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Hydroxychloroquine in recurrent pregnancy loss: data from a French prospective multicenter registry.Human Reproduction (Oxford, England) Jun 2024What are the outcomes of pregnancies exposed to hydroxychloroquine (HCQ) in women with a history of recurrent pregnancy loss (RPL), and what factors predict the course...
STUDY QUESTION
What are the outcomes of pregnancies exposed to hydroxychloroquine (HCQ) in women with a history of recurrent pregnancy loss (RPL), and what factors predict the course of these pregnancies beyond the first trimester?
SUMMARY ANSWER
In our cohort of pregnancies in women with a history of RPL exposed to HCQ early in pregnancy, we found that the only factor determining the success of these pregnancies was the number of previous miscarriages.
WHAT IS KNOWN ALREADY
Dysregulation of the maternal immune system plays a role in RPL. HCQ, with its dual immunomodulating and vascular protective effects, is a potential treatment for unexplained RPL.
STUDY DESIGN, SIZE, DURATION
The FALCO (Facteurs de récidive précoce des fausses couches) registry is an ongoing French multicenter infertility registry established in 2017 that includes women (aged from 18 to 49 years) with a history of spontaneous RPL (at least three early miscarriages (≤12 weeks of gestation (WG)) recruited from several university hospitals.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Spontaneous pregnancies enrolled in the FALCO registry with an exposure to HCQ (before conception or at the start of pregnancy) were included. Pregnancies concomitantly exposed to tumor necrosis factor inhibitors, interleukin-1 and -2 inhibitors, intravenous immunoglobulin, and/or intravenous intralipid infusion, were excluded. Concomitant treatment with low-dose aspirin (LDA), low-molecular weight heparin (LMWH), progesterone, and/or prednisone was allowed. All patients underwent the recommended evaluations for investigating RPL. Those who became pregnant received obstetric care in accordance with French recommendations and were followed prospectively. The main endpoint was the occurrence of a pregnancy continuing beyond 12 WG, and the secondary endpoint was the occurrence of a live birth.
MAIN RESULTS AND THE ROLE OF CHANCE
One hundred pregnancies with HCQ exposure in 74 women were assessed. The mean age of the women was 34.2 years, and the median number of previous miscarriages was 5. Concomitant exposure was reported in 78 (78%) pregnancies for prednisone, 56 (56%) pregnancies for LDA, and 41 (41%) pregnancies for LMWH. Sixty-two (62%) pregnancies ended within 12 WG, the other 38 (38%) continuing beyond 12 WG. The risk of experiencing an additional early spontaneous miscarriage increased with the number of previous miscarriages, but not with age. The distributions of anomalies identified in RPL investigations and of exposure to other drugs were similar between pregnancies lasting ≤12 WG and those continuing beyond 12WG. The incidence of pregnancies progressing beyond 12 WG was not higher among pregnancies with at least one positive autoantibody (Ab) (i.e. antinuclear Ab titer ≥1:160, ≥1 positive conventional and/or non-conventional antiphospholipid Ab, and/or positive results for ≥1 antithyroid Ab) without diminished ovarian reserve (18/51, 35.3%) than among those without such autoantibody (18/45, 40.0%) (P = 0.63). Multivariate analysis showed that having ≤4 prior miscarriages was the only factor significantly predictive for achieving a pregnancy > 12 WG, after adjustment for age and duration of HCQ use prior to conception (adjusted odds ratio (OR) = 3.13 [1.31-7.83], P = 0.01).
LIMITATIONS, REASONS FOR CAUTION
Our study has limitations, including the absence of a control group, incomplete data for the diagnostic procedure for RPL in some patients, and the unavailability of results from endometrial biopsies, as well as information about paternal age and behavioral factors. Consequently, not all potential confounding factors could be considered.
WIDER IMPLICATIONS OF THE FINDINGS
Exposure to HCQ in early pregnancy for women with a history of RPL does not seem to prevent further miscarriages, suggesting limited impact on mechanisms related to the maternal immune system.
STUDY FUNDING/COMPETING INTEREST(S)
The research received no specific funding, and the authors declare no competing interests.
TRIAL REGISTRATION NUMBER
clinicaltrial.gov NCT05557201.
PubMed: 38942601
DOI: 10.1093/humrep/deae146 -
Progress in Molecular Biology and... 2024Cardiovascular diseases (CVDs) are characterized by abnormalities in the heart, blood vessels, and blood flow. CVDs comprise a diverse set of health issues. There are... (Review)
Review
Cardiovascular diseases (CVDs) are characterized by abnormalities in the heart, blood vessels, and blood flow. CVDs comprise a diverse set of health issues. There are several types of CVDs like stroke, endothelial dysfunction, thrombosis, atherosclerosis, plaque instability and heart failure. Identification of a new drug for heart disease takes longer duration and its safety efficacy test takes even longer duration of research and approval. This chapter explores drug repurposing, nano-therapy, and plant-based treatments for managing CVDs from existing drugs which saves time and safety issues with testing new drugs. Existing drugs like statins, ACE inhibitor, warfarin, beta blockers, aspirin and metformin have been found to be useful in treating cardiac disease. For better drug delivery, nano therapy is opening new avenues for cardiac research by targeting interleukin (IL), TNF and other proteins by proteome interactome analysis. Nanoparticles enable precise delivery to atherosclerotic plaques, inflammation areas, and damaged cardiac tissues. Advancements in nano therapeutic agents, such as drug-eluting stents and drug-loaded nanoparticles are transforming CVDs management. Plant-based treatments, containing phytochemicals from Botanical sources, have potential cardiovascular benefits. These phytochemicals can mitigate risk factors associated with CVDs. The integration of these strategies opens new avenues for personalized, effective, and minimally invasive cardiovascular care. Altogether, traditional drugs, phytochemicals along with nanoparticles can revolutionize the future cardiac health care by identifying their signaling pathway, mechanism and interactome analysis.
Topics: Humans; Drug Repositioning; Drug Discovery; Animals; Heart Diseases
PubMed: 38942536
DOI: 10.1016/bs.pmbts.2024.02.001 -
JACC. Advances Jan 2024
PubMed: 38939824
DOI: 10.1016/j.jacadv.2023.100754 -
F1000Research 2024Rectal bleeding commonly occurs in elderly patients using blood thinners, posing management challenges due to limited guidance on reversal agents and medication restart...
INTRODUCTION
Rectal bleeding commonly occurs in elderly patients using blood thinners, posing management challenges due to limited guidance on reversal agents and medication restart criteria. This study aims to review the demographics and management of elderly patients with rectal bleeding while on blood thinners.
METHODS
A retrospective analysis of patients aged 60 or older presenting with rectal bleeding at West Suffolk Hospital's emergency department was conducted from January 2018 to December 2020. Data were extracted from electronic records, focusing on patients using blood thinners and adhering to British Society of Gastroenterology guidelines. All patients ceased blood-thinning medications upon admission. The hospital's ethics committee approved the study, which focused on demographics, diagnosis, and management, particularly regarding re-initiation of blood-thinning medicines.
RESULTS
During the study period, 170 patients were admitted to the emergency department of West Suffolk Hospital. 93 (54.71%) patients were included in the study. The average age of the participants was 82 years, and 62.3% were male. All patients were followed up for three months. Atrial fibrillation accounted for 52% of patients, while previous strokes accounted for 20%. The most typical pathology was diverticulosis.Regarding restarting of anticoagulants, Among patients on DOAC (Direct oral anticoagulant), 39% were restarted on discharge, 23% were switched to warfarin, and another 23% were not restarted; 15% planned to restart after seven days. For those on Warfarin, 62% were restarted on discharge, 22% stopped the medication, and the rest were switched to Dual Oral Anticoagulant. Among aspirin patients, 60% were restarted at discharge, while the remaining discontinued. All patients receiving clopidogrel and dual antiplatelet therapy were started at discharge. None of the patients were readmitted during the follow-up period of 3 months.
CONCLUSION
Restarting of blood-thinning drugs in patients with rectal bleeding is subject to individual patient variation. Necessitates more extensive trials to achieve greater standardization.
Topics: Humans; Male; Female; Aged; Retrospective Studies; Aged, 80 and over; Gastrointestinal Hemorrhage; Anticoagulants; Middle Aged; Rectum
PubMed: 38939367
DOI: 10.12688/f1000research.149548.1 -
Journal of Cardiothoracic Surgery Jun 2024Thoracic endovascular aortic repair (TEVAR) is a minimally invasive technique used to treat type B aortic dissections. Left subclavian artery (LSA) reconstruction is...
BACKGROUND
Thoracic endovascular aortic repair (TEVAR) is a minimally invasive technique used to treat type B aortic dissections. Left subclavian artery (LSA) reconstruction is required when treating patients with involvement of LSA. The best antiplatelet therapy after LSA reconstruction is presently uncertain.
METHODS
This study retrospectively analyzed 245 type B aortic dissection patients who underwent left subclavian artery revascularization during TEVAR. Out of 245 patients, 159 (64.9%) were in the single antiplatelet therapy (SAPT) group, receiving only aspirin, and 86 (35.1%) were in the dual antiplatelet therapy (DAPT) group, receiving aspirin combined with clopidogrel. During the 6-month follow-up, primary endpoints included hemorrhagic events (general bleeding and hemorrhagic strokes), while secondary endpoints comprised ischemic events (left upper limb ischemia, ischemic stroke, and thrombotic events), as well as death and leakage events. Both univariate and multivariate Cox regression analyses were performed on hemorrhagic and ischemic events, with the Kaplan-Meier method used to generate the survival curve.
RESULTS
During the six-month follow-up, the incidence of hemorrhagic events in the DAPT group was higher (8.2% vs. 30.2%, P < 0.001). No significant differences were observed in ischemic events, death, or leakage events among the different antiplatelet treatment schemes. Multivariate Cox regression analysis showed that DAPT (HR: 2.22, 95% CI: 1.07-4.60, P = 0.032) and previous chronic conditions (HR:3.88, 95% CI: 1.24-12.14, P = 0.020) significantly affected the occurrence of hemorrhagic events. Chronic conditions in this study encompassed depression, vitiligo, and cholecystolithiasis. Carotid subclavian bypass (CSB) group (HR:0.29, 95% CI: 0.12-0.68, P = 0.004) and single-branched stent graft (SBSG) group (HR:0.26, 95% CI: 0.13-0.50, P < 0.001) had a lower rate of ischemic events than fenestration TEVAR (F-TEVAR). Survival analysis over 6 months revealed a lower risk of bleeding associated with SAPT during hemorrhagic events (P = 0.043).
CONCLUSIONS
In type B aortic dissection patients undergoing LSA blood flow reconstruction after synchronous TEVAR, the bleeding risk significantly decreases with the SAPT regimen, and there is no apparent ischemic compensation within 6 months. Patients with previous chronic conditions have a higher risk of bleeding. The CSB group and SBSG group have less ischemic risk compared to F-TEVAR group.
Topics: Humans; Male; Female; Retrospective Studies; Platelet Aggregation Inhibitors; Subclavian Artery; Middle Aged; Aortic Dissection; Endovascular Procedures; Aortic Aneurysm, Thoracic; Aged; Clopidogrel; Aspirin; Aorta, Thoracic; Treatment Outcome; Blood Vessel Prosthesis Implantation; Postoperative Complications; Endovascular Aneurysm Repair
PubMed: 38937841
DOI: 10.1186/s13019-024-02932-3 -
The Journal of Pharmacology and... Jun 2024Estrogen receptor (ER)-negative breast cancers are known to be aggressive and unresponsive to anti-estrogen therapy, and triple negative breast cancers are associated...
Estrogen receptor (ER)-negative breast cancers are known to be aggressive and unresponsive to anti-estrogen therapy, and triple negative breast cancers are associated with poor prognosis and metastasis. Thus, new targeted therapies are needed. FOXM1 is abundantly expressed in human cancers and implicated in protecting tumor cells from oxidative stress by reducing the levels of intracellular reactive oxygen species (ROS). Aspirin, a prototypical anti-cancer agent with deleterious side effects, has been modified to release nitric oxide and hydrogen sulfide, called NOSH-aspirin (NOSH-ASA), generating a 'safer' class of new anti-inflammatory agents. We evaluated NOSH-ASA against (ER)-negative breast cancer using cell lines and a xenograft mouse model. NOSH-ASA strongly inhibited growth of MDA-MB-231 and SKBR3 breast cancer cells with low ICs of 90{plus minus}5 and 82{plus minus}5 nM, respectively, with marginal effects on a normal breast epithelial cell line. NOSH-ASA inhibited cell proliferation, caused G/G phase arrest, increased apoptosis, and was associated with increases in ROS. In MDA-MB-231 cell xenografts, NOSH-ASA reduced tumor size markedly, which was associated with reduced proliferation (decreased PCNA expression), induction of apoptosis (increased TUNEL positive cells), and increased ROS, while NF-kB and FoxM1 that were high in untreated xenografts were significantly reduced. mRNA data for FoxM1, p21 and CyclinD1 corroborated with the respective protein expressions and arrest of cells. Taken together, these molecular events contribute to NOSH-ASA mediated growth inhibition and apoptotic death of (ER)-negative breast cells in vitro and in vivo. Additionally, as a ROS-inducer and FOXM1-inhibitor, NOSH-ASA has potential as a targeted therapy. In this investigation, we examined the cellular effects and xenograft tumor inhibitory potential of NOSH-aspirin, an NO and HS-donating hybrid, against ER-negative breast cancer, which currently lacks effective therapeutic options. The induction of reactive oxygen species and subsequent downregulation of FOXM1 represents a plausible mechanism contributing to the observed decrease in cell proliferation and concurrent increase in apoptosis. NOSH-ASA demonstrated a remarkable reduction in tumor size by 90% without inducing any observable gross toxicity, underscoring its promising translational potential.
PubMed: 38936976
DOI: 10.1124/jpet.124.002240 -
European Journal of Vascular and... Jun 2024
PubMed: 38936687
DOI: 10.1016/j.ejvs.2024.06.041 -
Biochimie Jun 2024In hominids, including Homo sapiens, uric acid is the final product of purine catabolism. In contrast, other placental mammals degrade uric acid further to (S)-allantoin...
In hominids, including Homo sapiens, uric acid is the final product of purine catabolism. In contrast, other placental mammals degrade uric acid further to (S)-allantoin through enzymes such as urate oxidase (uricase), HIU hydrolase (HIUase), and OHCU decarboxylase. Some organisms, like frogs and fish, hydrolyze (S)-allantoin to allantoate and eventually to (S)-ureidoglycolate and urea, while marine invertebrates convert urea to ammonium. In H. sapiens, mutations in the uricase gene led to a reduction in the selection pressure for maintaining the integrity of the genes encoding the other enzymes of the purine catabolism pathway, leading to uric acid accumulation. Hyperuricemia, resulting from this accumulation, is linked to gout, cardiovascular disease, diabetes, and preeclampsia. Many commonly used drugs, such as aspirin, can also increase uric acid levels. Despite the apparent absence of these enzymes in H. sapiens, there appears to be production of transcripts for uricase (UOX), HIUase (URAHP), OHCU decarboxylase (URAD), and allantoicase (ALLC). While some URAHP transcripts are classified as long non-coding RNAs (lncRNAs), URAD and ALLC produce protein-coding transcripts. Given the presence of these transcripts in various tissues, we hypothesized that they may play a role in regulating purine catabolism and the pathogenesis of hyperuricemia-related diseases. Here we provide a focused examination of the unique aspects of purine catabolism in H. sapiens, the impact of uricase gene mutations, and the potential regulatory role of related transcripts. These findings open new avenues for research and therapeutic approaches to manage hyperuricemia and its associated diseases.
PubMed: 38936684
DOI: 10.1016/j.biochi.2024.06.010 -
Journal of the American Heart... Jun 2024Experimental preeclampsia (ePE) has been shown to have worsened outcome from stroke. We investigated the effect of low-dose aspirin, known to prevent preeclampsia, on...
BACKGROUND
Experimental preeclampsia (ePE) has been shown to have worsened outcome from stroke. We investigated the effect of low-dose aspirin, known to prevent preeclampsia, on stroke hemodynamics and outcome, and the association between the vasoconstrictor and vasodilator cyclooxygenase products thromboxane A and prostacyclin.
METHODS AND RESULTS
Middle cerebral artery occlusion was performed for 3 hours with 1 hour of reperfusion in normal pregnant rats on day 20 of gestation and compared with ePE treated with vehicle or low-dose aspirin (1.5 mg/kg per day). Multisite laser Doppler was used to measure changes in cerebral blood flow to the core middle cerebral artery and collateral vascular territories. After 30 minutes occlusion, phenylephrine was infused to increase blood pressure and assess cerebral blood flow autoregulation. Infarct and edema were measured using 2,3,5-triphenyltetrazolium chloride staining. Plasma levels of thromboxane A, prostacyclin, and inflammatory markers in plasma and cyclooxygenase levels in cerebral arteries were measured. ePE had increased infarction compared with normal pregnant rats (<0.05) that was reduced by aspirin (<0.001). ePE also had intact cerebral blood flow autoregulation and reduced collateral perfusion during induced hypertension that was also prevented by aspirin. Aspirin increased prostacyclin in ePE (<0.05) without reducing thromboxane B, metabolite of thromboxane A, or 8-isoprostane-prostaglandin-2α, a marker of lipid peroxidation. There were no differences in cyclooxygenase levels in cerebral arteries between groups.
CONCLUSIONS
Low-dose aspirin in ePE reduced infarction that was associated with increased vasodilator prostacyclin and improved collateral perfusion during induced hypertension. The beneficial effect of aspirin on the brain and cerebral circulation is likely multifactorial and worth further study.
PubMed: 38934871
DOI: 10.1161/JAHA.124.035990 -
Annals of Pediatric Cardiology 2024Aortico right atrial tunnel (ARAT) is a rare extracardiac communication between the aorta and the right atrium with two anatomical types. A recent global review...
BACKGROUND
Aortico right atrial tunnel (ARAT) is a rare extracardiac communication between the aorta and the right atrium with two anatomical types. A recent global review identified 59 patients.
METHODS
Patients with ARAT from two centers were analyzed for their demographics, symptoms, morphology, management, and follow-up thromboprophylaxis.
RESULTS
Among 21 patients including 8 males with a median age of 3 years (18 days-72 years) diagnosed as ARAT, 12 (57%) had posterior tunnels and 9 had anterior tunnels. Four patients had multiple exits. Eighteen tunnels were closed after arteriovenous circuit formation. Six patients (29%) weighing <10 kg presented early with heart failure. Transcatheter closure normalized the hemodynamics including in one infant after failed surgery. Two elderly patients (10%) above 60 years presented with angina and atrial fibrillation. The rest were asymptomatic. Occluders were positioned in the narrow proximal aortic end of the tunnel in all except two patients, where the distal atrial end was closed. All procedures were successful without complications. There was one late death after 1 year from subarachnoid hemorrhage. At a median follow-up of 96 months, all survivors were asymptomatic. Thromboprophylaxis with dual antiplatelets for 1-2 years followed earlier was recently changed to aspirin with Coumadin. Complete remodeling occurred when the proximal aortic end was closed, but partial persistence of the track was noted after distal closure.
CONCLUSIONS
This largest cohort of ARAT showed the safety and efficacy of transcatheter closure even in neonates. The narrow proximal aortic end should be the target for closure rather than the distal atrial end to achieve complete remodeling.
PubMed: 38933058
DOI: 10.4103/apc.apc_1_24