SAFETY AND PHARMACOKINETICS OF IGPRO20 (SUBCUTANEOUS IMMUNOGLOBULIN) AND IGPRO10 (INTRAVENOUS IMMUNOGLOBULIN) IN ADULTS WITH SYSTEMIC SCLEROSIS (SSC) – RESULTS FROM A PHASE 2 TRIAL

BackgroundSystemic sclerosis (SSc) is a severe, progressive multisystem rheumatic disease with high mortality, but without approved disease-modifying treatment to stop or reverse course of disease. Intravenous immunoglobulin G (IgG) may have a positive impact on SSc based upon available literature reports. However, to date, there have been no clinical trials evaluating subcutaneous IgG (SCIG) in SSc. In particular, the impact of pathologically altered skin in SSc on local safety and pharmacokinetics (PK) of SCIG has not been explored yet.ObjectivesThe primary and secondary objectives of this trial (NCT04137224) included safety, including local infusion safety, and bioavailability of subcutaneous IgG (IgPro20) in adults with diffuse cutaneous SSc (dcSSc).MethodsThis was a randomized, open-label, crossover study. Adult subjects with dcSSc diagnosis within 5 years from first non-Raynaud's phenomenon and modified Rodnan Skin Score of 15-45 at screening were randomized 1:1 to sequence A (IgPro20, 20% normal human subcutaneous immunoglobulin followed by IgPro10, 10% normal human intravenous immunoglobulin) or sequence B (IgPro10 followed by IgPro20). Each subject was to complete two treatment periods (16 weeks each), with up to 40 weeks (including screening) study duration for an individual subject. Doses received were 0.5g/kg/week split over two sessions for IgPro20, and 2g/kg/4 weeks split over 2-5 days for IgPro10. The primary endpoint was safety of IgPro20, described as treatment-emergent adverse events (TEAEs) and changes in clinical observations.Results27 subjects were randomized, with 13 subjects to sequence A and 14 subjects to sequence B. In total, 25 subjects completed the study. Of 27 treated subjects, 107 TEAEs occurred in 22 subjects (81.5%) over the 36-week study period, the majority of which were mild or moderate. The most common TEAEs (>10% of subjects) by preferred term (PT) were headache (12 events occurring in 6 subjects [22.2%]), COVID-19 (3 events occurring in 3 subjects [11.1%]), diarrhoea (3 events occurring in 3 subjects [11.1%]), and vomiting (3 events occurring in 3 subjects [11.1%]).A total of 10 serious AEs (SAEs) were reported in 6 subjects (Viral infection, Chronic gastritis, Vomiting, Dehydration, Upper gastrointestinal haemorrhage, Chest pain, Myocardial infarction, Myocardial ischemia, Breast cancer, Interstitial lung disease). Among these, one subject experienced 2 SAEs (myocardial ischemia & myocardial infarction) and was discontinued from study treatment. None of the SAEs were considered related to study treatment by the investigator, and no deaths were reported.For IgPro20, 14 infusion site reactions (ISRs) occurred in 5 subjects (19.2%), all were mild or moderate in severity. The most common ISRs were infusion site pain and infusion site swelling (3 events in 2 subjects each, 7.7%). In total, 686 IgPro20 infusions were performed, resulting in an overall ISR rate per infusion of 0.02, ie 2 ISRs per 100 infusions. No ISRs were reported for IgPro10.No clinically relevant trends in vital signs, body weight, clinical laboratory tests, electrocardiograms, or pulmonary function tests were observed.PK profiles and bioavailability in dcSSc subjects were similar to those observed in other approved indications such as Primary Immunodeficiency. Population relative bioavailability of IgPro20, based on dose-normalized, baseline-corrected AUC0-tau was 0.761 (90% CI: 0.7033, 0.8232), ie 76.1% compared to IgPro10 (intravenous IgG).ConclusionThe overall safety profiles of IgPro20 and IgPro10 in subjects with dcSSc were consistent with that in approved indications such as CIDP, including a relatively low ISR rate for IgPro20. PK profiles and bioavailability were also similar to other indications. This study indicates that subcutaneous administration of IgPro20 has acceptable safety, bioavailability and PK profiles in patients with dcSSc. AcknowledgementsEditorial assistance was provided by Meridian HealthComms Ltd., funded by CSL Behring.Disclosure of InterestsChristopher P Denton Speakers bureau: Ja ssen, Boehringer Ingelheim, Consultant of: GSK, CSL Behring, Boehringer Ingelheim, Merck, Roche, Sanofi, Grant/research support from: GSK, CSL Behring, Inventiva, Horizon, Otylia Kowal-Bielecka Speakers bureau: Abbvie, Janssen-Cilag, Boehringer Ingelheim, Medac, MSD, Novartis, Pfizer, Sandoz, Consultant of: Boehringer Ingelheim and Novartis, Grant/research support from: Received congress support from Abbvie, Boehringer Ingelheim, and Medac, Susanna Proudman Speakers bureau: Boehringer Ingelheim, Grant/research support from: Janssen, Marzena Olesińska Consultant of: AstraZeneca, Margitta Worm Consultant of: Novartis Pharma GmbH, Sanofi-Aventis Deutschland GmbH, DBV Technologies S.A, Aimmune Therapeutics UK Limited, Regeneron Pharmaceuticals, Inc, Leo Pharma GmbH, Boehringer Ingelheim Pharma GmbH &Co.KG, ALK-Abelló Arzneimittel GmbH, Kymab Limited, Amgen GmbH, Abbvie Deutschland GmbH & Co. KG, Pfizer Pharma GmbH, Mylan Germany GmbH (A Viatris Company), AstraZeneca GmbH, Lilly Deutschland GmbH and GlaxoSmithKline GmbH & Co. KG., Nicoletta Del Papa Speakers bureau: Janssen Cilag, Boehringer Ingelheim., Marco Matucci-Cerinic Speakers bureau: Biogen, Sandoz, Boehringer Ingelheim, Consultant of: CSL Behring, Boehringer Ingelheim, Grant/research support from: MSD, Chemomab, Jana Radewonuk Shareholder of: CSL Behring, Employee of: CSL Behring, Jeanine Jochems Shareholder of: CSL Behring, Employee of: CSL Behring, Amgad Shebl Shareholder of: CSL Behring, Employee of: CSL Behring, Anna Krupa Shareholder of: CSL Behring, Employee of: CSL Behring, Jutta Hofmann Shareholder of: CSL Behring, Employee of: CSL Behring, Maria Gasior Shareholder of: CSL Behring, Employee of: CSL Behring.

Special Issue. (Special Issue.)

This special issue contains 13 articles that discuss public health articles such as public perception, knowledge and factors influencing COVID-19 vaccine acceptability, determinants of enrolment in health insurance scheme among HIV patients, hypertension and associated factors among patients attending HIV clinic, determinants of visit-to-visit systolic blood pressure variability among Ghanaians with hypertension and diabetes mellitus, short-term outcomes among patients with subclinical hypothyroidism, association of erectile dysfunction with coronary artery disease, psychological correlates of COVID safety protocol adherence, ophthalmic services utilisation and associated factors, safe duration of silicon catheter replacement in urological patients, and leadership in health and medical education.

Challenges and Burdens in the Coronary Artery Disease Care Pathway for Patients Undergoing Percutaneous Coronary Intervention: A Contemporary Narrative Review.

Clinical and economic burdens exist within the coronary artery disease (CAD) care pathway despite advances in diagnosis and treatment and the increasing utilization of percutaneous coronary intervention (PCI). However, research presenting a comprehensive assessment of the challenges across this pathway is scarce. This contemporary review identifies relevant studies related to inefficiencies in the diagnosis, treatment, and management of CAD, including clinician, patient, and economic burdens. Studies demonstrating the benefits of integration and automation within the catheterization laboratory and across the CAD care pathway were also included. Most studies were published in the last 5-10 years and focused on North America and Europe. The review demonstrated multiple potentially avoidable inefficiencies, with a focus on access, appropriate use, conduct, and follow-up related to PCI. Inefficiencies included misdiagnosis, delays in emergency care, suboptimal testing, longer procedure times, risk of recurrent cardiac events, incomplete treatment, and challenges accessing and adhering to post-acute care. Across the CAD pathway, this review revealed that high clinician burnout, complex technologies, radiation, and contrast media exposure, amongst others, negatively impact workflow and patient care. Potential solutions include greater integration and interoperability between technologies and systems, improved standardization, and increased automation to reduce burdens in CAD and improve patient outcomes.

Observational study of imaging findings in COVID -19 related rhino-orbito-cerebral mucormycosis - a tertiary care center study

Background: There has been a tremendous increase in number of cases of rhino-orbitocerebral involvement with mucor in the COVID era, as reported from India. It is well established that management of ROCM involves early clinical and radiological diagnosis, reversal of underlying risk factors, prompt antifungal therapy and surgical debridement when indicated. Materials &Methods: Multiplanar MR imaging and CT scan were performed for brain, orbit and paranasal sinuses. All the cases were assessed for involvement of the paranasal sinuses, nasal cavities, orbits and brain. Results: 25 cases with ROCM were identified over 8 months. The mean age of the cases was 56.1 years. 18 of the 25 cases had a positive RT-PCR test result at the time of diagnosis with ROCM. 20 cases had poorly controlled diabetes mellitus, 2 had a hematological malignancy, 2 had chronic kidney disease and 1 had ischemic heart disease. There was involvement of the paranasal sinuses, nasal cavities, orbits and brain inclusing necrosis in most of the cases. The number of cases identified during the interval is much higher than the numbers presenting in the prior 2 years during equivalent intervals than those reported in the literature in different settings in the pre-pandemic era. Conclusions: Rhino-orbito mucormycosis can have aggressive necrosis of the involved paranasal sinuses and orbits with or without cerebral extension. Hence, the correct diagnosis is imperative as prompt antifungal drugs and surgical debridement can significantly reduce mortality and morbidity.

The potential role of SARS-CoV-2 infection in acute coronary syndrome and type 2 myocardial infarction (T2MI): Intertwining spread.

Coronavirus disease 2019 (COVID-19) is a novel pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It has been shown that SARS-CoV-2 infection-induced inflammatory and oxidative stress and associated endothelial dysfunction may lead to the development of acute coronary syndrome (ACS). Therefore, this review aimed to ascertain the link between severe SARS-CoV-2 infection and ACS. ACS is a spectrum of acute myocardial ischemia due to a sudden decrease in coronary blood flow, ranging from unstable angina to myocardial infarction (MI). Primary or type 1 MI (T1MI) is mainly caused by coronary plaque rupture and/or erosion with subsequent occlusive thrombosis. Secondary or type 2 MI (T2MI) is due to cardiac and systemic disorders without acute coronary atherothrombotic disruption. Acute SARS-CoV-2 infection is linked with the development of nonobstructive coronary disorders such as coronary vasospasm, dilated cardiomyopathy, myocardial fibrosis, and myocarditis. Furthermore, SARS-CoV-2 infection is associated with systemic inflammation that might affect coronary atherosclerotic plaque stability through augmentation of cardiac preload and afterload. Nevertheless, major coronary vessels with atherosclerotic plaques develop minor inflammation during COVID-19 since coronary arteries are not initially and primarily targeted by SARS-CoV-2 due to low expression of angiotensin-converting enzyme 2 in coronary vessels. In conclusion, SARS-CoV-2 infection through hypercytokinemia, direct cardiomyocyte injury, and dysregulation of the renin-angiotensin system may aggravate underlying ACS or cause new-onset T2MI. As well, arrhythmias induced by anti-COVID-19 medications could worsen underlying ACS.

Cardiac Manifestations Associated With Coronavirus Disease: A Case Report

Abstract This study presents a 47-year-old female patient, with a history of diabetes, who contracted SARS-CoV-2 and exhibited cardiovascular complications.

MSCs-exosomes in regeneration medicine: Current evidence and future perspectives

Exosomes, especially from mesenchymal stem cells, have attracted extensive attention in regeneration medicine. Mesenchymal stem cells derived exosomes (MSCs-exosomes) have shown anti-inflammatory, anti-oxidant, antiapoptosis and tissue regeneration effects in a variety of tissue injury repair models. MSCs-exosomes hold many excellent properties such as low immunogenicity, biocompatibility, and targeting capability. With the in-depth study on the generation and function of exosomes, MSCs-exosomes are considered to be the bright stars in the field of regenerative medicine. However, there are still many obstacles to overcome in terms of exosomes isolation, clinical trials and safety evaluation. In this article, what we should focus on about MSCs-exosomes in regeneration medicine will be discussed. Copyright © 2022 Centro Regional de Invest. Cientif. y Tecn.. All rights reserved.

Changes in clinical features and outcomes in three major critical diseases after COVID-19 pandemic: acute myocardial infarction, stroke, and cardiac arrest. (Special Issue: COVID-19 in the emergency department: epidemiology and changes throughout the pandemic.)

A few months after the onset of the coronavirus Disease 2019 (COVID-19) pandemic, the worse prognoses of acute myocardial infarction, ischemic and hemorrhagic stroke, and cardiac arrest were reported. This study aimed to investigate the changes in the characteristics and prognoses of these diseases in the emergency department (ED) over a year after pandemic's onset. This was a retrospective observational study. The year 2019 was defined as the pre-period, while the year from February 2020 to January 2021 was defined as the post-period. Adult patients diagnosed with acute myocardial infarction, ischemic stroke, hemorrhagic stroke, or cardiac arrest during the study period were included. The primary outcome was in-hospital mortality. Time series analyses using autoregressive integrated moving average (ARIMA)(p,d,q) model were performed to evaluate the changes between periods. A multivariable logistic regression analysis of factors affecting in-hospital mortality was performed. The proportions of patients with acute myocardial infarction (0.8% vs. 1.1%, p < 0.001), hemorrhagic stroke (1.0%vs. 1.2%, p = 0.011), and cardiac arrest (0.9% vs. 1.1%, p = 0.012) increased in the post-period. The post-period was independently associated with in-hospital mortality in acute myocardial infarction (adjusted odds ratio (aOR) 2.54, 95% confidence interval (95% CI) 1.06-6.08, p = 0.037) and hemorrhagic stroke (aOR 1.74, 95% CI 1.11-2.73, p = 0.016), but not for ischemic stroke or cardiac arrest. Over a year after onset of the COVID-19 pandemic in Korea, the number of patients with acute myocardial infarction, hemorrhagic stroke, and cardiac arrest in the ED increased. An independent association between the post-period and mortality was observed for acute myocardial infarction, and hemorrhagic stroke. This study provides important information for future studies and policies.

Covid19 Vaccines and the Misinterpretation of Perceived Side Effects

In the era of Covid 19 and mass vaccination programs, the anti-vaccination movement across the world is currently at an all-time high. Much of this anti-vaccination sentiment could be attributed to the alleged side effects that are perpetuated across social media from anti-vaccination groups. Fear mongering and misinformation being peddled by people with no scientific training to terrorise people into staying unvaccinated is not just causing people to remain susceptible to viral outbreaks, but could also be causing more side effects seen in the vaccination process. This brief review will offer data that may demonstrate that misinformation perpetuated by the anti-vaccination movement may be causing more deaths and side effects from any vaccine. A mini review of published literature has been conducted and found that mental stress clearly causes vasoconstriction and arterial constriction of the blood vessels. Therefore, if subjects are panicked, concerned, stressed or scared of the vaccination, their arteries will constrict and become smaller in and around the time of receiving the vaccine. This biological mechanism (the constriction of veins, arteries and vessels under mental stress) is the most likely cause for where there has been blood clots, strokes, heart attacks, dizziness, fainting, blurred vision, loss of smell and taste that may have been experienced shortly after vaccine administration. The extreme mental stress of the patient could most likely be attributed to the fear mongering and scare tactics used by various anti-vaccination groups. This paper does not aim to rule in or out every side effect seen, but it is highly likely that many apparent side effects seen shortly after a subject has received a vaccine could be the result of restricted or congested blood flow from blood vessel or arterial constriction caused by emotional distress or placebo based on fear around vaccines.

Risk factors for COVID-19 from interculturality and the preservation of ancestral knowledge

In December 2019, an outbreak of pneumonia cases emerged in Wuhan, China, which evolved into the COVID-19 pandemic. The purpose of the work is to design a community prevention strategy in the indigenous population of zone 3 at the starting point of the epidemiological characterization carried out. A longitudinal and prospective experimental explanatory study was conducted with deliberate intervention, descriptive and inferential statistical methods were used. It was identified that the age of 60 years or more pre- dominated in the subjects surveyed, which represented 9,7%, and the other risk group located at ages under 18 years, were located 17 for 4,5% of the sample, although the figure of both age groups of risk is not high, it is necessary to work with the indigenous population at the community level, ischemic heart disease, high blood pressure, diabetes mellitus and bronchial asthma were also identified as a risk. As social factors, extreme poverty, living alone, overcrowding and poor accessibility to health services. The community prevention strategy of Covid-19 in the indigenous population will favor the epidemiological control of the pandemic with probable economic and social impact added, which will guarantee a rational use of resources focused on the most vulnerable population.

Myocardial Ischemia in Patients with COVID-19 Infection: Between Pathophysiological Mechanisms and Electrocardiographic Findings.

Given the possible pathophysiological links between myocardial ischemia and SARS-CoV-2 infection, several studies have focused attention on acute coronary syndromes in order to improve patients' morbidity and mortality. Understanding the pathophysiological aspects of myocardial ischemia in patients infected with SARS-CoV-2 can open a broad perspective on the proper management for each patient. The electrocardiogram (ECG) remains the easiest assessment of cardiac involvement in COVID-19 patients, due to its non-invasive profile, accessibility, low cost, and lack of radiation. The ECG changes provide insight into the patient's prognosis, indicating either the worsening of an underlying cardiac illnesses or the acute direct injury by the virus. This indicates that the ECG is an important prognostic tool that can affect the outcome of COVID-19 patients, which important to correlate its aspects with the clinical characteristics and patient's medical history. The ECG changes in myocardial ischemia include a broad spectrum in patients with COVID-19 with different cases reported of ST-segment elevation, ST-segment depression, and T wave inversion, which are associated with severe COVID-19 disease.

Clinical and radiological characteristics of adult hospitalized Coronavirus disease-2019 patients of Dhaka, Bangladesh

The severity of Coronavirus disease-2019 (COVID-19) varies among individuals and some influential factors leads to critical infections and death. This study aimed to assess various clinical data of hospitalized patients and identify the determinants of critical COVID-19 infection. This was a cross-sectional study among hospitalized COVID-19 patients confirmed by reverse transcription polymerase chain reaction (RT-PCR). Data was collected from a single Centre between January to April 2021 by experienced physicians of Ad-din Medical College Hospital. All of the laboratory tests were performed by technical experts and the data was analyzed by Statistical package for the social sciences software. Among the study participants 25% were Intensive care unit (ICU) patients and the mean age of them were higher (59 years) than non-ICU (55 years) patients. Our analysis has identified diabetes mellitus (AOR=2.5, 95%CI: 1.1-5.4) and ischemic heart disease (AOR=3.1, 95%CI: 1.1-8.9) as significant predictor of critical outcome (ICU admission). Anemia (AOR=3.3, 95%CI: 1.5-7.4), lymphopenia (AOR=2.9, 95%CI: 1.2-7.1), and thrombocytopenia (AOR=4.2, 95%CI: 2.7-12.9) was also associated critical outcome. Biomarkers of kidney injury (creatinine, blood urea nitrogen), liver damage (alanine transaminase, aspartate aminotransferase, fibrinogen) and electrolyte imbalance (sodium and potassium level) were also significantly associated with critical infection. A higher d-dimer level (2.5) was the most important predictor (AOR=11.5, 95%CI: 5.4-24.6) of critical COVID 19 infections. The study has revealed socio-demographic, comorbidity, and radiological risk factors of critical COVID-19 infections. The identified risk factors would be considered for decision making during the treatment process.

Outcome, severity, and risk of mortality in patients with COVID-19 and chronic underlying diseases: a prospective study

Background: The novel coronavirus pandemic, severe acute respiratory syndrome CoV-2 (SARS COV-2), has become a global threat and rapidly spread worldwide. The COVID-19 pandemic has posed a number of challenges, the most notable of which is the management of patients with chronic underlying diseases. Objectives: The present study aimed to evaluate the risk of COVID-19 severity and mortality in patients with chronic underlying diseases.

Multicenter Randomized Trial of Everolimus in Pediatric Heart Transplantation

TEAMMATE is a multicenter randomized clinical trial of a novel immunosuppressive therapy that is studing children who have undergone recent heart transplantation. The primary goal is to determine whether a new rejection treatment (everolimus and low-dose tacrolimus) can reduce or prevent complications of transplant, including rejection, coronary artery disease, and kidney disease, when compared to usual care (tacrolimus and mycophenolate mofetil). The secondary goal is to acquire FDA approval of the first immunosuppression regimen for pediatric heart transplantation. The primary trial endpoint is a validated surrogate measurethe major adverse transplant event (MATE) scorewhich efficiently predicts long-term survival, and that has been accepted by the FDA (IND# 127980). The trial is being conducted at 25 centers, with leadership at Boston Childrens Hospital (Data Coordinating Center) and Stanford University (Clinical Coordinating Center). At the time of this annual report, enrollment is complete and the target has been met, with 211 patients randomized (60 in the last year). Each participant will be followed for 30 months. Additional accomplishments in Year 03 include one in-person Protocol Certification Training;successful execution of one Data and Safety Monitoring Board meeting;national presentation of research on everolimus dosing, baseline characteristics and recruitment strategies;and the continuation of endpoint adjudication and regulatory/data audit site visits.

Diagnosis and Treatment of Acute Myocardial Ischemia in Patients with COVID-19 Infection

Acute myocardial ischemia during coronavirus disease 2019 (COVID-19) infection can occur in two forms of acute myocardial infarction type І and II. In acute myocardial infarction type І, infection can cause inflammation, and inflammation causes the secretion and increase of cytokines such as interleukin 1, 6, and 8, as well as tumor necrosis factor (TNF) in the circulation. This mechanism causes the secretion of collagenase from activated macrophages, and the results of these reactions is a precursor to plaque rupture, increased coagulation, and thrombus formation. This mechanism causes acute myocardial infarction type І on atherosclerotic plaque. In these patients, primary percutaneous coronary intervention (PCI) is the treatment of choice, contrary to the initial theory that lytic therapy was the main treatment. In COVID conditions, the primary PCI time increases from 120 minutes to 180 minutes, and if the primary PCI takes more than 180 minutes, then lytic therapy is recommended. In acute myocardial infarction type II, patients usually do not have angina clinically, troponin rises slightly (less than 2 times normal), and do not have electrocardiogram changes as a sign of ischemia. However, patients with coronary heart disease have persistent chest pain with or without myocardial necrosis. During COVID-19 infection, due to release of interleukin, tumor necrosis alpha, and catecholamine, as well as hypoxia, acidosis, hypertension and/or hypotension, oxygen delivery and myocardial oxygen demand become disturbed, so acute myocardial infarction type II may occur. Supportive therapies are performed in these patients, and the treatment of acute underlying disease such as treatment with steroidal anti-inflammatory drugs and antiviral drugs is the main treatment. © 2021 Isfahan University of Medical Sciences(IUMS). All rights reserved.

Ischemic stroke in COVID 19 - management dilemmas

This article presents some points concerning management dilemmas that the authors would like to highlight, which were not specifically addressed in the published guidelines, "Consensus statement - suggested recommendations for acute stroke management during the COVID-19 pandemic: Expert group on behalf of the Indian Stroke Association" which was published recently. The authors emphasize that importance of recognizing that there are treatment dilemmas in COVID-19-related ischaemic stroke management, owing to its variable presentation, even while acknowledging that no definite guidelines are presently available on these.

Anti-ischemic therapy in patients with COVID-19 and acute coronary syndrome

Introduction. Since the end of 2019, the pandemic caused by SARS-CoV2 has affected hundreds of millions of people, and the number of indirectly affected is many times higher. In addition to directly affecting lung tissue, the coronavirus infection predisposes patients to thrombotic events responsible for the occurrence of cardiovascular complications. The aim of our study was to observe patients with COVID-19 and acute coronary syndrome (ACS) and to evaluate the efficacy of anti-ischemic therapy with beta-blockers, molsidomine and trimetazidine.

Focus issue on epidemiology and prevention. (Focus issue on epidemiology and prevention.)

This issue contains 18 articles that discuss COVID-19 and cardiovascular health. Topics include The Jessa Hospital experience for cardiac rehabilitation, cardiology training using technology, the value of sotagliflozin in patients with diabetes and heart failure detracted by an unexpected ending, Taking a stand against air pollution as a joint opinion from the World Heart Federation, American College of Cardiology, American Heart Association, and the European Society of Cardiology, a call to action for new global approaches to cardiovascular disease drug solutions, validation of risk scores for ischaemic stroke in atrial fibrillation across the spectrum of kidney function, the risk of atrial fibrillation in a Swedish nationwide cohort study, the physical activity paradox in cardiovascular disease and all-cause mortality, among others.