Background The global increase in caesarean section (CS) rates is concerning and a better understanding of this phenomenon can allow us to identify strategies to reduce it. Aims To determine the CS rate in two hospitals in Victoria-Australia, and analyse the contribution of specific obstetric population to changes in CS rates over time using the Robson classification. Materials and Methods Retrospective observational study of all women delivering at two hospitals in Victoria between July 2014 and June 2019. The overall CS rate, the size of each Robson group, the CS rate per group, and the absolute and relative contribution of each group to the overall CS rate were calculated. Additionally, trends over time and comparison between the two hospitals were also analysed. Results There were 7894 CS during the study period, giving an overall CS rate of 32.7%. The greatest contributor was Robson group 5 with 35.2%, followed by group 2 with 26.6% and lastly group 1 with 10.3%. Over the five-year period, CS rates at both hospitals increased 1.5% per year (95% CI: 0.1-2.9, p-value: 0.04) from 30.7% in 2015 to 36.0% in 2019. There were not major differences in the CS between the two hospitals. Conclusion The major groups contributing to our CS rate are groups 5, 2 and 1 and efforts aiming to reduce our CS rate should therefore target these groups. Strategies to reduce CS rates should include increasing the availability of VBAC, reviewing our protocols for IOL, and improving management and surveillance of labour.

Background: Vascular Endothelial Growth Factor A (VEGF-A) is a key mediator of angiogenesis, primarily signalling via VEGF Receptor 2 (VEGFR2). Endothelial cells also express the co-receptor Neuropilin-1 (NRP1) that potentiates VEGF-A/VEGFR2 signalling. VEGFR2 and NRP1 had distinct real-time ligand binding kinetics when monitored using Bioluminescence Resonance Energy Transfer (BRET). We previously characterised fluorescent VEGF-A isoforms tagged at a single site with tetramethylrhodamine (TMR). Here, we explore differences between VEGF-A isoforms in living cells that co-expressed both receptors. Experimental Approach: Receptor localisation was monitored in HEK293T cells expressing both VEGFR2 and NRP1 using a membrane-impermeant HaloTag and SnapTag technologies. To isolate ligand binding pharmacology at a defined VEGFR2/NRP1 complex, we developed an assay using NanoBiT complementation technology whereby heteromerization is required for luminescence emissions. Binding affinities and kinetics of VEGFR2-selective VEGF165b-TMR and non-selective VEGF165a-TMR were monitored using BRET from this defined complex. Key Results: Cell surface VEGFR2 and NRP1 were co-localised and formed a constitutive heteromeric complex. Despite being selective for VEGFR2, VEGF165b-TMR had a distinct kinetic ligand binding profile at the complex that largely remained elevated in cells over 90 minutes. VEGF165a-TMR bound to the VEGFR2/NRP1 complex with kinetics comparable to those of VEGFR2 alone. Using a binding-dead mutant of NRP1 had no impact on the binding kinetics or affinity of VEGF165a-TMR. Conclusions and Implications: This NanoBiT approach enabled real-time ligand binding to be quantified in living cells at 37°C from a specified complex between a receptor tyrosine kinase and its co-receptor for the first time.

Objective: To investigate the polymorphisms of genes in the steroidogenesis pathway to understand the etiological mechanisms to OC risk in the South Indian population Design: Case-Control Study Setting and Sample: Ovarian cancer cases (200) and healthy individuals (200) from the South Indian population. Methods: All the cases and controls were genotyped for SNPs by using allelic discrimination assay. Main outcome measures: Genetic distribution of SNPs of Steroidogenesis pathway genes in the South Indian population. Results: The observed results for rs743752, the homozygous CC genotype revealed significant association (OR; 1.68; 95%CI, 1.25-2.26; p =<0.05) and the dominant model, recessive model and additive model showed a significant association with an OR of 1.62; 95%CI, 1.09 – 2.42; p = 0.015, OR of 0.29, 95%CI, 0.14 – 0.60; p = <0.001 and OR of 1.68, 95%CI, 1.25 – 2.26); p = <0.001 respectively in cases and controls for OC risk. In rs10046, the heterozygous CT genotype (OR; 1.61; 95%CI 1.06 – 2.43; p = 0.023), the dominant (OR; 1.65; 95%CI, 1.11 – 2.45; p = 0.012) and the additive (OR; 1.46; 95%CI, 1.07 - 1.98; p = 0.015) models were found to be statistically significant. There was no significant association between rs605059 genotypes with ovarian cancer risk. Conclusions: To conclude, results indicated that the polymorphisms of CYP17A1 (rs743572) and CYP19A1 (rs10046) genes are associated with increased risk of ovarian cancer risk in South Indian population.

Background: Ibrutinib is associated with atrial fibrillation (AF), though echocardiographic predictors of AF have not been studied in this population. We sought to determine whether left atrial (LA) strain on transthoracic echocardiography could identify patients at risk for developing ibrutinib-related atrial fibrillation (IRAF). Methods: We performed a retrospective review of 66 patients who had an echocardiogram prior to ibrutinib treatment. LA strain was measured with TOMTEC Imaging Systems, obtaining peak atrial longitudinal strain (PALS) and peak atrial contraction strain (PACS) on 4-chamber and 2-chamber views. Statistical analysis was performed with Chi-square analysis, T-test, or binomial regression analysis, with a p-value < 0.05 considered statistically significant. Results: Twenty-two patients developed IRAF (33%). Age at initiation of ibrutinib was significantly associated with IRAF (65.1 years vs. 74.1 years, p = 0.002). Mean ibrutinib dose was lower among patients who developed IRAF (388.2 ± 121.7 vs. 448.6 ± 88.4, p = 0.025). E/e’ was significantly higher among patients who developed IRAF (11.5 vs. 9.3, p = 0.04). PALS was significantly lower in patients who developed AF (30.3% vs. 36.3%, p = 0.01). On multivariate regression analysis, age, PALS and PACS were significantly associated with IRAF. On multivariate regression analysis, only PACS remained significantly associated with IRAF while accounting for age. Conclusions: Age, ibrutinib dose, E/e’, and PALS on pre-treatment echocardiogram were significantly associated with development of IRAF. On multivariate regression analyses, age, PALS and PACS remained significantly associated with IRAF. Impaired LA mechanics add to the assessment of patients at risk for IRAF

Gastrointestinal symptoms are common findings in children with SARS-CoV-2 infection.Diarrhea and vomiting have been reported in about 8-9% of cases, reaching more than 20% in some studies. Children with gastrointestinal involvement appear to be younger than those without, but the severity of the disease seems to be similar between the two groups of subjects.Fecal shedding in children has been reported in 20-30% of children and has been observed both in those with and those without overt gastrointestinal involvement. Moreover, prolonged fecal elimination, lasting several days after negativization of real-time polymerase chain reaction assay on respiratory swabs, have been reported with variable frequency in children with SARS-CoV-2 infection. These observations raise the question regarding the possibility of oral-fecal transmission and the possible role of children in spreading the infection, particularly when they appear asymptomatic or with gastrointestinal symptoms but with no respiratory involvement, as well as during their convalescent phase.

Background: Subxiphoid incisional hernias are one of the complications following a median sternotomy, a surgical procedure to provide access to the mediastinum. Incidence has been reported between 1-4%, although the true incidence is not well known due to its asymptomatic nature. Method: A comprehensive search was performed on multiple sites. Keywords included “incisional hernia OR Subxiphoid hernia” AND “Median sternotomy OR Cardiac Surgery OR Coronary artery bypass graft OR Transplant OR Valve replacement”. Articles up to 1st of August 2020 were included in this study. Results: 8 articles were included in the study, with a total number of 132 patient identified. The incidence ranged from 0.81% to 3.44%. There was a mixture of repair method and follow up period reported. Recurrence post-repair ranged from 10% to 43%. Conclusion: Subxiphoid incisional hernias remains challenging to manage. We have discussed the incidence, risk factors, preventions, and management of subxiphoid incisional hernias including both the open and laparoscopic technique.

Background: Type A acute aortic dissection (TAAAD) is rapidly fatal without emergency surgical. Surgical outcomes have improved over the years with improvements in technique and postoperative care. Classically, supracomissural aortic replacement has been the standard of care. However, reintervention rates, particularly on the aortic root, in certain groups of patients shifted the focus towards improving long terms results of surgical repair. With regard to the aortic root, root replacement has been the gold standard. However, the surgical community realised that valve replacement in itself is a disease, and valve sparing aortic root replacement (VSRR) took centre stage in the care of these patients. Methods: We search the Pubmed and EMBASE for articles related to VSRR, composite valve conduit root (CVC) replacement, and the long terms results of both in TAAAD. Results: Supracomissural repair is limited by reintervention and CVC results are affected by complications related to the prosthetic valve. Conversely, VSRR is associated with good short-term outcomes, improvement in quality of life, and it is durable. Conclusion: VSRR is a sound technique in TAAAD in experienced hands.

Background: On January 2020, the WHO declared the novel coronavirus (2019-nCoV) outbreak as a public health emergency of international concern. Due to rapid spread 2019-nCoV, all countries started preventive and precautionary measures to prevent COVID-19 infection spread. These measures limited the population mobility and services provided, which subsequently Impact of on children with cancer and cancer care delivery in the many health centers in Saudi Arabia. Procedure: We did a cross sectional study to assess the impact on this outbreak on children with cancer with regard to all aspects of life including medical services provided, the specific precautions to prevent spread in cancer patients, mental, psychological effect and its affection on quality of life. Results: We collected 204 responses during a survey which assessed the impact on the treatment of cancer children at a tertiary institution during the COVID-19 pandemic. The majority of patients were receiving ongoing chemotherapy for leukemia/lymphoma. The majority of these patients (60.5%) reported a delay in treatment received due to hospital cancellation. Although, the majority of patients in our cohort complained of delayed treatment, fortunately none of the delays led to fatalities. In the context of global lockdowns and physical distancing to help flatten the COVID-19 curve, telemedicine has proved fundamental to keeping patients and their healthcare providers connected and safe. Children also faced multiple other difficulties such as psychosocial issues during the COVID-19 pandemic. Conclusion: Our long-term goals are to develop new programs which will enable children with cancer to emerge successfully during a pandemic.

Pediatric Recurrent Rosai-Dorfman Disease with germline heterozygous SLC29A3 and somatic MAP2K1 mutationsShruthi Suryaprakash, MD1, Amy George, RN2, Scott Langenburg, MD3, and Süreyya Savaşan, MD2,41Department of Pediatrics, Children’s hospital of Michigan, Detroit2Division of Hematology/Oncology, Children’s hospital of Michigan, Detroit3Division of Pediatric Surgery, Children’s hospital of Michigan, Detroit4Division of Hematology/Oncology and Blood and Marrow Transplant Program, Department of Pediatrics, Children’s Hospital of Michigan, Barbara Ann Karmanos Cancer Center, Central Michigan University College of Medicine, DetroitCorrespondence: Süreyya Savaşan, MD3901 Beaubien Blvd.Division of Hematology/OncologyBlood and Marrow Transplant ProgramChildren’s Hospital of MichiganDetroit, Michigan 48201E-mail: savas1s@cmich.eduPhone: 313-745-5516 Fax: 313-745-5237Text word count: 500Reference count: 16Tables and figures: 1Page number: 7Short running title: Germline and somatic mutations in recurrent Rosai-Dorfman diseaseKey words: recurrent RDD, germline SLC29A3 mutation, somatic MAP2K1 mutation, dysgammaglobulinemia, clonal T-LGL proliferation

Mutations in ciliary genes cause a spectrum of both overlapping and distinct clinical syndromes (ciliopathies). CEP120 and CC2D2A are paradigmatic examples for this genetic heterogeneity and pleiotropy as mutations in both cause Joubert syndrome but are also associated with skeletal ciliopathies and Meckel syndrome, respectively. The molecular basis for this phenotypical variability is not understood but basal exon skipping likely contributes to tolerance for deleterious mutations via preservation of the amount of expressed functional protein. Here we systematically review and annotate genetic variants described in CEP120- and CC2D2A-associated disease and confirm more severe clinical presentations with biallelic truncating CC2D2A mutations. Combining in silico and ex vivo studies, we identify alternative basal exon skipping in the kidney, with possible relevance for organ-specific disease manifestations. Finally, we propose a multimodal approach to classify exons amenable to exon skipping and by mapping reported variants, 14 truncating mutations in 7 CC2D2A exons were identified as potentially rescuable by targeted exon skipping, an approach that is already in clinical use for other inherited human diseases. We conclude that genotype-phenotype correlations for CC2D2A support the deleteriousness of null alleles and that CC2D2A, but not CEP120, offers potential for therapeutic exon skipping approaches.

Background and Purpose：Deepening of the upper eyelid sulcus (DUES) is recognized as an unfavorable and causeless side effect observed among long-term users of prostaglandin analogues (PGs). To elucidate the molecular pathology of DUES, we characterized thee-dimension (3D) cultures of human orbital fibroblasts (HOFs). Experimental Approach: HOF organoids were cultured without or with their adipogenic differentiation and at several concentrations (1, 100, 10000 nM) of PGs (bimatoprost acid; BIM-A, PGF2α, latanoprost acid; LAT-A). Their sizes, the mRNA expression of adipogenic related genes, extracellular matrix (ECM) and tissue inhibitors of metalloproteinases (TIMPs) were measured by electron microscope (EM) and the physical properties were measured by a micro-squeezer. Key Results: Adipogenesis caused significant downsizing of the organoids, and these were markedly inhibited in the presence of PGs in a concentration dependent manner. BIM-A was the most effective. The downsizing induced by PGs was also observed in conditions without adipogenesis. The size of each organoid under several conditions was inversely correlated with the mRNA expression profile of collagen 1 (COL1), which was also confirmed by immunolabeling. An mRNA expression profile similar to that for COL1 was also observed in Lysyl oxidase (LOX) and TIMP2. Analyses by EM and the micro squeezer clearly indicated that PGs induced an increase in ECM deposits and the physical solidity of the organoids. Conclusions and Implications: The findings reported herein indicate that PGs affects the expression of LOX, COL1 and TIMP2 which, in turn, modulate the 3D ECM network within the organoids, thus resulting in their downsizing.

In this review, we discuss recent publications on asthma and review the studies that have reported on the different aspects of the prevalence, risk factors and prevention, mechanisms, diagnosis and treatment of asthma. Many risk and protective factors and molecular mechanisms are involved in the development of asthma. Emerging concepts and challenges in implementing the exposome paradigm and its application in allergic diseases and asthma are reviewed, including genetic and epigenetic factors, microbial dysbiosis and environmental exposure, particularly to indoor and outdoor substances. The most relevant experimental studies further advancing the understanding of molecular and immune mechanisms with potential new targets for the development of therapeutics are discussed. A reliable diagnosis of asthma, disease endotyping and monitoring its severity are of great importance in the management of asthma. Correct evaluation and management of asthma comorbidity/multimorbidity, including interaction with asthma phenotypes and its value for the precision medicine approach and validation of predictive biomarkers are further detailed. Novel approaches and strategies in asthma treatment linked to mechanisms and endotypes of asthma, particularly biologicals, are critically appraised. Finally, due to the recent pandemics and its impact on patient management, we discuss the challenges, relationships, and molecular mechanisms between asthma, allergies, SARS-CoV-2 and Covid-19.

The Perceval Valve is a true sutureless aortic bioprosthesis. Overall, excellent performances have been demonstrated in terms of hemodynamic outcomes, safety and versatility of use; furthermore, as a sutureless valve option, it has shown to reduce the surgical burden, shortening the operative times and simplifying minimally invasive procedures. Since the valve has got a high frame profile, the recommended implantation technique requires a high and transverse aortotomy. In case of unplanned Perceval valve implantation, when an extended aortotomy is required, we have come up with a simple technique to reshape the aortic root before the valve is delivered in place: symmetry is pivotal to prevent folding issues and to improve the annular sealing. Although we discuss an out-of-recommendation use, in our experience that technique has shown to be safe and effective.

A definition of allergy is proposed, including its two stages: 1) hypersensitivity (without clinical manifestations) and 2) hyperreactivity with clinical signs. A specific immunologically mediated allergy depends on the presence of antibodies of different isotypes and immune T and B lymphocytes against an allergen. Nonspecific allergy is hypersensitivity and hyperreactivity of the immune system and any cells, as well as humoral systems, to the pathogen. Anergy is the second type of pathologically altered reduced reactivity that can be of allergen-specific (immune) and non-immune types.

Purpose Drug development strategies for genetic diseases depend critically on accurate knowledge of how pathogenic variants cause disease. For some well-studied genes, the direct effects of pathogenic variants are well documented as loss of function, gain of function or hypermorphic, or a combination of the two. For many genes, however, even the direction of effect of variants remains unclear. Classification of Mendelian disease genes in terms of whether pathogenic variants are loss or gain of function would directly inform drug development strategies. Methods We leveraged the recent dramatic increase in reported pathogenic variants to provide a novel approach to inferring the direction of effect of pathogenic variants. Specifically, we quantify the ratio of reported pathogenic variants that are missense compared to loss of function. Results We first show that for many genes that cause dominant Mendelian disease, the ratio of reported pathogenic missense variants is diagnostic of whether the gene causes disease through loss or gain of function, or a combination. Second, we identify a set of genes that appear to cause disease largely or entirely through gain of function or hypermorphic pathogenic variants. Conclusions We suggest a set of 16 genes suitable for drug developmental efforts utilizing direct inhibition.

Background and Purpose: Cannabis is the third most commonly used psychoactive substance of abuse, yet it also receives considerable attention as a potential therapeutic drug. Therefore, it is essential to fully understand the actions of cannabis in the human brain. The olfactory neuroepithelium (ON) represents an interesting surrogate model to study the effects of drugs in the brain, since it is closely related to the central nervous system, and sensory olfactory neurons are continually regenerated from populations of stem/progenitor cells that undergo neurogenesis throughout life. Experimental Approach: In this study, we used ON cells from chronic cannabis users and healthy control subjects to assess alterations in relevant cellular processes, and to identify changes in functional proteomic pathways due to cannabis consumption. Key Results: The ON cells from cannabis users exhibited alterations in the expression of proteins that were related to the cytoskeleton, cell proliferation and cell death, as well as, changes in proteins implicated in cancer, gastrointestinal and neurodevelopmental pathologies. Subsequent studies showed cannabis provoked an increase in cell size and morphological alterations evident through β-Tubulin III staining, as well as, enhanced beta-actin expression and a decrease in the ability of ON cells to undergo cell attachment, suggesting abnormalities of the cytoskeleton and cell adhesion system. Furthermore, these cells proliferated more and underwent less cell death. Conclusion and Implications: Our results indicate that cannabis may alter key processes of the developing brain, some of which are similar to those reported in mental disorders like DiGeorge syndrome, schizophrenia and bipolar disorder.

Background: To assess the effects of mitral valve (MV) replacement for functional mitral regurgitation (FMR) in patients with severe left ventricular (LV) dysfunction. Methods: 48 patients with secondary non-ischemic severe mitral regurgitation (MR) and left ventricle eject fraction (LVEF) less than 35% were underwent MV replacement. All surgeries were finished by one surgical team from January 2010 to December 2015. Twenty-three patients were females and the mean age was 60.21 ± 10.69 years (range, 29～75 years). The preoperative cardiac function classification was Ⅲ~Ⅳ (NYHA) in 40 patients. The mean follow-up time was five years. Results: Three patients (6.3%) died in hospital: 2 from low output syndrome and 1 from multi-organ failure induced by pulmonary infection. The mean postoperative intensive care unit (ICU) stay time was 4 days. The mean cardiopulmonary bypass time was 131.50 ± 3.92 min, and the mean aortic cross-clamping time was 85.39 ± 24.16 min. The left atrium diameter and the systolic pulmonary artery pressure (PAP) decreased significantly after surgery. The survival rates at 1 and 5 years were 83.3% and 54.6%, and 29 patients (60.4 %) were in NYHA class Ⅰ/Ⅱ during the follow-up time. Conclusions: Mitral valve replacement maybe offers symptomatic improvement and mid-term survival benefit for non-ischemic FMR in some patients with severe LV dysfunction.

In this paper, we study an eigenvalue problem for Schrödinger-Poisson system with indefinite nonlinearity and potential well as follows: -Δu+μV(x)u+K(x)Φu = λf(x)u+g(x)|u|p-2u in R3, -ΔΦ=K(x)u^2 in R3, where 4≤p<6, the parameters μ, λ>0, V∈ C(R3) is a potential well, and the functions f ∈ L3/2(R3) and g ∈ L∞(R3) are allowed to be sign-changing. It is well known that such a system with the potential being positive constant has two positive solutions when lim|x|→∞g(x)=g∞<0, K=0 in the set {x ∈ R3 : g(x)=0} and λ>λ1(f) with near λ1(f), where λ1(f) is the first eigenvalue of -Δ+ id in H1(R3) (see e.g. Huang et al., J. Differential Equations 255, 2463 (2013)). The main purpose is to obtain the existence and multiplicity of positive solutions without the above assumptions for g and K. The results are obtained via variational method and steep potential. Furthermore, we also consider the concentration of solutions as μ→∞.

Malignant triton tumor (MTT) is a very infrequent variant of the malignant peripheral nerve sheath tumor (MPNST) with rhabdomyoblastic differentiation. Up to 70% of cases are diagnosed in patients with neurofibromatosis type 1 (NF1). It is a highly aggressive pathology with early relapses occurring in up to 50% of patients. Despite multimodal treatment the prognosis is poor, with long term survival rates not exceeding 15%. We present the case of an adolescent male with known NF1 diagnosed with an aggressive retroperitoneal MTT and disseminated pulmonary disease.

Cancer of unknown primary (CUP) is a common diagnosis in adult oncology, but is extremely rare in pediatrics, with few published reports and none in the era of molecular profiling. Here, we describe a 13-year old boy with metastatic adenocarcinoma of unknown primary that was refractory to conventional chemotherapy. Molecular profiling revealed an activating ERBB2 D769Y variant. He subsequently achieved disease control on a lapatinib-containing regimen, and upon progression, he transiently responded to neratinib prior to dying from disease. Our case reports a rare example of pediatric CUP and highlights the utility of molecular profiling in these cases.

Abstract Patients at risk of severe forms of COVID 19 share metabolic disturbances, diabetes, hypertension, among which dysregulation of antioxydant defence mechanisms and orientation toward Th17 immunological response are predisposing factors for severe cellular lesions of Covid infection. We propose to act on NrF2, so as to protect tissues from oxydative burst, and cellular lesions characteristic of hyperinflammation of Covid 19. Bardoxolone acts upon Nrf2 and represses NfKappa B. It has been evaluated in diabetic nephropathy, but some patients suffered from overhydration and cardiac failure (Beacon study). In Covid infection, benefit-risk equation is different from long term use of this drug in diabetic nephropathy, in a disease potentialy lethal in a couple of weeks, with a short term risk of overhydration which could be seen as quite negligeable with a daily monitoring of weight. We advocate for an evaluation of Bardoxolone in recently infected Covid patients, with severe-Covid19-risk, in a framework of a strict evaluation of their cardio-vascular risk.

Abstract: In order to study the dynamic fracture characteristics of FRP reinforced concrete, the three-point bending experiment of FRP reinforced concrete beams with different initial crack-depth ratios was carried out by using MTS-810 hydraulic servo experiment machine. The initial crack-depth ratios are 0.2, 0.3, 0.4, 0.5 and 0.6 respectively. The effects of different initial crack-depth ratios on the load-crack opening displacement curve, failure process, the increment of critical crack-depth ratio and flexibility coefficient of FRP reinforced concrete three-point bending beam specimens were analyzed by displacement controlled monotonic loading method. Combined with Pearson correlation experiment formula, the correlation between initial crack-depth ratios and different fracture parameters was quantitatively analyzed. The conclusions can be drawn that, there are three obvious critical points in the fracture process of FRP reinforced concrete three-point bending beam: the starting point of concrete crack, the first peak point and the ultimate bearing capacity point. With the increase of the initial crack-depth ratio, the crack initiation load decreases, but the first peak load and ultimate load increase first and then decrease. It is found that the stress intensity factors of the three critical points increase first and then decrease with the increase of the initial crack-depth ratio, and when the initial crack-depth ratio is 0.4, the three kinds of stress intensity factors all reach the maximum value. The increment of critical crack-depth ratio and flexibility coefficient of FRP reinforced concrete beams are related to the initial crack-depth ratio, which can be used to reflect the influence of initial crack-depth ratio on the deformation capacity of concrete specimens. Keywords: FRP reinforced concrete; dynamic fracture; the initial crack-depth ratios; stress intensity factors; increment of critical crack-depth ratio; flexibility coefficient

Chloroquine (CQ) was and still considered as the most common agent in treatment and prophylaxis of malaria, it also possesses many different pharmacological and biological activities that make it able to be used as a therapy or adjuvant therapy for many types of diseases. CQ exhibits anticancer activity alone or as adjuvants with other agents against many kinds of tumors. Its activities also were approved as anti-inflammatory agent in rheumatoid and other autoimmune diseases like systemic lupus and rheumatic arthritis. Its important role in improvement of many metabolic disorders like hypertension, hyperglycemia, and lipid profile disturbances was also established. CQ can act against different microbial infections such as many types of virus, bacteria and fungus by different mechanisms of action. Furthermore, its dermatological role in treatment of many skin diseases was demonstrated. Recently, CQ showed very responsive role in curing and prevention of covoid-19 virus. This review summarizes intensively the multiple therapeutic applications of CQ and discusses the possible mechanisms of action for these applications.

A 41-year-old lady was referred to tertiary cardiothoracic surgery centre following embolisation of patent foramen ovale (PFO) closure device to septal leaflet of tricuspid valve with reopening of PFO. Two years earlier, she presented with thalamic stroke, and she was found to have a PFO following investigations. The following year she underwent transcatheter closure. Six months after the percutaneous closure, she presented again with significant periods of shortness of breath. Imaging studies revealed the migration and embolisation of PFO closure device to the septal leaflet of tricuspid valve with reopening of the foramen and significant tricuspid valve regurgitation. She underwent open heart surgery using cardiopulmonary bypass for retrieval of the device, closure of the foramen and repair of the tricuspid valve. The patient recovered well without any significant issues following surgery.