Search

Secretory leukocyte protease inhibitor (SLPI) is an important cationic protein involved in innate airway immunityandhighlyexpressed inmucosal secretions, shownto target and inhibit neutrophil elastase (NE), cathepsinGand trypsinactivitytolimit proteolytic activity. Inaddition tothe potent anti-protease activity, SLPIhas beendemonstratedto exert a direct anti-inflammatory effect, which is mediated via increased inhibition and competitive binding of NF-kB, regulating immune responses through limiting transcription of pro-inflammatory gene targets. In muco-obstructive lung disorders, suchasChronicObstructivePulmonaryDisease(COPD)andCysticFibrosis (CF), there is an observed elevation in airway SLPI protein concentrations as a result of increased lung inflammation and disease progression. However, studies have identified COPD patients presenting with diminished SLPI concentrations. Furthermore, there is a decrease in SLPI concentrations through cleavage and subsequent inactivation by NE degradation in Pseudomonas aeruginosa infected people with CF (pwCF). These observations suggest reduced SLPI protein levels may contribute to the compromising of airway immunity indicating a potential role of decreased SLPI levels in the pathogenesis of muco-obstructive lung disease. The Beta Epithelial Na+ Channel transgenic (ENaC-Tg) mousemodel phenotype exhibits characteristics which replicate the pathological features observed in conditions such as COPD and CF, including mucus accumulation, alterations in airway morphology and increased pulmonary inflammation. To evaluate the effect of SLPI in muco-obstructive pulmonary disease, ENaC-Tg mice were crossed with SLPI knock-out (SLPI-/-) mice, generating a ENaC-Tg/SLPI-/- colony to further investigate the role of SLPI in chronic lung disease and determine the effect of its ablation on disease pathogenesis. [ABSTRACT FROM AUTHOR]

The development of electric vehicles (EVs) has introduced novel technologies and manufacturing processes that expose workers to new risks of burn injury. We identified 6 patients who were admitted to our burn center for injuries that occurred while working in EV manufacturing facilities. The burns fell into 3 categories: flash flame burns due to lithium-ion battery explosions, high-voltage electrical injuries, and burns caused by contact with molten metal. Recognizing these recurrent patterns of injury should inform future prevention efforts and prepare health systems to evaluate and treat patients burned in EV manufacturing. [ABSTRACT FROM AUTHOR]

Radiotherapy (RT) treatment is an important strategy for the management of non-small cell lung cancer (NSCLC). Local recurrence amongst patients with late-stage NSCLC remains a challenge. The loss of PTEN has been associated with radio-resistance. This study aimed to examine the efficacy of RT combined with ataxia telangiectasia-mutated Rad3-related (ATR) inhibition using Ceralasertib in phosphatase and tensin homolog (PTEN)-depleted NSCLC cells and to assess early inflammatory responses indicative of radiation pneumonitis (RP) after combined-modality treatment. Small hairpin RNA (shRNA) transfections were used to generate H460 and A549 PTEN-depleted models. Ceralasertib was evaluated as a single agent and in combination with RT in vitro and in vivo. Histological staining was used to assess immune cell infiltration in pneumonitis-prone C3H/NeJ mice. Here, we report that the inhibition of ATR in combination with RT caused a significant reduction in PTEN-depleted NSCLC cells, with delayed DNA repair and reduced cell viability, as shown by an increase in cells in Sub G1. Combination treatment in vivo significantly inhibited H460 PTEN-depleted tumour growth in comparison to H460 non-targeting PTEN-expressing (NT) cell-line-derived xenografts (CDXs). Additionally, there was no significant increase in infiltrating macrophages or neutrophils except at 4 weeks, whereby combination treatment significantly increased macrophage levels relative to RT alone. Overall, our study demonstrates that ceralasertib and RT combined preferentially sensitises PTEN-depleted NSCLC models in vitro and in vivo, with no impact on early inflammatory response indicative of RP. These findings provide a rationale for evaluating ATR inhibition in combination with RT in NSCLC patients with PTEN mutations. [ABSTRACT FROM AUTHOR]

Objective: Medical decision-making is often uncertain. The positive predictive value (PPV) and negative predictive value (NPV) are conditional probabilities characterizing diagnostic tests and assessing diagnostic interventions in clinical medicine and epidemiology. The PPV is the probability that a patient has a specified disease, given a positive test result for that disease. The NPV is the probability that a patient does not have the disease, given a negative test result for that disease. Both values depend on disease incidence or prevalence, which may be highly uncertain for unfamiliar diseases, epidemics, etc. Probability distributions for this uncertainty are usually unavailable. We develop a non-probabilistic method for interpreting PPV and NPV with uncertain prevalence. Methods: Uncertainty in PPV and NPV is managed with the non-probabilistic concept of robustness in info-gap theory. Robustness of PPV or NPV estimates is the greatest uncertainty (in prevalence) at which the estimate's error is acceptable. Results: Four properties are demonstrated. Zeroing: best estimates of PPV or NPV have no robustness to uncertain prevalence; best estimates are unreliable for interpreting diagnostic tests. Trade-off: robustness increases as error increases; this trade-off identifies robustly reliable error in PPV or NPV. Preference reversal: sometimes sub-optimal PPV or NPV estimates are more robust to uncertain incidence or prevalence than optimal estimates, motivating reversal of preference from the putative optimum to the sub-optimal estimate. Trade-off between specificity and robustness to uncertainty: the robustness increases as test-specificity decreases. These four properties underlie the interpretation of PPV and NPV. Conclusions: The PPV and NPV assess diagnostic tests, but are sensitive to lack of knowledge that generates non-probabilistic uncertain prevalence and must be supplemented with robustness analysis. When uncertainties abound, as with unfamiliar diseases, assessing robustness is critical to avoiding erroneous decisions. [ABSTRACT FROM AUTHOR]

Methamphetamine intoxication frequently complicates inpatient burn admissions. While single-institution studies describe adverse outcomes during resuscitation, little is known about the risks of amphetamine intoxication on inpatient complications and perioperative management. The US National Trauma Data Bank was queried for burn encounters between 2017 and 2021. Amphetamine intoxication was identified on admission. Primary outcomes included death, stroke, and myocardial infarction (MI). Secondary outcomes included organ failure and surgical management. Multivariable regressions modeled outcomes adjusting for available covariates including demographics, TBSA burned, and inhalation injury. Bonferroni adjustments were applied. Our study identified a total of 73,968 primary burn encounters with toxicology screens. Among these, 800 cases (1.1%) were found to have positive methamphetamine drug screens upon admission. Methamphetamine users were significantly older (41.7 vs 34.9 years, P  < .001), had a greater percentage of males (69.6 vs 65.4, P  = .045), were more likely to have inhalation injury (P  < .001), and had larger %TBSA burns (16% vs 13%, P  < .001). Methamphetamine users were no more likely to die, experience MI, or experience stroke during admission. In contrast, methamphetamine users were significantly more likely to have alcohol withdrawal (P  = .019), acute kidney injury (AKI) (P  < .001), deep vein thrombosis (P  = .001), pulmonary embolism (PE) (P  = .039), sepsis (P  = .026), and longer intensive care unit (ICU) stays (P  < .001). Methamphetamine use was associated with a longer number of days to the first procedure (P  = .005). Of all patients who required surgery (15.0%), methamphetamine users required significantly more total debridements and reconstructive procedures (P  < .001). While not associated with mortality, methamphetamine intoxication was associated with an increased risk of many complications including PE, deep vein thrombosis, AKI, sepsis, and longer ICU stays. Methamphetamine intoxication was associated with delays in surgical care. [ABSTRACT FROM AUTHOR]

Neutrophil-derived proteases are critical to the pathology of many inflammatory lung diseases, both chronic and acute. These abundant enzymes play roles in key neutrophil functions, such as neutrophil extracellular trap formation and reactive oxygen species release. They may also be released, inducing tissue damage and loss of tissue function. Historically, the neutrophil serine proteases (NSPs) have been the main subject of neutrophil protease research. Despite highly promising cell-based and animal model work, clinical trials involving the inhibition of NSPs have shown mixed results in lung disease patients. As such, the cutting edge of neutrophil-derived protease research has shifted to proteases that have had little-to-no research in neutrophils to date. These include the cysteine and serine cathepsins, the metzincins and the calpains, among others. This review aims to outline the previous work carried out on NSPs, including the shortcomings of some of the inhibitor-orientated clinical trials. Our growing understanding of other proteases involved in neutrophil function and neutrophilic lung inflammation will then be discussed. Additionally, the potential of targeting these more obscure neutrophil proteases will be highlighted, as they may represent new targets for inhibitor-based treatments of neutrophil-mediated lung inflammation. [ABSTRACT FROM AUTHOR]

In order to overcome the traditional thin-walled tubes' shortcomings of fixed crashworthiness and poor environmental adaptability, a magnetorheological bionic energy-absorbing element (MBEE) inspired by the horsetail structure was proposed and applied to design of thin-walled tubes in achieving variable and controllable crashworthiness. Theoretical analysis, numerical analysis, and optimization were conducted to perform in-depth study toward improving crashworthiness and associated controllability of the MBEE. In theoretical analysis, the theoretical models of total energy-absorption and crashworthiness' controllability were developed. In numerical analysis, a compression of MBEE under a constant loading speed was simulated using a finite element (FE) software and simulation results showed that: (1). differences on the total energy-absorption of magnetorheological fluid and structural framework in the compression of the MBEE predicted by FE simulation and theoretical model were only 3.49% and 2.16%, respectively. (2). the controllability of the MBEE's crashworthiness was up to 27.73% at the beginning of compression, but decreased to 12.29% when the total length of MBEE was compressed by nearly 67%. (3). the controllability of the MBEE's crashworthiness predicted by theoretical model and simulation also had high consistency. Finally, the parametric study and optimization were conducted to obtain the MBEE with optimal cross-sectional geometric shape filled into the traditional 9-cell thin-walled tube. When compared with the traditional 9-cell thin-walled tube, the total energy-absorption of the tube filled by the optimal MBEE was increased by 251.16%, and the specific energy absorption ( SEA ) of its structural framework was increased by 58.66%. In addition, the initial controllability η int of this filled tube's crashworthiness was up 22.24%. [ABSTRACT FROM AUTHOR]

Outer membrane vesicles (OMVs) are small, spherical structures released from the outer membranes of Gram-negative bacteria into the surrounding environment. Investigations into OMVs range from their biogenesis and cargo composition to their ability to transfer virulence factors and modulate host immune responses. This emerging understanding of OMVs has unveiled their pivotal role in the pathogenicity of infectious diseases, shedding light on their interactions with host cells, their contributions to inflammation, their potential involvement in antimicrobial resistance, and their promising use for the development of novel treatments and therapies. Numerous studies have associated the OMVs of pathogenic bacteria with the exacerbation of inflammatory diseases, underlining the significance of understanding the mechanisms associated with these vesicles to find alternatives for combating these conditions. Additionally, OMVs possess the ability to act as decoys, absorbing and neutralizing antibiotics, which significantly diminishes the efficacy of a broad spectrum of antimicrobial agents. Another subtopic of interest is OMVs produced by commensal microbiota. These vesicles are increasingly acknowledged for their mutualistic functions, significantly influencing their host's physiology and immune responses. Consequently, OMVs play a crucial role in maintaining a balanced gut microbiota by fostering symbiotic relationships that significantly contribute to the overall health and well-being of the host. This comprehensive review aims to provide an up-to-date review of OMVs derived from Gram-negative bacteria, summarizing current research findings, and elucidating the multifaceted role of these vesicles in diverse biological contexts. [ABSTRACT FROM AUTHOR]

Achieving health equity is forefront in national discussions on healthcare structuring. Burn injuries transcend racial and socioeconomic boundaries. Burn center funding ranges from safety-net to for-profit without an understanding of how funding mechanisms translate into equity outcomes. We hypothesized that health equity would be highest at safety-net facilities and lowest at for-profit centers. All verified and non-verified American Burn Association burn centers were collated in 2022. Safety-net status, for-profit status, and health equity rating were extracted from national datasets. Equity ratings were compared across national burn centers and significance was determined with comparative statistics and ordinal logistic regression. On an equity grade of A–D (A is the best), 27.6% of centers were rated A, 27.6% rated B, 41.5% rated C, and 3.3% rated D. About 17.1% of all burn centers were designated as for-profit compared to 21.1% of centers that were safety-net. About 73.1% of safety-net centers scored an A rating, and 14.3% of for-profit centers scored an A rating. Safety-net centers were 21.8 times more likely (P <.001) to have the highest equity score compared to nonsafety-net centers. There was an 80% decrease in the odds of having a rating of A for for-profit centers compared to nonprofit centers (P =.04). Safety-net centers had the highest equity ratings while for-profit burn centers scored the lowest. For-profit funding mechanisms may lead to the delivery of less equitable burn care. Burn centers should focus on health equity in the triage and management of their patients. [ABSTRACT FROM AUTHOR]

The treatment of burn patients using amphetamines is challenging due hemodynamic liabilty and altered physiology. Wide variation exists in the operative timing for this patient population. We hypothesize that burn excision in patients admitted with amphetamine positivity is safe regardless of timing. Data from two verified burn centers between 2017 and 2022 with differing practice patterns in operative timing for amphetamine-positive patients. Center A obtains toxicology only on admission and proceeds with surgery based on hemodynamic status and operative urgency, whereas Center B sends daily toxicology until a negative test results. The primary outcome was the use of vasoactive agents during the index operation, modeled using logistic regression adjusting for burn severity and hospital days to index operation. Secondary outcomes included death and inpatient complications. A total of 270 patients were included, and there were no significant differences in demographics or burn characteristics between centers. Center A screened once and Center B obtained a median of four screens prior to the surgery. The adjusted OR of requiring vasoactive support intraoperatively was not associated with negative toxicology result (P =.821). Having a body surface area burned >20% conferred a significantly higher risk of vasoactive support (adj. OR 13.42 [3.90–46.23], P <.001). Mortality, number of operations, stroke, and hospital length of stay were similar between cohorts. Comparison between two verified burn centers indicates that waiting until a negative amphetamine toxicology result does not impact intraoperative management or subsequent burn outcomes. Serial toxicology tests are unnecessary to guide operative timing of burn patients with amphetamine use. [ABSTRACT FROM AUTHOR]

The care required to recover serious burn injuries is costly. In the United States, these costs are often borne by patients. Examining the relationship between out-of-pocket (OOP) costs and health-related quality of life (HRQL) is important to support burn survivors. Financial data from a regional burn center were merged with data in the Burn Model System (BMS) National Database. HRQL outcomes included VA-Rand 12 (VR-12) physical component summary (PCS) and mental component summary (MCS) scores. Participant surveys were conducted at 6-, 12-, and 24-months post-injury. VR-12 scores were evaluated using generalized linear models and adjusted for potential confounders (age, sex, insurance/payer, self-identified race/ethnicity, measures of burn injury severity). 644 participants were included, of which 13% (84) had OOP costs. The percentage of participants with OOP costs was 34% for commercial/private, 22% for Medicare, 8% for other, 4% for self-pay, and 0% for workers' compensation and Medicaid. For participants with OOP expenses, median payments were $875 with an IQR of $368–1728. In addition to markers of burn injury severity, OOP costs were negatively associated with PCS scores at 6-months (coefficient −0.002, P <.001) and 12-months post-injury (coefficient −0.001, P =.004). There were no significant associations with PCS scores at 24 months post-injury or MCS scores at any interval. Participants with commercial/private or Medicare payer had higher financial liability than other payers. Higher OOP expenses were negatively associated with physical HRQL for at least 12 months after injury. Financial toxicity occurs after burn injury and providers should target resources accordingly. [ABSTRACT FROM AUTHOR]

Investigations of abiotic and biotic contributions to dissolved organic carbon (DOC) are required to constrain microbial habitability in continental subsurface fluids. Here we investigate a large (101–283 mg C/L) DOC pool in an ancient (>1Ga), high temperature (45–55 °C), low biomass (102−104 cells/mL), and deep (3.2 km) brine from an uranium-enriched South African gold mine. Excitation-emission matrices (EEMs), negative electrospray ionization (–ESI) 21 tesla Fourier-transform ion cyclotron resonance mass spectrometry (FT-ICR MS), and amino acid analyses suggest the brine DOC is primarily radiolytically oxidized kerogen-rich shales or reefs, methane and ethane, with trace amounts of C3–C6 hydrocarbons and organic sulfides. δ2H and δ13C of C1–C3 hydrocarbons are consistent with abiotic origins. These findings suggest water-rock processes control redox and C cycling, helping support a meagre, slow biosphere over geologic time. A radiolytic-driven, habitable brine may signal similar settings are good targets in the search for life beyond Earth. A deep, ancient, and uranium-rich brine in South Africa reveals evidence of radiolytically oxidized kerogen and C1–C3 hydrocarbons with abiotic isotopic signatures that support a low biomass microbial community over time. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV) frequently is measured at high levels in COPD using sputum quantitative polymerase chain reaction, whereas airway immunohistochemistry analysis has shown EBV detection to be common in severe disease. Is valaciclovir safe and effective for EBV suppression in COPD? The Epstein-Barr Virus Suppression in COPD (EViSCO) trial was a randomized double-blind placebo-controlled trial conducted at the Mater Hospital Belfast, Northern Ireland. Eligible patients had stable moderate-to-severe COPD and sputum EBV (measured using quantitative polymerase chain reaction) and were assigned randomly (1:1) to valaciclovir (1 g tid) or matching placebo for 8 weeks. The primary efficacy outcome was sputum EBV suppression (defined as ≥ 90% sputum viral load reduction) at week 8. The primary safety outcome was the incidence of serious adverse reactions. Secondary outcome measures were FEV 1 and drug tolerability. Exploratory outcomes included changes in quality of life, sputum cell counts, and cytokines. From November 2, 2018, through March 12, 2020, 84 patients were assigned randomly (n = 43 to valaciclovir). Eighty-one patients completed trial follow-up and were included in the intention-to-treat analysis of the primary outcome. A greater number of participants in the valaciclovir group achieved EBV suppression (n = 36 [87.8%] vs n = 17 [42.5%]; P <.001). Valaciclovir was associated with a significant reduction in sputum EBV titer compared with placebo (–90,404 copies/mL [interquartile range, –298,000 to –15,200 copies/mL] vs –3,940 copies/mL [interquartile range, –114,400 to 50,150 copies/mL]; P =.002). A statistically nonsignificant 24-mL numerical FEV 1 increase was shown in the valaciclovir group (difference, –44 mL [95% CI, –150 to 62 mL]; P =.41). However, a reduction in sputum white cell count was noted in the valaciclovir group compared with the placebo group (difference, 2.89 [95% CI, 1.5 × 106-7.4 × 106]; P =.003). Valaciclovir is safe and effective for EBV suppression in COPD and may attenuate the sputum inflammatory cell infiltrate. The findings from the current study provide support for a larger trial to evaluate long-term clinical outcomes. ClinicalTrials.gov; No.: NCT03699904; URL: www.clinicaltrials.gov [Display omitted] [ABSTRACT FROM AUTHOR]

Cellular senescence is a state of permanent cell cycle arrest triggered by various intrinsic and extrinsic stressors. Cellular senescence results in impaired tissue repair and remodeling, loss of physiological integrity, organ dysfunction, and changes in the secretome. The systemic accumulation of senescence cells has been observed in many age-related diseases. Likewise, cellular senescence has been implicated as a risk factor and driving mechanism in chronic obstructive pulmonary disease (COPD) pathogenesis. Airway epithelium exhibits hallmark features of senescence in COPD including activation of the p53/p21WAF1/CIP1 and p16INK4A/RB pathways, leading to cell cycle arrest. Airway epithelial senescent cells secrete an array of inflammatory mediators, the so-called senescence-associated secretory phenotype (SASP), leading to a persistent low-grade chronic inflammation in COPD. SASP further promotes senescence in an autocrine and paracrine manner, potentially contributing to the onset and progression of COPD. In addition, cellular senescence in COPD airway epithelium is associated with telomere dysfunction, DNA damage, and oxidative stress. This review discusses the potential mechanisms of airway epithelial cell senescence in COPD, the impact of cellular senescence on the development and severity of the disease, and highlights potential targets for modulating cellular senescence in airway epithelium as a potential therapeutic approach in COPD. [ABSTRACT FROM AUTHOR]

While single-institution studies have described the relationship between hypothermia, burn severity, and complications, there are no national estimates on how temperature on admission impacts hospital mortality. This study aims to evaluate the relationship between admission temperature and complications on a national scale to expose opportunities for improved outcomes. The US National Trauma Data Bank (NTDB) was analyzed between 2007-2018. Mortality was modeled using multivariable logistic regression including burn severity variables (% total burn surface area (TBSA), inhalation injury, emergency department (ED) temperature), demographics, and facility variables. Temperature was parsed into three categories: hypothermia (<36.0°C), euthermia (36.0-37.9°C), and hyperthermia (≥38.0°C). 116,796 burn encounters were included of which 77.9% were euthermic, 20.6% were hypothermic and 1.45% were hyperthermic on admission. For every 1.0C drop in body temperature from 36.0°C, mortality increased by 5%. Both hypothermia and hyperthermia were independently associated with increased odds of mortality when controlling for age, gender, inhalation injury, number of comorbidities, and %TBSA burned (p<.001). All temperatures below 36.0°C were significantly associated with increased odds of mortality. Patients with ED temperatures between 32.5-33.5°C had the highest odds of mortality (22.0, 95% CI 15.6-31.0, p<.001). ED hypothermia and hyperthermia are independently associated with mortality even when controlling for known covariates associated with inpatient death. These findings underscore the importance of early warming interventions both at the prehospital stage and upon ED arrival. ED temperature could become a quality metric in benchmarking burn centers to improve mortality. [ABSTRACT FROM AUTHOR]

Steroid receptor coactivator 3 (SRC-3) is most strongly expressed in regulatory T cells (Tregs) and B cells, suggesting that it plays an important role in the regulation of Treg function. Using an aggressive E0771 mouse breast cell line syngeneic immune-intact murine model, we observed that breast tumors were "permanently eradicated" in a genetically engineered tamoxifen-inducible Treg-cell-specific SRC-3 knockout (KO) female mouse that does not possess a systemic autoimmune pathological phenotype. A similar eradication of tumor was noted in a syngeneic model of prostate cancer. A subsequent injection of additional E0771 cancer cells into these mice showed continued resistance to tumor development without the need for tamoxifen induction to produce additional SRC-3 KO Tregs. SRC-3 KO Tregs were highly proliferative and preferentially infiltrated into breast tumors by activating the chemokine (C-C motif) ligand (Ccl) 19/Ccl21/chemokine (C-C motif) receptor (Ccr)7 signaling axis, generating antitumor immunity by enhancing the interferon-γ/C-X-C motif chemokine ligand (Cxcl) 9 signaling axis to facilitate the entrance and function of effector T cells and natural killer cells. SRC-3 KO Tregs also show a dominant effect by blocking the immune suppressive function of WT Tregs. Importantly, a single adoptive transfer of SRC-3 KO Tregs into wild-type E0771 tumor-bearing mice can completely abolish preestablished breast tumors by generating potent antitumor immunity with a durable effect that prevents tumor reoccurrence. Therefore, treatment with SRC-3-deleted Tregs represents an approach to completely block tumor growth and recurrence without the side effects that typically accompany immune checkpoint modulators. [ABSTRACT FROM AUTHOR]

Due to the significant effects of the human anatomical characteristics on the injury mechanism of passenger in traffic accidents, it is necessary to develop human body FEM (Finite Element Model) with detailed anatomical characteristics. However, traditional development of a human body FEM is an extremely complicated process. In particular, the meshing of human body is a huge and time-consuming project. In this paper, a new fast methodology based on CPD (Coherent Point Drift) and RBF (Radial Basis Function) was proposed to achieve the rapid developing the FEM of human bone with detailed anatomical characteristics. In this methodology, the mesh morphing technology based the RBF was used to generate FEM mesh in the geometry extracted from the target CT (Computed Tomography) data. In order to further improve the accuracy and speed of mesh morphing, the target geometric feature points required in the mesh morphing process were realized via the rapid and automatic generation based on the point-cloud registration technology of the CPD algorithm. Finally, this new methodology was used to generate a 3-year-old ribcage FEM consisting of a total of 27,728 elements with mesh size 3–5 mm based on the THUMS (Total Human Model for Safety) adult model. In the entire process of generating this new ribcage model, it only took about 2.7 s. The average error between the new FEM and target geometries was only about 2.7 mm. This indicated that the new FEM well described the detailed anatomical characteristics of target geometry, thus importantly revealing that the mesh quality of the new FEM was basically similar to that of source FEM. [ABSTRACT FROM AUTHOR]

Lattice structures and thin-walled tubes are two types of energy-absorbers widely studied and applied in engineering practice. In this study, a new type of lattice-structure filled thin-walled tube (LFT) was proposed by combining these two energy absorbers and designed via a new explainable data mining method. In this new type of LFT, a BCC-Z (Body- centred cubic unit cell with vertical struts) lattice structure was filled into a square thin-walled tube. Then, the new LFT was parameterized by five design variables, that is, the number of layers in the longitudinal direction (n), number of cells in the transverse direction (m), rod diameter (d), tube thickness (t) and height difference between tube and lattice structures (h). Using Latin hypercubic sampling algorithm, 150 design cases were generated. Numerical models were then developed to simulate their crush behavior, and the simulation dataset was used for data mining. The results showed that (1) Filling the BBC-Z lattice structure into a thin-walled tube can significantly improve the energy absorption (EA) capacity of the structure. (2) SEA (Specific Energy Absorption) of LFT significantly increased by increasing the rod diameter d, number of cells in the transverse direction m and number of layers in longitudinal direction n. (3) The decision trees generated in the data mining process indicated that the rod diameter d of the lattice structure is the key design variable that has most significant impact on EA, followed by m and n. (4) The design rules to build LFTs with high EA efficiency (SEA ≥ 16 kJ/kg and CFE (Crush Force Efficiency)≥45%), high total EA (SEA ≥ 16 kJ/kg and EA ≥ 6 kJ) and lightweight (SEA ≥ 16 kJ/kg and Mass ≤ 0.45 kg) were obtained from decision trees. The ideal configurations of LFT corresponding to these three objectives are: d > 2 mm, n > 2 and m > 3 for high EA efficiency; d > 2 mm, n > 2 and m > 3 for high total EA; and d > 2 mm, n > 2, m ≤ 4 and t ≤ 1.7 mm for lightweight. [ABSTRACT FROM AUTHOR]

Background: Cisplatin (CDDP) is a mainstay treatment for advanced head and neck squamous cell carcinomas (HNSCC) despite a high frequency of innate and acquired resistance. We hypothesised that tumours acquire CDDP resistance through an enhanced reductive state dependent on metabolic rewiring. Methods: To validate this model and understand how an adaptive metabolic programme might be imprinted, we performed an integrated analysis of CDDP-resistant HNSCC clones from multiple genomic backgrounds by whole-exome sequencing, RNA-seq, mass spectrometry, steady state and flux metabolomics. Results: Inactivating KEAP1 mutations or reductions in KEAP1 RNA correlated with Nrf2 activation in CDDP-resistant cells, which functionally contributed to resistance. Proteomics identified elevation of downstream Nrf2 targets and the enrichment of enzymes involved in generation of biomass and reducing equivalents, metabolism of glucose, glutathione, NAD(P), and oxoacids. This was accompanied by biochemical and metabolic evidence of an enhanced reductive state dependent on coordinated glucose and glutamine catabolism, associated with reduced energy production and proliferation, despite normal mitochondrial structure and function. Conclusions: Our analysis identified coordinated metabolic changes associated with CDDP resistance that may provide new therapeutic avenues through targeting of these convergent pathways. [ABSTRACT FROM AUTHOR]

Due to the significant effects of the human anatomical characteristics on the injury mechanism of passenger in traffic accidents, it is necessary to develop human body FEM (Finite Element Model) with detailed anatomical characteristics. However, traditional development of a human body FEM is an extremely complicated process. In particular, the meshing of human body is a huge and time-consuming project. In this paper, a new fast methodology based on CPD (Coherent Point Drift) and RBF (Radial Basis Function) was proposed to achieve the rapid developing the FEM of human bone with detailed anatomical characteristics. In this methodology, the mesh morphing technology based the RBF was used to generate FEM mesh in the geometry extracted from the target CT (Computed Tomography) data. In order to further improve the accuracy and speed of mesh morphing, the target geometric feature points required in the mesh morphing process were realized via the rapid and automatic generation based on the point-cloud registration technology of the CPD algorithm. Finally, this new methodology was used to generate a 3-year-old ribcage FEM consisting of a total of 27,728 elements with mesh size 3–5 mm based on the THUMS (Total Human Model for Safety) adult model. In the entire process of generating this new ribcage model, it only took about 2.7 s. The average error between the new FEM and target geometries was only about 2.7 mm. This indicated that the new FEM well described the detailed anatomical characteristics of target geometry, thus importantly revealing that the mesh quality of the new FEM was basically similar to that of source FEM. [ABSTRACT FROM AUTHOR]

Background: The transversus abdominus plane (TAP) block reduces postoperative donor site pain in patients undergoing autologous breast reconstruction with an abdominally based flap. This study aimed to determine the effect of TAP blocks on rates of conversion to chronic opioid use. Methods: The Clinformatics Data Mart was queried from 2003 to 2019, extracting adult encounters for abdominally based free and pedicled flaps based on common procedural terminology (CPT) codes. Patients were excluded if they had filled a narcotic prescription 1 year to 30 days prior to surgery. The exposure variable—TAP block—was identified by CPT codes. Outcomes were evaluated using morphine milligram equivalents (MME) from prescriptions filled between 30 days prior to and 30 days after surgery. Chronic opioid use (COU) was defined as receiving 4 unique prescriptions or a 60-day supply between 30 and 180 days after surgery. Results: Of the 4091 patients, (mean age 51.2 ± 9.0 years), 181 (4.4%) had a TAP block placed. Perioperative MMEs/day, postoperative COU, and length of stay did not differ in patients who received a TAP block (p = 0.142; p = 0.271). Significant predictors of risk of conversion to COU included younger age, pedicled abdominal flap, Elixhauser comorbidity index score > 3, filling a psychiatric medication prescription, and filling a benzodiazepine prescription. Conclusions: In patients undergoing autologous breast reconstruction with abdominally based flap reconstruction, TAP blocks do not decrease perioperative MME/day, conversion to chronic opioid use, or length of stay. These data suggest that intraoperative TAP block placement may be a low-yield opioid-reduction strategy. Level of evidence: Level III, risk/prognostic study [ABSTRACT FROM AUTHOR]

Disparities in socioeconomic status and minority status affect the risk of burn injury and the severity of that injury, thus affecting the subsequent cost of care. We aimed to characterize the demographic details surrounding receipt of financial assistance due to burn injury and its relationship with health-related quality of life scores. Participants ≥18 from Burn Model System National Longitudinal Database (BMS) with complete demographic data were included (n = 4330). Nonresponders to financial assistance questions were analyzed separately. The remaining sample (n = 1255) was divided into participants who received financial assistance because of burn injury, those who received no financial assistance, and those who received financial assistance before injury and as a result of injury. A demographic and injury-characteristic comparison was conducted. Health-related quality of life metrics (Satisfaction with Life, Short Form-12/Veterans RAND 12-Item Health Survey, Community Integration Questionnaire Social Component, and the Post-Traumatic Growth Inventory) were analyzed preinjury, then 6-months, 1-year, and 2-years postinjury. A matched cohort analysis compared these scores. When compared to their no financial assistance counterparts, participants receiving financial assistance due to burns were more likely to be minorities (19% vs 14%), have more severe injuries (%TBSA burn 21% vs 10%), and receive workers' compensation (24% vs 9%). They also had lower health-related quality of life scores on all metrics except the post-traumatic growth inventory. Financial assistance may aid in combating disparities in posttraumatic growth scores for participants at the greatest risk of financial toxicity but does not improve other health-related quality of life metrics. [ABSTRACT FROM AUTHOR]

Secretory leucoprotease inhibitor (SLPI) has multifaceted functions, including inhibition of protease activity, antimicrobial functions, and anti-inflammatory properties. In this study, we show that SLPI plays a role in controlling pulmonary Pseudomonas aeruginosa infection. Mice lacking SLPI were highly susceptible to P. aeruginosa infection, however there was no difference in bacterial burden. Utilising a model of P. aeruginosa LPS-induced lung inflammation, human recombinant SLPI (hrSLPI) administered intraperitoneally suppressed the recruitment of inflammatory cells in the bronchoalveolar lavage fluid (BALF) and resulted in reduced BALF and serum levels of inflammatory cytokines and chemokines. This anti-inflammatory effect of hrSLPI was similarly demonstrated in a systemic inflammation model induced by intraperitoneal injection of LPS from various bacteria or lipoteichoic acid, highlighting the broad anti-inflammatory properties of hrSLPI. Moreover, in bone-marrow-derived macrophages, hrSLPI reduced LPS-induced phosphorylation of p-IkB-α, p-IKK-α/β, p-P38, demonstrating that the anti-inflammatory effect of hrSLPI was due to the inhibition of the NFκB and MAPK pathways. In conclusion, administration of hrSLPI attenuates excessive inflammatory responses and is therefore, a promising strategy to target inflammatory diseases such as acute respiratory distress syndrome or sepsis and could potentially be used to augment antibiotic treatment. [ABSTRACT FROM AUTHOR]

Introduction: Pathologic remodeling of the brain following ischemic stroke results in neuronal loss, increased inflammation, oxidative stress, astrogliosis, and a progressive decrease in brain function. We recently demonstrated that stimulation of steroid receptor coactivator 3 with the small-molecule stimulator MCB-613 improves cardiac function in a mouse model of myocardial ischemia. Since steroid receptor coactivators are ubiquitously expressed in the brain, we reasoned that an MCB-613 derivative (MCB-10-1), could protect the brain following ischemic injury. To test this, we administered MCB-10-1 to rats following middle cerebral artery occlusion and reperfusion. Methods: Neurologic impairment and tissue damage responses were evaluated on day 1 and day 4 following injury in rats treated with control or 10-1. Results: We show that 10-1 attenuates injury post-stroke. 10-1 decreases infarct size and mitigates neurologic impairment. When given within 30 min post middle cerebral artery occlusion and reperfusion, 10-1 induces lasting protection from tissue damage in the ischemic penumbra concomitant with: (1) promotion of reparative microglia; (2) an increase in astrocyte NRF2 and GLT-1 expression; (3) early microglia activation; and (4) attenuation of astrogliosis. Discussion: Steroid receptor coactivator stimulation with MCB-10- 1 is a potential therapeutic strategy for reducing inflammation and oxidative damage that cause neurologic impairment following an acute ischemic stroke. [ABSTRACT FROM AUTHOR]

The diversity and relative abundances of tetraether lipids produced by archaea and bacteria in soils and sediments are increasingly used to assess environmental change. For instance, the TetraEther indeX of 86 carbon atoms (TEX 86), based on archaeal isoprenoidal glycerol dialkyl glycerol tetraether (iGDGT) lipids, is frequently applied to reconstruct past sea-surface temperatures (SSTs). Yet, it is unknown how the ratio fully responds to environmental and/or geochemical variations and if the produced signals are largely the adaptive response by Thaumarchaeota to oceanographic effects associated with climate or seasonal temperature changes in the upper water column. We present the results of a four push-core transect study of surface sediments collected along an environmental gradient at the Cathedral Hill hydrothermal-vent system in Guaymas Basin, Gulf of California. The transect crosses a region where advecting hydrothermal fluids reach 155 ∘ C within the upper 21 cm below the seafloor (cm b.s.f.) close to the vent center to near-ambient conditions at the vent periphery. The recovered iGDGTs closest to the vent center experienced high rates of turnover with up to 94 % of the lipid pool being lost within the upper 21 cm b.s.f. Here, we show that the turnover is non-selective across TEX 86 GDGT lipids and does not affect the ratio independently. However, as evident by TEX 86 ratios being highly correlated to the Cathedral Hill vent sediment porewater temperatures (R2=0.84), the ratio can be strongly impacted by the combination of severe lipid loss coupled with the addition of in situ iGDGT production from archaeal communities living in the vent sediments. The resulting overprint produces absolute temperature offsets of up to 4 ∘ C based on the TEX 86H calibration relative to modern climate records of the region. The overprint is also striking given the flux of iGDGTs from the upper water column is estimated to be ∼ 93 % of the combined intact polar lipid (IPL) and core GDGT lipid pool initially deposited on the seafloor. A model to correct the overprint signal using IPLs is therefore presented that can similarly be applied to all near-surface marine sediment systems where calibration models or climate reconstructions are made based on the TEX 86 measure. [ABSTRACT FROM AUTHOR]

Background: One of the most feared complications following treatment of Dupuytren contracture is complex regional pain syndrome (CRPS). This study aims to provide a national perspective on the incidence of CRPS following treatment of Dupuytren contracture and identify patient factors to target for risk reduction. Methods: Using the Truven MarketScan databases from 2007 to 2016, individuals aged ≥18 years who developed CRPS within 1 year of treatment of Dupuytren contracture were identified using the International Classification of Disease diagnosis code for CRPS. Predictor variables included: age, sex, employment status, region, type of procedure, and concurrent carpal tunnel surgery. Multivariable logistic regression was used to analyze outcomes. Results: In all, 48 327 patients received treatment for Dupuytren contracture, including collagenase injection (13.6%); percutaneous palmar fasciotomy (10.3%); open palmar fasciotomy (3.9%); palmar fasciectomy with 0 (10.8%), 1 (29.2%), or multiple (19.6%) digit releases; or a combination of these procedures (12.8%). One hundred forty-five patients (0.31%) were diagnosed with CRPS at a mean of 3.4 months (standard deviation, 2.3) following treatment. Significant predictors of CRPS included female sex (odds ratio [OR], 2.02; P <.001), Southern region (OR, 1.80; P =.022), long-term disability status (OR, 4.73; P =.035), palmar fasciectomy with release of 1 (OR, 5.91; P =.003) or >1 digit (OR, 13.32; P <.001), or multiple concurrent procedures for Dupuytren contracture (OR, 8.23; P =.001). Conclusions: Based on national commercial claims data, there is a lower incidence of CRPS following treatment of Dupuytren contracture than previously reported. Risk factors identified should help with preoperative counseling and assist clinicians in targeting risk reduction measures. [ABSTRACT FROM AUTHOR]

Limited evidence suggests that obesity adversely affects burn outcomes. However, the impacts of body mass index (BMI) across the continuum have not been fully characterized. Therefore, we aimed to characterize outcomes after burn injury across the BMI continuum. We hypothesized that "normal" BMI (18.5-24.9) would have the lowest mortality and complication rates. The US National Trauma Data Bank (NTDB) was queried for adult burn-injured patients from 2007 to 2015. Admission BMI was calculated and grouped according to World Health Organization (WHO) classification. The primary outcome was in-hospital mortality. Secondary outcomes of time to wound closure, length of stay, and inpatient complications were similarly assessed. Of the 116,008 burn patient encounters that were identified, 7243 underwent at least one operation for wound closure. Mortality was lowest in the overweight (P = .039) and obese I cohorts (BMI 25-29.9, 30.0-34.9) at 2.9% and increased in both directions of the BMI continuum to 4.1% in the underweight (P = .032) and 5.1% in the morbidly obese (class III) group (P = .042). Time to final wound closure was longest in the two BMI extremes. BMI ≥40 was associated with increased intensive care unit days, ventilator days, renal and cardiac complications. BMI <18.5 had increased hospital days and rates of sepsis. Aberrations in metabolism associated with both increases and decreases of body weight may cause pathophysiologic changes that lead to worsened outcomes in burn-injured patients. In addition to morbidly obese patients, underweight patients also experience increased burn-related death and complications. In contrast, overweight BMI patients may have greater physiologic reserves without the burden of obesity or sarcopenia. [ABSTRACT FROM AUTHOR]

Purpose: Health care insurance claims databases are becoming a more common data source for studies of medication safety during pregnancy. While pregnancies have historically been identified in such databases by pregnancy outcomes, International Classification of Diseases, 10th revision Clinical Modification (ICD‐10‐CM) Z3A codes denoting weeks of gestation provide more granular information on pregnancies and pregnancy periods (i.e., start and end dates). The purpose of this study was to develop a process that uses Z3A codes to identify pregnancies, pregnancy periods, and links infants within a commercial health insurance claims database. Methods: We identified pregnancies, gestation periods, pregnancy outcomes, and linked infants within the US‐based Optum Research Database between 2015 and 2020 via a series of algorithms utilizing diagnosis and procedure codes on claims. The diagnosis and procedure codes included ICD‐10‐CM codes, Current Procedural Terminology (CPT) codes, and Healthcare Common Procedure Coding System (HCPCS) codes. Results: We identified 1 030 874 pregnancies among 841 196 women of reproductive age. Of pregnancies with livebirth outcomes, 84% were successfully linked to infants. The prevalence of pregnancy outcomes (livebirth, stillbirth, ectopic, molar, and abortion) was similar to national estimates. Conclusions: This process provides an opportunity to study drug safety and care patterns during pregnancy and may be replicated in other claims databases containing ICD‐10‐CM, CPT, and HCPCS codes. Work is underway to validate and refine the various algorithms. [ABSTRACT FROM AUTHOR]

Background: Electronic health record (EHR) databases provide an opportunity to facilitate characterization and trends in patients with COVID-19. Methods: Patients with COVID-19 were identified based on an ICD-10 diagnosis code for COVID-19 (U07.1) and/or a positive SARS-CoV-2 viral lab result from January 2020 to November 2020. Patients were characterized in terms of demographics, healthcare utilization, clinical comorbidities, therapies, laboratory results, and procedures/care received, including critical care, intubation/ventilation, and occurrence of death were described, overall and by month. Results: There were 393,773 patients with COVID-19 and 56,996 with a COVID-19 associated hospitalization. A greater percentage of patients hospitalized with COVID-19 relative to all COVID-19 cases were older, male, African American, and lived in the Northeast and South. The most common comorbidities before admission/infection date were hypertension (40.8%), diabetes (29.5%), and obesity (23.8%), and the most common diagnoses during hospitalization were pneumonia (59.6%), acute respiratory failure (44.8%), and dyspnea (28.0%). A total of 85.7% of patients hospitalized with COVID-19 had CRP values > 10 mg/L, 75.5% had fibrinogen values > 400 mg/dL, and 76.8% had D-dimer values > 250 ng/mL. Median values for platelets, CRP, lactate dehydrogenase, D-dimer, and fibrinogen tended to decrease from January-March to November. The use of chloroquine/hydroxychloroquine during hospitalization peaked by March (71.2%) and was used rarely by May (5.1%) and less than 1% afterwards, while the use of remdesivir had increased by May (10.0%) followed by dexamethasone by June (27.7%). All-cause mortality was 3.2% overall and 15.0% among those hospitalized; 21.0% received critical care and 16.0% received intubation/ventilation/ECMO. Conclusions: This study characterizes US patients with COVID-19 and their management during hospitalization over the first eleven months of this disease pandemic. [ABSTRACT FROM AUTHOR]

Background: Dorsal wrist ganglion cysts arise from the leakage of synovial fluid through tears in the scapholunate ligament and/or dorsal wrist capsule. An analogous disruption of the dorsal capsule is created with routine portal placement during wrist arthroscopy. We hypothesized that wrist arthroscopy would predispose to wrist ganglions. Methods: Using the Truven MarketScan Outpatient Services Database from 2015 to 2016, patients who underwent wrist arthroscopy and developed an ipsilateral wrist ganglion were identified. Exclusion criteria included ganglion diagnosis preceding arthroscopy and bilateral pathology. Postoperative ganglion diagnosis was modeled with logistic regression. Predictor variables included age, gender, comorbidities, and arthroscopic procedure. Results: In all, 2420 patients underwent wrist arthroscopy. Thirty (1.24%) were diagnosed with an ipsilateral wrist ganglion at a mean time of 4.0 months (standard deviation: 2.4, range: 0.2-9.0). Significant predictors of ganglion diagnosis included female gender (odds ratio [OR]: 4.0, P <.01) and triangular fibrocartilage complex and/or joint debridement (OR: 0.13, P <.01). By comparison, among all 24,718,751 outpatients who had not undergone wrist arthroscopy, 39,832 patients had a diagnosis of a wrist ganglion cyst (0.16%). Conclusions: Wrist arthroscopy is associated with a postoperative rate of ganglion cyst formation that is nearly 8 times the rate in the general population. Additional studies are needed to investigate techniques that minimize the risk of this complication. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) complicates the treatment of burn injuries. Foot burns in diabetic patients are challenging problems with unfavorable outcomes. National-scale evaluations are needed, especially with regard to limb salvage. We aim to characterize lower-extremity burns in persons with DM and evaluate the likelihood of amputation. The National Trauma Data Bank (NTDB) was queried from 2007 to 2015 extracting encounters with primary burn injuries of the feet using International Classification of Diseases (ICD) 9th edition codes. Logistic regression modeled predictors of lower-extremity amputation. Covariables included age, sex, race/ethnicity, comorbidities including DM, % burn TBSA, mechanism, and region of burn center. Poisson regression evaluated temporal incidence rate changes in DM foot burns. Of 116,796 adult burn encounters, 7963 (7%) had foot burns. Of this group, 1308 (16%) had DM. 5.6% of encounters with DM foot burns underwent amputation compared to 1.5% of non-DM encounters (P < .001). Independent predictors of lower-extremity amputation included DM (odds ratio 3.70, 95% confidence interval 2.98-4.59), alcohol use, smoking, chronic kidney disease, and burn size >20%, African-American/black race, male sex, and age >40 years (all P < .01). The incidence of DM foot burns increased over the study period with an incidence rate ratio of 1.07 (95% confidence interval 1.05-1.10, P < .001). In conclusion, DM was associated with nearly a 4-fold increase in amputation after adjusting for covariables. Furthermore, the incidence of DM foot burns is increasing. Strategies for optimizing care in persons with DM foot burns are need to improve limb salvage. [ABSTRACT FROM AUTHOR]

Background: There are limited data on risk factors for serious outcomes and death from COVID-19 among patients representative of the U.S.Population: The objective of this study was to determine risk factors for critical care, ventilation, and death among hospitalized patients with COVID-19.Methods: This was a cohort study using data from Optum's longitudinal COVID-19 electronic health record database derived from a network of healthcare provider organizations across the US. The study included patients with confirmed COVID-19 (presence of ICD-10-CM code U07.1 and/or positive SARS-CoV-2 test) between January 2020 and November 2020. Patient characteristics and clinical variables at start of hospitalization were evaluated for their association with subsequent serious outcomes (critical care, mechanical ventilation, and death) using odds ratios (OR) and 95% confidence intervals (CI) from logistic regression, adjusted for demographic variables.Results: Among 56,996 hospitalized COVID-19 patients (49.5% male and 72.4% ≥ 50 years), 11,967 received critical care, 9136 received mechanical ventilation, and 8526 died. The median duration of hospitalization was 6 days (IQR: 4, 11), and this was longer among patients that experienced an outcome: 11 days (IQR: 6, 19) for critical care, 15 days (IQR: 8, 24) for mechanical ventilation, and 10 days (IQR: 5, 17) for death. Dyspnea and hypoxemia were the most prevalent symptoms and both were associated with serious outcomes in adjusted models. Additionally, temperature, C-reactive protein, ferritin, lactate dehydrogenase, D-dimer, and oxygen saturation measured during hospitalization were predictors of serious outcomes as were several in-hospital diagnoses. The strongest associations were observed for acute respiratory failure (critical care: OR, 6.30; 95% CI, 5.99-6.63; ventilation: OR, 8.55; 95% CI, 8.02-9.11; death: OR, 3.36; 95% CI, 3.17-3.55) and sepsis (critical care: OR, 4.59; 95% CI, 4.39-4.81; ventilation: OR, 5.26; 95% CI, 5.00-5.53; death: OR, 4.14; 95% CI, 3.92-4.38). Treatment with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers during hospitalization were inversely associated with death (OR, 0.57; 95% CI, 0.54-0.61).Conclusions: We identified several clinical characteristics associated with receipt of critical care, mechanical ventilation, and death among COVID-19 patients. Future studies into the mechanisms that lead to severe COVID-19 disease are warranted. [ABSTRACT FROM AUTHOR]

Rationale: Although the cysteine protease cathepsin S has been implicated in the pathogenesis of several inflammatory lung diseases, its role has not been examined in the context of acute respiratory distress syndrome, a condition that still lacks specific and effective pharmacological treatments. Objectives: To characterize the status of cathepsin S in acute lung inflammation and examine the role of cathepsin S in disease pathogenesis. Methods: Human and mouse model BAL fluid samples were analyzed for the presence and activity of cathepsin S and its endogenous inhibitors. Recombinant cathepsin S was instilled directly into the lungs of mice. The effects of cathepsin S knockout and pharmacological inhibition were examined in two models of acute lung injury. Protease-activated receptor-1 antagonism was used to test a possible mechanism for cathepsin S–mediated inflammation. Measurements and Main Results: Pulmonary cathepsin S concentrations and activity were elevated in acute respiratory distress syndrome, a phenotype possibly exacerbated by the loss of the endogenous antiprotease cystatin SN. Direct cathepsin S instillation into the lungs induced key pathologies of acute respiratory distress syndrome, including neutrophilia and alveolar leakage. Conversely, in murine models of acute lung injury, genetic knockdown and prophylactic or therapeutic inhibition of cathepsin S reduced neutrophil recruitment and protein leakage. Cathepsin S may partly mediate its pathogenic effects via protease-activated receptor-1, because antagonism of this receptor abrogated cathepsin S–induced airway inflammation. Conclusions: Cathepsin S contributes to acute lung injury and may represent a novel therapeutic target for acute respiratory distress syndrome. [ABSTRACT FROM AUTHOR]