recreational cannabis (p<0.05); had higher physician (2.9 vs. 2.1) and patient (6.0 vs. 4.2) global scores, and pain (6.2 vs. 4.7) (p<0.0001). Pain (95.5%), sleeping (82.3%) and anxiety (58.9%) were the most commonly treated symptoms; 78.2% of current/past-users reported medical cannabis was at least somewhat effective. Most rheumatologists reported being uncomfortable to authorise medical cannabis, primarily due to lack of evidence, knowledge, and product standardisation. CONCLUSIONS: Medical cannabis use among rheumatology patients in Ontario was two-fold higher than that reported for the general population of similar age. Use was associated with more severe disease, pain, and prior recreational use. Reported lack of research, knowledge, and product standardisation were barriers for rheumatologist use authorisation.

Biohydrogenation of 1,3-Butadiene to 1-Butene under Acetogenic Conditions by Acetobacterium wieringae.

The environmental fate and transformation mechanism(s) of 1,3-butadiene (BD) under anoxic conditions remain largely unexplored. Anaerobic consortia that can biohydrogenate BD to stoichiometric amounts of 1-butene at a maximum rate of 205.7 ± 38.6 µM day-1 were derived from freshwater river sediment. The formation of 1-butene occurred only in the presence of both H2 and CO2 with concomitant acetate production, suggesting the dependence of BD biohydrogenation on acetogenesis. The 16S rRNA gene-targeted amplicon sequencing revealed the enrichment and dominance of a novel Acetobacterium wieringae population, designated as strain N, in the BD-biohydrogenating community. Multiple genes encoding putative ene-reductases, candidate catalysts for the hydrogenation of the C═C bond in diene compounds, were annotated on the metagenome-assembled genome of strain N, and thus attributed the BD biohydrogenation activity to strain N. Our findings emphasize an essential but overlooked role of certain Acetobacterium members (e.g., strain N) contributing to the natural attenuation of BD in contaminated subsurface environments (e.g., sediment and groundwater). Future efforts to identify and characterize the ene-reductase(s) responsible for BD biohydrogenation in strain N hold promise for the development of industrial biocatalysts capable of stereoselective conversion of BD to 1-butene.

Apophysomyces variabilis as an emerging pathogen in Mainland China.

BACKGROUND: Mucormycosis is a rare form of invasive, rapidly progressive and lethal opportunistic fungal infection caused by Mucorales. Although Rhizopus arrhizus (R. arrhizus) is the most commonly isolated Mucorales worldwide, infections caused by Apophysomyces variabilis (A. variabilis) are increasing. OBJECTIVES AND METHODS: We present a case of necrotizing fasciitis caused by A. variabilis in an immunocompetent woman. In order to further understand the characteristics of the strain isolated from the patient, we identified the strain through ITS sequencing, assessed the ability to tolerate salt concentrations and temperature conditions, in addition to performing in vitro drug susceptibility testing against common antifungal agents. RESULTS: The strain showed 98.76% identity with A. variabilis in the NCBI database, and it was found to tolerate higher temperatures and salt concentrations than previously reported strains. The strain was sensitive to amphotericin B and posaconazole, but not to voriconazole, itraconazole, 5-fluorocytosine and echinocandins. CONCLUSIONS: This case indicates that Mucorales caused by A. variabilis should be recognised as an emerging pathogen that can cause a high mortality rate in the absence of prompt diagnosis and proper treatment in China, aggressive surgical debridement combined with prompt and appropriate antifungal treatment may improve outcomes.

An Access Control Scheme Based on Blockchain and Ciphertext Policy-Attribute Based Encryption.

Ciphertext policy-attribute-based encryption (CP-ABE), which provides fine-grained access control and ensures data confidentiality, is widely used in data sharing. However, traditional CP-ABE schemes often choose to outsource data to untrusted third-party cloud service providers for storage or to verify users' access rights through third parties, which increases the risk of privacy leakage and also suffers from the problem of opaque permission verification. This paper proposes an access control scheme based on blockchain and CP-ABE, which is based on multiple authorization centers and supports policy updating. In addition, blockchain technology's distributed, decentralized, and tamper-proof features are utilized to solve the trust crisis problem in the data-sharing process. Security analysis and performance evaluation show that the proposed scheme improves the computational efficiency by 18%, 26%, and 68% compared to previous references. The proposed scheme also satisfies the indistinguishability under chosen-plaintext attack (IND-CPA).

ApoE-modified liposomes encapsulating resveratrol and salidroside alleviate manifestations of Alzheimer's disease in APP/PS-1 mice.

OBJECTIVE: Alzheimer's disease (AD) is a neurodegenerative disease that is associated with aging and is influenced by both genetic and environmental factors. Several studies and clinical trials have demonstrated that resveratrol (Res) and salidroside (Sal) are not only biologically safe but also influence AD biomarker trajectories. However, their clinical applications have been quite limited due to poor specificity, low solubility, and insufficient blood-brain barrier (BBB) penetration. Therefore, we developed a nano-drug delivery system in which Res and Sal were encapsulated in liposomes, which were surface-modified with ApoE (ApoE-Res/Sal-Lips) to compensate for these deficiencies. METHOD: In this study, ApoE-Res/Sal-Lips were prepared using a standard thin-film hydration method for liposomes. Then, cellular uptake of the loaded liposomes was assessed in vitro using fluorescent staining assays. A BBB model was constructed to investigate the capacity of the liposomes to cross the BBB in vitro, and the ability of liposomes to target the brain was observed by in vivo imaging. In addition, the neuroprotective effects of the different liposome formulations in APP/PS-1 mice were evaluated by measuring the changes in levels of oxidative, anti-inflammatory, and anti-apoptotic factors in the mice brains. RESULTS: In vitro, ApoE-Res/Sal-Lips increased the uptake of Res and Sal by bEnd.3 and N2a cells, enhanced BBB penetration, and improved transport efficiency. In vivo, the ApoE-Res/Sal-Lips were found to alleviate AD pathological symptoms, reduce learning and memory impairments, and improve brain function. CONCLUSION: ApoE-Res/Sal-Lips provide a new method for the treatment of AD.

Multiple stimulus-response berberine plus baicalin micelles with particle size-charge-release triple variable properties for breast cancer therapy.

OBJECTIVE: The aim was to develop a nanoscale drug delivery system with enzyme responsive and acid sensitive particle size and intelligent degradation aiming to research the inhibitory effect on breast cancer. SIGNIFICANCE: The delivery system addressed the problems of tissue targeting, cellular internalization, and slow drug release at the target site, which could improve the efficiency of drug delivery and provide a feasible therapeutic approach for breast cancer. METHODS: The acid sensitive functional material DSPE-PEG2000-dyn-PEG-R9 was synthesized by Michael addition reaction. Then, the berberine plus baicalin intelligent micelles were prepared by thin-film hydration. Subsequently, we characterized the physical and chemical properties of berberine plus baicalin intelligent micelles, evaluated its anti-tumor effects in vivo and in vitro. RESULTS: The target molecule was successfully synthesized, and the intelligent micelles showed excellent chemical and physical properties, delayed drug release and high encapsulation efficiency. In vitro and in vivo experiments also confirmed that the intelligent micelles could effectively target tumor sites, penetrate tumor tissues, enrich in tumor cells, inhibit tumor cell proliferation, inhibit tumor cell invasion and migration, and induce tumor cell apoptosis. CONCLUSION: Berberine plus baicalin intelligent micelles have excellent anti-tumor effects and no toxicity to normal tissues, which provides a new potential drug delivery strategy for the treatment of breast cancer.

Organohalide Respiration with Diclofenac by Dehalogenimonas.

Diclofenac (DCF) is a pharmaceutically active contaminant frequently found in aquatic ecosystems. The transformation pathways and microbiology involved in the biodegradation of DCF, particularly under anoxic conditions, remain poorly understood. Here, we demonstrated microbially mediated reductive dechlorination of DCF in anaerobic enrichment culture derived from contaminated river sediment. Over 90% of the initial 76.7 ± 3.6 µM DCF was dechlorinated at a maximum rate of 1.8 ± 0.3 µM day-1 during a 160 days' incubation. Mass spectrometric analysis confirmed that 2-(2-((2-chlorophenyl)amino)phenyl)acetic acid (2-CPA) and 2-anilinophenylacetic acid (2-APA) were formed as the monochlorinated and nonchlorinated DCF transformation products, respectively. A survey of microbial composition and Sanger sequencing revealed the enrichment and dominance of a new Dehalogenimonas population, designated as Dehalogenimonas sp. strain DCF, in the DCF-dechlorinating community. Following the stoichiometric conversion of DCF to 2-CPA (76.0 ± 2.1 µM) and 2-APA (3.7 ± 0.8 µM), strain DCF cell densities increased by 24.4 ± 4.4-fold with a growth yield of 9.0 ± 0.1 × 108 cells per µmol chloride released. Our findings expand the metabolic capability in the genus Dehalogenimonas and highlight the relevant roles of organohalide-respiring bacteria for the natural attenuation of halogenated contaminants of emerging concerns (e.g., DCF).

Impact of proton pump inhibitor management committee's multifaceted interventions on acid suppressant prescribing patterns in outpatient and emergency departments.

BACKGROUND: A nationwide campaign for rational proton pump inhibitor (PPI) use launched in 2015 had a positive impact for hospitalized patients PPI use. But there were few studies focusing on the rational use of PPIs in outpatients. In 2018, the PPI management committee conducted a year-long intervention on the appropriate use of PPIs in outpatient and emergency departments, including clinical pharmacist interventions and stewardship interventions. The purpose of this study was to examine the impact of the PPI management committee's multifaceted interventions by comparing the real-world acid suppressant prescribing patterns for outpatients before (2017) and after intervention (2019) at a Chinese tertiary teaching hospital. METHODS: Prescriptions containing any acid suppressant in outpatient and emergency departments in baseline (2017) and postintervention (2019) periods were extracted from the hospital information system and the prescription automatic screening system. Acid suppressant prescribing patterns were evaluated based on primary diagnoses and patient demographics. The prescribed acid suppressants stratified using age groups (< 7, 7-17, 18-45, 46-65, 66-85 and > 85 years) were also examined. RESULT: The utilization rate of acid suppressant in 2017 and 2019 was 2.5% (41,165/1,619,366) and 2.2% (49,550/2,236,471), respectively (P < 0.0001). 60,135 acid suppressant prescriptions were obtained in 2017 and 73,275 in 2019. The rate of acid suppressant prescriptions for the approved indications significantly increased from 62.6% (2017) to 65.4% (2019) (P < 0.0001). Prescriptions diagnosed as abnormal symptoms, signs and clinical manifestations, decreased in 2019 (13.0% vs. 16.5%, P < 0.0001). The most frequently prescribed PPIs differed between 2017 and 2019 (rabeprazole 2017 vs. esomeprazole 2019). Omeprazole was the most common PPI and cimetidine was the most common H2RA prescribed to patients aged < 18 years in 2017 and 2019. A total of CNY11.83 million was spent on acid suppressants in 2019, accounting for about 48.7% of total medication cost, increased by 11.3% from 2017 (37.4%). CONCLUSION: The proportion of acid suppressant prescriptions for approved indications was enhanced after the PPI management committee's multifaceted interventions, but there were still some problems in the selection of acid suppressants.

Reversibly Modulating the Blood-Brain Barrier by Laser Stimulation of Molecular-Targeted Nanoparticles.

The blood-brain barrier (BBB) is highly selective and acts as the interface between the central nervous system and circulation. While the BBB is critical for maintaining brain homeostasis, it represents a formidable challenge for drug delivery. Here we synthesized gold nanoparticles (AuNPs) for targeting the tight junction specifically and demonstrated that transcranial picosecond laser stimulation of these AuNPs post intravenous injection increases the BBB permeability. The BBB permeability change can be graded by laser intensity, is entirely reversible, and involves increased paracellular diffusion. BBB modulation does not lead to significant disruption in the spontaneous vasomotion or the structure of the neurovascular unit. This strategy allows the entry of immunoglobulins and viral gene therapy vectors, as well as cargo-laden liposomes. We anticipate this nanotechnology to be useful for tissue regions that are accessible to light or fiberoptic application and to open new avenues for drug screening and therapeutic interventions in the central nervous system.

Probing Neuropeptide Volume Transmission In Vivo by Simultaneous Near-Infrared Light-Triggered Release and Optical Sensing.

Neuropeptides are abundant signaling molecules in the central nervous system. Yet remarkably little is known about their spatiotemporal spread and biological activity. Here, we developed an integrated optical approach using Plasmonic nAnovesicles and cell-based neurotransmitter fluorescent engineered reporter (CNiFER), or PACE, to probe neuropeptide signaling in the mouse neocortex. Small volumes (fL to pL) of exogenously supplied somatostatin-14 (SST) can be rapidly released under near-infrared light stimulation from nanovesicles implanted in the brain and detected by SST2 CNiFERs with nM sensitivity. Our measurements reveal reduced but synchronized SST transmission within 130 µm, and markedly smaller and delayed transmission at longer distances. These measurements enabled a quantitative estimation of the SST loss rate due to peptide degradation and binding. PACE offers a new tool for determining the spatiotemporal scales of neuropeptide volume transmission and signaling in the brain.

Single cell RNA sequencing identifies IGFBP5 and QKI as ciliated epithelial cell genes associated with severe COPD.

BACKGROUND: Whole lung tissue transcriptomic profiling studies in chronic obstructive pulmonary disease (COPD) have led to the identification of several genes associated with the severity of airflow limitation and/or the presence of emphysema, however, the cell types driving these gene expression signatures remain unidentified. METHODS: To determine cell specific transcriptomic changes in severe COPD, we conducted single-cell RNA sequencing (scRNA seq) on n = 29,961 cells from the peripheral lung parenchymal tissue of nonsmoking subjects without underlying lung disease (n = 3) and patients with severe COPD (n = 3). The cell type composition and cell specific gene expression signature was assessed. Gene set enrichment analysis (GSEA) was used to identify the specific cell types contributing to the previously reported transcriptomic signatures. RESULTS: T-distributed stochastic neighbor embedding and clustering of scRNA seq data revealed a total of 17 distinct populations. Among them, the populations with more differentially expressed genes in cases vs. controls (log fold change >|0.4| and FDR = 0.05) were: monocytes (n = 1499); macrophages (n = 868) and ciliated epithelial cells (n = 590), respectively. Using GSEA, we found that only ciliated and cytotoxic T cells manifested a trend towards enrichment of the previously reported 127 regional emphysema gene signatures (normalized enrichment score [NES] = 1.28 and = 1.33, FDR = 0.085 and = 0.092 respectively). Among the significantly altered genes present in ciliated epithelial cells of the COPD lungs, QKI and IGFBP5 protein levels were also found to be altered in the COPD lungs. CONCLUSIONS: scRNA seq is useful for identifying transcriptional changes and possibly individual protein levels that may contribute to the development of emphysema in a cell-type specific manner.