<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Aging brain and can you explain it in depth? [/INST] Aging is a major risk factor for most common neurodegenerative diseases, including mild cognitive impairment, dementias including Alzheimers disease, cerebrovascular disease, Parkinsons disease, and Lou Gehrigs disease. While much research has focused on diseases of aging, there are few informative studies on the molecular biology of the aging brain (usually spelled ageing brain in British English) in the absence of neurodegenerative disease or the neuropsychological profile of healthy older adults. However, research suggests that the aging process is associated with several structural, chemical, and functional changes in the brain as well as a host of neurocognitive changes. Recent reports in model organisms suggest that as organisms age, there are distinct changes in the expression of genes at the single neuron level. This page is devoted to reviewing the changes associated with healthy aging.

Structural changes
Aging entails many physical, biological, chemical, and psychological changes and the brain is no exception to this phenomenon. These various changes have attempted to be mapped by conceptual models like the Scaffolding Theory of Aging and Cognition (STAC) in 2009. The STAC model looks at factors like neural changes to the white matter, dopamine depletion, shrinkage, and cortical thinning .CT scans have found that the cerebral ventricles expand as a function of age. More recent MRI studies have reported age-related regional decreases in cerebral volume. Regional volume reduction is not uniform; some brain regions shrink at a rate of up to 1% per year, whereas others remain relatively stable until the end of the life-span. The brain is very complex, and is composed of many different areas and types of tissue, or matter. The different functions of different tissues in the brain may be more or less susceptible to age-induced changes.  The brain matter can be broadly classified as either grey matter, or white matter. Grey matter consists of cell bodies in the cortex and subcortical nuclei, whereas white matter consists of tightly packed myelinated axons connecting the neurons of the cerebral cortex to each other and with the periphery.

Loss of neural circuits and brain plasticity
Brain plasticity refers to the brains ability to change structure and function. This ties into the common phrase, "if you dont use it, you lose it," which is another way of saying, if you dont use it, your brain will devote less somatotopic space for it. One proposed mechanism for the observed age-related plasticity deficits in animals is the result of age-induced alterations in calcium regulation.  The changes in our abilities to handle calcium will ultimately influence neuronal firing and the ability to propagate action potentials, which in turn would affect the ability of the brain to alter its structure or function (i.e. its plastic nature). Due to the complexity of the brain, with all of its structures and functions, it is logical to assume that some areas would be more vulnerable to aging than others. Two circuits worth mentioning here are the hippocampal and neocortical circuits.  It has been suggested that age-related cognitive decline is due in part not to neuronal death but to synaptic alterations. Evidence in support of this idea from animal work has also suggested that this cognitive deficit is due to functional and biochemical factors such as changes in enzymatic activity, chemical messengers, or gene expression in cortical circuits.

Thinning of the cortex
Advances in MRI technology have provided the ability to see the brain structure in great detail in an easy, non-invasive manner in vivo. Bartzokis et al., has noted that there is a decrease in grey matter volume between adulthood and old age, whereas white matter volume was found to increase from age 19–40, and decline after this age. Studies using Voxel-based morphometry have identified areas such as the insula and superior parietal gyri as being especially vulnerable to age-related losses in grey matter of older adults. Sowell et al., reported that the first 6 decades of an individuals life were correlated with the most rapid decreases in grey matter density, and this occurred over dorsal, frontal, and parietal lobes on both interhemispheric and lateral brain surfaces. It is also worth noting that areas such as the cingulate gyrus, and occipital cortex surrounding the calcarine sulcus appear exempt from this decrease in grey matter density over time.  Age effects on grey matter density in the posterior temporal cortex appear more predominantly in the left versus right hemisphere, and were confined to posterior language cortices. Certain language functions such as word retrieval and production were found to be located to more anterior language cortices, and deteriorate as a function of age. Sowell et al., also reported that these anterior language cortices were found to mature and decline earlier than the more posterior language cortices. It has also been found that the width of sulcus not only increases with age, but also with cognitive decline in the elderly.

Age-related neuronal morphology
There is converging evidence from cognitive neuroscientists around the world that age-induced cognitive deficits may not be due to neuronal loss or cell death, but rather may be the result of small region-specific changes to the morphology of neurons. Studies by Duan et al., have shown that dendritic arbors and dendritic spines of cortical pyramidal neurons decrease in size and/or number in specific regions and layers of human and non-human primate cortex as a result of age (Duan et al., 2003; morph). A 46% decrease in spine number and spine density has been reported in humans older than 50 compared with younger individuals. An electron microscopy study in monkeys reported a 50% loss in spines on the apical dendritic tufts of pyramidal cells in prefrontal cortex of old animals (27–32 years old) compared with young ones (6–9 years old).

Neurofibrillary tangles
Age-related neuro-pathologies such as Alzheimers disease, Parkinsons disease, diabetes, hypertension and arteriosclerosis make it difficult to distinguish the normal patterns of aging.  One of the important differences between normal aging and pathological aging is the location of neurofibrillary tangles.  Neurofibrillary tangles are composed of paired helical filaments (PHF). In normal, non-demented aging, the number of tangles in each affected cell body is relatively low and restricted to the olfactory nucleus, parahippocampal gyrus, amygdala and entorhinal cortex.  As the non-demented individual ages, there is a general increase in the density of tangles, but no significant difference in where tangles are found. The other main neurodegenerative contributor commonly found in the brain of patients with AD is amyloid plaques.  However, unlike tangles, plaques have not been found to be a consistent feature of normal aging.

Role of oxidative stress
Cognitive impairment has been attributed to oxidative stress, inflammatory reactions and changes in the cerebral microvasculature.  The exact impact of each of these mechanisms in affecting cognitive aging is unknown.  Oxidative stress is the most controllable risk factor and is the best understood.  The online Merriam-Webster Medical Dictionary defines oxidative stress as,  "physiological stress on the body that is caused by the cumulative damage done by free radicals inadequately neutralized by antioxidants and that is to be associated with aging."  Hence oxidative stress is the damage done to the cells by free radicals that have been released from the oxidation process.
Compared to other tissues in the body, the brain is deemed unusually sensitive to oxidative damage. Increased oxidative damage has been associated with neurodegenerative diseases, mild cognitive impairment and individual differences in cognition in healthy elderly people.  In normal aging, the brain is undergoing oxidative stress in a multitude of ways.  The main contributors include protein oxidation, lipid peroxidation and oxidative modifications in nuclear and mitochondrial DNA.  Oxidative stress can damage DNA replication and inhibit repair through many complex processes, including telomere shortening in DNA components.  Each time a somatic cell replicates, the telomeric DNA component shortens.  As telomere length is partly inheritable, there are individual differences in the age of onset of cognitive decline.

DNA damage
At least 25 studies have demonstrated that DNA damage accumulates with age in the mammalian brain.  This DNA damage includes the oxidized nucleoside 8-hydroxydeoxyguanosine (8-OHdG), single- and double-strand breaks, DNA-protein crosslinks and malondialdehyde adducts (reviewed in Bernstein et al.).  Increasing DNA damage with age has been reported in the brains of the mouse, rat, gerbil, rabbit, dog, and human.  Young 4-day-old rats have about 3,000 single-strand breaks and 156 double-strand breaks per neuron, whereas in rats older than 2 years the level of damage increases to about 7,400 single-strand breaks and 600 double-strand breaks per neuron.Lu et al. studied the transcriptional profiles of the human frontal cortex of individuals ranging from 26 to 106 years of age. This led to the identification of a set of genes whose expression was altered after age 40.  They further found that the promoter sequences of these particular genes accumulated oxidative DNA damage, including 8-OHdG, with age (see DNA damage theory of aging).  They concluded that DNA damage may reduce the expression of selectively vulnerable genes involved in learning, memory and neuronal survival, initiating a pattern of brain aging that starts early in life.

Chemical changes
In addition to the structural changes that the brain incurs with age, the aging process also entails a broad range of biochemical changes. More specifically, neurons communicate with each other via specialized chemical messengers called neurotransmitters. Several studies have identified a number of these neurotransmitters, as well as their receptors, that exhibit a marked alteration in different regions of the brain as part of the normal aging process.

Dopamine
An overwhelming number of studies have reported age-related changes in dopamine synthesis, binding sites, and number of receptors.  Studies using positron emission tomography (PET) in living human subjects have shown a significant age-related decline in dopamine synthesis, notably in the striatum and extrastriatal regions (excluding the midbrain).  Significant age-related decreases in dopamine receptors D1, D2, and D3 have also been highly reported.  A general decrease in D1 and D2 receptors has been shown, and more specifically a decrease of D1 and D2 receptor binding in the caudate nucleus and putamen.  A general decrease in D1 receptor density has also been shown to occur with age.  Significant age-related declines in dopamine receptors, D2 and D3 were detected in the anterior cingulate cortex, frontal cortex, lateral temporal cortex, hippocampus, medial temporal cortex, amygdala, medial thalamus, and lateral thalamus One study also indicated a significant inverse correlation between dopamine binding in the occipital cortex and age.  Postmortem studies also show that the number of D1 and D2 receptors decline with age in both the caudate nucleus and the putamen, although the ratio of these receptors did not show age-related changes. The loss of dopamine with age is thought to be responsible for many neurological symptoms that increase in frequency with age, such as decreased arm swing and increased rigidity. Changes in dopamine levels may also cause age-related changes in cognitive flexibility.

Serotonin
Decreasing levels of different serotonin receptors and the serotonin transporter, 5-HTT, have also been shown to occur with age. Studies conducted using PET methods on humans, in vivo, show that levels of the 5-HT2 receptor in the caudate nucleus, putamen, and frontal cerebral cortex, decline with age.  A decreased binding capacity of the 5-HT2 receptor in the frontal cortex was also found, as well as a decreased binding capacity of the serotonin transporter, 5-HHT, in the thalamus and the midbrain.  Postmortem studies on humans have indicated decreased binding capacities of serotonin and a decrease in the number of S1 receptors in the frontal cortex and hippocampus as well as a decrease in affinity in the putamen.

Glutamate
Glutamate is another neurotransmitter that tends to decrease with age.  Studies have shown older subjects to have lower glutamate concentration in the motor cortex compared to younger subjects A significant age-related decline especially in the parietal gray matter, basal ganglia, and to a lesser degree, the frontal white matter, has also been noted. Although these levels were studied in the normal human brain, the parietal and basal ganglia regions are often affected in degenerative brain diseases associated with aging and it has therefore been suggested that brain glutamate may be useful as a marker of brain diseases that are affected by aging.

Neuropsychological changes
Changes in orientation
Orientation is defined as the awareness of self in relation to ones surroundings Often orientation is examined by distinguishing whether a person has a sense of time, place, and person. Deficits in orientation are one of the most common symptoms of brain disease, hence tests of orientation are included in almost all medical and neuropsychological evaluations. While research has primarily focused on levels of orientation among clinical populations, a small number of studies have examined whether there is a normal decline in orientation among healthy aging adults.  Results have been somewhat inconclusive. Some studies suggest that orientation does not decline over the lifespan. For example, in one study 92% of normal elderly adults (65–84 years) presented with perfect or near perfect orientation. However some data suggest that mild changes in orientation may be a normal part of aging. For example, Sweet and colleagues concluded that "older persons with normal, healthy memory may have mild orientation difficulties. In contrast, younger people with normal memory have virtually no orientation problems" (p. 505). So although current research suggests that normal aging is not usually associated with significant declines in orientation, mild difficulties may be a part of normal aging and not necessarily a sign of pathology.

Changes in attention
Many older adults notice a decline in their attentional abilities. Attention is a broad construct that refers to "the cognitive ability that allows us to deal with the inherent processing limitations of the human brain by selecting information for further processing" (p. 334). Since the human brain has limited resources, people use their attention to zone in on specific stimuli and block out others.
If older adults have fewer attentional resources than younger adults, we would expect that when two tasks must be carried out at the same time, older adults performance will decline more than that of younger adults. However, a large review of studies on cognition and aging suggest that this hypothesis has not been wholly supported. While some studies have found that older adults have a more difficult time encoding and retrieving information when their attention is divided, other studies have not found meaningful differences from younger adults. Similarly, one might expect older adults to do poorly on tasks of sustained attention, which measure the ability to attend to and respond to stimuli for an extended period of time. However, studies suggest that sustained attention shows no decline with age. Results suggest that sustained attention increases in early adulthood and then remains relatively stable, at least through the seventh decade of life. More research is needed on how normal aging impacts attention after age eighty.
It is worth noting that there are factors other than true attentional abilities that might relate to difficulty paying attention. For example, it is possible that sensory deficits impact older adults attentional abilities. In other words, impaired hearing or vision may make it more difficult for older adults to do well on tasks of visual and verbal attention.

Changes in memory
Many different types of memory have been identified in humans, such as declarative memory (including episodic memory and semantic memory), working memory, spatial memory, and procedural memory. Studies done, have found that memory functions, more specifically those associated with the medial temporal lobe are especially vulnerable to age-related decline. A number of studies utilizing a variety of methods such as histological, structural imaging, functional imaging, and receptor binding have supplied converging evidence that the frontal lobes and frontal-striatal dopaminergic pathways are especially affected by age-related processes resulting in memory changes.

Changes in language
Changes in performance on verbal tasks, as well as the location, extent, and signal intensity of BOLD signal changes measured with functional MRI, vary in predictable patterns with age.  For example, behavioral changes associated with age include compromised performance on tasks related to word retrieval, comprehension of sentences with high syntactic and/or working memory demands, and production of such sentences.

Genetic changes
Variation in the effects of aging among individuals can be attributed to both genetic, health, and environmental factors. As in so many other science disciplines, the  nature and nurture debate is an ongoing conflict in the field of cognitive neuroscience. The search for genetic factors has always been an important aspect in trying to understand neuro-pathological processes. Research focused on discovering the genetic component in developing Autosomal Dominant (AD) has also contributed greatly to the understanding the genetics behind normal or "non-pathological" aging.
Autosomal Dominant (AD) - Autosomal dominant is a pattern of inheritance characteristic of some genetic disorders. "Autosomal" means that the gene in question is located on one of the numbered, or non-sex, chromosomes. "Dominant" means that a single copy of the mutated gene (from one parent) is enough to cause the disorder.The human brain shows a decline in function and a change in gene expression. This modulation in gene expression may be due to oxidative DNA damage at promoter regions in the genome.  Genes that are down-regulated over the age of 40 include:

GluR1 AMPA receptor subunit
NMDA R2A receptor subunit (involved in learning)
Subunits of the GABA-A receptor
Genes involved in long-term potentiation e.g. calmodulin 1 and CAM kinase II alpha.
Calcium signaling genes
Synaptic plasticity genes
Synaptic vesicle release and recycling genesGenes that are upregulated include:

Genes associated with stress response and DNA repair
Antioxidant defence

Epigenetic age analysis of brain regions
The cerebellum is the youngest brain region (and probably body part) in centenarians according to an epigenetic biomarker of tissue age known as epigenetic clock: it is about 15 years younger than expected in a centenarian. By contrast, all brain regions and brain cells appear to have roughly the same epigenetic age in subjects who are younger than 80. These findings suggest that the cerebellum is protected from aging effects, which in turn could explain why the cerebellum exhibits fewer neuropathological hallmarks of age related dementias compared to other brain regions.

Delaying the effects of aging
The process of aging may be inevitable; however, one may potentially delay the effects and severity of this progression.
While there is no consensus of efficacy, the following are reported as delaying cognitive decline:

High level of education
Physical exercise
Staying intellectually engaged, i.e. reading and mental activities (such as crossword puzzles)
Maintaining social and friendship networks
Maintaining a healthy diet, including omega-3 fatty acids, and protective antioxidants.

"Super Agers"
Longitudinal research studies have recently conducted genetic analyses of centenarians and their offspring to identify biomarkers as protective factors against the negative effects of aging. In particular, the cholesteryl ester transfer protein (CETP) gene is linked to prevention of cognitive decline and Alzheimers disease. Specifically, valine CETP homozygotes but not heterozygotes experienced a relative 51% less decline in memory compared to a reference group after adjusting for demographic factors and APOE status.

Cognitive reserve
The ability of an individual to demonstrate no cognitive signs of aging despite an aging brain is called cognitive reserve. This hypothesis suggests that two patients might have the same brain pathology, with one person experiencing noticeable clinical symptoms, while the other continues to function relatively normally.  Studies of cognitive reserve explore the specific biological, genetic and environmental differences which make one person susceptible to cognitive decline, and allow another to age more gracefully.

Nun Study
A study funded by the National Institute of Aging followed a group of 678 Roman Catholic sisters and recorded the effects of aging. The researchers used autobiographical essays collected as the nuns joined their Sisterhood. Findings suggest that early idea density, defined by number of ideas expressed and use of complex prepositions in these essays, was a significant predictor of lower risk for developing Alzheimers disease in old age.  Lower idea density was found to be significantly associated with lower brain weight, higher brain atrophy, and more neurofibrillary tangles.

Hypothalamus inflammation and GnRH
In a recent study (published May 1, 2013), it is suggested that the inflammation of the hypothalamus may be connected to our overall aging bodies. They focused on the activation of the protein complex NF-κB in mice test subjects, which showed increased activation as mice test subjects aged in the study. This activation not only affects aging, but affects a hormone known as GnRH, which has shown new anti-aging properties when injected into mice outside the hypothalamus, while causing the opposite effect when injected into the hypothalamus. Itll be some time before this can be applied to humans in a meaningful way, as more studies on this pathway are necessary to understand the mechanics of GnRHs anti-aging properties.

Inflammation
A study found that myeloid cells are drivers of a maladaptive inflammation element of brain-ageing in mice and that this can be reversed or prevented via inhibition of their EP2 signalling.

Aging disparities
For certain demographics, the effects of normal cognitive aging are especially pronounced. Differences in cognitive aging might be tied to the lack of or reduced access to medical care and, as a result, suffer disproportionately from negative health outcomes. As the global population grows, diversifies, and grays, there is an increasing need to understand these inequities.

Race
African Americans
In the United States, Black and African American demographics disproportionately experience metabolic dysfunction with age. This has many downstream effects, but the most prominent of these is the toll on cardiovascular health. Metabolite profiles of the healthy aging index - a score that assesses neurocognitive function, among other correlates of health through the years - are associated with cardiovascular disease. Healthy cardiovascular function is critical for maintaining neurocognitive efficiency into old age. Attention, verbal learning, and cognitive set ability are related to diastolic blood pressure, triglyceride levels, and HDL cholesterol levels, respectively.

Latinos
The Latino demographic is most likely to develop metabolic syndrome - the combination of high blood pressure, high blood sugar, elevated triglyceride levels, and abdominal obesity - which not only increases the risk of cardiac events and type II diabetes but also is associated with lower neurocognitive function during midlife.  Among different Latin heritages, frequency of the dementia-predisposing apoE4 allele was highest for Caribbean Latinos (Cubans, Dominicans, and Puerto Ricans) and lowest among mainland Latinos (Mexicans, Central Americans, and South Americans). Conversely, frequency of the neuroprotective apoE2 allele was highest for Caribbean Latinos and lowest for those of mainland heritage.

Indigenous Peoples
Indigenous populations are often understudied in research. Reviews of current literature studying natives in Australia, Brazil, Canada, and the United States from participants aged 45 to 94 years old reveal varied prevalence rates for cognitive impairment not related to dementia, from 4.4% to 17.7%. These results can be interpreted in the context of culturally biased neurocognitive tests, preexisting health conditions, poor access to healthcare, lower educational attainment, and/or old age.

Sex
Women
Compared to their male counterparts, womens scores on the Mini Mental State Exam (MMSE) tend to decline at slightly faster rates with age. Males with mild cognitive impairment tend to show more microstructural damage than females with MCI, but seem to have a greater cognitive reserve due to larger absolute brain size and neuronal density. As a result, women tend to manifest symptoms of cognitive decline at lower thresholds than men do. This effect seems to be moderated by educational attainment - higher education is associated with later diagnosis of mild cognitive impairment as neuropathological load increases.

Transgender Individuals
LGBT elders face numerous disparities as they approach end-of-life </s>


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<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Cephalohematoma and can you explain it in depth? [/INST] A cephalohaematoma is a hemorrhage of blood between the skull and the periosteum of any age human, including a newborn baby secondary to rupture of blood vessels crossing the periosteum.  Because the swelling is subperiosteal, its boundaries are limited by the individual bones, in contrast to a caput succedaneum.

Symptoms and signs
Swelling appears after 2-3 days after birth. If severe the child may develop jaundice, anemia or hypotension.  In some cases it may be an indication of a linear skull fracture or be at risk of an infection leading to osteomyelitis or meningitis. The swelling of a cephalohematoma takes weeks to resolve as the blood clot is slowly absorbed from the periphery towards the centre. In time the swelling hardens (calcification) leaving a relatively softer centre so that it appears as a depressed fracture </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Retrograde ejaculation and can you explain it in depth? [/INST] Retrograde ejaculation occurs when semen which would be ejaculated via the urethra is redirected to the urinary bladder. Normally, the sphincter of the bladder contracts before ejaculation, sealing the bladder which besides inhibiting the release of urine also prevents a reflux of seminal fluids into the male bladder during ejaculation. The semen is forced to exit via the urethra, the path of least resistance. When the bladder sphincter does not function properly, retrograde ejaculation may occur. It can also be induced deliberately by a male as a primitive form of male birth control (known as coitus saxonicus) or as part of certain alternative medicine practices. The retrograde-ejaculated semen, which goes into the bladder, is excreted with the next urination.

Signs and symptoms
Retrograde ejaculation is sometimes referred to as a "dry orgasm." Retrograde ejaculation is one symptom of male infertility. A man may notice during masturbation that despite the occurrence of orgasm, no accompanying ejaculation was produced. Another underlying cause for this phenomenon may be ejaculatory duct obstruction.
During a male orgasm, sperm are released from the epididymis and travel via small tubes called the vas deferens. The sperm mix with seminal fluid in the seminal vesicles, prostate fluid from the prostate gland, and lubricants from the bulbourethral gland. During climax, muscles at the end of the bladder neck tighten to prevent retrograde flow of semen. In retrograde ejaculation, these bladder neck muscles are either very weak or the nerves controlling the muscles have been damaged.

Causes
A malfunctioning bladder sphincter, leading to retrograde ejaculation, may be a result either of:

Autonomic nervous system dysfunction. (Dysautonomia)
Operation on the prostate. It is a common complication of transurethral resection of the prostate, a procedure in which prostate tissue is removed, slice by slice, through a resectoscope passed along the urethra.It can also be caused by a retroperitoneal lymph node dissection for testicular cancer if nerve pathways to the bladder sphincter are damaged, with the resulting retrograde ejaculation being either temporary or permanent. Modern nerve-sparing techniques seek to reduce this risk; however, it may also occur as the result of Green Light Laser prostate surgery.
Surgery on the bladder neck accounted for about ten percent of the cases of retrograde ejaculation or anejaculation reported in a literature review.Retrograde ejaculation is a common side effect of medications, such as tamsulosin, that are used to relax the muscles of the urinary tract, treating conditions such as benign prostatic hyperplasia. By relaxing the bladder sphincter muscle, the likelihood of retrograde ejaculation is increased.
The medications that mostly cause it are antidepressant and antipsychotic medication, as well as NRIs such as atomoxetine; patients experiencing this phenomenon tend to quit the medications.Retrograde ejaculation can also be a complication of diabetes, especially in cases of diabetics with long term poor blood sugar control. This is due to neuropathy of the bladder sphincter. Post-pubertal males (aged 17 to 20 years) who experience repeated episodes of retrograde ejaculation are often diagnosed with urethral stricture disease shortly after the initial complaint arises. It is currently not known whether a congenital malformation of the bulbous urethra is responsible, or if pressure applied to the base of the penis or perineum immediately preceding ejaculatory inevitability may have inadvertently damaged the urethra. This damage is most often seen within 0.5 cm of the ejaculatory duct (usually distal to the duct).

Conditions which can affect bladder neck muscle
Medications to treat high blood pressure, benign prostate hyperplasia, mood disorders, surgery on the prostate and nerve injury (which may occur in multiple sclerosis, spinal cord injury or diabetes).

Diagnosis
Diagnosis is usually determined after a medical professional performs a urinalysis on a urine specimen that is obtained shortly after ejaculation. In cases of retrograde ejaculation, the specimen will contain an abnormal level of sperm. Especially in case of orgasmic anejaculation, anejaculation can often be confused with retrograde ejaculation, and they share some fundamental aspects of the cause. Urinalysis is used to distinguish between them.

Tests
The genitals are physically examined to ensure that there are no anatomical problems. The urine will be tested for the presence of semen. If there are no sperm in the urine, it may be due to damage to the prostate as a result of surgery or prior radiation therapy.

Treatments
The treatment depends on the cause. Medications may work for retrograde ejaculation but only in a few cases. Surgery rarely is the first option for retrograde ejaculation and the results have proven to be inconsistent. Medications do not help retrograde ejaculation if there has been permanent damage to the prostate or the testes from radiation. Medications also do not help if prostate surgery has resulted in damage to the muscles or nerves. Medications only work if there has been mild nerve damage caused by diabetes, multiple sclerosis, or mild spinal cord injury.

Medications
Tricyclic antidepressants like imipramine.
Antihistamines like chlorphenamine.
Decongestants like ephedrine and phenylephrine.These medications tighten the bladder neck muscles and prevent semen from going backwards into the bladder. However, the medications do have many side effects and they have to be taken at least 1–2 hours prior to sexual intercourse. In many cases, the medications fail to work at the right time because most men are not able to predict when they will have an orgasm.

Infertility treatments
If a couple is experiencing infertility as a result of retrograde ejaculation and medications are not helping, the collection of the semen collection may undergo a special procedure. First, the patient alkalinizes his urine by intake of sodium bicarbonate (3g dissolved in water in the evening before bed, and then another dose after complete bladder emptying  right before going to the laboratory) </s>


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<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Agenesis and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Melasma and can you explain it in depth? [/INST] Melasma (also known as chloasma faciei,: 854  or the mask of pregnancy when present in pregnant women) is a tan or dark skin discoloration. Melasma is thought to be caused by sun exposure, genetic predisposition, hormone changes, and skin irritation. Although it can affect anyone, it is particularly common in women, especially pregnant women and those who are taking oral or patch contraceptives or hormone replacement therapy medications.

Signs and symptoms
The symptoms of melasma are dark, irregular, well-demarcated, hyperpigmented macules to patches. These patches often develop gradually over time. Melasma does not cause any other symptoms beyond the cosmetic discoloration. Patches can vary in size from 0.5 cm to larger than 10 cm depending on the person. Its location can be categorized as centrofacial, malar, or mandibular. The most common is centrofacial, in which patches appear on the cheeks, nose, upper lip, forehead, and chin. The mandibular category accounts for patches on the bilateral rami, while the malar location accounts for patches only on the nose and cheeks.

Cause
The exact cause of melasma is unknown.Melasma is thought to be the stimulation of melanocytes (cells in the dermal layer, which transfer the pigment melanin to the keratinocytes of skin) when the skin is exposed to ultraviolet light from the sun. Small amounts of sun exposure can make melasma return to the skin after it has faded, which is why people with melasma often get it again and again, particularly in the summer.Pregnant women often get melasma, or chloasma, known as the mask of pregnancy. Birth-control pills and hormone replacement therapy also can trigger melasma. The discoloration usually disappears spontaneously over a period of several months after giving birth or stopping the oral contraceptives or hormone treatment.Genetic predisposition is also a major factor in determining whether someone will develop melasma. People with the Fitzpatrick skin type III or greater from African, Asian, or Hispanic descent are at a much higher risk than others. In addition, women with a light brown skin type who are living in regions with intense sun exposure are particularly susceptible to developing this condition.The incidence of melasma also increases in patients with thyroid disease. It is thought that the overproduction of melanocyte-stimulating hormone  brought on by stress can cause outbreaks of this condition. Other rare causes of melasma include allergic reaction to medications and cosmetics.

Addisons disease
Melasma suprarenale (Latin - above the kidneys) is a symptom of Addisons disease, particularly when caused by pressure or minor injury to the skin, as discovered by FJJ Schmidt of Rotterdam in 1859.

Diagnosis
Types
The two different kinds of melasma are epidermal and dermal.

Epidermal melasma results from melanin pigment that is elevated in the suprabasal layers of the epidermis.Dermal melasma occurs when the dermal macrophages have an elevated melanin level. Melasma is usually diagnosed visually or with assistance of a Woods lamp (340 - 400 nm wavelength). Under Woods lamp, excess melanin in the epidermis can be distinguished from that of the dermis. This is done by looking at how dark the melasma appears; dermal melasma appears darker than epidermal melasma under the Woods lamp.

Severity
The severity of facial melasma may be assessed by colorimetry, mexametry, and the melasma area and severity index (MASI) score.

Differential diagnoses
Melasma should be differentiated from freckles, solar lentigo, toxic melanoderma, Riehls melanosis, post-inflammatory hyperpigmentation, friction melanosis, ochronosis (endogenous and exogenous), cutaneous erythematosus lupus.  Additionally, it should not be confused with phytophotodermatosis, pellagra, endogenous phototoxicity, nevus of Ota, café au lait macules, seborrheic keratosis, Civattes poikiloderma, acquired bilateral nevus of ota-like macules (Horis nevus), periorbital hyperpigmentation, erythrose pigmentaire peribuccale of Brocq, erythromelanosis follicularis faciei, facial acanthosis nigricans, and actinic lichen planus.Also, cases of drug-induced pigmentation have been reported, caused by amiodarone, or hydroquinone-induced exogenous ochronosis (see ochronosis treatment)

Treatment
Assessment by a dermatologist can help guide treatment. Treatments to hasten the fading of the discolored patches include:

Topical depigmenting agents, such as hydroquinone (HQ) either in over-the-counter (OTC - 2%) or prescription (4%) strength </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Pneumocystosis and can you explain it in depth? [/INST] Pneumocystosis is a fungal infection that most often presents as Pneumocystis pneumonia in people with HIV/AIDS or poor immunity. It usually causes cough, difficulty breathing and fever, and can lead to respiratory failure. Involvement outside the lungs is rare but, can occur as a disseminated type affecting lymph nodes, spleen, liver, bone marrow, eyes, kidneys, thyroid, gastrointestinal tract or other organs. If occurring in the skin, it usually presents as nodular growths in the ear canals or underarms.It is caused by Pneumocystis jirovecii, a fungus which is usually breathed in and found in the lungs of healthy people without causing disease, until the persons immune system becomes weakened.Diagnosis is by identifying the organism from a sample of fluid from affected lungs or a biopsy. Prevention in high risk people, and treatment in those affected is usually with trimethoprim/sulfamethoxazole (co-trimoxazole).The prevalence is unknown. Less than 3% of cases do not involve the lungs. The first cases of pneumocystosis affecting lungs were described in premature infants in Europe following the Second World War.

Signs and symptoms
Pneumocystosis is generally an infection in the lungs. Involvement outside the lungs is rare but, can occur as a disseminated type affecting lymph nodes, bone marrow, liver or spleen. It may also affect skin, eyes, kidneys, thyroid, heart, adrenals and gastrointestinal tract.

Lungs
When the lungs are affected there is usually a dry cough, difficulty breathing and fever, usually present for longer than four weeks. There may be chest pain, shivering or tiredness. The oxygen saturation is low. The lungs may fail to function.

Eyes
Pneumocystosis in eyes may appear as a single or multiple (up to 50) yellow-white plaques in the eyes choroid layer or just beneath the retina. Vision is usually not affected and it is typically found by chance.

Skin
If occurring in the skin, pneumocystosis most often presents as nodular growths in the ear canals of a person with HIV/AIDS. There may be fluid in the ear. Skin involvement may appear outside the ear, usually palms, soles or underarms; as a rash, or small bumps with a dip. It can occur on the face as brownish bumps and plaques. The bumps may be tender and the ulcerate. Infection in the ear may result in a perforated ear drum or destruction of the mastoid bone. The nerves in the head may be affected.

Cause
Pneumocystosis is caused by Pneumocystis jirovecii, a fungus which is generally found in the lungs of healthy people, without causing disease until the persons immune system becomes weakened.

Risk factors
Pneumocystosis occurs predominantly in people with HIV/AIDS. Other risk factors include chronic lung disease, cancer, autoimmune diseases, organ transplant, or taking corticosteroids.

Diagnosis
Diagnosis of Pneumocystis pneumonia is by identifying the organism from a sample of sputum, fluid from affected lungs or a biopsy. A chest X-ray of affected lungs show widespread shadowing in both lungs, with a "bat-wing" pattern and ground glass appearance. Giemsa or silver stains can be used to identify the organism, as well as direct immunofluorescence of infected cells.Diagnosis in the eye involves fundoscopy </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Bladder exstrophy and can you explain it in depth? [/INST] Bladder exstrophy  is a congenital anomaly that exists along the spectrum of the exstrophy-epispadias complex, and most notably involves protrusion of the urinary bladder through a defect in the abdominal wall. Its presentation is variable, often including abnormalities of the bony pelvis, pelvic floor, and genitalia. The underlying embryologic mechanism leading to bladder exstrophy is unknown, though it is thought to be in part due to failed reinforcement of the cloacal membrane by underlying mesoderm.
Exstrophy means the inversion of a hollow organ.

Signs and symptoms
The classic manifestation of bladder exstrophy presents with:
A defect in the abdominal wall occupied by both the exstrophied bladder as well as a portion of the urethra
A flattened puborectal sling
Separation of the pubic symphysis
Shortening of a pubic rami
External rotation of the pelvis.Females frequently have a displaced and narrowed  vaginal orifice, a bifid clitoris, and divergent labia.

Cause
The cause is not yet clinically established but is thought to be in part due to failed reinforcement of the cloacal membrane by underlying mesoderm.

Diagnosis
In a small retrospective study of 25 pregnancies five factors were found to be strongly associated with a prenatal diagnosis of bladder exstrophy:
Inability to visualize the bladder on ultrasound
A lower abdominal bulge
A small penis with anteriorly displaced scrotum
A low set umbilical insertion
Abnormal widening of the iliac crestsWhile a diagnosis of bladder exstrophy was made retrospectively in a majority of pregnancies, in only three cases was a prenatal diagnosis made.

Management
The extreme rarity of the disease limits the surgical opportunities to practice the complex closure required in these patients. For this reason, patients have the best outcomes when the bladder closures are performed at high volume centers where surgical and nursing teams have extensive experience in caring for the disease. The highest volume center in the United States, and the world, is the Johns Hopkins Hospital in Baltimore, Maryland; they have seen over 1300 exstrophy patients in the past 50 years.Upon delivery, the exposed bladder is irrigated and a non-adherent film is placed to prevent as much contact with the external environment as possible. In the event the child was not born at a medical center with an appropriate exstrophy support team then transfer will likely follow. Upon transfer, or for those infants born at a medical center able to care for bladder exstrophy, imaging may take place in the first few hours of life prior to the child undergoing surgery.Primary (immediate) closure is indicated only in those patients with a bladder of appropriate size, elasticity, and contractility as those patients are most likely to develop a bladder of adequate capacity after early surgical intervention.Conditions that are absolute contraindications despite bladder adequacy include duplication of the penis or scrotum and significant bilateral hydronephrosis.

Surgery
Modern therapy is aimed at surgical reconstruction of the bladder and genitalia. Both males and females are born with this anomaly. Treatment is similar.
In males treatments have been:
In the modern staged repair of exstrophy (MSRE) the initial step is closure of the abdominal wall, often requiring a pelvic osteotomy. This leaves the patient with penile epispadias and urinary incontinence. At approximately 2–3 years of age, the patient then undergoes repair of the epispadias after testosterone stimulation </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Myocardial infarction and can you explain it in depth? [/INST] A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may travel into the shoulder, arm, back, neck or jaw. Often it occurs in the center or left side of the chest and lasts for more than a few minutes. The discomfort may occasionally feel like heartburn. Other symptoms may include shortness of breath, nausea, feeling faint, a cold sweat or feeling tired. About 30% of people have atypical symptoms. Women more often present without chest pain and instead have neck pain, arm pain or feel tired. Among those over 75 years old, about 5% have had an MI with little or no history of symptoms. An MI may cause heart failure, an irregular heartbeat, cardiogenic shock or cardiac arrest.Most MIs occur due to coronary artery disease. Risk factors include high blood pressure, smoking, diabetes, lack of exercise, obesity, high blood cholesterol, poor diet and excessive alcohol intake. The complete blockage of a coronary artery caused by a rupture of an atherosclerotic plaque is usually the underlying mechanism of an MI. MIs are less commonly caused by coronary artery spasms, which may be due to cocaine, significant emotional stress (commonly known as Takotsubo syndrome or broken heart syndrome) and extreme cold, among others. A number of tests are useful to help with diagnosis, including electrocardiograms (ECGs), blood tests and coronary angiography. An ECG, which is a recording of the hearts electrical activity, may confirm an ST elevation MI (STEMI), if ST elevation is present. Commonly used blood tests include troponin and less often creatine kinase MB.Treatment of an MI is time-critical. Aspirin is an appropriate immediate treatment for a suspected MI. Nitroglycerin or opioids may be used to help with chest pain; however, they do not improve overall outcomes. Supplemental oxygen is recommended in those with low oxygen levels or shortness of breath. In a STEMI, treatments attempt to restore blood flow to the heart and include percutaneous coronary intervention (PCI), where the arteries are pushed open and may be stented, or thrombolysis, where the blockage is removed using medications. People who have a non-ST elevation myocardial infarction (NSTEMI) are often managed with the blood thinner heparin, with the additional use of PCI in those at high risk. In people with blockages of multiple coronary arteries and diabetes, coronary artery bypass surgery (CABG) may be recommended rather than angioplasty. After an MI, lifestyle modifications, along with long-term treatment with aspirin, beta blockers and statins, are typically recommended.Worldwide, about 15.9 million myocardial infarctions occurred in 2015. More than 3 million people had an ST elevation MI, and more than 4 million had an NSTEMI. STEMIs occur about twice as often in men as women. About one million people have an MI each year in the United States. In the developed world, the risk of death in those who have had an STEMI is about 10%. Rates of MI for a given age have decreased globally between 1990 and 2010. In 2011, an MI was one of the top five most expensive conditions during inpatient hospitalizations in the US, with a cost of about $11.5 billion for 612,000 hospital stays.

Terminology
Myocardial infarction (MI) refers to tissue death (infarction) of the heart muscle (myocardium) caused by ischaemia, the lack of oxygen delivery to myocardial tissue. It is a type of acute coronary syndrome, which describes a sudden or short-term change in symptoms related to blood flow to the heart. Unlike the other type of acute coronary syndrome, unstable angina, a myocardial infarction occurs when there is cell death, which can be estimated by measuring by a blood test for biomarkers (the cardiac protein troponin). When there is evidence of an MI, it may be classified as an ST elevation myocardial infarction (STEMI) or Non-ST elevation myocardial infarction (NSTEMI) based on the results of an ECG.The phrase "heart attack" is often used non-specifically to refer to myocardial infarction. An MI is different from—but can cause—cardiac arrest, where the heart is not contracting at all or so poorly that all vital organs cease to function, thus might lead to death. It is also distinct from heart failure, in which the pumping action of the heart is impaired. However, an MI may lead to heart failure.

Signs and symptoms
Chest pain that may or may not radiate to other parts of the body is the most typical and significant symptom of myocardial infarction. It might be accompanied by other symptoms such as sweating.

Pain
Chest pain is one of the most common symptoms of acute myocardial infarction and is often described as a sensation of tightness, pressure, or squeezing. Pain radiates most often to the left arm, but may also radiate to the lower jaw, neck, right arm, back, and upper abdomen. The pain most suggestive of an acute MI, with the highest likelihood ratio, is pain radiating to the right arm and shoulder. Similarly, chest pain similar to a previous heart attack is also suggestive. The pain associated with MI is usually diffuse, does not change with position, and lasts for more than 20 minutes. It might be described as pressure, tightness, knifelike, tearing, burning sensation (all these are also manifested during other diseases). It could be felt as an unexplained anxiety, and pain might be absent altogether. Levines sign, in which a person localizes the chest pain by clenching one or both fists over their sternum, has classically been thought to be predictive of cardiac chest pain, although a prospective observational study showed it had a poor positive predictive value.Typically, chest pain because of ischemia, be it unstable angina or myocardial infarction, lessens with the use of nitroglycerin, but nitroglycerin may also relieve chest pain arising from non-cardiac causes.

Other
Chest pain may be accompanied by sweating, nausea or vomiting, and fainting, and these symptoms may also occur without any pain at all. In women, the most common symptoms of myocardial infarction include shortness of breath, weakness, and fatigue. Women are more likely to have unusual or unexplained tiredness and nausea or vomiting as symptoms. Women having heart attacks are more likely to have palpitations, back pain, labored breath, vomiting, and left arm pain than men, although the studies showing these differences had high variability. Women are less likely to report chest pain during a heart attack and more likely to report nausea, jaw pain, neck pain, cough, and fatigue, although these findings are inconsistent across studies. Women with heart attacks also had more indigestion, dizziness, loss of appetite, and loss of consciousness. Shortness of breath is a common, and sometimes the only symptom, occurring when damage to the heart limits the output of the left ventricle, with breathlessness arising either from low oxygen in the blood, or pulmonary edema. Other less common symptoms include weakness, light-headedness, palpitations, and abnormalities in heart rate or blood pressure. These symptoms are likely induced by a massive surge of catecholamines from the sympathetic nervous system, which occurs in response to pain and, where present, low blood pressure. Loss of consciousness due to inadequate blood flow to the brain and cardiogenic shock, and sudden death, frequently due to the development of ventricular fibrillation, can occur in myocardial infarctions. Cardiac arrest, and atypical symptoms such as palpitations, occur more frequently in women, the elderly, those with diabetes, in people who have just had surgery, and in critically ill patients.

Absence
"Silent" myocardial infarctions can happen without any symptoms at all. These cases can be discovered later on electrocardiograms, using blood enzyme tests, or at autopsy after a person has died. Such silent myocardial infarctions represent between 22 and 64% of all infarctions, and are more common in the elderly, in those with diabetes mellitus and after heart transplantation. In people with diabetes, differences in pain threshold, autonomic neuropathy, and psychological factors have been cited as possible explanations for the lack of symptoms. In heart transplantation, the donor heart is not fully innervated by the nervous system of the recipient.

Risk factors
The most prominent risk factors for myocardial infarction are older age, actively smoking, high blood pressure, diabetes mellitus, and total cholesterol and high-density lipoprotein levels. Many risk factors of myocardial infarction are shared with coronary artery disease, the primary cause of myocardial infarction, with other risk factors including male sex, low levels of physical activity, a past family history, obesity, and alcohol use. Risk factors for myocardial disease are often included in risk factor stratification scores, such as the Framingham Risk Score. At any given age, men are more at risk than women for the development of cardiovascular disease. High levels of blood cholesterol is a known risk factor, particularly high low-density lipoprotein, low high-density lipoprotein, and high triglycerides.Many risk factors for myocardial infarction are potentially modifiable, with the most important being tobacco smoking (including secondhand smoke). Smoking appears to be the cause of about 36% and obesity the cause of 20% of coronary artery disease. Lack of physical activity has been linked to 7–12% of cases. Less common causes include stress-related causes such as job stress, which accounts for about 3% of cases, and chronic high stress levels.

Diet
There is varying evidence about the importance of saturated fat in the development of myocardial infarctions. Eating polyunsaturated fat instead of saturated fats has been shown in studies to be associated with a decreased risk of myocardial infarction, while other studies find little evidence that reducing dietary saturated fat or increasing polyunsaturated fat intake affects heart attack risk. Dietary cholesterol does not appear to have a significant effect on blood cholesterol and thus recommendations about its consumption may not be needed. Trans fats do appear to increase risk. Acute and prolonged intake of high quantities of alcoholic drinks (3–4 or more daily) increases the risk of a heart attack.

Genetics
Family history of ischemic heart disease or MI, particularly if one has a male first-degree relative (father, brother) who had a myocardial infarction before age 55 years, or a female first-degree relative (mother, sister) less than age 65 increases a persons risk of MI.Genome-wide association studies have found 27 genetic variants that are associated with an increased risk of myocardial infarction. The strongest association of MI has been found with chromosome 9 on the short arm p at locus 21, which contains genes CDKN2A and 2B, although the single nucleotide polymorphisms that are implicated are within a non-coding region. The majority of these variants are in regions that have not been previously implicated in coronary artery disease. The following genes have an association with MI: PCSK9, SORT1, MIA3, WDR12, MRAS, PHACTR1, LPA, TCF21, MTHFDSL, ZC3HC1, CDKN2A, 2B, ABO, PDGF0, APOA5, MNF1ASM283, COL4A1, HHIPC1, SMAD3, ADAMTS7, RAS1, SMG6, SNF8, LDLR, SLC5A3, MRPS6, KCNE2.

Other
The risk of having a myocardial infarction increases with older age, low physical activity, and low socioeconomic status. Heart attacks appear to occur more commonly in the morning hours, especially between 6AM and noon. Evidence suggests that heart attacks are at least three times more likely to occur in the morning than in the late evening. Shift work is also associated with a higher risk of MI. And one analysis has found an increase in heart attacks immediately following the start of daylight saving time.Women who use combined oral contraceptive pills have a modestly increased risk of myocardial infarction, especially in the presence of other risk factors. The use of non-steroidal anti inflammatory drugs (NSAIDs), even for as short as a week, increases risk.Endometriosis in women under the age of 40 is an identified risk factor.Air pollution is also an important modifiable risk. Short-term exposure to air pollution such as carbon monoxide, nitrogen dioxide, and sulfur dioxide (but not ozone) have been associated with MI and other acute cardiovascular events. For sudden cardiac deaths, every increment of 30 units in Pollutant Standards Index correlated with an 8% increased risk of out-of-hospital cardiac arrest on the day of exposure. Extremes of temperature are also associated.A number of acute and chronic infections including Chlamydophila pneumoniae, influenza, Helicobacter pylori, and Porphyromonas gingivalis among others have been linked to atherosclerosis and myocardial infarction. As of 2013, there is no evidence of benefit from antibiotics or vaccination, however, calling the association into question. Myocardial infarction can also occur as a late consequence of Kawasaki disease.Calcium deposits in the coronary arteries can be detected with CT scans. Calcium seen in coronary arteries can provide predictive information beyond that of classical risk factors. High blood levels of the amino acid homocysteine is associated with premature atherosclerosis; whether elevated homocysteine in the normal range is causal is controversial.In people without evident coronary artery disease, possible causes for the myocardial infarction are coronary spasm or coronary artery dissection.

Mechanism
Atherosclerosis
The most common cause of a myocardial infarction is the rupture of an atherosclerotic plaque on an artery supplying heart muscle. Plaques can become unstable, rupture, and additionally promote the formation of a blood clot that blocks the artery; this can occur in minutes. Blockage of an artery can lead to tissue death in tissue being supplied by that artery. Atherosclerotic plaques are often present for decades before they result in symptoms.The gradual buildup of cholesterol and fibrous tissue in plaques in the wall of the coronary arteries or other arteries, typically over decades, is termed atherosclerosis. Atherosclerosis is characterized by progressive inflammation of the walls of the arteries. Inflammatory cells, particularly macrophages, move into affected arterial walls. Over time, they become laden with cholesterol products, particularly LDL, and become foam cells. A cholesterol core forms as foam cells die. In response to growth factors secreted by macrophages, smooth muscle and other cells move into the plaque and act to stabilize it. A stable plaque may have a thick fibrous cap with calcification. If there is ongoing inflammation, the cap may be thin or ulcerate. Exposed to the pressure associated with blood flow, plaques, especially those with a thin lining, may rupture and trigger the formation of a blood clot (thrombus). The cholesterol crystals have been associated with plaque rupture through mechanical injury and inflammation.

Other causes
Atherosclerotic disease is not the only cause of myocardial infarction, but it may exacerbate or contribute to other causes. A myocardial infarction may result from a heart with a limited blood supply subject to increased oxygen demands, such as in fever, a fast heart rate, hyperthyroidism, too few red blood cells in the bloodstream, or low blood pressure. Damage or failure of procedures such as percutaneous coronary intervention or coronary artery bypass grafts may cause a myocardial infarction. Spasm of coronary arteries, such as Prinzmetals angina may cause blockage.

Tissue death
If impaired blood flow to the heart lasts long enough, it triggers a process called the ischemic cascade; the heart cells in the territory of the blocked coronary artery die (infarction), chiefly through necrosis, and do not grow back. A collagen scar forms in their place. When an artery is blocked, cells lack oxygen, needed to produce ATP in mitochondria. ATP is required for the maintenance of electrolyte balance, particularly through the Na/K ATPase. This leads to an ischemic cascade of intracellular changes, necrosis and apoptosis of affected cells.Cells in the area with the worst blood supply, just below the inner surface of the heart (endocardium), are most susceptible to damage. Ischemia first affects this region, the subendocardial region, and tissue begins to die within 15–30 minutes of loss of blood supply. The dead tissue is surrounded by a zone of potentially reversible ischemia that progresses to become a full-thickness transmural infarct. The initial "wave" of infarction can take place over 3–4 hours. These changes are seen on gross pathology and cannot be predicted by the presence or absence of Q waves on an ECG. The position, size and extent of an infarct depends on the affected artery, totality of the blockage, duration of the blockage, the presence of collateral blood vessels, oxygen demand, and success of interventional procedures.Tissue death and myocardial scarring alter the normal conduction pathways of the heart, and weaken affected areas. The size and location puts a person at risk of abnormal heart rhythms (arrhythmias) or heart block, aneurysm of the heart ventricles, inflammation of the heart wall following infarction, and rupture of the heart wall that can have catastrophic consequences.Injury to the myocardium also occurs during re-perfusion. This might manifest as ventricular arrhythmia. The re-perfusion injury is a consequence of the calcium and sodium uptake from the cardiac cells and the release of oxygen radicals during reperfusion. No-reflow phenomenon—when blood is still unable to be distributed to the affected myocardium despite clearing the occlusion—also contributes to myocardial injury. Topical endothelial swelling is one of many factors contributing to this phenomenon.

Diagnosis
Criteria
A myocardial infarction, according to current consensus, is defined by elevated cardiac biomarkers with a rising or falling trend and at least one of the following:
Symptoms relating to ischemia
Changes on an electrocardiogram (ECG), such as ST segment changes, new left bundle branch block, or pathologic Q waves
Changes in the motion of the heart wall on imaging
Demonstration of a thrombus on angiogram or at autopsy.

Types
A myocardial infarction is usually clinically classified as an ST-elevation MI (STEMI) or a non-ST elevation MI (NSTEMI). These are based on ST elevation, a portion of a heartbeat graphically recorded on an ECG. STEMIs make up about 25–40% of myocardial infarctions. A more explicit classification system, based on international consensus in 2012, also exists. This classifies myocardial infarctions into five types:
Spontaneous MI related to plaque erosion and/or rupture fissuring, or dissection
MI related to ischemia, such as from increased oxygen demand or decreased supply, e.g. coronary artery spasm, coronary embolism, anemia, arrhythmias, high blood pressure, or low blood pressure
Sudden unexpected cardiac death, including cardiac arrest, where symptoms may suggest MI, an ECG may be taken with suggestive changes, or a blood clot is found in a coronary artery by angiography and/or at autopsy, but where blood samples could not be obtained, or at a time before the appearance of cardiac biomarkers in the blood
Associated with coronary angioplasty or stents
Associated with percutaneous coronary intervention (PCI)
Associated with stent thrombosis as documented by angiography or at autopsy
Associated with CABG
Associated with spontaneous coronary artery dissection in young, fit women

Cardiac biomarkers
There are many different biomarkers used to determine the presence of cardiac muscle damage. Troponins, measured through a blood test, are considered to be the best, and are preferred because they have greater sensitivity and specificity for measuring injury to the heart muscle than other tests. A rise in troponin occurs within 2–3 hours of injury to the heart muscle, and peaks within 1–2 days. The level of the troponin, as well as a change over time, are useful in measuring and diagnosing or excluding myocardial infarctions, and the diagnostic accuracy of troponin testing is improving over time. One high-sensitivity cardiac troponin can rule out a heart attack as long as the ECG is normal.Other tests, such as CK-MB or myoglobin, are discouraged. CK-MB is not as specific as troponins for acute myocardial injury, and may be elevated with past cardiac surgery, inflammation or electrical cardioversion; it rises within 4–8 hours and returns to normal within 2–3 days. Copeptin may be useful to rule out MI rapidly when used along with troponin.

Electrocardiogram
Electrocardiograms (ECGs) are a series of leads placed on a persons chest that measure electrical activity associated with contraction of the heart muscle. The taking of an ECG is an important part of the workup of an AMI, and ECGs are often not just taken once but may be repeated over minutes to hours, or in response to changes in signs or symptoms.ECG readouts product a waveform with different labelled features. In addition to a rise in biomarkers, a rise in the ST segment, changes in the shape or flipping of T waves, new Q waves, or a new left bundle branch block can be used to diagnose an AMI. In addition, ST elevation can be used to diagnose an ST segment myocardial infarction (STEMI). A rise must be new in V2 and V3 ≥2 mm (0,2 mV) for males or ≥1.5 mm (0.15 mV) for females or ≥1 mm (0.1 mV) in two other adjacent chest or limb leads. ST elevation is associated with infarction, and may be preceded by changes indicating ischemia, such as ST depression or inversion of the T waves. Abnormalities can help differentiate the location of an infarct, based on the leads that are affected by changes. Early STEMIs may be preceded by peaked T waves. Other ECG abnormalities relating to complications of acute myocardial infarctions may also be evident, such as atrial or ventricular fibrillation.

Imaging
Noninvasive imaging plays an important role in the diagnosis and characterisation of myocardial infarction. Tests such as chest X-rays can be used to explore and exclude alternate causes of a persons symptoms. Echocardiography may assist in modifying clinical suspicion of ongoing myocardial infarction in patients that cant be ruled out or ruled in following initial ECG and Troponin testing. Myocardial perfusion imaging has no role in the acute diagnostic algorithm, however it can confirm a clinical suspicion of Chronic Coronary Syndrome when the patients history, physical examination (including cardiac examination) ECG, and cardiac biomarkers suggest coronary artery disease.Echocardiography, an ultrasound scan of the heart, is able to visualize the heart, its size, shape, and any abnormal motion of the heart walls as they beat that may indicate a myocardial infarction. The flow of blood can be imaged, and contrast dyes may be given to improve image. Other scans using radioactive contrast include SPECT CT-scans using thallium, sestamibi (MIBI scans) or tetrofosmin; or a PET scan using Fludeoxyglucose or rubidium-82. These nuclear medicine scans can visualize the perfusion of heart muscle. SPECT may also be used to determine viability of tissue, and whether areas of ischemia are inducible.Medical societies and professional guidelines recommend that the physician confirm a person is at high risk for Chronic Coronary Syndrome before conducting diagnostic non-invasive imaging tests to make a diagnosis, as such tests are unlikely to change management and result in increased costs. Patients who have a normal ECG and who are able to exercise, for example, most likely do not merit routine imaging.

Differential diagnosis
There are many causes of chest pain, which can originate from the heart, lungs, gastrointestinal tract, aorta, and other muscles, bones and nerves surrounding the chest. In addition to myocardial infarction, other causes include angina, insufficient blood supply (ischemia) to the heart muscles without evidence of cell death, gastroesophageal reflux disease; pulmonary embolism, tumors of the lungs, pneumonia, rib fracture, costochondritis, heart failure and other musculoskeletal injuries. Rarer severe differential diagnoses include aortic dissection, esophageal rupture, tension pneumothorax, and pericardial effusion causing cardiac tamponade. The chest pain in an MI may mimic heartburn. Causes of sudden-onset breathlessness generally involve the lungs or heart – including pulmonary edema, pneumonia, allergic reactions and asthma, and pulmonary embolus, acute respiratory distress syndrome and metabolic acidosis. There are many different causes of fatigue, and myocardial infarction is not a common cause.

Prevention
There is a large crossover between the lifestyle and activity recommendations to prevent a myocardial infarction, and those that may be adopted as secondary prevention after an initial myocardial infarction, because of shared risk factors and an aim to reduce atherosclerosis affecting heart vessels. The influenza vaccine also appear to protect against myocardial infarction with a benefit of 15 to 45%.

Primary prevention
Lifestyle
Physical activity can reduce the risk of cardiovascular disease, and people at risk are advised to engage in 150 minutes of moderate or 75 minutes of vigorous-intensity aerobic exercise a week. Keeping a healthy weight, drinking alcohol within the recommended limits, and quitting smoking reduce the risk of cardiovascular disease.Substituting unsaturated fats such as olive oil and rapeseed oil instead of saturated fats may reduce the risk of myocardial infarction, although there is not universal agreement. Dietary modifications are recommended by some national authorities, with recommendations including increasing the intake of wholegrain starch, reducing sugar intake (particularly of refined sugar), consuming five portions of fruit and vegetables daily, consuming two or more portions of fish per week, and consuming 4–5 portions of unsalted nuts, seeds, or legumes per week. The dietary pattern with the greatest support is the Mediterranean diet. Vitamins and mineral supplements are of no proven benefit, and neither are plant stanols or sterols.Public health measures may also act at a population level to reduce the risk of myocardial infarction, for example by reducing unhealthy diets (excessive salt, saturated fat, and trans fat) including food labeling and marketing requirements as well as requirements for catering and restaurants, and stimulating physical activity. This may be part of regional cardiovascular disease prevention programs or through the health impact assessment of regional and local plans and policies.Most guidelines recommend combining different preventive strategies. A 2015 Cochrane Review found some evidence that such an approach might help with blood pressure, body mass index and waist circumference. However, there was insufficient evidence to show an effect on mortality or actual cardio-vascular events.

Medication
Statins, drugs that act to lower blood cholesterol, decrease the incidence and mortality rates of myocardial infarctions. They are often recommended in those at an elevated risk of cardiovascular diseases.Aspirin has been studied extensively in people considered at increased risk of myocardial infarction. Based on numerous studies in different groups (e.g. people with or without diabetes), there does not appear to be a benefit strong enough to outweigh the risk of excessive bleeding. Nevertheless, many clinical practice guidelines continue to recommend aspirin for primary prevention, and some researchers feel that those with very high cardiovascular risk but low risk of bleeding should continue to receive aspirin.

Secondary prevention
There is a large crossover between the lifestyle and activity recommendations to prevent a myocardial infarction, and those that may be adopted as secondary prevention after an initial myocardial infarct. Recommendations include stopping smoking, a gradual return to exercise, eating a healthy diet, low in saturated fat and low in cholesterol, drinking alcohol within recommended limits, exercising, and trying to achieve a healthy weight. Exercise is both safe and effective even if people have had stents or heart failure, and is recommended to start gradually after 1–2 weeks. Counselling should be provided relating to medications used, and for warning signs of depression. Previous studies suggested a benefit from omega-3 fatty acid supplementation but this has not been confirmed.

Medications
Following a heart attack, nitrates, when taken for two days, and ACE-inhibitors decrease the risk of death. Other medications include:
Aspirin is continued indefinitely, as well as another antiplatelet agent such as clopidogrel or ticagrelor ("dual antiplatelet therapy" or DAPT) for up to twelve months. If someone has another medical condition that requires anticoagulation (e.g. with warfarin) this may need to be adjusted based on risk of further cardiac events as well as bleeding risk. In those who have had a stent, more than 12 months of clopidogrel plus aspirin does not affect the risk of death.Beta blocker therapy such as metoprolol or carvedilol is recommended to be started within 24 hours, provided there is no acute heart failure or heart block. The dose should be increased to the highest tolerated. Contrary to what was long believed, the use of beta blockers does not appear to affect the risk of death, possibly because other treatments for MI have improved. When beta blocker medication is given within the first 24–72 hours of a STEMI no lives are saved. However, 1 in 200 people were prevented from a repeat heart attack, and another 1 in 200 from having an abnormal heart rhythm. Additionally, for 1 in 91 the medication causes a temporary decrease in the hearts ability to pump blood.ACE inhibitor therapy should be started within 24 hours, and continued indefinitely at the highest tolerated dose. This is provided there is no evidence of worsening kidney failure, high potassium, low blood pressure, or known narrowing of the renal arteries. Those who cannot tolerate ACE inhibitors may be treated with an angiotensin II receptor antagonist.Statin therapy has been shown to reduce mortality and subsequent cardiac events and should be commenced to lower LDL cholesterol. Other medications, such as ezetimibe, may also be added with this goal in mind.Aldosterone antagonists (spironolactone or eplerenone) may be used if there is evidence of left ventricular dysfunction after an MI, ideally after beginning treatment with an ACE inhibitor.

Other
A defibrillator, an electric device connected to the heart and surgically inserted under the skin, may be recommended. This is particularly if there are any ongoing signs of heart failure, with a low left ventricular ejection fraction and a New York Heart Association grade II or III after 40 days of the infarction. Defibrillators detect potentially fatal arrhythmia and deliver an electrical shock to the person to depolarize a critical mass of the heart muscle.

Management
A myocardial infarction requires immediate medical attention. Treatment aims to preserve as much heart muscle as possible, and to prevent further complications. Treatment depends on whether the myocardial infarction is a STEMI or NSTEMI. Treatment in general aims to unblock blood vessels, reduce blood clot enlargement, reduce ischemia, and modify risk factors with the aim of preventing future MIs. In addition, the main treatment for myocardial infarctions with ECG evidence of ST elevation (STEMI) include thrombolysis or percutaneous coronary intervention, although PCI is also ideally conducted within 1–3 days for NSTEMI. In addition to clinical judgement, risk stratification may be used to guide treatment, such as with the TIMI and GRACE scoring systems.

Pain
The pain associated with myocardial infarction is often treated with nitroglycerin, a vasodilator, or opioid medications such as morphine. Nitroglycerin (given under the tongue or injected into a vein) may improve blood supply to the heart. It is an important part of therapy for its pain relief effects, though there is no proven benefit to mortality. Morphine or other opioid medications may also be used, and are effective for the pain associated with STEMI. There is poor evidence that morphine shows any benefit to overall outcomes, and there is some evidence of potential harm.

Antithrombotics
Aspirin, an antiplatelet drug, is given as a loading dose to reduce the clot size and reduce further clotting in the affected artery. It is known to decrease mortality associated with acute myocardial infarction by at least 50%. P2Y12 inhibitors such as clopidogrel, prasugrel and ticagrelor are given concurrently, also as a loading dose, with the dose depending on whether further surgical management or fibrinolysis is planned. Prasugrel and ticagrelor are recommended in European and American guidelines, as they are active more quickly and consistently than clopidogrel. P2Y12 inhibitors are recommended in both NSTEMI and STEMI, including in PCI, with evidence also to suggest improved mortality. Heparins, particularly in the unfractionated form, act at several points in the clotting cascade, help to prevent the enlargement of a clot, and are also given in myocardial infarction, owing to evidence suggesting improved mortality rates. In very high-risk scenarios, inhibitors of the platelet glycoprotein αIIbβ3a receptor such as eptifibatide or tirofiban may be used.There is varying evidence on the mortality benefits in NSTEMI. A 2014 review of P2Y12 inhibitors such as clopidogrel found they do not change the risk of death when given to people with a suspected NSTEMI prior to PCI, nor do heparins change the risk of death. They do decrease the risk of having a further myocardial infarction.

Angiogram
Primary percutaneous coronary intervention (PCI) is the treatment of choice for STEMI if it can be performed in a timely manner, ideally within 90–120 minutes of contact with a medical provider. Some recommend it is also done in NSTEMI within 1–3 days, particularly when considered high-risk. A 2017 review, however, did not find a difference between early versus later PCI in NSTEMI.PCI involves small probes, inserted through peripheral blood vessels such as the femoral artery or radial artery into the blood vessels of the heart. The probes are then used to identify and clear blockages using small balloons, which are dragged through the blocked segment, dragging away the clot, or the insertion of stents. Coronary artery bypass grafting is only considered when the affected area of heart muscle is large, and PCI is unsuitable, for example with difficult cardiac anatomy. After PCI, people are generally placed on aspirin indefinitely and on dual antiplatelet therapy (generally aspirin and clopidogrel) for at least a year.

Fibrinolysis
If PCI cannot be performed within 90 to 120 minutes in STEMI then fibrinolysis, preferably within 30 minutes of arrival to hospital, is recommended. If a person has had symptoms for 12 to 24 hours evidence for effectiveness of thrombolysis is less and if they have had symptoms for more than 24 hours it is not recommended. Thrombolysis involves the administration of medication that activates the enzymes that normally dissolve blood clots. These medications include tissue plasminogen activator, reteplase, streptokinase, and tenecteplase. Thrombolysis is not recommended in a number of situations, particularly when associated with a high risk of bleeding or the potential for problematic bleeding, such as active bleeding, past strokes or bleeds into the brain, or severe hypertension. Situations in which thrombolysis may be considered, but with caution, include recent surgery, use of anticoagulants, pregnancy, and proclivity to bleeding. Major risks of thrombolysis are major bleeding and intracranial bleeding. Pre-hospital thrombolysis reduces time to thrombolytic treatment, based on studies conducted in higher income countries, however it is unclear whether this has an impact on mortality rates.

Other
In the past, high flow oxygen was recommended for everyone with a possible myocardial infarction. More recently, no evidence was found for routine use in those with normal oxygen levels and there is potential harm from the intervention. Therefore, oxygen is currently only recommended if oxygen levels are found to be low or if someone is in respiratory distress.If despite thrombolysis there is significant cardiogenic shock, continued severe chest pain, or less than a 50% improvement in ST elevation on the ECG recording after 90 minutes, then rescue PCI is indicated emergently.Those who have had cardiac arrest may benefit from targeted temperature management with evaluation for implementation of hypothermia protocols. Furthermore, those with cardiac arrest, and ST elevation at any time, should usually have angiography. Aldosterone antagonists appear to be useful in people who have had an STEMI and do not have heart failure.

Rehabilitation and exercise
Cardiac rehabilitation benefits many who have experienced myocardial infarction, even if there has been substantial heart damage and resultant left ventricular failure. It should start soon after discharge from the hospital. The program may include lifestyle advice, exercise, social support, as well as recommendations about driving, flying, sports participation, stress management, and sexual intercourse. Returning to sexual activity after myocardial infarction is a major concern for most patients, and is an important area to be discussed in the provision of holistic care.In the short-term, exercise-based cardiovascular rehabilitation programs may reduce the risk of a myocardial infarction, reduces a large number of hospitalizations from all causes, reduces hospital costs, improves health-related quality of life, and has a small effect on all-cause mortality. Longer-term studies indicate that exercise-based cardiovascular rehabilitation programs may reduce cardiovascular mortality and myocardial infarction.

Prognosis
The prognosis after myocardial infarction varies greatly depending on the extent and location of the affected heart muscle, and the development and management of complications. Prognosis is worse with older age and social isolation. Anterior infarcts, persistent ventricular tachycardia or fibrillation, development of heart blocks, and left ventricular impairment are all associated with poorer prognosis. Without treatment, about a quarter of those affected by MI die within minutes and about forty percent within the first month. Morbidity and mortality from myocardial infarction has however improved over the years due to earlier and better treatment: in those who have a STEMI in the United States, between 5 and 6 percent die before leaving the hospital and 7 to 18 percent die within a year.It is unusual for babies to experience a myocardial infarction, but when they do, about half die. In the short-term, neonatal survivors seem to have a normal quality of life.

Complications
Complications may occur immediately following the myocardial infarction or may take time to develop. Disturbances of heart rhythms, including atrial fibrillation, ventricular tachycardia and fibrillation and heart block can arise as a result of ischemia, cardiac scarring, and infarct location. Stroke is also a risk, either as a result of clots transmitted from the heart during PCI, as a result of bleeding following anticoagulation, or as a result of disturbances in the hearts ability to pump effectively as a result of the infarction. Regurgitation of blood through the mitral valve is possible, particularly if the infarction causes dysfunction of the papillary muscle. Cardiogenic shock as a result of the heart being unable to adequately pump blood may develop, dependent on infarct size, and is most likely to occur within the days following an acute myocardial infarction. Cardiogenic shock is the largest cause of in-hospital mortality. Rupture of the ventricular dividing wall or left ventricular wall may occur within the initial weeks. Dresslers syndrome, a reaction following larger infarcts and a cause of pericarditis is also possible.Heart failure may develop as a long-term consequence, with an impaired ability of heart muscle to pump, scarring, and an increase in the size of the existing muscle. Aneurysm of the left ventricle myocardium develops in about 10% of MI and is itself a risk factor for heart failure, ventricular arrhythmia, and the development of clots.Risk factors for complications and death include age, hemodynamic parameters (such as heart failure, cardiac arrest on admission, systolic blood pressure, or Killip class of two or greater), ST-segment deviation, diabetes, serum creatinine, peripheral vascular disease, and elevation of cardiac markers.

Epidemiology
Myocardial infarction is a common presentation of coronary artery disease. The World Health Organization estimated in 2004, that 12.2% of worldwide deaths were from ischemic heart disease; with it being the leading cause of death in high- or middle-income countries and second only to lower respiratory infections in lower-income countries. Worldwide, more than 3 million people have STEMIs and 4 million have NSTEMIs a year. STEMIs occur about twice as often in men as women.Rates of death from ischemic heart disease (IHD) have slowed or declined in most high-income countries, although cardiovascular disease still accounted for one in three of all deaths in the US in 2008. For example, rates of death from cardiovascular disease have decreased almost a third between 2001 and 2011 in the United States.In contrast, IHD is becoming a more common cause of death in the developing world. For example, in India, IHD had become the leading cause of death by 2004, accounting for 1.46 million deaths (14% of total deaths) and deaths due to IHD were expected to double during 1985–2015. Globally, disability adjusted life years (DALYs) lost to ischemic heart disease are predicted to account for 5.5% of total DALYs in 2030, making it the second-most-important cause of disability (after unipolar depressive disorder), as well as the leading cause of death by this date.

Social determinants of health
Social determinants such as neighborhood disadvantage, immigration status, lack of social support, social isolation, access to health services play an important role in myocardial infarction risk and survival. Studies have shown that low socioeconomic status is associated with an increased risk of poorer survival. There are well-documented disparities in myocardial infarction survival by socioeconomic status, race, education, and census-tract-level poverty.Race: In the U.S. African Americans have a greater burden of myocardial infarction and other cardiovascular events. On a population level, there is a higher overall prevalence of risk factors that are unrecognized and therefore not treated, which places these individuals at a greater likelihood of experiencing adverse outcomes and therefore potentially higher morbidity and mortality.Socioeconomic status: Among individuals who live in the low-socioeconomic (SES) areas, which is close to 25% of the US population, myocardial infarctions (MIs) occurred twice as often compared with people who lived in higher SES areas.Immigration status: In 2018 many lawfully present immigrants who are eligible for coverage remain uninsured because immigrant families face a range of enrollment barriers, including fear, confusion about eligibility policies, difficulty navigating the enrollment process, and language and literacy challenges. Uninsured undocumented immigrants are ineligible for coverage options due to their immigration status.Health care access: Lack of health insurance and financial concerns about accessing care were associated with delays in seeking emergency care for acute myocardial infarction which can have significant, adverse consequences on patient outcomes.Education: Researchers found that compared to people with graduate degrees, those with lower educational attainment appeared to have a higher risk of heart attack, dying from a cardiovascular event, and overall death.

Society and culture
Depictions of heart attacks in popular media often include collapsing or loss of consciousness which are not common symptoms; these depictions contribute to widespread misunderstanding about the symptoms of myocardial infarctions, which in turn contributes to people not getting care when they should.

Legal implications
At common law, in general, a myocardial infarction is a disease, but may sometimes be an injury. This can create coverage issues in the administration of no-fault insurance schemes such as workers compensation. In general, a heart attack is not covered; however, it may be a work-related injury if it results, for example, from unusual emotional stress or unusual exertion. In addition, in some jurisdictions, heart attacks had by persons in particular occupations such as police officers may be classified as line-of-duty injuries by statute or policy. In some countries or states, a person having had an MI may be prevented from participating in activity that puts other peoples lives at risk, for example driving a car or flying an airplane.

References
Sources
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Blumenthal RS, Margolis S (2007). Heart Attack Prevention 2007. Johns Hopkins Health. ISBN 978-1-933087-47-4.
Dwight J (16 June 2016). "Chest pain, breathlessness, fatigue".  In Timothy Cox (ed.). Oxford Textbook of Medicine: Cardiovascular Disorders. Jeremy Dwight. Oxford University Press. pp. 39–47. ISBN 978-0-19-871702-7.
Gaziano TA, Gaziano JM (15 September 2016). "Global Evolving Epidemiology, Natural History, and Treatment Trends of Myocardial Infarction".  In Morrow DA (ed.). Myocardial Infarction: A Companion to Braunwalds Heart Disease. Elsevier. pp. 11–21. ISBN 978-0-323-35943-6.
Morrow DA, Bohula EA (15 September 2016). "Heart Failure and Cardiogenic Shock After Myocardial Infarction".  In Morrow DA (ed.). Myocardial Infarction: A Companion to Braunwalds Heart Disease. Elsevier. pp. 295–313. ISBN 978-0-323-35943-6.
Morrow DA, Braunwald E (15 September 2016). "Classification and Diagnosis of Acute Coronary Syndromes".  In Morrow DA (ed.). Myocardial Infarction: A Companion to Braunwalds Heart Disease. Elsevier. pp. 1–10. ISBN 978-0-323-35943-6.
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