Pseudomonas aeruginosa inhibits quorum-sensing mechanisms of soft rot pathogen Lelliottia amnigena RCE to regulate its virulence factors and biofilm formation

The quorum-sensing (QS) cascade is responsible for the colonization and phenotypic behavior of the pathogenic organism and the regulation of diverse signal molecules. The disruption of the quorum-sensing system is an effective strategy to overcome the possibility of antibiotic resistance development in the pathogen. The quorum quenching does not kill the microbes. Instead, it hinders the expression of pathogenic traits. In the present experiment, Pseudomonas aeruginosa RKC1 was used to extract the metabolites responsible for quorum-sensing inhibition in soft rot pathogen Lelliottia amnigena RCE. During the initial screening, P. aeruginosa RKC1 was found to be most promising and inhibits violacein of Chromobacterium violaceum MTCC2656 pyocyanin, swarming-swimming motility of P. aeruginosa MTCC2297. The characterization of metabolites produced by the microbes which are responsible for quorum-sensing inhibition through GC-MS is very scarce in scientific literature. The ethyl acetate extract of P. aeruginosa RKC1 inhibits biofilm formation of L. amnigena RCE while inhibiting growth at higher concentrations. The GC-MS analysis suggested that Cyclic dipeptides (CDPs) such as Cyclo (L-prolyl-L-valine), Cyclo (Pro-Leu), and Cyclo(D-phenylalanyl-L-prolyl) were predominantly found in the ethyl acetate extract of the P. aeruginosa RKC1 (93.72%). This diketopiperazine (DKPs) exhibited quorum-sensing inhibition against the pathogen in liquid media during the active growth phase and regulated diverse metabolites of the pathogen. Moreover, the metabolites data from the clear zone around wells showed a higher concentration of DKSs (9.66%) compared to other metabolites. So far, very few reports indicate the role of DKPs or CDPs in inhibiting the quorum-sensing system in plant pathogenic bacteria. This is one such report that exploits metabolites of P. aeruginosa RKC1. The present investigation provided evidence to use quorum-sensing inhibitor metabolites, to suppress microbes' pathogenesis and thus develop an innovative strategy to overcome antibiotic resistance.Peer reviewe

Association of SNP–SNP Interactions of Surfactant Protein Genes with Pediatric Acute Respiratory Failure

The hallmarks of pediatric acute respiratory failure (ARF) are dysregulated inflammation and surfactant dysfunction. The objective is to study association of surfactant protein (SP) genes’ single nucleotide polymorphisms (SNPs) with ARF and its morbidity: pulmonary dysfunction at discharge (PDAD), employing a single-, two-, and three-SNP interaction model. We enrolled 468 newborn controls and 248 children aged ≤ 24 months with ARF; 86 developed PDAD. Using quantitative genetic principles, we tested the association of SP genes SNPs with ARF and PDAD. We observed a dominant effect of rs4715 of the SFTPC on ARF risk. In a three-SNP model, we found (a) 34 significant interactions among SNPs of SFTPA1, SFTPA2, and SFTPC associated with ARF (p = 0.000000002–0.05); 15 and 19 of those interactions were associated with increased and decreased risk for ARF, respectively; (b) intergenic SNP–SNP interactions of both hydrophobic and hydrophilic SP genes associated with PDAD (p = 0.00002–0.03). The majority of intra- and intergenic interactions associated with ARF involve the SFTPA2 SNPs, whereas most of the intra- and intergenic interactions associated with PDAD are of SFTPA1 SNPs. We also observed a dominant effect of haplotypes GG of SFTPA1 associated with increased and AA of SFTPC associated with decreased ARF risk (p = 0.02). To the best of our knowledge, this is the first study showing an association of complex interactions of SP genes with ARF and PDAD. Our data indicate that SP genes polymorphisms may contribute to ARF pathogenesis and subsequent PDAD and/or may serve as markers for disease susceptibility in healthy children

Trends in Costs of Birth Hospitalization and Readmissions for Late Preterm Infants

Background: The objective is to study previously unexplored trends of birth hospitalization and readmission costs for late preterm infants (LPIs) in the United States between 2005 and 2016. Methods: We conducted a retrospective analysis of claims data to study healthcare costs of birth hospitalization and readmissions for LPIs compared to term infants (TIs) using a large private insurance database. We used a generalized linear regression model to study birth hospitalization and readmission costs. Results: A total of 2,123,143 infants were examined (93.2% TIs; 6.8% LPIs). The proportion of LPIs requiring readmission was 4.2% compared to 2.1% of TIs, (p < 0.001). The readmission rate for TIs decreased during the study period. LPIs had a higher mean cost of birth hospitalization (25,700 vs. 3300 USD; p < 0.001) and readmissions (25,800 vs. 14,300 USD; p < 0.001). For LPIs, birth hospitalization costs increased from 2007 to 2013, and decreased since 2014. Conversely, birth hospitalization costs of TIs steadily increased since 2005. The West region showed higher birth hospitalization costs for LPIs. Conclusions: LPIs continue to have a higher cost of birth hospitalization and readmission compared to TIs, but these costs have decreased since 2014. Standardization of birth hospitalization care for LPIs may reduce costs and improve quality of care and outcomes

Sex and SP-A2 Dependent NAD(H) Redox Alterations in Mouse Alveolar Macrophages in Response to Ozone Exposure: Potential Implications for COVID-19

Co-enzyme nicotinamide adenine dinucleotide (NAD(H)) redox plays a key role in macrophage function. Surfactant protein (SP-) A modulates the functions of alveolar macrophages (AM) and ozone (O3) exposure in the presence or absence of SP-A and reduces mouse survival in a sex-dependent manner. It is unclear whether and how NAD(H) redox status plays a role in the innate immune response in a sex-dependent manner. We investigated the NAD(H) redox status of AM from SP-A2 and SP-A knockout (KO) mice in response to O3 or filtered air (control) exposure using optical redox imaging technique. We found: (i) In SP-A2 mice, the redox alteration of AM in response to O3 showed sex-dependence with AM from males being significantly more oxidized and having a higher level of mitochondrial reactive oxygen species than females; (ii) AM from KO mice were more oxidized after O3 exposure and showed no sex differences; (iii) AM from female KO mice were more oxidized than female SP-A2 mice; and (iv) Two distinct subpopulations characterized by size and redox status were observed in a mouse AM sample. In conclusions, the NAD(H) redox balance in AM responds to O3 in a sex-dependent manner and the innate immune molecule, SP-A2, contributes to this observed sex-specific redox response

Large epiphrenic diverticula: a rare case presentation

A 70-year old female was admitted to hospital with heartburn and chronic halitosis since 5 years. She was on proton pump inhibitors for the same. Her complaints worsened during the last one-year. Workup comprising of esophagogastro- duodenoscopy, esophageal manometry, 3D computed tomography scan showed rightsided epiphrenic diverticula measuring 10x10 cm with wide mouth about 5 cm with hypertensive lower esophageal sphincter. Patient underwent a video assisted thoracoscopic surgery for esophageal diverticulectomy using two 45 mm staplers. On day 5, the patient developed leak, which was managed by a covered esophageal stent placement. Patient started on oral feeds from day 3 and the esophageal leak healed completely within 2 weeks. Literature suggests that esophageal leaks treated conservatively took approximately 30-40 days on an average for healing. Literature search did not reveal esophageal leak managed by stent with faster recovery (2 weeks). This is one of the largest epiphrenic diverticuli reported in literature

Impact of Ozone, Sex, and Gonadal Hormones on Bronchoalveolar Lavage Characteristics and Survival in SP-A KO Mice Infected with <i>Klebsiella pneumoniae</i>

Surfactant protein A (SP-A) plays an important role in innate immunity. The sex-dependent survival of infected SP-A knockout (KO) mice has been observed. Our goal was to study the impact of ozone (O3) and sex, as well as gonadal hormones, on the bronchoalveolar lavage (BAL) readouts and survival, respectively, of Klebsiella pneumoniae-infected SP-A KO mice. Male and female SP-A KO mice were exposed to O3 or filtered air and infected with K. pneumoniae. We studied markers of inflammation and tissue damage at 4, 24, and 48 h, as well as the survival over 14 days, of gonadectomized (Gx) mice implanted with control pellets (CoP) or hormone (5α-dihydrotestosterone (DHT) in female gonadectomized mice (GxF) or 17β-estradiol (E2) in male gonadectomized mice (GxM)). We observed: (1) an increase in neutrophil and macrophage inflammatory protein-2 levels as time progressed post-infection, and O3 exposure appeared to increase this response; (2) an increase in lactate dehydrogenase, total protein, oxidized protein, and phospholipids in response to O3 with no consistent sex differences in studied parameters; and (3) a reduction in survival of the GxM and CoP mice, the GxM and E2 mice, and the GxF and DHT mice but not for the GxF and CoP mice after O3. Without SP-A, (a) sex was found to have a minimal impact on BAL cellular composition and tissue damage markers, and (b) the impact of gonadal hormones on survival was found to involve different mechanisms than in the presence of SP-A

Impact of Ozone, Sex, and Gonadal Hormones on Bronchoalveolar Lavage Characteristics and Survival in SP-A KO Mice Infected with Klebsiella pneumoniae

Surfactant protein A (SP-A) plays an important role in innate immunity. The sex-dependent survival of infected SP-A knockout (KO) mice has been observed. Our goal was to study the impact of ozone (O3) and sex, as well as gonadal hormones, on the bronchoalveolar lavage (BAL) readouts and survival, respectively, of Klebsiella pneumoniae-infected SP-A KO mice. Male and female SP-A KO mice were exposed to O3 or filtered air and infected with K. pneumoniae. We studied markers of inflammation and tissue damage at 4, 24, and 48 h, as well as the survival over 14 days, of gonadectomized (Gx) mice implanted with control pellets (CoP) or hormone (5&alpha;-dihydrotestosterone (DHT) in female gonadectomized mice (GxF) or 17&beta;-estradiol (E2) in male gonadectomized mice (GxM)). We observed: (1) an increase in neutrophil and macrophage inflammatory protein-2 levels as time progressed post-infection, and O3 exposure appeared to increase this response; (2) an increase in lactate dehydrogenase, total protein, oxidized protein, and phospholipids in response to O3 with no consistent sex differences in studied parameters; and (3) a reduction in survival of the GxM and CoP mice, the GxM and E2 mice, and the GxF and DHT mice but not for the GxF and CoP mice after O3. Without SP-A, (a) sex was found to have a minimal impact on BAL cellular composition and tissue damage markers, and (b) the impact of gonadal hormones on survival was found to involve different mechanisms than in the presence of SP-A

Cardiovascular complications in kidney transplant recipients with COVID-19: A case series

Kidney transplant recipients (KTRs) are at a higher risk for developing severe COVID-19 which can be associated with cardiovascular complications. We studied five KTRs recipients infected with COVID-19 who developed severe cardiovascular complications. Two patients presented with ST segment myocardial infarction and two with clinically suspected myocarditis. One patient presented with atrial fibrillation. Two of these patients developed cardiogenic shock. Inflammatory markers were at peak during the event in four of these who had presented with severe COVID-19. Coronary angiography done in two patients with STEMI did not reveal any evidence of atherosclerotic coronary artery disease. Also, based on the cardiovascular (CV) risk estimation by Framingham score, four patients had low CV risk and one patient had intermediate CV risk. All five patients survived. Even with low CV risk, KTRs can develop myocardial injury and arrhythmias solely because of severe COVID-19

Clinical course and outcomes of COVID-19 in kidney transplant recipients

Introduction: Kidney transplant recipients (KTR) are at increased risk of morbidity and mortality due to coronavirus disease 2019 (COVID-19). This study aimed to explore the clinical characteristics and outcomes of COVID-19 in KTR. Methods: We reviewed the clinical profile, outcomes, and immunological responses of recipients admitted with COVID-19. We determined the risk factors for mortality and severe COVID-19. Results: Out of 452 recipients on follow-up, 60 were admitted with COVID-19. Prevalent comorbidities were hypertension (71%), diabetes (40%), lung disease (17%). About 27% had tuberculosis. The median Sequential Organ Failure Assessment score at presentation was 3 (interquartile range [IQR] 1–5). There was a high incidence of diarrhea (52%) and anemia (82%). Treatment strategies included antimetabolite withdrawal (85%), calcineurin inhibitor decrease or withdrawal (64%), increased steroids (53%), hydroxychloroquine (21%), remdesivir (28.3%), and tocilizumab (3.3%). Severe COVID-19 occurred in 34 (56.4%) patients. During a median follow-up of 42.5 days (IQR 21–81 days), 83% developed acute kidney injury (AKI) and eight (13%) died. Mortality was associated with the baseline graft dysfunction, hypoxia at admission, lower hemoglobin and platelets, higher transaminases, higher C reactive protein, diffuse radiological lung involvement, hypotension requiring inotropes, and Kidney Diseases Improving Global Outcomes (KDIGO) stage 3 AKI (univariate analysis). Around 57% of patients remained RT-PCR positive at the time of discharge. By the last follow-up, 66.6% of patients developed IgM (immunoglobulin M) antibodies and 82.3% of patients developed IgG antibodies. Conclusion: COVID-19 in kidney transplant recipients is associated with a high risk of AKI and significant mortality