Absence Of Bacterial Infection Research Articles

3D-printed porous titanium rods equipped with vancomycin-loaded hydrogels and polycaprolactone membranes for intelligent antibacterial drug release

Implant-related infections pose significant challenges to orthopedic surgeries due to the high risk of severe complications. The widespread use of bioactive prostheses in joint replacements, featuring roughened surfaces and tight integration with the bone marrow cavity, has facilitated bacterial proliferation and complicated treatment. Developing antibacterial coatings for orthopedic implants has been a key research focus in recent years to address this critical issue. Researchers have designed coatings using various materials and antibacterial strategies. In this study, we fabricated 3D-printed porous titanium rods, incorporated vancomycin-loaded mPEG750-b-PCL2500 gel, and coated them with a PCL layer. We then evaluated the antibacterial efficacy through both in vitro and in vivo experiments. Our coating passively inhibits bacterial biofilm formation and actively controls antibiotic release in response to bacterial growth, providing a practical solution for proactive and sustained infection control. This study utilized 3D printing technology to produce porous titanium rod implants simulating bioactive joint prostheses. The porous structure of the titanium rods was used to load a thermoresponsive gel, mPEG750-b-PCL2500 (PEG: polyethylene glycol; PCL: polycaprolactone), serving as a novel drug delivery system carrying vancomycin for controlled antibiotic release. The assembly was then covered with a PCL membrane that inhibits bacterial biofilm formation early in infection and degrades when exposed to lipase solutions, mimicking enzymatic activity during bacterial infections. This setup provides infection-responsive protection and promotes drug release. We investigated the coating’s controlled release, antibacterial capability, and biocompatibility through in vitro experiments. We established a Staphylococcus aureus infection model in rabbits, implanting titanium rods in the femoral medullary cavity. We evaluated the efficacy and safety of the composite coating in preventing implant-related infections using imaging, hematology, and pathology. In vitro experiments demonstrated that the PCL membrane stably protects encapsulated vancomycin during PBS immersion. The PCL membrane rapidly degraded at a lipase concentration of 0.2 mg/mL. The mPEG750-b-PCL2500 gel ensured stable and sustained vancomycin release, inhibiting bacterial growth. We investigated the antibacterial effect of the 3D-printed titanium material, coated with PCL and loaded with mPEG750-b-PCL2500 hydrogel, using a rabbit Staphylococcus aureus infection model. Imaging, hematology, and histopathology confirmed that our composite antibacterial coating exhibited excellent antibacterial effects and infection prevention, with good safety in trials. Our results indicate that the composite antibacterial coating effectively protects vancomycin in the hydrogel from premature release in the absence of bacterial infection. The outer PCL membrane inhibits bacterial growth and prevents biofilm formation. Upon contact with bacterial lipase, the PCL membrane rapidly degrades, releasing vancomycin for antibacterial action. The mPEG750-b-PCL2500 gel provides stable and sustained vancomycin release, prolonging its antibacterial effects. Our composite antibacterial coating demonstrates promising potential for clinical application.

Multifunctional chemoreactive nanosonosensitizers exert antitumoral, antibacterial and wound healing effects on malignant peripheral nerve sheath tumors

Currently, surgery is the only available and effective clinical strategy for treating malignant peripheral nerve sheath tumors. However, even with complete surgical resection, poor physical health or cachexia can cause wound delay or infection. To solve this critical issue, DSF-CuO2@DMSN nanoparticles were rationally designed. These nanoparticles have been engineered to exert high performance and synergistic sonodynamic/chemodynamic/chemotherapeutic tumor treatment under the stimulation of ultrasound by producing reactive oxygen species and dithiocarbamate − copper complexes in situ in response to the tumor-specific acidic and hypoxic microenvironment. When mixed with thermosensitive hydrogels, the therapeutic effects of nanosonosensitizers can be precisely limited to the working areas. Significant inhibition of proliferation, increases in apoptosis and death in tumor cells and xenograft all demonstrated the antitumoral capability of DSF-CuO2@DMSN under ultrasound stimulation. The upregulated expression of caspase-3 related proteins and the results of RNA sequencing indicated the induction of cell apoptosis, autophagy, or cell death after treatment. Moreover, DSF-CuO2@DMSN induced strong antibacterial effects and wound healing abilities under the activation of ultrasound, with quick wound closure and the absence of bacterial infection in in vitro and in vivo experiments. Altogether, the multifunctional DSF-CuO2@DMSN nanoagents can provide a distinct postoperative therapeutic strategy for both tumor inhibition and wound recovery.

Utility of Procalcitonin in Clinical Practice

The rise of multi-resistant infections and complications associated with the overuse of antibiotics has led to the implementation of antibiotic stewardship strategies as a marker of patient safety and quality. Using biomarkers that can accurately predict the presence or absence of bacterial infection, thus signaling the need for antibiotic use, or supporting appropriate and safe discontinuation, has become an increasingly relevant strategy for antibiotic stewardship. Evidence supporting procalcitonin for antimicrobial stewardship has focused mostly on lower respiratory tract infections and sepsis. This review discusses the most relevant evidence to support the use of procalcitonin in clinical practice.

191. Predictive Value of Procalcitonin across Disease States within an Inpatient Veteran Population

Abstract Background Procalcitonin (PCT) can be elevated with certain bacterial infections. Debate continues as to how to best use this biomarker to guide antibiotic use. The primary objective of this study was to evaluate the correlation of PCT levels and the presence of bacterial infection on admission in the total population and in different disease states. Methods This was a multicenter retrospective cross-sectional study of patients admitted with specified infectious diagnoses to two VA Medical Centers from 4/1/2019 to 7/1/2021. Patients were stratified into 4 cohorts for analysis; those with COVID-19, sepsis from respiratory source_(S-R), sepsis from non-respiratory source (S-NR), and respiratory source without sepsis (R). Electronic medical records were reviewed to collect the following: initial procalcitonin, cultures, SIRS criteria, comorbidities (CKD, ESRD, HF, immunosuppressed, surgery within the 7 days), and c-reactive protein. PCT elevation was defined as ≥0.25 ng/mL. The frequency of positive cultures within 72 hours was evaluated for patients with elevated and normal PCT levels to determine the diagnostic performance of PCT overall and for each cohort. Results 632 of 664 patients were evaluated in this study. PCT is elevated twice as often in the septic groups as compared to the non-septic groups (figure 1). Positive predictive value (PPV) varies from 27% to 63% as compared to negative predictive value (NPV) 53%-79% among the disease state groups (figure 2). Although small numbers, the NPV of PCT improves to 83% in patients with elevated temperature and white blood cells (WBC) (figure 3). Figure 1Figure 2Figure 3 Conclusion The findings that NPV of PCT appears to be better than PPV, support current recommendations against using this as a diagnostic tool, but rather as a tool to assist with antibiotic de-escalation. Further studies are necessary to confirm whether there are specific markers such as temperature or WBC which may improve the NPV. Our data suggests PCT is less helpful in identifying the presence or absence of bacterial infection in septic versus non-septic patients. Disclosures All Authors: No reported disclosures.

Procalcitonin levels in children affected by severe malaria compared to those with uncomplicated malaria in the absence of bacterial infection: a cross-sectional study

BackgroundProcalcitonin is an inflammatory marker strongly associated with the presence of bacterial infection. It has been considered raised in severe malaria infection as opposed to uncomplicated malaria. There are suggestions that it may be raised only when there is concomitant unnoticeable bacterial infection during a malaria crisis. We aimed to assess the difference in plasma procalcitonin levels between children affected by severe and uncomplicated malaria.MethodsWe assessed plasma procalcitonin levels in 83 children diagnosed with malaria with no clinical and biological evidence of concomitant bacterial infection. Severity of malaria was established using WHO guidelines. Procalcitonin was determined using the ELISA method. Non-parametric Mann-Whitney U test was used to compare medians across the 2 groups. Statistical significance was set for all p values < 0.05.ResultsOf the 83 participants, 28 had uncomplicated malaria, and 55 had severe malaria. PCT levels were obtained in 24 and 40 subjects of each group, respectively, and were similar in both groups; [2.76 (2.52–2.93) vs 2.74 (2.52–2.98) ng/ml, p = 0.916]. The parasite density was lower in the uncomplicated malaria group than in the severe malaria group, but not statistically significant; [22,192 (9110–44 654) vs 31 684 (13 960–73 500) parasites/μl, p = 0.178]. There was no correlation between the parasite density in the general study population and PCT levels (r = 0.072, p = 0.572).ConclusionIn the absence of overt bacterial infection, procalcitonin levels are not different between children affected with uncomplicated malaria and those with severe malaria. Therefore, bacterial infection should be thoroughly checked for in children with raised serum procalcitonin diagnosed with severe malaria.

Antibiotic stewardship: Early discontinuation of antibiotics based on procalcitonin level in COVID-19 pneumonia.

Procalcitonin (PCT) levels rise in systemic inflammation, especially if bacterial in origin. COVID-19, caused by the novel coronavirus SARS-CoV-2, presents with acute respiratory distress syndrome. Elevated procalcitonin in COVID-19 is considered as a marker for severity of disease. There is no study available that indicates whether elevated PCT in COVID-19 is associated with inflammation or superimposed bacterial infection. The objective of this study is to evaluate the association between PCT levels and superadded bacterial infection, and the effect of discontinuation of antibiotic in the low PCT (<0.25ng/ml) group on patients' outcomes. A retrospective chart review of patients admitted with COVID-19 pneumonia at a single tertiary care centre. We collected information on demographics, co-morbidities, PCT level, antibiotic use, culture results for bacterial infection, hospital length of stay (LOS) and mortality. Continuous variables were summarized with the sample median, interquartile range, mean and range. Categorical variables were summarized with number and percentage of patients. We studied a total of 147 patients with COVID-19 pneumonia. 101 (69%) patients had a low PCT level (< 0.25ng/ml). Bacterial culture results were negative for all patients, except 1 who had a markedly elevated PCT level (141.ng/ml). In patients with low PCT, 42% received no antibiotics, 59% received antibiotics initially, 32 (57%) patients antibiotic discontinued early (within 24hours) and their culture remained negative for bacterial infections during hospitalizations. LOS was shorter (6days in low PCT group compared to 9days) in high PCT group. LOS was 1day shorter (5days vs 6days) in no antibiotic group compared to antibiotic group. Our study examines the association between PCT level and superadded bacterial infection in COVID-19 pneumonia. Our results demonstrate that most patients admitted with COVID-19have a low PCT (<0.25ng/ml), which suggests no superadded bacterial infection and supports the previously published literature regarding low PCT in viral pneumonia. Procalcitonin level remains low in the absence of bacterial infection. Early de-escalation/discontinuation of antibiotics is safe without adverse outcomes in COVID-19 pneumonia. Early de-escalation/discontinuation of antibiotics is associated with lower LOS.

Post-COVID morphologically proved endocarditis: infective and nonbacterial forms

PurposeTo study clinical features of endocarditis and its possible mechanisms (infective and nonbacterial) in the long-term period after acute COVID-19.MethodsThree patients (two male and one female, age 64, 39 and 46 years) diagnosed with postcovid endocarditis were included in the study. One patient had severe bilateral coronavirus pneumonia; the other two had only fever and weakness. The diagnosis of COVID-19 was confirmed by seroconversion. The time of admission after COVID-19 was from 4 to 7 months. All patients had study for anti-heart antibodies (AHA), EchoCG, Holter ECG, and endomyocardial biopsy (EMB) with PCR for SARS-Cov2 and cardiotropic viruses. The indication for EMB was suspected myocarditis. Blood cultures and procalcitonin levels were tested in one patient due to a prolonged febrile fever.ResultsTwo variants of postcovid endocarditis have been diagnosed. The first variant was detected in two patients by EMB only. This patients had severe lymphocytic and giant cell myocarditis. In addition, EMB showed signs of lymphocytic endocarditis with infiltrates, marked thickening and fibrosis of the endocardium (Fig. 1). Some biopsy specimen were represented by fresh thrombotic masses, infiltrated with neutrophilic leukocytes. No intraventricular thrombus was detected on EchoCG and MRI. The second variant of postcovid endocarditis developed in a patient with bicuspid aortic valve and met the criteria of infectious endocarditis 2015: mobile vegetations on the valve with aortic regurgitation II, splenomegaly, irregular fever up to 39°C for six months, marked increase of CRP, procalcitonin and ferritin, hypochromic anemia, LV EF 25%. Blood culture was negative. After intravenous therapy with antibiotics and immunoglobulin, EMB confirmed the active lymphocytic myocarditis and only slight fibrosis of right ventricular endocardium. The bacteriological study of endocardium was negative. SARS-Cov-2 RNA was detected by PCR in myocardial biopsy specimens of two patients; the biopsy of one patient is in the study now. All patients had significantly elevated antibody titers to various cardiac antigens, but the level of antibodies to endothelial antigens remained completely normal. It is possible to suggest an active deposition of immune complexes in the endothelium. Two surviving patients receive steroid therapy (in case of IE with antibiotics).ConclusionsSARS-Cov-2 infection induces the prolonged non-bacterial thromboendocarditis or infective endocarditis. In both cases, autoimmune mechanisms play a significant role, as evidenced by the simultaneous lymphocytic/giant cell myocarditis and high titers of AHA. Long-term persistence of coronavirus in the myocardium can also be considered as an etiological factor of endocarditis. In favor of this hypothesis is the parietal thrombosis in the absence of bacterial infection. Corticosteroids and anticoagulants should be considered for the treatment of postcovid endocarditis.Funding AcknowledgementType of funding sources: None. Figure 1. The EMB in in postcovid endocarditis

Retrospective review of 27 European cases of fatal elephant endotheliotropic herpesvirus-haemorrhagic disease reveals evidence of disseminated intravascular coagulation

Elephant endotheliotropic herpesvirus haemorrhagic disease (EEHV-HD) is widely acknowledged as the most common cause of mortality in young Asian elephants (Elephas maximus) in captivity. The objective of the current study was to perform a blinded, retrospective pathology review of European EEHV-HD fatalities, constituting the largest systematic assessment of EEHV-HD pathology to date. Findings between viral genotypes were compared with the aim to investigate if disseminated intravascular coagulation (DIC) could be substantiated as a significant complicating factor, thereby increasing the understanding of disease pathophysiology. Immunohistochemical staining confirmed endothelial cell (EC) damage and the presence of EC intranuclear inclusion bodies, demonstrating a direct viral cytopathic effect. Microthrombi were observed in 63% of cases in several organs, including lungs, which, together with widespread haemorrhage and thrombocytopenia reported in EEHV-HD case reports, supports the presence of overt DIC as a serious haemostatic complication of active EEHV infection. Death was attributed to widespread vascular damage with multi-organ dysfunction, including severe acute myocardial haemorrhage and subsequent cardiac failure. Systemic inflammation observed in the absence of bacterial infection may be caused by cytokine release syndrome. Findings reinforce the necessity to investigate cytokine responses and haemostatic status during symptomatic and asymptomatic EEHV viraemia, to potentially support the use of anti-inflammatory treatment in conjunction with anti-viral therapy and cardiovascular support.

First reported case of safe and efficacious use of tocilizumab for treatment of hyperinflammatory syndrome associated with COVID‐19 in an allogeneic stem cell transplant patient

First reported case of safe and efficacious use of tocilizumab for treatment of hyperinflammatory syndrome associated with COVID‐19 in an allogeneic stem cell transplant patient

PAINFUL FINGERS AND TOES REVEAL A CASE OF NON-SMALL CELL LUNG CANCER

SESSION TITLE: Medical Student/Resident Lung Cancer Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: As a paraneoplastic syndrome, the association of hypercoagulability states (HCS) in cancer patients has been well established and can have an adverse effect on quality of life and survival. (1) The findings of HCS such as venous thromboembolism (VTE), embolic strokes, arterial thromboembolic events (ATE) and nonbacterial thrombotic endocarditis (NBTE) should make the clinician suspicious of an underlying malignancy. The deposition of thrombi on previously undamaged heart valves in the absence of bacterial infection is known as NBTE and is often discovered at time of autopsy or in late-stage cancer. (2) Here we describe a case of lung adenocarcinoma, who presented with multiple HCS at the time of diagnosis, including painful digits caused by ATE propagated by NBTE. CASE PRESENTATION: A 56 year old female with a 30 pack year smoking history presented with a myriad of complaints including dyspnea, fatigue, nausea, hematemesis and headache for one month. Most bothersome were her painful, blue-discolored fingers and toes (Fig. 1) that were cool to touch with palpable pulses. CXR identified a large left upper lobe lung mass and follow-up CT (Fig. 2) identified that the mass involved the pulmonary hilum with bilateral mediastinal lymphadenopathy. A bronchoalveolar lavage confirmed lung adenocarcinoma on cytology. MRI brain was performed which identified multiple infarcts of an embolic source. Lower extremity doppler studies revealed bilateral arterial and venous occlusions. She was treated with apixaban after EGD identified no source of bleed. Transesophageal echocardiography identified severe mitral regurgitation (MR) (Fig. 3) with small vegetations on both mitral valve leaflets consistent with NBTE—the source of her disseminated embolisms. She received mediastinal radiation and a chemotherapy regimen of carboplatin, pemetrexed, and pembrolizumab. For congestive heart failure (CHF) due to severe MR, she was discharged on metoprolol and furosemide. She returned one month later to the ICU in cardiogenic shock due to worsening CHF. She passed away one week later under hospice care. DISCUSSION: Since HCS have first been recognized in gastric cancer by Trousseau in 1865, multiple cancers, including lung cancer, have been associated with HCS. (3) Recommendations are that high-risk cancer patients (4) be offered prophylactic anticoagulation should no significant bleeding risk exist. (5) In general, NBTE and ATE were often reported after cancer diagnosis (6,7,8,9) and acute heart failure caused by NBTE is a rare clinical event reported only in a few case reports. (6,7) Our patient exemplifies the extensive findings of HCS as a manifestation of lung adenocarcinoma. CONCLUSIONS: This case shows a unique clinical presentation of NBTE, VTE, ATE, cerebral embolic infarction, and heart failure at the time of diagnosis of lung adenocarcinoma. Such HCS should be recognized as herald signs in underlying cancer. Reference #1: 1.Connolly GC, Francis CW. Cancer-associated thrombosis. Hematology Am Soc Hematol Educ Program. 2013;2013:684-691. doi:10.1182/asheducation-2013.1.684 2.el-Shami K, Griffiths E, Streiff M. Nonbacterial thrombotic endocarditis in cancer patients: pathogenesis, diagnosis, and treatment. Oncologist. 2007;12(5):518-523. doi:10.1634/theoncologist.12-5-518 3.Connolly GC, Dalal M, Lin J, Khorana AA. Incidence and predictors of venous thromboembolism (VTE) among ambulatory patients with lung cancer. Lung Cancer. 2012;78(3):253-258. doi:10.1016/j.lungcan.2012.09.007 Reference #2: 4.Khorana AA, Kuderer NM, Culakova E, Lyman GH, Francis CW. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood. 2008;111(10):4902-4907. doi:10.1182/blood-2007-10-116327 5.Key NS, Khorana AA, Kuderer NM, Bohlke K, Lee AYY, Arcelus JI, Wong SL, Balaban EP, Flowers CR, Francis CW, Gates LE, Kakkar AK, Levine MN, Liebman HA, Tempero MA, Lyman GH, Falanga A. Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer: ASCO Clinical Practice Guideline Update. J Clin Oncol. 2020 Feb 10;38(5):496-520. doi: 10.1200/JCO.19.01461. Epub 2019 Aug 5. PubMed PMID: 31381464. 6.Lee JM, Lim JH, Kim JS, Park JS, Memon A, Lee SK, Nam HS, Cho JH, Kwak SM, Lee HL, Kim HJ, Hong GJ, Ryu JS. Multiple hypercoagulability disorders at presentation of non-small-cell lung cancer. Tuberc Respir Dis (Seoul). 2014 Jul;77(1):34-7. doi: 10.4046/trd.2014.77.1.34. Epub 2014 Jul 31. PubMed PMID: 25114702; PubMed Central PMCID: PMC4127411. Reference #3: 7.Taniyama D, Yamamoto R, Kawasaki M, Kamata H, Miyamoto K, Mashimo S, et al. Nonbacterial thrombotic endocarditis leading to acute heart failure due to aortic stenosis in a patient with lung cancer. Intern Med 2013;52:1617-20. 8.Lopez JA, Ross RS, Fishbein MC, Siegel RJ. Nonbacterial thrombotic endocarditis: a review. Am Heart J. 1987;113(3):773-784. doi:10.1016/0002-8703(87)90719-8 9.Navi BB, Reiner AS, Kamel H, et al. Risk of Arterial Thromboembolism in Patients With Cancer. J Am Coll Cardiol. 2017;70(8):926-938. doi:10.1016/j.jacc.2017.06.047 DISCLOSURES: No relevant relationships by Milica Antic, source=Web Response No relevant relationships by Jeffrey Bloomer, source=Web Response No relevant relationships by Sara Ruiz Aguinaga, source=Web Response

CaMK4-dependent phosphorylation of Akt/mTOR underlies Th17 excessive activation in experimental autoimmune prostatitis.

Chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS) is a complicated syndrome characterized by genitourinary pain in the absence of bacterial infection. Th17 cell-driven autoimmunity has been proposed as a cause of CP/CPPS. However, the factors that promote Th17-driven autoimmunity in experimental autoimmune prostatitis (EAP) and the molecular mechanisms are still largely unknown. Here, we showed that Th17 cells were excessively activated, and blockade of IL-17A could effectively ameliorate various symptoms in EAP. Furthermore, we revealed that calcium/calmodulin-dependent kinase Ⅳ (CaMK4), especially Thr196 p-CaMK4 was increased in the Th17 cells of the EAP group, which were activated by intracellular cytosolic Ca2+ . Pharmacologic and genetic inhibition of CaMK4 decreased the proportion of Th17 cells, and the protein and mRNA level of IL-17A, IL-22, and RORγt. The phosphorylation of CaMK4 was dependent on the increase in intracellular cytosolic Ca2+ concentration in Th17 cells. A mechanistic study demonstrated that inhibition of CaMK4 reduced IL-17A production by decreasing the phosphorylation of Akt-mTOR, which was well accepted to positively regulate Th17 differentiation. Collectively, our results demonstrated that Ca2+ -CaMK4-Akt/mTOR-IL-17A axis inhibition may serve as a promising therapeutic strategy for CP/CPPS.

Possible Cause of Inflammatory Storm and Septic Shock in Patients Diagnosed with (COVID-19)

The novel coronavirus (SARS-CoV-2) infection which has been known as Coronavirus diseases 2019 COVID-19 has become an endemic emergent situation by the World Health Organization. So far, no successful specific treatment has been found for this disease. As has been reported, most of non-survivor patients with COVID-19 (70%) had septic shock which was significantly higher than survived ones. Although the exact pathophysiology of septic shock in these patients is still unclear, it seems to be possible that part of it would be due to the administration of empiric antibiotics with inflammatory properties especially in the absence of bacterial infection. Herein, we have reviewed possible molecular pathways of septic shock in the patients who have received antibiotics with inflammatory properties which mainly is release of interleukin 1β (IL-1β), IL-6, and tumor necrosis factor α (TNF- α) through different routes. Altogether, we highly recommend clinicians to look after those antibiotics with anti-inflammatory activity for both empiric antibiotic therapy and reducing the inflammation to prevent septic shock in patients with diagnosed COVID-19.

Inhibition of PDE4 Induces Hypothermia in Mice

Type 4 cyclic nucleotide phosphodiesterases (PDE4s), a group of isoenzymes that hydrolyze and inactivate the second messenger cAMP, are established targets for development of enzyme inhibitors with anti‐inflammatory properties. While testing the anti‐inflammatory effects of a nonselective PDE4 inhibitor in a murine model of bacterial lung infection, we noticed that PDE4 inhibition per se induced significant hypothermia in the animals in the absence of bacterial infection. Because drug‐induced hypothermia may critically impact our animal model, and the role cAMP‐phosphodiesterases play in the regulation of body temperature is poorly understood, we further explored this observation. We found that treatment with a number of structurally distinct PAN‐PDE4 inhibitors, including Rolipram, Roflumilast and RS25344 (all 1 mg/kg, i.p.), but not the PDE3‐selective inhibitor Cilostamide, induced a rapid decrease in core body temperature of C57Bl6 mice as measured with a rectal thermometer at 30 min after drug application, suggesting that hypothermia in mice is a class‐effect of PDE4 inhibitors. PDE4 inhibitor‐induced hypothermia was considerable (~4°C drop), rapid in onset (max effect is reached within 20–30 min), and long lasting (core body temperature remains below controls for up to 5 h). As little as 40 μg/kg of the archetypal PDE4 inhibitor Rolipram induced a hypothermic effect. Similar or higher doses of Rolipram were used in most published animal studies. Thus, the reported findings are likely associated with, or at least paralleled by, drug‐induced hypothermia. The initial decrease in body temperature after PDE4 inhibitor injection is so rapid that it is no different from heat dissipation after euthanasia, suggesting that PDE4 inhibition affects central body temperature regulation so that both heat‐generating (e.g. shivering/non‐shivering thermogenesis) as well as heat‐preserving (e.g. skin vasoconstriction) mechanisms are simultaneously suspended, either by lowering the cold defense set point or by impairing its enforcement. Indeed, PDE4 inhibitor treatment induced a temporary heat‐loss via tail vasodilation as assessed by thermography. Consistent with the idea of an effect on central body temperature regulation, hypothermia was induced by moderate doses (≤1 mg/kg) of various brain‐penetrant PDE4 inhibitors. Conversely, YM976, a PDE4 inhibitor that does not cross the blood‐brain barrier, had no effect. Finally, to begin delineating the mechanism of drug‐induced hypothermia, we show that a blockade of serotonergic‐ and dopaminergic‐, but not β‐adrenergic‐, histaminergic‐ or opiate receptors, can alleviate PDE4 inhibitor‐induced hypothermia.Support or Funding InformationSupported by grants from the Cystic Fibrosis Foundation (SALEH18H0,RICHTE16GO) and the NIH (HL76125, HL141473, HL066299).

On-demand storage and release of antimicrobial peptides using Pandora's box-like nanotubes gated with a bacterial infection-responsive polymer.

Background: Localized delivery of antimicrobial agents such as antimicrobial peptides (AMPs) by a biomaterial should be on-demand. Namely, AMPs should be latent and biocompatible in the absence of bacterial infection, but released in an amount enough to kill bacteria immediately in response to bacterial infection.Methods: To achieve the unmet goal of such on-demand delivery, here we turned a titanium implant with titania nanotubes (Ti-NTs) into a Pandora's box. The box was loaded with AMPs (HHC36 peptides, with a sequence of KRWWKWWRR) inside the nanotubes and “closed” (surface-modified) with a pH-responsive molecular gate, poly(methacrylic acid) (PMAA), which swelled under normal physiological conditions (pH 7.4) but collapsed under bacterial infection (pH ≤ 6.0). Thus, the PMAA-gated Ti-NTs behaved just like a Pandora's box. The box retarded the burst release of AMPs under physiological conditions because the gate swelled to block the nanotubes opening. However, it was opened to release AMPs to kill bacteria immediately when bacterial infection occurred to lowering the pH (and thus made the gate collapse).Results: We demonstrated such smart excellent bactericidal activity against a panel of four clinically important bacteria, including Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus. In addition, this box was biocompatible and could promote the osteogenic differentiation of human mesenchymal stem cells. Both in vitro and in vivo studies confirmed the smart “on-demand” bactericidal activity of the Pandora's box. The molecularly gated Pandora's box design represents a new strategy in smart drug delivery.

Cast Bronchitis in a Cystic Fibrosis Child: Experience with Direct Instillation of Dornase Alfa as an Adjunct Treatment Agent

Introduction: Lobar atelectasis is one of the common problems in patients with cystic fibrosis and can be a cause of respiratory symptoms in these patients even in the absence of bacterial infection. Case Presentation: Here we introduce a 9-year-old boy with cystic fibrosis who had many admissions because of respiratory distress due to lung collapse mainly caused by plastic bronchitis. Conclusions: In a number of patients with cystic fibrosis, lobar atelectasis is seen which is resistant to medical treatments. Early fiberoptic bronchoscopy as a measure for mechanical removal of the blocking agent and sometimes direct injection of drugs like dornase alfa into the bronchus is a successful modality in the treatment of lobar collapses in chronic pulmonary diseases.

Atorvastatin increases the production of proinflammatory cytokines and decreases the survival of Escherichia coli-infected mice

To assess whether the immunosuppressive effects of atorvastatin outweigh its antibacterial ones in an infection, mice were infected with Escherichia coli and administered atorvastatin; survival rates were then monitored. Mice treated with atorvastatin post-infection showed a remarkable decrease in their survival rate. On the other hand, the higher the level of serum IFN-γ in the infected mice treated with atorvastatin, the lower was the survival rate. Levels of IL-4 were markedly depressed in all groups infected with E. coli and treated with atorvastatin. Since atorvastatin inhibits IFN-γ expression in the absence of bacterial infection, we examined whether bacterial lipopolysaccharide (LPS) was the element capable of overriding this inhibition. Mouse peripheral blood mononuclear cells were treated with atorvastatin and lipopolysaccharide ex vivo then proinflammatory (IFN-γ, TNFα, IL-6) and prohumoral/regulatory (IL-4, IL-13, IL-10) cytokine levels were analyzed in culture supernatants. While proinflammatory cytokine levels were decreased upon treatment with atorvastatin alone, their levels were markedly elevated by treatment with LPS, bacterial lysate or bacterial culture supernatant. On the other hand, atorvastatin exerted an inhibitory effect on production of the prohumoral/regulatory cytokines. Our data indicates that any consideration for statins as antimicrobial treatment should assess the possible adverse outcomes.

Procalcitonin in hemodialysis patients presenting with fever or chills to the emergency department.

We sought to assess the role of procalcitonin in discriminating severe bacterial infections requiring antibiotic treatment from non-bacterial causes of fever or chills in chronic dialysis patients. Chronic hemodialysis patients who were admitted to the emergency room due to fever and/or chills were recruited to the study. The presence or absence of bacterial infection was defined after recruitment conclusion by an infectious disease specialist who was blinded to procalcitonin results. Procalcitonin levels were compared between infected and non-infected patients. Out of 54 patients recruited, 22 (41%) patients eventually diagnosed with infection. Mean (± SD) procalcitonin values were 4.3 (± 5.5) ng/ml among cases, 1.0 (± 2.0) ng/ml among controls with no infection (p = 0.02). A cutoff PCT value of 1ng/ml or higher had 77% sensitivity and 59% specificity for the diagnosis of severe infection. Procalcitonin cannot usefully identify hemodialysis patient with bacterial infection.

Absence of bacteria in intracranial aneurysms.

This study aimed to detect the presence of bacteria in the walls of both unruptured and ruptured aneurysms in a French population. Patients treated between January 2018 and July 2018 were included in a prospective study when specimens from ruptured or unruptured aneurysm walls were obtained intraoperatively. Samples from superficial temporal artery, dura mater, and middle meningeal artery were obtained from each patient during the same surgical procedure to be used as a negative control. Direct bacterial analysis, aerobic and anaerobic bacterial culture, and bacterial DNA detection were performed on each sample. There were 21 women and 9 men with a mean age at treatment of 54 years (range 31-70 years). Eighteen patients were smokers. Hypertension was present in 18 patients and hyperlipidemia in 5 patients. Chronic alcoholism was found in 6 patients. Polycystic kidney disease was present in 1 patient. Fifteen patients had multiple intracranial aneurysms. Ten patients had a ruptured aneurysm and 20 had an unruptured aneurysm. The mean diameter of all aneurysms was 8.5 mm (range 2.5-50 mm). No presence of bacteria was detected with direct bacterial analysis and culture in any of the samples. No bacterial DNA was detected in any of the samples. Unlike in Finnish patients, no bacterial presence was found in the wall of aneurysms in French patients. This absence of bacterial infection might explain the lower risk of aneurysm rupture in the French population compared to the Finnish population.

Relationship between acute kidney injury and serum procalcitonin (PCT) concentration in critically ill patients with influenza infection

IntroductionSerum procalcitonin (PCT) concentration could be increased in patients with renal dysfunction in the absence of bacterial infection. ObjectiveTo determine the interactions among serum renal biomarkers of acute kidney injury (AKI) and serum PCT concentration, in patients admitted to the intensive care unit (ICU) due to lung influenza infection. DesignSecondary analysis of a prospective multicentre observational study. Setting148 Spanish ICUs. PatientsICU patients admitted with influenza infection without bacterial co-infection. Clinical, laboratory and hemodynamic variables were recorded. AKI was classified as AKI I or II based on creatinine (Cr) concentrations (≥1.60–2.50mg/dL and Cr≥2.51–3.99mg/dL, respectively). Patients with chronic renal disease, receiving renal replacement treatment or with Cr>4mg/dL were excluded. Spearman's correlation, simple and multiple linear regression analysis were performed. InterventionsNone. ResultsOut of 663 patients included in the study, 52 (8.2%) and 10 (1.6%) developed AKI I and II, respectively. Patients with AKI were significantly older, had more comorbid conditions and were more severally ill. PCT concentrations were higher in patients with AKI (2.62 [0.60–10.0]ng/mL vs. 0.40 [0.13–1.20]ng/mL, p=0.002). Weak correlations between Cr/PCT (rho=0.18) and Urea (U)/PCT (rho=0.19) were identified. Simple linear regression showed poor interaction between Cr/U and PCT concentrations (Cr R2=0.03 and U R2=0.018). Similar results were observed during multiple linear regression analysis (Cr R2=0.046 and U R2=0.013). ConclusionsAlthough PCT concentrations were slightly higher in patients with AKI, high PCT concentrations are not explained by AKI and could be warning sign of a potential bacterial infection.

Relationship between acute kidney injury and serum procalcitonin (PCT) concentration in critically ill patients with influenza infection

IntroductionSerum procalcitonin (PCT) concentration could be increased in patients with renal dysfunction in the absence of bacterial infection. ObjectiveTo determine the interactions among serum renal biomarkers of acute kidney injury (AKI) and serum PCT concentration, in patients admitted to the intensive care unit (ICU) due to lung influenza infection. DesignSecondary analysis of a prospective multicentre observational study. Setting148 Spanish ICUs. PatientsICU patients admitted with influenza infection without bacterial co-infection. Clinical, laboratory and hemodynamic variables were recorded. AKI was classified as AKI I or II based on creatinine (Cr) concentrations (≥1.60–2.50mg/dL and Cr≥2.51–3.99mg/dL, respectively). Patients with chronic renal disease, receiving renal replacement treatment or with Cr>4mg/dL were excluded. Spearman's correlation, simple and multiple linear regression analysis were performed. InterventionsNone. ResultsOut of 663 patients included in the study, 52 (8.2%) and 10 (1.6%) developed AKI I and II, respectively. Patients with AKI were significantly older, had more comorbid conditions and were more severally ill. PCT concentrations were higher in patients with AKI (2.62 [0.60–10.0]ng/mL vs. 0.40 [0.13–1.20]ng/mL, p=0.002). Weak correlations between Cr/PCT (rho=0.18) and Urea (U)/PCT (rho=0.19) were identified. Simple linear regression showed poor interaction between Cr/U and PCT concentrations (Cr R2=0.03 and U R2=0.018). Similar results were observed during multiple linear regression analysis (Cr R2=0.046 and U R2=0.013). ConclusionsAlthough PCT concentrations were slightly higher in patients with AKI, high PCT concentrations are not explained by AKI and could be warning sign of a potential bacterial infection.