Sequelae Of Disease Research Articles

Utilizing HCoV-OC43 to better understand the neurological impact of COVID-19

As the COVID-19 pandemic enters its fifth year, research tools to study the SARS-CoV-2 (CoV-2) virus are critical, and many researchers have turned to another beta coronavirus: HCoV-OC43 (OC43). OC43 is a ubiquitous pathogen that now causes a common cold, but its emergence in 1890 closely coincided with and likely produced the catastrophic Russian Flu pandemic. Beyond their historical parallels, OC43 and CoV-2 share similar genetics and disease sequelae. Both viruses induce respiratory symptoms. Additionally, OC43 infection can result in acute neurological dysfunction in children, and exposure to OC43 has been linked to long-term neurological disorders in adults. Similarly, CoV-2 can produce acute neuropathology and the phenomenon of prolonged symptoms known as Long-COVID that typically impacts the brain. Mouse models have been developed to study the pathogenesis of both OC43 and CoV-2, thereby facilitating research on the neurological sequelae associated with either infection. These models have been further utilized to test therapeutic interventions against both viruses, as researchers seek to establish the potential for using OC43 as a proxy for CoV-2. Further, because mouse models of the two betacoronaviruses exhibit neurological sequelae, using OC43 likely could provide insight into the impact of COVID-19 on the brain. OC43 requires a lower biosafety level than CoV-2, which makes it accessible to more researchers resulting in expeditious scientific progress in the ongoing COVID-19 pandemic.

Considerations in the development of the International Multicenter Pediatric Portal Hypertension Registry

AbstractPortal hypertension, a common sequela of chronic liver disease, is complicated by variceal hemorrhage, one of its most serious complications. Evidence‐based approaches to managing variceal hemorrhage are limited by the scarcity of data related to this rare entity. Multicenter international registries are increasingly utilized to garner critical information about rare diseases. The International Multicenter Pediatric Portal Hypertension Registry (IMPPHR) was developed to acquire pediatric data about the mortality of first variceal hemorrhage and approaches to primary and second prophylaxis of variceal hemorrhage with a goal of improving outcomes in children with portal hypertension. IMPPHR evolved from pediatric portal hypertension symposia at the Baveno V and VI meetings in 2010 and 2015, with a formal executive committee initiating the development of IMPPHR in 2019. The registry opened in 2020, with data closure in 2024, including information from 44 centers and >700 subjects. The complexities and approaches to developing IMPPHR are described.

Minimally invasive treatment with radiofrequency ablation and kyphoplasty for avascular necrosis of the spine in sickle cell disease: illustrative case.

Avascular necrosis (AVN) of the spine is a rare sequela of chronic sickle cell disease (SCD) in which the shape of the sickled red blood cells interfere with the normal vascular supply of vertebral bodies. In this report, the authors describe a case of progressive spinal AVN treated with radiofrequency ablation (RFA) and kyphoplasty for the patient's persistent lower back pain. A 38-year-old male with long-standing spinal AVN due to SCD had been managed conservatively with hydroxyurea and oral opioid analgesics for several years until breakthrough episodes of low-back pain began to occur with an inability to perform activities of daily life. The patient's condition progressed to involve multiple vertebral bodies, leading to a refractory response. Bipedicular RFA directed at L3 and L4 with kyphoplasty was proposed as a novel, minimally invasive approach. The patient was found to have lasting postoperative relief. Patients with pain attributed to a sickle cell crisis can benefit from RFA and kyphoplasty to potentially eliminate or minimize symptoms from spinal AVN due to chronic SCD not responding to conservative management. https://thejns.org/doi/10.3171/CASE24343.

Whole blood gene expression analysis of spontaneous hypertriglyceridemia in dogs suggests an underlying pro-thrombotic process.

Hypertriglyceridemia (HTG) is influenced by multiple genetic and environmental factors. Spontaneous, idiopathic HTG is common in the Miniature Schnauzer dog and presumed to have a strong genetic influence in this breed. To define genes that are differentially expressed in dogs with HTG, we performed RNA sequencing on peripheral blood of 13 Miniature Schnauzers with HTG and 18 controls. We identified 110 differentially expressed genes (DEGs). Pathway analysis suggests an ongoing pro-thrombotic, endothelial activation process in dogs with HTG. The gene with the largest fold change (5.4 ± 1.4, Padj = 4.4E-04), SERPINE1, encodes plasminogen activator inhibitor 1 (PAI-1), a known risk factor for atherosclerosis and thrombosis. Other top DEGs, including SHANK3, MMRN1, and FZD7, are involved in endothelial activation. Two of the top DEGs, ARHGAP29 and ARHGAP21, inhibit pro-thrombotic pathways and are potentially protective of disease sequelae. Top DEGs, including SERPINE1 and ARHGAP21, have also been linked to metabolic syndrome or its features (e.g. insulin resistance) in humans and animal models. Our findings indicate that HTG in the Miniature Schnauzer dog has similar features to HTG and metabolic syndrome in humans, highlighting the potential use of the dog as a spontaneous model for further research into the etiology and effects of HTG.

New idea of Fuke Qianjin capsule in treating sequelae of pelvic inflammatory disease: Anti-inflammatory in the early stage and reparative in the later stage

Ethnopharmacological relevanceSequelae of pelvic inflammatory disease (SPID) occurs in female internal genitalia and surrounding connective tissue. Recent clinical studies have shown that the traditional Chinese medicine Fuke Qianjin capsule (FKQ) can shorten the course of this disease, but its pharmacological effects and potential mechanism have not been fully elucidated. Aim of the studyThis study aimed to investigate the efficacy and underlying mechanisms of FKQ in the treatment of SPID. MethodsIn this study, we first established a mixed infection model to explore the protective effect of FKQ on common pathogens of SPID. Afterwards, mixed bacterial infection and mechanical injury were used in a SPID rat model to explore the protective mechanism of FKQ on SPID rats. Inflammation, repair and immune cells were tested. ResultsFKQ has a protective effect against infections caused by SPID pathogenic bacterial and may reduce mortality from mixed infections. In the SPID model, FKQ improved pathological damage to the uterus, reduced the area of uterine fibrosis, and inhibited the levels of cytokines (TNF-α, IL-6, IL-1β, IL-18, TGF-β1 and VEGF) caused by pathogenic bacteria. Moreover, FKQ treatment reduced the accumulation of NLRP3, Caspase-1, GSDMD Vimentin, and Cytokeratin 18 in the uterus and suppressed the expression of TGF-β1 and VEGF in the fallopian tubes, thereby reducing inflammation and promoting mucosal repair. In addition, FKQ can restore the immune function balance of SPID rats by increasing the proportion of Treg cells in the spleen and thymus in a rat model of SPID, reducing the proportion of Th17 lymphocytes, and promoting an immunological balance of Treg/Th17 cells, thereby regulating the immune system of the body. ConclusionIn summary, FKQ treatment for SPID is the result of a fourfold combination of antibacterial, anti-inflammatory, reparative and immune-enhancing activities.

Beyond acute infection: mechanisms underlying post-acute sequelae of COVID-19 (PASC).

Immune dysregulation is a key aspect of post-acute sequelae of coronavirus disease 2019 (PASC), also known as long COVID, with sustained activation of immune cells, T cell exhaustion, skewed B cell profiles, and disrupted immune communication thereby resulting in autoimmune-related complications. The gut is emerging as a critical link between microbiota, metabolism and overall dysfunction, potentially sharing similarities with other chronic fatigue conditions and PASC. Immunothrombosis and neurological signalling dysfunction emphasise the complex interplay between the immune system, blood clotting, and the central nervous system in the context of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Clear research gaps in the design of PASC studies, especially in the context of longitudinal research, stand out as significant areas of concern.

Understanding the Sequelae of Invasive Meningococcal Disease in the United States.

Invasive meningococcal disease (IMD) is an uncommon but serious and potentially fatal condition that can result in reduced life expectancy and a broad spectrum of sequelae, many of which may be lifelong and devastating for those who survive the acute disease period. In the United States of America (USA), vaccination is available against the five meningococcal serogroups (A, B, C, W, and Y), but meningococcal vaccination rates among healthy USA adolescents and individuals at high risk because of medical conditions are low, rendering them vulnerable to IMD and its sequelae. Despite the severity of the disease, the clinical impact and rates of IMD sequelae in the USA are poorly understood, as USA-specific data are limited, and the methodology of existing research is heterogenous. This commentary presents clinical experts' perspectives on IMD sequelae based on the available published evidence and direct clinical experience. Among sequelae previously identified in a global systematic literature review, 16 conditions were considered as related to IMD by the present authors. These sequelae include short- and long-term physical, neurological, and emotional consequences that impose a substantial humanistic burden on survivors and their caregivers and result in considerable healthcare and societal costs. This commentary highlights existing knowledge gaps concerning IMD sequelae, including the unclear relationship between IMD and mental health disorders, the contribution of sequelae to the disease burden, prevalence of late-onset sequelae among survivors, and timing of the development of sequelae in different age groups. Addressing these knowledge gaps can inform decisions regarding clinical management in the post-acute period and help quantify the impact of prevention through meningococcal vaccination.

Covid-19 Related Seizures

Background: The Coronavirus (Sars-CoV-2, COVID-19) has been evolving its viral strains, prevalence, symptomatology, and sequelae of disease for the past three years. Although the most recognized COVID-19 symptoms involve the respiratory tract; neurological symptoms have been documented. Specifically, seizures have specifically been discussed in the literature but remain both under-recognized and under-reported in clinical practice. Aim: To review of the literature of adult patients with COVID-19 and seizures and integrate into clinical practice in the acute care environment; from presentation to the emergency Department to discharge. Methods: A narrative literature review was conducted to identify all reported clinical studies involving adult patients with COVID-19 and de novo seizures from MEDLINE, yielding 108 relevant publication titles and abstracts. Additional three relevant studies were discovered through manual search of reference lists of included studies. After excluding non-related publications, 58 publications underwent full-text review. Reporting of results was guided by the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR). Results: Data was organized into the following themes in the literature: prevalence of seizure occurrence in patients with COVID-19; pathophysiology discussing possible cause; CSF and EEG findings in these patients, and outcomes both in and out of hospital. Conclusion: Seizures were reported as both the presenting symptom of COVID-19 infection and a sequelae of the disease. Heterogeneity identified in both severity and pathogenesis of disease may partly account for the variability in reporting. Seizures may occur as single incidences, with no further implication to the patient or they may occur in the context of New Onset Refractory Status Epilepticus. Patients may require critical care for management of Status Epilepticus or encephalopathy with accompanying seizures. Clinician vigilance is essential in identifying COVID-19 infection in patients presenting to Emergency Services with seizures. Early recognition impacts patient care both in-hospital and at post-discharge follow-up.

A Machine Learning Approach to Identifying Risk Factors for Long COVID-19

Long-term sequelae of coronavirus disease 2019 (COVID-19) infection are common and can have debilitating consequences. There is a need to understand risk factors for Long COVID-19 to give impetus to the development of targeted yet holistic clinical and public health interventions to reduce its associated healthcare and economic burden. Given the large number and variety of predictors implicated spanning health-related and sociodemographic factors, machine learning becomes a valuable tool. As such, this study aims to employ machine learning to produce an algorithm to predict Long COVID-19 risk, and thereby identify key predisposing factors. Longitudinal cohort data were sourced from the UK’s “Understanding Society: COVID-19 Study” (n = 601 participants with past symptomatic COVID-19 infection confirmed by serology testing). The random forest classification algorithm demonstrated good overall performance with 97.4% sensitivity and modest specificity (65.4%). Significant risk factors included early timing of acute COVID-19 infection in the pandemic, greater number of hours worked per week, older age and financial insecurity. Loneliness and having uncommon health conditions were associated with lower risk. Sensitivity analysis suggested that COVID-19 vaccination is also associated with lower risk, and asthma with an increased risk. The results are discussed with emphasis on evaluating the value of machine learning; potential clinical utility; and some benefits and limitations of machine learning for health science researchers given its availability in commonly used statistical software.

German general practitioners' experiences of managing post-COVID-19 syndrome: A qualitative interview study.

The management of the long-term sequelae of coronavirus disease 2019 (COVID-19) infection, known as post-COVID-19 syndrome (PCS), continues to challenge the medical community, largely owing to a significant gap in the understanding of its aetiology, diagnosis and effective treatment. To examine general practitioners' (GPs) experiences of caring for patients with PCS and to identify unmet care needs and opportunities for improvement. This study follows a qualitative design, using in-depth semi-structured telephone interviews with GPs (N = 31) from across Germany. Interviews were audio-recorded, transcribed verbatim and analysed using qualitative content analysis. GPs reported that they were often the first point of contact for patients with persistent symptoms following SARS-CoV-2 infection, with symptoms typically resolving within weeks. While ongoing symptomatic COVID-19 is perceived to be more common, the relevance of PCS to GP practices is considerable given its severe impact on patients' functioning, social participation and the substantial time required for patient care. GPs coordinate diagnosis and treatment but face challenges because of the unclear definition of PCS and difficulties in attributing symptoms, resulting in a cautious approach to ICD-10 coding. Interviewees highlight lengthy diagnostic pathways and barriers to accessing specialist care. The findings confirm the high functional limitations and psychosocial burden of PCS on patients, and the central role of GPs in their care. The study suggests a need for further research and health policy measures to support GPs in navigating diagnostic uncertainty, interprofessional communication and the limited evidence on effective treatments.

SARS-CoV-2 spike S1 protein induces microglial NLRP3-dependent neuroinflammation and cognitive impairment in mice

Cognitive impairment is often found at the acute stages and sequelae of coronavirus disease 2019 (COVID-19), and the underlying mechanisms remain unclear. The S1 protein from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might be a cause of cognitive impairment associated with COVID-19. The nucleotide-binding domain, leucine-rich–containing family, pyrin domain–containing-3 (NLRP3) inflammasome and neuroinflammation play important roles in Alzheimer's disease (AD) with cognitive impairment. However, their roles remain unknown in COVID-19 with cognitive impairment. We stimulated BV2 cells with S1 protein in vitro and injected the hippocampi of wild-type (WT) mice, NLRP3 knockout (KO), and microglia NLRP3 KO mice in vivo with S1 protein to induce cognitive impairment. We assessed exploratory behavior as associative memory using novel object recognition and Morris water maze tests. Neuroinflammation was analyzed using immunofluorescence and western blotting to detect inflammatory markers. Co-localized NLRP3 and S1 proteins were investigated using confocal microscopy. We found that S1 protein injection led to cognitive impairment, neuronal loss, and neuroinflammation by activating NLRP3 inflammation, and this was reduced by global NLRP3 KO and microglia NLRP3 KO. Furthermore, TAK 242, a specific inhibitor of Toll-like receptor-4, resulted in a significant reduction in NLRP3 and pro-IL-1β in BV2 cells with S1 protein stimulation. These results reveal a distinct mechanism through which the SARS-CoV-2 spike S1 protein promotes NLRP3 inflammasome activation and induces excessive inflammatory responses.

The short-term and long-term prognosis of discharged COVID-19 patients in Guangdong during the first wave of pandemic

COVID-19 survivors concerning about the rehabilitation and sustained sequelae of Coronavirus Disease 2019 (COVID-19) infection. We aimed to investigate the sequelae of patients’ psychological and physical condition and its related factors in the early and late stages. This longitudinal study tracked 281 COVID-19 patients discharged from hospitals in Guangdong, China, for one year. Assessments occurred at 2,4,12,24 and 48 weeks post-discharge. We define 2 weeks, 4 weeks, and 12 weeks as early stage, and 24 weeks and 48 weeks as late stage. Psychological health was measured using the Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7), Posttraumatic Stress Disorder Checklist for DSM-5 (PCL-5), and Pittsburgh Sleep Quality Index (PSQI) scales. Physical health was assessed through laboratory tests, chest computed tomography (CT) scans, and pulmonary function tests. Data were analyzed using multivariate regression models to evaluate the influence of demographic and clinical variables on health outcomes. COVID-19 survivors exhibited psychological and physical sequelae in both the early and late stages. Compared to the early stage, the proportions of patients with depression (early stage 14.6%, late stage 4.6%), anxiety (early stage 8.9%, late stage 5.3%), PTSD(early stage 3.6%, late stage 0.7%), abnormal liver function (early stage 24.6%, late stage 11.0%), abnormal cardiac function (early stage 10.0%, late stage 7.8%), abnormal renal function (early stage 20.6%, late stage 11.0%) and abnormal pulmonary function (early stage 40.9%, late stage 13.5%) were significantly reduced in the late stage. Factors such as gender, age, severity of COVID-19, hospitalization duration, and various comorbidities were significantly associated with these sequelae. We noticed that psychological and physical sequelae occurred to COVID-19 survivors in short and long stages, and these would gradually decrease as time went on. Male gender, age > 50 years old, severe clinical condition, longer hospitalization time and comorbidity history were related factors that significantly affected the rehabilitation of COVID-19 patients.

Optimized administration of human embryonic stem cell-derived immunity-and-matrix regulatory cells for mouse lung injury and fibrosis

BackgroundLung injury and pulmonary fibrosis (PF), frequently arising as sequelae of severe and acute lung disease, currently face a dearth of effective therapeutic potions. Mesenchymal stem cells (MSCs) with immunomodulatory and tissue repair functions have immense potential to treat lung injury and PF. However, the optimal route of administration, timing, and frequency of dosing remain elusive. Human embryonic stem cell-derived immunity-and-matrix-regulatory cells (IMRCs) have shown therapeutic potential for lung injury and PF.MethodsTo ascertain the optimal therapeutic regimen for IMRCs in PF, we conducted an experimental study. Utilizing a mouse model of PF induced by bleomycin (BLM), IMRCs were administered via either a single or double intravenous (IV) or intratracheal (IT) injection on the first and seventh days post-BLM induction.ResultsOur findings revealed that IV infusion of IMRCs surpassed IT infusion in enhancing survival rates, facilitating body weight recovery, and optimizing Ashcroft and Szapiel scores among the model mice. Notably, IV administration exhibited a more profound ability to mitigate lung inflammation and fibrosis. Moreover, earlier and more frequent administrations of IMRCs were found to be advantageous in enhancing their therapeutic effects. Specifically, early administration with two IV infusions significantly improved body weight, lung organ coefficient, pulmonary ventilation and diffusion functions, and PF. This was accompanied by an increase in alveolar type I and II epithelial cells and a suppression of macrophage infiltration via CD24.ConclusionCollectively, these results suggested that IMRCs infusion ameliorated lung injury by promoting lung regeneration and inhibiting macrophage infiltration in a route, time, and frequency-dependent manner.

12475 Revisiting Myxedema Coma

Abstract Disclosure: M.H. Islam: None. D.R. Jimenez Corado: None. S. Siddiqui: None. M.F. Aquino Camey: None. S. Yeasmin: None. Background: Myxedema coma is a rare and life-threatening complication of hypothyroidism.Although it is rare in the era of better diagnostics and treatment modalities, its life-threatening nature mandates its timely recognition and better understanding. Case:81-year-old female with a history of hypothyroidism (unclear medication compliance) and alcohol use disorder was admitted due to alcohol withdrawal and treated with benzodiazepines. A few days prior to the presentation, she was found to have worsening confusion, unsteady gait, and multiple falls. On presentation, she was hemodynamically stable, tremulous, anxious, and oriented to person only. Blood work was remarkable for mild transaminitis. CT scan of the head revealed sequelae of microvascular disease. The day after admission, she was noted to be lethargic, and benzodiazepines were held. Later, she became hypothermic, hypotensive, bradycardic, and hyponatremic. Further investigation was pursued, revealing a TSH of 55 (normal 0.27 to 4.2 mlU/L), free T4 of <0.10 ng/dL (normal 0.8-1.7 ng/dL), free T3 of <1.0 pg/mL (normal 2.2-4 pg/mL), and cortisol of 10.7 ug/dL. Due to concerns of myxedema coma, she was started on stress dose steroids and IV levothyroxine. She was transferred to the ICU as her mental status continued to deteriorate; she underwent endotracheal intubation and received additional doses of IV levothyroxine and liothyronine. After a few days, her clinical condition and her cortisol, free T4, and free T3 levels improved; she was extubated and later discharged with an adjusted levothyroxine dose. Conclusion: It is of absolute importance to keep myxedema coma as a differential diagnosis when evaluating encephalopathic elderly patients, especially those with a history of thyroid disorders.There is a paucity of evidence to suggest a clear benefit of combining levothyroxine-liothyronine over levothyroxine alone. Treating initially with intravenous levothyroxine over oral is beneficial, as GI absorption and bioavailability are likely variable and unpredictable. In this case, oral liothyronine was used with IV levothyroxine to speed up clinical and biochemical recovery.Adrenal insufficiency often coexists with hypothyroidism, with considerable overlap in clinical features like hypotension, hypoglycemia, and hyponatremia. Administration of levothyroxine before steroids can lead to a rapid increase in metabolic rate and subsequent depletion of the existing reserves. Considering this, it can be said with fair confidence that patients need prior or concomitant stress doses of corticosteroids on an emergent basis. Later, biochemical testing can be done to evaluate the functioning of the hypothalamic-pituitary-adrenal axis and then adjust steroid doses accordingly. Presentation: 6/1/2024

Role of Transforming Growth Factor-β in Pathogenesis of Pulmonary Fibrosis in COVID-19, Post-COVID Syndrome, Oncological and Chronic Inflammatory Lung Diseases

INTRODUCTION: Persistent post-COVID syndrome is the persistent physical, medical and cognitive sequelae of coronavirus disease 2019 (COVID-19), including persistent immunosuppression, pulmonary, cardiac and vascular fibrosis which lead to increased mortality and impair the quality of life of patients. АIM: To analyze the completed foreign and domestic studies on the pathophysiology of transforming growth factor-β (TGF-β) in conditions of COVID-19, post-COVID syndrome, oncological and chronic inflammatory lung diseases. Mast cells are among the main producers of inflammatory cytokines in COVID-19, their stimulation leads to the release of many proinflammatory cytokines, such as interleukin 1β, tumor necrosis factor α, interleukin 6, and also TGF-β. The basis of the pathogenesis of post-COVID syndrome is the overexpression of TGF-β leading to a prolonged state of immunosuppression and fibrosis. TGF-β acts as a tumor suppressor inhibiting proliferation and inducing apoptosis in the early stages of oncogenesis; plays an important role in most cellular biological processes leading to remodeling of the airway structures; is involved in epithelial changes, in subepithelial fibrosis, remodeling of smooth muscle of airways and in microvascular changes; induces resistance to glucocorticosteroids; stimulates the production of blood coagulation factor XII, thereby leading to development of potentially fatal complications, such as pulmonary embolism and ischemic stroke. CONCLUSION: In this literature review, a structured analysis of a multicomponent role of TGF-β in the pathogenesis of post-COVID syndrome, pulmonary fibrosis in COVID-19, tumors of respiratory system, chronic obstructive pulmonary disease, bronchial asthma, is given. A possible use of TGF-β as a biomarker of severe and moderate degree of COVID-19 is substantiated.

Refinement and optimisation of Neisseria gonorrhoeae NHBA and MetQ vaccine candidates

Neisseria gonorrhoeae has a significant impact on reproductive health with an estimated 82 million new cases of infection per year worldwide. Due to the ongoing emergence of multidrug-resistant N. gonorrhoeae strains, the high number of asymptomatic cases, and the risk of disease sequelae, the development of a gonococcal vaccine is urgently needed. We have previously described two potential gonococcal vaccine antigens, cNHBA (C-terminal fragment of the Neisseria Heparin Binding Antigen) and MetQ (methionine-binding protein). This study aimed to optimise these antigens for improved immune responses and to facilitate vaccine production, by investigating cNHBA fusions with the full-length MetQ protein or N-terminal and C-terminal MetQ fragments (Met1 and Met2, respectively) adjuvanted with aluminium hydroxide. The cNHBA and MetQ fragments and fusion antigens were all immunogenic in mice, generating a predominantly IgG1 response. Antibodies mediated bacterial killing via both serum bactericidal activity (SBA) and opsonophagocytic activity (OPA), and reduced adherence to cervical and urethral epithelial cells. Among the antigen fusions tested, MetQ-cNHBA and cNHBA-Met2 generated the highest SBA, OPA and adherence blocking titres and are proposed as promising optimised antigens for N. gonorrhoeae vaccine development.

EP289 - Laparoscopic Management of Cholecystocoloic Fistula as a Day Surgery Case – A Case Report

Abstract Introduction Cholecystocoloic fistula (CF) is a rare sequelae of biliary stone disease with a 2% prevalence, previously it was considered a contraindication for laparoscopic management. Preoperative diagnosis can be very challenging, the pathognomonic triad of Pneumobilia, chronic diarrhoea, and vitamin K malabsorption should raise a high index of suspicion but is not always present, furthermore, preoperative imaging (EUS, ERCP, and Barium enema) help in the diagnosis, however, those are not routine practice in investigating typical biliary colic presentation. Case presentation We report a Cholecystocoloic fistula diagnosed intraoperatively and successfully managed with a laparoscopic approach. A 63-year-old male with a background of hemiplegia and aphasia followed a surgical treatment for intracranial haemorrhage 12 years ago. He presented with recurrent attacks of acute calculus cholecystitis investigated by US and CT scans, and both have failed to detect CF. During his previous admission, he was managed conservatively and added to the elective laparoscopic cholecystectomy list. His surgery was challenging, Intraoperative findings revealed a gallbladder adherent to the surrounding omentum and transverse colon, with a fistulous communication of the gallbladder fundus to the transverse colon, the fistula was divided, and the colonic opening was sutured. The surgery was uneventful and he was discharged home after 18 hours with no postoperative complications. Conclusion A high index of suspicion should be raised for Cholecystocoloic fistula diagnosis intraoperatively, especially with a history of long-term recurrent cholecystitis even in the absence of usual presentation and imaging. Moreover, a laparoscopic approach is possible and successful in experienced hands.

ShaShen-MaiDong decoction attenuates bleomycin-induced pulmonary fibrosis by inhibiting TGF-β/smad3, AKT/MAPK, and YAP/TAZ pathways

Ethnopharmacological relevancePulmonary fibrosis (PF) is progressive and terminal lung disease, which is also the most common sequelae of Corona Virus Disease (2019) (COVID-19) survivors. Unfortunately, there is currently no cure for PF. ShaShen-MaiDong decoction (SMT), a traditional Chinese medicine, has been employed in treating various lung diseases, which may offer potential therapeutic benefits for PF. Aim of the studyTo investigate the antifibrotic efficacy of SMT and its major active ingredients as well as the underlying mechanisms for treating PF. Materials and methodsFist, we build the UPLC-MS based qualitative and quantitative profiling for the quality control of SMT. Then, the antifibrotic efficacy of SMT was investigated in bleomycin (BLM)-induced PF mice model. Network pharmacology was used to predict the mechanism and active components of SMT for the treatment of PF, which was further verified in vitro and in vivo. ResultsSMT improved the weight loss and attenuated hydroxyproline, inflammatory cytokines, and collagen deposition in BLM-induced PF mice model in a dose-dependent manner. Mechanistically, as predicted by network pharmacology analysis, SMT and its active compounds (kaempferol, quercetin, and isorhamnetin) regulated the mitogen-activated protein kinase (MAPK) signaling pathways, TGF-β/Smad signaling pathway, and YAP/TAZ signaling pathway, which was further verified in the PF mice and TGF-β-induced A549 cell model. Moreover, SMT balanced the proportions of increased CD4+ and decreased CD8+ T cells in the peripheral blood of PF mice model. ConclusionsConsidering the high mortality and complex pathogenesis of fibrotic diseases, our results provide novel evidence that SMT would be beneficial for pulmonary fibrosis therapy by modulating MAPK, TGF-β/Smad, and YAP/TAZ signaling pathways at same time.

Plasma monomeric ApoA1 and high-density lipoprotein bound ApoA1 are markedly decreased and associated with low levels of lipophilic antioxidants in sickle cell disease: A potential new pathway for therapy.

Patients with sickle cell disease (SCD) exhibit high levels of reactive oxygen species and low plasma levels of lipophilic antioxidants, which may contribute to end-organ damage and disease sequelae. Apolipoprotein A1, the major apolipoprotein of high-density lipoprotein (HDL), is mainly secreted by the intestine and liver in the form of monomeric ApoA1 (mApoA1) present in plasma. Cholesterol and α-tocopherol are delivered to ApoA1 via the ATP-binding cassette transporter, subfamily A, member 1 (ABCA1). We measured cholesterol, mApoA1, ApoA1, and lipophilic antioxidants in the plasma of 17 patients with SCD and 40 healthy volunteers. Mean HDL cholesterol (-C) levels in SCD patients and healthy subjects were 59.3 and 48.1 mg/dL, respectively, and plasma lutein, zeaxanthin, and α-tocopherol were 64.0%, 68.7%, and 9.1% lower, respectively. To compare SCD to healthy subjects with similar HDL-C, we also performed subgroup analyses of healthy subjects with HDL-C above or below the mean. In SCD, the mApoA1 level was 30.4 μg/mL; 80% lower than 141 μg/mL measured in healthy volunteers with similar HDL-C (56.7 mg/dL). The mApoA1 level was also 38.4% greater in the higher versus lower HDL-C subgroups (p = .002). In the higher HDL-C subgroup, lutein and zeaxanthin transported by HDL were 48.9% (p = .01) and 41.9% (p = .02) higher, respectively, whereas α-tocopherol was 31.7% higher (p = .003), compared to the lower HDL-C subgroup. Plasma mApoA1 may be a marker of the capacity of HDL to capture and deliver liposoluble antioxidants, and treatments which raise HDL may benefit patients with high oxidative stress as exemplified by SCD.

Pulmonary Function, Functional Capacity, Respiratory, and Locomotor Muscle Strength after Severe to Critically Ill COVID-19: A Long-Term Study.

The sequelae of post-coronavirus disease 2019 (COVID-19) pneumonia on lung function, exercise capacity, and quality of life were observed in both shortterm and long-term. However, the study about the respiratory and locomotor muscle strength in severe and critically ill COVID-19 survivors are still limited. Therefore, we aimed to examine long-term pulmonary function, functional capacities, and respiratory and locomotor body muscle strength in severe to critically ill post-COVID-19 survivors. A prospective observational study was conducted in 22 post-COVID-19 pneumonia and healthy adults. Clinical characteristics during admission, pulmonary function, functional capacity, respiratory muscles, and locomotor muscles strength were examined at 1, 3, and 6 months after discharge from the hospital. The generalized linear mixed model showed that percent predicted of forced expiratory volume in the 1 second (%FEV1), percent predicted of forced vital capacity (%FVC), maximum inspiratory pressure (MIP), handgrip strength, 6-minute walk distance, and five times sit to stand (5TSTS) were significantly lower in post-COVID-19 pneumonia patients than in healthy subjects during the follow-up period. The percent predicted of maximal voluntary ventilation (%MVV), and locomotor muscle strength were not different between the two groups throughout the follow-up period. Among post-COVID-19 pneumonia patients, %FEV1, %FVC, %MVV, 5TSTS, locomotor muscle strength significantly improved at three months compared to baseline at 1 month. Pulmonary function, functional capacity, respiratory, and locomotor muscle strength of survivors from COVID-19 were impaired and recovery was observed after three to six months. These emphasized the need to evaluate the long-term consequences of COVID-19.