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PloS One 2024To investigate the therapeutic effect and mechanism of sivelestat sodium on acute lung injury (AIL).
OBJECTIVE
To investigate the therapeutic effect and mechanism of sivelestat sodium on acute lung injury (AIL).
METHODS
A rat model for ALI/acute respiratory distress syndrome (ALI/ARDS) was established. Pathological examination of lung tissue was conducted to assess lung injury. Blood gas in the arteries was measured using a blood analyzer. Changes in PaO2, PaO2/FiO2, and lung wet/dry (W/D) weight ratio were carefully compared. ELISA assay was conducted to estimate cell adhesion and inflammation response. Finally, real-time reverse transcription polymerase chain reaction and western blotting assay was used to determine the activation of PI3K/AKT/mTOR pathway.
RESULTS
ARDS in vivo model was successfully constructed by LPS injection. Compared with the sham group, PaO2 and PaO2/FiO2 were significantly lower in the vehicle group, while the lung W/D ratio, the lung injury score, NE, VCAM-1, IL-8 andTNF-αwere significantly increased. After treatment with different doses of sivelestat sodium, we found PaO2, PaO2/FiO2 were prominently increased, while the lung W/D ratio, the lung injury score, NE, VCAM-1, IL-8, TNF-α levels were decreased in the dose-dependent manner. Meanwhile, compared with the vehicle group, the expression levels of Bax, PI3K, Akt and mTOR were significantly lower, and the expression of Bcl-2 was significantly higher after injection with sivelestat sodium.
CONCLUSION
Sivelestat sodium has an interventional effect on ALI in sepsis by inhibiting the PI3K/AKT/mTOR signalling pathway.
Topics: Animals; TOR Serine-Threonine Kinases; Acute Lung Injury; Signal Transduction; Proto-Oncogene Proteins c-akt; Phosphatidylinositol 3-Kinases; Rats; Male; Glycine; Sulfonamides; Rats, Sprague-Dawley; Lung; Disease Models, Animal
PubMed: 38935660
DOI: 10.1371/journal.pone.0302721 -
JAMA Network Open Jun 2024Varenicline is the most effective sole pharmacotherapy for smoking cessation. If used in combination with nicotine replacement therapy (NRT), cessation rates may be... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Varenicline is the most effective sole pharmacotherapy for smoking cessation. If used in combination with nicotine replacement therapy (NRT), cessation rates may be further improved, but the efficacy and safety of the combination need to be evaluated.
OBJECTIVE
To examine whether hospitalized smokers treated with varenicline and NRT lozenges achieve higher prolonged smoking abstinence rates compared with those treated with varenicline alone.
DESIGN, SETTING, AND PARTICIPANTS
A double-blind, placebo-controlled randomized clinical trial was conducted in adult medical or surgical inpatients of 5 Australian public hospitals with a history of smoking 10 cigarettes or more per day, interested in quitting, and available for 12-month follow-up between May 1, 2019, and May 1, 2021 (final 12-month data collection in May 2022). Data analysis was performed from June 1 to August 30, 2023.
INTERVENTIONS
A 12-week varenicline regimen was initiated during hospitalization at standard doses in all participants. Participants were randomized to additionally use NRT (2 mg) or placebo lozenges if there was an urge to smoke. Behavioral support (Quitline) was offered to all participants.
MAIN OUTCOMES AND MEASURES
The primary outcome was biochemically verified sustained abstinence at 6 months. Secondary outcomes included self-reported prolonged abstinence, 7-day point prevalence abstinence (3, 6, and 12 months), and medicine-related adverse events.
RESULTS
A total of 320 participants (mean [SD] age, 52.5 [12.1] years; 183 [57.2%] male) were randomized. The conduct of biochemical verification was affected by COVID-19 restrictions; consequently, the biochemically verified abstinence in the intervention vs control arms (18 [11.4%] vs 16 [10.1%]; odds ratio [OR], 1.14; 95% CI, 0.56-2.33) did not support the combination therapy. The secondary outcomes in the intervention vs control arms of 7-day point prevalence abstinence at 6 months (54 [34.2%] vs 37 [23.4%]; OR, 1.71; 95% CI, 1.04-2.80), prolonged abstinence at 12 months (47 [29.9%] vs 30 [19.1%]; OR, 1.77; 95% CI, 1.05-3.00), and 7-day point prevalence abstinence at 12-months (48 [30.6%] vs 31 [19.7%]; OR, 1.79; 95% CI, 1.07-2.99) significantly improved with the combination therapy. The self-reported 6-month prolonged abstinence (61 [38.6%] vs 47 [29.7%]; OR, 1.49; 95% CI, 0.93-2.39) favored the combination therapy but was not statistically significant. Medicine-related adverse events were similar in the 2 groups (102 [74.5%] in the intervention group vs 86 [68.3%] in the control group).
CONCLUSIONS AND RELEVANCE
In this randomized clinical trial of the combination of varenicline and NRT lozenges in hospitalized adult daily smokers, the combination treatment improved self-reported abstinence compared with varenicline alone, without compromising safety, but it did not improve biochemically validated abstinence.
TRIAL REGISTRATION
anzctr.org.au Identifier: ACTRN12618001792213.
Topics: Humans; Varenicline; Male; Female; Smoking Cessation; Tobacco Use Cessation Devices; Middle Aged; Double-Blind Method; Adult; Smoking Cessation Agents; Australia; Hospitalization; Smokers; Aged; Treatment Outcome; Nicotine Replacement Therapy
PubMed: 38935378
DOI: 10.1001/jamanetworkopen.2024.18120 -
Immunity, Inflammation and Disease Jun 2024Particulate β-glucans (WGP) are natural compounds with regulatory roles in various biological processes, including tumorigenesis and inflammatory diseases such as...
BACKGROUND
Particulate β-glucans (WGP) are natural compounds with regulatory roles in various biological processes, including tumorigenesis and inflammatory diseases such as allergic asthma. However, their impact on mast cells (MCs), contributors to airway hyperresponsiveness (AHR) and inflammation in asthma mice, remains unknown.
METHODS
C57BL/6 mice underwent repeated OVA sensitization without alum, followed by Ovalbumin (OVA) challenge. Mice received daily oral administration of WGP (OAW) at doses of 50 or 150 mg/kg before sensitization and challenge. We assessed airway function, lung histopathology, and pulmonary inflammatory cell composition in the airways, as well as proinflammatory cytokines and chemokines in the bronchoalveolar lavage fluid (BALF).
RESULTS
The 150 mg/kg OAW treatment mitigated OVA-induced AHR and airway inflammation, evidenced by reduced airway reactivity to aerosolized methacholine (Mch), diminished inflammatory cell infiltration, and goblet cell hyperplasia in lung tissues. Additionally, OAW hindered the recruitment of inflammatory cells, including MCs and eosinophils, in lung tissues and BALF. OAW treatment attenuated proinflammatory tumor necrosis factor (TNF)-α and IL-6 levels in BALF. Notably, OAW significantly downregulated the expression of chemokines CCL3, CCL5, CCL20, CCL22, CXCL9, and CXCL10 in BALF.
CONCLUSION
These results highlight OAW's robust anti-inflammatory properties, suggesting potential benefits in treating MC-dependent AHR and allergic inflammation by influencing inflammatory cell infiltration and regulating proinflammatory cytokines and chemokines in the airways.
Topics: Animals; Asthma; Mast Cells; Mice; Disease Models, Animal; Administration, Oral; Mice, Inbred C57BL; beta-Glucans; Cytokines; Inflammation; Ovalbumin; Respiratory Hypersensitivity; Bronchoalveolar Lavage Fluid; Lung
PubMed: 38934407
DOI: 10.1002/iid3.1333 -
Therapeutics and Clinical Risk... 2024Incorporating unfamiliar therapies into practice requires effective longitudinal learning and the optimal way to achieve this is debated. Though not a novel therapy,...
BACKGROUND
Incorporating unfamiliar therapies into practice requires effective longitudinal learning and the optimal way to achieve this is debated. Though not a novel therapy, ketamine in critical care has a paucity of data and variable acceptance, with limited research describing intensivist perceptions and utilization. The Coronavirus-19 pandemic presented a particular crisis where providers rapidly adapted analgosedation strategies to achieve prolonged, deep sedation due to a surge of severe acute respiratory distress syndrome (ARDS).
QUESTION
How does clinical experience with ketamine impact the perception and attitude of clinicians toward this therapy?
METHODS
We conducted a mixed-methods study using quantitative ketamine prescription data and qualitative focus group data. We analyzed prescription patterns of ketamine in a tertiary academic ICU during two different time points: pre-COVID-19 (March 1-June 30, 2019) and during the COVID-19 surge (March 1-June 30, 2020). Two focus groups (FG) of critical care attendings were held, and data were analyzed using the Framework Method for content analysis.
RESULTS
Four-hundred forty-six medical ICU patients were mechanically ventilated (195 pre-COVID-19 and 251 during COVID-19). The COVID-19 population was more likely to receive ketamine (81[32.3%] vs 4 [2.1%], p < 0.001). Thirteen respondents participated across two FG sessions (Pre-COVID = 8, Post-COVID=5). The most prevalent attitude among our respondents was discomfort, with three key themes identified as follows: 1) lack of evidence regarding ketamine, 2) lack of personal experience, and 3) desire for more education and protocols.
CONCLUSION
Despite a substantial increase in ketamine prescription during COVID-19, intensivists continued to feel discomfort with utilization. Factors contributing to this discomfort include a lack of evidence, a lack of experience, and a desire for more education and protocols. Increase in experience with ketamine alone was not sufficient to minimize provider discomfort. These findings should inform future curricula and call for process improvement to optimize continuing education.
PubMed: 38934016
DOI: 10.2147/TCRM.S462760 -
Pain Research & Management 2024Hip arthroplasty is a common procedure with high costs and difficult rehabilitation. It causes postoperative pain, and this can reduce mobility which extends in-patient... (Review)
Review
Hip arthroplasty is a common procedure with high costs and difficult rehabilitation. It causes postoperative pain, and this can reduce mobility which extends in-patient time. An optimal analgesia regime is crucial to identify. Opioids produce effective pain relief but are associated with nausea, vomiting, and respiratory depression which can hinder physiotherapy and discharge. Finding alternatives has been of interest in recent years, particularly fascial blocks. These are anaesthetic injections beneath fascia which spread to nerves providing pain relief from surgery and are used with a general or spinal anaesthetic. Two of these blocks which are of interest to total hip arthroplasty are the quadratus lumborum block and fascia iliaca block. Studies have investigated the effectiveness of these blocks through patient factors, primarily pain scores, opioid consumption, and other secondary outcomes such as ambulation and length of stay. This review takes a narrative approach and investigates the literature around the topic. Pain and opioid consumption were the most widely reported outcomes, reported in 90% and 86% of studies. 83% of these studies reported positive effects on pain scores when FIB was utilised. 80% of these studies reported positive effects on opioid consumption when FIB was used. When QLB block was utilised, pain and opioid consumption were positively impacted in 82% of studies. This paper has been written with the intention of reviewing current literature to give an impression of the effectiveness of the blocks and propose potential areas for future work on the blocks.
Topics: Humans; Nerve Block; Arthroplasty, Replacement, Hip; Pain, Postoperative; Abdominal Muscles; Fascia; Pain Management
PubMed: 38933897
DOI: 10.1155/2024/4518587 -
Frontiers in Immunology 2024Community-acquired pneumonia (CAP) is a global health concern, with 25% of cases attributed to (). Viral infections like influenza A virus (IAV), respiratory syncytial...
INTRODUCTION
Community-acquired pneumonia (CAP) is a global health concern, with 25% of cases attributed to (). Viral infections like influenza A virus (IAV), respiratory syncytial virus (RSV), and human metapneumovirus (hMPV) increase the risk of , leading to severe complications due to compromised host immunity.
METHODS
We evaluated the efficacy of an anti-PhtD monoclonal antibody (mAb) cocktail therapy (PhtD3 + 7) in improving survival rates in three viral/bacterial coinfection models: IAV/, hMPV/, and RSV/.
RESULTS
The PhtD3 + 7 mAb cocktail outperformed antiviral mAbs, resulting in prolonged survival. In the IAV/ model, it reduced bacterial titers in blood and lungs by 2-4 logs. In the hMPV/ model, PhtD3 + 7 provided greater protection than the hMPV-neutralizing mAb MPV467, significantly reducing bacterial titers. In the RSV/ model, PhtD3 + 7 offered slightly better protection than the antiviral mAb D25, uniquely decreasing bacterial titers in blood and lungs.
DISCUSSION
Given the threat of antibiotic resistance, our findings highlight the potential of anti-PhtD mAb therapy as an effective option for treating viral and secondary pneumococcal coinfections.
Topics: Animals; Humans; Antibodies, Monoclonal; Streptococcus pneumoniae; Mice; Superinfection; Coinfection; Respiratory Syncytial Virus Infections; Metapneumovirus; Influenza A virus; Disease Models, Animal; Pneumococcal Infections; Female; Mice, Inbred BALB C; Paramyxoviridae Infections; Antibodies, Viral
PubMed: 38933273
DOI: 10.3389/fimmu.2024.1364622 -
Frontiers in Cardiovascular Medicine 2024Severe tricuspid regurgitation (TR) causing cyanosis with patent foramen ovale (PFO) and right-to-left atrial shunting requires a precise diagnosis for optimal therapy....
BACKGROUND
Severe tricuspid regurgitation (TR) causing cyanosis with patent foramen ovale (PFO) and right-to-left atrial shunting requires a precise diagnosis for optimal therapy. Tricuspid valve prolapse (TVP) can lead to TR and is sometimes overlooked, especially in complex cases with factors like pulmonary hypertension (PH). We present an infant with cyanosis and profound TR after high-altitude exposure, initially misattributed to PH but found to be primarily due to spontaneous chordae tendineae rupture and TVP. This case underscores the challenges in diagnosing TR-induced cyanosis.
CASE PRESENTATION
The 3-month-old infant rapidly developed cyanosis, hypoxemia, right atrial enlargement, severe tricuspid regurgitation (TR), and patent foramen ovale (PFO) shunting after high-altitude exposure. Although echocardiography revealed tricuspid valve prolapse (TVP), initial consideration linked TR and right-to-left shunting to pulmonary hypertension (PH) due to the temporal correlation with rapid altitude exposure. Despite hemodynamic stability and the absence of respiratory distress after respiratory support and combined PH medication therapy, the persistent hypoxemia did not reverse as expected. This treatment outcome and repeated echocardiograms reminded us that TR was primarily caused by TVP rather than PH alone. Intraoperative exploration confirmed that TVP was caused by a rupture of TV chordae tendineae and anterior papillary muscle head, and the chordae tendineae/papillary muscle connection was reconstructed. After surgery, this patient was noncyanotic with an excellent long-term prognosis, a trivial TR with normal TV function being observed echocardiographically.
CONCLUSIONS
TR-induced cyanosis can be not only a consequence of PH and right-sided heart dilation but also a primary condition. Repetitive reassessment should be undertaken with caution, particularly when patients are not improving on therapy in the setting of conditions known to predisposition to secondary TR. Since TVP caused by rupture of the chordae or papillary muscles is rare but fatal in children, early diagnosis is clinically substantial to proper management and satisfactory long-term outcomes.
PubMed: 38932987
DOI: 10.3389/fcvm.2024.1335218 -
Frontiers in Public Health 2024This work describes a sustainable and replicable initiative to optimize multi-disciplinary care and uptake of clinical best practices for patients in a pediatric...
BACKGROUND
This work describes a sustainable and replicable initiative to optimize multi-disciplinary care and uptake of clinical best practices for patients in a pediatric intensive care unit in Low/Middle Income Countries and to understand the various factors that may play a role in the reduction in child mortality seen after implementation of the Quality Improvement Initiative.
METHODS
This was a longitudinal assessment of a quality improvement program with the primary outcome of intubated pediatric patient mortality. The program was assessed 36 months following implementation of the quality improvement intervention using a -test with linear regression to control for co-variates. An Impact Pathway model was developed to describe potential pathways for improvement, and context was added with an exploratory analysis of adoption of the intervention and locally initiated interventions.
RESULTS
147 patients were included in the sustainability cohort. Comparing the initial post-implementation cohort to the sustainability cohort, the overall PICU unexpected extubations per 100 days mechanical ventilation decreased significantly from baseline (6.98) to the first year post intervention (3.52; < 0.008) but plateaued without further significant decrease in the final cohort (3.0; = 0.73), whereas the mortality decreased from 22.4 (std 0.42) to 9.5% (std 0.29): value: 0.002 (confidence intervals: 0.05;0.21). The regression model that examined age, sex, diagnosis and severity of illness (via aggregate Pediatric Risk of Mortality (PRISM) scores between epochs) yielded an adjusted R-squared (adjusting for the number of predictors) value of 0.046, indicating that approximately 4.6% of the variance in mortality was explained by the predictors included in the model. The overall significance of the regression model was supported by an F-statistic of 3.198 ( = 0.00828). age, weight, diagnosis, and severity of illness. 15 new and locally driven quality practices were observed in the PICU compared to the initial post-implementation time period. The Impact Pathway model suggested multiple unique potential pathways connecting the improved patient outcomes with the intervention components.
CONCLUSION
Sustained improvements were seen in the care of intubated pediatric patients. While some of this improvement may be attributable to the intervention, it appears likely that the change is multifactorial, as evidenced by a significant number of new quality improvement projects initiated by the local clinical team. Although currently limited by available data, the use of Driver Diagram and Impact Pathway models demonstrates several proposed causal pathways and holds potential for further elucidating the complex dynamics underlying such improvements.
Topics: Humans; Intensive Care Units, Pediatric; Quality Improvement; Male; Female; Child, Preschool; Infant; Child; Longitudinal Studies; Developing Countries; Child Mortality; Respiration, Artificial
PubMed: 38932785
DOI: 10.3389/fpubh.2024.1411681 -
Acta Dermato-venereologica Jun 2024To examine the prevalence of comorbidities in Chinese urticaria patients and assess medication use patterns across different ages (6-11 years, 12-17 years, above 18...
To examine the prevalence of comorbidities in Chinese urticaria patients and assess medication use patterns across different ages (6-11 years, 12-17 years, above 18 years), a retrospective cohort study was performed in 192,647 urticaria patients within the Health Database. After 1:1 propensity score matching, 166,921 people were divided into the urticaria group and the control group, and the follow-up data were collected within 2 years. During the 12-month and 24-month follow-up period, significant comorbidities identified included allergic rhinitis and asthma, with distinct patterns observed across age groups. Chronic urticaria patients often have complications, such as allergic rhinitis, upper respiratory infection, oropharyngeal infection, and dental caries. The study underscores the need for age-specific treatment strategies in urticaria management.
Topics: Humans; Retrospective Studies; Child; Male; Adolescent; Female; China; Comorbidity; Prevalence; Age Factors; Young Adult; Chronic Urticaria; Adult; Rhinitis, Allergic; Time Factors; Urticaria; Risk Factors; Propensity Score; Middle Aged; Databases, Factual; Asthma; East Asian People
PubMed: 38932592
DOI: 10.2340/actadv.v104.24050 -
Cancer Science Jun 2024Atypical L858R or other L858X mutations in the epidermal growth factor receptor (EGFR) gene, beyond the classical EGFR mutation caused by c.2573 T > G, have been...
Outcomes in non-small cell lung cancer with uncommon epidermal growth factor receptor L858 substitutions under first-line epidermal growth factor receptor tyrosine kinase inhibitors: A large real-world cohort study.
Atypical L858R or other L858X mutations in the epidermal growth factor receptor (EGFR) gene, beyond the classical EGFR mutation caused by c.2573 T > G, have been identified in non-small cell lung cancer (NSCLC), yet their genomic features and survival benefits with EGFR tyrosine kinase inhibitor (TKI) treatment have not been fully explored. We retrospectively enrolled 489 NSCLC patients with baseline tumor tissue/plasma samples carrying uncommon EGFR (N = 124), EGFR (N = 17), or classical EGFR mutations (N = 348). The comparison of molecular features was performed using treatment-naïve tumor tissues. Survival benefits and resistance mechanisms of first-line EGFR TKI treatment were studied in an advanced disease subcohort. NSCLCs harboring uncommon EGFR had lower TP53 mutation prevalence (p = 0.04) and chromosome instability scores (p = 0.02) than those with classical EGFR. Concomitant EGFR mutations were enriched in NSCLCs with EGFR (p < 0.01), with cooccurrence in those carrying EGFR. Patients with uncommon EGFR experienced improved progression-free survival (PFS) compared to those with classical EGFR (median: 13.0 vs. 10.0 months, hazard ratio [HR]: 0.57, 95% confidence interval [CI]: 0.41-0.80). The association remained significant when adjusting for sex, age, histological subtype, TKI category, and anti-vascular therapy (HR: 0.55, 95% CI: 0.39-0.77). Furthermore, EGFR patients showed enhanced first-line PFS (vs. classical EGFR, HR: 0.26, 95% CI: 0.10-0.67), potentially benefiting more from afatinib. Additionally, NSCLCs with uncommon EGFR and classical EGFR had similar resistance profiles to EGFR TKIs. In conclusion, NSCLCs carrying atypical EGFR L858 aberrations, which had fewer TP53 mutations and higher chromosome stability, exhibited improved PFS under first-line EGFR TKIs than those with the classical EGFR.
PubMed: 38932450
DOI: 10.1111/cas.16250