The preventive effect and mechanism of Dayuanyin in hypoxic pulmonary hypertension through NF-kappaB signaling pathway.

Dayuanyin (DYY) has been shown to reduce lung inflammation in both coronavirus disease 2019 (COVID-19) and lung injury. This experiment was designed to investigate the efficacy and mechanism of action of DYY against hypoxic pulmonary hypertension (HPH) and to evaluate the effect of DYY on the protection of lung function. Animal welfare and experimental procedures are approved and in accordance with the provision of the Animal Ethics Committee of the Institute of Materia Medica, Chinese Academy of Medical Science. Male C57/BL6J mice were randomly divided into 4 groups: control group, model group, DYY group (800 mg.kg-1), and positive control sildenafil group (100 mg.kg-1). The animals were given control solvents or drugs by gavage three days in advance. On day 4, the animals in the model group, DYY group and sildenafil group were kept in a hypoxic chamber containing 10% +/- 0.5% oxygen, and the animals in the control group were kept in a normal environment, and the control solvent or drugs continued to be given continuously for 14 days. The right ventricular systolic pressure, right ventricular hypertrophy index, organ indices and other metrics were measured in the experimental endpoints. Meantime, the expression levels of the inflammatory factors in mice lung tissues were measured. The potential therapeutic targets of DYY on pulmonary hypertension were predicted using network pharmacology, the expression of nuclear factor kappa B (NF- kappaB) signaling pathway-related proteins were measured by Western blot assay. It was found that DYY significantly reduced the right ventricular systolic pressure, attenuated lung injury and decreased the expression of inflammatory factors in mice. It can also inhibit hypoxia-induced activation of NF- kappaB signaling pathway. DYY has a protective effect on lung function, as demonstrated by DYY has good efficacy in HPH, and preventive administration can slow down the disease progression, and its mechanism may be related to inhibit the activation of NF-kappaB and signal transducer and activator of transcription 3 (STAT3) by DYY.Copyright © 2023, Chinese Pharmaceutical Association. All rights reserved.

Efficacy of Sildenafil in Patients with Severe COVID-19 and Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is common in severe coronavirus disease 2019 (COVID-19) and worsens the prognosis. Sildenafil, a phosphodiesterase-5 inhibitor, is approved for PAH treatment but little is known about its efficacy in cases of severe COVID-19 with PAH. This study aimed to investigate the clinical efficacy of sildenafil in patients with severe COVID-19 and PAH. Intensive care unit (ICU) patients were randomly assigned to receive sildenafil or a placebo, with 75 participants in each group. Sildenafil was administered orally at 0.25 mg/kg t.i.d. for one week in a placebo-controlled, double-blind manner as an add-on therapy alongside the patient's routine treatment. The primary endpoint was one-week mortality, and the secondary endpoints were the one-week intubation rate and duration of ICU stay. The mortality rate was 4% vs. 13.3% (p = 0.078), the intubation rate was 8% and 18.7% (p = 0.09), and the length of ICU stay was 15 vs. 19 days (p < 0.001) for the sildenafil and placebo groups, respectively. If adjusted for PAH, sildenafil treatment significantly reduced mortality and intubation risks: OR = 0.21 (95% CI: 0.05-0.89) and OR = 0.26 (95% CI: 0.08-0.86), respectively. Sildenafil demonstrated some clinical efficacy in patients with severe COVID-19 and PAH and should be considered as an add-on therapy in these patients.

Chronic Chilblain Like Lesions Associated with the Covid-19 Pandemic

Background/Aims We report the features of chronic chilblain-like digital lesions newly presenting since the start of the covid-19 pandemic. Comparison with primary perniosis and acrocyanosis, reveals a unique phenotype which appears to be a long-covid phenomenon. Methods The case records of 26 patients with new onset persistent chilblain-like lesions presenting to the Rheumatology service of St George's University Hospital, London between Autumn 2020 and Spring 2022 were reviewed. Demographic and clinical features, serology, imaging, treatment response and outcome up to Summer 2022 were collated retrospectively. Results Chilblain-like lesions first occurred between September and March;2019/ 2020 6 cases, 2020/2021 18 cases and 2021/2022 2 cases. Mean age 35.4 (17-60) years, 88% female, 85% white, all non-smokers. Median body mass index (BMI) 20.2, range 17.0 - 33.2. BMI underweight (<18.5) in 27%. All cases reported new red-purple-blue colour changes of the fingers, some with pain, swelling and pruritis, affecting both hands in 12, one hand in 6, and both hands and feet in 8 cases. There was a past history of cold sensitivity or primary Raynaud's in 54%. Covid was confirmed in 3 cases, 2 - 8 months prior to onset of chilblain-like symptoms. Possible covid, unconfirmed, was suspected in 5 cases, 1 - 11 months earlier. Affected digits appeared diffusely erythro-cyanotic in 81%, with blotchy discrete maculo-papular erythematous lesions in 42%, some with both features. Involvement was asymmetric in 54%, thumbs spared in 69%. Complement was low in 50% (8/16), ANA positive in 26% (6/23). MRI of hands showed phalangeal bone marrow oedema in keeping with osteitis in 4 of 7 cases. More severe signs and symptoms were associated with low BMI, low C3/4 and a past history of cold sensitivity or Raynauds. Cold avoidance strategies were sufficient for 58%. Pain prompted a trial of NSAIDs, aspirin, nitrates, calcium channel blockers, hydroxychloroquine, oral or topical corticosteroid or topical tacrolimus in 42%. In general, these were minimally effective or not tolerated. 4 severe cases received sildenafil or tadalafil, effective in 2. In 27% complete remission occurred during the first summer season after symptoms commenced, median duration 6 (range 2 - 10) months. In the remaining 19 cases, chilblain-like symptoms returned or worsened in the subsequent second winter period, with 6 of 19 entering remission the following summer. For the remaining 13 persistent cases the total duration of symptoms spans more than a year, and in four cases more than 2 years. Conclusion This series illustrates a distinct chronic chilblain-like condition. Features similar to primary perniosis include female predominance, middle age, pruritic painful blotchy lesions, asymmetry and low BMI. Features in keeping with acrocyanosis include chronicity, extensive diffuse erythro-cyanotic discoloration, relative improvement in warm weather and lack of association with smoking.

Mild Androgen Insensitivity Syndrome presenting in male with infertility and sexual difficulties

Androgen insensitivity syndrome has a wide spectrum of presentations. It results from a mutation in androgen receptor (AR) gene. It ranges from mild androgen insensitivity syndrome (MAIS) which is the mildest form to complete androgen insensitivity syndrome (CAIS). In case of MAIS, the abnormality that can be observed appears to be male infertility and sexual difficulties including premature ejaculation and erectile dysfunction. In this case report, we discuss a case of MAIS in a 37-year-old male who presented with infertility, premature ejaculation, and secondary erectile dysfunction.Copyright © 2023, Ibn Sina Trust. All rights reserved.

Czech Cardiovascular Research and Innovation Day 2022

The proceedings contain 67 papers. The topics discussed include: role of endomyocardial biopsy in differential diagnosis of non- -ischemic cardiomyopathy;metformin treatment is associated with improved quality of life and outcome in patients with diabetes and advanced heart failure (HFREF);translational research in the field of inherited arrhythmias;same day discharge via a dedicated radial lounge - results of 1-year experience during the COVID-19 pandemic;functional assessment of microcirculation in takotsubo cardiomyopathy - a pilot study;an interplay of genetics and inflammation affecting left ventricular reverse remodeling in dilated cardiomyopathy;sildenafil inhibits pulmonary hypertension induced by left heart pressure overload in rats;predicting long-term survival after an ischemic stroke;and longitudinal trends in blood pressure, prevalence, awareness, treatment, and control of hypertension in the Czech population. are there any sex differences?.

COVID-19 Infection: A Review of Summarized Clinical Trials Study for the Treatment

Background: Coronavirus Disease 2019 (COVID-19) is a widely infectious and pathogenic viral infection. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) was reported in Wu-han, China, and spread throughout the world. Coronavirus is indeed an enveloped RNA virus of the ge-nus Betacoronavirus, which is transmitted to birds, humans as well as other mammals. The fastest human to human transition has been generally established. On July 19, 2020, the WHO has reported total confirmed cases: 1,40, 43,176, total confirmed new cases: 1,66,735, total deaths: 5,97,583, and total new deaths: 4,496 globally. Material(s) and Method(s): In this review, the Clinical trial database is analyzed and systematically summarized drugs which are in the recruiting phase and the completion phase of the clinical trial. Result(s): Total 383 clinical trials are listed, involving more than 350 medicines such as Deferoxamine, Favipiravir, DAS181, Tocilizumab Injection, Sarilumab, Placebo, Sildenafil citrate tablets, Sargramo-stim, Lopinavir/ritonavir, Remdesivir, Bevacizumab, Tetrandrine, Fingolimod, Methylprednisolone, Plaquenil, Tocilizumab, Hydroxychloroquine, Abidol hydrochloride, Bevacizumab Injection, Methyl-prednisolone, Amoxicillin-clavulanate, Moxifloxacin, Sarilumab, Darunavir, Cobicistat, etc. Conclusion(s): There is no commercially authorized antiviral treatment or vaccine suitable for use against COVID-19. However, clinical trials represent an effective approach because they facilitate the development of new types of pharmaceutical drugs.Copyright © 2021 Bentham Science Publishers.

Paediatric Aps - Children Are Not Just Small Adults

Introduction/Background: Antiphospholipid syndrome (APS) is a rare autoimmune multisystem disease characterised by thrombosis and pregnancy morbidity in the presence of persistently elevated titres of: lupus anticoagulant, anticardiolipin and/or anti-glycoprotein 1. It may be primary (occurring alone) or secondary (in combination with another disease, most commonly systemic lupus erythematosus (SLE)). Recent publications highlighted clinical criteria limitations for children and raised awareness of the burden and prevalence of non-criteria manifestations in this population. This case report adds further weight to the need to raise multi-specialty awareness of non-criteria manifestations to aid recognition and treatment of this rare condition with potentially severe sequelae. Description/Method: 13-year-old female with SLE diagnosed aged 8 in India with bilateral optic neuritis occurring two months later. ANA positive at diagnosis with low complement and thrombocytopenia. Treated with prednisolone and hydroxychloroquine. Patient moved to the UK aged 9;initial abnormal bloods: mildly positive ANA (ENA negative), thrombocytopenia, strong lupus anticoagulant. As serology not strongly suggestive and optic neuritis rare in lupus diagnosis questioned. Ophthalmology review confirmed bilateral optic atrophy without evidence of previous vasculitis. There was debate whether the postretinal demyelination was due to antiphospholipid syndrome or a primary demyelinating condition. Hydroxychloroquine stopped and azathioprine started. Following normal neurology investigations (brain, spine MRI/MRV/MRA) concluded if patient developed new APSrelated symptoms or worsening visual evoked potentials anticoagulation would be discussed. Patient remained stable over four years with chronic thrombocytopenia and ESR persistently elevated. Azathioprine changed to Mycophenolate mofetil (MMF) due to side effects. Routine medication monitoring bloods in 2022 showed ESR 97, CRP 78, Platelets 61. Review identified vasculitic rash on soles of both feet with palpable nodules and normal pulses. Further investigation confirmed antiphospholipid antibody triple positivity. Aspirin commenced, hydroxychloroquine restarted, MMF dose increased and rituximab administered. Left foot rash settled but right progressed with toe discolouration and numbness. Skin biopsy considered but not performed due to skin integrity concerns. Foot pulses remained present and normal. Bilateral lower limb doppler reported as normal;increased symptoms resulted in CT angiogram which revealed bilateral non-occlusive popliteal thrombus and left pulmonary embolus. Subsequent echocardiogram was normal. Patient was anticoagulated with low molecular weight heparin followed by warfarin. Vascular surgical team advocated medical management and patient received seven infusions of Iloprost followed by Sildenafil. She achieved near total resolution of skin changes to toes with only minimal loss of skin over tip of right great toe. Patient will now require long-termanticoagulation. Discussion/Results: APS was considered in initial differential diagnosis but patient did not meet current clinical criteria as no past evidence of thrombosis. Lupus anticoagulant was consistently strongly positive and anticardiolipin repeatedly negative. As anti-B2 glycoprotein 1 antibody is not routinely tested and must be verbally requested, it was only checked once (negative) prior to discovery of triple positivity. ANA reported as strongly positive at time of SLE diagnosis but reviewing original notes from India titre was 1:100 and therefore not highly convincing. ENA negative and complement and white cell count normal on repeat testing since. Therefore, it is probable that this patient has primary APS as opposed to secondary APS in association with SLE. However, it is possible that this patient may develop more symptoms of SLE over time. When this patient presented with foot rash there were high numbers of children presenting with varying severity of painful, itchy toes coined 'covid toes' due to suspected lin to SARS-CoV-2 infection. Patient had exposure history, and COVID antibody serology was difficult to interpret due to recent vaccination. Dermatology found appearance to be consistent with 'covid toes' and advised supportive treatment. The triple APS antibody positivity result provided probable aetiology. Providing evidence of thrombus was problematic with false reassurance from apparently normal lower limb arterial doppler when actually popliteal arteries were not checked in view of the presence of normal flow proximally at the groin and distally in the feet. This case highlights the need to continue to search for thrombus in presence of high titres antiphospholipid antibodies and particularly in the case of triple positivity as although patient presented with colour change to toes, she was entirely asymptomatic from her PE and her left foot improved spontaneously despite a left popliteal thrombus also being present. Key learning points/Conclusion: Non-criteria manifestation of thrombocytopenia (occurs in 25% paediatric APS patients) was present throughout and patient had past history of haematuria (a recognised renal non-criteria manifestation). A paediatric specific APS criteria including these may have resulted in earlier detection of triple antiphospholipid antibody positivity and thus earlier treatment escalation and possible avoidance of thrombus. It has been reported that a high proportion of children with positive antiphospholipid antibodies don't develop a thrombus. However, it is interesting that our patient was entirely asymptomatic from her pulmonary embolus which was an incidental finding on her CT angiogram. This prompts a discussion about how much imaging should be performed in those with high levels of persistent positive antiphospholipid antibodies. Rituximab resulted in normalisation of platelet count and ESR for the first time since initial presentation. Anticardiolipin antibodies normalised, lupus anticoagulant decreased from strong to moderate and anti- B2 glycoprotein levels decreased but remained positive. Rituximab is a recognised treatment for catastrophic antiphospholipid syndrome (CAPS) but not routinely used in APS. The consistently raised ESR in an apparently clinically well patient is a reminder to continue to search for causes of inflammation. As the CRP was largely in normal range, this demonstrates the unique value of the ESR. In view of anti-B2 glycoprotein 1 antibody requiring to be verbally requested, discussions are ongoing with the laboratory department regarding the possibility of electronic request and a comment with recommendation to check other two antiphospholipid antibodies following one positive antibody result. As a result of this case, a plan will be put in place to ensure annual screening of antiphospholipid antibodies in all juvenile SLE patients in our care. It is hoped that this case report promotes discussion amongst the paediatric rheumatology community regarding further research required for development of paediatric specific APS criteria and management.

Efficacy of sildenafil and high-dose anakinra in an MIS-C patient with pulmonary vasculitis: A case report.

Multisystem inflammatory syndrome in children (MIS-C) is a newly identified clinical entity still not very well known in terms of epidemiology, pathogenesis, and long-term outcome. Pulmonary involvement with acute respiratory failure is an unusual life-threatening complication of MIS-C, often a reason for admission to the pediatric intensive care unit (PICU) and the use of mechanical ventilation. We present a case of a 7-year-old male patient, previously healthy, hospitalized for MIS-C, treated with intravenous immunoglobulins (IVIG), high dose methylprednisolone, and anakinra. After 2 days of the aforementioned therapy, the patient presented with hypoxia (SatO2: 85% in ambient air room) and breathing difficulties. A chest computed tomography (CT) scan showed the presence of multiple bilateral basal parenchymal thickening and small basal pleural effusion and an arterial blood gas analysis revealed severe hypoxia (PaO2/FiO2 ratio, 170 mmHg). Because of a worsening of respiratory distress, the patient was transferred to the PICU, where invasive mechanical ventilation and a continuous infusion of anakinra (12 mg/kg/day) were started. An echocardiogram was performed, which showed an increase in pulmonary pressure (40 mmHg) with normal heart ejection fraction (55%), and the hypothesis of pulmonary vasculitis involving the pulmonary arterioles was made. Therefore, therapy with sildenafil (0.15 mg/kg/day) was promptly set up, with an immediate improvement of the clinical picture of respiratory failure, reduction of pulmonary pressure (23 mmHg), and subsequent extubation at 36 h with a regular clinical course until discharge. As far as we know, our case represents the first report of pulmonary vasculitis in an MIS-C patient. The use of sildenafil and high-dose continuous anakinra may represent a rescue therapy in cases of MIS-C with pulmonary vasculitis or with difficulty in extubation, allowing a short-term hospitalization in intensive care and improving the long-term outcome in these patients.

Role of Sildenafil in Severe COVID-19 Pneumonia in Infancy-A Case Series

SARS-CoV-2 virus primarily affects the respiratory system, although other organ systems are also involved. Though pulmonary arterial hypertension (PAH) has been described in as a sequela of COVID pneumonia in adults, only a coincidental association between pre-existing PAH and SARS-CoV-2 infection in children has been reported. To our knowledge, severe COVID pneumonia-causing PAH in children, especially in infancy has not been reported yet. With the meteoric spread of the pandemic and rapid development of newer mutated variants, the timely discovery of new drugs is near impossible. The idea of repurposing existing drugs to treat COVID-19 is an attractive strategy, especially if they are already approved (for other indications) and have well-established safety profiles. Sildenafil specifically targets pulmonary vasodilation, endothelial function, and vascular remodelling. It hence has emerged as an effective first-line oral therapeutic agent for patients with symptomatic PAH in all age groups. We present a case series of four cases where Sildenafil has been repurposed for the treatment of PAH associated with severe COVID-19 pneumonia in infancy. Copyright © 2022 by author(s).

SARS-Cov-2 infection in patients with univentricular heart after fontan operation

Background and Aim: COVID-19 pandemic caused by SARS-Cov-2 coronavirus affects all groups of patients. Although pediatric pop-ulation seems to be less affected with milder or asymptomatic course of SARS-CoV-2 infection, there are few groups of patients with potential high risk of severe or fatal course of coronavirus dis-ease. These include children with congenital heart defects. The aim of this study was to evaluate the course of SARS-Cov-2 infection in patients with univentricular heart after Fontan operation. Method(s): From September 2020 to May 2021 (before vccination started in pediatric population in Poland) we screen all 38 Fontan patients admitted to Cardiology Department, Polish Mother's Memorial Hospital Research Institute for SARS-Cov2 antibodies. Result(s): We found positive SARS-Cov-2 antibodies in 21 unvac-cinated Fontan patients (55% of all hospitalized Fontan patients), 15 boys (71%) and 6 girls in the age 3-22 years (mean 11 years). 14 patients (67%) had hypoplastic left heart syndrome. Course of SARS-CoV-2 infection: asymptomatic course in 11(52%) patients, fever in 7 (33%) patients, cough 4 (19%) patients, diar-rhoea in 2 patients, loss of smell and taste-1 patient. One, 18 years old patient suffered from Covid fog symptoms (impairment of sus-tained attention and memory problems), he hasn't notice any SARS-Cov-2 symptoms but the level of antiobodies was high. Only 3 patients were hospitalized in acute SARS Cov2 infection: 2 due beacause of need for intravenous rehydratation during severe diarrhoea, 1 because of JET (junctional ectopic tachycardia) during fever. There was no case of PIMS (pediatric inflammatory multi-system syndrome) in study group. Medications used in study group: aspirin in 19 (90 %), warfarin in 2, spironolactone in 18 (86%), sildenafil in 9 (43%), angiotensyn-converting enzyme inhibitors in 17 (81%), beta-blockers in 4 (19%) of patients. Conclusion(s): 1. In our study severe congenital heart defect such as univentricular heart was not a risk factor of severe course of SARS-Cov-2 infection. 2. Absence of PIMS in analized group of patients may be connected with changed immunologic response in Fontan patients and chronic use of ASA (acetylsalicylic acid). 3. The impact of SARS CoV 2 infection on patients with congenital heart defects needs further studies.

"BUT I AM TOO YOUNG FOR THIS": EARLY PRESENTATION OF USUAL INTERSTITIAL PNEUMONIA

SESSION TITLE: Diagnosis of Lung Disease through Pathology Case Posters SESSION TYPE: Case Report Posters PRESENTED ON: 10/19/2022 12:45 pm - 01:45 pm INTRODUCTION: Usual interstitial pneumonia (UIP) is a histological term used to describe a pattern of interstitial fibrosis with alternating areas of the normal lung with temporal fibrosis and architectural alteration due to chronic scarring or honeycomb change. It is a subset of idiopathic interstitial pneumonias (IPF) that usually presents in the sixth and seventh decades of life with progressive dyspnea on exertion and productive cough. CASE PRESENTATION: We present a 46 y/o man with a history of thyroid disease, hypertension and a former smoker of 20 pack-year smoking. Presented to ED complaining of low oxygen saturation with pulse oximetry at home with readings between 60-80%. Accompanied with progressive dyspnea on exertion and unintentional weight loss of 80 pounds in the last year. Also referred productive cough of white sputum that was worse in the morning. Home nebulized Albuterol therapy did not provide improvement. Denied recent viral respiratory infections, night sweats, environmental exposures nor family history of lung disease. DISCUSSION: Physical exam demonstrated bilateral expiratory dry crackles and pulse oximetry oxygen saturation at room air of 78%. RBBB evidenced on EKG. Bloodwork showed polycythemia with hemoglobin of 17.8;ABG's with pH: 7.40, Pco2: 42.2, PO2: 59.8, HCO3: 26, O2 sat: 90.8 and ideal PO2: 85.6 consistent with metabolic alkalosis with BMP CO2 of 30, A/a gradient: 43.0. Mycoplasma IgM, Influenza A & B and COVID-19 antigen test were negative. CXR with increased vascular markings, chest CT demonstrated small pericardial effusion, bilateral coarse interstitial pulmonary markings and bronchiectasis suggestive of chronic interstitial lung disease with no specific pattern. Left heart catheterization revealed right ventricular hypertrophy, normal EF >55%, and no evidence of coronary disease. Alpha-1 antitrypsin: 158, EPO: 6.5, HIV, and hepatitis panel were all negative. Rheumatology work up with only an ANA antibody positive, with titer 1:160. Patient underwent VATS procedure with wedge biopsy of the right upper and middle lobe that revealed usual interstitial pneumonia pattern. Patient improved and was discharged on home oxygen 3L. At follow-up, treatment was started with Nintedanib and Sildenafil Citrate. He had clinical improvement and oxygen requirements decreased to intermittent oxygen. CONCLUSIONS: Patients with interstitial pulmonary fibrosis experience slow progressive decline with typical clinical presentation over 60 years of age. This case remarks the importance of the need for stratification of interstitial lung disease classification, when pattern and history are non specific, with the use of VATS procedure for early start of treatment. Our patient with no environmental exposure or connective tissue disease had an uncommon early presentation of usual interstitial pneumonia. Reference #1: Tibana, R.C.C., Soares, M.R., Storrer, K.M. et al. Clinical diagnosis of patients subjected to surgical lung biopsy with a probable usual interstitial pneumonia pattern on high-resolution computed tomography. BMC Pulm Med 20, 299 (2020). https://doi.org/10.1186/s12890-020-01339-9 DISCLOSURES: No relevant relationships by Jesse Aleman No relevant relationships by Carlos Martinez Crespí no disclosure submitted for Jean Ramos;No relevant relationships by Alexandra Rodriguez Perez No relevant relationships by Paola Vazquez No relevant relationships by Nahomie Veguilla Rivera

IMPAIRED BETA-2ADRENERGIC ENDOTHELIUM-DEPENDENT VASODILATION IS REVERSED BY PHOSPHODIESTERASE INHIBITION IN PATIENTS PREVIOUSLY HOSPITALIZED WITH COVID-19

Objective: Endothelial dysfunction is thought to underlie many of the complications of COVID-19 but to what degree this persists after recovery is unknown. Here we examine endothelial function in subjects previously hospitalized with COVID- 19, those with mild symptoms who were not hospitalized and negative controls (absence of SARS-CoV-2-antibodies). Endothelial function was measured as pulse wave response to the β2 adrenergic agonist salbutamol (PWRS) which is mediated through the nitric oxide - cyclic guanosine monophosphate pathway (NO-cGMP). Design and method: Echocardiography was used to exclude subjects with cardiac abnormalities. Tonometry of the radial artery (SphygmoCor, AtCor Medical, Sydney, Australia) was performed in duplicate by a single operator before and after inhalation of 200 mcg of salbutamol using a spacer device. The PWRS was taken as the change from baseline in augmentation index (Aix) as calculated by the SphygmoCor system. In a sub-sample, PWRS was assessed in the presence and absence of the phosphodiesterase type 5 inhibitor sildenafil which inhibits the breakdown of cGMP. Results: We recruited 88 subjects (49 men) aged 47.9 ± 14.3 (mean ± SD) years of whom 32 were previously hospitalized with COVID-19 (~6 months). Subjects previously hospitalized with COVID-19 were all previously assessed in a dedicated pulmonary clinic. Age, gender, BMI, smoking status, diabetes and estimated 10-year cardiovascular risk (Q-RISKâ3) were similar between the groups. Administration of salbutamol reduced AIx in controls and those with mild COVID-19 but produced an increase in AIx in previously hospitalized COVID-19 cases (mean [95% CI]): -2.85 [-5.52, -0.188] %, -2.32 [-5.17,0.54] %, and 3.03 [0.06, 6.00] % respectively, P = 0.017 between the groups. In a sub-sample (11 hospitalized and 11 non-hospitalized) the PWRS was measured again 30 minutes after oral administration of sildenafil 25 mg. This produced a greater reduction in AIx: -5.28 [-9.00, -1.54] % in non-hospitalized and a reduction: -3.90 [-7.60, -0.21] % in hospitalized patients, and an overall improvement in the PWRS (P = 0.006). Conclusions: In subjects previously hospitalized with severe COVID-19, endothelial function is impaired for many months after hospital discharge and the impaired NO-cGMP mediated vasodilation may be reversed by sildenafil.

A novel approach for drug discovery-drug repurposing

Drug repurposing refers to finding a new indication for a pre-existing drug. It is a novel way of drug discovery that greatly reduces the time and money spent in the drug discovery process. This approach is associated with a better chance of successful drug approval. Both previously approved drugs as well as drugs that have failed in the trials conducted for their original indication can be repurposed. Even drugs withdrawn from market for their original indication can be repurposed for a new indication. Starting with Sildenafil which is the oldest example of repurposed drug to the recently repurposed drug tocilizumab for COVID-19, the list of repurposed drugs is a big one. The regulatory pathway to be followed for a repurposed drug is different from that for a new chemical entity. Furthermore, the period of marketing exclusivity for repurposed drug is only 3 years as against the 20 years of patent protection period for new drug. The strategy for drug repurposing may be a serendipitous one or hypothesis driven one. The hypothesis driven strategy includes the experimental and computational approaches. Computational approaches for drug discovery, especially the Connectivity map approach, offer a lot of scope to understand the drug-disease-gene link, thereby acting as a kick-starter for drug repurposing. Drug repurposing has real potential to offer a cure for rare genetic conditions and cancers. This review covers the various drug repurposing approaches in detail, the regulatory pathway for repurposed drugs, salient examples of repurposed drugs and also the challenges associated with drug repurposing.

Chronic lung disease following covid-19 in an infant

Case Report Chronic respiratory sequelae are well documented in adults after COVID-19 infection, however, in young children and infants, evidence is still evolving. Here we report an infant with significant chronic respiratory complications after COVID-19. Case Report A 10 month old female with no significant past medical history was admitted to the PICU secondary to hypoxemia, respiratory distress, and respiratory failure following COVID-19 infection in January 2021. She was also positive for Rhinovirus and Enterovirus. CXR displayed worsening bilateral alveolar infiltrates, and she developed subsequent pneumothorax requiring a chest tube. Apart from mechanical ventilation, she received supportive treatment and broad spectrum antibiotics. Cardiac echocardiogram revealed pulmonary hypertension, PFO, and PDA. Due to worsening respiratory status and hypoxemia, she received bronchodilators, inhaled nitric oxide, sildenafil, steroids, and magnesium. After 3 weeks, her respiratory status improved and she was discharged. The patient required another hospitalization in March and an ER visit in April for persistent cough and shortness of breath. After evaluation by pulmonology, she began inhaled steroids and airway clearance treatments including chest physical therapy, hypertonic saline, and bronchodilators. Further workup ruled out cystic fibrosis, primary ciliary dyskinesia, and immunodeficiency. Chest CT showed diffuse bilateral patchy airspace opacities representing atelectasis and scarring. Despite a short period of improvement, the patient was hospitalized for respiratory distress in June, where she was hypoxemic and diagnosed with pneumonia. She required repeated outpatient visits to the PCP for persistent respiratory symptoms. PDA closure was performed in September. The patient continues to have persistent respiratory symptoms addressed with outpatient respiratory treatment regimen. Conclusion As we have ruled out other underlying causes, the patient's chronic lung disease and persistent respiratory symptoms occurred most probable secondary to COVID-19. This case report highlights the importance of monitoring respiratory symptoms in pediatric patients with severe COVID-19 infection for early identification of chronic respiratory sequelae.

Sildenafil for treating patients with COVID-19 and perfusion mismatch: a pilot randomized trial.

BACKGROUND: SARS-CoV-2 seems to affect the regulation of pulmonary perfusion. Hypoperfusion in areas of well-aerated lung parenchyma results in a ventilation-perfusion mismatch that can be characterized using subtraction computed tomography angiography (sCTA). This study aims to evaluate the efficacy of oral sildenafil in treating COVID-19 inpatients showing perfusion abnormalities in sCTA. METHODS: Triple-blinded, randomized, placebo-controlled trial was conducted in Chile in a tertiary-care hospital able to provide on-site sCTA scans and ventilatory support when needed between August 2020 and March 2021. In total, 82 eligible adults were admitted to the ED with RT-PCR-confirmed or highly probable SARS-COV-2 infection and sCTA performed within 24 h of admission showing perfusion abnormalities in areas of well-aerated lung parenchyma; 42 were excluded and 40 participants were enrolled and randomized (1:1 ratio) once hospitalized. The active intervention group received sildenafil (25 mg orally three times a day for seven days), and the control group received identical placebo capsules in the same way. Primary outcomes were differences in oxygenation parameters measured daily during follow-up (PaO2/FiO2 ratio and A-a gradient). Secondary outcomes included admission to the ICU, requirement of non-invasive ventilation, invasive mechanical ventilation (IMV), and mortality rates. Analysis was performed on an intention-to-treat basis. RESULTS: Totally, 40 participants were enrolled (20 in the placebo group and 20 in the sildenafil group); 33 [82.5%] were male; and median age was 57 [IQR 41-68] years. No significant differences in mean PaO2/FiO2 ratios and A-a gradients were found between groups (repeated-measures ANOVA p = 0.67 and p = 0.69). IMV was required in 4 patients who received placebo and none in the sildenafil arm (logrank p = 0.04). Patients in the sildenafil arm showed a significantly shorter median length of hospital stay than the placebo group (9 IQR 7-12 days vs. 12 IQR 9-21 days, p = 0.04). CONCLUSIONS: No statistically significant differences were found in the oxygenation parameters. Sildenafil treatment could have a potential therapeutic role regarding the need for IMV in COVID-19 patients with specific perfusion patterns in sCTA. A large-scale study is needed to confirm these results. TRIAL REGISTRATION: Sildenafil for treating patients with COVID-19 and perfusion mismatch: a pilot randomized trial, NCT04489446, Registered 28 July 2020, https://clinicaltrials.gov/ct2/show/NCT04489446 .

Is this scleroderma lung or COVID-19 lung?

Case report-IntroductionThis is a case of Pakistani female with limited systemic sclerosis and associated mild interstitial lung disease. The lung disease was complicated by SARS-COV-2 related pneumonitis in April 2020 and that led to treatment challenges.She was previously seen in multiple private hospitals and labelled as Rheumatoid arthritis. She was being treated with long term steroids and Methotrexate. After her initial presentation to our Rheumatology services, her diagnosis was correctly revised to Systemic Sclerosis with phenotype of CREST. Her treatment was adjusted to Vasodilators and Mycophenolate due to skin and Lung involvement.Case report-Case descriptionThis is a case of 40-year-old Pakistani female who had been having multiple joint pains since 2010. She also experienced severe Raynaud's.She presented to our Rheumatology clinic in December 2018. Her symptoms included recurrent digital ulcers, tight and tough skin at fingers and Raynaud's worse during winter months. Her examination confirmed peripheral cyanosis with multiple digital ulcers with superimposed infection, marked sclerodactyly and calcinosis. She was started on Vasodilator therapy including calcium channel blocker and PDE5 inhibitor due to severity of ulceration. Infection was managed with prolonged course of antimicrobial therapy. Her immunology showed positive anti nRNP/Sm. Anti-centromere and anti Scl 70 were negative. Her condition fit description of CREST (Calcinosis, RP, Oesophageal dysmotility, telangiectasia). Her management included weaning off Methotrexate and reduction in the dose of corticosteroids.In February 2019, Respiratory work up showed normal Chest radiograph, High resolution CT chest showing no significant abnormality and FEV1 82%, FVC 86%, and DLCO 77%. Her PASP was 25mmHg. Overall, her condition remained stable over the course of next year. Her medication included Cellcept, low dose prednisolone, hydroxychloroquine, and Sildenafil. More importantly, Digital ulcers have been well controlled with combined vasodilator therapy.In April 2020, she developed SARS-CoV-2 with mild respiratory symptoms and was admitted to a different hospital. Fortunately, she responded well to ward based supportive and symptomatic treatment with no need for respiratory support. Subsequently, she has seen a different respiratory physician and had repeat imaging of chest which has led to dilemma whether the ground glass opacities in both lungs is due to scleroderma lung or COVID-19 related lung disease. She was given high dose prednisolone by the respiratory physician which has been reduced in rheumatology clinic. The new findings on chest imaging are sequelae of SARS-COV-2.Case report-DiscussionThis case highlights few important points as below:Systemic sclerosis diagnosis was not made for many years even though she has had severe digital ulcers for a long time. She was being managed as Rheumatoid arthritis. Systemic sclerosis remains a difficult disease to diagnose and is still under recognised.SARS-COV-2 related illness has not affected this patient adversely despite the fact of being on long term maintenance prednisolone of 7.5mg daily dose and Cellcept 2gm. Her cellcept was temporarily stopped during acute illness.We know that viral pneumonitis can present with typical ground glass opacities in bilateral areas of lungs and differential diagnosis does include connective tissue related lung disease but this lady had no significant respiratory involvement prior to COVID-19 illness and follow up scan will help to decide if this is disease progression or related to viral cause.Case report-Key learning pointsThere are multiple learning points in this case:Continuity of care under same primary team can avoid confusion related to diagnosis and diagnosis related complications. This lady had none, or mild subclinical lung involvement related to systemic sclerosis prior to contracting COVID-19 illness. Her CT chest findings after the episode of SARS-COV-2 were attributed to systemic sclerosis as she was seen by different respiratory team. This conti uity is not always possible, but MDT collaboration needs to be improved across hospitals and across various departments.Systemic sclerosis remains an under diagnosed and under recognized complex rheumatic disorder and more primary care physicians need to be educated so they can appropriately refer these cases to Rheumatology services.Multi-disciplinary collaboration between Rheumatology, Respiratory and other specialties is the key point to manage these complex cases.This case also highlights an interesting observation that presence of significant immune disorder and immunosuppressant medication does not always equate to worse outcome if patient contracts SARS-COV-2. Supportive care, appropriate observation, and temporary suspension of DMARD in such cases can avoid any further complications.

No Time to Waste: Real-World Repurposing of Generic Drugs as a Multifaceted Strategy Against COVID-19.

Real-world drug repurposing-the immediate "off-label" prescribing of drugs to address urgent clinical needs-is an indispensable strategy gaining rapid traction in the current COVID-19 crisis. Although off-label prescribing (ie, for a nonapproved indication) is legal in most countries, it tends to shift the burden of liability and cost to physicians and patients, respectively. Nevertheless, in urgent public health crises, it is often the only realistic source of a meaningful potential solution. To be considered for real-world repurposing, drug candidates should ideally have a track record of safety, affordability, and wide accessibility. Although thousands of such drugs are already available, the absence of a central repository of off-label uses presents a barrier to the immediate identification and selection of the safest, potentially useful interventions. Using the current COVID-19 pandemic as an example, we provide a glimpse at the extensive literature that supports the rationale behind six generic drugs, in four classes, all of which are affordable, supported by decades of safety data, and pleiotropically target the underlying pathophysiology that makes COVID-19 so dangerous. Having previously fast-tracked this paper to publication in summary form, we now expand on why cimetidine/famotidine (histamine type-2 receptor antagonists), dipyridamole (antiplatelet agent), fenofibrate/bezafibrate (cholesterol/triglyceride-lowering agents), and sildenafil (phosphodiesterase-5 inhibitor) are worth considering for patients with COVID-19 based on their antiviral, anti-inflammatory, renoprotective, cardioprotective, and anticoagulation properties. These examples also reveal the unlimited opportunity to future-proof public health by proactively mining, synthesizing, and cataloging the off-label treatment opportunities of thousands of safe, well-established, and affordable generic drugs.