Acute or chronic? Failing left ventricle in a 34 year old

Submission content Introduction: An unusual case of a very young patient without previously known cardiac disease presenting with severe left ventricular failure, detected by a point of care echocardiogram. Main Body: A 34 year old previously well man was brought to hospital after seeing his general practitioner with one month of progressive shortness of breath on exertion. This began around the time the patient received his second covid-19 vaccination. He was sleeping in a chair as he was unable to lie flat. Abnormal observations led the GP to call an ambulance. In the emergency department, the patient required oxygen 5L/min to maintain SpO2 >94%, but he was not in respiratory distress at rest. Blood pressure was 92/53mmHg, mean 67mmHg. Point of care testing for COVID-19 was negative. He was alert, with warm peripheries. Lactate was 1.0mmol/L and he was producing more than 0.5ml/kg/hr of urine. There was no ankle swelling. ECG showed sinus tachycardia. He underwent CT pulmonary angiography which demonstrated no pulmonary embolus, but there was bilateral pulmonary edema. Troponin was 17ng/l, BNP was 2700pg/ml. Furosemide 40mg was given intravenously by the general medical team. Critical care outreach asked for an urgent intensivist review given the highly unusual diagnosis of pulmonary edema in a man of this age. An immediate FUSIC Heart scan identified a dilated left ventricle with end diastolic diameter 7cm and severe global systolic impairment. The right ventricle was not severely impaired, with TAPSE 18mm. There was no significant pericardial effusion. Multiple B lines and trace pulmonary effusions were identified at the lung bases. The patient was urgently discussed with the regional cardiac unit in case of further deterioration, basic images were shared via a cloud system. A potential diagnosis of vaccination-associated myocarditis was considered,1 but in view of the low troponin, the presentation was felt most likely to represent decompensated chronic dilated cardiomyopathy. The patient disclosed a family history of early cardiac death in males. Aggressive diuresis was commenced. The patient was admitted to a monitored bed given the potential risk of arrhythmia or further haemodynamic deterioration. Advice was given that in the event of worsening hypotension, fluids should not be administered but the cardiac centre should be contacted immediately. Formal echocardiography confirmed the POCUS findings, with ejection fraction <35%. He was initiated on ACE inhibitors and beta adrenergic blockade. His symptoms improved and he was able to return home and to work, and is currently undergoing further investigations to establish the etiology of his condition. Conclusion(s): Early echocardiography provided early evidence of a cardiac cause for the patient's presentation and highlighted the severity of the underlying pathology. This directed early aggressive diuresis and safety-netting by virtue of discussion with a tertiary cardiac centre whilst it was established whether this was an acute or decompensated chronic pathology. Ultrasound findings: PLAX, PSAX and A4Ch views demonstrating a severely dilated (7cm end diastolic diameter) left ventricle with global severe systolic impairment.

Incidencia, Características y Evolución de las Endocarditis Nosocomiales Durante la Pandemia COVID-19

Introducción: La pandemia COVID-19 ha podido tener influencia en la incidencia de endocarditis infecciosa nosocomial (EIN). Objetivos: Describir la incidencia, características y evolución de la EIN durante la pandemia COVID-19. Material y métodos: Estudio retrospectivo unicéntrico incluyendo las EIN definidas, según los criterios de Duke, desde marzo 2020 hasta marzo 2021. Se dividieron a los pacientes en ingreso por COVID-19 (grupo COVID) o por otros motivos (grupo no COVID). Se comparó la incidencia de EIN con el mismo periodo de 2019-2020. Resultados: Durante el periodo de estudio se diagnosticaron 22 EIN, 7 (31,8%) en COVID, 15 (68,2%) en no COVID. La incidencia fue 9,7 casos/10.000 ingresos (22/22.596). La incidencia en el mismo periodo 2019-2020 fue 4,6/10.000 (10/21.668), siendo la diferencia significativa (OR 1,91, IC95% 1,03-3,96, p = 0,038). Durante el periodo 2020-2021, la incidencia de EIN en COVID fue 24,6/10.000 (7/2.846) frente a 7,5/10.000 (15/19.750) en no COVID, siendo la diferencia significativa (OR 3,23 IC95% 1,32-7,95, p < 0,001). La mediana de edad fue 75 años (RIQ 68-80), siendo varones 68,2%. La mediana de Índice de Charlson fue 5 (RIQ 4-6). Un 36,4% presentaban válvula protésica, mientras un 22,7% valvulopatías significativa no protésica. Los pacientes COVID habían recibido más frecuentemente inmunosupresores (71,4% vs. 13,3%, p = 0,014), sin otras diferencias entre grupos. El foco primario fue considerado vascular en 86,4% (19/22;10 por vía periférica (VP), 5 por catéter venoso central (CVC), 4 no se pudo diferenciar origen entre VP o CVC). 3 pacientes presentaron foco no vascular (1 genitourinario, 2 gastrointestinal). No hubo diferencias entre grupos. Las manifestaciones fueron: fiebre 95,5%;insuficiencia cardiaca 68,2%;embolismos 45,5%;ictus 40,9%;insuficiencia renal 40,9%;bacteriemia persistente 38,1%;y shock séptico 14,3%. Los pacientes no COVID presentaron con más frecuencia clínica subaguda (0 vs. 46,7%, p = 0,042), sin otras diferencias estadísticamente significativas. La etiología fue: estafilococos coagulasa negativo 6 (27,3%);Enterococcus faecalis 6 (27,3%);Staphylococcus aureus 4 (18,2%);Candida albicans 3 (13,6%). En 3 casos no hubo aislamiento microbiológico (13.6%). No hubo diferencias entre grupos. La mortalidad a 30 días fue 45,5%, siendo la EIN o sus complicaciones la causa en todos los casos salvo 1 (no COVID). No hubo diferencias de mortalidad entre grupos (28,6% vs. 53,3%, p = 0,381). Conclusiones: La incidencia de EIN ha aumentado durante la pandemia, especialmente en pacientes ingresados por COVID-19. El foco primario de las EIN fue predominantemente vascular. Afectaron frecuentemente a pacientes con comorbilidad y patología valvular previa. Las manifestaciones, etiología y evolución fueron similares en COVID y no COVID, destacando una elevada frecuencia de eventos embólicos, especialmente ictus. Las EIN asocian elevada morbimortalidad y es importante extremar las medidas de prevención.

Hypercapnia Increases ACE2 Protein Expression and Pseudo-SARSCoV- 2 Virus Entry in Airway Epithelial Cells by Augmenting Cellular Cholesterol

Rationale: Individuals with COPD who develop COVID-19 are at increased risk of hospitalization, ICU admission and death. COPD is associated with increased airway epithelial expression of ACE2, the receptor mediating SARS-CoV-2 entry into cells. Hypercapnia commonly develops in advanced COPD and is associated with frequent and potentially fatal pulmonary infections. We previously reported that hypercapnia increases viral replication, lung injury and mortality in mice infected with influenza A virus. Also, global gene expression profiling of primary human bronchial epithelial (HBE) cells showed that elevated CO2 upregulates expression of cholesterol biosynthesis genes, including HMGCS1, and downregulates ATP-binding cassette (ABC) transporters that promote cholesterol efflux. Given that cellular cholesterol is important for entry of viruses into cells, in the current study we assessed the impact of hypercapnia on regulation of cellular cholesterol levels, and resultant effects on expression of ACE2 and entry of Pseudo-SARS-CoV-2 in cultured HBE, BEAS-2B and VERO cells, and airway epithelium of mice. Methods: Differentiated HBE, BEAS-2B or VERO cells were pre-incubated in normocapnia (5% CO2, PCO2 36 mmHg) or hypercapnia (15% CO2, PCO2 108 mmHg), both with normoxia, for 4 days. Expression of ACE2 and sterol regulatory element binding protein 2 (SREPB2), the master regulator of cholesterol synthesis, was assessed by immunoblot or immunofluorescence. Cholesterol was measured in cell lysates by Amplex red assay. Cells cultured in normocapnia or hypercapnia were also infected with Pseudo SARS-CoV-2, a Neon Green reporter baculovirus. For in vivo studies, C57BL/6 mice were exposed to normoxic hypercapnia (10% CO2/21% O2) for 7 days, or air as control, and airway epithelial expression of ACE2, SREBP2, ABCA1, ABCG1 and HMGCS1 was assessed by immunofluorescence. SREBP2 was blocked using the small molecules betulin or AM580, and cellular cholesterol was disrupted using MβCD. Results: Hypercapnia increased expression and activation of SREBP2 and decreased expression of ABC transporters, thereby augmenting epithelial cholesterol levels. Elevated CO2 also augmented ACE2 expression and Pseudo-SARSCoV- 2 entry into epithelial cells in vitro and in vivo. These effects were all reversed by blocking SREBP2 or disrupting cellular cholesterol. Conclusion: Hypercapnia augments cellular cholesterol levels by altering expression of cholesterol biosynthetic enzymes and efflux transporters, leading to increased epithelial expression of ACE2 and entry of Pseudo-SARS-CoV-2 into cells. These findings suggest that ventilatory support to limit hypercapnia or pharmacologic interventions to decrease cellular cholesterol might reduce viral burden and improve clinical outcomes of SARSCoV- 2 infection in advanced COPD and other severe lung diseases.

HSP90 Modulates T2R Bitter Taste Receptor Nitric Oxide Production and Innate Immune Responses in Human Airway Epithelial Cells and Macrophages

Bitter taste receptors (T2Rs) are G protein-coupled receptors (GPCRs) expressed in various cell types including ciliated airway epithelial cells and macrophages. T2Rs in these two innate immune cell types are activated by bitter products, including those secreted by Pseudomonas aeruginosa, leading to Ca2+-dependent activation of endothelial nitric oxide (NO) synthase (eNOS). NO enhances mucociliary clearance and has direct antibacterial effects in ciliated epithelial cells. NO also increases phagocytosis by macrophages. Using biochemistry and live-cell imaging, we explored the role of heat shock protein 90 (HSP90) in regulating T2R-dependent NO pathways in primary sinonasal epithelial cells, primary monocyte-derived macrophages, and a human bronchiolar cell line (H441). Immunofluorescence showed that H441 cells express eNOS and T2Rs and that the bitter agonist denatonium benzoate activates NO production in a Ca2+- and HSP90-dependent manner in cells grown either as submerged cultures or at the air–liquid interface. In primary sinonasal epithelial cells, we determined that HSP90 inhibition reduces T2R-stimulated NO production and ciliary beating, which likely limits pathogen clearance. In primary monocyte-derived macrophages, we found that HSP-90 is integral to T2R-stimulated NO production and phagocytosis of FITC-labeled Escherichia coli and pHrodo-Staphylococcus aureus. Our study demonstrates that HSP90 serves as an innate immune modulator by regulating NO production downstream of T2R signaling by augmenting eNOS activation without impairing upstream Ca2+ signaling. These findings suggest that HSP90 plays an important role in airway antibacterial innate immunity and may be an important target in airway diseases such as chronic rhinosinusitis, asthma, or cystic fibrosis.

Adopting Intrinsic Hydrophilic Thermoplastic Starch Composites to Fabricate Antifogging Sustainable Films with High Antibiosis and Transparency

Fogging on transparent surfaces such as goggles causes a series of hazards to users. To fabricate antifogging and low-haze transparent renewable polymer materials, intrinsic hydrophilicity with high water adsorption capability of thermoplastic starch (TPS) had been adopted. Strikingly, when benzoic acid (BA) was blended with thermoplastic starch (TPS-BA), the haze of TPS-BA was only 7.8% when it suffered the cold and warm method of antifogging measurement with 87% transmittance. Simultaneously, TPS-BA achieved an 18 mm inhibition zone for Staphylococcus aureus. To reveal the antifogging mechanism of TPS-BA films, the surficial and interior structure features were evaluated by three-dimensional optical scanner, scanning electron microscopy (SEM), contact angle testing, small-angle X-ray scattering (SAXS), X-ray diffraction (XRD), temperature-dependent Fourier transform infrared (FTIR), dynamic mechanical analysis (DMA), and so on. The incorporation of BA resulted in the roughness (Rq), water contact angle (WCA), and crystallinity of the TPS-BA film decreasing from 6.5 to 0.68 μm, 65.1 to 39.9°, and 13.6 to 6.3%, respectively. The amorphous matrix and smooth surface reduced the scattered light, allowing the TPS-BA film to achieve low haze performance and high transmittance. Importantly, the diversified and weakened hydrogen bonds formed among starch, BA, and glycerol could inhibit the formation of starch crystalline regions and allowed hydroxyl groups to quickly bond with water. Thus, when TPS-BA is placed in a high-humidity surrounding, an "expressway"is constructed for water molecules diffusing into the TPS-BA matrix. This novel low-haze, antifogging, sustainable, and facilely fabricated TPS with antibacterial properties is a promising candidate in disposable medical goggles to fight against COVID-19. © 2021 American Chemical Society. All rights reserved.

Molecular Docking Study on Several Benzoic Acid Derivatives against SARS-CoV-2.

Several derivatives of benzoic acid and semisynthetic alkyl gallates were investigated by an in silico approach to evaluate their potential antiviral activity against SARS-CoV-2 main protease. Molecular docking studies were used to predict their binding affinity and interactions with amino acids residues from the active binding site of SARS-CoV-2 main protease, compared to boceprevir. Deep structural insights and quantum chemical reactivity analysis according to Koopmans' theorem, as a result of density functional theory (DFT) computations, are reported. Additionally, drug-likeness assessment in terms of Lipinski's and Weber's rules for pharmaceutical candidates, is provided. The outcomes of docking and key molecular descriptors and properties were forward analyzed by the statistical approach of principal component analysis (PCA) to identify the degree of their correlation. The obtained results suggest two promising candidates for future drug development to fight against the coronavirus infection.