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Frontiers in Pharmacology 2024Heart failure is the most costly cardiovascular disorder. New treatments are urgently needed. This study aims to evaluate the safety, pharmacokinetics, and...
Safety, tolerability, pharmacokinetics, and pharmacodynamics of a soluble guanylate cyclase stimulator, HEC95468, in healthy volunteers: a randomized, double-blinded, placebo-controlled phase 1 trial.
Heart failure is the most costly cardiovascular disorder. New treatments are urgently needed. This study aims to evaluate the safety, pharmacokinetics, and pharmacodynamic profile of HEC95468, a soluble guanylate cyclase (sGC) stimulator, in healthy volunteers. Sixty-two, eighteen, and forty-eight participants were enrolled in the single ascending dose (SAD) study, the food effect (FE) study, and the multiple ascending dose (MAD) study, respectively. The study conforms to good clinical practice and the Declaration of Helsinki. Overall, HEC95468 was safe and tolerable; a higher proportion of HEC95468-treated participants reported mild headaches, dizziness, decreased blood pressure, increased heart rate, and gastrointestinal-related treatment-emergent adverse events (TEAEs), similar to the sGC stimulators riociguat and vericiguat. In terms of pharmacokinetic parameters, the maximum observed plasma concentration (C) and the area under the concentration-time curve (AUC) were dose-proportional over the dose range. Moderate accumulation was observed after multiple administrations of HEC95468. Systolic blood pressure (SBP) and diastolic blood pressure decreased, while 3',5'-cyclic guanosine monophosphate (cGMP) concentration in plasma increased and heart rate was induced. Vasoactive hormones (renin, angiotensin II, and norepinephrine) in plasma were compensatorily elevated after oral administration. These data supported further clinical trials of HEC95468 in the treatment of heart failure and pulmonary arterial hypertension. http://www.chinadrugtrials.org.cn, identifier CTR20210064.
PubMed: 38933676
DOI: 10.3389/fphar.2024.1359939 -
Frontiers in Pharmacology 2024We conducted an overview to assess immune adverse effects associated with the COVID-19 vaccine, guiding safer choices and providing evidence-based information to...
BACKGROUND
We conducted an overview to assess immune adverse effects associated with the COVID-19 vaccine, guiding safer choices and providing evidence-based information to clinicians.
METHODS
Forty-three studies on adverse effects of vaccines were reviewed from PubMed, Embase, and Web of Science. Single-arm meta-analyses estimated summary effects, incidence, presentation, etc. An overview using single-arm meta-analysis and reported the findings following the guidelines outlined in the 'Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) specifically focusing on myocarditis and thrombosis. After screening 2,591 articles, 42 studies met the inclusion criteria. Methodological quality was evaluated using AMSTAR 2. Disagreements were resolved via consensus. Data analysis utilized a random-effects model in R software to estimate incidence rates of selected adverse events.
RESULTS
After removing 1,198 duplicates and screening out irrelevant articles from a total of 2,591, we included 42 studies. Adverse reactions to vaccinations include myocarditis, thrombosis, skin reactions, GBS, etc. thrombosis and myocarditis are the most dangerous diseases associated with vaccination. Myocarditis occurred in 6% of Vector vaccine recipients, compared to 61% of mRNA vaccine recipients. Thrombosis was more common after Vector vaccination (91%) than after mRNA vaccination (9%). Furthermore, eight studies conducted anti-PF4 antibody tests and yielded a positivity rate of 67%. Meta-analysis showed that among all patients with Vaccine-induced Thrombotic Thrombocytopenia, cerebral venous sinus thrombosis occurred in 66%, and intracranial hemorrhage occurred in 43%. The rates of deep vein thrombosis and pulmonary thromboembolism in vaccinated patients were 13% and 23%, respectively, with a pooled case fatality rate of 30%.
CONCLUSION
The results of this overview indicate the majority of adverse reactions are self-limiting and require minimal intervention, while rare occurrences such as myocarditis and thrombosis pose a potentially fatal threat.
PubMed: 38933672
DOI: 10.3389/fphar.2024.1308768 -
Cureus May 2024Takayasu arteritis (TA) is an autoimmune entity of unknown aetiology causing granulomatous thickening of large and medium-sized arteries. Common symptoms include...
Takayasu arteritis (TA) is an autoimmune entity of unknown aetiology causing granulomatous thickening of large and medium-sized arteries. Common symptoms include claudication, headaches, dizziness, syncope, visual changes, and palpitations. Diverse cardiac manifestations, such as ischemic heart disease, significant aortic regurgitation, and pulmonary hypertension, are associated with TA, although they rarely manifest as congestive heart failure. Radio-imaging, including CT angiography and MR angiography, along with more invasive procedures such as conventional angiography, are often used for diagnosis. Treatment is done with corticosteroids, steroid-sparing agents, biologics, and revascularization procedures. Here, we have a case of a 17-year-old Indian female who presented to us with a complaint of abdominal pain. She was diagnosed with Hashimoto's thyroiditis a few years ago, along with a history of congestive heart failure. On general examination, blood pressure was asymmetrical in the upper limbs with the presence of bilateral carotid bruit. There was also the presence of extensive scaly lesions on the extensor surface of all four limbs, suggestive of psoriasis. Radio-imaging confirmed the diagnosis of TA. CT angiography also showed total occlusion of the celiac trunk and proximal left gastric artery, which was likely the cause of her symptoms. The patient received treatment with corticosteroids in conjunction with methotrexate, along with other supportive drugs. TA with congestive heart failure has been occasionally described in the literature, while the association of TA with psoriasis is much rarer. The simultaneous occurrence of various autoimmune diseases is common, but the triad of Hashimoto thyroiditis, psoriasis, and TA with an initial presentation of heart failure is unique. Due to the common co-occurrence of autoimmune conditions, early and thorough patient evaluation with comprehensive studies is imperative for optimal health outcomes.
PubMed: 38933629
DOI: 10.7759/cureus.61153 -
Cureus May 2024Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by type II and type III hypersensitivity reactions that affect multiple organs, including the...
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by type II and type III hypersensitivity reactions that affect multiple organs, including the joints, heart, lungs, brain, skin, and kidneys. Patients with SLE can experience a range of symptoms, ranging from fever and joint pain to a distinctive butterfly facial rash. Severe complications may encompass conditions such as diffuse alveolar hemorrhage (DAH), pulmonary hypertension, and lupus nephritis, among others. Among them, DAH, a critical pulmonary complication in SLE, involves bleeding from interstitial capillaries and alveoli due to immune complex damage. This case report describes a patient who was initially misdiagnosed but later confirmed to have SLE. The patient presented with persistent symptoms, including cough, dyspnea, and fever, over two weeks and subsequently developed hematuria and hemoptysis within the last two days. The progression of symptoms led to an acute exacerbation, resulting in her admission to the emergency department. Subsequent evaluations confirmed the diagnosis of lupus nephritis and DAH. This case highlights the importance of considering SLE in the differential diagnosis of unexplained systemic symptoms and underscores the urgent need for medical intervention in DAH to substantially reduce mortality.
PubMed: 38933624
DOI: 10.7759/cureus.61161 -
Cureus May 2024Pneumatosis cystoides intestinalis (PCI) is a rare disease wherein air accumulates in the intestinal subserosa and submucosa, causing multiple gaseous cysts within the...
Pneumatosis cystoides intestinalis (PCI) is a rare disease wherein air accumulates in the intestinal subserosa and submucosa, causing multiple gaseous cysts within the gastrointestinal wall. While PCI has various known risk factors, reports identifying muscular diseases as a factor are scarce. The aim of this study is to elucidate the clinical characteristics of PCI in muscle disease. We present a case series of five cases, including two cases of Duchenne muscular dystrophy (DMD) and three cases of rare congenital myopathies. All cases are of male patients, with poor intestinal peristalsis and constipation, who underwent tube feeding and mechanical ventilation via tracheostomy. They had no signs of severe complications, such as intestinal necrosis, and all of them improved with conservative treatment. Case 1 is a 23-year-old man with DMD who developed cardiopulmonary arrest at the age of 20 years. Pulmonary hemorrhage occurred three months before the incidental detection of PCI in the ascending colon, which resolved with conservative oxygen treatment. Case 2 is a 25-year-old man with DMD who progressed to immobility necessitating tracheostomy at the age of 20 years. He experienced persistent abdominal pain and nausea, and PCI was detected in the cecum and ascending colon. He showed near-complete resolution of PCI after three months of conservative treatment. Case 3 is a six-year-old boy with reducing body myopathy. Constipation was diagnosed at four years of age. He experienced intermittent bloody stools, leading to the incidental detection of PCI at six years of age. After two months of conservative treatment, the PCI resolved with no subsequent recurrence. Case 4 is a 33-year-old man with infantile severe myotubular myopathy. He required mechanical ventilation immediately after birth and later underwent tracheostomy and tube feeding due to complications. At the age of 27 years, PCI was incidentally detected on abdominal CT. He had episodes of remission and worsening for a few years; however, PCI completely resolved after three years. Case 5 is a 27-year-old man with nemaline myopathy. At the age of 14 years, he had persistent bloody stools. After lower gastrointestinal endoscopy, he was diagnosed with PCI with numerous rectal cysts. PCI required no specific therapeutic intervention. There was spontaneous resolution of PCI and bloody stools. Given that PCI lacks specific symptoms and cases with muscular diseases often experience abdominal issues, many cases are liable to be overlooked or misdiagnosed. Cases with muscular diseases complaining of persistent abdominal symptoms should undergo radiographic imaging to rule out PCI.
PubMed: 38933611
DOI: 10.7759/cureus.61188 -
Turk Gogus Kalp Damar Cerrahisi Dergisi Apr 2024This study aimed to provide nuanced insights in managing patients with a history of coronavirus disease 2019 (COVID-19) pneumonia undergoing coronary artery bypass...
BACKGROUND
This study aimed to provide nuanced insights in managing patients with a history of coronavirus disease 2019 (COVID-19) pneumonia undergoing coronary artery bypass grafting.
METHODS
This retrospective cohort study involved 168 patients (131 males, 37 females; mean age: 61.2±9.7 years; range, 51 to 72 years) undergoing isolated coronary artery bypass grafting surgery between December 2021 and December 2023. The study examined factors such as age, sex, comorbidities, blood test results, vaccination status, operative parameters, and postoperative complications. Patients' health records were reviewed to confirm the presence of previous COVID-19 pneumonia and vaccination status. Patients were divided into two groups based on their history of COVID-19 pneumonia: Group 1 included 140 who had not been diagnosed with COVID-19 pneumonia, and Group 2 included 28 patients who had a documented history of COVID-19 pneumonia. Postoperative pulmonary complications, including atelectasis, pleural effusion, acute respiratory distress syndrome, and pneumonia, were noted.
RESULTS
Patients with a history of COVID-19 pneumonia (Group 2, n=28) demonstrated significantly higher seropositivity for COVID-19 (89.3% 29.3%, p=0.001) compared to those without a history (Group 1, n=140). Although pulmonary complications were higher in Group 2 (17.9% 3.6%, p=0.013), postoperative mortality rates did not differ significantly between the groups. Pleural effusion was markedly higher in Group 2 (14.3% 2.1%, p=0.015). Vaccination did not significantly affect perioperative and postoperative outcomes, except for a minor difference in postoperative drainage volume.
CONCLUSION
This study highlights the impact of prior COVID-19 pneumonia on postoperative outcomes in coronary artery bypass grafting patients. Although there was a rise in pulmonary complications, the mortality rates stayed similar among individuals with and without a prior history of COVID-19 pneumonia. Vaccination did not significantly influence outcomes, emphasizing the need for further research with larger cohorts to validate and expand upon these findings.
PubMed: 38933321
DOI: 10.5606/tgkdc.dergisi.2024.25993 -
Frontiers in Immunology 2024The diagnosis of tuberculosis (TB) disease and TB infection (TBI) remains a challenge, and there is a need for non-invasive and blood-based methods to differentiate TB...
INTRODUCTION
The diagnosis of tuberculosis (TB) disease and TB infection (TBI) remains a challenge, and there is a need for non-invasive and blood-based methods to differentiate TB from conditions mimicking TB (CMTB), TBI, and healthy controls (HC). We aimed to determine whether combination of cytokines and established biomarkers could discriminate between 1) TB and CMTB 2) TB and TBI 3) TBI and HC.
METHODS
We used hemoglobin, total white blood cell count, neutrophils, monocytes, C-reactive protein, and ten Meso Scale Discovery analyzed cytokines (interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, interferon (IFN)-ɣ, and tumor necrosis factor (TNF)-α) in TruCulture whole blood tubes stimulated by lipopolysaccharides (LPS), zymosan (ZYM), anti-CD3/28 (CD3), and unstimulated (Null) to develop three index tests able to differentiate TB from CMTB and TBI, and TBI from HC.
RESULTS
In 52 persons with CMTB (n=9), TB (n=23), TBI (n=10), and HC (n=10), a combination of cytokines (LPS-IFN-ɣ, ZYM-IFN-ɣ, ZYM-TNF-α, ZYM-IL-1β, LPS-IL-4, and ZYM-IL-6) and neutrophil count could differentiate TB from CMTB with a sensitivity of 52.2% (95% CI: 30.9%-73.4%) and a specificity of 100 % (66.4%-100%). Null- IFN-ɣ, Null-IL-8, CD3-IL-6, CD3-IL-8, CD3-IL-13, and ZYM IL-1b discriminated TB from TBI with a sensitivity of 73.9% (56.5% - 91.3%) and a specificity of 100% (69.2-100). Cytokines and established biomarkers failed to differentiate TBI from HC with ≥ 98% specificity.
DISCUSSION
Selected cytokines may serve as blood-based add-on tests to detect TB in a low-endemic setting, although these results need to be validated.
Topics: Humans; Cytokines; Male; Female; Adult; Biomarkers; Tuberculosis; Middle Aged; Blood Culture; Diagnosis, Differential; Young Adult; Aged; Mycobacterium tuberculosis; Sensitivity and Specificity
PubMed: 38933274
DOI: 10.3389/fimmu.2024.1397941 -
Frontiers in Medicine 2024The fetal haemodynamic response to acute episodes of hypoxaemia are well characterised. However, how these responses change when the hypoxaemia becomes more chronic in...
INTRODUCTION
The fetal haemodynamic response to acute episodes of hypoxaemia are well characterised. However, how these responses change when the hypoxaemia becomes more chronic in nature such as that associated with fetal growth restriction (FGR), is less well understood. Herein, we utilised a combination of clinically relevant MRI techniques to comprehensively characterize and differentiate the haemodynamic responses occurring during acute and chronic periods of fetal hypoxaemia.
METHODS
Prior to conception, carunclectomy surgery was performed on non-pregnant ewes to induce FGR. At 108-110 days (d) gestational age (GA), pregnant ewes bearing control ( = 12) and FGR ( = 9) fetuses underwent fetal catheterisation surgery. At 117-119 days GA, ewes underwent MRI sessions where phase-contrast (PC) and T oximetry were used to measure blood flow and oxygenation, respectively, throughout the fetal circulation during a normoxia and then an acute hypoxia state.
RESULTS
Fetal oxygen delivery (DO) was lower in FGR fetuses than controls during the normoxia state but cerebral DO remained similar between fetal groups. Acute hypoxia reduced both overall fetal and cerebral DO. FGR increased ductus venosus (DV) and foramen ovale (FO) blood flow during both the normoxia and acute hypoxia states. Pulmonary blood flow (PBF) was lower in FGR fetuses during the normoxia state but similar to controls during the acute hypoxia state when PBF in controls was decreased.
CONCLUSION
Despite a prevailing level of chronic hypoxaemia, the FGR fetus upregulates the preferential streaming of oxygen-rich blood via the DV-FO pathway to maintain cerebral DO. However, this upregulation is unable to maintain cerebral DO during further exposure to an acute episode of hypoxaemia. The haemodynamic alterations required at the level of the liver and lung to allow the DV-FO pathway to maintain cerebral DO, may have lasting consequences on hepatic function and pulmonary vascular regulation after birth.
PubMed: 38933113
DOI: 10.3389/fmed.2024.1340012 -
Viruses Jun 2024Influenza A virus (IAV) infections in swine are usually subclinical, but they can reach high morbidity rates. The mortality rate is normally low. In this study, six...
Spontaneous Lethal Outbreak of Influenza A Virus Infection in Vaccinated Sows on Two Farms Suggesting the Occurrence of Vaccine-Associated Enhanced Respiratory Disease with Eosinophilic Lung Pathology.
Influenza A virus (IAV) infections in swine are usually subclinical, but they can reach high morbidity rates. The mortality rate is normally low. In this study, six vaccinated, spontaneously deceased sows revealed IAV infection and enhanced neutrophilic bronchopneumonia with unexpectedly large numbers of infiltrating eosinophils. The purpose of this study was to characterize these lung lesions with special emphasis on the phenotypes of inflammatory cells, the presence of eosinophilic peroxidase (EPO), and neutrophil extracellular traps (NETs). The number of Sirius red-stained eosinophils was significantly higher in the lungs of IAV-infected sows compared to healthy pigs, indicating a migration of eosinophils from blood vessels into the lung tissue stimulated by IAV infection. The detection of intra- and extracellular EPO in the lungs suggests its contribution to pulmonary damage. The presence of CD3 T lymphocytes, CD20 B lymphocytes, and Iba-1 macrophages indicates the involvement of cell-mediated immune responses in disease progression. Furthermore, high numbers of myeloperoxidase-positive cells were detected. However, DNA-histone-1 complexes were reduced in IAV-infected sows, leading to the hypothesis that NETs are not formed in the IAV-infected sows. In conclusion, our findings in the lungs of IAV-infected vaccinated sows suggest the presence of so far unreported field cases of vaccine-associated enhanced respiratory disease.
Topics: Animals; Swine; Lung; Swine Diseases; Orthomyxoviridae Infections; Female; Influenza Vaccines; Influenza A virus; Disease Outbreaks; Eosinophils; Extracellular Traps; Vaccination; Eosinophil Peroxidase
PubMed: 38932247
DOI: 10.3390/v16060955 -
Viruses May 2024Severe fever with thrombocytopenia syndrome (SFTS) is a potentially fatal tick-borne zoonosis caused by SFTS virus (SFTSV). In addition to tick bites, animal-to-human...
Severe fever with thrombocytopenia syndrome (SFTS) is a potentially fatal tick-borne zoonosis caused by SFTS virus (SFTSV). In addition to tick bites, animal-to-human transmission of SFTSV has been reported, but little is known about feline SFTSV infection. In this study, we analyzed data on 187 cats with suspected SFTS to identify biomarkers for SFTS diagnosis and clinical outcome. Body weight, red and white blood cell and platelet counts, and serum aspartate aminotransferase and total bilirubin levels were useful for SFTS diagnosis, whereas alanine aminotransferase, aspartate aminotransferase and serum SFTSV RNA levels were associated with clinical outcome. We developed a scoring model to predict SFTSV infection. In addition, we performed a phylogenetic analysis to reveal the relationship between disease severity and viral strain. This study provides comprehensive information on feline SFTS and could contribute to the protection of cat owners, community members, and veterinarians from the risk of cat-transmitted SFTSV infection.
Topics: Animals; Cats; Phlebovirus; Cat Diseases; Phylogeny; Severe Fever with Thrombocytopenia Syndrome; Male; Female; Biomarkers; RNA, Viral; Severity of Illness Index; Aspartate Aminotransferases; Alanine Transaminase
PubMed: 38932167
DOI: 10.3390/v16060874