REALM-DCM: A Phase 3, Multinational, Randomized, Placebo-Controlled Trial of ARRY-371797 in Patients With Symptomatic LMNA-Related Dilated Cardiomyopathy.

BACKGROUND: LMNA (lamin A/C)-related dilated cardiomyopathy is a rare genetic cause of heart failure. In a phase 2 trial and long-term extension, the selective p38α MAPK (mitogen-activated protein kinase) inhibitor, ARRY-371797 (PF-07265803), was associated with an improved 6-minute walk test at 12 weeks, which was preserved over 144 weeks. METHODS: REALM-DCM (NCT03439514) was a phase 3, randomized, double-blind, placebo-controlled trial in patients with symptomatic LMNA-related dilated cardiomyopathy. Patients with confirmed LMNA variants, New York Heart Association class II/III symptoms, left ventricular ejection fraction ≤50%, implanted cardioverter-defibrillator, and reduced 6-minute walk test distance were randomized to ARRY-371797 400 mg twice daily or placebo. The primary outcome was a change from baseline at week 24 in the 6-minute walk test distance using stratified Hodges-Lehmann estimation and the van Elteren test. Secondary outcomes using similar methodology included change from baseline at week 24 in the Kansas City Cardiomyopathy Questionnaire-physical limitation and total symptom scores, and NT-proBNP (N-terminal pro-B-type natriuretic peptide) concentration. Time to a composite outcome of worsening heart failure or all-cause mortality and overall survival were evaluated using Kaplan-Meier and Cox proportional hazards analyses. RESULTS: REALM-DCM was terminated after a planned interim analysis suggested futility. Between April 2018 and October 2022, 77 patients (aged 23-72 years) received ARRY-371797 (n=40) or placebo (n=37). No significant differences (P>0.05) between groups were observed in the change from baseline at week 24 for all outcomes: 6-minute walk test distance (median difference, 4.9 m [95% CI, -24.2 to 34.1]; P=0.82); Kansas City Cardiomyopathy Questionnaire-physical limitation score (2.4 [95% CI, -6.4 to 11.2]; P=0.54); Kansas City Cardiomyopathy Questionnaire-total symptom score (5.3 [95% CI, -4.3 to 14.9]; P=0.48); and NT-proBNP concentration (-339.4 pg/mL [95% CI, -1131.6 to 452.7]; P=0.17). The composite outcome of worsening heart failure or all-cause mortality (hazard ratio, 0.43 [95% CI, 0.11-1.74]; P=0.23) and overall survival (hazard ratio, 1.19 [95% CI, 0.23-6.02]; P=0.84) were similar between groups. No new safety findings were observed. CONCLUSIONS: Findings from REALM-DCM demonstrated futility without safety concerns. An unmet treatment need remains among patients with LMNA-related dilated cardiomyopathy. REGISTRATION: URL: https://classic.clinicaltrials.gov; Unique Identifiers: NCT03439514, NCT02057341, and NCT02351856.

The mechanosensitive Piezo1 channel exacerbates myocardial ischaemia/reperfusion injury by activating caspase-8-mediated PANoptosis.

PANoptosis is a newly discovered type of cell death characterized by pyroptosis, apoptosis and/or necroptosis and has been implicated in the inflammatory response. Piezo1 is a mechanosensitive ion channel that plays important roles in physiological development and various diseases. However, whether cardiomyocytes undergo PANoptosis during myocardial ischaemia/reperfusion (I/R) injury and the role of Piezo1 in this process remain largely unexplored. In this study, our results revealed that the expression levels of the main components of the PANoptosome, including caspase-8, caspase-3, NLRP3, caspase-1, GSDMD, RIPK1, RIPK3 and MLKL, were significantly upregulated in I/R heart tissues over time, indicating the occurrence of PANoptosis in I/R hearts. Accordingly, Piezo1 expression was significantly upregulated in I/R-injured hearts and hypoxia/reoxygenation (H/R)-treated cardiomyocytes. In contrast, pharmacological inhibition of Piezo1 by the inhibitor GsMTx4 in mice markedly attenuated the I/R-mediated decline in cardiac contractile function and increases in infarct size, apoptosis, oxidative stress and inflammation accompanied by the inhibition of PANoptosis-related mediators in I/R hearts. Consistently, the effects of Piezo1 on calcium influx and PANoptosis were further verified by GsMTx4 and Piezo1 activator Yoda1 in H/R-treated cardiomyocytes in vitro. Moreover, caspase-8 rather than calcium influx was required for H/R-induced PANoptosis in vitro. Mechanistically, Piezo1 interacts with caspase-8, a key initial activator of the PANoptosome complex, which subsequently activates cardiomyocyte PANoptosis, leading to cardiac dysfunction. In summary, these data suggest that Piezo1 is a new cardiac mechanosensor that promotes cardiac I/R injury possibly through the caspase-8-mediated activation of cardiomyocyte PANoptosis and highlight that Piezo1 may represent a new target for treating ischaemic heart disease.

Longevity of acrylic and cobalt-chromium removable partial dentures-A ten-year retrospective survival analysis of 1246 denture-wearing patients.

OBJECTIVES: to assess the survival rates of removable partial dentures (RPDs) and identify factors impacting their longevity. METHODS: electronic health records were retrieved of patients aged ≥18 who received RPDs between 2010 - 2021 with a follow-up of ≥ three months. Data extracted included demographics, medical history, dental charting, periodontal screening and recording scores, prostheses details and related interventions, including new dentures/denture remakes, and maintenance. Multivariate Mixed-Effect Cox regression was performed to identify potential RPD survival risk factors. Reduced model selection was reached using a backward step-down by comparing the performance of these multivariable models using the ANOVA test. RESULTS: 1893 RPDs from 1246 patients were included, with a median follow-up of 21.8 months (range from 3 to 131.3 months). Three hundred and twelve patients received a maxillary RPD, 460 received a mandibular RPD, and the remaining 474 patients received both maxillary and mandibular RPDs. Metal-based RPDs had a median survival of 73 months (95%CI: 70 - 82) versus 45 months (95% CI: 37-67) for acrylic ones. Multivariable mixed effects Cox model showed that the lifespans of RPDs were longer amongst patients receiving more maintenance care within three months [Hazards Ratio (HR)=0.89 (0.83, 0.96)] and after three months [HR=0.53 (0.46, 0.61)] of denture delivery, patients wearing both maxillary and mandibular RPDs [HR=0.67 (0.52, 0.87)], and patients receiving metal-based RPDs [HR=0.31 (0.23, 0.42)]. CONCLUSIONS: Metal-based dentures, dual arch restoration, and increased maintenance positively impact the survival of RPDs. CLINICAL SIGNIFICANCE: Adapting consent and warranty practices is advised to reflect RPD performance variations.

The role of the immunoproteasome in cardiovascular disease.

The ubiquitinproteasome system (UPS) is the main mechanism responsible for the intracellular degradation of misfolded or damaged proteins. Under inflammatory conditions, the immunoproteasome, an isoform of the proteasome, can be induced, enhancing the antigen-presenting function of the UPS. Furthermore, the immunoproteasome also serves nonimmune functions, such as maintaining protein homeostasis and regulating signalling pathways, and is involved in the pathophysiological processes of various cardiovascular diseases (CVDs). This review aims to provide a comprehensive summary of the current research on the involvement of the immunoproteasome in cardiovascular diseases, with the ultimate goal of identifying novel strategies for the treatment of these conditions.

Development of a nomogram for identifying periodontitis cases in Denmark.

Although self-reported health outcomes are of importance, attempts to validate a clinical applicable instrument (e.g., nomogram) combining sociodemographic and self-reported information on periodontitis have yet to be performed to identify periodontitis cases. Clinical and self-reported periodontitis, along with sociodemographic data, were collected from 197 adults. Akaike information criterion models were developed to identify periodontitis, and nomograms developed based on its regression coefficients. The discriminatory capability was evaluated by receiver-operating characteristic curves. Decision curve analysis was performed. Smoking [OR 3.69 (95%CI 1.89, 7.21)], poor/fair self-rated oral health [OR 6.62 (95%CI 3.23, 13.56)], previous periodontal treatment [OR 9.47 (95%CI 4.02, 22.25)], and tooth loss [OR 4.96 (95%CI 2.47, 9.97)], determined higher probability of having "Moderate/Severe Periodontitis". Age [OR 1.08 (95%CI 1.05, 1.12)], low educational level [OR 1.65 (95%CI 1.34, 2.23)], poor/fair self-rated oral health [OR 3.57 (95%CI 1.82, 6.99)], and previous periodontal treatment [OR 6.66 (95%CI 2.83, 15.68)] determined higher probability for "Any Periodontitis". Both nomograms showed excellent discriminatory capability (AUC of 0.83 (95%CI 0.75, 0.91) and 0.81 (95% CI 0.74, 0.88), good calibration, and slight overestimation of high risk and underestimation of low risk. Hence, our nomograms could help identify periodontitis among adults in Denmark.

Nonmesothelial Spindle Cell Tumors of Pleura and Pericardium.

Spindle cell lesions of the pleura and pericardium are rare. Distinction from sarcomatoid mesothelioma, which has a range of morphologic patterns, can be difficult, but accurate diagnosis matters. This article provides practical guidance for the diagnosis of pleural spindle cell neoplasms, focusing on primary lesions.

Atom-Level Tandem Catalysis in Lithium Metal Batteries.

High-energy-density lithium metal batteries (LMBs) are limited by reaction or diffusion barriers with dissatisfactory electrochemical kinetics. Typical conversion-type lithium sulfur battery systems exemplify the kinetic challenges. Namely, before diffusing or reacting in the electrode surface/interior, the Li(solvent)x + dissociation at the interface to produce isolated Li+, is usually a prerequisite fundamental step either for successive Li+ "reduction" or for Li+ to participate in the sulfur conversions, contributing to the related electrochemical barriers. Thanks to the ideal atomic efficiency (100 at%), single atom catalysts (SACs) have gained attention for use in LMBs toward resolving the issues caused by the five types of barrier-restricted processes, including polysulfide/Li2S conversions, Li(solvent)x + desolvation, and Li0 nucleation/diffusion. In this perspective, the tandem reactions including desolvation and reaction or plating and corresponding catalysis behaviors are introduced and analyzed from interface to electrode interior. Meanwhile, the principal mechanisms of highly efficient SACs in overcoming specific energy barriers to reinforce the catalytic electrochemistry are discussed. Lastly, the future development of high-efficiency atomic-level catalysts in batteries is presented.

3D amide proton transfer-weighted imaging may be useful for diagnosing early-stage breast cancer: a prospective monocentric study.

BACKGROUND: We investigated the value of three-dimensional amide proton transfer-weighted imaging (3D-APTWI) in the diagnosis of early-stage breast cancer (BC) and its correlation with the immunohistochemical characteristics of malignant lesions. METHODS: Seventy-eight women underwent APTWI and dynamic contrast-enhanced (DCE)-MRI. Pathological results were categorized as either benign (n = 43) or malignant (n = 37) lesions. The parameters of APTWI and DCE-MRI were compared between the benign and malignant groups. The diagnostic value of 3D-APTWI was evaluated using the area under the receiver operating characteristic curve (ROC-AUC) to establish a diagnostic threshold. Pearson's correlation was used to analyze the correlation between the magnetization transfer asymmetry (MTRasym) and immunohistochemical characteristics. RESULTS: The MTRasym and time-to-peak of malignancies were significantly lower than those of benign lesions (all p < 0.010). The volume transfer constant, rate constant, and wash-in and wash-out rates of malignancies were all significantly greater than those of benign lesions (all p < 0.010). ROC-AUCs of 3D-APTWI, DCE-MRI, and 3D-APTWI+DCE to differential diagnosis between early-stage BC and benign lesions were 0.816, 0.745, and 0.858, respectively. Only the difference between AUCAPT+DCE and AUCDCE was significant (p < 0.010). When a threshold of MTRasym for malignancy for 2.42%, the sensitivity and specificity of 3D-APTWI for BC diagnosis were 86.5% and 67.6%, respectively; MTRasym was modestly positively correlated with pathological grade (r = 0.476, p = 0.003) and Ki-67 (r = 0.419, p = 0.020). CONCLUSIONS: 3D-APTWI may be used as a supplementary method for patients with contraindications of DCE-MRI. MTRasym can imply the proliferation activities of early-stage BC. RELEVANCE STATEMENT: 3D-APTWI can be an alternative diagnostic method for patients with early-stage BC who are not suitable for contrast injection. KEY POINTS: • 3D-APTWI reflects the changes in the microenvironment of early-stage breast cancer. • Combined 3D-APTWI is superior to DCE-MRI alone for early-stage breast cancer diagnosis. • 3D-APTWI improves the diagnostic accuracy of early-stage breast cancer.

Innovative Percutaneous 3 Stitch Suture Technique for Site Closure in Venoarterial Extracorporeal Membrane Oxygenation Decannulation Without Direct Artery Repair: A Case Series.

No previous studies have reported the use of a percutaneous suture technique performed by bedside intensivists for site closure during decannulation without direct artery repair in venoarterial extracorporeal membrane oxygenation (VA-ECMO) cases. Thus, the objective of this study was to evaluate the safety and effectiveness of this alternative approach. This retrospective study included 26 consecutive patients who underwent percutaneous VA-ECMO decannulation at Maoming People's Hospital. Bedside percutaneous suture technique performed by intensivists facilitated cannula site closure. Primary outcome was successful closure without additional interventions. Secondary outcomes included procedural time, surgical conversion rate, complications (bleeding, vascular/wound complications, neuropathy, lymphocele), procedure-related death. Follow-up ultrasound were conducted within 6 months after discharge. All patients achieved successful site hemostasis with a median procedural time of 28 minutes. Procedure-related complications included minor bleeding (7.7%), acute lower limb ischemia (15.4%), venous thrombus (11.5%), minor arterial stenosis (7.7%), wound infection (4.2%), delayed healing (15.4%), and wound secondary suturing (6.3%). No procedure-related deaths occurred. Follow-up vascular ultrasound revealed two cases (7.7%) of minor arterial stenosis. The perivascular suture technique may offer intensivists a safe and effective alternative method for access site closure without direct artery suture during ECMO decannulation.

ACE2 Rescues Sepsis-Associated Encephalopathy by Reducing Inflammation, Oxidative Stress, and Neuronal Apoptosis via the Nrf2/Sestrin2 Signaling Pathway.

Neuroinflammation and oxidative stress contribute to the progression of sepsis-associated encephalopathy (SAE). Angiotensin-converting enzyme 2 (ACE2) is considered to be a neuroprotective factor due to its anti-inflammatory and antioxidant properties. However, the role of ACE2 on myeloid cells in regulating SAE and the underlying mechanism warrants further exploration. SAE was induced in ACE2 transgenic (TG), knockout (KO), and bone marrow (BM) chimeric mice by cecal ligation and puncture (CLP). The expression levels of apoptosis-, oxidation- and neuroinflammation-associated mediators and morphological changes were monitored by quantitative real-time PCR analyses and histological examinations in the cortex of septic mice. The contents of angiotensin (Ang) II and Ang-(1-7) along with the activity of ACE2 were examined with commercial kits. The expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and Sestrin2 was detected by immunoblotting analysis. Our results indicated that the expression of cortical ACE2 was significantly reduced in the early phase of CLP-induced sepsis. Moreover, ACE2 overexpression in TG mice conferred neuroprotection against sepsis, as evidenced by alleviated neuronal apoptosis, oxidative stress, and proinflammatory M1-like microglial polarization, accompanied by upregulation of the Ang-(1-7), Nrf2, and Sestrin2 protein levels. Conversely, ACE2 deficiency in KO mice exacerbated SAE. The neuroprotective effects of ACE2 were further confirmed in wild-type mice transplanted with ACE2-TG and KO BM cells. Therefore, our data suggest that myeloid ACE2 exerts a protective role in the pathogenesis of SAE, potentially by activating Ang-(1-7)-Nrf2/sestrin2 signaling pathway, and highlight that upregulating ACE2 expression and activity may represent a promising approach for the treatment of SAE in patients with sepsis.

Chewing Disability Is Associated With Cognitive Impairment Among Older Adults: A Population-Based Cohort Study.

BACKGROUND: Chewing disability is associated with impaired quality of life, potentially leading to depression, and cognitive impairment. Although the chewing-ability-cognition relationship has been explored, examining whether depression mediates this relationship remains unclear. We investigated the association between chewing disability and cognitive impairment development and a potential mediation via depression among older persons. METHODS: Older persons without cognitive impairment at baseline (n = 973) from the 3 waves of the Panel on Health and Ageing of Singaporean Elderly were investigated. The outcome was incident cognitive impairment by the end of the study, while the exposure was chewing disability over the study period. Time-varying depression was the mediator. Time-fixed confounders included sex, ethnicity, education, marital status, living arrangement, and housing type, and time-varying confounders included age, smoking, cardiovascular diseases, diabetes, number of teeth, and denture wearing. We used marginal structural modeling to evaluate the effect of chewing disability on cognitive impairment development. RESULTS: After 6 years, 11% developed cognitive impairment, and chewing disability was reported by 33%. Chewing disability was associated with higher odds of developing cognitive impairment (OR 1.43, 95% CI: 1.09, 1.87), of which 85.3% was explained by the controlled direct effect of chewing disability, whereas the remaining 14.7% could be eliminated if there was no depression. CONCLUSIONS: Our findings indicate an association between chewing disability and cognitive impairment, while the role of depression could not be fully elucidated. Oral health should be incorporated as part of older persons' care for its potential to assess the risk for other systemic conditions.

Sugar-sweetened beverage consumption and periodontitis among adults: A population-based cross-sectional study.

AIM: Investigating the association between sugar-sweetened beverages (SSBs) and periodontitis and whether the awareness of diabetes modifies this relationship. MATERIALS AND METHODS: Cross-sectional analysis was conducted using the National Health and Nutrition Examination Survey (NHANES III) data involving US adults aged 30-50. Periodontitis was classified according to the Centers for Disease Control and Prevention and American Academy of Periodontology (CDC-AAP), and SSB consumption as dichotomous (<5 or ≥5, <7 or ≥7 and <14 or ≥14 times/week), ordinal and continuous variables. Confounders included family income poverty ratio, education, race/ethnicity, sex, age, food energy intake, smoking and alcohol. Odds ratios (ORs) were obtained by logistic regressions using inverse probability weighting. Effect modification analysis was performed considering self-reported diabetes. RESULTS: Among 4473 cases analysed, 198 self-reported diabetes. SSBs were associated with periodontitis when individuals consumed ≥5 (OR 1.64; 95% confidence interval [CI] = 1.30-2.06), ≥7 (OR 1.92; 95% CI = 1.50-2.46) and ≥14 (OR 2.19; 95% CI = 1.50-3.18) times/week. The combined effect of consuming SSBs (≥5 and ≥14 times/week) and self-reported diabetes had less impact than the cumulative effect. CONCLUSIONS: SSB consumption was associated with higher odds of periodontitis, and the estimates were reduced among those with awareness of diabetes.

Incidence, mortality and survival rates of lip, oral cavity and salivary glands cancers in Singapore: A half-century time trend analysis (1968-2017).

OBJECTIVES: To examine trends in incidence and mortality and evaluate overall survival (OS) of oral cancer in Singapore between 1968 and 2017. METHODS: All diagnosed oral cancers by anatomical sites and population size were extracted from the Singapore Cancer Registry and the Department of Statistics Singapore. The trend of age-standardized incidence rate (ASIR) and mortality rate (ASMR) (per 100 000 person-years) of the lip, oral cavity and salivary gland cancers were evaluated by Prais-Winsten regressions for each ethnicity and gender. Kaplan-Meier curves were performed to evaluate the OS by anatomical sites in each age group by ethnicity and sex. RESULTS: Overall, 49, 3494 and 1066 people were diagnosed, and 28, 2310 and 476 died from lip, oral cavity and salivary gland cancers, respectively. The oral cavity cancer ASIR and ASMR reduced from 3.07 (1968-1972) to 2.01(2008-2012) and from 2.06 (1978-1982) to 1.21 (2013-2017) per 100 000 person-years, respectively, with both highest in Indians throughout the whole period. Male:Female ratio ranged from 3.43 (1973-1977) to 1.75 (2013-2017) and from 3.41 (1978-1982) to 2.40 (2013-2017) for ASIR and ASMR, respectively. However, both salivary gland cancer ASIR and ASMR increased from 0.50 (1968-1972) to 0.80 (2008-2012) and from 0.18 (1968-1982) to 0.42 (1988-1992) per 100 000 person-years, respectively, with both higher in males since 1993. Oral cavity cancer ASIR decreased for males aged ≥60, and Indian females ≥25, but increased among Chinese females aged ≥60. Oral cavity cancer ASMR decreased among Chinese aged 25-59, and among Malay males and Indian females. Salivary gland cancer ASIR increased among Chinese males aged ≥60 and Malay males aged 25-59; while ASMR increased among Chinese males aged ≥60. The median OS for oral cavity, lip and salivary gland cancers were 3.0, 9.3 and 18.1 years, respectively, with females surviving longer than males. CONCLUSIONS: Singapore has experienced a decline in the incidence and mortality of lip, oral cancer, an increase in in the incidence and mortality of salivary gland cancer, with an increase in the median overall survival rate. Monitoring the magnitude of oral cancer burden and the demographic, and temporal variations is necessary for tailoring health planning and setting priorities for future clinical care and research.

Research Progress of Hippocampal Dopamine System Changes in Perioperative Neurocognitive Disorders.

Perioperative neurocognitive disorders (PND) are a cognitive impairment that occurs after anesthesia, especially in elderly patients and significantly affects their quality of life. The hippocampus, as a critical region for cognitive function and an important location in PND research, has recently attracted increasing attention. However, in the hippocampus the impact of anesthesia and its underlying mechanisms remain unclear. This review focuses on investigation of the effects of anesthesia on the hippocampal dopamine (DA) system and explores its potential association with PND. Through comprehensive review of existing studies, it was found that anesthesia affects the hippocampus through various pathways involved in metabolism, synaptic plasticity and oxygenation. Anesthesia may also influence the DA neurotransmitter system in the brain which plays a role in emotions, rewards, learning and memory functions. Specifically, anesthesia may participate in the pathogenesis of PND by affecting the DA system within the hippocampus. Future studies should explore the molecular mechanisms of these effects through techniques such as neuroimaging to study real-time effects to improve animal models to better simulate clinical observations. For clinical application, it is recommended that physicians exercise caution when selecting and managing anesthetic drugs by adopting comprehensive cognitive assessment methods to reduce post-anesthesia cognitive risk. Overall, this review provides a better understanding of the relationship between the hippocampal DA system and perioperative neurocognitive function and provides valuable guidance for prevention and treatment strategies for PND.

ACE2 Expressed on Myeloid Cells Alleviates Sepsis-Induced Acute Liver Injury via the Ang-(1-7)-Mas Receptor Axis.

Sepsis-induced acute liver injury (ALI) is common in intensive care units. Angiotensin-converting enzyme 2 (ACE2) plays a vital role in hepatic fibrosis and steatosis; however, its role in sepsis-induced ALI remains unclear. This study found that hepatic ACE2 expression in cecal ligation and puncture (CLP)-treated mice significantly decreased 24 h after CLP. ACE2-transgenic (TG) mice exhibited a significant improvement in CLP-induced ALI, accompanied by the inhibition of hepatocyte apoptosis, oxidative stress, and inflammation, while ACE2-knockout mice demonstrated an opposite trend. During sepsis-induced ALI, ACE2-TG could also elevate the Ang-(1-7) and Mas receptor (MasR) levels in liver tissues. Interestingly, the MasR inhibitor A779 abrogated the favorable effects of ACE2 on CLP-induced ALI. In a bone marrow transplantation experiment, the ACE2-TG transplantation group showed significantly improved inflammation and liver dysfunction, less hepatocyte apoptosis, and reduced oxidative stress after CLP compared with the wild-type transplantation group. In contrast, the ACE2-knockout group showed poor inflammatory response and liver dysfunction, significantly more hepatocyte apoptosis, and elevated oxidative stress than the wild-type transplantation group after CLP. ACE2 protects against sepsis-induced ALI by inhibiting hepatocyte apoptosis, oxidative stress, and inflammation via the Ang-(1-7)-Mas receptor axis. Thus, targeting ACE2 may be a promising novel strategy for preventing and treating sepsis-induced ALI.

Zinc deficiency enhances sensitivity to influenza A associated bacterial pneumonia in mice.

Although zinc deficiency (secondary to malnutrition) has long been considered an important contributor to morbidity and mortality of infectious disease (e.g. diarrhea disorders), epidemiologic data (including randomized controlled trials with supplemental zinc) for such a role in lower respiratory tract infection are somewhat ambiguous. In the current study, we provide the first preclinical evidence demonstrating that although diet-induced acute zinc deficiency (Zn-D: ~50% decrease) did not worsen infection induced by either influenza A (H1N1) or methicillin-resistant staph aureus (MRSA), Zn-D mice were sensitive to the injurious effects of superinfection of H1N1 with MRSA. Although the mechanism underlying the sensitivity of ZnD mice to combined H1N1/MRSA infection is unclear, it was noteworthy that this combination exacerbated lung injury as shown by lung epithelial injury markers (increased BAL protein) and decreased genes related to epithelial integrity in Zn-D mice (surfactant protein C and secretoglobins family 1A member 1). As bacterial pneumonia accounts for 25%-50% of morbidity and mortality from influenza A infection, zinc deficiency may be an important pathology component of respiratory tract infections.