Prediabetes and major adverse cardiac events after acute coronary syndrome: An overestimated concept.

BACKGROUND: Unlike diabetes, the effect of prediabetes on outcomes in patients with acute coronary syndrome (ACS) who underwent percutaneous coronary intervention (PCI) is not much investigated. We investigated the association between fasting glycemic status and major adverse cardiovascular and cerebrovascular events (MACCE) in patients with ACS undergoing PCI and had mid to long-term follow-up after coronary stenting. METHODS: Registry-based retrospective cohort study included ACS patients who underwent PCI at the Tehran Heart Center from 2015 to 2021 with a median follow-up of 378 days. Patients were allocated into normoglycemic, prediabetic, and diabetic groups. The primary and secondary outcomes were MACCE and its components, respectively. Unadjusted and adjusted Cox models were used to evaluate the association between glycemic status and outcomes. RESULTS: Among 13 682 patients, 3151 (23%) were prediabetic, and 5834 (42.6%) were diabetic. MACCE risk was significantly higher for diabetic versus normoglycemic (adjusted hazard ratio [aHR]: 1.22, 95% confidence interval [CI]: 1.06-1.41), but nonsignificantly higher for prediabetic versus normoglycemic (aHR: 0.95, 95% CI: 0.78-1.10). All-cause mortality risk was significantly higher in diabetic versus normoglycemic (aHR: 1.42, 95% CI: 1.08-1.86), but nonsignificantly higher for prediabetic versus normoglycemic (aHR: 1.15, 95% CI: 0.84-1.59). Among other components of MACCE, only coronary artery bypass grafting was significantly higher in diabetic patients, and not prediabetic, compared with normoglycemic. CONCLUSIONS: Prediabetic ACS patients undergoing PCI, unlike diabetics, are not at increased risk of MACCE and all-cause mortality. While prediabetic patients could be regarded as having the same risk as nondiabetics, careful consideration to provide more intensive pre- and post-PCI care in diabetic patients is mandatory.

Whole-exome sequencing to identify undiagnosed primary immunodeficiency disorders in children with community-acquired sepsis, admitted in the pediatric intensive care unit.

BACKGROUND: Whole-exome sequencing (WES) provides a powerful diagnostic tool for identifying primary immunodeficiency diseases (PIDs). This study explores the utility of this approach in uncovering previously undiagnosed PIDs in children with community-acquired sepsis (CAS), with a medical history of recurrent infections or a family history of PIDs. METHODS: We performed WES on DNA samples extracted from the blood of the 34 enrolled patients, followed by bioinformatic analysis for variant calling, annotation, and prioritization. We also performed a segregation analysis in available family members to confirm the inheritance patterns and assessed the potential impact of the identified variants on protein function. RESULTS: From 34 patients enrolled in the study, 29 patients (85%) with previously undiagnosed genetic diseases, including 28 patients with PIDs and one patient with interstitial lung and liver disease, were identified. We identified two patients with severe combined immunodeficiency (SCID), patients with combined immunodeficiency (CID), six patients with combined immunodeficiency with syndromic features (CID-SF), four patients with defects in intrinsic and innate immunity, four patients with congenital defects of phagocyte function (CPDF), and six patients with the disease of immune dysregulation. Autoinflammatory disorders and predominantly antibody deficiency were diagnosed in one patient each. CONCLUSION: Our findings demonstrate the potential of WES in identifying undiagnosed PIDs in children with CAS. Implementing WES in the clinical evaluation of CAS patients with a warning sign for PIDs can aid in their timely diagnosis and potentially lead to improved patient care.

Incidence of acute kidney injury (AKI) and outcomes in COVID-19 patients with and without antiviral medications: A retrospective study.

BACKGROUND: Acute kidney injury is a complication of COVID-19 and is associated with severity. Despite no specific antiviral treatment strategy, lopinavir/ritonavir and remdesivir have been used. Data on the association between AKI and receiving antiviral agents with outcomes in hospitalized patients with COVID-19 is scarce. We aimed to determine the incidence of AKI and its outcomes in COVID-19 patients with and without antiviral medications. METHODS: We conducted a retrospective study on hospitalized adult patients with SARS-CoV-2 infection in a tertiary center. The primary endpoint was determining mortality, intensive care unit (ICU) admission, and length of hospitalization affected by AKI development using antiviral agents. The logistic regression method was used to explore the predictive effects of AKI and antiviral therapy on composite outcomes (i.e., mortality, ICU admission, and prolonged hospitalization) in four defined groups by AKI development/not and utilizing antivirals/not. We used IBM SPSS version 24.0 software for statistical analysis. RESULTS: Out of 833 COVID-19 patients who were included, 75 patients were treated with antiviral agents and developed AKI. There was a significant difference in the occurrence of AKI and using antiviral medications (p = 0.001). Also, the group using antiviral agents and the development of AKI had the highest rate of preexisting hypertension (p = 0.002). Of note, the group of patients who used antiviral agents and also developed AKI had the most remarkable association with our composite outcome (p<0.0001), especially ICU admission (OR = 15.22; 95% CI: 8.06-27.32). CONCLUSIONS: The presence of AKI among COVID-19 patients treated with antiviral agents is linked to increased severity and mortality. Therefore, it is imperative to explore preventive measures for AKI development in patients receiving antiviral therapy. Larger-scale randomized controlled trials may be warranted to provide a more comprehensive understanding of these associations.

The clinical application of ctDNA to predict response to neoadjuvant chemoradiotherapy in patients with locally-advanced rectal cancer.

Colorectal cancer is a major cause of cancer-related deaths worldwide. A third of colorectal cancers reside in the rectum. Many patients with rectal cancer present in the locally-advanced stage which needs multi-modality therapy usually starting with neoadjuvant chemo-radiotherapy followed by surgery and adjuvant systemic chemotherapy. Total neoadjuvant therapy, defined as the preoperative administration of both neoadjuvant chemoradiotherapy and systemic chemotherapy is also an evolving treatment that can be delivered if indications for preoperative chemotherapy exist. Identifying biomarkers to predict response to neoadjuvant therapy, can improve patient selection for a non-surgical, active surveillance approach. Circulating tumor DNA (ctDNA) can be detected in about 75% of patients with locally-advanced rectal cancer (LARC) at the baseline and in about 15-20% of patients in the post-neoadjuvant, or postoperative setting. ctDNA clearance rate after delivering neoadjuvant chemoradiotherapy, or integrating baseline ctDNA with other conventional markers of clinical response can be a promising marker to select and monitor patients on the "watch and wait" approach. In this article, we aimed to integrate the recent findings and provide a unique insight into the utilization of preoperative ctDNA to predict clinical response in patients with LARC. We also sought to highlight the potential areas for future research in this field. Further studies with a larger number of participants from diverse populations and settings are needed to increase external validity of such investigations and determine the role of ctDNA in guiding clinical decisions and management of patients with LARC.

Diagnostic Role of Circulating Endocan Levels in Obstructive Sleep Apnea: A Systematic Review and Meta-Analysis.

Endocan, as an endothelial cell damage marker, plays role in several cardiovascular and non-cardiovascular diseases. This systematic review and meta-analysis evaluates the role of endocan as a potential diagnostic or prognostic biomarker for obstructive sleep apnea (OSA). International databases including PubMed, Embase, Web of Science, and Scopus were searched for relevant studies assessing endocan levels in OSA patients compared with healthy controls or within different severities or comorbidities of OSA. Random-effect meta-analysis was performed in order to calculate the standardized mean difference (SMD) and 95% confidence interval (CI) of serum/plasma endocan in all comparisons. A total of 10 studies were included in our systematic review, among which seven were used in meta-analysis. Meta-analysis showed that endocan levels were significantly higher in patients with OSA compared with healthy controls (SMD 1.29, 95% CI 0.64-1.93, P < .001) and this was not different between serum and plasma subgroups. However, there was no statistical difference between severe and non-severe OSA patients (SMD .64, 95% CI -.22 to 1.50, P = .147). Considerably, higher endocan levels in patients with OSA in comparison with non-OSA individuals might have clinical implications. This association warrants further research due to its potential use as a diagnostic and prognostic biomarker.

Age and gender differences of basic electrocardiographic values and abnormalities in the general adult population; Tehran Cohort Study.

BACKGROUND: Although several studies are available regarding baseline Electrocardiographic (ECG) parameters and major and minor ECG abnormalities, there is considerable controversy regarding their age and gender differences in the literature. METHODS: Data from 7630 adults aged ≥ 35 from the Tehran Cohort Study registered between March 2016 and March 2019 were collected. Basic ECG parameters values and abnormalities related to arrhythmia, defined according to the American Heart Association definitions, were analyzed and compared between genders and four distinct age groups. The odds ratio of having any major ECG abnormality between men and women, stratified by age, was calculated. RESULTS: The average age was 53.6 (± 12.66), and women made up 54.2% (n = 4132) of subjects. The average heart rate (HR) was higher among women(p < 0.0001), while the average values of QRS duration, P wave duration, and RR intervals were higher among men(p < 0.0001). Major ECG abnormalities were observed in 2.9% of the study population (right bundle branch block, left bundle branch block, and Atrial Fibrillation were the most common) and were more prevalent among men compared to women but without statistical significance (3.1% vs. 2.7% p = 0.188). Moreover, minor abnormalities were observed in 25.9% of the study population and again were more prevalent among men (36.4% vs. 17% p < 0.001). The prevalence of major ECG abnormalities was significantly higher in participants older than 65. CONCLUSION: Major and minor ECG abnormalities were roughly more prevalent in male subjects. In both genders, the odds of having major ECG abnormalities surge with an increase in age.

Feature tracking cardiac magnetic resonance imaging to assess cardiac manifestations of systemic diseases.

Feature-tracking cardiac magnetic resonance (FT-CMR), with the ability to quantify myocardial deformation, has a unique role in the evaluation of subclinical myocardial abnormalities. This review aimed to evaluate the clinical use of cardiac FT-CMR-based myocardial strain in patients with various systemic diseases with cardiac involvement, such as hypertension, diabetes, cancer-therapy-related toxicities, amyloidosis, systemic scleroderma, myopathies, rheumatoid arthritis, thalassemia major, and coronavirus disease 2019 (COVID-19). We concluded that FT-CMR-derived strain can improve the accuracy of risk stratification and predict cardiac outcomes in patients with systemic diseases prior to symptomatic cardiac dysfunction. Furthermore, FT-CMR is particularly useful for patients with diseases or conditions which are associated with subtle myocardial dysfunction that may not be accurately detected with traditional methods. Compared to patients with cardiovascular diseases, patients with systemic diseases are less likely to undergo regular cardiovascular imaging to detect cardiac defects, whereas cardiac involvement in these patients can lead to major adverse outcomes; hence, the importance of cardiac imaging modalities might be underestimated in this group of patients. In this review, we gathered currently available data on the newly introduced role of FT-CMR in the diagnosis and prognosis of various systemic conditions. Further research is needed to define reference values and establish the role of this sensitive imaging modality, as a robust marker in predicting outcomes across a wide spectrum of patients.

7-year outcomes in diabetic patients after coronary artery bypass graft in a developing country.

BACKGROUND: Revascularization in diabetic patients with coronary artery disease remains a challenge in cardiology practice. Although clinical trials have reported the mid-term superiority of coronary artery bypass grafting (CABG) surgery over percutaneous coronary intervention in these patients, little is known about the long-term outcomes of CABG in diabetic patients compared to non-diabetics, particularly in developing countries. METHODS: Between 2007 and 2016, we recruited all patients who underwent isolated CABG in a tertiary care cardiovascular center in a developing country. The patients were followed at 3-6 months and 12 months after surgery, and then annually. The study endpoints were 7-year all-cause mortality and major adverse cardiac and cerebrovascular events (MACCE). RESULTS: Of 23,873 patients (17,529 males, mean age 65.67 years) who underwent CABG, 9227 (38.65%) patients were diagnosed with diabetes. After adjustment for potential confounders, patients with diabetes experienced a 31% increase in MACCE seven years after surgery compared to the non-diabetic patients (HR = 1.31, 95% CI: 1.25-1.38, P-value < 0.0001). Meanwhile, diabetes contributes to a 52% increase in the risk of all-cause mortality after CABG (HR = 1.52, 95% CI: 1.42-1.61, P-value < 0.0001). CONCLUSIONS: Our study showed a higher risk of all-cause mortality and MACCE at seven years in diabetic patients undergoing isolated CABG. The outcomes in the studied center in a developing country were comparable to western centers. The high incidence of adverse outcomes in the long term in diabetic patients implies that not only short-term but long-term measures should be taken to improve the CABG outcomes in this challenging patient population.

Coronavirus disease 2019 (COVID-19) in pediatric patients with autoimmune disorders.

Coronavirus disease 2019 (COVID-19) infection in pediatric patients with autoimmune disorders is an area of particular concern since autoimmune diseases can increase the risk of complications from the virus. However, as the infection rates were significantly higher in adults compared to children, this at-risk group of children was relatively underrepresented in COVID-19 research. The underlying inflammatory basis of autoimmune diseases and medications that affect the immune system, such as corticosteroids, could increase the risk of severe infection in this group of patients. COVID-19 could reportedly lead to a variety of alterations in the immune system. These alterations are plausibly dependent on the underlying immune-mediated diseases or prior use of immunomodulatory drugs. Patients administrating immunomodulatory agents, especially those with severe immune system dysregulation, can experience severe symptoms of COVID-19. Nonetheless, receiving immunosuppressive medications can benefit patients by preventing cytokine storm syndromes and lung tissue damage, threatening outcomes of COVID-19. CONCLUSION: In this review, we sought to evaluate the currently available literature on the impact of autoimmune disease and its related therapeutic approaches on the COVID-19 infection course of disease in children and reflect on the gaps in the evidence and the need for further research in this field. WHAT IS KNOWN: • The majority of children infected with COVID-19 demonstrate mild to moderate clinical manifestations compared to adults, whereas those children with pre-existing autoimmune conditions are at a greater risk for severe symptoms. •There is currently limited understanding of the pathophysiology and clinical outcomes of COVID-19 in pediatric patients with autoimmune disorders due to scattered reports and inadequate evidence. WHAT IS NEW: • Generally, children with autoimmune disorders have more unfavorable outcomes than healthy children; yet, the severity is not extreme, and is highly dependent on their autoimmune disease type and severity, as well as the medication they are taking.

The role of interleukins in pathogenesis and prognosis of atrial fibrillation.

INTRODUCTION: Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia. Moreover, it is mentioned as one of the important causes of death due to heart disease, which imposes an undeniable financial burden on public health systems. Almost 1 out of 4 individuals aged 40 to 55 will experience AF at some point during their life. Increasing the pressure or the volume of the atria over time leads to the activation of fibroblasts, resulting in the accumulation of extracellular matrix and fibrosis. By disturbing electrical conduction, fibrosis creates microreentrant circuits, which can develop into AF. AREAS COVERED: In this article, we evaluated the vital role of interleukins and inflammatory mediators in the pathogenesis, prognosis, and treatment of AF. We also discussed the importance of the broader use of interleukins in the clinical management of AF patients. EXPERT OPINION: Interleukins and inflammatory markers can be used as markers of diagnosis, cardiovascular events, and mortality in AF patients. Finally, the utilization of substances upregulating IL-10, such as resolvin D1 (RvD1), or applying IL-6 down-regulators and inhibitors, including anti-IL-6 antibodies, colchicine, and C1q/tumor necrosis factor-related protein-9 (CTRP9), are effective in the reduction of atrial interstitial fibrosis and treating AF patients.

Interleukins are mediators of the immune system, which play vital roles, directly or indirectly, in many immune responses and have a wide range of effects on the systems in the body. Similarly, these interleukins can have versatile roles in igniting or attenuating cardiovascular disorders. However, due to the complexity and variability of their effects on the cardiovascular system, research is still ongoing to capture a complete and realistic image of the role of interleukins in the development of cardiovascular disorders. Atrial fibrillation occurs following the irregular rhythm of the beat in the atria. Subsequently, the normal blood flow from the atria to the ventricles will be disturbed. Atrial fibrillation is the most common heart arrhythmia that might need medical care. However, the probability of severe atrial fibrillation outcomes or symptoms is higher in people with underlying comorbidities. This review investigates the role of interleukins in the occurrence of atrial fibrillation and its long-term complications. Atrial fibrillation usually begins as occasional brief episodes that start and stop spontaneously, but it can progress to more persistent forms that are associated with an increased risk of stroke and heart failure.. Interleukins and inflammatory mediators can enhance atrial fibrillation by worsening the conductance of the electrical signal and by boosting the fibrogenesis and structural remodeling of the atria. Currently, based on the role of interleukins in atrial fibrillation, therapeutic methods are being developed to prevent and attenuate its serious consequences. These therapeutic methods can impressively affect and improve the lives of millions of people suffering from this disorder. [Figure: see text].

Investigation of the female infertility risk associated with anti-cancer therapy.

Female infertility is a significant health issue worldwide with a rising incidence. Anti-cancer therapy is one of the most important reasons for increasing infertility. Although anti-cancer treatment increases the rate of survival, it decreases the quality of life through its side effects. The most substantial side effects are sexual dysfunction and infertility. Breast cancer is the most common cancer. The first-line treatment of breast cancer is chemotherapy by alkylating agents like cyclophosphamide, which leads to infertility. For instance, persistent chemotherapy-induced amenorrhea among breast cancer patients could affect almost half of the patients that undergo such therapy. However, some agents or therapeutic methods can ameliorate these intoxicating effects. Chemotherapy plus gonadotropin-releasing hormone agonist, in breast cancer patients, can not only improve overall survival but also reduce ovarian toxicity. Age plays an essential role in chemotherapy-induced amenorrhea. Chemotherapy at a younger age can reduce the risk of infertility. Gynecological cancers including uterine and ovarian cancer, which have high mortality rates, are the most related cancers to infertility. Surgery is the primary treatment of gynecological cancers. Studies demonstrated that fertility-sparing surgery is a better option than radical surgery. In addition, neoadjuvant chemotherapy is mostly a better option than primary cytoreductive surgery in terms of survival and fertility. Immune checkpoint inhibitors (ICIs) have recently played a major role in treating various cancer types. However, ICIs are associated with hypophysitis, which affects ovaries and can lead to infertility. There are some options for ovarian preservation such as embryo cryopreservation, oocyte cryopreservation, ovarian transposition, ovarian tissue cryopreservation, and ovarian suppression by GnRH agonists. Anti-müllerian hormone level can be utilized to monitor the ovarian reserve. Moreover, to avoid fertility loss, approaches such as using transplantation of human placenta mesenchymal stem cells, administrating anti-inflammatory agents and hormone therapy are under investigation.

Advances in pharmacotherapy for neuroblastoma.

INTRODUCTION: Neuroblastoma is the most prevalent cancer type diagnosed within the first year after birth and accounts for 15% of deaths from pediatric cancer. Despite the improvements in survival rates of patients with neuroblastoma, the incidence of the disease has increased over the last decade. Neuroblastoma tumor cells harbor a vast range of variable and heterogeneous histochemical and genetic alterations which calls for the need to administer individualized and targeted therapies to induce tumor regression in each patient. AREAS COVERED: This paper provides reviews the recent clinical trials which used chemotherapeutic and/or targeted agents as either monotherapies or in combination to improve the response rate in patients with neuroblastoma, and especially high-risk neuroblastoma. It also reviews some of the prominent preclinical studies which can provide the rationale for future clinical trials. EXPERT OPINION: Although some distinguished advances in pharmacotherapy have been made to improve the survival rate and reduce adverse events in patients with neuroblastoma, a more comprehensive understanding of the mechanisms of tumorigenesis, resistance to therapies or relapse, identifying biomarkers of response to each specific drug, and developing predictive preclinical models of the tumor can lead to further breakthroughs in the treatment of neuroblastoma.

Resistance mechanisms to programmed cell death protein 1 and programmed death ligand 1 inhibitors.

Introduction: In the past few years, administrating monoclonal humanized antibodies, namely checkpoint inhibitors, against programmed cell death protein 1 (PD-1), and its ligand (PD-L1), has yielded reassuring tumor regression rates. Anti-PD-1/PD-L1 checkpoint inhibitors disrupt the engagement of PD-1 on T-cells and their ligands on tumor or other target cells and reactivate the tumor-specific T infiltrating lymphocytes (TILs), which are mostly in a state of anergy before the PD-1/PD-L1 blockade. However, a limited number of patients initially respond, and the others show a primary (innate) resistance. Moreover, the rate of relapse and tumor progression after a partial, or even complete response (secondary or acquired resistance) is relatively considerable.Areas covered: This paper presents a comprehensive discussion on the mechanisms of primary and secondary resistance to PD-1/PD-L1 blockade. Loss of T-cell infiltration or T-cell exclusion, lack of PD-L1 or PD-1 expression, and also lack of tumor immunogenicity are among the most important mechanisms, and also biomarkers of resistance in patients undergoing PD-1/PD-L1 blockade. Several somatic mutations in tumors are known to be related to at least one of the resistance mechanisms.Expert opinion: Identification of the novel resistance mechanisms suggests further combinatorial therapies to tackle primary and secondary resistance to PD-1/PD-L1 blockade.

Immune checkpoint inhibition in classical hodgkin lymphoma.

Introduction: Hodgkin lymphoma (HL) accounts for 10% of lymphoma cases every year. HL is often curable by conventional chemotherapy and radiotherapy. However, in case of relapsed or refractory HL (r/r HL) after autologous hematopoietic stem cell transplantation (ASCT), few treatment options are currently available. Blockade of the immune checkpoint receptors, programmed death receptor-1 (PD-1), or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expressed on T-cells, and their ligands expressed on tumor-associated antigen-presenting cells (APCs), and Hodgkin and Reed/Sternberg (HRS) cells can remove inhibitory signals from anti-tumor T cells. Checkpoint blockade using monoclonal antibodies could be a potential treatment. Nivolumab and pembrolizumab are approved antibodies for the treatment of r/r HL.Areas covered: This paper provides a comprehensive discussion of checkpoint inhibitors in HL treatment, including the most important clinical trials with mono- or combination therapies as a first or second-line treatment of HL.Expert opinion: Relatively high response rates and an acceptable safety profile of checkpoint inhibitors make them an effective therapy for HL. The combination of checkpoint inhibition with other conventional cancer treatments and identifying the mechanisms responsible for resistance to checkpoint inhibition may improve the efficacy and safety of this immunotherapy, and enhance patient quality of life.

Immune checkpoint inhibition in COVID-19: risks and benefits.

INTRODUCTION: Immune checkpoint inhibition (ICI) is a novel cancer immunotherapy, which is administered in patients with metastatic, refractory, or relapsed solid cancer types. Since the initiation of the Coronavirus Disease 2019 (COVID-19) pandemic, many studies have reported a higher severity and mortality rate of COVID-19 among patients with cancer in general. AREAS COVERED: The immunomodulatory effects of ICI can modify the patients' immune system function in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. There is controversy over whether the severity of COVID-19 in cancer patients who previously received ICI compared to other patients with cancer has increased. There is evidence that the upregulation of immune checkpoint molecules in T cells, lymphopenia, and inflammatory cytokine secretion are associated with the severity of COVID-19 symptoms. EXPERT OPINION: ICI can interrupt the T cell exhaustion and depletion by interrupting the inhibitory signaling of checkpoint molecules in T cells, and augments the immune system response in COVID-19 patients with lymphopenia. However, ICI may also increase the risk of cytokine release syndrome. ICI can be considered not only as a cancer immunotherapy but also as immunotherapy in COVID-19. More studies are needed to assess the safety of ICI in COVID-19 patients with or without cancer.