<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Hearing loss and explain in detail? [/INST] Hearing loss is a partial or total inability to hear. Hearing loss may be present at birth or acquired at any time afterwards.  Hearing loss may occur in one or both ears. In children, hearing problems can affect the ability to acquire spoken language, and in adults it can create difficulties with social interaction and at work. Hearing loss can be temporary or permanent. Hearing loss related to age usually affects both ears and is due to cochlear hair cell loss. In some people, particularly older people, hearing loss can result in loneliness. Deaf people usually have little to no hearing.Hearing loss may be caused by a number of factors, including: genetics, ageing, exposure to noise, some infections, birth complications, trauma to the ear, and certain medications or toxins. A common condition that results in hearing loss is chronic ear infections. Certain infections during pregnancy, such as cytomegalovirus, syphilis and rubella, may also cause hearing loss in the child. Hearing loss is diagnosed when hearing testing finds that a person is unable to hear 25 decibels in at least one ear. Testing for poor hearing is recommended for all newborns. Hearing loss can be categorized as mild (25 to 40 dB), moderate (41 to 55 dB), moderate-severe (56 to 70 dB), severe (71 to 90 dB), or profound (greater than 90 dB). There are three main types of hearing loss: conductive hearing loss, sensorineural hearing loss, and mixed hearing loss.About half of hearing loss globally is preventable through public health measures. Such practices include immunization, proper care around pregnancy, avoiding loud noise, and avoiding certain medications. The World Health Organization recommends that young people limit exposure to loud sounds and the use of personal audio players to an hour a day in an effort to limit exposure to noise. Early identification and support are particularly important in children. For many, hearing aids, sign language, cochlear implants and subtitles are useful. Lip reading is another useful skill some develop. Access to hearing aids, however, is limited in many areas of the world.As of 2013 hearing loss affects about 1.1 billion people to some degree. It causes disability in about 466 million people (5% of the global population), and moderate to severe disability in 124 million people. Of those with moderate to severe disability 108 million live in low and middle income countries. Of those with hearing loss, it began during childhood for 65 million. Those who use sign language and are members of Deaf culture may see themselves as having a difference rather than a disability. Many members of Deaf culture oppose attempts to cure deafness and some within this community view cochlear implants with concern as they have the potential to eliminate their culture. The terms hearing impairment or hearing loss are often viewed negatively as emphasizing what people cannot do, although the terms are still regularly used when referring to deafness in medical contexts.

Definition
Hearing loss is defined as diminished acuity to sounds which would otherwise be heard normally. The terms hearing impaired or hard of hearing are usually reserved for people who have relative inability to hear sound in the speech frequencies. The severity of hearing loss is categorized according to the increase in intensity of sound above the usual level required for the listener to detect it.
Deafness is defined as a degree of loss such that a person is unable to understand speech, even in the presence of amplification. In profound deafness, even the highest intensity sounds produced by an audiometer (an instrument used to measure hearing by producing pure tone sounds through a range of frequencies) may not be detected. In total deafness, no sounds at all, regardless of amplification or method of production, can be heard.
Speech perception is another aspect of hearing which involves the perceived clarity of a word rather than the intensity of sound made by the word. In humans, this is usually measured with speech discrimination tests, which measure not only the ability to detect sound, but also the ability to understand speech. There are very rare types of hearing loss that affect speech discrimination alone.  One example is auditory neuropathy, a variety of hearing loss in which the outer hair cells of the cochlea are intact and functioning, but sound information is not faithfully transmitted by the auditory nerve to the brain.Use of the terms "hearing impaired", "deaf-mute", or "deaf and dumb" to describe deaf and hard of hearing people is discouraged by many in the deaf community as well as advocacy organizations, as they are offensive to many deaf and hard of hearing people.

Hearing standards
Human hearing extends in frequency from 20 to 20,000 Hz, and in intensity from 0 dB to 120 dB HL or more. 0 dB does not represent absence of sound, but rather the softest sound an average unimpaired human ear can hear; some people can hear down to −5 or even −10 dB.  Sound is generally uncomfortably loud above 90 dB and 115 dB represents the threshold of pain. The ear does not hear all frequencies equally well: hearing sensitivity peaks around 3,000 Hz.  There are many qualities of human hearing besides frequency range and intensity that cannot easily be measured quantitatively. However, for many practical purposes, normal hearing is defined by a frequency versus intensity graph, or audiogram, charting sensitivity thresholds of hearing at defined frequencies.  Because of the cumulative impact of age and exposure to noise and other acoustic insults, typical hearing may not be normal.

Signs and symptoms
difficulty using the telephone
loss of sound localization
difficulty understanding speech, especially of children and women whose voices are of a higher frequency.
difficulty understanding speech in the presence of background noise (cocktail party effect)
sounds or speech sounding dull, muffled or attenuated
need for increased volume on television, radio, music and other audio sourcesHearing loss is sensory, but may have accompanying symptoms:

pain or pressure in the ears
a blocked feelingThere may also be accompanying secondary symptoms:

hyperacusis, heightened sensitivity with accompanying auditory pain to certain intensities and frequencies of sound, sometimes defined as "auditory recruitment"
tinnitus, ringing, buzzing, hissing or other sounds in the ear when no external sound is present
vertigo and disequilibrium
tympanophonia, also known as autophonia, abnormal hearing of ones own voice and respiratory sounds, usually as a result of a patulous (a constantly open) eustachian tube or dehiscent superior semicircular canals
disturbances of facial movement (indicating a possible tumour or stroke) or in persons with Bells palsy

Complications
Hearing loss is associated with Alzheimers disease and dementia. The risk increases with the hearing loss degree. There are several hypotheses including cognitive resources being redistributed to hearing and social isolation from hearing loss having a negative effect. According to preliminary data, hearing aid usage can slow down the decline in cognitive functions.Hearing loss is responsible for causing thalamocortical dysrthymia in the brain which is a cause for several neurological disorders including tinnitus and visual snow syndrome.

Cognitive decline
Hearing loss is an increasing concern especially in aging populations. The prevalence of hearing loss increases about two-fold for each decade increase in age after age 40. While the secular trend might decrease individual level risk of developing hearing loss, the prevalence of hearing loss is expected to rise due to the aging population in the US. Another concern about aging process is cognitive decline, which may progress to mild cognitive impairment and eventually dementia. The association between hearing loss and cognitive decline has been studied in various research settings. Despite the variability in study design and protocols, the majority of these studies have found consistent association between age-related hearing loss and cognitive decline, cognitive impairment, and dementia. The association between age-related hearing loss and Alzheimers disease was found to be nonsignificant, and this finding supports the hypothesis that hearing loss is associated with dementia independent of Alzheimer pathology. There are several hypothesis about the underlying causal mechanism for age-related hearing loss and cognitive decline. One hypothesis is that this association can be explained by common etiology or shared neurobiological pathology with decline in other physiological system. Another possible cognitive mechanism emphasize on individuals cognitive load. As people developing hearing loss in the process of aging, the cognitive load demanded by auditory perception increases, which may lead to change in brain structure and eventually to dementia. One other hypothesis suggests that the association between hearing loss and cognitive decline is mediated through various psychosocial factors, such as decrease in social contact and increase in social isolation. Findings on the association between hearing loss and dementia have significant public health implication, since about 9% of dementia cases are associated with hearing loss.

Falls
Falls have important health implications, especially for an aging population where they can lead to significant morbidity and mortality. Elderly people are particularly vulnerable to the consequences of injuries caused by falls, since older individuals typically have greater bone fragility and poorer protective reflexes. Fall-related injury can also lead to burdens on the financial and health care systems. In literature, age-related hearing loss is found to be significantly associated with incident falls. There is also a potential dose-response relationship between hearing loss and falls—greater severity of hearing loss is associated with increased difficulties in postural control and increased prevalence of falls. The underlying causal link between the association of hearing loss and falls is yet to be elucidated. There are several hypotheses that indicate that there may be a common process between decline in auditory system and increase in incident falls, driven by physiological, cognitive, and behavioral factors. This evidence suggests that treating hearing loss has potential to increase health-related quality of life in older adults.

Depression
Depression is one of the leading causes of morbidity and mortality worldwide. In older adults, the suicide rate is higher than it is for younger adults, and more suicide cases are attributable to depression. Different studies have been done to investigate potential risk factors that can give rise to depression in later life. Some chronic diseases are found to be significantly associated with risk of developing depression, such as coronary heart disease, pulmonary disease, vision loss and hearing loss. Hearing loss can attribute to decrease in health-related quality of life, increase in social isolation and decline in social engagement, which are all risk factors for increased risk of developing depression symptoms.

Spoken language ability
Post-lingual deafness is hearing loss that is sustained after the acquisition of language, which can occur due to disease, trauma, or as a side-effect of a medicine. Typically, hearing loss is gradual and often detected by family and friends of affected individuals long before the patients themselves will acknowledge the disability. Post-lingual deafness is far more common than pre-lingual deafness. Those who lose their hearing later in life, such as in late adolescence or adulthood, face their own challenges, living with the adaptations that allow them to live independently.
Prelingual deafness is profound hearing loss that is sustained before the acquisition of language, which can occur due to a congenital condition or through hearing loss before birth or in early infancy. Prelingual deafness impairs an individuals ability to acquire a spoken language in children, but deaf children can acquire spoken language through support from cochlear implants (sometimes combined with hearing aids). Non-signing (hearing) parents of deaf babies (90–95% of cases) usually go with oral approach without the support of sign language, as these families lack previous experience with sign language and cannot competently provide it to their children without learning it themselves. Unfortunately, this may in some cases (late implantation or not sufficient benefit from cochlear implants) bring the risk of language deprivation for the deaf baby because the deaf baby would not have a sign language if the child is unable to acquire spoken language successfully. The 5–10% of cases of deaf babies born into signing families have the potential of age-appropriate development of language due to early exposure to a sign language by sign-competent parents, thus they have the potential to meet language milestones, in sign language in lieu of spoken language.

Causes
Hearing loss has multiple causes, including ageing, genetics, perinatal problems and acquired causes like noise and disease.  For some kinds of hearing loss the cause may be classified as of unknown cause.
There is a progressive loss of ability to hear high frequencies with aging known as presbycusis. For men, this can start as early as 25 and women at 30. Although genetically variable, it is a normal concomitant of ageing and is distinct from hearing losses caused by noise exposure, toxins or disease agents. Common conditions that can increase the risk of hearing loss in elderly people are high blood pressure, diabetes, or the use of certain medications harmful to the ear. While everyone loses hearing with age, the amount and type of hearing loss is variable.Noise-induced hearing loss (NIHL), also known as acoustic trauma, typically manifests as elevated hearing thresholds (i.e. less sensitivity or muting). Noise exposure is the cause of approximately half of all cases of hearing loss, causing some degree of problems in 5% of the population globally. The majority of hearing loss is not due to age, but due to noise exposure. Various governmental, industry and standards organizations set noise standards. Many people are unaware of the presence of environmental sound at damaging levels, or of the level at which sound becomes harmful. Common sources of damaging noise levels include car stereos, childrens toys, motor vehicles, crowds, lawn and maintenance equipment, power tools, gun use, musical instruments, and even hair dryers. Noise damage is cumulative; all sources of damage must be considered to assess risk. In the US, 12.5% of children aged 6–19 years have permanent hearing damage from excessive noise exposure.  The World Health Organization estimates that half of those between 12 and 35 are at risk from using personal audio devices that are too loud. Hearing loss in adolescents may be caused by loud noise from toys, music by headphones, and concerts or events.Hearing loss can be inherited. Around 75–80% of all these cases are inherited by recessive genes, 20–25% are inherited by dominant genes, 1–2% are inherited by X-linked patterns, and fewer than 1% are inherited by mitochondrial inheritance.  Syndromic deafness occurs when there are other signs or medical problems aside from deafness in an individual, such as Usher syndrome, Stickler syndrome, Waardenburg syndrome, Alports syndrome, and neurofibromatosis type 2. Nonsyndromic deafness occurs when there are no other signs or medical problems associated with the deafness in an individual.Fetal alcohol spectrum disorders are reported to cause hearing loss in up to 64% of infants born to alcoholic mothers, from the ototoxic effect on the developing fetus plus malnutrition during pregnancy from the excess alcohol intake. Premature birth can be associated with sensorineural hearing loss because of an increased risk of hypoxia, hyperbilirubinaemia, ototoxic medication and infection as well as noise exposure in the neonatal units. Also, hearing loss in premature babies is often discovered far later than a similar hearing loss would be in a full-term baby because normally babies are given a hearing test within 48 hours of birth, but doctors must wait until the premature baby is medically stable before testing hearing, which can be months after birth. The risk of hearing loss is greatest for those weighing less than 1500 g at birth.
Disorders responsible for hearing loss include auditory neuropathy, Down syndrome, Charcot–Marie–Tooth disease variant 1E, autoimmune disease, multiple sclerosis, meningitis, cholesteatoma, otosclerosis, perilymph fistula, Ménières disease, recurring ear infections, strokes, superior semicircular canal dehiscence, Pierre Robin, Treacher-Collins, Usher Syndrome, Pendred Syndrome, and Turner syndrome, syphilis, vestibular schwannoma, and viral infections such as measles, mumps, congenital rubella (also called German measles) syndrome, several varieties of herpes viruses, HIV/AIDS, and West Nile virus.
Some medications may reversibly affect hearing. These medications are considered ototoxic. This includes loop diuretics such as furosemide and bumetanide, non-steroidal anti-inflammatory drugs (NSAIDs) both over-the-counter (aspirin, ibuprofen, naproxen) as well as prescription (celecoxib, diclofenac, etc.), paracetamol, quinine, and macrolide antibiotics. Others may cause permanent hearing loss. The most important group is the aminoglycosides (main member gentamicin) and platinum based chemotherapeutics such as cisplatin and carboplatin.In addition to medications, hearing loss can also result from specific chemicals in the environment: metals, such as lead; solvents, such as toluene (found in crude oil, gasoline and automobile exhaust, for example); and asphyxiants. Combined with noise, these ototoxic chemicals have an additive effect on a persons hearing loss. Hearing loss due to chemicals starts in the high frequency range and is irreversible. It damages the cochlea with lesions and degrades central portions of the auditory system. For some ototoxic chemical exposures, particularly styrene, the risk of hearing loss can be higher than being exposed to noise alone. The effects is greatest when the combined exposure include impulse noise. A 2018 informational bulletin by the US Occupational Safety and Health Administration (OSHA) and the National Institute for Occupational Safety and Health (NIOSH) introduces the issue, provides examples of ototoxic chemicals, lists the industries and occupations at risk and provides prevention information.There can be damage either to the ear, whether the external or middle ear, to the cochlea, or to the brain centers that process the aural information conveyed by the ears.  Damage to the middle ear may include fracture and discontinuity of the ossicular chain.  Damage to the inner ear (cochlea) may be caused by temporal bone fracture.  People who sustain head injury are especially vulnerable to hearing loss or tinnitus, either temporary or permanent.

Pathophysiology
Sound waves reach the outer ear and are conducted down the ear canal to the eardrum, causing it to vibrate. The vibrations are transferred by the 3 tiny ear bones of the middle ear to the fluid in the inner ear. The fluid moves hair cells (stereocilia), and their movement generates nerve impulses which are then taken to the brain by the cochlear nerve.  The auditory nerve takes the impulses to the brainstem, which sends the impulses to the midbrain. Finally, the signal goes to the auditory cortex of the temporal lobe to be interpreted as sound.Hearing loss is most commonly caused by long-term exposure to loud noises, from recreation or from work, that damage the hair cells, which do not grow back on their own.Older people may lose their hearing from long exposure to noise, changes in the inner ear, changes in the middle ear, or from changes along the nerves from the ear to the brain.

Diagnosis
Identification of a hearing loss is usually conducted by a general practitioner medical doctor, otolaryngologist, certified and licensed audiologist, school or industrial audiometrist, or other audiometric technician. Diagnosis of the cause of a hearing loss is carried out by a specialist physician (audiovestibular physician) or otorhinolaryngologist.
Hearing loss is generally measured by playing generated or recorded sounds, and determining whether the person can hear them. Hearing sensitivity varies according to the frequency of sounds. To take this into account, hearing sensitivity can be measured for a range of frequencies and plotted on an audiogram. Other method for quantifying hearing loss is a hearing test using a mobile application or hearing aid application, which includes a hearing test. Hearing diagnosis using mobile application is similar to the audiometry procedure. Audiograms, obtained using mobile applications, can be used to adjust hearing aid applications. Another method for quantifying hearing loss is a speech-in-noise test. which gives an indication of how well one can understand speech in a noisy environment. Otoacoustic emissions test is an objective hearing test that may be administered to toddlers and children too young to cooperate in a conventional hearing test. Auditory brainstem response testing is an electrophysiological test used to test for hearing deficits caused by pathology within the ear, the cochlear nerve and also within the brainstem.
A case history (usually a written form, with questionnaire) can provide valuable information about the context of the hearing loss, and indicate what kind of diagnostic procedures to employ. Examinations include otoscopy, tympanometry, and differential testing with the Weber, Rinne, Bing and Schwabach tests. In case of infection or inflammation, blood or other body fluids may be submitted for laboratory analysis.  MRI and CT scans can be useful to identify the pathology of many causes of hearing loss.
Hearing loss is categorized by severity, type, and configuration. Furthermore, a hearing loss may exist in only one ear (unilateral) or in both ears (bilateral).  Hearing loss can be temporary or permanent, sudden or progressive. The severity of a hearing loss is ranked according to ranges of nominal thresholds in which a sound must be so it can be detected by an individual. It is measured in decibels of hearing loss, or dB HL. There are three main types of hearing loss: conductive hearing loss, sensorineural hearing loss, and mixed hearing loss. An additional problem which is increasingly recognised is auditory processing disorder which is not a hearing loss as such but a difficulty perceiving sound. The shape of an audiogram shows the relative configuration of the hearing loss, such as a Carhart notch for otosclerosis, noise notch for noise-induced damage, high frequency rolloff for presbycusis, or a flat audiogram for conductive hearing loss. In conjunction with speech audiometry, it may indicate central auditory processing disorder, or the presence of a schwannoma or other tumor.
People with unilateral hearing loss or single-sided deafness (SSD) have difficulty in hearing conversation on their impaired side, localizing sound, and understanding speech in the presence of background noise.  One reason for the hearing problems these patients often experience is due to the head shadow effect.

Prevention
It is estimated that half of cases of hearing loss are preventable. About 60% of hearing loss in children under the age of 15 can be avoided. There are a number of effective preventative strategies, including: immunization against rubella to prevent congenital rubella syndrome, immunization against H. influenza and S. pneumoniae to reduce cases of meningitis, and avoiding or protecting against excessive noise exposure. The World Health Organization also recommends immunization against measles, mumps, and meningitis, efforts to prevent premature birth, and avoidance of certain medication as prevention. World Hearing Day is a yearly event to promote actions to prevent hearing damage.
Noise exposure is the most significant risk factor for noise-induced hearing loss that can be prevented. Different programs exist for specific populations such as school-age children, adolescents and workers. Education regarding noise exposure increases the use of hearing protectors. The use of antioxidants is being studied for the prevention of noise-induced hearing loss, particularly for scenarios in which noise exposure cannot be reduced, such as during military operations.

Workplace noise regulation
Noise is widely recognized as an occupational hazard. In the United States, the National Institute for Occupational Safety and Health (NIOSH) and the Occupational Safety and Health Administration (OSHA) work together to provide standards and enforcement on workplace noise levels. The hierarchy of hazard controls demonstrates the different levels of controls to reduce or eliminate exposure to noise and prevent hearing loss, including engineering controls and personal protective equipment (PPE). Other programs and initiative have been created to prevent hearing loss in the workplace. For example, the Safe-in-Sound Award was created to recognize organizations that can demonstrate results of successful noise control and other interventions. Additionally, the Buy Quiet program was created to encourage employers to purchase quieter machinery and tools. By purchasing less noisy power tools like those found on the NIOSH Power Tools Database and limiting exposure to ototoxic chemicals, great strides can be made in preventing hearing loss.Companies can also provide personal hearing protector devices tailored to both the worker and type of employment. Some hearing protectors universally block out all noise, and some allow for certain noises to be heard. Workers are more likely to wear hearing protector devices when they are properly fitted.Often interventions to prevent noise-induced hearing loss have many components. A 2017 Cochrane review found that stricter legislation might reduce noise levels.  Providing workers with information on their sound exposure levels was not shown to decrease exposure to noise. Ear protection, if used correctly, can reduce noise to safer levels, but often, providing them is not sufficient to prevent hearing loss. Engineering noise out and other solutions such as proper maintenance of equipment can lead to noise reduction, but further field studies on resulting noise exposures following such interventions are needed. Other possible solutions include improved enforcement of existing legislation and better implementation of well-designed prevention programmes, which have not yet been proven conclusively to be effective. The conclusion of the Cochrane Review was that further research could modify what is now regarding the effectiveness of the evaluated interventions.The Institute for Occupational Safety and Health of the German Social Accident Insurance has created a hearing impairment calculator based on the ISO 1999 model for studying threshold shift in relatively homogeneous groups of people, such as workers with the same type of job.  The ISO 1999 model estimates how much hearing impairment in a group can be ascribed to age and noise exposure.  The result is calculated via an algebraic equation that uses the A-weighted sound exposure level, how many years the people were exposed to this noise, how old the people are, and their sex. The models estimations are only useful for people without hearing loss due to non-job related exposure and can be used for prevention activities.

Screening
The United States Preventive Services Task Force recommends neonatal hearing screening for all newborns.The American Academy of Pediatrics advises that children should have their hearing tested several times throughout their schooling:
When they enter school
At ages 6, 8, and 10
At least once during middle school
At least once during high schoolWhile the American College of Physicians indicated that there is not enough evidence to determine the utility of screening in adults over 50 years old who do not have any symptoms, the American Language, Speech Pathology and Hearing Association recommends that adults should be screened at least every decade through age 50 and at three-year intervals thereafter, to minimize the detrimental effects of the untreated condition on quality of life. For the same reason, the US Office of Disease Prevention and Health Promotion included as one of Healthy People 2020 objectives: to increase the proportion of persons who have had a hearing examination.

Management
Management depends on the specific cause if known as well as the extent, type and configuration of the hearing loss. Sudden hearing loss due to an underlying nerve problem may be treated with corticosteroids.Most hearing loss, that resulting from age and noise, is progressive and irreversible, and there are currently no approved or recommended treatments.  A few specific kinds of hearing loss are amenable to surgical treatment.  In other cases, treatment is addressed to underlying pathologies, but any hearing loss incurred may be permanent. Some management options include hearing aids, cochlear implants, middle ear implants, assistive technology, and closed captioning. This choice depends on the level of hearing loss, type of hearing loss, and personal preference. Hearing aid applications are one of the options for hearing loss management. For people with bilateral hearing loss, it is not clear if bilateral hearing aids (hearing aids in both ears) are better than a unilateral hearing aid (hearing aid in one ear).

Epidemiology
Globally, hearing loss affects about 10% of the population to some degree. It caused moderate to severe disability in 124.2 million people as of 2004 (107.9 million of whom are in low and middle income countries). Of these 65 million acquired the condition during childhood. At birth ~3 per 1000 in developed countries and more than 6 per 1000 in developing countries have hearing problems.Hearing loss increases with age. In those between 20 and 35 rates of hearing loss are 3% while in those 44 to 55 it is 11% and in those 65 to 85 it is 43%.A 2017 report by the World Health Organization estimated the costs of unaddressed hearing loss and the cost-effectiveness of interventions, for the health-care sector, for the education sector and as broad societal costs.  Globally, the annual cost of unaddressed hearing loss was estimated to be in the range of $750–790 billion international dollars.
The International Organization for Standardization (ISO) developed the ISO 1999 standards for the estimation of hearing thresholds and noise-induced hearing impairment. They used data from two noise and hearing study databases, one presented by Burns and Robinson (Hearing and Noise in Industry, Her Majestys Stationery Office,  London, 1970) and by Passchier-Vermeer (1968). As race are some of the factors that can affect the expected distribution of pure-tone hearing thresholds several other national or regional datasets exist, from Sweden,  Norway, South Korea, the United States and Spain.In the United States hearing is one of the health outcomes measure by the National Health and Nutrition Examination Survey (NHANES), a survey research program conducted by the National Center for Health Statistics. It examines health and nutritional status of adults and children in the United States.  Data from the United States in 2011-2012 found that rates of hearing loss has declined among adults aged 20 to 69 years, when compared with the results from an earlier time period (1999-2004). It also found that adult hearing loss is associated with increasing age, sex, ethnicity, educational level, and noise exposure.  Nearly one in four adults had audiometric results suggesting noise-induced hearing loss. Almost one in four adults who reported excellent or good hearing had a similar pattern (5.5% on both sides and 18% on one side). Among people who reported exposure to loud noise at work, almost one third had such changes.

Social and cultural aspects
People with extreme hearing loss may communicate through sign languages. Sign languages convey meaning through manual communication and body language instead of acoustically conveyed sound patterns. This involves the simultaneous combination of hand shapes, orientation and movement of the hands, arms or body, and facial expressions to express a speakers thoughts. "Sign languages are based on the idea that vision is the most useful tool a deaf person has to communicate and receive information".Deaf culture refers to a tight-knit cultural group of people whose primary language is signed, and who practice social and cultural norms which are distinct from those of the surrounding hearing community. This community does not automatically include all those who are clinically or legally deaf, nor does it exclude every hearing person. According to Baker and Padden, it includes any person or persons who "identifies him/herself as a member of the Deaf community, and other members accept that person as a part of the community," an example being children of deaf adults with normal hearing ability.  It includes the set of social beliefs, behaviors, art, literary traditions, history, values, and shared institutions of communities that are influenced by deafness and which use sign languages as the main means of communication.  Members of the Deaf community tend to view deafness as a difference in human experience rather than a disability or disease.  When used as a cultural label especially within the culture, the word deaf is often written with a capital D and referred to as "big D Deaf" in speech and sign. When used as a label for the audiological condition, it is written with a lower case d.There also multiple educational institutions for both deaf and Deaf people, that usually use sign language as the main language of instruction. Famous institutions include Gallaudet University and the National Technical Institute for the Deaf in the US, and the National University Corporation of Tsukuba University of Technology in Japan.

Research
Stem cell transplant and gene therapy
A 2005 study achieved successful regrowth of cochlea cells in guinea pigs. However, the regrowth of cochlear hair cells does not imply the restoration of hearing sensitivity, as the sensory cells may or may not make connections with neurons that carry the signals from hair cells to the brain. A 2008 study has shown that gene therapy targeting Atoh1 can cause hair cell growth and attract neuronal processes in embryonic mice. Some hope that a similar treatment will one day ameliorate hearing loss in humans.Recent research, reported in 2012 achieved growth of cochlear nerve cells resulting in hearing improvements in gerbils, using stem cells. Also reported in 2013 was regrowth of hair cells in deaf adult mice using a drug intervention resulting in hearing improvement. The Hearing Health Foundation in the US has embarked on a project called the Hearing Restoration Project. Also Action on Hearing Loss in the UK is also aiming to restore hearing.Researchers reported in 2015 that genetically deaf mice which were treated with TMC1 gene therapy recovered some of their hearing. In 2017, additional studies were performed to treat Usher syndrome and here, a recombinant adeno-associated virus seemed to outperform the older vectors.

Audition
Besides research studies seeking to improve hearing, such as the ones listed above, research studies on the deaf have also been carried out in order to understand more about audition. Pijil and Shwarz (2005) conducted their study on the deaf who lost their hearing later in life and, hence, used cochlear implants to hear. They discovered further evidence for rate coding of pitch, a system that codes for information for frequencies by the rate that neurons fire in the auditory system, especially for lower frequencies as they are coded by the frequencies that neurons fire from the basilar membrane in a synchronous manner. Their results showed that the subjects could identify different pitches that were proportional to the frequency stimulated by a single electrode. The lower frequencies were detected when the basilar membrane was stimulated, providing even further evidence for rate coding.

See also
Deaf hearing
H.870
Otologics
Safe listening
World Hearing Day

References
External links

Hearing loss at Curlie
National Institute for the Prevention of Deafness and other Communication Disorders
Global Costs of unaddressed hearing loss and cost-effectiveness of interventions World Health Organization. 2017. Internet archive on 12 May 2020.
Deafness and Hearing Loss. World Health Organization.  2022. Internet archive on 9 June 2022 ISBN 978-92-4-151204-6.

Occupational Noise and Hearing Loss Prevention U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health. (6 February 2018).
Preventing Hearing Loss Caused by Chemical (Ototoxicity) and Noise Exposure Safety and Health Information Bulletin (SHIB). U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health.  doi:10.26616/NIOSHPUB2018124 (8 March 2018). Publication No. 2018-124.
Themann, Christa L.; Morata, Thais; Afanuh, Susan (27 September 2019). "Using Total Worker Health® concepts to address hearing health". U.S </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Language delay and explain in detail? [/INST] A language delay is a language disorder in which a child fails to develop language abilities at the usual age-appropriate period in their developmental timetable. It particularly affects deaf children who are denied sign language. It is most commonly seen in children ages two to seven years-old and can continue into adulthood. The reported prevalence of language delay ranges from 2.3 to 19 percent.Language is a uniquely human form of communication that entails the use of words in a standard and structured way. Language is distinct from communication. Communication is a two-stage process. The first stage is the process of encoding the message into a set of words (or signs in the case of Sign Languages) and sentence structures that convey the required meaning, i.e. into language. In the second stage, language is translated into motor commands that control the articulators (hands, face, body, lungs, vocal cords, mouth, tongue, teeth, etc.), thereby creating speech.
Language delays are distinct from speech delays, in which the development of the mechanical and motor aspects of speech production are delayed. Many tend to confuse language delay with speech delay or even just late talker. All of these have different telltale signs and determining factors. Speech delay seems to be more similar to late talker compared to language delay.  Speech is the verbal motor production of language, while language is a means of communication. Because language and speech are independent, they may be individually delayed. For example, a child may be delayed in speech (i.e., unable to produce intelligible speech sounds), but not delayed in language because they use a Sign Language. Additionally, language delay encompasses the entirety of language developmental progress being slowed and not just the speech aspects.
Language delays are recognized by comparing language development of children to recognized developmental milestones. They are presented in a variety of ways, as every individual child has a unique set of language skills and deficiencies that are identifiable through many different screenings and tools. There are different causes leading to language delay; it is often a result of another developmental disorder and treatment requires analysis of the unique individual causes. The condition is frequently observed early on, among two- and three-year-olds. Early language delays are only considered risk-factors in leading to more severe language disorders.

Language Development
The anatomical language centers of the brain are the Brocas and Wernickes area. These two areas include all aspects of the development of language. The Brocas area is the motor portion of language at the left posterior inferior frontal gyrus and involves speech production. The Wernickes area is the sensory portion of language at the posterior part of the left superior temporal gyrus and involves auditory verbal comprehension.There are recognizable speech and language developmental milestones in children. For children with language delays, milestones in their language development may be different or slowed. Recent studies have shown the different milestones for children with language delay compared to children with normal language development. Language delays are often identified when a child strays from the expected developments in the timeline of typical speech and language developmental milestones that researchers agree on. Children can stray slightly from the confines of the expected timeline; however, if a child is observed to be largely straying from the expected timeline, the childs caretaker should consult with a medical specialist.

Timeline of typical speech and language developmental milestones
This timeline only provides a very general and brief outline of expected developments from birth to age five, individual children can still exhibit varying development patterns as this timeline only serves as a general guideline. This timeline is only one model, other models regarding language development exist. The development of language remains a theoretical mystery.

Around 2 months, babies can make "cooing" sounds.Around 4 months, babies can respond to voices.Around 6 months, babies begin to babble and respond to names.Around 9 months, babies begin to produce mama/dada - appropriate terms and are able to imitate one word at a time.Around 12 months, toddlers can typically speak one or more words. They can produce two words with meaning.Around 15 months, toddlers begin to produce jargon, which is defined as "pre-linguistic vocalizations in which infants use adult-like stress and intonation".Around 18 months, toddlers can produce 10 words and follow simple commands.Around 24 months, toddlers begin to produce 2-3 words and phases that use "I", "Me", and "you", indicating possession. They are about 25% intelligible.Around 3 years, toddlers are able to use language in numerical terms.
Based on the milestones set for typical toddlers, if the child tends to have a lot of or very long delays, they may be deemed as having language delay. However, proper testing by a professional like a speech therapist or a doctors confirmation will be required to determine if a child has language delay. Although these milestones are the typical milestones for a child, they should not be followed strictly as they are mere guidelines.

Language development in language delay
Early developmental language delay is characterized by slow language development in preschoolers. Language development for children with language delay takes longer than the general timeline provided above. It is not only slower, but also presents itself in different forms. For example, a child with a language delay could have weaker language skills such as the ability to produce phrases at 24 months-old. They may find themselves producing language that is different from language norms in developing children.

Types of Language Delay
A language delay is commonly divided into receptive and expressive categories. Both categories are essential in developing effective communication.
Receptive language refers to the process of understanding language, both verbal (spoken) and nonverbal (written, gestural). This may involve gaining information from sounds and words, visual information from surrounding environment, written information and grammar.Expressive language refers to the use of sentences (made of words or signs) to communicate messages to others. It enables children to express their needs and wants to the people around them, interact with others and develop their language skills in speech and writing. Some expressive language skills include putting words together into sentences, being able to label objects in an environment and describing events and actions.

Receptive Language Delay
Children that are diagnosed with receptive language delay have difficulties understanding language. They may have trouble with receptive language skills such as identifying vocabulary and basic concepts, understanding gestures, following directions and answering questions. The number of language skills that children have difficulties with can differ greatly, with some having trouble with only a single skill and others having trouble with multiple.

Expressive Language Delay
A child diagnosed with expressive language delay (ELD) has trouble with language usage in some way. As this diagnosis is very broad, each child diagnosed with ELD can be very different in terms of the language skills they have problems with. Some may have difficulty with using the correct words and vocabulary, some have trouble forming sentences and others are unable to sequence information together coherently. Expressive language symptoms come in many forms and each one is treated with different methods.

Presentation and Diagnosis
A language delay is most commonly identified around 18 months of age with an enhanced well-baby visit. It presents itself in many forms and can be comorbid or develop as a result of other developmental delays. It is important to remember that language delays act and develop differently individually. Language delay is different than individual variation in language development, and is defined by children falling behind on the timeline for recognized milestones.

Screening
Regular appointments with a pediatrician in infancy can help identify signs of language delay. According to the American Academy of Pediatrics (AAP), formal screening for language delay is recommended at three ages: 9, 18, and 24–30 months. Screening is a two-part process: first, a general developmental screening using tools such as the Parents Evaluation of Developmental Status or Ages and Stages Questionnaire (ASQ-3); and second, specific screening for autism spectrum disorder using tools like the Modified Checklist for Autism in Toddlers. Not all patients with language delay have autism spectrum disorder, so the AAP recommends both screens to assess for delays in developmental milestones.However, the US Preventive Services Task Force (last updated in 2015) has determined that there is insufficient evidence to recommend screening for language delay in children under the age of 5. Other national panels, including the UK National Screening Committee and Canadian Task Force for Preventive Health Care, have also concluded that there is limited evidence on the benefits of screening all infants for language delay.

Early signs and symptoms (red flags)
There are several red flags in early infancy and childhood that may indicate a need for evaluation by a pediatrician. For example, language delay can present as a lack of communicative gestures or sounds. Language delay in children is associated with increased difficulty with reading, writing, attention, and/or socialization.  In addition, an inability to engage in social exchanges is a sign of language delay at all ages.Communicative deficits at specific ages and milestones might indicate language delay, including:

Not smiling at 3 months
Not turning the head toward sounds at 4 months
Not laughing or responding to sounds at 6 months
Not babbling at 9 months
Not pointing and using gestures at 12 months
Not producing more than 5 words at 18 months
Not producing more than 50 words at 24 months
Losing language and/or social skills after 36 monthsLater in life, important signs include:

A lack of speech
An inability to comprehend, process, or understand language presented to the child

Consequences of Language Delay
Language delay is a risk factor for other types of developmental delay, including social, emotional, and cognitive delay. Language delay can impact behavior, reading and spelling ability, and overall IQ scores. Some children may outgrow deficits in reading and writing while others do not. Other conditions associated with language delay include attention-deficit/hyperactivity disorder, autism spectrum disorder, and social communication disorder.

Causes
Language delays are the most frequent developmental delays, and can occur for many reasons. A delay can be due to being a "late bloomer", "late talker", or a more serious problem. Such delays can occur in conjunction with a lack of mirroring of facial responses, unresponsiveness or unawareness of certain noises, a lack of interest in playing with other children or toys, or no pain response to stimuli.

Socio-economic factors
Socio-economic status
Children from families of low educational level are more likely to have delays and difficulties in expressive language. While language development is not directly affected by the socioeconomic level of a family, the conditions that are associated with the socioeconomic level affects the process of language development to a certain extent. A childs early vocabulary development can be influenced by socioeconomic status via maternal speech, which varies according to the socioeconomic status of the family. Mothers with higher education levels are more likely to use rich vocabulary and speak in longer utterances when interacting with their children, which helps them develop their productive vocabulary more than children from a lower socioeconomic status.Poverty is also a high risk factor for language delay as it results in a lack of access appropriate therapies and services. The likelihood of those requiring early intervention for language delays actually receiving help is extremely low compared to those that dont actually need it.

Natural/medical factors
Hearing loss
The process of children acquiring language skills involves hearing sounds and words from their caregivers and surroundings. Hearing loss causes that lack of these sound inputs, causing these children to have difficulties learning to use and understand language, which will eventually lead to delayed speech and language skills.  For example, they may struggle with putting sentences together, understanding speech from other people or using the correct grammar, which are some language skills that typically developing children possess.
Autism
There is strong evidence that autism is commonly associated with language delay.  Children with autism may have difficulties in developing language skills and understanding what is being said to them. They may also have troubles communicating non-verbally by using hand gestures, eye contact and facial expressions. The extent of their language usage is heavily influenced by their intellectual and social developments. The range of their skills can be very different and on opposite ends of a spectrum. Many children with autism develop some speech and language skills, but not like typically developing children, and with uneven progress.Asperger syndrome, which is classified under the broad umbrella term of autistic spectrum disorder, however, is not associated with language delay. Children diagnosed with Asperger syndrome have decent language skills but use language in different ways from others. They may not be able to understand the use of language devices, such as irony and humor, or conversation reciprocity between involved parties.Heritability
Genes have a very big influence in the presence of language impairments. Neurobiological and genetic mechanisms have a strong influence on late language emergence. A child with a family history of language impairments is more likely to have delayed language emergence and persistent language impairments. They are also 2 times more likely to be late talkers as compared to those with no such family history.Genetic abnormalities may also be a cause of language delays. In 2005, researchers found a connection between expressive language delay and a genetic abnormality: a duplicate set of the same genes that are missing in individuals with Williams-Beuren syndrome. Also so called XYY syndrome can often cause speech delay.Twins

Being a twin increases the chance of speech and language delays. Reasons for this are thought to include less one-on-one time with parents, the premature birth of twins, and the companionship of their twin sibling reducing their motivation to talk to others. A twin study has also shown that genetic factors have an important role in language delay. Monozygotic twin pairs (identical twins) recorded a higher consistency than dizygotic twin (fraternal twins) pairs, revealing monozygotic twins experiencing early vocabulary delay is attributed to genetic etiology. The environmental factors that influences both twins also play a big role in causing early language delay, but only when it is transient.Gender
Research has shown that boys are at greater risk for delayed language development than girls. Almost all developmental disorders that affect communication, speech and language skills are more common in males than in females. British scientists have found that the male sex hormone (testosterone) levels were related to the development of both autism and language disorders, which explains why boys are at a greater risk of developmental disorders biologically.Perinatal conditions
There is a high prevalence of early language delay among toddlers with neonatal brachial plexus palsy. Hand usage and gestures are part of the motor system and have been proven correlate to comprehension and production aspects in language development. An interruption in the hand/arm usage caused by this condition during stages of language development could possibly cause these children to experience language delays.Stress during pregnancy is associated with language delay. High levels of prenatal stress can result in poorer general intellectual and language outcomes. Chemical exposure during pregnancy may also be a factor that causes language delays.

Environmental factors
Interactive communication and parental inputs
Psychosocial deprivation can cause language delays in children. An example of this is when a child does not spend enough time communicating with adults through ways such as babbling and joint attention. Research on early brain development shows that babies and toddlers have a critical need for direct interactions with parents and other significant care givers for healthy brain growth and the development of appropriate social, emotional, and cognitive skills.A study examining the role of interactive communication between parents and children has shown that parents language towards toddlers with language delay differ from parents language towards typically developing toddlers in terms of the quality of interaction. While late talkers and children with typical language development both receive similar quantitative parental input in terms of the number of utterances and words, parents of late talkers are found to respond less often to their children than parents of children with typical language development. Parents of late talkers tend to change or introduce topics more often than other parents in order to engage their children in more talk rather than responding to their childs speech. They also seem to not provide an environment that is suitable for child engagement, nor do they establish routines that serve as a platform for communicative acts with their children. This, together with the fact that they respond less often to their children, shows that parents of late talkers do not follow their childs lead. Instead, these parents are more likely to adapt to the childs communication, which results in an "idiosyncratic feedback cycle" that worsens the childs language difficulties rather than help with their language acquisition.Birth Order
First-born children grow up in an environment that provides more possibilities of communicative interaction with adults, which differs from what is experienced by their younger siblings. Younger siblings are likely to have less one-on-one time with their parents or guardians. Older siblings also tend to talk for their younger siblings, giving them less opportunities to grow their language skills.Television viewing
Excessive television viewing is associated with delayed language development. Children who watched television alone were 8.47 times more likely to have language delay when compared to children who interacted with their caregivers during television viewing. Some educational television shows, such as Blues Clues, have been found to enhance a childs language development. But, as recommended by the American Academy of Pediatrics, children under the age of 2 should watch no television at all, and after age 2 watch no more than one to two hours of quality programming a day. Therefore, exposing such young children to television programs should be discouraged, especially television shows with no educational value. Parents should engage children in more conversational activities to avoid television-related delays to their children language development, which could impair their intellectual performance. However, in a study conducted by Dr. Birken of the Hospital for Sick Children, it was found that watching television while interacting with a parent of caregiver is actually beneficial for children who are bilingual. The study spanned four years, from 2011 to 2015, and was based on parent report and clinician observation. Over the four years it was found that if a bilingual child had interaction with an adult while watching television they did not experience language delay and it in fact helped them develop English, their second language.

Treatment
Studies have failed to find clear evidence that a language delay can be prevented by training or educating health care professionals in the subject. Overall, some of the reviews show positive results regarding interventions in language delay, but are not curative. To treat an already existing language delay a child would need Speech and Language Therapy to correct any deficits. These therapists can be found in schools, clinics, through home care agencies, and also colleges where Communication Sciences and Disorders are studied. Most young children with language delay recover to a normal range by five years of age.Aside from these, it is still encouraged for the childs parent to get involved. A few ways that a parent could get involved with helping to improve a childs language and speech skills includes speaking to their child with enthusiasm, engaging in conversations revolving what the child is focusing on, and reading to their child frequently.Social and play skills appear to be more difficult for children with language delays due to their decreased experience in conversation. Speech Pathologists utilize methods such as prompting to improve a childs social skills through play intervention </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Pili multigemini and explain in detail? [/INST]  </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Inborn errors of metabolism and explain in detail? [/INST] Inborn errors of metabolism form a large class of genetic diseases involving congenital disorders of enzyme activities. The majority are due to defects of single genes that code for enzymes that facilitate conversion of various substances (substrates) into others (products). In most of the disorders, problems arise due to accumulation of substances which are toxic or interfere with normal function, or due to the effects of reduced ability to synthesize essential compounds. Inborn errors of metabolism are now often referred to as congenital metabolic diseases or inherited metabolic disorders. To this concept its possible to include the new term of Enzymopathy. This term was created following the study of Biodynamic Enzymology, a science based on the study of the enzymes and their derivated products. Finally, inborn errors of metabolism were studied for the first time by British physician Archibald Garrod (1857–1936), in 1908. He is known for work that prefigured the "one gene-one enzyme" hypothesis, based on his studies on the nature and inheritance of alkaptonuria. His seminal text, Inborn Errors of Metabolism, was published in 1923.

Classification and symptoms of metabolic diseases
Traditionally the inherited metabolic diseases were classified as disorders of carbohydrate metabolism, amino acid metabolism, organic acid metabolism, or lysosomal storage diseases. In recent decades, hundreds of new inherited disorders of metabolism have been discovered and the categories have proliferated. Following are some of the major classes of congenital metabolic diseases, with prominent examples of each class.
Because of the enormous number of these diseases the wide range of systems affected badly, nearly every "presenting complaint" to a healthcare provider may have a congenital metabolic disease as a possible cause, especially in childhood and adolescence. The following are examples of potential manifestations affecting each of the major organ systems.

Diagnostic
Dozens of congenital metabolic diseases are now detectable by newborn screening tests, especially expanded testing using mass spectrometry. gas chromatography–mass spectrometry-based technology with an integrated analytics system, which has now made it possible to test a newborn for over 100 mm genetic metabolic disorders. Because of the multiplicity of conditions, many different diagnostic tests are used for screening. An abnormal result is often followed by a subsequent "definitive test" to confirm the suspected diagnosis.

Common screening tests used in the last sixty years:

Ferric chloride test (detects abnormal metabolites in urine)
Ninhydrin paper chromatography (detects abnormal amino acid patterns)
Guthrie test (detects excessive amounts of specific amino acids in blood) The dried blood spot can be used for multianalyte testing using Tandem Mass Spectrometry (MS/MS). This given an indication for a disorder. The same has to be further confirmed by enzyme assays, IEX-Ninhydrin, GC/MS or DNA Testing.
Quantitative measurement of amino acids in plasma and urine
IEX-Ninhydrin post-column derivitization liquid ion chromatography (detects abnormal amino acid patterns and quantitative analysis)
Urine organic acid analysis by gas chromatography–mass spectrometry
Plasma acylcarnitine analysis by mass spectrometry
Urine purine and pyrimidine analysis by gas chromatography-mass spectrometrySpecific diagnostic tests (or focused screening for a small set of disorders):

Tissue biopsy: liver, muscle, brain, bone marrow
Skin biopsy and fibroblast cultivation for specific enzyme testing
Specific DNA testingA 2015 review reported that even with all these diagnostic tests, there are cases when "biochemical testing, gene sequencing, and enzymatic testing can neither confirm nor rule out an IEM, resulting in the need to rely on the patients clinical course". A 2021 review showed that several neurometabolic disorders 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.

Treatment
In the middle of the 20th century the principal treatment for some of the amino acid disorders was restriction of dietary protein and all other care was simply management of complications. In the past twenty years, new medications, enzyme replacement, gene therapy, and organ transplantation have become available and beneficial for many previously untreatable disorders. Some of the more common or promising therapies are listed:

Epidemiology
In a study in British Columbia, the overall incidence of the inborn errors of metabolism were estimated to be 40 per 100,000 live births or 1 in 2,500 births, overall representing more than approximately 15% of single gene disorders in the population. While a Mexican study established an overall incidence of 3.4: 1000 live newborns and a carrier detection of 6.8:1000 NBS.

References
Further reading
Price, Nicholas C; Stevens, Lewis (1996). Principi di enzimologia [Principles of enzymology] (in Italian). A. Delfino. ISBN 978-88-7287-100-3. OCLC 879866185.
Mazzucato, Fernando; Giovagnoni, Andrea (2019) </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Congenital dyserythropoietic anemia type IV and explain in detail? [/INST]  </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Folliculitis decalvans and explain in detail? [/INST] Folliculitis decalvans is an inflammation of the hair follicle that leads to bogginess or induration of involved parts of the scalp along with pustules, erosions, crusts, ulcers, and scale.: 649 : 760–1  It begins at a central point and spreads outward, leaving scarring, sores, and, due to the inflammation, hair loss in its wake.  No permanent cure has been found for this condition, but there is promise in a regimen of dual therapy with rifampin 300 mg twice daily and clindamycin 300 mg twice daily. This new treatment can be used to control the condition, and tests have indicated that after 3 to 5 months long uninterrupted courses of treatment, many patients have seen limited to no recurrence.

Causes
There is no certainty about the cause of this disorder, but the bacterial species Staphylococcus aureus has a central role and can be detected in the lesions of most patients </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Wrinkly skin syndrome and explain in detail? [/INST] Wrinkly skin syndrome (WSS) is a rare genetic condition characterized by sagging, wrinkled skin, low skin elasticity, and delayed fontanel (soft spot) closure along with a range of other symptoms. The disorder exhibits an autosomal recessive inheritance pattern with mutations in the ATP6V0A2 gene, leading to abnormal glycosylation events. There are only about 30 known cases of WSS as of 2010. Given its rarity and symptom overlap to other dermatological conditions, reaching an accurate diagnosis is difficult and requires specialized dermatological testing. Limited treatment options are available but long-term prognosis is variable from patient-to-patient, on the basis of individual case studies. Some skin symptoms recede with increasing age while progressive neurological advancement of the disorder causes seizures and mental deterioration later in life for some patients.

Symptoms and signs
The predominant clinical symptoms of wrinkly skin syndrome are wrinkled and inelastic skin over the face, backs of hands/fingers, tops of feet, and abdomen, delayed closure of the fontanel (babys soft spot), and increased palmar and plantar creases in the hands and feet, respectively.Patients may experience a wide variety of symptoms (see table). The assortment of symptoms displayed and symptom severity (particularly  growth and developmental delays) vary from patient to patient.

Microscopic analysis of epidermal samples of a four-month year old with WSS revealed an irregular pattern of elastic fiber distribution. Fewer elastic fibers are present in the papillary dermis and fragmented elastic fibers in the reticular dermis are observed. Epidermal samples from the same patient subjected to electron microscopy revealed that elastin fibers display abnormally high levels of fragmentation and clumping of microfibrils, with little amorphous elastin. Within collagen bundles, collagen fibrils are of irregular shape and thickness. These disruptions of the patients connective tissue play a role in the inelasticity of the skin and wrinkling.

Mechanism
Importance of the ATP6V0A2 pump
Vacuolar ATPases (V-ATPase) regulate the pH of the subcellular compartments found within the endosomal membrane system. V-ATPases are multiprotein complexes composed of two functional domains, a V0 domain, and a V1 domain. The V1 domain catalyzes the hydrolysis of ATP in order to power the pumping of protons through the V0 channel, which spans the lipid bilayer of endosomal compartments. Vacuolar ATPases are also localized within the plasma membrane of both renal cells and osteoclasts. In osteoclasts, V-ATPases are required for pumping protons onto the bone surface. The protons are then used for bone resorption. In renal cells, V-ATPases are used to pump protons into the urine. This facilitates bicarbonate reabsorption into the blood. The ATP6V0A2 gene encodes the a2 isoform of the a-subunit (present in the V0 domain). The a2 subunit anchors the V-ATPase to the membrane, and it is also directly involved with proton transport. ATP6V0A2 is encoded by the ATP6V0A2 gene. The ATP6V0A2 pump is found in virtually all cells and is thought to play an important role in the process of vesicular fusion in the secretory pathway, including the secretion of extracellular matrix components.

Function of the Golgi apparatus in protein maturation
The most important subcellular structure in the context of wrinkly skin syndrome (WSS), is the Golgi apparatus. The Golgi apparatus is an important part of the endomembrane system because it processes proteins and lipids prior to their delivery to the plasma membrane and/or secretion into the extracellular environment. The Golgi is organized into a polarized series of membrane-bound stacks, called cisternae, through which proteins are trafficked in sequence once they leave the endoplasmic reticulum (ER), where the proteins and lipids are synthesized. Proteins destined for secretion or delivery to the plasma membrane arrive first at the cis-Golgi, before being trafficked through the medial and trans-Golgi. In the Golgi, proteins undergo extensive post-translational modifications (PTMs). In the context of WSS, the most significant PTM events are the glycosylation of proteins comprising the extracellular matrix (ECM) of epidermal cells. The two types of glycosylation events in the Golgi are N-linked glycosylation and O-linked glycosylation. Glycosylation of proteins destined for secretion occurs through the forward movement of proteins throughout the Golgi apparatus. The proteins destined for secretion are then trafficked to the plasma membrane in secretory vesicles. Retrograde (backward) transport in the Golgi apparatus is also important. In order to retain the enzymes responsible for protein glycosylation in the correct regions of the Golgi, there must be retrograde transport of these enzymes back into the Golgi apparatus. In addition, retrograde transport serves a quality control function, by shuttling misfolded proteins back into the ER or retaining them within the Golgi itself until proper protein folding and maturation is completed. The activity of protein-modifying enzymes, like glycosyltransferases and glycosidases, relies on the lumenal pH of the Golgi apparatus. Cisternal pH becomes increasingly acidic (lower pH) with progression from cis- to trans- regions of the Golgi. Disruption of decreasing pH can impart significant effects on the efficiency and sequence of glycosylation events. Maintenance of the pH gradient across the Golgi is instrumental for proper post-translational modification of proteins prior to secretion. Retrograde transport and pH regulation are therefore vital to the proper functioning of the Golgi apparatus.

Genetic causes of WSS
Patients with both missense and/or nonsense mutations of the ATP6V0A2 gene have been shown to phenotypically express wrinkly skin syndrome (WSS) or autosomal recessive cutis laxa type II (ARCL II) (another cutis laxa disorder). Some consider WSS to be a milder variant of ARCL II, but the genetic causes of WSS are not yet known. A large number of patients with WSS and ARCL II show a loss-of-function in the a2-subunit. These mutations in ATP6V0A2 are associated with defective glycan biosynthesis and defective Golgi apparatus structure. However, the exact mechanism of how mutations in the ATP6V0A2 gene lead to these effects is unclear.

Aberrant Golgi functioning and clinical symptoms of WSS
WSS is characterized by defects in the elastic fiber system that comprises the extracellular matrix of epidermal cells. The skins elastic fiber system consists of elastin (which is normally non-glycosylated) and glycosylated proteins (fibulin, fibronectin, and collagen). It is speculated that either abnormal glycosylation and/or impaired secretion of proteins caused by ATP6V0A2 dysfunction lead to WSS. The ATP6V0A2 pump is highly expressed within the Golgi apparatus. ATP6V0A2 is primarily found within the medial-Golgi and the trans-Golgi. ATP6V0A2 acidifies the medial- and trans-Golgi so that their resident enzymes (e.g. glycosidases and glycosyltransferases) function properly. Therefore, mutations in the ATP6V0A2 gene reduce the ability of ATP6V0A2 to produce the necessary pH gradient for these glycosylation enzymes, which results in abnormal N- and O-linked glycosylation. Because the physical properties of skin rely heavily on the structural proteins of the elastic fiber system of epidermal cells, abnormal glycosylation can lead to structural defects in the elastic fibers, and therefore lead to the inelastic skin seen in WSS. WSS patients may also have defective secretion of another ECM component of the skin called tropoelastin. The process of secreting tropoelastin from the cell is dependent on the acidic pH of vesicles. It is thought that increased pH levels (lower acidity) lead to the premature aggregation (coacervation) of tropoelastin inside the vesicle. The process of coacervation is thought to be essential for proper elastin assembly in the ECM. Coacervation must occur outside of the cell within the ECM ( the ECM has a more alkaline environment than the vesicle) for proper elastic fiber assembly. However, defective ATP6V0A2 pumps in the vesicle increase the lumenal pH of the vesicle, leading to premature coacervation and defective elastic fiber assembly. The abnormal assembly and glycosylation of proteins used to make elastic fibers explains the connective tissue phenotypes associated with ARCL2 and WSS but does not explain the neurodevelopmental disorders or growth defects of these patients (18). Elastin is not required for brain or bone growth. However, it is believed that abnormal/impaired secretion of the brain and bone-specific ECM proteins caused by dysregulation of Golgi acidification is what leads to the neural and skeletal defects in ARCL2.

Diagnosis
Accurate diagnosis of wrinkly skin syndrome generally requires specialized dermatological assessment. In addition to assessment of clinical physical symptoms, diagnosis may be aided by:
x-rays to identify joint abnormalities
ophthalmologic evaluation of hypertelorism, downslanting eyes, and myopia
brain MRI scans to evaluate the degree of microcephaly
genetic screening for congenital disorders of glycosylation (CDG)
skin biopsy and histological analysis
genetic screening for mutations in the ATP6VOA2 geneThe pigmentation patterns observed in skin biopsies reveal a characteristic lack of elastic fibers in the papillary dermis and clumping of elastic fibers in the reticular dermis. Despite assessment of each of these diagnostic factors, a definitive diagnosis differentiating WSS from cutis laxa requires genetic testing.

Differential diagnosis
Several symptoms are shared with cutis laxa type II (CLT2) including wrinkling of skin, microcephaly, and developmental delay which has made proper diagnosis difficult in several cases. However, the severity of skin abnormalities and facial dysmorphia is greater in cutis laxa type II.

Management
While there is no corrective cure for the disease, some symptoms can be managed therapeutically and/or monitored. Therapeutic treatment options include physical therapy to improve muscular development while patient growth and osteoporosis can be monitored via developmental assessments and bone density scans, respectively.

Prognosis
Long-term progression of this disorder varies between patients. Due to therapeutic interventions for developmental symptoms, long-term outcomes are improved by diagnosis of the disorder during childhood. In some cases, dermatological symptoms subside while associated neurological symptoms may worsen with age, including frequency of seizures and mental deterioration.

Epidemiology
As of January 2020, only ~ 30 cases of wrinkly skin syndrome have been reported. The majority of reported cases have come from Middle Eastern regions such as Iraq, Saudi Arabia, and Oman. Both males and females of Middle Eastern descent have been reported to be affected. Consanguineous (marriage of first-cousins) relationships are a prevalent feature of parents with children diagnosed with WSS. Such marriages and relationships are more common in Middle Eastern regions </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Neonatal stroke and explain in detail? [/INST] Neonatal stroke, similar to a stroke which occurs in adults, is defined as a disturbance to the blood supply of the developing brain in the first 28 days of life. This description includes both ischemic events, which results from a blockage of vessels, and hypoxic events, which results from a lack of oxygen to the brain tissue, as well as some combination of the two.  One treatment with some proven benefits is hypothermia, but may be most beneficial in conjunction with pharmacological agents. Well-designed clinical trials for stroke treatment in neonates are lacking, but some current studies involve the transplantation of neural stem cells and umbilical cord stem cells; it is not yet known if this therapy is likely to be successful.Neonatal strokes may lead to cerebral palsy, learning difficulties, or other disabilities. A neonatal stroke occurs in approximately 1 in 4000 births, but is likely much higher due to the lack of noticeable symptoms.

Presentation
A neonatal stroke is one that occurs in the first 28 days of life, though a late presentation is not uncommon (as contrasted with perinatal stroke, which occurs from 28 weeks gestation through the first 7 days of life). 80% of neonatal strokes are ischemic, and their presentation is varied, making diagnosis very difficult. The most common manifestation of neonatal strokes are seizures, but other manifestations include lethargy, hypotonia, apnoea, and hemiparesis. Seizures can be focal or generalized in nature. Stroke accounts for about 10% of seizures in term neonates.

Risk factors
Many different risk factors play a role in causing a neonatal stroke. Some maternal disorders that may contribute to neonatal strokes include: autoimmune disorders, coagulation disorders, prenatal cocaine exposure, infection, congenital heart disease, diabetes, and trauma. Placental disorders that increase the risk of stroke include placental thrombosis, placental abruption, placental infection, and chorioamnionitis. Other disorders that may increase the risk of a neonatal stroke are blood, homocysteine and lipid disorders, such as polycythemia, disseminated intravascular coagulopathy, prothrombin mutation, lipoprotein (a) deficiency, factor VIII deficiency (hemophilia A), and factor V Leiden mutation.  Infectious disorders such as central nervous system (CNS) infection or systemic infection may also contribute.Many infants who have a neonatal stroke also follow an uncomplicated pregnancy and delivery without identifiable risk factors, which exemplifies the necessity for further research on this subject.

Mechanism
A neonatal stroke in the developing brain involves excitotoxicity, oxidative stress, and inflammation, which accelerate cell death through necrosis or apoptosis, depending on the region of the brain and severity of stroke. The pathophysiology of neonatal stroke may include thrombosis and thrombolysis, and  vascular reactivity. Apoptosis mechanisms may have a more prominent role in developing an ischemic brain injury in neonatal humans than in adult brain ischemia, as a majority of cells die in the environment where edema developed after a neonatal stroke. There is an increased inflammatory response after hypoxia-ischemia, which corresponds to extensive neuronal apoptosis. Apoptosis involves the mitochondrial release of cytochrome c and apoptosis-inducing factor (AIF), which activate caspase-dependent and –independent execution pathways, respectively. Injury may also occur due to O2 accumulation via the production of O2 by microglia, a type of glial cell that are responsible for immune response in the CNS, but their role in injury after neonatal stroke is still relatively unknown. As observed by Alberi, et al., progressive atrophy in the ipsilateral hemisphere over three weeks after the stroke occurred, suggesting that a neonatal stroke has long-lasting effects on neuronal viability and the potential for a prolonged therapeutic window for alleviating the progression of cell death.

Diagnosis
Neonatal strokes occur in approximately 1 in 4000 births, but this number is likely much higher due to lack of noticeable symptoms at time of birth.  They generally present with seizures, but only half to three quarters of cases have identifiable causes. Diagnosis often occurs around 36 hours after onset of neonatal stroke due to the interval between stroke and clinical presentation, if any occurs at all. Neonatal strokes can be confirmed with neuroimaging or neuropathalogical studies, and other various imaging techniques can be used to diagnose neonatal strokes, such as ultrasound, Doppler sonography, computerized tomography (CT) scan, CT angiography, and multimodal MR.

Prevention
Some evidence suggests that magnesium sulfate administered to mothers prior to early preterm birth reduces the risk of cerebral palsy in surviving neonates. Due to the risk of adverse effects treatments may have, it is unlikely that treatments to prevent neonatal strokes or other hypoxic events would be given routinely to pregnant women without evidence that their fetus was at extreme risk or has already sustained an injury or stroke. This approach might be more acceptable if the pharmacologic agents were endogenously occurring substances (those that occur naturally in an organism), such as creatine or melatonin, with no adverse side-effects.
Because of the period of high neuronal plasticity in the months after birth, it may be possible to improve the neuronal environment immediately after birth in neonates considered to be at risk of neonatal stroke. This may be done by enhancing the growth of axons and dendrites, synaptogenesis and myelination of axons with systemic injections of neurotrophins or growth factors which can cross the blood–brain barrier.

Treatment
Treatment remains controversial with regards to the risk/benefit ratio, which differs significantly from treatment of stroke in adults. Presence or possibility of organ or limb impairment  and bleeding risks  are possible with treatments using antithrombotic agents.

Therapeutic Hypothermia
Hypothermia treatment induced by head cooling or systemic cooling administered within 6 hours of birth for 72 hours has proven beneficial in reducing death and neurological impairments at 18 months of age. This treatment does not completely protect the injured brain and may not improve the risk of death in the most severely hypoxic-ischemic neonates and has also not been proven beneficial in preterm infants. Combined therapies of hypothermia and pharmacological agents or growth factors to improve neurological outcomes are most likely the next direction for damaged neonatal brains, such as after a stroke.

Other Treatments
A successful use of urokinase in a newborn with an aortic clot has been reported, but the bleeding risks associated with thrombolytic agents are still unclear.Heparin, an anticoagulant, treatments have been used in cases of cerebro-venous sinus thrombosis (CVST) in order to stop thrombosis extension and recurrence, to induce thrombosis resolution, and to prevent further brain damage.
In the case of extremely high intracranial pressure, surgical removal of hematoma may be beneficial.

Prognosis
Of the infants that survive, there may be as many as 1 million a year that develop cerebral palsy, learning difficulties or other disabilities. Cerebral palsy is the most common physical disability in childhood, and it is characterized by a lack of control of movement. Other neurological defects that can occur after a neonatal stroke include hemiparesis and hemi-sensory impairments   Some studies suggest that when tested as toddlers and preschoolers, children who previously had neonatal strokes fall within normal ranges of cognitive development. Less is known about longer-term cognitive outcome, but there has been evidence that cognitive deficits may emerge later in childhood when more complex cognitive processes are expected to develop.

Research Direction
Well-designed clinical trials for stroke treatment in neonates are lacking  Recent clinical trials show that therapeutic intervention by brain cooling beginning up to 6 hours after perinatal asphyxia reduces cerebral injury and may improve outcome in term infants, indicating cell death is both delayed and preventable Pancaspase inhibition and Casp3-selective inhibition have been found to be neuroprotective in neonatal rodents with models of neonatal brain injury, which may lead to pharmacological intervention  In a study done by Chauvier, et al., it is suggested that a Caspase inhibitor, TRP601, is a candidate for neuroprotective strategy in prenatal brain injury conditions. They found a lack of detectable side effects in newborn rodents and dogs. This may be a useful treatment in combination with hypothermia.MRI has proven valuable for defining brain injury in the neonate, but animal models are still needed to identify causative mechanisms and to develop neuroprotective therapies. In order to model human fetal or neonatal brain injury, one needs a species in which a similar proportion of brain development occurs in utero, the volume of white to grey matter is similar to the human brain, an insult can be delivered at an equivalent stage of development, the physiological outcome of the insult can be monitored, and neurobehavioral parameters can be tested. Some animals that meet these criteria are sheep, non-human primates, rabbits, spiny mice, and guinea pigs.Transplantation of neural stem cells and umbilical cord stem cells is currently being trialed in neonatal brain injury, but it is not yet known if this therapy is likely to be successful.

References
Further reading
Nelson, KB; Lynch, JK (March 2004). "Stroke in newborn infants". Lancet Neurology. 3 (3): 150–8. doi:10.1016/s1474-4422(04)00679-9. PMID 14980530. S2CID 11194017.
Nelson, K. B. (29 January 2007). "Perinatal Ischemic Stroke" </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Subclinical infection and explain in detail? [/INST] A subclinical infection — sometimes called a preinfection or inapparent infection — is an infection that, being subclinical, is nearly or completely asymptomatic (no signs or symptoms). A subclinically infected person is thus a paucisymptomatic or asymptomatic carrier of a microbe, intestinal parasite, or virus that usually is a pathogen causing illness, at least in some individuals. Many pathogens spread by being silently carried in this way by some of their host population. Such infections occur both in humans and animals.An example of an asymptomatic infection is a  mild common cold that is not noticed by the infected individual. Since subclinical infections often occur without eventual overt sign, their existence is only identified  by microbiological culture or DNA techniques such as polymerase chain reaction.

Infection transmission/signs
An individual may only develop signs of an infection after a period of subclinical infection, a duration that  is called the incubation period. This is the case, for example, for subclinical sexually transmitted diseases such as AIDS and genital warts. It is thought that individuals with such subclinical infections, and those that never develop overt illness, creates a reserve of individuals that can transmit an infectious agent to infect other individuals. Because such cases of infections do not come to clinical attention, health statistics can often fail to measure the true prevalence of an infection in a population, and this prevents the accurate modeling of its infectious transmission.

Types of subclinical infections
The following pathogens (together with their symptomatic illnesses) are known to be carried asymptomatically, often in a large percentage of the potential host population:

Host tolerance
Fever and sickness behavior and other signs of infection are often taken to be due to them. However, they are evolved physiological and behavioral responses of the host to clear itself of the infection </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Pineoblastoma and explain in detail? [/INST]  </s>