<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 Attention deficit hyperactivity disorder and can you explain it in depth? [/INST] Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by excessive amounts of inattention, hyperactivity, and impulsivity that are pervasive, impairing in multiple contexts, and otherwise age-inappropriate.ADHD symptoms arise from executive dysfunction, and emotional dysregulation is often considered a core symptom. In children, problems paying attention may result in poor school performance. ADHD is associated with other neurodevelopmental and mental disorders as well as some non-psychiatric disorders, which can cause additional impairment, especially in modern society. Although people with ADHD struggle to focus on tasks they are not particularly interested in completing, they are often able to maintain an unusually prolonged and intense level of attention for tasks they do find interesting or rewarding; this is known as hyperfocus.
The precise causes of ADHD are unknown in the majority of cases. Genetic factors play an important role; ADHD tends to run in families and has a heritability rate of 74%. Toxins and infections during pregnancy and brain damage may be environmental risks.
It affects about 5–7% of children when diagnosed via the DSM-IV criteria, and 1–2% when diagnosed via the ICD-10 criteria. Rates are similar between countries and differences in rates depend mostly on how it is diagnosed. ADHD is diagnosed approximately twice as often in boys than in girls, and 1.6 times more often in men than in women, although the disorder is overlooked in girls or diagnosed in later life because their symptoms sometimes differ from diagnostic criteria. About 30–50% of people diagnosed in childhood continue to have ADHD in adulthood, with 2.58% of adults estimated to have ADHD which began in childhood. In adults, hyperactivity is usually replaced by inner restlessness, and adults often develop coping skills to compensate for their impairments. The condition can be difficult to tell apart from other conditions, as well as from high levels of activity within the range of normal behavior. ADHD has a negative impact on patients health related quality of life and that this may be further exacerbated by, or may increase the risk of, other psychiatric conditions such as anxiety and depression.ADHD management recommendations vary and usually involve some combination of medications, counseling, and lifestyle changes. The British guideline emphasises environmental modifications and education for individuals and carers about ADHD as the first response. If symptoms persist, parent-training, medication, or psychotherapy (especially cognitive behavioral therapy) can be recommended based on age. Canadian and American guidelines recommend medications and behavioral therapy together, except in preschool-aged children for whom the first-line treatment is behavioral therapy alone. Stimulant medications are the most effective pharmaceutical treatment, although there may be side effects and any improvements will be reverted if medication is ceased.ADHD, its diagnosis, and its treatment have been considered controversial since the 1970s. These controversies have involved doctors, teachers, policymakers, parents, and the media. Topics have included causes of ADHD and the use of stimulant medications in its treatment. ADHD is now a well-validated clinical diagnosis in children and adults, and the debate in the scientific community mainly centers on how it is diagnosed and treated. ADHD was officially known as attention deficit disorder (ADD) from 1980 to 1987; prior to the 1980s, it was known as hyperkinetic reaction of childhood. Symptoms similar to those of ADHD have been described in medical literature dating back to the 18th century.

Signs and symptoms
Inattention, hyperactivity (restlessness in adults), disruptive behavior, and impulsivity are common in ADHD. Academic difficulties are frequent as are problems with relationships. The symptoms can be difficult to define, as it is hard to draw a line at where normal levels of inattention, hyperactivity, and impulsivity end and significant levels requiring interventions begin.According to the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) and its text revision (DSM-5-TR), symptoms must be present for six months or more to a degree that is much greater than others of the same age. This requires at least six symptoms of either inattention or hyperactivity/impulsivity for those under 17 and at least five symptoms for those 17 years or older. The symptoms must be present in at least two settings (e.g., social, school, work, or home), and must directly interfere with or reduce quality of functioning. Additionally, several symptoms must have been present before age twelve.

Subtypes
ADHD is divided into three primary presentations:
predominantly inattentive (ADHD-PI or ADHD-I)
predominantly hyperactive-impulsive (ADHD-PH or ADHD-HI)
combined type (ADHD-C).The table "Symptoms" lists the symptoms for ADHD-I and ADHD-HI from two major classification systems. Symptoms which can be better explained by another psychiatric or medical condition which an individual has are not considered to be a symptom of ADHD for that person.

Girls and women with ADHD tend to display fewer hyperactivity and impulsivity symptoms but more symptoms of inattention and distractibility.Symptoms are expressed differently and more subtly as the individual ages.: 6  Hyperactivity tends to become less overt with age and turns into inner restlessness, difficulty relaxing or remaining still, talkativeness or constant mental activity in teens and adults with ADHD.: 6–7  Impulsivity in adulthood may appear as thoughtless behaviour, impatience, irresponsible spending and sensation-seeking behaviours,: 6  while inattention may appear as becoming easily bored, difficulty with organization, remaining on task and making decisions, and sensitivity to stress.: 6 Although not listed as an official symptom for this condition, emotional dysregulation or mood lability is generally understood to be a common symptom of ADHD.: 6  People with ADHD of all ages are more likely to have problems with social skills, such as social interaction and forming and maintaining friendships. This is true for all presentations. About half of children and adolescents with ADHD experience social rejection by their peers compared to 10–15% of non-ADHD children and adolescents. People with attention deficits are prone to having difficulty processing verbal and nonverbal language which can negatively affect social interaction. They also may drift off during conversations, miss social cues, and have trouble learning social skills.Difficulties managing anger are more common in children with ADHD as are delays in speech, language and motor development. Poorer handwriting is more common in children with ADHD. Poor handwriting in many situations can be a side effect of ADHD in itself due to decreased attentiveness but when its a constant problem it may also be in part due to both Dyslexic and Dysgraphic individuals having higher rates of ADHD than the general population, with 3 in 10 people who have dyslexia also having ADHD. Although it causes significant difficulty, many children with ADHD have an attention span equal to or greater than that of other children for tasks and subjects they find interesting.

Comorbidities
Psychiatric
In children, ADHD occurs with other disorders about two-thirds of the time.Other neurodevelopmental conditions are common comorbidities. Autism spectrum disorder (ASD), co-occurring at a rate of 21% in those with ADHD, affects social skills, ability to communicate, behaviour, and interests. Both ADHD and ASD can be diagnosed in the same person. Learning disabilities have been found to occur in about 20–30% of children with ADHD. Learning disabilities can include developmental speech and language disorders, and academic skills disorders. ADHD, however, is not considered a learning disability, but it very frequently causes academic difficulties. Intellectual disabilities and Tourettes syndrome are also common.
ADHD is often comorbid with disruptive, impulse control, and conduct disorders. Oppositional defiant disorder (ODD) occurs in about 25% of children with an inattentive presentation and 50% of those with a combined presentation. It is characterised by angry or irritable mood, argumentative or defiant behavior and vindictiveness which are age-inappropriate. Conduct disorder (CD) occurs in about 25% of adolescents with ADHD. It is characterised by aggression, destruction of property, deceitfulness, theft and violations of rules. Adolescents with ADHD who also have CD are more likely to develop antisocial personality disorder in adulthood. Brain imaging supports that CD and ADHD are separate conditions, wherein conduct disorder was shown to reduce the size of ones temporal lobe and limbic system, and increase the size of ones orbitofrontal cortex, whereas ADHD was shown to reduce connections in the cerebellum and prefrontal cortex more broadly. Conduct disorder involves more impairment in motivation control than ADHD. Intermittent explosive disorder is characterised by sudden and disproportionate outbursts of anger and co-occurs in individuals with ADHD more frequently than in the general population.Anxiety and mood disorders are frequent comorbidities. Anxiety disorders have been found to occur more commonly in the ADHD population, as have mood disorders (especially bipolar disorder and major depressive disorder). Boys diagnosed with the combined ADHD subtype are more likely to have a mood disorder. Adults and children with ADHD sometimes also have bipolar disorder, which requires careful assessment to accurately diagnose and treat both conditions.Sleep disorders and ADHD commonly co-exist. They can also occur as a side effect of medications used to treat ADHD. In children with ADHD, insomnia is the most common sleep disorder with behavioral therapy being the preferred treatment. Problems with sleep initiation are common among individuals with ADHD but often they will be deep sleepers and have significant difficulty getting up in the morning. Melatonin is sometimes used in children who have sleep onset insomnia. Specifically, the sleep disorder restless legs syndrome has been found to be more common in those with ADHD and is often due to iron deficiency anemia. However, restless legs can simply be a part of ADHD and requires careful assessment to differentiate between the two disorders. Delayed sleep phase disorder is also a common comorbidity of those with ADHD.There are other psychiatric conditions which are often co-morbid with ADHD, such as substance use disorders. Individuals with ADHD are at increased risk of substance abuse.: 9  This is most commonly seen with alcohol or cannabis.: 9  The reason for this may be an altered reward pathway in the brains of ADHD individuals, self-treatment and increased psychosocial risk factors.: 9  This makes the evaluation and treatment of ADHD more difficult, with serious substance misuse problems usually treated first due to their greater risks. Other psychiatric conditions include reactive attachment disorder, characterised by a severe inability to appropriately relate socially, and sluggish cognitive tempo, a cluster of symptoms that potentially comprises another attention disorder and may occur in 30–50% of ADHD cases, regardless of the subtype. Individuals with ADHD are 4x more likely to develop and be diagnosed with an eating disorder (Anorexia, Bulimia, Binge Eating, ARFID) compared to those without ADHD. Individuals with diagnosed eating disorders are 2.6x more likely to have ADHD than those without eating disorders, though these numbers are likely much lower than actual rates, due to limitations with screening and diagnosis in marginalized populations.

Trauma
ADHD, trauma, and Adverse Childhood Experiences are also comorbid, which could in part be potentially explained by the similarity in presentation between different diagnoses. The symptoms of ADHD and PTSD can have significant behavioral overlap with ADHD—in particular, motor restlessness, difficulty concentrating, distractibility, irritability/anger, emotional constriction or dysregulation, poor impulse control, and forgetfulness are common in both. This could result in trauma-related disorders or ADHD being mis-identified as the other. Additionally, traumatic events in childhood are a risk factor for ADHD - it can lead to structural brain changes and the development of ADHD behaviors. Finally, the behavioral consequences of ADHD symptoms cause a higher chance of the individual experiencing trauma (and therefore ADHD leads to a concrete diagnosis of a trauma-related disorder).

Non-psychiatric
Some non-psychiatric conditions are also comorbidities of ADHD. This includes epilepsy, a neurological condition characterised by recurrent seizures. There are well established associations between ADHD and obesity, asthma  and sleep disorders, and an association with celiac disease. Children with ADHD have a higher risk for migraine headaches, but have no increased risk of tension-type headaches. In addition, children with ADHD may also experience headaches as a result of medication.A 2021 review reported that several neurometabolic disorders caused by inborn errors of metabolism converge on common neurochemical mechanisms that interfere with biological mechanisms also considered central in ADHD pathophysiology and treatment. This highlights the importance of close collaboration between health services to avoid clinical overshadowing.

Suicide risk
Systematic reviews conducted in 2017 and 2020 found strong evidence that ADHD is associated with increased suicide risk across all age groups, as well as growing evidence that an ADHD diagnosis in childhood or adolescence represents a significant future suicidal risk factor. Potential causes include ADHDs association with functional impairment, negative social, educational and occupational outcomes, and financial distress. A 2019 meta-analysis indicated a significant association between ADHD and suicidal spectrum behaviors (suicidal attempts, ideations, plans, and completed suicides); across the studies examined, the prevalence of suicide attempts in individuals with ADHD was 18.9%, compared to 9.3% in individuals without ADHD, and the findings were substantially replicated among studies which adjusted for other variables. However, the relationship between ADHD and suicidal spectrum behaviors remains unclear due to mixed findings across individual studies and the complicating impact of comorbid psychiatric disorders. There is no clear data on whether there is a direct relationship between ADHD and suicidality, or whether ADHD increases suicide risk through comorbidities.

IQ test performance
Certain studies have found that people with ADHD tend to have lower scores on intelligence quotient (IQ) tests. The significance of this is controversial due to the differences between people with ADHD and the difficulty determining the influence of symptoms, such as distractibility, on lower scores rather than intellectual capacity. In studies of ADHD, higher IQs may be over-represented because many studies exclude individuals who have lower IQs despite those with ADHD scoring on average nine points lower on standardized intelligence measures. In individuals with high intelligence, there is increased risk of a missed ADHD diagnosis, possibly because of compensatory strategies in highly intelligent individuals.Studies of adults suggest that negative differences in intelligence are not meaningful and may be explained by associated health problems.

Causes
ADHD is generally claimed to be the result of neurological dysfunction in processes associated with the production or use of dopamine and norepinephrine in various brain structures, but there are no confirmed causes. It may involve interactions between genetics and the environment.

Genetics
ADHD has a high heritability of 74%, meaning that 74% of the presence of ADHD in the population is due to genetic factors. There are multiple gene variants which each slightly increase the likelihood of a person having ADHD; it is polygenic and arises through the combination of many gene variants which each have a small effect. The siblings of children with ADHD are three to four times more likely to develop the disorder than siblings of children without the disorder.Arousal is related to dopaminergic functioning, and ADHD presents with low dopaminergic functioning. Typically, a number of genes are involved, many of which directly affect dopamine neurotransmission. Those involved with dopamine include DAT, DRD4, DRD5, TAAR1, MAOA, COMT, and DBH. Other genes associated with ADHD include SERT, HTR1B, SNAP25, GRIN2A, ADRA2A, TPH2, and BDNF. A common variant of a gene called latrophilin 3 is estimated to be responsible for about 9% of cases and when this variant is present, people are particularly responsive to stimulant medication. The 7 repeat variant of dopamine receptor D4 (DRD4–7R) causes increased inhibitory effects induced by dopamine and is associated with ADHD. The DRD4 receptor is a G protein-coupled receptor that inhibits adenylyl cyclase. The DRD4–7R mutation results in a wide range of behavioral phenotypes, including ADHD symptoms reflecting split attention. The DRD4 gene is both linked to novelty seeking and ADHD. The genes GFOD1 and CDH13 show strong genetic associations with ADHD. CHD13s association with ASD, schizophrenia, bipolar disorder, and depression make it an interesting candidate causative gene. Another candidate causative gene that has been identified is ADGRL3. In zebrafish, knockout of this gene causes a loss of dopaminergic function in the ventral diencephalon and the fish display a hyperactive/impulsive phenotype.For genetic variation to be used as a tool for diagnosis, more validating studies need to be performed. However, smaller studies have shown that genetic polymorphisms in genes related to catecholaminergic neurotransmission or the SNARE complex of the synapse can reliably predict a persons response to stimulant medication. Rare genetic variants show more relevant clinical significance as their penetrance (the chance of developing the disorder) tends to be much higher. However their usefulness as tools for diagnosis is limited as no single gene predicts ADHD. ASD shows genetic overlap with ADHD at both common and rare levels of genetic variation.

Environment
In addition to genetics, some environmental factors might play a role in causing ADHD. Alcohol intake during pregnancy can cause fetal alcohol spectrum disorders which can include ADHD or symptoms like it. Children exposed to certain toxic substances, such as lead or polychlorinated biphenyls, may develop problems which resemble ADHD. Exposure to the organophosphate insecticides chlorpyrifos and dialkyl phosphate is associated with an increased risk; however, the evidence is not conclusive. Exposure to tobacco smoke during pregnancy can cause problems with central nervous system development and can increase the risk of ADHD. Nicotine exposure during pregnancy may be an environmental risk.Extreme premature birth, very low birth weight, and extreme neglect, abuse, or social deprivation also increase the risk as do certain infections during pregnancy, at birth, and in early childhood. These infections include, among others, various viruses (measles, varicella zoster encephalitis, rubella, enterovirus 71). At least 30% of children with a traumatic brain injury later develop ADHD and about 5% of cases are due to brain damage.Some studies suggest that in a small number of children, artificial food dyes or preservatives may be associated with an increased prevalence of ADHD or ADHD-like symptoms, but the evidence is weak and may only apply to children with food sensitivities. The European Union has put in place regulatory measures based on these concerns. In a minority of children, intolerances or allergies to certain foods may worsen ADHD symptoms.Individuals with hypokalemic sensory overstimulation are sometimes diagnosed as having attention deficit hyperactivity disorder (ADHD), raising the possibility that a subtype of ADHD has a cause that can be understood mechanistically and treated in a novel way. The sensory overload is treatable with oral potassium gluconate.

Research does not support popular beliefs that ADHD is caused by eating too much refined sugar, watching too much television, parenting, poverty or family chaos; however, they might worsen ADHD symptoms in certain people.

Society
The youngest children in a class have been found to be more likely to be diagnosed as having ADHD, possibly due to them being developmentally behind their older classmates. They also appear to use ADHD medications at nearly twice the rate of their peers.In some cases, an inappropriate diagnosis of ADHD may reflect a dysfunctional family or a poor educational system, rather than any true presence of ADHD in the individual. In other cases, it may be explained by increasing academic expectations, with a diagnosis being a method for parents in some countries to get extra financial and educational support for their child. Behaviors typical of ADHD occur more commonly in children who have experienced violence and emotional abuse.

Pathophysiology
Current models of ADHD suggest that it is associated with functional impairments in some of the brains neurotransmitter systems, particularly those involving dopamine and norepinephrine. The dopamine and norepinephrine pathways that originate in the ventral tegmental area and locus coeruleus project to diverse regions of the brain and govern a variety of cognitive processes. The dopamine pathways and norepinephrine pathways which project to the prefrontal cortex and striatum are directly responsible for modulating executive function (cognitive control of behavior), motivation, reward perception, and motor function; these pathways are known to play a central role in the pathophysiology of ADHD. Larger models of ADHD with additional pathways have been proposed.

Brain structure
In children with ADHD, there is a general reduction of volume in certain brain structures, with a proportionally greater decrease in the volume in the left-sided prefrontal cortex. The posterior parietal cortex also shows thinning in individuals with ADHD compared to controls. Other brain structures in the prefrontal-striatal-cerebellar and prefrontal-striatal-thalamic circuits have also been found to differ between people with and without ADHD.The subcortical volumes of the accumbens, amygdala, caudate, hippocampus, and putamen appears smaller in individuals with ADHD compared with controls. Structural MRI studies have also revealed differences in white matter, with marked differences in inter-hemispheric asymmetry between ADHD and typically developing youths Functional MRI fMRI studies have revealed a number of differences between ADHD and control brains.  Independent component analysis performed on resting-state fMRI data have revealed that individuals with the inattentive type of ADHD have significantly more independent components are required to describe the variance of this data.

Neurotransmitter pathways
Previously, it had been suggested that the elevated number of dopamine transporters in people with ADHD was part of the pathophysiology, but it appears the elevated numbers may be due to adaptation following exposure to stimulant medication. Current models involve the mesocorticolimbic dopamine pathway and the locus coeruleus-noradrenergic system. ADHD psychostimulants possess treatment efficacy because they increase neurotransmitter activity in these systems. There may additionally be abnormalities in serotonergic, glutamatergic, or cholinergic pathways.

Executive function and motivation
The symptoms of ADHD arise from a deficiency in certain executive functions (e.g., attentional control, inhibitory control, and working memory). Executive functions are a set of cognitive processes that are required to successfully select and monitor behaviors that facilitate the attainment of ones chosen goals. The executive function impairments that occur in ADHD individuals result in problems with staying organised, time keeping, excessive procrastination, maintaining concentration, paying attention, ignoring distractions, regulating emotions, and remembering details. People with ADHD appear to have unimpaired long-term memory, and deficits in long-term recall appear to be attributed to impairments in working memory. Due to the rates of brain maturation and the increasing demands for executive control as a person gets older, ADHD impairments may not fully manifest themselves until adolescence or even early adulthood.ADHD has also been associated with motivational deficits in children. Children with ADHD often find it difficult to focus on long-term over short-term rewards, and exhibit impulsive behavior for short-term rewards.

Paradoxical reaction to neuroactive substances
Another sign of the structurally altered signal processing in the central nervous system in this group of people is the conspicuously common Paradoxical reaction (c. 10–20% of patients). These are unexpected reactions in the opposite direction as with a normal effect, or otherwise significant different reactions. These are reactions to neuroactive substances such as local anesthetic at the dentist, sedative, caffeine, antihistamine, weak neuroleptics and central and peripheral painkillers. Since the causes of paradoxical reactions are at least partly genetic, it may be useful in critical situations, for example before operations, to ask whether such abnormalities may also exist in family members.

Diagnosis
ADHD is diagnosed by an assessment of a persons behavioral and mental development, including ruling out the effects of drugs, medications, and other medical or psychiatric problems as explanations for the symptoms. ADHD diagnosis often takes into account feedback from parents and teachers with most diagnoses begun after a teacher raises concerns. It may be viewed as the extreme end of one or more continuous human traits found in all people. Imaging studies of the brain do not give consistent results between individuals; thus, they are only used for research purposes and not a diagnosis.In North America and Australia, DSM-5 criteria are used for diagnosis, while European countries usually use the ICD-10. The DSM-IV criteria for diagnosis of ADHD is 3–4 times more likely to diagnose ADHD than is the ICD-10 criteria. ADHD is alternately classified as neurodevelopmental disorder or a disruptive behavior disorder along with ODD, CD, and antisocial personality disorder. A diagnosis does not imply a neurological disorder.Associated conditions that should be screened for include anxiety, depression, ODD, CD, and learning and language disorders. Other conditions that should be considered are other neurodevelopmental disorders, tics, and sleep apnea.Self-rating scales, such as the ADHD rating scale and the Vanderbilt ADHD diagnostic rating scale, are used in the screening and evaluation of ADHD. Electroencephalography is not accurate enough to make an ADHD diagnosis.

Classification
Diagnostic and Statistical Manual
As with many other psychiatric disorders, a formal diagnosis should be made by a qualified professional based on a set number of criteria. In the United States, these criteria are defined by the American Psychiatric Association in the DSM. Based on the DSM-5 criteria published in 2013 and the DSM-5-TR criteria published in 2022, there are three presentations of ADHD:
ADHD, predominantly inattentive type, presents with symptoms including being easily distracted, forgetful, daydreaming, disorganization, poor concentration, and difficulty completing tasks.
ADHD, predominantly hyperactive-impulsive type, presents with excessive fidgeting and restlessness, hyperactivity, and difficulty waiting and remaining seated.
ADHD, combined type, is a combination of the first two presentations.This subdivision is based on presence of at least six (in children) or five (in older teenagers and adults) out of nine long-term (lasting at least six months) symptoms of inattention, hyperactivity–impulsivity, or both. To be considered, several symptoms must have appeared by the age of six to twelve and occur in more than one environment (e.g. at home and at school or work). The symptoms must be inappropriate for a child of that age and there must be clear evidence that they are causing social, school or work related problems.The DSM-5 and the DSM-5-TR also provide two diagnoses for individuals who have symptoms of ADHD but do not entirely meet the requirements. Other Specified ADHD allows the clinician to describe why the individual does not meet the criteria, whereas Unspecified ADHD is used where the clinician chooses not to describe the reason.

International Classification of Diseases
In the eleventh revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-11) by the World Health Organization, the disorder is classified as Attention deficit hyperactivity disorder (with the code 6A05). The defined subtypes are similar to those of the DSM-5: predominantly inattentive presentation (6A05.0); predominantly hyperactive-impulsive presentation(6A05.1); combined presentation (6A05.2). However, the ICD-11 includes two residual categories for individuals who do not entirely match any of the defined subtypes: other specified presentation (6A05.Y) where the clinician includes detail on the individuals presentation; and presentation unspecified (6A05.Z) where the clinician does not provide detail.In the tenth revision (ICD-10), the symptoms of hyperkinetic disorder were analogous to ADHD in the ICD-11. When a conduct disorder  (as defined by ICD-10) is present, the condition was referred to as hyperkinetic conduct disorder. Otherwise, the disorder was classified as disturbance of activity and attention, other hyperkinetic disorders or hyperkinetic disorders, unspecified. The latter was sometimes referred to as hyperkinetic syndrome.

Social construct theory
The social construct theory of ADHD suggests that, because the boundaries between normal and abnormal behavior are socially constructed (i.e. jointly created and validated by all members of society, and in particular by physicians, parents, teachers, and others), it then follows that subjective valuations and judgements determine which diagnostic criteria are used and thus, the number of people affected. This difference means using DSM-IV criteria could diagnose ADHD at rates three to four times higher than ICD-10 criteria. Thomas Szasz, a supporter of this theory, has argued that ADHD was "invented and then given a name".

Adults
Adults with ADHD are diagnosed under the same criteria, including that their signs must have been present by the age of six to twelve. The individual is the best source for information in diagnosis, however others may provide useful information about the individuals symptoms currently and in childhood; a family history of ADHD also adds weight to a diagnosis.: 7, 9  While the core symptoms of ADHD are similar in children and adults, they often present differently in adults than in children: for example, excessive physical activity seen in children may present as feelings of restlessness and constant mental activity in adults.: 6 Worldwide, it is estimated that 2.58% of adults have persistent ADHD (where the individual currently meets the criteria and there is evidence of childhood onset), and 6.76% of adults have symptomatic ADHD (meaning that they currently meet the criteria for ADHD, regardless of childhood onset). In 2020, this was 139.84 million and 366.33 million affected adults respectively. Around 15% of children with ADHD continue to meet full DSM-IV-TR criteria at 25 years of age, and 50% still experience some symptoms.: 2  As of 2010, most adults remain untreated. Many adults with ADHD without diagnosis and treatment have a disorganised life, and some use non-prescribed drugs or alcohol as a coping mechanism. Other problems may include relationship and job difficulties, and an increased risk of criminal activities.: 6  Associated mental health problems include depression, anxiety disorders, and learning disabilities.Some ADHD symptoms in adults differ from those seen in children. While children with ADHD may climb and run about excessively, adults may experience an inability to relax, or may talk excessively in social situations.: 6  Adults with ADHD may start relationships impulsively, display sensation-seeking behavior, and be short-tempered.: 6  Addictive behavior such as substance abuse and gambling are common.: 6  This led to those who presented differently as they aged having outgrown the DSM-IV criteria.: 5–6  The DSM-5 criteria does specifically deal with adults unlike that of DSM-IV, which does not fully take into account the differences in impairments seen in adulthood compared to childhood.: 5 For diagnosis in an adult, having symptoms since childhood is required. Nevertheless, a proportion of adults who meet the criteria for ADHD in adulthood would not have been diagnosed with ADHD as children. Most cases of late-onset ADHD develop the disorder between the ages of 12-16 and may therefore be considered early adult or adolescent-onset ADHD.

Differential diagnosis
The DSM provides potential differential diagnoses - potential alternate explanations for specific symptoms. Assessment and investigation of clinical history determines which is the most appropriate diagnosis. The DSM-5 suggests ODD, intermittent explosive disorder, and other neurodevelopmental disorders (such as stereotypic movement disorder and Tourettes disorder), in addition to specific learning disorder, intellectual developmental disorder, ASD, reactive attachment disorder, anxiety disorders, depressive disorders, bipolar disorder, disruptive mood dysregulation disorder, substance use disorder, personality disorders, psychotic disorders, medication-induced symptoms, and neurocognitive disorders. Many but not all of these are also common comorbidities of ADHD. The DSM-5-TR also suggests post-traumatic stress disorder.Symptoms of ADHD, such as low mood and poor self-image, mood swings, and irritability, can be confused with dysthymia, cyclothymia or bipolar disorder as well as with borderline personality disorder.: 10  Some symptoms that are due to anxiety disorders, personality disorder, developmental disabilities or intellectual disability or the effects of substance abuse such as intoxication and withdrawal can overlap with ADHD. These disorders can also sometimes occur along with ADHD. Medical conditions which can cause ADHD-type symptoms include: hyperthyroidism, seizure disorder, lead toxicity, hearing deficits, hepatic disease, sleep apnea, drug interactions, untreated celiac disease, and head injury.Primary sleep disorders may affect attention and behavior and the symptoms of ADHD may affect sleep. It is thus recommended that children with ADHD be regularly assessed for sleep problems. Sleepiness in children may result in symptoms ranging from the classic ones of yawning and rubbing the eyes, to hyperactivity and inattentiveness. Obstructive sleep apnea can also cause ADHD-type symptoms.

Management
The management of ADHD typically involves counseling or medications, either alone or in combination. While treatment may improve long-term outcomes, it does not get rid of negative outcomes entirely. Medications used include stimulants, atomoxetine, alpha-2 adrenergic receptor agonists, and sometimes antidepressants. In those who have trouble focusing on long-term rewards, a large amount of positive reinforcement improves task performance. ADHD stimulants also improve persistence and task performance in children with ADHD. "Recent evidence from observational and registry studies indicates that pharmacological treatment of ADHD is associated with increased achievement and decreased absenteeism at school, a reduced risk of trauma-related emergency hospital visits, reduced risks of suicide and attempted suicide, and decreased rates of substance abuse and criminality".

Behavioral therapies
There is good evidence for the use of behavioral therapies in ADHD. They are the recommended first-line treatment in those who have mild symptoms or who are preschool-aged. Psychological therapies used include: psychoeducational input, behavior therapy, cognitive behavioral therapy, interpersonal psychotherapy, family therapy, school-based interventions, social skills training, behavioral peer intervention, organization training, and parent management training. Neurofeedback has greater treatment effects than non-active controls for up to 6 months and possibly a year following treatment, and may have treatment effects comparable to active controls (controls proven to have a clinical effect) over that time period. Despite efficacy in research, there is insufficient regulation of neurofeedback practice, leading to ineffective applications and false claims regarding innovations. Parent training may improve a number of behavioral problems including oppositional and non-compliant behaviors.There is little high-quality research on the effectiveness of family therapy for ADHD—but the existing evidence shows that it is similar to community care, and better than placebo. ADHD-specific support groups can provide information and may help families cope with ADHD.Social skills training, behavioral modification, and medication may have some limited beneficial effects in peer relationships. Stable, high-quality friendships with non-deviant peers protect against later psychological problems.

Medication
Stimulants
Methylphenidate and amphetamine or its derivatives are first-line treatments for ADHD as they are considered the most effective pharmaceutical treatments. About 70 percent respond to the first stimulant tried and as few as 10 percent respond to neither amphetamines nor methylphenidate. Stimulants may also reduce the risk of unintentional injuries in children with ADHD. Magnetic resonance imaging studies suggest that long-term treatment with amphetamine or methylphenidate decreases abnormalities in brain structure and function found in subjects with ADHD. A 2018 review found the greatest short-term benefit with methylphenidate in children, and amphetamines in adults.The likelihood of developing insomnia for ADHD patients taking stimulants has been measured at between 11 and 45 percent for different medications, and may be a main reason for discontinuation. Other side effects, such as tics, decreased appetite and weight loss, or emotional lability, may also lead to discontinuation. Stimulant psychosis and mania are rare at therapeutic doses, appearing to occur in approximately 0.1% of individuals, within the first several weeks after starting amphetamine therapy. The safety of these medications in pregnancy is unclear. Symptom improvement is not sustained if medication is ceased.The long-term effects of ADHD medication have yet to be fully determined, although stimulants are generally beneficial and safe for up to two years for children and adolescents.
Regular monitoring has been recommended in those on long-term treatment. There are indications suggesting that stimulant therapy for children and adolescents should be stopped periodically to assess continuing need for medication, decrease possible growth delay, and reduce tolerance. Although potentially addictive at high doses, stimulants used to treat ADHD have low potential for abuse. Treatment with stimulants is either protective against substance abuse or has no effect.: 12 The majority of studies on nicotine and other nicotinic agonists as treatments for ADHD have shown favorable results; however, no nicotinic drug has been approved for ADHD treatment. Caffeine was formerly used as a second-line treatment for ADHD. It is considered less effective than methylphenidate or amphetamine but more so than placebo for children with ADHD. Pseudoephedrine and ephedrine do not affect ADHD symptoms.Modafinil has shown some efficacy in reducing the severity of ADHD in children and adolescents. It may be prescribed off-label to treat ADHD.

Non-stimulants
There are a number of non-stimulant medications, such as Viloxazine, atomoxetine, bupropion, guanfacine, amantadine (effective in children and adolescents but still not been seen for adults), and clonidine, that may be used as alternatives, or added to stimulant therapy. There are no good studies comparing the various medications; however, they appear more or less equal with respect to side effects. For children, stimulants appear to improve academic performance while atomoxetine does not.Atomoxetine, due to its lack of addiction liability, may be preferred in those who are at risk of recreational or compulsive stimulant use, although evidence is lacking to support its use over stimulants for this reason.: 13  Evidence supports its ability to improve symptoms when compared to placebo.Amantadine was shown to induce similar improvements in children treated methylphenidate, with less frequent side effects. A 2021 retrospective study showed showed that amantadine may serve as an effective adjunct to stimulants for ADHD–related symptoms and appears to be a safer alternative to second- or third-generation antipsychotics.There is little evidence on the effects of medication on social behaviors. Antipsychotics may also be used to treat aggression in ADHD.

Guidelines
Guidelines on when to use medications vary by country. The United Kingdoms National Institute for Health and Care Excellence recommends use for children only in severe cases, though for adults medication is a first-line treatment. Conversely, most United States guidelines recommend medications in most age groups. Medications are especially not recommended for preschool children. Underdosing of stimulants can occur, and can result in a lack of response or later loss of effectiveness. This is particularly common in adolescents and adults as approved dosing is based on school-aged children, causing some practitioners to use weight-based or benefit-based off-label dosing instead.

Exercise
Regular physical exercise, particularly aerobic exercise, is an effective add-on treatment for ADHD in children and adults, particularly when combined with stimulant medication (although the best intensity and type of aerobic exercise for improving symptoms are not currently known). The long-term effects of regular aerobic exercise in ADHD individuals include better behavior and motor abilities, improved executive functions (including attention, inhibitory control, and planning, among other cognitive domains), faster information processing speed, and better memory. Parent-teacher ratings of behavioral and socio-emotional outcomes in response to regular aerobic exercise include: better overall function, reduced ADHD symptoms, better self-esteem, reduced levels of anxiety and depression, fewer somatic complaints, better academic and classroom behavior, and improved social behavior. Exercising while on stimulant medication augments the effect of stimulant medication on executive function. It is believed that these short-term effects of exercise are mediated by an increased abundance of synaptic dopamine and norepinephrine in the brain.

Diet
Dietary modifications are not recommended as of 2019 by the American Academy of Pediatrics, the National Institute for Health and Care Excellence, or the Agency for Healthcare Research and Quality due to insufficient evidence.
A 2013 meta-analysis found less than a third of children with ADHD see some improvement in symptoms with free fatty acid supplementation or decreased eating of artificial food coloring. These benefits may be limited to children with food sensitivities or those who are simultaneously being treated with ADHD medications. This review also found that evidence does not support removing other foods from the diet to treat ADHD. A 2014 review found that an elimination diet results in a small overall benefit in a minority of children, such as those with allergies. A 2016 review stated that the use of a gluten-free diet as standard ADHD treatment is not advised. A 2017 review showed that a few-foods elimination diet may help children too young to be medicated or not responding to medication, while free fatty acid supplementation or decreased eating of artificial food coloring as standard ADHD treatment is not advised. Chronic deficiencies of iron, magnesium and iodine may have a negative impact on ADHD symptoms. There is a small amount of evidence that lower tissue zinc levels may be associated with ADHD. In the absence of a demonstrated zinc deficiency (which is rare outside of developing countries), zinc supplementation is not recommended as treatment for ADHD. However, zinc supplementation may reduce the minimum effective dose of amphetamine when it is used with amphetamine for the treatment of ADHD.

Prognosis
ADHD persists into adulthood in about 30–50% of cases. Those affected are likely to develop coping mechanisms as they mature, thus compensating to some extent for their previous symptoms. Children with ADHD have a higher risk of unintentional injuries. Effects of medication on functional impairment and quality of life (e.g. reduced risk of accidents) have been found across multiple domains. Rates of smoking among those with ADHD are higher than in the general population at about 40%.Individuals with ADHD are significantly overrepresented in prison populations. Although there is no generally accepted estimate of ADHD prevalence among inmates, a 2015 meta-analysis estimated a prevalence of 25.5%, and a larger 2018 meta-analysis estimated the frequency to be 26.2%. ADHD is more common among longer-term inmates; a 2010 study at Norrtälje Prison, a high-security prison in Sweden, found an estimated ADHD prevalence of 40%.

Epidemiology
ADHD is estimated to affect about 6–7% of people aged 18 and under when diagnosed via the DSM-IV criteria. When diagnosed via the ICD-10 criteria, rates in this age group are estimated around 1–2%. Children in North America appear to have a higher rate of ADHD than children in Africa and the Middle East; this is believed to be due to differing methods of diagnosis rather than a difference in underlying frequency.  As of 2019, it was estimated to affect 84.7 million people globally. If the same diagnostic methods are used, the rates are similar between countries. ADHD is diagnosed approximately three times more often in boys than in girls. This may reflect either a true difference in underlying rate, or that women and girls with ADHD are less likely to be diagnosed.Rates of diagnosis and treatment have increased in both the United Kingdom and the United States since the 1970s. Prior to 1970, it was rare for children to be diagnosed with ADHD, while in the 1970s rates were about 1%. This is believed to be primarily due to changes in how the condition is diagnosed and how readily people are willing to treat it with medications rather than a true change in how common the condition is. It was believed changes to the diagnostic criteria in 2013 with the release of the DSM-5 would increase the percentage of people diagnosed with ADHD, especially among adults.Due to disparities in the treatment and understanding of ADHD between caucasian and non-caucasian populations, many non-caucasian children go undiagnosed and unmedicated. It was found that within the US that there was often a disparity between caucasian and non-caucasian understandings of ADHD. This led to a difference in the classification of the symptoms of ADHD, and therefore, its misdiagnosis. It was also found that it was common in non-caucasian families and teachers to understand the symptoms of ADHD as behavioral issues, rather than mental illness.Crosscultural differences in diagnosis of ADHD can also be attributed to the long-lasting effects of harmful, racially targeted medical practices. Medical pseudosciences, particularly those that targeted African American populations during the period of slavery in the US, lead to a distrust of medical practices within certain communities. The combination of ADHD symptoms often being regarded as misbehavior rather than as a psychiatric condition, and the use of drugs to regulate ADHD, result in a hesitancy to trust a diagnosis of ADHD. Cases of misdiagnosis in ADHD can also occur due to stereotyping of non-caucasian individuals. Due to ADHDs subjectively determined symptoms, medical professionals may diagnose individuals based on stereotyped behavior or misdiagnose due to differences in symptom presentation between Caucasian and non-Caucasian individuals.

History
Hyperactivity has long been part of the human condition. Sir Alexander Crichton describes "mental restlessness" in his book An inquiry into the nature and origin of mental derangement written in 1798. He made observations about children showing signs of being inattentive and having the "fidgets". The first clear description of ADHD is credited to George Still in 1902 during a series of lectures he gave to the Royal College of Physicians of London. He noted both nature and nurture could be influencing this disorder.Alfred Tredgold proposed an association between brain damage and behavioral or learning problems which was able to be validated by the encephalitis lethargica epidemic from 1917 through 1928.The terminology used to describe the condition has changed over time and has included: minimal brain dysfunction in the DSM-I (1952), hyperkinetic reaction of childhood in the DSM-II (1968), and attention-deficit disorder with or without hyperactivity in the DSM-III (1980). In 1987, this was changed to ADHD in the DSM-III-R, and in 1994 the DSM-IV in split the diagnosis into three subtypes: ADHD inattentive type, ADHD hyperactive-impulsive type, and ADHD combined type. These terms were kept in the DSM-5 in 2013 and in the DSM-5-TR in 2022. Prior to the DSM, terms included minimal brain damage in the 1930s.In 1934, Benzedrine became the first amphetamine medication approved for use in the United States. Methylphenidate was introduced in the 1950s, and enantiopure dextroamphetamine in the 1970s. The use of stimulants to treat ADHD was first described in 1937. Charles Bradley gave the children with behavioral disorders Benzedrine and found it improved academic performance and behavior.Once neuroimaging studies were possible, studies conducted in the 1990s provided support for the pre-existing theory that neurological differences - particularly in the frontal lobes - were involved in ADHD. During this same period, a genetic component was identified and ADHD was acknowledged to be a persistent, long-term disorder which lasted from childhood into adulthood.ADHD was split into the current three sub-types because of a field trial completed by Lahey and colleagues.

Controversy
ADHD, its diagnosis, and its treatment have been controversial since the 1970s. The controversies involve clinicians, teachers, policymakers, parents, and the media. Positions range from the view that ADHD is within the normal range of behavior to the hypothesis that ADHD is a genetic condition. Other areas of controversy include the use of stimulant medications in children, the method of diagnosis, and the possibility of overdiagnosis. In 2009, the National Institute for Health and Care Excellence, while acknowledging the controversy, states that the current treatments and methods of diagnosis are based on the dominant view of the academic literature. In 2014, Keith Conners, one of the early advocates for recognition of the disorder, spoke out against overdiagnosis in a The New York Times article. In contrast, a 2014 peer-reviewed medical literature review indicated that ADHD is underdiagnosed in adults.With widely differing rates of diagnosis across countries, states within countries, races, and ethnicities, some suspect factors other than the presence of the symptoms of ADHD are playing a role in diagnosis, such as cultural norms. Some sociologists consider ADHD to be an example of the medicalization of deviant behavior, that is, the turning of the previously non-medical issue of school performance into a medical one. Most healthcare providers accept ADHD as a genuine disorder, at least in the small number of people with severe symptoms. Among healthcare providers the debate mainly centers on diagnosis and treatment in the much greater number of people with mild symptoms.The nature and range of desirable endpoints of ADHD treatment vary among diagnostic standards for ADHD. In most studies, the efficacy of treatment is determined by reductions in ADHD symptoms. However, some studies have included subjective ratings from teachers and parents as part of their assessment of ADHD treatment efficacies. By contrast, the subjective ratings of children undergoing ADHD treatment are seldom included in studies evaluating the efficacy of ADHD treatments.
There have been notable differences in the diagnosis patterns of birthdays in school-age children. Those born relatively younger to the school starting age than others in a classroom environment are shown to be more likely diagnosed with ADHD. Boys who were born in December in which the school age cut-off was December 31 were shown to be 30% more likely to be diagnosed and 41% to be treated than others born in January. Girls born in December had a diagnosis percentage of 70% and 77% treatment more than ones born the following month. Children who were born at the last 3 days of a calendar year were reported to have significantly higher levels of diagnosis and treatment for ADHD than children born at the first 3 days of a calendar year. The studies suggest that ADHD diagnosis is prone to subjective analysis.

Research directions
Possible positive traits
Possible positive traits of ADHD are a new avenue of research, and therefore limited.A 2020 review found that creativity may be associated with ADHD symptoms, particularly divergent thinking and quantity of creative achievements, but not with the disorder of ADHD itself – i.e. it has not been found to be increased in people diagnosed with the disorder, only in people with subclinical symptoms or those that possess traits associated with the disorder. Divergent thinking is the ability to produce creative solutions which differ significantly from each other and consider the issue from multiple perspectives. Those with ADHD symptoms could be advantaged in this form of creativity as they tend to have diffuse attention, allowing rapid switching between aspects of the task under consideration; flexible associative memory, allowing them to remember and use more distantly-related ideas which is associated with creativity; and impulsivity, which causes people with ADHD symptoms to consider ideas which others may not have. However, people with ADHD may struggle with convergent thinking, which is a cognitive process through which a set of obviously relevant knowledge is utilized in a focused effort to arrive at a single perceived best solution to a problem.A 2020 article suggested that historical documentation supported Leonardo da Vincis difficulties with procrastination and time management as characteristic of ADHD and that he was constantly on the go, but often jumping from task to task.

Possible biomarkers for diagnosis
Reviews of ADHD biomarkers have noted that platelet monoamine oxidase expression, urinary norepinephrine, urinary MHPG, and urinary phenethylamine levels consistently differ between ADHD individuals and non-ADHD controls. These measurements could potentially serve as diagnostic biomarkers for ADHD, but more research is needed to establish their diagnostic utility </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 Shaken baby syndrome and can you explain it in depth? [/INST] Shaken baby syndrome (SBS), also known as abusive head trauma (AHT), is the leading cause of fatal head injuries in children younger than two years. Diagnosing the syndrome has proved both challenging and contentious for medical professionals, in that objective witnesses to the initial trauma are generally unavailable. This is said to be particularly problematic when the trauma is deemed non accidental. Some medical professionals propose that SBS is the result of respiratory abnormalities leading to hypoxia and swelling of the brain  The courtroom has become a forum for conflicting theories with which generally accepted medical literature has not been reconciled. Often there are no outwardly visible signs of trauma, despite the presence of severe internal brain and eye . Complications include seizures, visual impairment, cerebral palsy, cognitive impairment, and death.The cause may be blunt trauma, vigorous shaking, or a combination of both. Often this occurs as a result of a caregiver becoming frustrated due to the child crying. Diagnosis can be difficult as symptoms may be nonspecific. A CT scan of the head is typically recommended if a concern is present. If there are concerning findings on the CT scan, a full work-up for child abuse should occur, including an eye exam and skeletal survey. Retinal hemorrhage is highly associated with AHT, occurring in 78% of cases of AHT versus 5% of cases of non-abusive head trauma.Educating new parents appears to be beneficial in decreasing rates of the condition. SBS is estimated to occur in three to four per 10,000 babies a year. It occurs most frequently in those less than five years of age. The risk of death is about 25%. The diagnosis include retinal bleeds, multiple fractures of the long bones, and subdural hematomas (bleeding in the brain). These signs have evolved through the years as the accepted and recognized signs of child abuse. Medical professionals strongly suspect shaking as the cause of injuries when a young child presents with retinal bleed, fractures, soft tissue injuries, or subdural hematoma that cannot be explained by accidental trauma or other medical conditions.Retinal hemorrhage (bleeding) occurs in around 85% of SBS cases and the severity of retinal hemorrhage correlates with severity of head injury. The type of retinal bleeds are often believed to be particularly characteristic of this condition, making the finding useful in establishing the diagnosis.Fractures of the vertebrae, long bones, and ribs may also be associated with SBS. Dr. John Caffey reported in 1972 that metaphyseal avulsions (small fragments of bone torn off where the periosteum covering the bone and the cortical bone are tightly bound together) and "bones on both the proximal and distal sides of a single joint are affected, especially at the knee".Infants may display irritability, failure to thrive, alterations in eating patterns, lethargy, vomiting, seizures, bulging or tense fontanels (the soft spots on a babys head), increased size of the head, altered breathing, and dilated pupils.

Risk factors
Caregivers that are at risk for becoming abusive often have unrealistic expectations of the child and may display "role reversal", expecting the child to fulfill the needs of the caregiver. Substance abuse and emotional stress, resulting for example from financial troubles, are other risk factors for aggression and impulsiveness in caregivers. Caregivers of any gender can cause SBS. Although it had been previously speculated that SBS was an isolated event, evidence of prior child abuse is a common finding. In an estimated 33–40% of cases, evidence of prior head injuries, such as old intracranial bleeds, is present.

Mechanism
Effects of SBS are thought to be diffuse axonal injury, oxygen deprivation and swelling of the brain, which can raise pressure inside the skull and damage delicate brain tissue, although witnessed shaking events have not led to such injuries.
Traumatic shaking occurs when a child is shaken in such a way that its head is flung backwards and forwards. In 1971, Guthkelch, a neurosurgeon, hypothesized that such shaking can result in a subdural hematoma, in the absence of any detectable external signs of injury to the skull. The article describes two cases in which the parents admitted that for various reasons they had shaken the child before it became ill. Moreover, one of the babies had retinal hemorrhages. The association between traumatic shaking, subdural hematoma and retinal hemorrhages was described in 1972 and referred to as whiplash shaken infant syndrome.  The injuries were believed to occur because shaking the child subjected the head to acceleration–deceleration and rotational forces.

Force
There has been controversy regarding the amount of force required to produce the brain damage seen in SBS. There is broad agreement, even amongst skeptics, that shaking of a baby is dangerous and can be fatal.A biomechanical analysis published in 2005 reported that "forceful shaking can severely injure or kill an infant, this is because the cervical spine would be severely injured and not because subdural hematomas would be caused by high head rotational accelerations... an infant head subjected to the levels of rotational velocity and acceleration called for in the SBS literature, would experience forces on the infant neck far exceeding the limits for structural failure of the cervical spine. Furthermore, shaking cervical spine injury can occur at much lower levels of head velocity and acceleration than those reported for SBS."  Other authors were critical of the mathematical analysis by Bandak, citing concerns about the calculations the author used concluding "In light of the numerical errors in Bandaks neck force estimations, we question the resolute tenor of Bandaks conclusions that neck injuries would occur in all shaking events."  Other authors critical of the model proposed by Bandak concluding "the mechanical analogue proposed in the paper may not be entirely appropriate when used to model the motion of the head and neck of infants when a baby is shaken." Bandak responded to the criticism in a letter to the editor published in Forensic Science International in February 2006.

Diagnosis
Diagnosis can be difficult as symptoms may be nonspecific. A CT scan of the head is typically recommended if a concern is present. It is unclear how useful subdural haematoma, retinal hemorrhages, and encephalopathy are alone at making the diagnosis.

Triad
While the findings of SBS are complex and many, they are often incorrectly referred to as a "triad" for legal proceedings; distilled down to retinal hemorrhages, subdural hematomas, and encephalopathy.SBS may be misdiagnosed, underdiagnosed, and overdiagnosed, and caregivers may lie or be unaware of the mechanism of injury. Commonly, there are no externally visible signs of the condition. Examination by an experienced ophthalmologist is critical in diagnosing shaken baby syndrome, as particular forms of ocular bleeding are strongly associated with AHT. Magnetic resonance imaging may also depict retinal hemorrhaging but is much less sensitive than an eye exam. Conditions that are often excluded by clinicians include hydrocephalus, sudden infant death syndrome (SIDS), seizure disorders, and infectious or congenital diseases like meningitis and metabolic disorders. CT scanning and magnetic resonance imaging are used to diagnose the condition. Conditions that often accompany SBS/AHT include classic patterns of skeletal fracturing (rib fractures, corner fractures), injury to the cervical spine (in the neck), retinal hemorrhage, cerebral bleed or atrophy, hydrocephalus, and papilledema (swelling of the optic disc).The terms non-accidental head injury or inflicted traumatic brain injury have been used in place of "abusive head trauma" or "SBS".

Classification
The term abusive head trauma (AHT) is preferred as it better represents the broader potential causes.
The US Centers for Disease Control and Prevention identifies SBS as "an injury to the skull or intracranial contents of an infant or young child (< 5 years of age) due to inflicted blunt impact and/or violent shaking". In 2009, the American Academy of Pediatrics recommended the use of the term AHT to replace SBS, in part to differentiate injuries arising solely from shaking and injuries arising from shaking as well as trauma to the head.The Crown Prosecution Service for England and Wales recommended in 2011 that the term shaken baby syndrome be avoided and the term non accidental head injury (NAHI) be used instead.

Differential diagnosis
Vitamin C deficiency
Some authors have suggested that certain cases of suspected shaken baby syndrome may result from vitamin C deficiency. This contested hypothesis is based upon a speculated marginal, near scorbutic condition or lack of essential nutrient(s) repletion and a potential elevated histamine level. However, symptoms consistent with increased histamine levels, such as low blood pressure and allergic symptoms, are not commonly associated with scurvy as clinically significant vitamin C deficiency. A literature review of this hypothesis in the journal Pediatrics International concluded the following: "From the available information in the literature, concluded that there was no convincing evidence to conclude that vitamin C deficiency can be considered to be a cause of shaken baby syndrome."The proponents of such hypotheses often question the adequacy of nutrient tissue levels, especially vitamin C, for those children currently or recently ill, bacterial infections, those with higher individual requirements, those with environmental challenges (e.g. allergies), and perhaps transient vaccination-related stresses.  At the time of this writing, infantile scurvy in the United States is practically nonexistent.  No cases of scurvy mimicking SBS or sudden infant death syndrome have been reported, and scurvy typically occurs later in infancy, rarely causes death or intracranial bleeding, and is accompanied by other changes of the bones and skin and invariably an unusually deficient dietary history.In one study vaccination was shown not associated with retinal hemorrhages.

Gestational problems
Gestational problems affecting both mother and fetus, the birthing process, prematurity and nutritional deficits can accelerate skeletal and hemorrhagic pathologies that can also mimic SBS, even before birth.

Prevention
Interventions by neonatal nurses include giving parents information about abusive head trauma, normal infant crying and reasons for crying, teaching how to calm an infant, and how to cope if the infant was inconsolable may reduce rates of SBS.

Treatment
Treatment involves monitoring intracranial pressure (the pressure within the skull). Treatment occasionally requires surgery, such as to place a cerebral shunt to drain fluid from the cerebral ventricles, and, if an intracranial hematoma is present, to drain the blood collection.

Prognosis
Prognosis depends on severity and can range from total recovery to severe disability to death when the injury is severe.
One third of these patients die, one third survives with a major neurological condition, and only one third survives in good condition; therefore shaken baby syndrome puts children at risk of long-term disability.  The most frequent neurological impairments are learning disabilities, seizure disorders, speech disabilities, hydrocephalus, cerebral palsy, and visual disorders.

Epidemiology
Small children are at particularly high risk for the abuse that causes SBS given the large difference in size between the small child and an adult. SBS usually occurs in children under the age of two but may occur in those up to age five. In the US, deaths due to SBS constitute about 10% of deaths due to child abuse.

History
In 1971, Norman Guthkelch proposed that whiplash injury caused subdural bleeding in infants by tearing the veins in the subdural space. The term "whiplash shaken infant syndrome" was introduced by Dr. John Caffey, a pediatric radiologist, in 1973, describing a set of symptoms found with little or no external evidence of head trauma, including retinal bleeds and intracranial bleeds with subdural or subarachnoid bleeding or both. Development of computed tomography and magnetic resonance imaging techniques in the 1970s and 1980s advanced the ability to diagnose the syndrome.

Legal issues
The Presidents Council of Advisers on Science and Technology (PCAST) noted in its September 2016 report that there are concerns regarding the scientific validity of forensic evidence of abusive head trauma that "require urgent attention". Similarly, the Maguire model, suggested in 2011 as a potential statistical model for determining the probability that a childs trauma was caused by abuse, has been questioned.  A proposed clinical prediction rule with high sensitivity and low specificity, to rule out Abusive Head Trauma, has been published.In July 2005, the Court of Appeals in the United Kingdom heard four appeals of SBS convictions: one case was dropped, the sentence was reduced for one, and two convictions were upheld.  The court found that the classic triad of retinal bleeding, subdural hematoma, and acute encephalopathy are not 100% diagnostic of SBS and that clinical history is also important. In the Courts ruling, they upheld the clinical concept of SBS but dismissed one case and reduced another from murder to manslaughter. In their words: "Whilst a strong pointer to NAHI [non-accidental head injury] on its own we do not think it possible to find that it must automatically and necessarily lead to a diagnosis of NAHI. All the circumstances, including the clinical picture, must be taken into account."The court did not believe the "unified hypothesis", proposed by British physician J. F. Geddes and colleagues, as an alternative mechanism for the subdural and retinal bleeding found in suspected cases of SBS.  The unified hypothesis proposed that the bleeding was not caused by shearing of subdural and retinal veins but rather by cerebral hypoxia, increased intracranial pressure, and increased pressure in the brains blood vessels.  The court reported that "the unified hypothesis [could] no longer be regarded as a credible or alternative cause of the triad of injuries": subdural haemorrhage, retinal bleeding and encephalopathy due to hypoxemia (low blood oxygen) found in suspected SBS.On 31 January 2008, the Wisconsin Court of Appeals granted Audrey A. Edmunds a new trial based on "competing credible medical opinions in determining whether there is a reasonable doubt as to Edmundss guilt." Specifically, the appeals court found that "Edmunds presented evidence that was not discovered until after her conviction, in the form of expert medical testimony, that a significant and legitimate debate in the medical community has developed in the past ten years over whether infants can be fatally injured through shaking alone, whether an infant may suffer head trauma and yet experience a significant lucid interval prior to death, and whether other causes may mimic the symptoms traditionally viewed as indicating shaken baby or shaken impact syndrome."In 2012, A </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 Glucocorticoid remediable aldosteronism and can you explain it in depth? [/INST] Glucocorticoid remediable aldosteronism also describable as aldosterone synthase hyperactivity, is an autosomal dominant disorder in which the increase in aldosterone secretion produced by ACTH is no longer transient.
It is a cause of primary hyperaldosteronism.

Symptoms and signs
Patients with GRA may be asymptomatic, but the following symptoms can be present:
Fatigue
Headache
High blood pressure
Hypokalemia
Intermittent or temporary paralysis
Muscle spasms
Muscle weakness
Numbness
Polyuria
Polydipsia
Tingling
Hypernatraemia
Metabolic alkalosis

Normal Physiology
Aldosterone synthase is a steroid hydroxylase cytochrome P450 oxidase enzyme involved in the generation of aldosterone. It is localized to the mitochondrial inner membrane </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 Cervical fracture and can you explain it in depth? [/INST] A cervical fracture, commonly called a broken neck, is a fracture of any of the seven cervical vertebrae in the neck. Examples of common causes in humans are traffic collisions and diving into shallow water. Abnormal movement of neck bones or pieces of bone can cause a spinal cord injury resulting in loss of sensation, paralysis, or usually instant death.

Causes
Considerable force is needed to cause a cervical fracture. Vehicle collisions and falls are common causes.  A severe, sudden twist to the neck or a severe blow to the head or neck area can cause a cervical fracture.
Although high energy trauma is often associated with cervical fractures in the younger population, low energy trauma is more common in the geriatric population. In a study from Norway the most common cause was falls and the relative incidence of CS-fx increased significantly with age.Sports that involve violent physical contact carry a risk of cervical fracture, including American football, association football (especially the goalkeeper), ice hockey, rugby, and wrestling. Spearing an opponent in football or rugby, for instance, can cause a broken neck. Cervical fractures may also be seen in some non-contact sports, such as gymnastics, skiing, diving, surfing, powerlifting, equestrianism, mountain biking, and motor racing.
Certain penetrating neck injuries can also cause cervical fracture which can also cause internal bleeding among other complications.
Execution by hanging is intended to cause a fatal cervical fracture. The knot in the noose is placed to the left of the condemned, so that at the end of the drop, the head is jolted sharply upwards and to the right. The force breaks the neck, causing an immediate loss of consciousness and death within a few minutes.

Diagnosis
Physical examination
A medical history and physical examination can be sufficient in clearing the cervical spine. Notable clinical prediction rules to determine which patients need medical imaging are Canadian C-spine rule and the National Emergency X-Radiography Utilization Study (NEXUS).

Choice of medical imaging
In children, a CT scan of the neck is indicated in more severe cases such as neurologic deficits, whereas X-ray is preferable in milder cases, by both US and UK guidelines. Swedish guidelines recommend CT rather than X-ray in all children over the age of 5.
In adults, UK guidelines are largely similar as in children. US guidelines, on the other hand, recommend CT in all cases where medical imaging is indicated, and that X-ray is only acceptable where CT is not readily available.

Radiographic detection
On CT scan or X-ray, a cervical fracture may be directly visualized. In addition, indirect signs of injury by the vertebral column are incongruities of the vertebral lines, and/or increased thickness of the prevertebral space:

Classification
There are proper names for several types of cervical fractures, including:

Fracture of C1, including Jefferson fracture
Fracture of C2, including Hangmans fracture
Flexion teardrop fracture – a fracture of the anteroinferior aspect of a cervical vertebraThe AO Foundation has developed a descriptive system for cervical fractures, the AOSpine subaxial cervical spine fracture classification system.

Surgery indication
The indication to surgically stabilize a cervical fracture can be estimated from the Subaxial Injury Classification (SLIC). In this system, a score of 3 or less indicates that conservative management is appropriate, a score of 5 or more indicates that surgery is needed, and a score of 4 is equivocal. The score is the sum from 3 different categories: morphology, discs and ligaments, and neurology:

Treatment
Complete immobilization of the head and neck should be done as early as possible and before moving the patient. Immobilization should remain in place until movement of the head and neck is proven safe. In the presence of severe head trauma, cervical fracture must be presumed until ruled out. Immobilization is imperative to minimize or prevent further spinal cord injury. The only exceptions are when there is imminent danger from an external cause, such as becoming trapped in a burning building.
Non-steroidal anti-inflammatory drugs, such as Aspirin or Ibuprofen, are contraindicated because they interfere with bone healing. Paracetamol is a better option. Patients with cervical fractures will likely be prescribed medication for pain control.
In the long term, physical therapy will be given to build strength in the muscles of the neck to increase stability and better protect the cervical spine.
Collars, traction and surgery can be used to immobilize and stabilize the neck after a cervical fracture.

Cervical collar
Minor fractures can be immobilized with a cervical collar without need for traction or surgery. A soft collar is fairly flexible and is the least limiting but can carry a high risk of further neck damage in patients with osteoporosis. It can be used for minor injuries or after healing has allowed the neck to become more stable.
A range of manufactured rigid collars are also used, usually comprising a firm plastic bi-valved shell secured with Velcro straps and removable padded liners.  The most frequently prescribed are the Aspen, Malibu, Miami J, and Philadelphia collars. All these can be used with additional chest and head extension pieces to increase stability.

Rigid braces
Rigid braces that support the head and chest are also prescribed.  Examples include the Sterno-Occipital Mandibular Immobilization Device (SOMI), Lerman Minerva and Yale types. Special patients, such as very young children or non-cooperative adults, are sometimes still immobilized in medical plaster of paris casts, such as the Minerva cast.

Traction
Traction can be applied by free weights on a pulley or a halo type brace. The halo brace is the most rigid cervical brace, used when limiting motion to the minimum that is essential, especially with unstable cervical fractures. It can provide stability and support during the time (typically 8–12 weeks) needed for the cervical bones to heal.

Surgery
Surgery may be needed to stabilize the neck and relieve pressure on the spinal cord. A variety of surgeries are available depending on the injury. Surgery to remove a damaged intervertebral disc may be done to relieve pressure on the spinal cord. The discs are cushions between the vertebrae </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 Hypercalcaemia and can you explain it in depth? [/INST] Hypercalcemia, also spelled hypercalcaemia, is a high calcium (Ca2+) level in the blood serum. The normal range is 2.1–2.6 mmol/L (8.8–10.7 mg/dL, 4.3–5.2 mEq/L), with levels greater than 2.6 mmol/L defined as hypercalcemia. Those with a mild increase that has developed slowly typically have no symptoms. In those with greater levels or rapid onset, symptoms may include abdominal pain, bone pain, confusion, depression, weakness, kidney stones or an abnormal heart rhythm including cardiac arrest.Most outpatient cases are due to primary hyperparathyroidism and inpatient cases due to cancer. Other causes of hypercalcemia include sarcoidosis, tuberculosis, Paget disease, multiple endocrine neoplasia (MEN), vitamin D toxicity, familial hypocalciuric hypercalcaemia and certain medications such as lithium and hydrochlorothiazide. Diagnosis should generally include either a corrected calcium or ionized calcium level and be confirmed after a week. Specific changes, such as a shortened QT interval and prolonged PR interval, may be seen on an electrocardiogram (ECG).Treatment may include intravenous fluids, furosemide, calcitonin, intravenous bisphosphonate, in addition to treating the underlying cause. The evidence for furosemide use, however, is poor. In those with very high levels, hospitalization may be required. Haemodialysis may be used in those who do not respond to other treatments. In those with vitamin D toxicity, steroids may be useful. Hypercalcemia is relatively common. Primary hyperparathyroidism occurs in 1–7 per 1,000 people, and hypercalcaemia occurs in about 2.7% of those with cancer.

Signs and symptoms
The neuromuscular symptoms of hypercalcaemia are caused by a negative bathmotropic effect due to the increased interaction of calcium with sodium channels. Since calcium blocks sodium channels and inhibits depolarization of nerve and muscle fibers, increased calcium raises the threshold for depolarization. This results in diminished deep tendon reflexes (hyporeflexia), and skeletal muscle weakness.Other symptoms include cardiac arrhythmias (especially in those taking digoxin), fatigue, nausea, vomiting (emesis), loss of appetite, abdominal pain, & paralytic ileus. If kidney impairment occurs as a result, manifestations can include increased urination, urination at night, and increased thirst. Psychiatric manifestation can include emotional instability, confusion, delirium, psychosis, and stupor. Calcium deposits known as limbus sign may be visible in the eyes.Symptoms are more common at high calcium blood values (12.0 mg/dL or 3 mmol/L). Severe hypercalcaemia (above 15–16 mg/dL or 3.75–4 mmol/L) is considered a medical emergency: at these levels, coma and cardiac arrest can result. The high levels of calcium ions decrease the neuron membrane permeability to sodium ions, thus decreasing excitability, which leads to hypotonicity of smooth and striated muscle. This explains the fatigue, muscle weakness, low tone and sluggish reflexes in muscle groups. The sluggish nerves also explain drowsiness, confusion, hallucinations, stupor or coma. In the gut this causes constipation. Hypocalcaemia causes the opposite by the same mechanism.

Hypercalcaemic crisis
A hypercalcaemic crisis is an emergency situation with a severe hypercalcaemia, generally above approximately 14 mg/dL (or 3.5 mmol/L).The main symptoms of a hypercalcaemic crisis are oliguria or anuria, as well as somnolence or coma. After recognition, primary hyperparathyroidism should be proved or excluded.In extreme cases of primary hyperparathyroidism, removal of the parathyroid gland after surgical neck exploration is the only way to avoid death. The diagnostic program should be performed within hours, in parallel with measures to lower serum calcium. Treatment of choice for acutely lowering calcium is extensive hydration and calcitonin, as well as bisphosphonates (which have effect on calcium levels after one or two days).

Causes
Primary hyperparathyroidism and malignancy account for about 90% of cases of hypercalcaemia.Causes of hypercalcemia can be divided into those that are PTH dependent or PTH independent.

Parathyroid function
Primary hyperparathyroidism
Solitary parathyroid adenoma
Primary parathyroid hyperplasia
Parathyroid carcinoma
Multiple endocrine neoplasia (MEN1 & MEN2A)
Familial isolated hyperparathyroidism
Lithium use
Familial hypocalciuric hypercalcemia/familial benign hypercalcemia

Cancer
Solid tumour with metastasis (e.g. breast cancer or classically squamous cell carcinoma, which can be PTHrP-mediated)
Solid tumour with humoral mediation of hypercalcaemia (e.g. lung cancer, most commonly non-small cell lung cancer or kidney cancer, phaeochromocytoma)
Haematologic cancers (multiple myeloma, lymphoma, leukaemia)
Ovarian small cell carcinoma of the hypercalcemic type

Vitamin-D disorders
Hypervitaminosis D (vitamin D intoxication)
Elevated 1,25(OH)2D (see calcitriol under Vitamin D) levels (e.g. sarcoidosis and other granulomatous diseases such as tuberculosis, berylliosis, histoplasmosis, Crohns disease, and granulomatosis with polyangiitis)
Idiopathic hypercalcaemia of infancy
Rebound hypercalcaemia after rhabdomyolysis

High bone-turnover
Hyperthyroidism
Multiple myeloma
Prolonged immobilization
Pagets disease
Thiazide use
Vitamin A intoxication

Kidney failure
Tertiary hyperparathyroidism
Aluminium intoxication
Milk-alkali syndrome

Other
Acromegaly
Adrenal insufficiency
Zollinger–Ellison syndrome
Williams Syndrome

Diagnosis
Diagnosis should generally include either a calculation of corrected calcium or direct measurement of ionized calcium level and be confirmed after a week. This is because either high or low serum albumin levels does not show the true levels of ionised calcium. There is, however, controversy around the usefulness of corrected calcium as it may be no better than total calcium.Once calcium is confirmed to be elevated, a detailed history taken from the subject, including review of medications, any vitamin supplementations, herbal preparations, and previous calcium values. Chronic elevation of calcium with absent or mild symptoms often points to primary hyperparathyroidism or Familial hypocalciuric hypercalcemia. For those who has underlying malignancy, the cancers may be sufficiently severe to show up in history and examination to point towards the diagnosis with little laboratory investigations.If detailed history and examination does not narrow down the differential diagnoses, further laboratory investigations are performed. Intact PTH (iPTH, biologically active parathyroid hormone molecules) is measured with immunoradiometric or immunochemoluminescent assay. Elevated (or high-normal) iPTH with high urine calcium/creatinine ratio (more than 0.03) is suggestive of primary hyperparathyroidism, usually accompanied by low serum phosphate. High iPTH with low urine calcium/creatinine ratio is suggestive of familial hypocalciuric hypercalcemia. Low iPTH should be followed up with Parathyroid hormone-related protein (PTHrP) measurements (though not available in all labs). Elevated PTHrP is suggestive of malignancy. Normal PTHrP is suggestive of multiple myeloma, vitamin A excess, milk-alkali syndrome, thyrotoxicosis, and immobilisation. Elevated Calcitriol is suggestive of lymphoma, sarcoidosis, granulomatous disorders, and excessive calcitriol intake. Elevated calcifediol is suggestive of vitamin D or excessive calcifediol intake.The normal range is 2.1–2.6 mmol/L (8.8–10.7 mg/dL, 4.3–5.2 mEq/L), with levels greater than 2.6 mmol/L defined as hypercalcaemia. Moderate hypercalcaemia is a level of 2.88–3.5 mmol/L (11.5–14 mg/dL) while severe hypercalcaemia is > 3.5 mmol/L (>14 mg/dL).

ECG
Abnormal heart rhythms can also result, and ECG findings of a short QT interval suggest hypercalcaemia. Significant hypercalcaemia can cause ECG changes mimicking an acute myocardial infarction. Hypercalcaemia has also been known to cause an ECG finding mimicking hypothermia, known as an Osborn wave.

Treatments
The goal of therapy is to treat the hypercalcaemia first and subsequently effort is directed to treat the underlying cause.

Fluids and diuretics
Initial therapy:
hydration, increasing salt intake, and forced diuresis.
hydration is needed because many patients are dehydrated due to vomiting or kidney defects in concentrating urine.
increased salt intake also can increase body fluid volume as well as increasing urine sodium excretion, which further increases urinary calcium excretion.
after rehydration, a loop diuretic such as furosemide can be given to permit continued large volume intravenous salt and water replacement while minimizing the risk of blood volume overload and pulmonary oedema. In addition, loop diuretics tend to depress calcium reabsorption by the kidney thereby helping to lower blood calcium levels
can usually decrease serum calcium by 1–3 mg/dL within 24 hours
caution must be taken to prevent potassium or magnesium depletion

Bisphosphonates and calcitonin
Additional therapy:
bisphosphonates are pyrophosphate analogues with high affinity for bone, especially areas of high bone-turnover.
they are taken up by osteoclasts and inhibit osteoclastic bone resorption
current available drugs include (in order of potency): (1st gen) etidronate, (2nd gen) tiludronate, IV pamidronate, alendronate (3rd gen) zoledronate and risedronate
all people with cancer-associated hypercalcaemia should receive treatment with bisphosphonates since the first line therapy (above) cannot be continued indefinitely nor is it without risk. Further, even if the first line therapy has been effective, it is a virtual certainty that the hypercalcaemia will recur in the person with hypercalcaemia of malignancy. Use of bisphosphonates in such circumstances, then, becomes both therapeutic and preventative
people in kidney failure and hypercalcaemia should have a risk-benefit analysis before being given bisphosphonates, since they are relatively contraindicated in kidney failure.
Denosumab is a bone anti-resorptive agent that can be used to treat hypercalcemia in patients with a contraindication to bisphosphonates such as severe kidney failure or allergy.
Calcitonin blocks bone resorption and also increases urinary calcium excretion by inhibiting calcium reabsorption by the kidney
Usually used in life-threatening hypercalcaemia along with rehydration, diuresis, and bisphosphonates
Helps prevent recurrence of hypercalcaemia
Dose is 4 international units per kilogram via subcutaneous or intramuscular route every 12 hours, usually not continued indefinitely due to quick onset of decreased response to calcitonin

Other therapies
rarely used, or used in special circumstances
plicamycin inhibits bone resorption (rarely used)
gallium nitrate inhibits bone resorption and changes structure of bone crystals (rarely used)
glucocorticoids increase urinary calcium excretion and decrease intestinal calcium absorption
no effect on calcium level in normal or primary hyperparathyroidism
effective in hypercalcaemia due to osteolytic malignancies (multiple myeloma, leukaemia, Hodgkins lymphoma, carcinoma of the breast) due to antitumour properties
also effective in hypervitaminosis D and sarcoidosis
dialysis usually used in severe hypercalcaemia complicated by kidney failure. Supplemental phosphate should be monitored and added if necessary
phosphate therapy can correct the hypophosphataemia in the face of hypercalcaemia and lower serum calcium

Other animals
Research has led to a better understanding of hypercalcemia in non-human animals. Often the causes of hypercalcemia have a correlation to the environment in which the organisms live. Hypercalcemia in house pets is typically due to disease, but other cases can be due to accidental ingestion of plants or chemicals in the home. Outdoor animals commonly develop hypercalcemia through vitamin D toxicity from wild plants within their environments.

Household pets
Household pets such as dogs and cats are found to develop hypercalcemia. It is less common in cats, and many feline cases are idiopathic. In dogs, lymphosarcoma, Addison’s disease, primary hyperparathyroidism, and chronic kidney failure are the main causes of hypercalcemia, but there are also environmental causes usually unique to indoor pets. Ingestion of small amounts of calcipotriene found in psoriasis cream can be fatal to a pet. Calcipotriene causes a rapid rise in calcium ion levels. Calcium ion levels can remain high for weeks if untreated and lead to an array of medical issues. There are also cases of hypercalcemia reported due to dogs ingesting rodenticides containing a chemical similar to calcipotriene found in psoriasis cream. Additionally, ingestion of household plants is a cause of hypercalcemia. Plants such as Cestrum diurnum, and Solanum malacoxylon contain ergocalciferol or cholecalciferol which cause the onset of hypercalcemia. Consuming small amounts of these plants can be fatal to pets </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 Isovaleric acidemia and can you explain it in depth? [/INST] Isovaleric acidemia is a rare autosomal recessive metabolic disorder which disrupts or prevents normal metabolism of the branched-chain amino acid leucine. It is a classical type of organic acidemia.

Symptoms and signs
A characteristic feature of isovaleric acidemia is a distinctive odor of sweaty feet. This odor is caused by the buildup of a compound called isovaleric acid in affected individuals.In about half of cases, the signs and symptoms of this disorder become apparent within a few days after birth and include poor feeding, vomiting, seizures, and lack of energy that can progress to coma. These medical problems are typically severe and can be life-threatening. In the other half of cases, the signs and symptoms of the disorder appear during childhood and may come and go over time. They are often triggered by an infection or by eating an increased amount of protein-rich foods.

Genetics
The disorder has an autosomal recessive inheritance pattern, which means the defective gene is located on an autosome, and two copies of the gene - one from each parent - must be inherited to be affected by the disorder. The parents of a child with an autosomal recessive disorder are carriers of one copy of the defective gene, but are usually not affected by the disorder.Mutations in both copies of the IVD gene result in isovaleric acidemia.

Pathophysiology
The enzyme encoded by IVD, isovaleric acid-CoA dehydrogenase (EC 1.3.99.10), plays an essential role in breaking down proteins from the diet </s>