Dual PI3Kδ/γ Inhibitor Duvelisib Prevents Development of Neuropathic Pain in Model of Paclitaxel-Induced Peripheral Neuropathy.

The development of painful paclitaxel-induced peripheral neuropathy (PIPN) represents a major dose-limiting side effect of paclitaxel chemotherapy. Here we report a promising effect of duvelisib (Copiktra), a novel FDA-approved PI3Kδ/γ isoform-specific inhibitor, in preventing paclitaxel-induced pain-like behavior and pronociceptive signaling in DRGs and spinal cord dorsal horn (SCDH) in rat and mouse model of PIPN. Duvelisib blocked the development of mechanical hyperalgesia in both males and females. Moreover, duvelisib prevented paclitaxel-induced sensitization of TRPV1 receptors, and increased PI3K/Akt signaling in small-diameter DRG neurons and an increase of CD68+ cells within DRGs. Specific optogenetic stimulation of inhibitory neurons combined with patch-clamp recording revealed that duvelisib inhibited paclitaxel-induced weakening of inhibitory, mainly glycinergic control on SCDH excitatory neurons. Enhanced excitatory and reduced inhibitory neurotransmission in the SCDH following PIPN was also alleviated by duvelisib application. In summary, duvelisib showed a promising ability to prevent neuropathic pain in PIPN. The potential use of our findings in human medicine may be augmented by the fact that duvelisib is an FDA-approved drug with known side effects.SIGNIFICANCE STATEMENT We show that duvelisib, a novel FDA-approved PI3Kδ/γ isoform-specific inhibitor, prevents the development of paclitaxel-induced pain-like behavior in males and females and prevents pronociceptive signaling in DRGs and spinal cord dorsal horn in rat and mouse model of paclitaxel-induced peripheral neuropathy.

Wavelength-switchable ultraviolet light-emitting diodes.

Dual-wavelength ultraviolet light-emitting diodes (UV-LEDs) exhibiting two discrete emission peaks of comparable intensities are reported in this work. Furthermore, this is the first report where complete switching between these two peaks was achieved by simply changing the duty cycle of the pulsed-mode excitation. While earlier reports on dual-wavelength emission were based on complex multi-stage devices, our device layer-structure was nominally similar to single-wavelength LEDs, and the special properties were realized solely through the use of specifically designed AlGaN alloys. The molecular beam epitaxy (MBE) method was chosen for this work, which can operate at significantly wider growth-parameter ranges than other more commonly used techniques. The dual-wavelength nature of our LEDs was brought about by the deliberate incorporation of nanometer-scale alloy fluctuations in the quantum well based active regions by modulating the relative surface diffusion rates of Ga/Al adatoms. The wavelength selectivity was linked to the variation in thermally assisted carrier delocalization, transport, and subsequent recombination processes in regions of different compositional inhomogeneities.

Adding an extension piece to the end of the purge side arm of the Impella device can prevent the incidence of the cassette breaking and decrease the Impella device failure rate: Impact of practice change on patient outcome.

Background: Impella 5.5® with Smart Assist is a minimally invasive Left Ventricular Assist Devices (LVAD) approved by the Food and Drug Administration (FDA) for treating ongoing cardiogenic shock for up to 14 days. The Impella® intends to reduce ventricular workload and provide the circulatory support necessary for myocardial recovery.Research Question: Compared to standard practice, does adding an extension piece to the purge tube side arm of the Impella® Device decrease the incidence of device failure and positively impact the health outcome of adult patients receiving Impella® support?Study Design and Methods: A retrospective chart review of ICU patients was done at a tertiary care center from August 2018 to August 2022 to assess the differences in patient outcomes related to Impella® Device utilization before and after the implementation of the extension piece to the purge tube sidearm. Among patients reviewed, a total of 20 were included in our review, with seven not having the purge tube side arm extension added, while 13 patients had the extension.Results: The two study groups had no significant difference in patient health outcomes. Additionally, there were no instances of device failure requiring explanation without the extension tubing. However, there were no cases of the purge cassette cracking with the addition of the extension tubing.Conclusion: The addition of extension tubing to the purge cassette of the Impella® Device did not impact patient health outcomes or the incidence of device failure. There was a complete reduction in the incidence of the purge cassette cracking, which could reduce the potential for infection or device failure over a long period of mechanical support. There is a need for long-term prospective studies to confirm the results.

A Novel Antigen, Otubain Cysteine Peptidase of Leishmania donovani, for the Serodiagnosis of Visceral Leishmaniasis and for Monitoring Treatment Response.

Tests for visceral leishmaniasis (VL) are not uniformly effective for all endemic regions. In a serological assay, a novel antigen, otubain cysteine peptidase, compared with rK39, showed comparable sensitivity with Indian VL serum samples and prominently increased sensitivity with Brazilian samples, as well as improved monitoring of the treatment response.

Design and implementation of water purification system based on deep ultraviolet light emitting diodes and a multi-pass geometry reactor.

A novel reactor was designed and implemented for water purification using deep ultraviolet light emitting diodes (LEDs). The focus was on minimizing the number of LEDs required for effective germicidal action. Simulation studies were carried out on the flow of water as well as the irradiance of UV. Variation was made in the beam divergence of the UV sources and reflectivity of optical coatings used for photon recycling. Based on optimized reactor designs, water purification was carried out both in the static and flow-through configuration. Water from various sources was spiked with a known bacterial strain, exposure studies were carried out and germicidal effect was determined. Our results indicate that under optimal design, a 3 mL volume of water shows a three order inactivation using a single UV-LED in a static reactor in 180 s. For a flow-through geometry, only three LEDs were used in the reactor implementation, and a multi-pass procedure was used to purify 150 mL of water from an Escherichia coli CFU count of 4.3 × 104/mL to 12/mL. While slow, this process requires less than 2 W, and can be powered from rechargeable sources. Faster processes can be implanted using multiple such reactor units in parallel, and can be optimized to the requirement and power levels.

Leishmania donovani Aurora kinase: A promising therapeutic target against visceral leishmaniasis.

BACKGROUND: Aurora kinases are key mitotic kinases executing multiple aspects of eukaryotic cell-division. The apicomplexan homologs being essential for survival, suggest that the Leishmania homolog, annotated LdAIRK, may be equally important. METHODS: Bioinformatics, stage-specific immunofluorescence microscopy, immunoblotting, RT-PCR, molecular docking, in-vitro kinase assay, anti-leishmanial activity assays, flow cytometry, fluorescence microscopy. RESULTS: Ldairk expression is seen to vary as the cell-cycle progresses from G1 through S and finally G2M and cytokinesis. Kinetic studies demonstrate their enzymatic activity exhibiting a Km and Vmax of 6.12µM and 82.9pmoles·min(-1)mg(-1) respectively against ATP using recombinant Leishmania donovani H3, its physiological substrate. Due to the failure of LdAIRK-/+ knock-out parasites to survive, we adopted a chemical knock-down approach. Based on the conservation of key active site residues, three mammalian Aurora kinase inhibitors were investigated to evaluate their potential as inhibitors of LdAIRK activity. Interestingly, the cell-cycle progressed unhindered, despite treatment with GSK-1070916 or Barasertib, inhibitors with greater potencies for the ATP-binding pocket compared to Hesperadin, which at nanomolar concentrations, severely compromised viability at IC50s 105.9 and 36.4nM for promastigotes and amastigotes, respectively. Cell-cycle and morphological studies implicated their role in both mitosis and cytokinesis. CONCLUSION: We identified an Aurora kinase homolog in L. donovani implicated in cell-cycle progression, whose inhibition led to aberrant changes in cell-cycle progression and reduced viability. GENERAL SIGNIFICANCE: Human homologs being actively pursued drug targets and the observations with LdAIRK in both promastigotes and amastigotes suggest their potential as therapeutic-targets. Importantly, our results encourage the exploration of other proteins identified herein as potential novel drug targets.

Integration of poly-3-(hydroxybutyrate-co-hydroxyvalerate) production by Haloferax mediterranei through utilization of stillage from rice-based ethanol manufacture in India and its techno-economic analysis.

Haloferax mediterranei has potential for economical industrial-scale production of polyhydroxyalkanoate (PHA) as it can utilize cheap carbon sources, has capacity for nonsterile cultivation and allows simple product recovery. Molasses-based Indian distilleries are converting themselves to cereal-based distilleries. Waste stillage (14 l) of rice-based ethanol industry was used for the production of PHA by H. mediterranei in the simple plug-flow reactor configuration of the activated sludge process. Cells utilized stillage and accumulated 63 ± 3 % PHA of dry cell weight and produced 13.12 ± 0.05 g PHA/l. The product yield coefficient was 0.27 while 0.14 g/l h volumetric productivity was reached. Simultaneous lowering of 5-day biochemical oxygen demand and chemical oxygen demand values of stillage by 82 % was attained. The biopolymer was characterized as poly-3-(hydroxybutyrate-co-17.9 mol%-hydroxyvalerate) (PHBV). Directional properties of decanoic acid jointly with temperature-dependent water solubility in decanoic acid were employed for two-step desalination of the spent stillage medium in a cylindrical baffled-tank with an immersed heater and a stirrer holding axial and radial impellers. 99.3 % of the medium salts were recovered and re-used for PHA production. The cost of PHBV was estimated as US$2.05/kg when the annual production was simulated as 1890 tons. Desalination contributed maximally to the overall cost. Technology and cost-analysis demonstrate that PHA production integrated with ethanol manufacture is feasible in India. This study could be the basis for construction of a pilot plant.

Production of poly-3-(hydroxybutyrate-co-hydroxyvalerate) by Haloferax mediterranei using rice-based ethanol stillage with simultaneous recovery and re-use of medium salts.

Haloferax mediterranei holds promise for competitive industrial-scale production of polyhydroxyalkanoate (PHA) because cheap carbon sources can be used thus lowering production costs. Although high salt concentration in production medium permits a non-sterile, low-cost process, salt disposal after process completion is a problem as current environmental standards do not allow total dissolved solids (TDS) above 2000 mg/l in discharge water. As the first objective of this work, the waste product of rice-based ethanol industry, stillage, was used for the production of PHA by H. mediterranei in shake flasks. Utilization of raw stillage led to 71 ± 2% (of dry cell weight) PHA accumulation and 16.42 ± 0.02 g/l PHA production. The product yield coefficient was 0.35 while 0.17 g/l h volumetric productivity was attained. Simultaneous reduction of BOD5 and COD values of stillage by 83% was accomplished. The PHA was isolated by osmotic lysis of cells, purification by sodium dodecyl sulfate and organic solvents. The biopolymer was identified as poly-3-(hydroxybutyrate-co-15.4 mol%-hydroxyvalerate) (PHBV). This first report on utilization of rice-based ethanol stillage for PHBV production by H. mediterranei is currently the most cost effective. As the second objective, directional properties of decanoic acid together with temperature dependence of water solubility in decanoic acid were applied for two-stage desalination of the spent stillage medium. We report for the first time, recovery and re-use of 96% of the medium salts for PHA production thus removing the major bottleneck in the potential application of H. mediterranei for industrial production of PHBV. Final discharge water had TDS content of 670 mg/l.

Cell Death in Leishmania donovani promastigotes in response to Mammalian Aurora Kinase B Inhibitor- Hesperadin.

Deciphering how hesperadin, a repurposed mammalian aurora kinase B inhibitor, affects the cellular pathways in Leishmania donovani might be beneficial. This investigation sought to assess the physiological effects of hesperadin on promastigotes of L. donovani, by altering the duration of treatment following exposure to hesperadin. Groups pre-treated with inhibitors such as EGTA, NAC, and z-VAD-fmk before hesperadin exposure were also included. Morphological changes by microscopy, ATP and ROS changes by luminometry; DNA degradation using agarose gel electrophoresis and metacaspase levels through RT-PCR were assessed. Flow cytometry was used to study mitochondrial depolarization using JC-1 and MitoTracker Red; mitochondrial-superoxide accumulation using MitoSOX; plasma membrane modifications using Annexin-V and propidium iodide, and lastly, caspase activation using ApoStat. Significant alterations in promastigote morphology were noted. Caspase activity and mitochondrial-superoxide rose early after exposure whereas mitochondrial membrane potential demonstrated uncharacteristic variations, with significant functional disturbances such as leakage of superoxide radicals after prolonged treatments. ATP depletion and ROS accumulation demonstrated inverse patterns, genomic DNA showed fragmentation and plasma membrane showed Annexin-V binding, soon followed by propidium iodide uptake. Multilobed macronuclei and micronuclei accumulated in hesperadin exposed cells before they disintegrated into necrotic debris. The pathologic alterations were unlike the intrinsic or extrinsic pathways of classical apoptosis and suggest a caspase-mediated cell death most akin to mitotic-catastrophe. Most likely, a G2/M transition block caused accumulation of death signals, disorganized spindles and mechanical stresses, causing changes in morphology, organellar functions and ultimately promastigote death. Thus, death was a consequence of mitotic-arrest followed by ablation of kinetoplast functions, often implicated in L. donovani killing.

Dual effect of anandamide on spinal nociceptive transmission in control and inflammatory conditions.

Anandamide (AEA) is an important modulator of nociception in the spinal dorsal horn, acting presynaptically through Cannabinoid (CB1) and Transient receptor potential vanilloid (TRPV1) receptors. The role of AEA (1 µM, 10 µM, and 30 µM) application on the modulation of nociceptive synaptic transmission under control and inflammatory conditions was studied by recording miniature excitatory postsynaptic currents (mEPSCs) from neurons in spinal cord slices. Inhibition of the CB1 receptors by PF514273, TRPV1 by SB366791, and the fatty acid amide hydrolase (FAAH) by URB597 was used. Under naïve conditions, the AEA application did not affect the mEPSCs frequency (1.43±0.12 Hz) when all the recorded neurons were considered. The mEPSC frequency increased (180.0±39.2%) only when AEA (30 µM) was applied with PF514273 and URB597. Analysis showed that one sub-population of neurons had synaptic input inhibited (39.1% of neurons), the second excited (43.5%), whereas 8.7% showed a mixed effect and 8.7% did not respond to the AEA. With inflammation, the AEA effect was highly inhibitory (72.7%), while the excitation was negligible (9.1%), and 18.2% were not modulated. After inflammation, more neurons (45.0%) responded even to low AEA by mEPSC frequency increase with PF514273/URB597 present. AEA-induced dual (excitatory/inhibitory) effects at the 1st nociceptive synapse should be considered when developing analgesics targeting the endocannabinoid system. These findings contrast the clear inhibitory effects of the AEA precursor 20:4-NAPE application described previously and suggest that modulation of endogenous AEA production may be more favorable for analgesic treatments.

Automatic ARDS surveillance with chest X-ray recognition using convolutional neural networks.

OBJECTIVE: This study aims to design, validate and assess the accuracy a deep learning model capable of differentiation Chest X-Rays between pneumonia, acute respiratory distress syndrome (ARDS) and normal lungs. MATERIALS AND METHODS: A diagnostic performance study was conducted using Chest X-Ray images from adult patients admitted to a medical intensive care unit between January 2003 and November 2014. X-ray images from 15,899 patients were assigned one of three prespecified categories: "ARDS", "Pneumonia", or "Normal". RESULTS: A two-step convolutional neural network (CNN) pipeline was developed and tested to distinguish between the three patterns with sensitivity ranging from 91.8% to 97.8% and specificity ranging from 96.6% to 98.8%. The CNN model was validated with a sensitivity of 96.3% and specificity of 96.6% using a previous dataset of patients with Acute Lung Injury (ALI)/ARDS. DISCUSSION: The results suggest that a deep learning model based on chest x-ray pattern recognition can be a useful tool in distinguishing patients with ARDS from patients with normal lungs, providing faster results than digital surveillance tools based on text reports. CONCLUSION: A CNN-based deep learning model showed clinically significant performance, providing potential for faster ARDS identification. Future research should prospectively evaluate these tools in a clinical setting.

Clinical Outcomes With Extracorporeal Membrane Oxygenation for Interstitial Lung Disease: Systematic Review and Meta-Analysis.

The evidence on indications, outcomes, and complications with the use of extracorporeal membrane oxygenation (ECMO) in the setting of interstitial lung disease (ILD) is limited in the existing literature. We performed a systematic review and meta-analysis for the use of ECMO in the setting of ILD to study the prognostic factors associated with in-hospital mortality. Eighteen unique studies with a total of 1,356 patients on ECMO for ILD were identified out of which 76.5% were on ECMO as a bridge to transplant (BTT) and the rest as a bridge to recovery (BTR). The overall in-hospital mortality was 45.76%, with 71.3% and 37.8% for BTR and BTT, respectively. Among the various prognostic factors, mortality was lower with younger age (mean difference = 3.15, 95% confidence interval [CI] = 0.82-5.49), use of awake veno-arterial (VA)-ECMO compared to veno-venous (VV)-ECMO (unadjusted odds ratio [OR] = 0.22, 95% CI = 0.13-0.37) in the overall cohort. In the setting of BTT, the use of VA-ECMO had a decreased hazard ratio (HR) compared to VV-ECMO (adjusted HR = 0.34, 95% CI = 0.15-0.81, p = 0.015). The findings of our meta-analysis are critical but are derived from retrospective studies with small sample sizes and thus are of low to very low-GRADE certainty.

Applied Artificial Intelligence in Healthcare: A Review of Computer Vision Technology Application in Hospital Settings.

Computer vision (CV), a type of artificial intelligence (AI) that uses digital videos or a sequence of images to recognize content, has been used extensively across industries in recent years. However, in the healthcare industry, its applications are limited by factors like privacy, safety, and ethical concerns. Despite this, CV has the potential to improve patient monitoring, and system efficiencies, while reducing workload. In contrast to previous reviews, we focus on the end-user applications of CV. First, we briefly review and categorize CV applications in other industries (job enhancement, surveillance and monitoring, automation, and augmented reality). We then review the developments of CV in the hospital setting, outpatient, and community settings. The recent advances in monitoring delirium, pain and sedation, patient deterioration, mechanical ventilation, mobility, patient safety, surgical applications, quantification of workload in the hospital, and monitoring for patient events outside the hospital are highlighted. To identify opportunities for future applications, we also completed journey mapping at different system levels. Lastly, we discuss the privacy, safety, and ethical considerations associated with CV and outline processes in algorithm development and testing that limit CV expansion in healthcare. This comprehensive review highlights CV applications and ideas for its expanded use in healthcare.

PROGNOSTIC PERFORMANCE OF SERIAL DETERMINATION OF THE SOCIETY FOR CARDIOVASCULAR ANGIOGRAPHY AND INTERVENTIONS SHOCK CLASSIFICATION IN ADULTS WITH CRITICAL ILLNESS.

ABSTRACT: Purpose: The aim of the study is to evaluate whether serial assessment of shock severity can improve prognostication in intensive care unit (ICU) patients. Materials and Methods: This is a retrospective cohort of 21,461 ICU patient admissions from 2014 to 2018. We assigned the Society for Cardiovascular Angiography and Interventions (SCAI) Shock Stage in each 4-h block during the first 24 h of ICU admission; shock was defined as SCAI Shock stage C, D, or E. In-hospital mortality was evaluated using logistic regression. Results: The admission SCAI Shock stages were as follows: A, 39.0%; B, 27.0%; C, 28.9%; D, 2.6%; and E, 2.5%. The SCAI Shock stage subsequently increased in 30.6%, and late-onset shock developed in 30.4%. In-hospital mortality was higher in patients who had shock on admission (11.9%) or late-onset shock (7.3%) versus no shock (4.3%). Persistence of shock predicted higher mortality (adjusted OR = 1.09; 95% CI = 1.06-1.13, for each ICU block with shock). The mean SCAI Shock stage had higher discrimination for in-hospital mortality than the admission or maximum SCAI Shock stage. Dynamic modeling of the SCAI Shock classification improved discrimination for in-hospital mortality (C-statistic = 0.64-0.71). Conclusions: Serial application of the SCAI Shock classification provides improved mortality risk stratification compared with a single assessment on admission, facilitating dynamic prognostication.

Antibiotic Prophylaxis in Patients On Extracorporeal Membrane Oxygenation: A Systematic Review.

Despite the frequent use of prophylactic antibiotics in hospitals for extracorporeal membrane oxygenation (ECMO) patients, the Extracorporeal Life Support Organization (ELSO) Infectious Disease Task Force does not recommend routine antibiotic prophylaxis due to a lack of compelling evidence. We assessed the effectiveness of prophylactic antibiotics in ECMO patients. We conducted a comprehensive search of multiple databases from their inception up to September 6, 2023, on various databases using keywords like "antibiotics," "prophylaxis," "extracorporeal membrane oxygenation," and "ECMO." Newcastle-Ottawa Scale (NOS) was used to assess the quality of the included research. We collected data using Microsoft Excel version 2016, mean and standard deviations were calculated for continuous data, while frequencies and percentages were calculated for binomial data. A total of three studies was included in the review with a total of 8,954 participants, of which 4,483 (50.06%) received antibiotic prophylaxis, and 1,131 (25.22%) were female. The administration of antibiotics prophylactically was associated with reduction in rate of mortality, the risk of infections, and complications like acute kidney injury and diarrhea. Although there have been some benefits on antibiotic prophylaxis, prospective research, and possibly the creation of tailored, ECMO-specific bundles will be needed to identify efficient ways to prevent ECMO infection.

Novel Machine Learning Identifies 5 Asthma Phenotypes Using Cluster Analysis of Real-World Data.

BACKGROUND: Asthma classification into different subphenotypes is important to guide personalized therapy and improve outcomes. OBJECTIVES: To further explore asthma heterogeneity through determination of multiple patient groups by using novel machine learning (ML) approaches and large-scale real-world data. METHODS: We used electronic health records of patients with asthma followed at the Cleveland Clinic between 2010 and 2021. We used k-prototype unsupervised ML to develop a clustering model where predictors were age, sex, race, body mass index, prebronchodilator and postbronchodilator spirometry measurements, and the usage of inhaled/systemic steroids. We applied elbow and silhouette plots to select the optimal number of clusters. These clusters were then evaluated through LightGBM's supervised ML approach on their cross-validated F1 score to support their distinctiveness. RESULTS: Data from 13,498 patients with asthma with available postbronchodilator spirometry measurements were extracted to identify 5 stable clusters. Cluster 1 included a young nonsevere asthma population with normal lung function and higher frequency of acute exacerbation (0.8 /patient-year). Cluster 2 had the highest body mass index (mean ± SD, 44.44 ± 7.83 kg/m2), and the highest proportion of females (77.5%) and Blacks (28.9%). Cluster 3 comprised patients with normal lung function. Cluster 4 included patients with lower percent of predicted FEV1 of 77.03 (12.79) and poor response to bronchodilators. Cluster 5 had the lowest percent of predicted FEV1 of 68.08 (15.02), the highest postbronchodilator reversibility, and the highest proportion of severe asthma (44.9%) and blood eosinophilia (>300 cells/µL) (34.8%). CONCLUSIONS: Using real-world data and unsupervised ML, we classified asthma into 5 clinically important subphenotypes where group-specific asthma treatment and management strategies can be designed and deployed.

Assessing Right Ventricle Over Time in Patients on Veno-Venous Extracorporeal Membrane Oxygenation: Insights From Serial Echocardiography.

Extracorporeal membrane oxygenation (ECMO) is often used in acute respiratory distress syndrome (ARDS) with refractory hypoxemia. There is limited literature highlighting the development of right ventricular (RV) failure while on ECMO. We conducted a retrospective multicenter observational study including 70 patients who were placed on veno-venous (VV)-ECMO for respiratory failure at Mayo Clinic, Jacksonville, and Mayo Clinic, Rochester, between January 2018 and June 2022 and had at least two post-ECMO transthoracic echoes. The primary outcomes were the incidence and progression of RV dysfunction and dilatation. The secondary outcome was in-patient mortality. Among 70 patients in our cohort, 60.6% had a normal RV function at the time of ECMO placement, whereas only 42% had a normal RV function at the second post-ECMO echo. On multinomial regression, a moderate decrease in RV function was associated with ECMO flow (odds ratio [OR] = 2.32, p = 0.001) and ECMO duration (OR = 1.01, p = 0.01). A moderately dilated RV size was also associated with ECMO flow (OR = 2.62, p < 0.001) and ECMO duration (OR = 1.02, p = 0.02). An increasing degree of RV dysfunction was associated with worse outcomes. Our study showed that the increasing duration and flow of VV-ECMO correlated with progressive RV dilatation and dysfunction, which were associated with poor survival.

Association of antibiotics with the outcomes in COVID-19 pneumonia patients with elevated PCT levels.

OBJECTIVE: To assess antibiotics impact on outcomes in COVID-19 pneumonia patients with varying procalcitonin (PCT) levels. METHODS: This retrospective cohort study included 3665 COVID-19 pneumonia patients hospitalized at five Mayo Clinic sites (March 2020 to June 2022). PCT levels were measured at admission. Patients' antibiotics use and outcomes were collected via the Society of Critical Care Medicine (SCCM) Viral Infection and Respiratory Illness Universal Study (VIRUS) registry. Patients were stratified into high and low PCT groups based on the first available PCT result. The distinction between high and low PCT was demarcated at both 0.25 ng/ml and 0.50 ng/ml. RESULTS: Our cohort consisted of 3665 patients admitted with COVID-19 pneumonia. The population was predominantly male, Caucasian and non-Hispanic. With the PCT cut-off of 0.25 ng/ml, 2375 (64.8 %) patients had a PCT level <0.25 ng/mL, and 1290 (35.2 %) had PCT ≥0.25 ng/ml. While when the PCT cut off of 0.50 ng/ml was used we observed 2934 (80.05 %) patients with a PCT <0.50 ng/ml while 731(19.94 %) patients had a PCT ≥0.50 ng/ml. Patients with higher PCT levels exhibited significantly higher rates of bacterial infections (0.25 ng/ml cut-off: 4.2 % vs 7.9 %; 0.50 ng/ml cut-off: 4.6 % vs 9.2 %). Antibiotics were used in 66.0 % of the cohort. Regardless of the PCT cutoffs, the antibiotics group showed increased hospital length of stay (LOS), intensive care unit (ICU) admission rate, and mortality. However, early de-escalation (<24 h) of antibiotics correlated with reduced hospital LOS, ICU LOS, and mortality. These results were consistent even after adjusting for confounders. CONCLUSION: Our study shows a substantial number of COVID-19 pneumonia patients received antibiotics despite a low incidence of bacterial infections. Therefore, antibiotics use in COVID pneumonia patients with PCT <0.5 in the absence of clinical evidence of bacterial infection has no beneficial effect.

Regulation of miR-155 biogenesis in cystic fibrosis lung epithelial cells: antagonistic role of two mRNA-destabilizing proteins, KSRP and TTP.

Cystic fibrosis (CF) is characterized by a massive pro-inflammatory phenotype in the lung arising from profound expression of inflammatory genes, including interleukin-8 (IL-8). We have previously reported that IL-8 mRNA is stabilized in CF lung epithelial cells, resulting in concomitant hyper-expression of IL-8 protein through elevated expression of miR-155. We therefore investigated what factors promote the enhanced aberrant expression of miR-155 in CF. Here we report for the first time, the role of mRNA-destabilizing inflammatory RNA-binding proteins, KSRP and TTP, in the regulation of miR-155 biogenesis in CF lung epithelial cells. We find that KSRP and TTP have an antagonistic role in miR-155 biogenesis. While KSRP promotes enhanced processing of miR-155 precursors to mature miR-155, over-expression of TTP in the CF lung epithelial cells suppresses expression of miR-155. We find that TTP induces the expression of miR-1, which appears to be a regulator of miR-155 biogenesis in CF lung epithelial cells. These data provide novel insights into the mechanisms that induce hyper-inflammatory phenotype of CF, and are potential candidates for anti-inflammatory therapeutics for CF.