Identifying consistent echocardiographic thresholds for risk stratification in pulmonary arterial hypertension.

Several indices of right heart remodeling and function have been associated with survival in pulmonary arterial hypertension (PAH). Outcome analysis and physiological relationships between variables may help develop a consistent grading system. Patients with Group 1 PAH followed at Stanford Hospital who underwent right heart catheterization and echocardiography within 2 weeks were considered for inclusion. Echocardiographic variables included tricuspid annular plane systolic excursion (TAPSE), right ventricular (RV) fractional area change (RVFAC), free wall strain (RVFWS), RV dimensions, and right atrial volumes. The main outcome consisted of death or lung transplantation at 5 years. Mathematical relationships between variables were determined using weighted linear regression and severity thresholds for were calibrated to a 20% 1-year mortality risk. PAH patients (n = 223) had mean (SD) age of 48.1 (14.1) years, most were female (78%), with a mean pulmonary arterial pressure of 51.6 (13.8) mmHg and pulmonary vascular resistance index of 22.5(6.3) WU/m2. Measures of right heart size and function were strongly related to each other particularly RVFWS and RVFAC (R 2 = 0.82, p < 0.001), whereas the relationship between TAPSE and RVFWS was weaker (R 2 = 0.28, p < 0.001). Death or lung transplantation at 5 years occurred in 78 patients (35%). Guided by outcome analysis, we ascertained a uniform set of parameter thresholds for grading the severity of right heart adaptation in PAH. Using these quantitative thresholds, we, then, validated the recently reported REVEAL-echo score (AUC 0.68, p < 0.001). This study proposes a consistent echocardiographic grading system for right heart adaptation in PAH guided by outcome analysis.

Disease characteristics, treatments, and outcomes of patients with pulmonary arterial hypertension treated with selexipag in real-world settings from the SPHERE registry (SelexiPag: tHe usErs dRug rEgistry).

BACKGROUND: Selexipag is an oral prostacyclin receptor agonist, indicated for pulmonary arterial hypertension to delay disease progression and reduce the risk of pulmonary arterial hypertension-related hospitalization. SelexiPag: tHe usErs dRug rEgistry (NCT03278002) was a US-based, prospective, real-world registry of selexipag-treated patients. METHODS: Adults with pulmonary hypertension (enrolled 2016-2020) prescribed selexipag were followed for ≤18 months, with data collected at routine clinic visits. Patients were defined as newly or previously initiated if they had started selexipag ≤60 days or >60 days, respectively, before enrollment. RESULTS: The registry included 829 patients (430 newly initiated, 399 previously initiated; 759 with pulmonary arterial hypertension), of whom 55.6% were World Health Organization functional class (FC) 3/4; 57.3% were intermediate or high risk per Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) 2.0. In patients with pulmonary arterial hypertension, 18-month discontinuation rates for adverse events were 22.0%, 32.0%, and 11.9%, and 18-month survival rates were 89.4%, 84.2%, and 94.5% in the overall, newly, and previously initiated patient populations, respectively. From baseline to month 18, most patients had stable or improved FC and stable or improved REVEAL 2.0 risk category status. Discontinuation for adverse events, hospitalization, and survival were similar regardless of patients' individually tolerated selexipag maintenance dose. No new safety signals were identified. CONCLUSIONS: In this real-world analysis of patients initiating selexipag, most patients had stable or improved FC and REVEAL 2.0 risk category. Similar to the GRIPHON trial, outcomes with selexipag in this real-world study were comparable across maintenance dose strata, with no new safety signals.

On power and its corrupting effects: the effects of power on human behavior and the limits of accountability systems.

Power is an all-pervasive, and fundamental force in human relationships and plays a valuable role in social, political, and economic interactions. Power differences are important in social groups in enhancing group functioning. Most people want to have power and there are many benefits to having power. However, power is a corrupting force and this has been a topic of interest for centuries to scholars from Plato to Lord Acton. Even with increased knowledge of power's corrupting effect and safeguards put in place to counteract such tendencies, power abuse remains rampant in society suggesting that the full extent of this effect is not well understood. In this paper, an effort is made to improve understanding of power's corrupting effects on human behavior through an integrated and comprehensive synthesis of the neurological, sociological, physiological, and psychological literature on power. The structural limits of justice systems' capability to hold powerful people accountable are also discussed.

On the beauty of sadness: it's okay to say, I am sad, thank you.

We live in times when our culture is obsessed with happiness. The value of almost every aspect of our lives is increasingly judged in terms of their contribution to our happiness. Happiness has become the ultimate goal by which values and priorities are constructed and the only thing for which any action in pursuit of does not require justification. In contrast, sadness is increasingly abnormalized and pathologized. In this paper, an effort is made to counteract the narrative that sadness, a critical aspect of human life is abnormal or a pathological condition. The evolutionary benefits of sadness and its place in human flourishing are discussed. A rebranding of sadness is proposed that emphasizes the free expression of sadness in everyday greetings to remove it from its current negative state and promote many of its benefits including post-traumatic growth and resilience.

On stimulus persistence and human behavior: the stimulus persistence unification theory.

A person trapped in a building engulfed in a raging fire, a person dealing with severe chronic disease, people dealing with a virus pandemic, and people fighting in a protracted war may appear dissimilar but are fundamentally in a similar situation and their behaviors follow a predictable and similar pattern. In this paper, the behaviors of rational people dealing with a significant persistent unpleasant, or dangerous stimulus that is inescapable are elucidated. The unique modulatory effects of stimulus persistence on human behavior as well as the role of means and interest are discussed.

On the theory of mental representation block. a novel perspective on learning and behavior.

Understanding the mechanisms behind memory, learning, and behavior is crucial to human development and significant research has been done in this area. Classical and operant conditioning and other theories of learning have elucidated different mechanisms of learning and how it modulates behavior. Even with advances in this area, questions remain on how to unlearn faulty ideas or extinguish maladaptive behaviors. In this paper, a novel theory to improve our understanding of this area is proposed. The theory proposes that as a consequence of the brain's energy efficiency evolutionary adaptations, all learning following memory consolidation, reconsolidation, and repeated reinforcements or strengthening over time, results in a phenomenon called mental representation block. The implications of this block on learning and behavior are significant and broad and include cognitive biases, belief in a creator or God, close-mindedness, dogmatism, physician misdiagnosis, racism, homophobia, and transphobia, susceptibility to deception and indoctrination, hate and love, artificial intelligence and creativity.

Oxidative/Nitroxidative Stress and Multiple Sclerosis.

Multiple sclerosis (MS) is a multifactorial, central nervous system, immune-mediated disease characterized by inflammation, demyelination, and neurodegeneration. Evidence suggests a steady rise in MS prevalence over the past five decades in the United States and around the world. Even with increased understanding of immunology, the specific etiological trigger of MS remains unknown. Evidence suggests that oxidative/nitroxidative stress is an important contributor to MS etiology, progression, and clinical symptoms. A multifaceted treatment approach aimed at counteracting oxidative/nitroxidative stress including MS disease-modifying medications, Mediterranean style diet, stress-relieving activities, smoking and alcohol cessation, exercise, and peer support programs is the best way to treat the disease.

Towards a Comprehensive Theory of Love: The Quadruple Theory.

Scholars across an array of disciplines including social psychologists have been trying to explain the meaning of love for over a century but its polysemous nature has made it difficult to fully understand. In this paper, a quadruple framework of attraction, resonance or connection, trust, and respect are proposed to explain the meaning of love. The framework is used to explain how love grows and dies and to describe brand love, romantic love, and parental love. The synergistic relationship between the factors and how their variations modulate the intensity or levels of love are discussed.

On maternal Post-Partum/Natal depression. A global underrecognized problem and the need for better Treatment strategies.

BACKGROUND: Maternal Postpartum (PPD) or Postnatal Depression (PND) is believed to be the commonest medical complication postpartum. Evidence suggests a significantly higher prevalence of the disease compared to the often reported 10-15%. METHOD: Studies were identified by accessing several databases including PubMed/Medline, PubMed Central, EBSCO, and PsycINFO. RESULTS: Vitamin D (VD) deficiency, hormonal levels alteration (estrogen, progesterone, testosterone, oxytocin, and prolactin), thyroid dysfunction, and increased oxidative stress, play a critical role in PPD etiopathogenesis and pathophysiology. CONCLUSIONS: Treatment strategies should include an integrated approach of antidepressants and psychotherapy, melatonin, diet, sleep improvement, exercise, VD and antioxidants supplementation, and economic and social support.

Towards a comprehensive theory of obesity and a healthy diet: The causal role of oxidative stress in food addiction and obesity.

BACKGROUND: Obesity is a major public health problem whose prevalence has been rapidly increasing in the United States (U.S), and globally. It is one of the leading causes of preventable deaths globally and contributes to the development of many diseases. METHODS: The search was limited to studies published in English and other languages involving both animal and human subjects. Articles selected included preclinical studies, randomized clinical trials RCTs, observational studies, meta-analyses, narrative and systemic reviews providing primary quantitative data with a measure of obesity or food addiction as an outcome. Over 5000 articles were found in the first round of search which was filtered to 506 articles. RESULTS: Oxidative stress plays a critical role in food addiction and is both a cause and mediator of obesity. Reactive oxygen species play a direct role in adipogenesis and oxidative stress modulates all factors involved in obesity including genetics, sleep, gut microbiome, insulin, ghrelin, inflammation, adipokines, leptin, stress, HPA axis, and the hypothalamus. CONCLUSIONS: The idea of thinking of combating obesity from the lens of calorie count, low carbohydrate, high or low-fat, vegetarian, vegan, plant-based, or animal-based diet is fundamentally wrong. The best way to look at obesity is through the framework of systemic redox homeostasis. Since redox homeostasis is tilted towards increased reactive oxygen species production, and excessive antioxidant intake can result in oxidative stress, an antioxidant and prooxidant food ratio of 2:3 per meal is the ideal nutritional ratio for good health and ideal weight. A ratio of 3:4 is ideal for obese individuals because of their state of chronic oxidative stress and inflammation. Physical activity, sleep quality, psychological stress, maternal prenatal diet and oxidative stress promoting disease conditions are important modulators of oxidative stress and obesity.

Towards a comprehensive etiopathogenetic and pathophysiological theory of multiple sclerosis.

Background: Multiple sclerosis (MS) is a neurodegenerative disease caused by dysfunction of the immune system that affects the central nervous system (CNS). It is characterized by demyelination, chronic inflammation, neuronal and oligodendrocyte loss and reactive astrogliosis. It can result in physical disability and acute neurological and cognitive problems. Despite the gains in knowledge of immunology, cell biology, and genetics in the last five decades, the ultimate etiology or specific elements that trigger MS remain unknown. The objective of this review is to propose a theoretical basis for MS etiopathogenesis.Methods: Search was done by accessing PubMed/Medline, EBSCO, and PsycINFO databases. The search string used was "(multiple sclerosis* OR EAE) AND (pathophysiology* OR etiopathogenesis)". The electronic databases were searched for titles or abstracts containing these terms in all published articles between January 1, 1960, and June 30, 2019. The search was filtered down to 362 articles which were included in this review.Results: A framework to better understand the etiopathogenesis and pathophysiology of MS can be derived from four essential factors; mitochondria dysfunction (MtD) & oxidative stress (OS), vitamin D (VD), sex hormones and thyroid hormones. These factors play a direct role in MS etiopathogenesis and have a modulatory effect on many other factors involved in the disease.Conclusions: For better MS prevention and treatment outcomes, efforts should be geared towards treating thyroid problems, sex hormone alterations, VD deficiency, sleep problems and melatonin alterations. MS patients should be encouraged to engage in activities that boost total antioxidant capacity (TAC) including diet and regular exercise and discouraged from activities that promote OS including smoking and alcohol consumption.

On the potential harmful effects of E-Cigarettes (EC) on the developing brain: The relationship between vaping-induced oxidative stress and adolescent/young adults social maladjustment.

INTRODUCTION: Evidence suggests that in convenience stores across the United States (U.S), sales of e-cigarettes (EC) continue to grow, indicating their rising popularity. ECs have been touted as a means for traditional cigarette (TC) smokers to quit smoking. However, the dramatic increase in the number of adolescents and young adults using e-cigarettes (vaping) in America is a cause for concern as their long-term effects remain unknown. METHODS: Search was done by accessing PubMed/Medline, EBSCO, and PsycINFO databases. The search string used was "(Cigarettes OR E-Cigarettes* OR Vaping) AND (Oxidative Stress* OR Reactive Oxygen Species (ROS)) AND (Adolescents OR Teens OR Young Adults)". The electronic databases were searched for titles or abstracts containing these terms in all published articles between January 1, 1970, and June 30, 2019. Over 3000 articles were found in the first round of search which was filtered to 129 articles. RESULTS: Oxidative Stress is a critical underlying molecular factor that drives the harmful effects of traditional cigarettes. The developing brain is particularly vulnerable to the harmful effects of oxidative stress and e-cigarettes just like traditional cigarettes induces oxidative stress. Many e-cigarette components including the flavoring, vapor, e-liquids and metallic coil, trigger oxidative stress, indicating that both nicotine and non-nicotine e-cigarette use may be harmful. CONCLUSIONS: E-cigarettes use could potentially play a role in adolescent/young adults social maladjustments including poor learning and academic performance, increased aggressive and impulsive behavior, poor sleep quality, attention deficits, impaired memory, and cognition, and increased depression and suicidal ideation. The government, parents, school authorities and clinicians should be advised on these potentially harmful effects.

On the Neurobiological Role of Oxidative Stress in Alcohol-Induced Impulsive, Aggressive and Suicidal Behavior.

Objectives: Alcohol abuse is known to result in behavioral impairments (such as increased impulsivity, aggressive, and suicidal behavior), but the neurobiological basis for these behavioral impairments remains unknown. The objective of this review is to propose a neurobiological basis for alcohol-induced aggression, impulsivity, and suicidal behavior. Methods: Search was done by accessing PubMed/Medline, EBSCO, and PsycINFO databases. The search string used was "(Alcohol OR Alcoholism* OR Alcohol Abuse) AND (Behavior* OR Behavioral Impairment or Disorder) AND (Oxidative Stress OR Reactive Oxygen Species)." The electronic databases were searched for titles or abstracts containing these terms in all published articles between January 1, 1960, and May 31, 2019. The search was limited to studies published in English and other languages involving both animal and human subjects. Articles selected included randomized clinical trials (RCTs), observational studies, meta-analyses, and both systemic and narrative reviews, providing both quantitative and qualitative information with a measure of alcohol abuse or alcoholism as an outcome. Exclusion criteria were unpublished data of any form, including conference proceedings and dissertation. New key terms were identified (new term included: "Antioxidants, Neurotransmitters, Dopamine, Serotonin, GABA, Glutamate. Aggression, Impulsivity, Suicidal Behavior, hippocampus, prefrontal cortex, limbic system, psychiatric disorders, PTSD, Anxiety, Depression. These new terms were searched with Alcohol or Alcoholism or Alcohol Abuse and Oxidative Stress separately resulting in the identification of over 3000 articles. 196 were included in this article. Results: Multiple lines of evidence indicate that oxidative stress (OS) plays a critical underlying role in alcohol toxicity and behavioral impairments. Conclusions/Importance: People diagnosed with PTSD, anxiety disorder, depression, and those with a personality high in psychoticism as measured by the P Scale of the Eysenck Personality Questionnaire, with comorbid alcohol abuse or alcohol use disorder (AUD), may display increased impulsivity, aggression, and suicidal behavior because of the potentiating effect of alcohol-induced OS on their elevated brain oxidative status. Antioxidant therapy should be an integral part of acute alcohol intoxication and AUD treatment. Further research is necessary to fully understand the relationship between OS and alcohol-induced behavioral impairments.

Towards a comprehensive understanding of the contributions of mitochondrial dysfunction and oxidative stress in the pathogenesis and pathophysiology of Huntington's disease.

Huntington's disease (HD) is a rare autosomal dominant disorder affecting the corticostriatal area of the brain. HD is driven by elongated cytosine-adenine-guanine (CAG) repeat (36 repeats or more) on the short arm of chromosome 4p16.3 in the Huntingtin gene (HTTg) which encode the huntingtin protein (HTT). Although the polyglutamine expansion within HTT is the causative factor in the pathogenesis of HD, the underlying mechanisms that provoke this expansion and the resulting neurodegeneration and clinical symptoms are not fully understood. In this paper, the critical role played by mitochondria dysfunction and oxidative stress in HTT expansion, HD progression, and clinical symptoms are elucidated. Their interactions with the key factors in the disease, as well as treatment strategies, are discussed.

On the central role of mitochondria dysfunction and oxidative stress in Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is the commonest cause of dementia, with approximately 5 million new cases occurring annually. Despite decades of research, its complex pathophysiology and etiopathogenesis presents a major hindrance to the development of an effective treatment and prevention strategy. Aging is the biggest risk factor for the development of AD, and the total number of older people in the population is going to significantly increase in the next decades, suggesting that AD incidence and prevalence is likely to increase in the future. This makes the need for a better understanding of the disease to be extremely urgent. METHODS: A search was done by accessing PubMed/Medline, EBSCO, and PsycINFO databases. The search string used was "(dementia* OR Alzheimer's) AND (pathophysiology* OR pathogenesis)". New key terms were identified (new term included "vitamin D, thyroid hormone, mitochondria dysfunction, oxidative stress, testosterone, estrogen, melatonin, progesterone, luteinizing hormone, amyloid-ß (Aß), and hyperphosphorylated tau"). The electronic databases were searched for titles or abstracts containing these terms in all published articles between January 1, 1965, and January 31, 2019. The search was limited to studies published in English and other languages involving both animal and human subjects. RESULTS: Mitochondria dysfunction and oxidative stress play a critical role in AD etiopathogenesis and pathophysiology. CONCLUSION: AD treatment and prevention strategies must be geared towards improving mitochondrial function and attenuating oxidative stress.

On the Etiopathogenesis and Pathophysiology of Alzheimer's Disease: A Comprehensive Theoretical Review.

Alzheimers' disease (AD) is the most common cause of dementia, with an estimated 5 million new cases occurring annually. Among the elderly, AD shortens life expectancy, results in disability, decreases quality of life, and ultimately, leads to institutionalization. Despite extensive research in the last few decades, its heterogeneous pathophysiology and etiopathogenesis have made it difficult to develop an effective treatment and prevention strategy. Aging is the biggest risk factor for AD and evidence suggest that the total number of older people in the population is going to increase astronomically in the next decades. Also, there is evidence that air pollution and increasing income inequality may result in higher incidence and prevalence of AD. This makes the need for a comprehensive understanding of the etiopathogenesis and pathophysiology of the disease extremely critical. In this paper, a quintuple framework of thyroid dysfunction, vitamin D deficiency, sex hormones, and mitochondria dysfunction and oxidative stress are used to provide a comprehensive description of AD etiopathogenesis and pathophysiology. The individual role of each factor, their synergistic and genetic interactions, as well as the limitations of the framework are discussed.

On Energy Efficiency and the Brain's Resistance to Change: The Neurological Evolution of Dogmatism and Close-Mindedness.

The brain has been described as very resistant to change. However, why it does this has not been fully explained. In this paper, I propose that resilience to the disruption of consolidated memory is at the heart of the brain's resistance to change, and this resilience is a consequence of its energy efficiency evolutionary adaptations. I discussed the implications of this energy efficiency adaptation on dogmatism, close-mindedness, and artificial intelligence.

On the need for the development of a cancer early detection, diagnostic, prognosis, and treatment response system.

Cancer is the second leading cause of noncommunicable disease deaths in the world. In 2018, there were over 18 million new cancer cases and approximately 10 million people died from the disease globally. In 2019, almost two million new cases of cancer will be diagnosed in USA and over 600,000 people are expected to die from the disease. The incidence of cancer is expected to rise because of lifestyle changes and a rapidly aging population. Evidence suggests that early detection is critical to reducing cancer morbidity and mortality. In this paper, the development of an integrated smart wearable and biomarker detection system is proposed to help reduce cancer morbidity and mortality. The potential benefits and limitations of the system are discussed.