In clinical practice, combined heart and liver dysfunctions coexist in the setting of the main heart and liver diseases because of complex cardiohepatic interactions. It is becoming increasingly crucial to identify these interactions between heart and liver in order to ensure an effective management of patients with heart or liver disease to provide an improvement in overall prognosis and therapy. In this review, we aim to summarize the cross-talk between heart and liver in the setting of the main pathologic conditions affecting these organs. Accordingly, we present the clinical manifestation, biochemical profiles, and histological findings of cardiogenic ischemic hepatitis and congestive hepatopathy due to acute and chronic heart failure, respectively. In addition, we discuss the main features of cardiac dysfunction in the setting of liver cirrhosis, nonalcoholic fatty liver disease, and those following liver transplantation. For many years, a mutual interaction between the heart and the liver has been established. Avicenna first pointed out the interactive effects between these two organs in his famous book titled as “Canon” (The Law). This interaction was described as dominance of the “heart warmth” over “liver coldness and wetness” and the dominance of “liver dryness” over “heart wetness”. According to traditional medicine, each organ is composed of four temperaments where the “wetness” and “dryness” are considered as a spectrum of “tissue moistures”,while “warmth” and “coldness” may be regarded as the basic metabolism of the organ. In normal condition, the heart’s temperament is “warm” and “dry” and the liver temperament is “warm” and “wet”. According to Avicenna, the presence of imbalancebetween the temperaments of human body describes the state of illness or organ disorder .Both heart and liver diseases are regarded as a seriousburden on health system and a leading cause of deterioration of quality of life and shortened life expectancy. In this review, we discuss the complex cardiohepatic interactions in the setting of the main heart and liver diseases.This review seeks to highlight how acute and chronic heart failure may lead to cardiogenic ischemic hepatitis and chronic congestive hepatopathy, respectively. In addition, this paper provides an overview on how chronic liver diseases including hepatic cirrhosis, nonalcoholic fatty liver disease (NAFLD), and conditions following liver transplantation (LT) may impair the cardiac performance and induce electrophysiological abnormalities in the absence of other cardiac disease. In each section, we discuss briefly the likely mechanisms underlying this association, clinical presentations, and diagnostic approaches.Congestive hepatopathy or chronic passive hepatic congestion refers to the congestion of liver parenchyma induced by impaired hepatic venous outflow secondary to a right-sided cardiac failure a.The underlying pathophysiological mechanisms include increased hepatic vein pressures, decreased hepatic blood flow, and decreased arterial oxygen saturation ,3. Main Congestive hepatopathy is usually subclinical. When symptomatic, patients may present with early satiety, malaise, mild jaundice, or intermittent right upper quadrant pain secondary to dilatation of the liver capsule. Physical examination is typically dominated by signs of cardiac failure including jugular vein distension, hepatojugular reflux, and peripheral edema. Spider angiomata, splenomegaly, and varices are rarely present ,7. The pPrimary laboratory finding in congestive hepatopathy is represented by mild hyperbilirubinemia, with a predominantly unconjugated fraction . ElevatiMild hypoalbuminemia and ascites may be present in patients with congestive hepatopathy. In these patients, the state of inadequate nutrition and hemodilution due to heart failure contributes substantially to the aggravation of hypoalbuminemia .Morphologically, congestive hepatopathy is associated with characteristic changes within the liver parenchyma ,13,14. ETreatment of congestive hepatopathy consists mainly of treating the underlying cardiac disease and improvement of cardiac output. Diuretics represent the main stay of pharmacological therapy. Unless contraindicated, angiotensin-converting enzyme (ACE) inhibitors and beta blockers are indicated in symptomatic congestive heart failure. A surgical approach may be indicated in the case of constrictive pericarditis, severe valvular heart disease, and ischemic cardiomyopathy ,18. For Cardiogenic ischemic hepatitis, known also as acute cardiogenic liver injury, is a clinical and histological syndrome characterized by a rapid and transient rise in serum transaminase levels due to acute fall in cardiac output leading to the reduction of hepatic blood flow  Figure b.Cardiogenic ischemic hepatitis has been estimated to emerge in 20–30% of patients with acute heart failure . The patAn acute cardiogenic liver injury is usually related to an acute coronary event, cardiac arrhythmia, or transient severe hypotension . FindingIn another report of patients with clinical and biochemical evidence of acute liver injury admitted to the coronary intensive care unit, the presence of acute liver injury has been shown to be associated with a decrease in hepatic blood flow and passive hepatic venous congestion . AdditioAcute cardiogenic hepatitis is usually asymptomatic. However, clinical signs may appear after a latency period of 2–24 h. Most commonly, patients exhibit symptoms resembling acute viral hepatitis such as weakness, apathy, and, in a minority of cases, mental confusion, flapping tremor, oliguria, jaundice, and hepatic coma ,27.The diagnostic approach of cardiogenic ischemic hepatitis is usually based on clinical presentation and laboratory finding. Non-invasive imaging as abdominal ultrasound can be supportive by showing signs liver congestion as dilation of the suprahepatic veins and inferior vena cava . PulmonaThe typical pattern in laboratory tests consists of rapid, transient rises in serum aminotransferase  and lactate dehydrogenase levels (LDH) with peak levels reaching between 10 and 20 times the upper limit of normal ,29.The ratio of serum ALT to lactate LDH less than 1.5 early in the course of liver injury is characteristic of cardiogenic injury . After cThe main histologic feature of acute cardiogenic ischemic hepatitis is characterized by hepatic necrosis around the central hepatic veins zone 3), a condition known as centrilobular necrosis. This zone has the poorest oxygen delivery, and will be most affected during a low hepatic blood flow , a condi.The management of cardiogenic ischemic hepatitis focuses on identifying and removing the precipitating cause. This may include medications with hypotensive or negative inotropic effects and other medications that likely may induce impairment of renal function.When needed, administration of oxygen and positive inotropic agents may help to restore an adequate organ perfusion .Cirrhotic cardiomyopathy (CCM) was first described in the late 1960s, although for many years, it was mistakenly presumed to result from a latent alcoholic cardiomyopathy . CCM repIn hepatic cirrhosis, portal hypertension results in splanchnic arterial vasodilation due to the release of potential liver-derived vasodilators factors such as carbon monoxide, nitric oxide, and prostacycline ,39. ThisPatients with liver cirrhosis present an impaired ventricular ejection of fraction under physical stress compared with non-cirrhotic subjects. This is mainly related to inadequate heart rate response and decreased myocardial contractility under exercise ,44.Alterations in β-adrenergic receptor function at the membrane of cardiac muscle cells have beenshown to be involved in the myocardial hyporesponsiveness of cirrhotic patients. It is well accepted that the long-term exposure of cardiomyocytes to high levels of noradrenalin usually present in cirrhosis due to enhanced sympathetic tone results in internalization, sequestration, and down regulation of β-adrenergic receptors on plasma membrane ,46.Experimental findings from animal models suggested that nitric oxide (NO) could play a negative inotropic effect in heart of cirrhotic rats . The actIn this context, arachidonoylethanolamide (AEA) or anandamide and 2-arachidonoylglycerol (2-AG) are the most widely studied endocannabinoids, exerting their effects via G protein-coupled cannabinoid receptors (CBRs). The activation of cannabinoid receptor type 1 (CB-1) has been shown to decrease the contractile response to β-adrenergic agonists. This cardiac adrenergic responsiveness was restored by blockage of CB-1 receptor . In addiAbnormalities of diastolic dysfunction are considered an early manifestation of CCM, and frequently precede the systolic dysfunction. Left ventricular diastolic dysfunction is characterized by a decrease in the rate and degree of left ventricular relaxation, together with presence elevated end-diastolic filling pressures . Unlike Liver cirrhosis was associated with changes in expression of collagen isoforms in ventricular heart tissue has been shown to be involved to correlate with diastolic dysfunction in cirrhosis. Ventricular cardiac tissue derived from cirrhotic rats showed an increased collagen type 1 content compared with sham animals, which subsequently contributes significantly to diastolic dysfunction by increasing the passive cardiac stiffness .A prolonged QT interval represents a common electrocardiographic finding in patients with cirrhosis and served as predictor of the increased risk of ventricular arrhythmia and/or sudden death . QT prolChronotropic incompetence is another consistent finding in CCM, and refers to the inability of the heart to increase adequately its rate to match the metabolic demands. Cardiovascular autonomic dysfunction has been suggested to play a role in enhancing chronotropic incompetence in patients with CCM .Considering the subclinical picture of CCM in the majority of patients, the diagnostic approach involves a combination of laboratory, clinical, electrocardiographic, and imaging evaluations. Electrocardiographic assessments may be helpful to identify cirrhotic patients with prolongations of QT interval and arrhythmias. Echocardiographic evaluation of the left ventricular systolic function usually shows a reduction of ventricular ejection of fraction at rest or under stress in response to catecholamine stimulation in the case of subtle systolic dysfunction. Diastolic impairment in CCM manifests mainly by reduced early (E) ventricular filling capacity and increased atrial (A) filling (E/A<1.0), in addition to prolongation of deceleration time (>200 ms) and isovolumetric relaxation time (ITVR > 80ms) .Biomarkers for cardiac dysfunction  might be elevated in early stages of CCM and usually reflect the severity of liver disease .CCM complicates several therapeutic approaches used in cirrhosis and heart failure. Although beta blockers are contraindicated in decompensated cirrhosis with ascites, these drugs have been shown to normalize the prolonged QT interval and might reduce the hyperdynamic load . ACE inhCardiovascular events and mainly heart failure represent a primary source of morbidity and mortality following LT. Heart failure may have an early-onset (within 30 days after transplantation) or in other cases may occur late (>30 days). In the postoperative period, heart failure may reach an overall incidence of 3.3% and may be associated with a mortality risk of 45%  Figure d.The cardiovascular stress due to surgery is considered a main contributor of early heart failure in liver transplanted patients. Takotsubo cardiomyopathy (TTC) or stress-induced cardiomyopathy represents a main cause of acute heart failure in the absence of coronary artery disease . TTC’s cSeveral pathophysiological mechanisms have been suggested to be involved in TTC. The exposure of myocardium to large concentrations of circulating catecholamines during LT makes the heart susceptible to adverse events including multivessel epicardial vasospasm . In addiIntraoperative triggers for TTC during liver transplantation surgery include cardiovascular stress, such uncontrolled bleeding, massive transfusions, and administration of high rates of vasoactive agents .Stress-induced cardiomyopathy is still an underestimated cause of acute heart failure in liver transplanted patients. Beside the exclusion of coronary disease, the diagnostic approach should involve the combination of clinical aspects to electrocardiographic and echocardiographic findings. Multiple studies have evaluated the risk factors for late cardiac events following LT. The severity of liver disease as quantified by Model of End Stage Liver Disease (MELD) score has been shown to be associated with adverse cardiac events following LT . This waIn addition to older age and male sex, several components of the metabolic syndrome factors including hypertension, hyperglycemia, dyslipidemia, and visceral obesity have been shown to be predictive for heart failure following LT ,78.In thHemodynamically stable patients are often treated with diuretics, ACE inhibitors, and beta blockers. Treatment with calcium channel blockers and fluid resuscitation is usually indicated for patients with severe left ventricular outflow tract obstruction and hemodynamic compromise. Inotropic agents can be administered only in absence of moderate or severe left ventricular outflow tract obstruction. In presence of TTC with thromboembolism, anticoagulation should be continued for at least three months .NAFLD encompasses a pathological condition characterized by ectopic deposition of adipose tissue in the liver, in the absence of secondary causes for hepatic fat accumulation, such as excessive alcohol intake, steatogenic drugs, and hereditary disorders . This te2) and in 85% of patients with morbid obesity (BMI = 40–59 kg/m2)  = 30–39.9 kg/m9 kg/m2) . There i9 kg/m2) . Accordi9 kg/m2) .The most common cardiac complications associated with NAFLD include coronary artery disease, and structural myocardial alterations in addition to cardiac arrhythmias. An increasing number of studies have addressed a link between coronary heart disease and NAFLD independently of traditional cardiovascular risk factors . PatientMoreover, the coronary microvascular and endothelial function assessed by the measurement of coronary flow reserve (CFR) has been shown to be impaired in patients with NAFLD compared with healthy subjects .Moreover, subjects with NAFLD have been shown to have common features of left ventricular diastolic dysfunction, which represents a key contributor to the development of heart failure . SimilarCardiac rhythm disturbances are also linked to NAFLD, probably due to an induction of cardiac autonomic dysfunction. Several arrhythmias are found in association with NAFLD such as atrial fibrillation, QT prolongation, and ventricular arrhythmias, which can predispose these patients to sudden cardiac death .The precise mechanisms linking NAFLD with cardiac complications are poorly understood. However, several pathophysiological mechanisms have been postulated to be involved such as insulin resistance, visceral adiposity, subclinical inflammation, dyslipidemia, and oxidative stress e 96]..96].NAFLD patients tend to present whole-body as well as hepatic insulin resistance, inducing disturbances in the transport of free fatty acids, thus leading to visceral and ectopic fat accumulation. Due to the increased lipogenesis, the lipid profile in these subjects consists in increased levels of triglyceride, low-density lipoprotein cholesterol (LDL-C), and very low-density lipoprotein cholesterol (VLDL-C), which are consequently linked to increased cardiovascular risks ,98.NAFLD is considered a chronic subclinical inflammatory condition through secreting proinflammatory cytokines and chemokines by both hepatocytes and by non-parenchymal cells such as stellate cells and Kupffer cells . SeveralIn addition to the role of abdominal obesity, which usually occurs in NAFLD, ectopic fat accumulation in other districts  leads to adipocytes dysfunction with consequent imbalance of pro- and anti-inflammatory cytokinesoriginating from adipose tissue termed adipokines ,102. In Oxidative stress appears to play a key role in promoting the progression from simple steatosis to NASH and increasing the cardiometabolic risk in NAFLD patients . It arisA high production of prothrombotic factors, mainly factors VII, IX, XI and XII, has been shown to be linked to NAFLD  and therIn recent years, novel hepatic tissue-specific molecules known as hepatokines have been described to determine cardiovascular effects. Fibroblast growth factor 21 (FGF-21) is a peptide predominantly produced and secreted by the liver and correlates with hepatic fat content and the severity of NAFLD . ElevateGiven the rapidly growing global burden of NAFLD and limitations of performing liver biopsy due to interobserver variability and procedure-related morbidity and mortality, recent recommendations suggested several noninvasive markers of fibrosis and steatosis . The NAFThe main clinical recommendations for the management of NAFLD include lifestyle modifications through a combination of physical activity, smoking cessation, appropriate dietary changes, and gradual weight loss. This approach has demonstrated to be an effective tool to improve the cardiovascular risk profile in NAFLD patients.Moreover, current guidelines recommend careful clinical screening and treatment for associated cardiometabolic risk factors including obesity, diabetes mellitus, dyslipidemia, and hypertension in all individuals with NAFLD. Bariatric surgery represents a recommended choice for morbidly obese individualsif lifestyle modifications and pharmacological approach have not yielded long-term success. It provides cardiovascular benefits in terms of reducing overall mortality by improving hepatic inflammation, metabolic syndrome components, and cardiac morphology ,117.Increasing evidence suggests that the heart synthesizes and secretes proteins referred to as cardiokines, which are involved in the inter-cellular and inter-organ communication . More thIt has been reported that cardiokinesnot only have local involvement in the stress response and damage repair, but also mediate several regulatory effects on extra-cardiac tissues . In the NOD-like receptor protein 3 (NLRP3) inflammasomeis the most widely studied inflammasome in myocardial tissue. It consists of a multi-protein signaling platform that acts as an intracellular innate immune sensor and its activation induces the transcription, maturation, and release of proinflammatory cytokines, in particular IL-1β and IL-18. In heart failure, three main triggers contribute to the activation of NLRP3 inflammasome components: adenosine triphosphate (ATP), mitochondrial DNA (mtDNA), and reactive oxygen species (ROS) . DespiteOlson’s group reported that the heart controls systemic energy metabolism, fat mass, and body weight via the heart specific microRNA-208a (miR-208a) and Mediator complex subunit 13 (MED13) signaling in rodent cardiomyocytes . MiR-208The co-existence of bidirectional communication was also confirmed in patients with heart failure . ImpaireIn this review paper, we highlight how acute and chronic heart failure may lead to acute hepatic injury and chronic congestive hepatopathy, clinical conditions that are often accompanied by specific clinical and laboratory manifestations. On the other hand, subjects with liver diseases, mainly hepatic cirrhosis and NAFLD, or those undergoing LT can develop heart systolic and diastolic dysfunctions in addition to electrophysiological cardiac abnormalities. In this regard, a better knowledge of the cardiohepatic interactions constitutes a key issuefor the management of cardiac and hepatic dysfunctions.Although still challenging, especially in multi-morbid patients, the early recognition of clinical signs and symptoms of simultaneous heart and liver injury has led to important benefits in terms of reduction of morbidity and mortality. This requires the involvement of a multidisciplinary approach to patients in order to manage the patients at early disease stages. Future research will unravel the molecular mechanisms implicated in the cardiohepatic interactions to further improve the diagnosis and therapy of these disturbances.


Viral diseases account for an increasing proportion of deaths worldwide. Viruses maneuver host cell machinery in an attempt to subvert the intracellular environment favorable for their replication. The mitochondrial network is highly susceptible to physiological and environmental insults, including viral infections. Viruses affect mitochondrial functions and impact mitochondrial metabolism, and innate immune signaling. Resurgence of host-virus interactions in recent literature emphasizes the key role of mitochondria and host metabolism on viral life processes. Mitochondrial dysfunction leads to damage of mitochondria that generate toxic compounds, importantly mitochondrial DNA, inducing systemic toxicity, leading to damage of multiple organs in the body. Mitochondrial dynamics and mitophagy are essential for the maintenance of mitochondrial quality control and homeostasis. Therefore, metabolic antagonists may be essential to gain a better understanding of viral diseases and develop effective antiviral therapeutics. This review briefly discusses how viruses exploit mitochondrial dynamics for virus proliferation and induce associated diseases. Mitochondria are intracellular organelles that are considered as the powerhouse of the cell. They comprise an outer membrane, an inner membrane and a matrix. The highly complex metabolic process of conversion of carbohydrates and fatty acids to adenosine triphosphate (ATP) occurs in mitochondria. During cellular stress, mitochondria rapidly increase energy production . MitochoViruses are obligate parasites that completely depend on host cell machinery for their replication and proliferation. They hijack host cell metabolism and cause substantial alterations in cellular and physiological functions . The rolIn this review, we discuss the importance of mitochondrial bioenergetics during specific viral infections and the impact on virus-induced mitochondrial dysfunction, leading to changes in innate immune responses. While there are common pathways that are affected during viral infections, such as inflammasome activation, we have separated individual viruses, as the observed changes in each virus may be distinct.Mitochondrial biogenesis is a complex process that involves coordination of both nuclear and mitochondrial genes to ensure precise function of proteins of the mitochondrial electron transport chain. Mitochondria are highly dynamic, but they cannot be generated de novo. Every mitochondrion consists of a porous outer membrane; the intermembranous space; an inner membrane where the electron transport chain (ETC) occurs; and a mitochondrial matrix, the main site for metabolic pathways such as the TCA cycle and fatty acid oxidation (FAO). Human mtDNA is a double-stranded, circular DNA molecule consisting of 16,569 base pairs . The mitMitochondrial homeostasis is maintained predominantly by mitochondrial dynamics and mitophagy , as depiViruses cause changes in mitochondrial function to promote viral translation and assembly. One theory is that virus–mitochondria interactions hamper mitochondria-associated antiviral signaling mechanisms . In hepaMitochondria originated from symbiotic bacteria but co-evolved with their host as most of the mitochondrial proteins are encoded by the nucleus. However, the mitochondrial genome encodes proteins critical for respiration. Mitochondria play a central role in cellular metabolism as key pathways such as TCA, FAO, oxidative phosphorylation (OXPHOS), calcium buffering, and heme biosynthesis occur in mitochondria . It is wEnzymes involved in metabolism are being extensively investigated due to similarities with immune regulators. Methylcrotonyl-CoA carboxylase 1 has been shown to be associated with TRAF6 and enhances MAVS signaling in order to induce antiviral type I IFN (interferon) secretion . Type 1 Mitochondrial structure and function can affect innate immune responses. The most direct effect of mitochondria on immune response is due to mitochondrial damage while it can also occur as a result of normal mitochondrial physiology and function. The innate immune system specifically recognizes pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) as alarmins in order to trigger the appropriate immune response . The relViral genomes usually replicate in the host cell cytoplasm, where they are not recognized by TLRs such as TLR3, TLR7 or TLR8 due to TLR localization to endosomes . HoweverMAVS is required to localize to the mitochondria to exert its function, indicating that the mitochondrial environment is essential for signal transduction . MAVS-deViruses impede mitochondrial biogenesis, causing alterations in mitochondrial function in order to promote viral translation and assembly. One theory is that virus–mitochondria interactions hamper mitochondria-associated antiviral signaling mechanisms ,91. The A novel severe acute respiratory syndrome-related coronavirus (SARS-CoV-2) has recently emerged as a serious pathogen that causes high morbidity and substantial mortality. It is causing a global pandemic and worldwide social and economic disruption. Patients with severe SARS-CoV-2 infection develop dyspnea that can rapidly manifest as acute respiratory distress syndrome, leading to death ,99,100. Human respiratory syncytial virus (RSV) of the Paramyxoviridae family is a single-stranded, negative-sense RNA virus that causes serious respiratory complications especially in infants and the older adults worldwide ,112. QuaInfluenza virus is a respiratory pathogen that causes contagious respiratory illness known as influenza or flu, which accounts for millions of deaths worldwide. The three main types of influenza virus that cause disease in humans are A, B, and C, which are classified based on antigenic differences in matrix and nucleoproteins . Once inHepatitis C virus (HCV) is a positive-strand RNA virus of family Flaviviridae. During infection, HCV proteins localize to mitochondrial membranes, induce ER stress and cause depletion of ER calcium stores, leading to mitochondrial dysfunction ,124. TheHepatitis B virus (HBV) belongs to the family Hepadnaviridae and its genome consists of a partially double-stranded circular DNA that replicates via an RNA intermediate. HBx, a regulatory protein of HBV, is associated with VDAC, localizes to mitochondrial membranes and affects the membrane potential, inducing remarkably high levels of calcium and ROS, leading to mitochondrial dysfunction . This HBMeasles virus consists of a negative-sense RNA genome that causes highly contagious respiratory sickness including pneumonia, seizures, brain damage, and even death. The attenuated measles virus of the Edmonston strain (MV-Edm) activates p62-mediated mitophagy in non-small-cell lung cancer (NSCLC) cells by disrupting MAVS and resulting in the significant inhibition of type I IFN responses . It utilDespite the exhilarating scientific advances in recent times that have identified many important metabolic pathways that might be targets in order to enhance immune responses, there continue to be new and exciting questions. Various aspects of mitochondrial dynamics, including mitophagy, have been of great interest, with recent studies showing that viruses circumvent host innate immune responses through altering mitochondrial functions. Viral infections induce metabolic re-programming, resulting in discrete bioenergetic phenotypes, strategically utilizing them for viral propagation and replication. Viruses exploit RIG-I-MDA5-MAVS antiviral signaling pathways and aim at disrupting mitochondrial membrane potential, mitochondrial-associated proteins and mitochondrial dynamics that essentially impede virus-induced type I IFN responses. Undeniably, there exists an intimate association between mitochondrial dynamics and viral infections. However, more comprehensive mechanistic studies and their significance to chronic pathology are necessary in understanding complex viral life cycle processes. A deeper understanding of tightly regulated mitochondrial functions such as bioenergetics, innate antiviral immunity, apoptosis, and inter-organelle cross-talk needs to be extensively investigated to analyze their effect on viral infections. The ultimate goal of identifying mechanisms, which may differ with individual viruses, may provide important information for targeted therapeutic interventions to redirect the immune response toward a less pathogenic response.


Exercise is an effective intervention for both the prevention and the treatment of obesity and insulin resistance because skeletal muscle secretes many bioactive proteins that contribute to the beneficial effect of exercise. It has been revealed that irisin plays an important role in metabolic homeostasis and both acute and chronic exercises increase circulating irisin in experimental animal models and in humans. Although previous studies have reported that the irisin-related signaling mechanism may play a beneficial role in the treatment of metabolic diseases including obesity, metabolic syndrome, insulin resistance, and diabetes mellitus, studies on whether irisin plays a key role in vascular function and vascular complications are still insufficient. Therefore, the current review aims to summarize the accumulating evidence showing the potential role of irisin, especially in vascular reactivity and vascular abnormalities such as atherosclerosis. Exercise is an effective intervention for both the prevention and the treatment of obesity and insulin resistance because skeletal muscle secretes many bioactive proteins that contribute to the beneficial effect of exercise ,2,3. ExeAlthough previous studies have reported that the irisin-related signaling mechanism plays a positive role in the treatment of metabolic diseases, CVD, and cerebral ischemia, studies on whether irisin plays a pivotal role in vascular function and vascular diseases are still scarce. Therefore, the focus of this review is to provide a comprehensive overview of studies concerning the potential role of irisin in vascular reactivity and atherosclerosis .Initially, irisin has been suggested as a protective exercise-induced hormone against diet-induced obesity, mediated by browning of subcutaneous WAT and thus increased thermogenesis . SubsequIn addition, it is reported that circulating irisin levels are also changed by liver disease. Polyzos et al. showed that serum irisin was higher in lean controls than in non-alcoholic fatty liver and non-alcoholic steatohepatitis patients . AnotherThese discrepant findings imply that the level of circulating irisin is dependent on several factors including the pathological condition, types of disease, production of irisin from skeletal muscles and adipose tissues, and disappearance in circulation. More detailed studies are needed to further understand the effect of the disease condition on the concentration of circulating irisin. Vascular dysfunction is a hallmark that is associated with atherosclerosis and occurs in chronic diseases including dyslipidemia, diabetes mellitus, hypertension, cerebrovascular diseases, CAD, and heart failure . Irisin Jiang et al. investigated the vasorelaxant effects of irisin on endothelium-dependent and -independent pathways using endothelium-intact and -denuded arteries in myography experiments ex vivo . They reOther research teams also investigated whether exogenous irisin treatment improved vascular function in aortas from experimental mouse models. For instance, Zhu et al. reported that exogenous administration of irisin  for 2 weeks improved acetylcholine (ACh)-induced endothelium-dependent relaxation which was diminished by 8 weeks by high fat diet-induced T2D in the mouse aorta ex vivo . Han et Several studies have also suggested that irisin treatment reduced the degree of carotid and aortic atherosclerotic plaque in apolipoprotein E-knock out mice, an atherosclerotic model ,51,52. TIt seems that irisin has beneficial effects on metabolic diseases such as obesity, insulin resistance, and T2D. Some animal studies have shown that exercise-induced irisin increases brain-derived neurotrophic factor which is linked to cognitive function and that exogenous administration of recombinant irisin increases cortical bone mass ,56. TakeAn important question from this review was whether irisin directly causes vasodilation or vasoconstriction in macro- and micro-vasculatures, and if so, what mechanisms are involved in the regulation of vascular activity. Several studies by different research groups have shown that irisin causes vasorelaxation in a dose-dependent manner through both endothelium-dependent and -independent mechanisms ,46. HoweTaken together, irisin might be a useful agent for treating abnormal vascular function such as hypertension and atherosclerosis. However, more detailed mechanistic studies and in vivo studies are necessary to establish the efficacy of irisin for treating vascular complications and atherosclerosis.


Organoids derived from human pluripotent stem cells (hPSCs) have emerged as important models for investigating human-specific aspects of development and disease. Here we discuss hPSC-derived organoids through the lens of development—highlighting how stages of human development align with the development of hPSC-derived organoids in the tissue culture dish. Using hPSC-derived lung and intestinal organoids as examples, we discuss the value and application of such systems for understanding human biology, as well as strategies for enhancing organoid complexity and maturity. During development, a small aggregate of pluripotent cells in the embryo are guided through a series of cell fate decisions to generate the incredible diversity of cell types required for human life. Along the way, multiple specialized cell types organize into complex 3D structures to build organs, which perform essential physiological tasks such as respiration in the lungs, nutrient absorption in the gut, and filtering of blood in the kidneys. For centuries, scientists have worked to understand the process of development and to identify the cellular and molecular cues that guide cells to generate a particular organ. Now, scientists are applying this knowledge to recapitulate development in a cell culture dish, guiding cells to organize into complex 3D models of human organ-like form and function, structures known as organoids.Organoids permit scientific investigation of human development, physiology, and disease at a scale and level of precision not previously possible. Traditionally, scientists have relied on a combination of animal models and human 2D cell culture models to investigate human biology. While these approaches have led to innumerable important discoveries, animal models and 2D cell culture models are not without their shortcomings. Animal models are complex, making it difficult to discern cause and effect for many experiments, provide limiting amounts of tissue for analysis, and by their nature are imperfect models of human physiology. Traditional human 2D cell culture models on the other hand are often too simple, containing a single cell type attached to the culture dish as a monolayer, or floating as single cells in suspension culture. Moreover, 2D cell culture models are typically derived from cancer or induced to a cancer-like state using viral oncogenes, permitting indefinite propagation of these models in vitro, but also leading to genomic instability that makes these models become less like the cell types they are derived from–3. In thMethods to establish primary organoids from many different human organs have been published, including the intestine , pancreaOrganoids can be established from healthy or diseased patient tissue and have numerous basic and translational applications including disease modeling, personalized medicine, and for the development of therapeutics. For instance, using material derived from patients organoid models of cystic fibrosis –20, polyWhile patient-derived organoids are commonly employed for in vitro modelling of human organ physiology, limited access to some patients and genetic diversity within the human population make patient-derived organoids less suitable for some studies. This has enhanced interest in the establishment of methods to generate organoids from human pluripotent stem cells (hPSCs), which are renewable, widely available, and are maintained under highly standardized culture conditions , 31. In Here we will provide an overview of the generation of hPSC-derived organoids, highlighting the contribution of developmental biology to understanding the physical and molecular cues that guide the development of cells in the culture dish. We will focus on directed differentiation of hPSCs towards definitive endoderm, en route to making hPSC-derived lung organoids (HLOs) and hPSC-derived intestinal organoids (HIOs). We discuss strategies to drive organoid maturation and to circumvent current limitations to organoid complexity. Finally, we discuss current and potential applications well suited to hPSC-derived organoids.To generate organoids, researchers harness the developmental potential of hPSCs, which have the capacity to differentiate into any cell type in the human body—a property known as pluripotency. hPSCs are established by isolating pluripotent embryonic stem cells from early human embryos , or by i-β signaling in vitro, hPSCs can be reproducibly differentiated towards a specific germ layer  axis. This leads to patterning of the endoderm into an anterior foregut domain, which gives rise to the thyroid, esophagus, trachea and lung, a posterior foregut domain giving rise to the stomach, liver and pancreas, a midgut domain which generates digestive portions of the intestine, and a hindgut domain giving rise to the remaining portions of the intestine including the majority of the colon Fig. . In relaThe response of hPSC-derived endoderm to cell signaling pathways in vitro is similar to that of endoderm undergoing development in vivo with respect to both inducing regional anterior posterior identity and to recapitulating aspects of gut tube morphogenesis. Studies from animal models point to a conserved signaling network involving WNT, FGF, and BMP signaling responsible for patterning regional identity in the vertebrate endoderm . In geneRemarkably, stimulation of FGF and WNT signaling in vitro is sufficient for both foregut and hindgut patterned hPSC-derived endoderm to engage morphogenic processes akin to the formation of the primitive gut tube in vivo, forming aggregates of epithelial progenitors and mesenchyme precursors that bud up from the culture dish and pinch off to form 3D spheroids , 64, 69.After patterning hPSC-derived endoderm towards a specific region along the anterior posterior axis and transitioning to 3D growth in extracellular matrix, cell fate is further refined to generate progenitors for specific organs, a step that is required for long-term growth.Methods to induce and maintain tissue-specific progenitors have relied on conserved transcription factors that are known to mark specific progenitor populations, such as NKX2.1 in lung epithelial progenitors and CDX2 in intestinal epithelial progenitors. These markers are useful to screen for conditions that enhance marker expression, signifying a more efficient and targeted differentiation towards a particular fate. This approach has identified Hedgehog, WNT, FGF, Retinoic acid (RA), and TGF-β signaling pathways as pathways that can be stimulated in culture to further differentiate foregut endoderm into lung progenitors , 62, 70 In directed differentiation protocols where 3D structures do not form naturally, regionalized endoderm is further differentiated towards specific progenitors in 2D culture which are then purified and embedded as single cells in extracellular matrix to facilitate self-organization and expansion into 3D structures. This approach has been utilized in the generation of various types of lung organoids , 63, 66.After progenitor cells are specified, nascent organoids are shifted from progenitor-inducing media to progenitor expansion and maintenance media, leading to continued organoid growth that mirrors aspects of organ development in vivo. For example, HIOs under maintenance conditions undergo an initial 2-week period of intestinal progenitor expansion, followed by the emergence of intestinal epithelial cell types, such as enterocytes and Goblet cells and LGR5+ intestinal stem cells , 69. ConMethods to generate hPSC-derived HLOs are more varied than those to generate HIOs. This may either reflect a fundamental difference in lung and intestinal progenitor cell specification, or may simply reflect preference for a particular protocol/method. HLOs share many aspects with fetal lung development as they expand in culture. HLOs maintained in conditions of high FGF signaling give rise first to NKX2.1+/SOX2+/SOX9+ epithelial cells, reminiscent of early lung progenitors . Alterna. Likewise, differentiation of alveolar type II cells from hPSC-derived lung endoderm is promoted by glucocorticoid and WNT signaling pathways, which have also been implicated in promoting alveolar cell fate specification in murine lung development [s exciting flexibility to model transitions between lung progenitor cell states in vitro using HLOs [Alternative to the methods described above, in which progenitor cells undergo expansion accompanied by stochastic differentiation, HLOs enriched for populations of specific lung epithelial progenitor cell types can also be generated. For example, conditions promoting long-term maintenance of nearly pure populations of lung epithelial progenitors, called bud-tip organoids (BTOs) have been established . Notablyelopment –82. The ing HLOs .A variety of approaches exist to drive maturation of organoids, which typically describe further patterning of organoids into domains of differentiated and progenitor cells, an increased proportion of differentiated cells, and increased functionality in differentiated cells. The simplest approach is to allow time for the organoids to mature; organoids exhibit an inherent capacity to mature and if left undisturbed in culture and typically increase in cellular diversity and continue to emulate features of early fetal organogenesis over time. However, this capacity is limited, as organoids cultured for multiple months still exhibit transcriptional and proteomic profiles consistent with fetal tissue rather than adult tissue. In addition, as organoids increase in size and complexity, issues such as nutrient and oxygen availability arise and can lead to necrosis in the organoid core.Intriguingly, transplantation of organoids into amenable sites in a mouse host results in maturation far beyond those of organoids cultured in vitro , 83–86. Undoubtedly, the in vivo environment presents chemical cues whose organoid maturing effects have yet to be recognized. Thus, there is likely much work to be done on refining culture conditions to promote maturation of hPSC-derived organoids. Indeed, even in the case of adult stem-derived organoids, refinement of the composition of organoid maintenance media greatly increases cellular diversity . In addiFinally, great interest exists in the development of bioengineered approaches that attempt to recapitulate physical and other forces acting as maturation cues during development that are not easily translated to the tissue culture dish. For instance, mechanical forces such as tension and extracellular matrix stiffness have long been appreciated as important cues for cellular differentiation and behavior . While MHeavily influenced by our understanding of forces that guide organ maturation during development, the above approaches offer promising avenues to mature hPSC-derived organoids in vitro. Moreover, recapitulation of organ maturation in the culture dish is by its very essence a reductive approach, promising exciting insights into human development and mechanisms of human disease.E.coli leads to enterocyte maturation in HIOs, suggesting microbe colonization can act as a maturing force in hPSC-derived organoids [Although much work remains to improve the complexity and reproducibility of hPSC-derived organoid cultures, hPSC-derived organoids have the potential to provide insight into important areas of medical research, including genetic disease, host-microbe interactions, emerging viral infections, and pre-term infant care. For example, HIOs have been applied to model the contribution of the microbiome to fetal development and human disease by infection with commensal or pathogenic microorganisms –103. Intrganoids . HLOs harganoids , 105. Ofrganoids , 107, suIn addition, hPSCs are amenable to genome engineering and provide an opportunity to derive iPSC lines from patients carrying disease-associated mutations, making hPSC-derived organoids particularly well suited for modeling genetic disease. iPSC lines derived from patients have been shown to recapitulate pathologic phenotypes in retinal , lung 2, 66, 78,hPSC-derived organoids are particularly applicable to modeling diseases associated with pre-term birth since they resemble developing fetal tissue , 37, 84.HIOs also present opportunities for application to pre-term or low birthweight-associated disease. In particular, a major issue for pre-term infants is nutrient delivery. In utero, nutrient delivery occurs through the placenta. In the neo-natal intensive care unit, doctors must choose between delivering nutrients parenterally , a highly invasive procedure leading to numerous complications, or enterally, which has high risk for the development of necrotizing enterocolitis (NEC). NEC is thought to arise due to a confluence of factors including epithelial barrier dysfunction in the immature fetal GI tract, likely mediated by microbial colonization, premature feeding, and associated inflammation , 117. MehPSC-derived organoids hold great potential for investigating human specific aspects of development and disease. In their current form, hPSC-derived organoids are excellent models of early fetal development, presenting opportunities to model congenital disease and to improve pre-term neonatology. Efforts are currently underway to increase the complexity and maturity of hPSC-derived organoids, with the eventual goal of using hPSC-derived organoids to model all stages of organ development, from fetal, through adulthood, and in aging. Achievement of this goal will have profound impact on human health, but in order to realize this great promise, important challenges will need to be addressed.A long-standing challenge for the field remains the standardization of hPSCs from different sources and across different laboratories. For the purposes of this review, we referred to pluripotent stem cells derived from embryos (ESCs) and patients (iPSCs) collectively as hPSCs; however, fundamental differences exist between ESCs and iPSCs, including their differentiation and tumorigenic potential. Epigenetic memory of the cell type of origin has been proposed to partially account for differences in differentiation potential among iPSC lines , 121, whAdditionally, because hPSC-derived organoids begin life as pluripotent cells, a unique challenge to application of hPSC-derived organoids is the presence of contaminating cell types in some differentiation protocols. These cells can be either incorrectly specified as the result of sub-optimal differentiation conditions or the result of cells failing to maintain lineage commitment, a result likely reflective of sub-optimal organoid maintenance conditions. As mentioned previously, having sub-pure mixed cultures are advantageous, permitting the co-derivation of mesenchyme and epithelium to generate organoids consisting of multiple germ layers. In other cases, cell types from different organs may be mixed to an extent that makes experimental interpretation meaningless in relation to human physiology. Thus, although there has been much progress made in recent years, particularly with the application of single-cell technologies to refine differentiation protocols, there is still much room for improvement.-derived organoids. While insights from the development of model organisms will undoubtably provide important context, as hPSC-derived organoids become more similar to the in vivo organs they model, uniquely human aspects of organ development and physiology will become apparent. Thus, benchmarking hPSC-derived organoids against both fetal and adult human tissue is a necessary step to ensure the accuracy of organoid systems [Another persistent challenge will be access to tissue necessary to benchmark in vitro systems , 40–45. It is remarkable how far hPSC-derived organoids have come in the approximately 20 years since the derivation of the first human pluripotent stem cell line : from es


Women with alcohol use disorder (AUD) experience more barriers to AUD treatment and are less likely to access treatment than men with AUD. A literature review identified several barriers to women seeking help: low perception of a need for treatment; guilt and shame; co-occurring disorders; employment, economic, and health insurance disparities; childcare responsibilities; and fear of child protective services. Women entering treatment present with more severe AUD and more complex psychological, social, and service needs than men. Treatment program elements that may reduce barriers to AUD treatment include provision of childcare, prenatal care, treatment for co-occurring psychological problems, and supplemental social services. Research has suggested that outcomes for women are best when treatment is provided in women-only programs that include female-specific content. To date, research on treatments tailored to the individual needs of women is limited, but research on mechanisms of change has suggested the importance of targeting anxiety and depression, affiliative statements in treatment, abstinence self-efficacy, coping skills, autonomy, and social support for abstinence. Future research should focus on early interventions, linkages between primary care or mental health clinics and AUD treatment settings, and integrated treatments for co-occurring AUD and other disorders. Further research should also explore novel treatment delivery approaches such as digital platforms and peer support groups. Historically, women with alcohol use disorder (AUD) have been an underserved population. In the United States, more than 5 million adult women, or 4.2% of the adult female population, meet criteria for current AUD.4® using the search terms “women,” “alcohol,” and “treatment,” and articles identified through selective reviews to identify key publications on trauma-informed treatment and substance use disorder (SUD) in female veterans.A smaller proportion of women than men received AUD treatment both in the past yearWomen seeking AUD treatment differ from men in their sociodemographic characteristics and psychological profiles. They experience some unique barriers to accessing treatment and present to treatment with some needs that differ from men in AUD treatment.Women seeking AUD treatment vary along a number of dimensions that may impact their access to treatment, treatment needs, and treatment response.Women who present to AUD treatment often have markedly different characteristics and backgrounds than men in these treatment settings. Such distinctions among women include younger age, more severe alcohol and drug use histories, less education, lower income, higher unemployment, more housing needs, more children living at home, and higher parental stress.8Compared to men, women who enter AUD/SUD treatment generally report higher levels of physical and mental health concerns. Rates of co-occurring disorders vary with the treatment setting and population. Epidemiologic data suggest that compared with men with AUD, women with AUD have a higher prevalence of co-occurring DSM-IV Axis I disorders (84.2% vs. 75.5%), a similar prevalence of other drug dependence (15.2% vs. 14.3%), a higher prevalence of mood and anxiety disorders , and a similar prevalence of personality disorders (36.5% vs. 33.3%).12Women who do not receive AUD treatment have some sociodemographic difference from women in AUD treatment. For example, a sample of women with AUD who were not in treatment but perceived a need for treatment were less educated, had a family income less than $75,000, and were more likely to use psychotropic medications compared to those who did not perceive a need for treatment.6Recent research has suggested that traditional gender expectations and lay beliefs about AUD may contribute to lower AUD treatment utilization among women. Lale and colleagues found that compared to men, women were more likely to attribute AUD to “bad character” and less likely to attribute AUD to genetics.17Compared to men, women are more likely to seek AUD treatment through a general versus substance use-specific health care sectorIn general, the literature is mixed regarding AUD treatment attrition and gender differences.In general, studies of mixed-gender treatment programs have found few gender differences in short-term outcomes for AUD across a range of interventions, samples, and sites, despite women at baseline generally presenting with more severe clinical issues.25Results have been more mixed regarding women’s long-term outcomes compared to men.Historically, gender has typically not been taken into consideration in psychopharmacologic treatment for AUD, and women have been underrepresented in AUD medication trials.A comprehensive review identified six major elements of SUD treatment programs for women that reduce barriers to treatment and/or address women’s unique needs.34Recognizing the unique treatment needs of women with AUD and SUD, SAMHSA published a set of evidence-based principles to guide gender-responsive treatment for women.7With increasing recognition of the unique clinical profiles of women with AUD has come increasing attention to whether AUD treatment programs are serving the needs of women. The 2018 SAMHSA annual survey of substance use treatment programs found that 49% of programs surveyed provided special programs or groups for women and 23% provided services for pregnant or postpartum women.35The need for specialized services for women has both an empirical and a clinical rationale. As reviewed earlier in this article, compared to men, women are less likely to seek AUD treatment, have different social contexts, present with different profiles of co-occurring disorders, and have a unique and complex set of service needs that may not be addressed in a standard, mixed-gender AUD treatment program.Single-gender treatment services seem appealing because they have the potential to provide an environment in which women may feel more comfortable sharing emotional and personal information. For instance, it is possible that among women who have a history of trauma or abuse from men, single-gender treatment might be preferable because of the possibility that participation in a mixed-gender program could trigger trauma-related symptoms. In addition, given the broader literature on the relative interactional dominance of men in mixed-gender groups, women may have more opportunities to participate when in women-only groups.Few studies have compared women’s outcomes from mixed-gender versus women-only programs that were not adapted with female-specific content. In one early study, Bride compared the outcomes for women who were in a mixed-gender program to the outcomes for women who later participated in the same program that had become a women-only program with no female-specific content.More extensive research has compared mixed-gender to single-gender programs that incorporate female-specific themes, services, or content. For example, interviewed providers of services for female veterans with SUD identified five female-specific themes and services that they viewed as key to treatment: a focus on safety; scheduling that accommodates women’s work and family responsibilities; flexibility in the resources provided; staff trained in serving women’s clinical needs; provision of on-site childcare; and a positive, supportive, nonconfrontational treatment environment.One of the earliest studies of women-only treatment with female-specific content was the Early Treatment of Women with Alcohol Addiction (EWA) study.49Some empirically supported treatments have been tested in female samples with any adaptation of the treatment to women’s treatment needs. Two studies compared behavioral couple therapy to individual treatment for women with AUD and their male partners.53Chronic care models for persons with serious mental illness and SUD are another empirically supported approach that has been tested in female samples without female-specific programming. These models have been developed and tested with homeless women who have AUD. The chronic care model emphasizes availability of a primary care provider, care management, education about alcohol, and referral to addiction services. Compared to women who received treatment as usual in a health care clinic for homeless women, women who participated in the chronic care program engaged with more SUD treatment services in the 3 months after starting the program.54There has been substantial research on women-only treatment with female-specific content. For example, Polcin and colleagues compared intensive, nine-session motivational interviewing (MI) for women with standard one-session MI.Another single-gender treatment with women-specific programming was developed by Epstein and colleagues. The outpatient, female-specific cognitive behavioral treatment (FS-CBT) was an adaptation of a the gender-neutral cognitive behavior therapy manual-guided treatment for AUD.61n = 16) for SUD against mixed-gender Group Drug Counseling .In a pilot study, Greenfield and colleagues tested a women-only Women’s Recovery Group  The “healing” section covers “recovery methods in four domains—relationships, beliefs, actions, and feelings.”70(p211) Both WPR and TSF were single-gender groups, facilitated by women clinicians, and provided compensation to offset potential childcare costs or other financial barriers to participation. The treatments resulted in similar improvements in alcohol and drug use, coping skills, and psychiatric functioning. The authors noted that female-specific treatment content might be less relevant to veterans than to their civilian counterparts because male-dominated military culture may diminish traditional gender experiences for women.Najavits and colleagues reported an RCT comparing the A Woman’s Path to Recovery (WPR) model to the gender-neutral 12-Step Facilitation (TSF) model for women veterans with SUD, the majority of whom  had current AUD.70In summary, several forms of empirically supported treatments have been tested and found to be efficacious with women, and several women-only treatments with female-specific content have been tested in rigorous RCTs. Overall, most of these studies have found limited evidence for superior alcohol use outcomes, but several of these studies have found greater satisfaction with the female-specific format and treatment content. Because these programs are appealing to women, they may increase women’s utilization of AUD treatment, and enhance both engagement and retention in AUD treatment.Treatment for co-occurring disorders may be indicated for the many women with AUD who present with additional mental health concerns. Interventions that address the co-occurrence of AUD with trauma and PTSD, mood disorders, and borderline personality disorder may be especially relevant for women.Given the highly elevated rates of trauma among women with AUD/SUD, SAMHSA has suggested that treatment for this population may benefit from adopting principles of trauma-informed care.Covington developed the Helping Women Recover program for the treatment of SUD.74An extension of trauma-informed care is treatment for co-occurring SUD and PTSD. In general, this co-occurrence is complex and difficult to treat because SUD and PTSD are reciprocally functional and often exacerbate each other.12Recently, integrated models of treatment for PTSD and SUD have been developed and tested with mixed results. For instance, Najavits developed Seeking Safety (SS), a CBT-based treatment model that aims to reduce co-occurring PTSD and SUD by enhancing coping skills.79Morrissey and colleagues studied another integrated treatment approach for women with SUD.76Another promising area of treatment development for women is integrated behavioral therapy for SUD and depression. Treating depression and AUD concurrently may be important because negative affect is a particularly salient trigger for drinking among women. In turn, regular heavy drinking may inhibit recovery from mood disorders. Further, more women than men with AUD have a co-occurring mood disorder, and there is an elevated suicide risk among women with AUD.Given that drinking and antidepressant use are generally contraindicated adds to the significance of concurrent treatment of AUD and depression to maximize the effectiveness of psychotropic medications.Research has demonstrated elevated rates  of borderline personality disorder (BPD) in women seeking treatment for AUD.The goal of understanding moderators and mechanisms of change in treatment is to identify how patient characteristics interact with treatments, identify variables key to successful change, and then develop or modify treatments to target those variables more efficiently in treatment. Currently, there are relatively limited data on moderators and mechanisms of change in alcohol use during and after AUD treatment for women. Moderators are defined as “specification variables” that impact the association between two other variables,Research on moderators of outcome has elucidated the need for heterogeneity in samples and helped to refine female-specific treatments.Hallgren and colleagues examined three hypothesized mechanisms of change—abstinence self-efficacy, coping skills, and therapeutic alliance—in outpatient AUD treatment for women.91Using Network Analysis, a novel statistical approach that uses multilevel vector autoregression estimation for multiple time series data to simultaneously examine change among several hypothesized mechanisms of change, Holzhauer and colleagues compared pathways to drinking reduction among women in gender-neutral versus FS-CBT.Going forward, continuing moderated mediation studies that examine the response of gender-specific moderators of response to medications or behavioral interventions for AUD, and the mechanisms by which these treatments operate for specific subpopulations, will help guide the development of personalized medicine for addiction.Since the National Institutes of Health mandate in 1994 that biomedical research include female participants in clinical research,Gaps in knowledge remain; however, increasingly sophisticated research approaches are available to continue to tackle the questions of how and which treatments work best for whom. The contemporary focus on personalized medicineA critical problem to resolve is treatment access and utilization. Only 15% of women with lifetime AUD ever seek treatment for it, and women experience multiple individual-based barriers to accessing treatment. In addition, systemic barriers to AUD treatment for women need attention, as a minority of substance use treatment services in the United States offer gender-segregated or female-specific programming. Extant literature suggests that women may prefer gender-segregated treatment for AUD but also suggests this treatment offers no added benefit in the absence of female-specific programming content. Thus, widespread availability of female-only treatment settings that include evidence-based female-specific interventions and content is likely to increase treatment utilization and enhance outcomes for women with AUD. In order to populate female-only treatment settings with female-specific programming, we need to develop an array of evidence-based options. A number of RCTs have yielded newly available, evidence-based female-specific treatment protocols for AUD and SUD treatment that are at least equivalent in positive outcomes to evidence-based control treatments.Notable areas of additional needed research on women and AUD treatment follow.Women who enter treatment for AUD present with greater addiction and more severe psychosocial issues than men. Secondary prevention research has focused on engaging women in treatment as well as on providing alcohol psychoeducation earlier in women’s problem drinking careers, which may help arrest the telescoped trajectory to AUD and SUD and the corresponding psychosocial decline.Women are more likely to self-identify as having an alcohol problem and enter AUD treatment through a medical or mental health portal than a substance use specialty clinic. For instance, women may obtain AUD treatment in the course of seeking treatment for a co-occurring psychiatric disorder, such as PTSD or depression, in a general mental health setting.Increasing rates of drug use among women point to a need for integrated AUD and SUD female-specific treatments. Although some evidence-based treatments are available,Testing telehealth platforms for individual and group AUD treatments may help reduce barriers to use among women. Likewise, testing ancillary smartphone applications that link women to in vivo coping skills training and social network support could enhance outcomes of existing in-person programs or serve as stand-alone aids for women who face insurmountable treatment entry barriers.Female-specific, coping-skills-based, peer support groups are not widely available. The evidence base for women’s Alcoholics Anonymous meetings needs to be established. In addition, the recent positive development of a recovery coach industry may help with in vivo social support especially for women, but research is necessary to establish an evidence base.Research on medications for women with AUD as one treatment element should continue. A precision medicine approach testing gender, genetic profiles, and specific medications is an important avenue to pursue.Research on mechanisms of change is crucial to untangle whether similar drinking outcomes of women and men with AUD are achieved via gender-specific pathways to change and to identify active ingredients and mediators of treatment change best suited for women with only AUD and for women with specific types of co-occurring disorders. New methodologies in statistics, neuroscience, and research design are helping to clarify these questions; however, additional research is needed to streamline and personalize optimally efficient treatment components for every woman seeking care for AUD.


Acute myocardial infarction (AMI) is usually caused by rupture of an atherosclerotic plaque leading to thrombotic occlusion of a coronary artery. Cardiovascular disease has recently emerged as the leading cause of death during hajj. Our aim is to demonstrate the AMI pilgrim’s related disparities and comparing them to non-pilgrim patients.P < 0.001) and showed significantly lower rates cardiovascular risk factors . Pilgrims were also less likely to receive thrombolytic therapy (P < 0.001), show lower rate of late AMI presentation (P < 0.001), develop more LV dysfunction post AMI (P < 0.001), and have critical CAD anatomy in their coronary angiography (P < 0.001 for MVD and = 0.02 for LM disease) compared to non-pilgrim AMI patients. Despite AMI pilgrims recorded higher rate of primary percutaneous coronary intervention (PPCI) procedures, they still showed poor hospital outcomes . Being a pilgrim and presence of significant left ventricular systolic dysfunction, post AMI was the two independent predictors of mortality among our studied patients .Out of 3044 of patients presented with AMI from January 2016 to August 2019, 1008 (33%) were pilgrims. They were older in age (Although AMI pilgrims had less cardiovascular risk factors and they were early revascularized, they showed higher rates of post myocardial infarction complication and poor hospital outcomes. Implementation of pre-hajj screening, awareness and education programs, and primary and secondary preventive measures should be taken in to consideration to improve AMI pilgrim’s outcome. Acute myocardial infarction (AMI) is usually caused by interaction of lipoprotein retention, inflammatory process, and rupture of an atherosclerotic plaque leading to thrombotic occlusion of a coronary artery. It is classified into ST-elevation myocardial infarction (STEMI) and non ST-elevation myocardial infarction (NSTEMI). These patients are generally treated with combination of medical therapy and revascularization with percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) , 2.Hajj is a great event, and it is one of the five Islamic pillars. Millions of pilgrims from different countries of the world come to the kingdom of Saudi Arabia for performing hajj. The overcrowding, hot climate, and huge physical stress expose the pilgrims to many health hazards. Cardiovascular disease has recently emerged as the leading cause of death during hajj , 4.Our center is the only cardiac center in the region providing tertiary care facility including PCI and CABG and hence receives all AMI patients deemed suitable for invasive assessment and management serving huge number of hajj patients with distinct racial, socioeconomic, and demographic characteristics.There are no studies done before comparing the AMI clinical and in-hospital outcome between pilgrims and non-pilgrims. Our aim is to demonstrate the possible disparities of demographics, clinical data, and in-hospital outcomes of AMI patients admitted to our specialized cardiac center in Makkah region, Saudi Arabia.It is a retrospectively collected data of the prospective single-center study that included 3044 patients who were admitted and underwent coronary angiography at the cardiac center—King Abdullah Medical City (KAMC)—from January 2016 till August 2019.All patients admitted to our cardiac center with established diagnosis of AMI  findings, elevated values of biochemical markers (biomarkers) of myocardial necrosis, and by imaging ) and undPatients with AMI treated conservatively and coronary angiography was not done because of preference of the patient or due to other reasons.Our study is designed to be a part of the standards of patient’s care, to investigate and improve quality of AMI management and outcomes among diverse population, general and cath consents were taken, and has received approval of the ethics committee/institutional review board of our institution (KAMC).All demographic data ), risk factors  according to guidelines [t-test or chi-squared test for continues and categorical data, respectively. Cox-regression analysis was also performed. For all analyses, a P value < 0.05 was considered significant and not significant if it is > 0.05.Statistical analysis was performed by the use of the SPSS software package , version 21.0. Data are presented as mean ± SD for continues data and percentage for categorical variables. Univariate analysis were done using A total of 3044 AMI patients were admitted to our cardiac center from January 2016 till August 2019 , showed less male gender  and more south Asian population compared to group II patients . Patients of group II had significantly higher prevalence history of DM, smoking, and obesity compared to group I . There were no observed significant differences between the two groups regarding the rates of HTN, hyperlipidemia, IHD, and previous coronary revascularization. Regarding to laboratory findings, AMI pilgrim patients had significantly lower HB level on presentation with higher BUN value suggestive of their dehydration compared to group II patients (P < 0.001) . Moreover, post AMI-LVEF was recorded lower among pilgrim patients compared to non-pilgrims . Also, pilgrim patients had higher prevalence of three vessel disease (3VD) and left main (LM) disease compared to non-pilgrims . Primary percutaneous coronary intervention (PPCI) was utilized relatively higher by pilgrims, and the recorded door to balloon time < 90 min was achieved higher by AMI pilgrim patients compared to non-pilgrims , there were no significant differences between the two groups. In Table P < 0.001, 0.004, 0.001, < 0.001, and 0.05, respectively, for pulmonary edema, cardiogenic shock, severe LV dysfunction, mechanical ventilation, and cardiac arrest, respectively). The total in-hospital mortality was 3%, and it is recorded higher among pilgrim patients compared to the second group . Incidence of both left ventricular thrombus formation post AMI and major bleeding did not differ between the two groups , arrhythmias (22%), and respiratory failure 13%) were the most common causes of death among our studied AMI patients  , one thousand and eight pilgrim AMI patients were admitted and treated in our center. Pilgrim patients presented with acute myocardial infarction were elderly compared to non-pilgrims, and this is expected, as these are people in such age category who come for the hajj pilgrimage after finishing all their essential responsibilities. This is prescribed in previous few studies, which conducted to assess pattern of CVD among pilgrims , 11. IntMoreover, from our interesting findings in the current study, those AMI pilgrims were less likely to receive thrombolytic therapy and showed lower rate of late presentation compared to non-pilgrims. This could be explained by during hajj, cath lab work full capacity 24 h, 12 h shift day same as night; however, residence of Makkah sometimes come from remote area that managed by drip and shift strategy while pilgrims are mostly within Makkah city. Also, those AMI hajj patients had higher prevalence of severe coronary artery disease (multi-vessel CAD and LM disease) compared to residence, and in spite of being early revascularized with PPCI, they still showed significant LV dysfunction in their echocardiogram post MI. This could be explained by many factors including genetic variation, degree of atherosclerosis, different thrombotic activity, distribution of collateral circulation, and severe physical and emotional stress they had been developed during hajj. Moreover, the utilization rate of PPCI was recorded relatively higher among pilgrim patients with higher achieved door to balloon time < 90 min. There are several factors could explain the significant improvement of the service provided to AMI hajj patients. First, the great effort and support of the government of Saudi Arabia through the ministry of health and hajj committee to implement the program of increasing hajj manpower included interventionist cardiologist working at our center during hajj seasons. Second, raise number of the working cath labs. Third, well establishment of organized network for urgent transport of the AMI hajj patients from all Al-Mashaer, primary, and secondary hospitals to our tertiary hospital; this includes air medevac transportation. Fourth, proper preparation of all Makkah hospitals with emergency situations and to provide short-term hospitalization services with immediate transfer to our center for intervention and urgent revascularization.Surprisingly, those AMI hajj patients who were early revascularized with PPCI, they showed significant higher rates of post AMI complications and poor outcomes. With respect of the mortality, the over all in-hospital mortality rate among our studied AMI patients was recorded (3%), and it was comparable to which reported by a recent AMI registry in Saudi Arabia ; howeverUnlike AMI pilgrims, non-pilgrim patients who presented with myocardial infarctions were younger in age with higher prevalence of cardiovascular risk factors. Our findings consisted with a recent multi-center registry study in 50 hospitals from various health care sectors in Saudi Arabia were conducted for AMI to evaluate the clinical characteristics, management, and outcomes of a representative sample of patients with acute myocardial infarction (AMI) in Saudi Arabia. It concluded that AMI patients in Saudi Arabia presented at relatively young age and had a high prevalence of CAD risk factors . This isInterestingly that all our AMI population had proper access to primary PCI with higher recorded rates than reported in the previous studies , 18–20. Finally, cardiogenic shock, arrhythmias, and respiratory failure were the most common causes of death among our patients with observed less recorded arrhythmic death among pilgrims compared to non-pilgrims. This is unclear but might be explained by different genetic factors, being early revascularized with PPCI  and early discharged from the hospital (late arrhythmias might be not detected).In conclusion, hajj is a major annual mass gathering of millions of people from all over the world, with different cultures, socioeconomic levels, knowledge, attitudes, and most importantly health statuses . The cauIdentification and awareness of the causes and clinical characters of those patients might reduce the hazards. This also highlights future strategic planning, motivations of more implementation of pre-hajj screening and education programs, and encourage the multidisplinary and multicentric cooperation in proper serving those high-risk pilgrims. Moreover, this study also refers to the need to develop optimal secondary prevention measures to be applied after hospital discharge as it was found that AMI residence non-pilgrim patients were younger at age and had multiple cardiovascular risk factors.The number of enrolled patients is limited due to the nature of single center study and selection of AMI patients only. Moreover, no follow-up data or long-term outcomes and that is because one group of our study was pilgrims; they were going back to their countries after doing hajj, and hence no follow-up were available. We hope to reduce the effect of this limitation by motivating more hospitals to conduct similar researches to create multicenter larger sample study in the future.We demonstrated disparities in baseline demographics, clinical characteristics, and hospital outcomes between AMI pilgrims and non-pilgrim patients. Although AMI pilgrims had less cardiovascular risk factors and were early revascularized, they showed higher rates of post myocardial infarction complication and poor hospital outcomes. The policy makers should take comprehensive, proper health coverage including implementation of pre-hajj screening and education programs, primary and secondary preventive measures, and proper awareness identifying those disparities into consideration.


Methotrexate (MTX) is a folate analog widely used against a range of diseases including malignancies and autoimmune disorders. Its high effectiveness-price ratio also won extensive application in ophthalmology. On the other hand, although MTX has an excellent pharmacological efficacy, MTX associated side effects in clinical use, which vary from patient to patient, are nonnegligible. There is no comparatively systematic review on MTX associated side effects and its risk factors. This review aimed to reveal novel clinical approaches of MTX and its adverse effects in order to provide a reference for ophthalmic scholars in clinical application of MTX. Until now, HD-MTX (with or without radiation therapy) is still the backbone of most modern chemotherapy regimens  in clinic , 106. HoFolate and folic acid play significant roles in the de novo synthesis of purines and thymidylate, which are required for DNA replication and repair . Funk anHowever, Arabelovic and associates' preliminary study showed a significant increase of MTX dose needed , since fAl-Dabagh et al. found that the reduction in efficacy of MTX cannot be ignored while folate supplementation did make a significant reduction in associated adverse effects . Salim eThere are no ophthalmic studies to demonstrate the protective effects of folic acid supplementation. Thus, although the folate supplementation is widely used among patients treated with low-dose MTX , 121, thMethotrexate, as one of the alternative pharmacological steroid-sparing immunosuppressive agents, is becoming more and more popular as the preferred treatment in several autoimmune conditions requiring long-term immunosuppression . Low-dosTo avoid side effects, split doses of MTX administration and folate supplementation are gradually being used in ophthalmic clinic. Prescription of 5 to 10 mg of folate supplementation has a significant role in MTX safety , but theWith the increasing long-term use of MTX, it is important to monitor patients' blood examination results, including blood routine and liver and renal functions. As pancytopenia can be a late manifestation , elevatiNumerous studies had been conducted to prove that MTX could be used as a well-tolerated, safe, and effective first-line treatment. Hence, the MTX administration should not continue to be stigmatized as a “cancer drug,” or to be discouraged because of associated adverse effects. Contrarily, the indication and the routes of administration are about to gradually widen.