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plasmodium lophurae plasmodium lophurae plasmodium lophurae is a parasite of the genus plasmodium subgenus giovannolaia. plasmodium lophurae scientific classification domain: eukaryota clade: diaphoretickes clade: tsar clade: sar clade: alveolata phylum: apicomplexa class: aconoidasida order: haemospororida family: plasmodiidae genus: plasmodium species: p. lophurae binomial name plasmodium lophuraecoggeshall, 1938 like all plasmodium species, p. lophurae has both vertebrate and insect hosts. the vertebrate hosts for this parasite are birds. description the parasite was first described by coggeshall in 1938 after being isolated from chickens. adult chickens demonstrate resistance to this parasite. distribution p. lophurae was discovered in sri lanka and is endemic to the southeast asia region. description p. lophurae can be isolated from a blood smear.

bladder bladder the bladder is a hollow organ in humans and other vertebrates that stores urine from the kidneys before disposal by urination. in humans the bladder is a distensible organ that sits on the pelvic floor. urine enters the bladder via the ureters and exits via the urethra. the typical adult human bladder will hold between 300 and 500 ml (10.14 and 16.91 fl oz) before the urge to empty occurs, but can hold considerably more. bladder1. human urinary system: 2. kidney, 3. renal pelvis, 4. ureter, 5. bladder, 6. urethra. (left side with frontal section) 7. adrenal gland vessels: 8. renal artery and vein, 9. inferior vena cava, 10. abdominal aorta, 11. common iliac artery and vein with transparency: 12. liver, 13. large intestine, 14. pelvisdetailsprecursorurogenital sinussystemurinary systemarterysuperior vesical arteryinferior vesical arteryumbilical arteryvaginal arteryveinvesical venous plexusnervevesical nervous plexusidentifierslatinvesica urinariameshd001743ta98a08.3.01.001ta23401fma15900anatomical terminology the latin phrase for "urinary bladder" is vesica urinaria, and the term vesical or prefix vesico - appear in connection with associated structures such as vesical veins. the modern latin word for "bladder" – cystis – appears in associated terms such as cystitis (inflammation of the bladder). structure further information: urination § anatomy of the bladder and outlet male and female urinary bladders in lateral cross-section in humans, the bladder is a hollow muscular organ situated at the base of the pelvis. in gross anatomy, the bladder can be divided into a broad fundus, a body, an apex, and a neck. the apex (also called the vertex) is directed forward toward the upper part of the pubic symphysis, and from there the median umbilical ligament continues upward on the back of the anterior abdominal wall to the umbilicus. the peritoneum is carried by it from the apex on to the abdominal wall to form the middle umbilical fold. the neck of the bladder is the area at the base of the trigone that surrounds the internal urethral orifice that leads to the urethra. in males the neck of the urinary bladder is next to the prostate gland. the bladder has three openings. the two ureters enter the bladder at ureteric orifices, and the urethra enters at the trigone of the bladder. these ureteric openings have mucosal flaps in front of them that act as valves in preventing the backflow of urine into the ureters, known as vesicoureteral reflux. between the two ureteric openings is a raised area of tissue called the interureteric crest. this makes the upper boundary of the trigone. the trigone is an area of smooth muscle that forms the floor of the bladder above the urethra. it is an area of smooth tissue for the easy flow of urine into and from this part of the bladder - in contrast to the irregular surface formed by the rugae. the walls of the bladder have a series of ridges, thick mucosal folds known as rugae that allow for the expansion of the bladder. the detrusor muscle is the muscular layer of the wall made of smooth muscle fibers arranged in spiral, longitudinal, and circular bundles. the detrusor muscle is able to change its length. it can also contract for a long time whilst voiding, and it stays relaxed whilst the bladder is filling. the wall of the urinary bladder is normally 3–5 mm thick. when well distended, the wall is normally less than 3 mm. nearby structures bladder location and associated structures in the male in men, the prostate gland lies outside the opening for the urethra. the middle lobe of the prostate causes an elevation in the mucous membrane behind the internal urethral orifice called the uvula of urinary bladder. the uvula can enlarge when the prostate becomes enlarged. the bladder is located below the peritoneal cavity near the pelvic floor and behind the pubic symphysis. in men, it lies in front of the rectum, separated by the recto-vesical pouch, and is supported by fibres of the levator ani and of the prostate gland. in women, it lies in front of the uterus, separated by the vesico-uterine pouch, and is supported by the elevator ani and the upper part of the vagina. blood and lymph supply the bladder receives blood by the vesical arteries and drained into a network of vesical veins. the superior vesical artery supplies blood to the upper part of the bladder. the lower part of the bladder is supplied by the inferior vesical artery, both of which are branches of the internal iliac arteries. in females, the uterine and vaginal arteries provide additional blood supply. venous drainage begins in a network of small vessels on the lower lateral surfaces of the bladder, which coalesce and travel with the lateral ligaments of the bladder into the internal iliac veins. the lymph drained from the bladder begins in a series of networks throughout the mucosal, muscular and serosal layers. these then form three sets of vessels: one set near the trigone draining the bottom of the bladder; one set draining the top of the bladder; and another set draining the outer undersurface of the bladder. the majority of these vessels drain into the external iliac lymph nodes. nerve supply the bladder receives both sensory and motor supply from sympathetic and the parasympathetic nervous systems. the motor supply from both sympathetic fibers, most of which arise from the superior and inferior hypogastric plexuses and nerves, and from parasympathetic fibers, which come from the pelvic splanchnic nerves. sensation from the bladder, relating to distension or to irritation (such as by infection or a stone) is transmitted primarily through the parasympathetic nervous system. these travel via sacral nerves to s2-4. from here, sensation travels to the brain via the dorsal columns in the spinal cord. microanatomy when viewed under a microscope the bladder can be seen to have an inner lining (called epithelium), three layers of muscle fibres, and an outer adventitia. the inner wall of the bladder is called urothelium, a type of transitional epithelium formed by three to six layers of cells; the cells may become more cuboidal or flatter depending on whether the bladder is empty or full. additionally, these are lined with a mucous membrane consisting of a surface glycocalyx that protects the cells beneath it from urine. the epithelium lies on a thin basement membrane, and a lamina propria. the mucosal lining also offers a urothelial barrier against the passing of infections. these layers are surrounded by three layers of muscle fibres arranged as an inner layer of fibres orientated longitudinally, a middle layer of circular fibres, and an outermost layer of longitudinal fibres; these form the detrusor muscle, which can be seen with the naked eye. the outside of the bladder is protected by a serous membrane called adventitia. vertical section of bladder wall layers of the bladder wall and cross-section of the detrusor muscle anatomy of the male bladder, showing transitional epithelium and part of the wall in a histological cut-out development further information: development of the urinary system in the developing embryo, at the hind end lies a cloaca. this, over the fourth to the seventh week, divides into a urogenital sinus and the beginnings of the anal canal, with a wall forming between these two inpouchings called the urorectal septum. the urogenital sinus divides into three parts, with the upper and largest part becoming the bladder; the middle part becoming the urethra, and the lower part changes depending on the biological sex of the embryo. the human bladder derives from the urogenital sinus, and it is initially continuous with the allantois. the upper and lower parts of the bladder develop separately and join together around the middle part of development. at this time the ureters move from the mesonephric ducts to the trigone. in males, the base of the bladder lies between the rectum and the pubic symphysis. it is superior to the prostate, and separated from the rectum by the recto-vesical pouch. in females, the bladder sits inferior to the uterus and anterior to the vagina; thus its maximum capacity is lower than in males. it is separated from the uterus by the vesico-uterine pouch. in infants and young children the urinary bladder is in the abdomen even when empty. function main article: urination urine, excreted by the kidneys, collects in the bladder because of drainage from two ureters, before disposal by urination (micturition). urine leaves the bladder via the urethra, a single muscular tube ending in an opening called the urinary meatus, where it exits the body. urination involves coordinated muscle changes involving a reflex based in the spine, with higher inputs from the brain. during urination, the detrusor muscle contracts, and the external urinary sphincter and muscles of the perineum relax, allowing urine to pass through the urethra and out of the body. the urge to pass urine stems from stretch receptors that activate when between 300 - 400 ml urine is held within the bladder. as urine accumulates, the rugae flatten and the wall of the bladder thins as it stretches, allowing the bladder to store larger amounts of urine without a significant rise in internal pressure. urination is controlled by the pontine micturition center in the brainstem. stretch receptors in the bladder signal the parasympathetic nervous system to stimulate the muscarinic receptors in the detrusor to contract the muscle when the bladder is distended. this encourages the bladder to expel urine through the urethra. the main receptor activated is the m3 receptor, although m2 receptors are also involved and whilst outnumbering the m3 receptors they are not so responsive. the main relaxant pathway is via the adenylyl cyclase camp pathway, activated via the β3 adrenergic receptors. the β2 adrenergic receptors are also present in the detrusor and even outnumber β3 receptors, but they do not have as important an effect in relaxing the detrusor smooth muscle. clinical significance

central drugs standard control organisation central drugs standard control organisation the central drugs standard control organisation (cdsco) is india's national regulatory body for cosmetics, pharmaceuticals and medical devices. it serves a similar function to the european medicines agency of the european union, the pmda of japan, the food and drug administration (fda) of the united states, and the medicines and healthcare products regulatory agency of the united kingdom, and the national medical products administration (nmpa) of china. the indian government has announced its plan to bring all medical devices, including implants and contraceptives under a review of the central drugs and standard control organisation (cdsco). central drugs standard control organisationorganisation overviewtyperegulatory bodyheadquartersnew delhi, indiaannual budget₹3,358 crore (us$420 million) (2021 - 2022) minister responsiblemansukh mandavia, minister of health and family welfareorganisation executivedr. v. g. somani, drugs controller general of indiaparent departmentdirectorate general of health services, ministry of health and family welfarewebsitecdsco.gov.in and www.cdscoonline.gov.in within the cdsco, the drug controller general of india (dcgi) regulates pharmaceutical and medical devices and is positioning within the ministry of health and family welfare. the dcgi is advised by the drug technical advisory board (dtab) and the drug consultative committee (dcc). divided into zonal offices, each one carries out pre-licensing and post-licensing inspections, post-market surveillance, and drug recalls (where necessary). manufacturers who deal with the authority required to name an authorized indian representative (air) to represent them in all dealings with the cdsco in india. though the cdsco has a good track record with the world health organization, it has also been accused of past collusion with independent medical experts and pharmaceutical companies. cdsco plans to open an international office in beijing, china. divisions central drugs standard control organization has 8 divisions: ba/be new drugs medical device & diagnostics dcc-dtab import & registration biological cosmetics clinical trials

covid-19 pandemic in queensland covid-19 pandemic in queensland the covid-19 pandemic in queensland is part of the ongoing worldwide pandemic of the coronavirus disease 2019 (covid-19) caused by severe acute respiratory syndrome coronavirus 2 (sars-cov-2). covid-19 pandemic in queenslanddiseasecovid-19virus strainsars-cov-2first outbreakwuhan, hubei, chinaconfirmed cases447,145 (as of 4 feb. 2022)active cases49,639 (as of 4 feb. 2022)hospitalised cases790 (as of 4 feb. 2022)critical cases48 (as of 4 feb. 2022)recovered2,323 (as of 17 january 2022)deaths268(as of 4 feb. 2022)fatality rate0.07%government websitewww.covid19.qld.gov.au timeline queensland police checkpoint at coolangatta on 4 april 2020 boundary street coolangatta, with barricades blocking access from new south wales covid-19 preventive measures stickers on a pedestrian signal pole in queensland 2020 on 29 january 2020, queensland was the first to declare a public health emergency. the legislation was strengthened on 6 february by the public health (declared public health emergencies) amendment bill 2020. in march, power was given directly to the chief health officer (rather than the health minister on behalf of the cabinet) to make 'directions', amongst other things allowing her to declare restrictions on movement, gatherings and business activities, to set social distancing or masking requirements, and to close borders. as of the end of july 2021, queensland had recorded the death of just 7 patients with covid-19. this fatality rate, of just under 1 per million residents, was the lowest not just in australia, but of any sizeable jurisdiction with its own policing and health powers, in the world. key directions made under the public health act 2005 include: 2 april – a person must not leave their principal place of residence except for essential needs including work, food, medical and exercise, outdoor gatherings only up to 2 persons or with members of household, receiving only to 2 visitors at a residence, and no gatherings in non-residences. 9 april – "non-essential" business, activity or undertaking must not be operated. "non-essential" businesses include cinemas, casinos, concerts, indoor sports, gyms, playgrounds, campgrounds, libraries. restrictions also apply to restaurants (take away or delivery only), churches, hairdressers etc. however, most construction, mining, manufacturing and retail businesses continued to operate. restricted entry into queensland was introduced, with only queensland residents and those considered an 'exempt person' being allowed to enter queensland by air, sea, rail or road from another state or territory. this was introduced in stages: stage 1 started on 26 march 2020, with stages 2 and 3 involving tightening the restrictions. stage 4, introduced on 11 april, was the most restrictive, every person crossing the border including queensland residents required a permit. in addition, a person who had been in a declared covid-19 hotspot in the previous 14 days had to self-quarantine for 14 days. closures of areas within queensland included: all camping areas within queensland national parks, state forests and recreation areas were closed on 26 march. closure of high visitation national parks including fraser island as well as all day use areas and visitor centres on 9 april. closure of queensland waters to cruise ships on 6 april. closure of surfers paradise, coolangatta and the spit beaches on 8 april. access to the torres strait islands has been restricted to prevent covid-19 from reaching the region, which has to date remained free of cases. 2021 on 1 february 2021, queensland opened its border to all australian states and territories except western australia. since the border closures were implemented, 6,855,750 border passes were issued. on 22 february, the first queenslander received a covid-19 vaccination at gold coast university hospital. she was a nurse who works in that hospital's covid-19 ward. on 28 february 2021, the "check in qld" qr code sign-in/contact tracing app was launched by the minister for health and ambulance services, yvette d'ath. it is based on the act "check in cbr" app. use of the app is not mandatory. on 12 march, princess alexandra hospital in brisbane went into lockdown after a doctor tested positive for covid-19. this was the beginning of one cluster in brisbane connected to that hospital. queensland had gone 59 days without any locally acquired covid-19 infections. due to a growing cluster in bondi, sydney, from 1am on 24 june, the queensland government declared all of greater sydney was a hotspot. border entry will be refused to anyone who lives in, or has visited: greater sydney, the blue mountains, central coast, wollongong or shellharbour. residents returning will be quarantined for 14 days. everyone entering queensland will have to complete a border declaration. brisbane lockdowns on 8 january 2021, a three-day lockdown was announced by annastacia palaszczuk to prevent spread of the more contagious uk strain of coronavirus that escaped from a brisbane hotel quarantine. the lockdown applied to all of greater brisbane including council areas of brisbane, ipswich, logan city, moreton bay and redland city from 6 pm that day. more than 2 million residents were affected. on 29 march at 5 pm, greater brisbane went into another three-day lockdown. the step was taken when a second cluster of the uk strain of covid-19 grew to seven people. two of them were an un-vaccinated nurse from princess alexandra hospital, and her sister. by 30 march another 8 locally acquired cases were reported, for a total of 10 new cases in the preceding 24 hours, and 2 separate clusters, both uk strain were identified. as of this date queensland had 78 active cases in hospitals. on 31 march in queensland 34,711 coronavirus tests and 7,596 vaccinations were conducted. on 1 april, the "three-day" lockdown was lifted five hours early at midday. though 10 new cases had been recorded in the previous 24 hours, there was only one case of community transmission, which was linked to the second cluster surrounding the infected nurse from the princess alexandra hospital. this cluster now numbered 12, up from 7 on 29 march. some restrictions introduced for the lockdown were maintained temporarily: all queenslanders had to carry a face-mask outside their home until 15 april, patrons at food or beverage venues had to stay seated, no dancing allowed, 30 person limit at private gatherings at homes statewide, businesses and churches could open, but have only one-person-per 2-square-metres of floor area, visitors were not permitted for 2 weeks at: aged or disabled care facilities, hospitals and prisons. on 28 june queensland recorded 3 new covid-19 cases overnight. 2 were locally acquired, one acquired overseas. a miner was found to be infected with the delta variant of covid-19 after returning from the northern territory. as a result of these cases, from 10pm on 29 june, masks became mandatory in these local government areas: brisbane gold coast ipswich logan lockyer valley moreton bay noosa redlands scenic rim region somerset sunshine coast region in addition: masks must be worn in workplaces when another person is present. dancing is again banned no more than 30 people are allowed inside homes. after the lockdown was expanded: masks mandatory when leaving the house. household visitors limited to 2 funerals restricted to 20 people weddings restricted to 10 people dancing and singing not allowed restaurants and cafes can only provide: take away home delivery. lockdown expansion on 29 june from 6pm the lockdown was expanded to new areas. all of: south east queensland townsville city magnetic island and palm island went into lockdown for 3 days, until 6pm on 2 july. this move was taken after a casual clerical worker from the prince charles hospital in brisbane, who worked outside the covid ward as a concierge, became infected with the delta variant and travelled from sandgate in brisbane to magnetic island and townsville where she visited markets. on 23 july, the border with nsw was closed from 1:00am due to locations outside greater sydney reporting covid-19 cases. from 6:00am on 23 july to 6:00am on 20 august the same rules will be used across the state, except for se queensland where masks were still required. in se queensland wearing a face mask is mandatory whenever outside the home, unless: in a car alone or with household members eating or drinking exercising outdoors alone or with household members it is unsafe on 24 july 2021, there was an anti-lockdown protest in brisbane. there were also protests in melbourne, and in sydney, where several people were arrested, infringement notices issued and over 50 people charged. on 31 july from 4pm, 11 lgas in south east queensland went into a snap lockdown for 3 days. this was after 6 new locally acquired cases of the delta covid variant. the areas affected were: brisbane, gold coast, ipswich, lockyer valley, logan, moreton bay, noosa, redlands, sunshine coast, somerset and scenic rim. one of the cases is a medical student at the university of queensland, who had been to many venues, including royal brisbane and women's hospital, the university of queensland, and the translational research institute at princess alexandra hospital. by 1 august there were 18 locally acquired cases of delta variant. deputy premier steven miles said that the 9 new cases were the greatest number since august 2020. on 2 august there were 15 new cases of covid-19, 2 overseas acquired. consequently, the south-east queensland's lockdown was extended until 4:00pm on 8 august (sunday). the same day, because of the extension, the ekka agricultural show was cancelled for the second year, 5 days before it was to be open to the public from 7 august (saturday). on 8 august the lockdown in se queensland ended, though some restrictions remained in force, including mandatory wearing of masks. on 9 august, cairns went into lockdown from 4:00pm for three days. this was due to an "unexpected" case of covid-19, a taxi driver who was infectious in the community for ten days. on 26 august the qld government announced its own dedicated regional covid-19 quarantine facility would be built near toowoomba wellcamp airport, 15 kilometres from toowoomba in queensland. construction started that day. on 17 december at 5am extra restrictions, published on 7 december, for unvaccinated people in queensland became effective. some venues will require proof of vaccination status, or a medical exemption for people wishing to enter their premises. on 18 december from 1am masks again became mandatory across the entire state in many public and outdoor places. on 31 december, the state had 2,266 new cases of covid-19 in the 12 hours between 7am and 7pm. there were nearly 14,000 active cases and 80 people in hospital being treated for covid with 1 in intensive care. 86.6% of the state population (aged 16+) had received 2 vaccine doses, 90.7% at least 1 dose. 2022 on 1 january 2022, the qld government announced that from 2 january, at 1am, masks will be mandatory indoors at many public venues. the rule covers cafes, clubs, indoor stadiums, pubs and sports arenas, except when seated, also hairdressers, libraries, nail salons and medical centre waiting rooms. where possible, remote work was urged. on 5 january there were 6,781 new cases reported, and over 32,000 active cases there were 265 people hospitalised in queensland for covid treatment, 10 in intensive care units (icu). 88 police officers, and another 28 queensland police service employees were infected with covid. another 272 were in isolation. on 6 january there was one death and 10,332 new cases reported, for over 42,000 active cases. the man, aged in his 80s, died on 27 december 2021. there were 284 people hospitalised for covid treatment, 12 in icu, 2 on ventilators. on 8 january there were 2 deaths, raising total deaths to 10. daily new cases were reported at 11,174, for 68,783 cases in total, and there were 62,919 active cases. one death was a man in his 30s, at his home on 5 january.there were 349 people hospitalised in queensland for covid treatment, 17 in icu, 3 on ventilators.a state-wide suspension of non-urgent elective surgery in public hospitals, until 1 march, was announced on 8 january by the state health minister. on 9 january there were no deaths reported. daily new cases were reported at 18,000, 4,320 from self-reported rapid antigen test results, and there were 80,563 active cases. there were 402 people hospitalised for covid treatment, 22 in icu, 5 on ventilators.also on 9 january, a 2-week delay in the start of the 2022 school year, to 7 february, was announced to avoid a predicted peak in covid cases. the end

of the school year was also going to be moved a week to 16 december, but this plan was later withdrawn. on 10 january, there were 9,581 new cases, 3,714 from rapid antigen test results. there were 419 people in hospital for covid treatment, 21 in icu, 7 on ventilators. on 12 january, there were 6 deaths, raising total deaths to 17, the highest daily death toll in queensland since the pandemic began, until 7 died on 16 january. 2 were in their 70s, 3 their 80s, 1 over 90. 5 had 2 doses of vaccine, 1 was not vaccinated. all had "significant underlying medical conditions." daily new cases were reported at 14,914, of them 2,812 from self-reported rapid antigen test results. there were 145,294 active cases, and 153,837 total covid-19 cases since march 2020. there were 556 people in hospital for covid treatment, 26 in icu, 10 on ventilators, all up on previous days. on 13 january, there were 3 deaths, raising total deaths to 20. 2 were in their 60s, 1 their 70s. all were un-vaccinated. daily new cases were at 23,630, of those 10,182 were from rat test results. there were 168,012 active cases, and 177,454 total covid-19 cases since march 2020. there were 589 people in hospital for covid treatment, 41 in icu, 15 on ventilators, all up on previous days. more deaths in queensland from covid had now been recorded in the previous 7 days, than in the prior two years of the pandemic. on 14 january, there were another 6 deaths, raising total deaths to 26. 1 was aged in their 20s, 1 their 70s, 2 their 80s and 2 their 90s. all had underlying health conditions. daily new cases were at 19,709, of those 42,707 were from pcr test results. there were 187,037 active cases, and 191,070 total covid-19 cases since march 2020. there were 649 people in hospital for covid treatment, 56 in icu, and 24 on ventilation, all up on previous days. on 15 january, there were another 3 deaths, raising total deaths to 29. they were aged in their 60s, 80s, and 1 was 103 years-old. daily new cases were at 17,445, of those 4,615 were from rat test results. there were 203,657 active cases, and 209,962 total covid-19 cases since march 2020. there were 670 people in hospital for covid treatment, up on previous days, and 49 in icu with 19 of them on ventilation. borders reopened covid-19 border checkpoint on the mount lindesay highway from queensland to new south wales, 16 january 2022 also on 15 january, at 1am all domestic travel restrictions were removed from queensland borders. checkpoints had been on border crossings for 471 days over the past 2 years. while in queensland, proof of vaccination is required for entry to non-essential venues. overseas travelers still have some restrictions. direct arrivals from a 'travel safe' country do not need to quarantine. on 16 january, there were 7 deaths, raising total state deaths to 36. of them, 2 were aged in their 80s, and 5 their 90s. 5 had 2 doses of covid vaccine, none had booster doses.daily new cases were at 15,122. 30,963 pcr tests were processed. there were 86,953 active cases, and 229,671 total covid-19 cases since march 2020. there were 702 people in hospital for covid treatment, up on previous days, and 47 in icu with 15 of them on ventilation. on 17 january, there were 16 deaths, a record high and raising total state deaths to 52. of those, 46 were during the omicron outbreak alone. of the 16 dead, 3 were aged in their 70s, 8 their 80s, 4 their 90s and 1 was over 100 years. 2 had one dose of covid vaccine, 10 had 2 doses, 4 were not vaccinated. none had a booster dose. daily new cases were at 15,962. 32,506 pcr test results were processed. there were 86,561 active cases, and 245,624 total covid-19 cases since march 2020. there were 819 people in hospital for covid treatment and 50 in icu with 18 of them on ventilation, all up on the previous days. on 23 january, there was an unauthorised protest march in mackay. some protesters split off from the main group, and went through the caneland central shopping centre. three men were arrested. charges included serious assault of a police officer, obstructing police, public nuisance. and failing to comply with a covid-19 public health direction. on 25 january, there were 9 deaths, raising total state deaths to 138. of the 9 dead, 2 were aged in their 50s, 2 their 70s, 3 their 80s and 2 their 90s. 1 had one dose of covid vaccine, 6 had 2 doses, 2 were not vaccinated. none had a booster dose. daily new cases were at 13,511. 31,956 covid tests were performed. there were 73,266 active cases, and 358,336 total covid-19 cases since march 2020. there were 889 people in hospital for covid treatment, up, and 47 in icu with 15 of them on ventilation, down, on the previous days. on 27 january, there were 18 deaths, raising total state deaths to 171. 9 had 2 doses of covid vaccine, 6 were not vaccinated (1 in their 30s), 3 had a booster dose. daily new cases were at 9,974. 19,091 covid tests were performed. active cases had fallen to 66,068, and there was 379,793 total covid-19 cases since march 2020 there were 818 people in hospital for covid treatment, and 54 in icu. on 29 january, there were 13 deaths, raising total state deaths to 196. of the 13 dead, 2 were aged in their 60s, 4 their 70s, 3 their 80s, 3 their 90s, and 1 was 105. 5 were not vaccinated, none had a booster dose. daily new cases were at 8,580. 22,945 covid tests were performed. active cases had fallen to 64,226, and there was 398,716 total covid-19 cases since march 2020 there were 745 people in hospital for covid treatment, and 41 in icu. on 4 february, there were 21 covid deaths in qld, the highest to date in any reporting period. it raised total state deaths to 268. they were aged from their 60s to their 90s and 7 were in aged care. 4 were not vaccinated, 2 had a booster dose. statewide 89.9% were fully vaccinated, 92.1% had at least 1 vaccine dose. daily new cases were down at 8,508. 23,968 covid tests were performed. active cases had fallen to 49,639, and there had been 447,145 cases since the pandemic began. there was 790 people in hospital (63 in a private hospital) for covid treatment, and 48 in icu. queensland regional accommodation centre opens on 5 february, the wellcamp covid quarantine facility (officially named the 'queensland regional accommodation centre') was due to receive its first guests, unvaccinated travelers from new zealand. event cancellations in 2020, the ekka agricultural show was cancelled and again in 2021 as south east queensland was then in lockdown. the big pineapple music festival was first postponed from may to november 2020 due to restriction of non-essential events to 500 patrons maximum. it was then cancelled in august. the next festival event was scheduled for saturday, 22 may 2021. "land forces 2020" international military exhibition scheduled for 1–3 september 2020, deferred until 1–3 june 2021. brisbane, and the gold coasts' new year's eve fireworks at the end of 2020 were cancelled. on 16 february 2021, the world surf league event the gold coast corona open was moved from snapper rocks to narrabeen in sydney. it was scheduled for 16–26 april 2021. all events of the brisbane open house planned in 2020 and 2021 were cancelled. the birdsville races were cancelled in 2020. in 2021 they were also "called off" and rescheduled to april 2022. the gympie music muster was cancelled in 2020, and 2021 due to restrictions imposed during the pandemic. statistics covid-19 cumulative cases in queensland covid-19 daily cases in queensland

off-the-grid off-the-grid off-the-grid or off-grid is a characteristic of buildings and a lifestyle designed in an independent manner without reliance on one or more public utilities. the term "off-the-grid" traditionally refers to not being connected to the electrical grid, but can also include other utilities like water, gas, and sewer systems, and can scale from residential homes to small communities. off-the-grid living allows for buildings and people to be self-sufficient, which is advantageous in isolated locations where normal utilities cannot reach and is attractive to those who want to reduce environmental impact and cost of living. generally, an off-grid building must be able to supply energy and potable water for itself, as well as manage food, waste and wastewater. a house using solar panels and rainwater harvesting energy energy for electrical power and heating can be generated on-site with renewable energy sources such as solar (particularly with photovoltaics), wind, or micro hydro. additional forms of energy include biomass, commonly in the form of wood, waste, and alcohol fuels and geothermal energy, which uses differences in the underground temperature to regular indoor air environments in buildings. it is possible to simply eliminate energy shortage with e.g. solar and wind tech such as in old order amish (while used and sanctioned, not all agree) and old order mennonite communities, and many amish people still use steam engines. electrical power grid-connected buildings receive electricity from power plants, which mainly use natural resources such as coal and natural gas as energy to convert into electrical power. 2017’s breakdown of world energy sources shows that the globe, mainly dependent on grid power, uses a majority of non-renewables, while popular renewables such as solar pv and wind power are a small portion. when off the grid, such as in africa where 55% people of do not have access to electricity, buildings and homes must take advantage of the renewable energy sources around them, because it is the most abundant and allows for self-sufficiency. solar photovoltaics solar photovoltaics (pv), which use energy from the sun, are one of the most popular energy solutions for off-grid buildings. pv arrays (solar panels) allow for energy from the sun to be converted into electrical energy. pv is dependent upon solar radiation and ambient temperature. other components needed in a pv system include charge controllers, inverters, and rapid shutdown controls. these systems give off-grid sites the ability to generate energy without grid connection. every quarter, bloomberg new energy finance evaluates manufacturers on their actual projects over the previous quarter and publish a list of tier 1 solar module (panel) manufacturers. wind turbines wind energy can be harnessed by wind turbines. wind turbines components consist of blades that get pushed by wind, gearboxes, controllers, generators, breaks, and a tower. the amount of mechanical power captured from a wind turbine is a factor of the wind speed, air density, blade rotational area, and the aerodynamic power coefficient of the turbine. micro-hydro where water is abundant, hydropower is a promising energy solution. large scale hydropower involves a dam and reservoir, and small scale micro-hydro can use turbines in rivers with constant levels of water. the amount of mechanical power generated is a factor of the flow of the stream, turbine size, water density, and power coefficient, similar to wind turbines. the energy from waves and tides can also provide power to coastal areas. batteries when renewables produce energy that is not currently needed, the electrical energy is usually directed to charge a battery. this solves intermittency issues caused by the non-constant production of renewables and allows for variations in building loads. common batteries include the lead-acid battery and lithium-ion battery. hybrid energy systems in order to protect against intermittency issues and system failures, many off-grid communities create hybrid energy systems. these combine traditional renewables like solar pv, and wind, micro-hydro, batteries or even diesel generators. this can be cheaper and more effective than extending or maintaining grids to isolated communities. radioisotope thermoelectric generator historically remote applications such as lighthouses, weather stations and the likes which draw a small but continuous amount of power were powered by radioisotope thermoelectric generators (rtgs) with the needed radioisotopes either extracted from spent nuclear fuel or produced in dedicated facilities. both the soviet union and the united states employed numerous such devices on earth and every deep space probe reaching beyond the orbit of mars (and even some in the inner solar system) has had an rtg to provide power where solar panels no longer deliver sufficient electricity per unit of mass. temperature control types of solar-energy passive off-grid cooling systems could be used for cooling houses and/or refrigeration – including some that do not require electrical components and are allowing for chemically-stored on-demand energy. such may be useful for climate change mitigation and adaptation. communications meshnets such as b.a.t.m.a.n. could be used to sustain or establish communications without conventional infrastructure. moreover, off-grid communications technologies could be used for environmental, security and agricultural monitoring as well as for emergency communications and coordination – such as for work assignation. healthcare drones have been used for off-grid healthcare, especially in the most remote regions of the world. with communications enabled, they deliver test samples, medicine, vaccines, food, water and anti-venoms. waste management small-scale waste management techniques in western europe, often for specific or standardized waste, were reported to mostly use one of two main strategies: aerobic (with plants) and anaerobic treatment (with biogas production). water and sanitation

classification of sleep disorders classification of sleep disorders classification of sleep disorders, as developed in the 19th century, used primarily three categories: insomnia, hypersomnia and nightmare. in the 20th century, increasingly in the last half of it, technological discoveries led to rapid advances in the understanding of sleep and recognition of sleep disorders. major sleep disorders were defined following the development of electroencephalography (eeg) in 1924 by hans berger. main articles: sleep disorder and sleep medicineclassification of sleep disordersspecialtysleep medicine three systems of classification are in use worldwide: the international classification of diseases (icd) developed by the world health organization (who) and intended for use by general and more specialized practitioners, the diagnostic and statistical manual (dsm) from the american psychiatric association (apa) for psychiatrists and general practitioners, and the international classification of sleep disorders (icsd), an advanced system cultured by the american academy of sleep medicine (aasm) for sleep specialists. the icd and dsm lump different disorders together while the icsd tends to split related disorders into multiple discrete categories. there has, over the last 60 years, occurred a slow confluence of the three systems of classification. diagnoses of sleep disorders are based on self-assessment questionnaires, clinical interview, physical examination and laboratory procedures. the validity and reliability of various sleep disorders are yet to be proved and need further research within the ever-changing field of "sleep medicine". admittedly, the development of sleep disorder classification remains as much an art as it is a science. history milestones the first book on sleep was published in 1830 by robert macnish; it described sleeplessness, nightmares, sleepwalking and sleep-talking. narcolepsy, hypnogogic hallucination, wakefulness and somnolence were mentioned by other authors of the nineteenth century. westphal in 1877 described first case of narcolepsy, the name coined later by gelineu in 1880 in association with cataplexy. lehermitte called it paroxysmal hypersomnia in 1930 to differentiate it from prolonged hypersomnia. roger in 1932 coined the term parasomnia and classified hypersomnia, insomnia and parasomnia. kleitman in 1939 recognized types of parasomnias as nightmares, night terrors, somniloquy (sleep-talking), somnambulism (sleepwalking), grinding of teeth, jactatians, enuresis, delirium, nonepileptic convulsions and personality dissociation. broughton in 1968 developed classification of the arousal disorders as confusional arousals: night terrors and sleep walking. insomnias were classified as primary and secondary until 1970 when they were recognized as symptoms of other disorders. sir william osler in 1906 correlated snoring, obesity and somnolence (sleepiness) to dicken's description of joe. charles burwell in 1956 recognized obstructive sleep apnea as pickwickian syndrome. circadian rhythm sleep disorders were discovered in 1981 by weitzman as delayed sleep phase syndrome in contrast to advanced sleep phase syndrome in 1979. evolution of classifications of sleep disorders year icsd icd dsm development 1955 icd-7r disturbance of sleep was seen as a symptom of other diseases 1965 icd-8 recognized as both a disease and a symptom of other diseases 1968 dsm-ii disorder of sleep as an independent category 1975 icd-9 organic sleep disorder, nonorganic sleep disorder and as symptom of other diseases 1979 nosology clinical classification into four major groups: disorder of initiating and maintaining sleep (dims) - insomnias, disorder of excessive sleep (does) - hypersomnias, disorder of sleep-wake schedule (circadian rhythm disorders) and parasomnias 1980 icd-cm dsm-iii manifestation of other disorders with physical manifestation, as sleep walking and sleep terror 1987 dsm-iii-r sleep disorders were classified into dysomnias and parasomnias. 1990 icsd expanded previous system into dysomnias, parasomnias, symptomatic and proposed disorder of sleep 1990 icd-10 organic sleep disorders included under nervous system disorder, nonorganic under psychiatric disorders and a third category as manifestation of other diseases 1994 dsm-iv dyssomnias, parasomnias, manifestation of mental disorders and other 1997 icsd-r first detailed classification of various sleep disorders dyssomnias intrinsic sleep disorders extrinsic sleep disorders circadian rhythm sleep disorders parasomnias arousal disorders sleep-wake transition disorders parasomnias usually associated with rem sleep other parasomnias sleep disorders associated with mental, neurologic, or other medical disorders associated with mental disorders associated with neurologic disorders associated with other medical disorders 4. proposed sleep disorders 2000 dsm-iv-tr primary sleep disorders dyssomnias insomnias hypersomnias recurrent hypersomnias narcolepsy breathing related sleep disorder circadian rhythm sleep disorders movement disorder of sleep parasomnias secondary sleep disorders associated with other mental disorders and substance use. 2005 icsd-2 most extensive classification of sleep disorders 2010 icd-10-cm three major categories, f51 as nonorganic sleep disorders, g47 organic sleep disorders and r- as symptoms of sleep disorders 2013 icsd-3 dsm-v lumping and splitting of sleep disorders and concordance of two systems 2015 icd-11 beta proposed beta version yet to be finalized in line with icds3 and dsm v the international classification of sleep disorders (icsd) main article: international classification of sleep disorders the international classification of sleep disorders (icsd) was produced by the american academy of sleep medicine (aasm) in association with the european sleep research society, the japanese society of sleep research, and the latin american sleep society. the classification was developed as a revision and update of the diagnostic classification of sleep and arousal disorders (dcsad) that was produced by both the association of sleep disorders centers (asdc) and the association for the psychophysiological study of sleep and was published in the journal sleep in 1979. disorder of initiating and maintain sleep (dims) - insomnias disorder of excessive sleep (does) - hypersomnias disorder of sleep wake schedule parasomnias the international classification of sleep disorders (icsd) uses a multiaxial system for stating and coding diagnoses both in clinical reports or for data base purposes. the axial system uses international classification of diseases (icd-9- cm) coding wherever possible. additional codes are included for procedures and physical signs of particular interest to sleep disorders clinicians and researchers. diagnoses and procedures are listed and coded on three main "axes." the axial system is arranged as follows: axis a icsd classification of sleep disorders axis b icd-9-cm classification of procedures axis c icd-9-cm classification of diseases (nonsleep diagnoses). icsd - i revised 1997 dyssomnias intrinsic sleep disorders extrinsic sleep disorders circadian rhythm sleep disorders parasomnias arousal disorders sleep-wake transition disorders parasomnias usually associated with rem sleep other parasomnias sleep disorders associated with mental, neurologic, or other medical disorders associated with mental disorders associated with neurologic disorders associated with other medical disorders proposed sleep disorders icsd 2 is tabulated in the main article international classification of sleep disorders icsd - 3 the last edition of icsd-3 is a unified classification of sleep disorders. it includes seven major categories: insomnia disorders, sleep-related breathing disorders, central disorders of hypersomnolence, circadian rhythm sleep-wake disorders, sleep-related movement disorders, parasomnias, and other sleep disorders. each of these categories has several subgroups: 1. insomnia chronic insomnia disorder short-term insomnia disorder other insomnia disorder 2. sleep-related breathing disorders obstructive sleep apnea (osa) disorders osa, adult osa, pediatric central sleep apnea syndromes central sleep apnea with cheyne-stokes breathing central sleep apnea due to a medical disorder without cheyne-stokes breathing central sleep apnea due to high altitude periodic breathing central sleep apnea due to a medication or substance primary central sleep apnea primary central sleep apnea of infancy primary central sleep apnea of prematurity treatment-emergent central sleep apnea sleep-related hypoventilation disorders obesity hypoventilation syndrome congenital central alveolar hypoventilation syndrome late-onset central hypoventilation with hypothalamic dysfunction idiopathic central alveolar hypoventilation sleep-related hypoventilation due to a medication or substance sleep-related hypoventilation due to a medical disorder sleep-related hypoxemia disorder isolated symptoms and normal variants 3. central disorders of hypersomnolence narcolepsy type 1 narcolepsy type 2 idiopathic hypersomnia kleine-levin syndrome hypersomnia due to a medical disorder hypersomnia due to a medication or substance hypersomnia associated with a psychiatric disorder insufficient sleep syndrome 4. circadian rhythm sleep-wake disorders delayed sleep-wake phase disorder advanced sleep-wake phase disorder irregular sleep-wake rhythm disorder non-24-h sleep-wake rhythm disorder shift work disorder jet lag disorder circadian sleep-wake disorder not otherwise specified 5. sleep-related movement disorders restless legs syndrome periodic limb movement disorder sleep-related leg cramps sleep-related bruxism sleep-related rhythmic movement disorder benign sleep myoclonus of infancy propriospinal myoclonus at sleep onset sleep-related movement disorder due to a medical disorder sleep-related movement disorder due to a medication or substance sleep-related movement disorder, unspecified isolated symptoms and normal variants excessive fragmentary myoclonus hypnagogic foot tremor and alternating leg muscle activation sleep starts (hypnic jerks) 6. parasomnias nrem-related parasomnias confusional arousals sleepwalking sleep terrors sleep-related eating disorder rem-related parasomnias rem sleep behavior disorder recurrent isolated sleep paralysis nightmare disorder other parasomnias exploding head syndrome sleep-related hallucinations sleep enuresis parasomnia due to a medical disorder parasomnia due to a medication or substance parasomnia, unspecified isolated symptoms and normal variants sleep talking international classification of disease (icd) icd-7r 1955 780.7 disturbance of sleep icd-8 1965 306.4 specific disorder of sleep 780.6 disturbance of sleep 327.0 organic disorders of initiating and maintaining sleep 327.00 organic insomnia, unspecified 327.01 insomnia due to medical condition classified elsewhere 327.02 insomnia due to mental disorder 327.09 other organic insomnia 327.1 organic disorder of excessive somnolence 327.10 organic hypersomnia, unspecified 327.11 idiopathic hypersomnia with long sleep time 327.12 idiopathic hypersomnia without long sleep time 327.13 recurrent hypersomnia 327.14 hypersomnia due to medical condition classified elsewhere 327.15 hypersomnia due to mental disorder 327.19 other organic hypersomnia 327.2 organic sleep apnea 327.20 organic sleep apnea, unspecified 327.21 primary central sleep apnea 327.22 high altitude periodic breathing 327.23 obstructive sleep apnea (adult)(pediatric) 327.24 idiopathic sleep related non-obstructive alveolar hypoventilation 327.25 congenital central alveolar hypoventilation syndrome 327.26 sleep related hypoventilation/hypoxemia in conditions classifiable elsewhere 327.27 central sleep apnea in conditions classified elsewhere 327.29 other organic sleep apnea 327.3 circadian rhythm sleep disorder 327.30 circadian rhythm sleep disorder, unspecified 327.31 circadian rhythm sleep disorder, delayed sleep phase type 327.32 circadian rhythm sleep disorder, advanced sleep phase type 327.33 circadian rhythm sleep disorder, irregular sleep-wake type 327.34 circadian rhythm sleep disorder, free-running type 327.35 circadian rhythm sleep disorder, jet lag type 327.36 circadian rhythm sleep disorder, shift work type 327.37 circadian rhythm sleep disorder in conditions classified elsewhere 327.39 other circadian rhythm sleep disorder 327.4 organic parasomnia 327.40 organic parasomnia, unspecified 327.41 confusional arousals 327.42 rem sleep behavior disorder 327.43 recurrent isolated sleep paralysis 327.44 parasomnia in conditions classified elsewhere 327.49 other organic parasomnia 327.5 organic sleep related movement disorders 327.51 periodic limb movement disorder 327.52 sleep related leg cramps 327.53 sleep related bruxism 327.59 other organic sleep related movement disorders 307.4 specific disorders of sleep of nonorganic origin 307.40 nonorganic sleep disorder, unspecified 307.41 transient disorder of initiating or maintaining sleep 307.42 persistent disorder of initiating or maintaining sleep 307.43 transient disorder of initiating or maintaining wakefulness 307.44 persistent disorder of initiating or maintaining wakefulness 307.45 circadian rhythm sleep disorder of nonorganic origin 307.46 sleep arousal disorder 307.47 other dysfunctions of sleep stages or arousal from sleep 307.48 repetitive intrusions of sleep 307.49 other specific disorders of sleep of nonorganic origin 780.5 sleep disturbances 780.50 sleep disturbance, unspecified 780.51 insomnia with sleep apnea, unspecified 780.52 insomnia, unspecified 780.53 hypersomnia with sleep apnea, unspecified 780.54 hypersomnia, unspecified 780.55 disruption of 24 hour sleep wake cycle, unspecified 780.56 dysfunctions associated with sleep stages or arousal from sleep 780.57 unspecified sleep apnea 780.58 sleep related movement disorder, unspecified 780.59 other sleep disturbances g47 sleep disorders excl.: nocturnal myoclonus (g25.80), nightmares (f51.5), nonorganic sleep disorders (f51.-), sleep terrors (f51.4), sleepwalking (f51.3) g47.2 disorders of the sleep-wake schedule g47.20 transient sleep wake schedule disorder g47.21 advanced sleep phase disorder g47.22 delayed sleep phase syndromes g47.23 irregular sleep-wake pattern g47.24 non 24 hour sleep wake cycle g47.28 other disorder of sleep wake schedule g47.3 sleep apnoea sleep related respiratory failure (ondine) excl. pickwickian syndrome (e66.2), sleep apnoea of newborn (p28.3) g47.30 alveolar hypoventilation syndrome g47.31 central sleep apnoea g47.32 obstructive sleep apnoea g47.38 other sleep apnoea g47.4 narcolepsy and cataplexy g47.40 narcolepsy g47.41 cataplexy g47.42 sleep paralysis g47.43 hypnogogic and hypnopompic hallucination g47.44 any combination of narcolepsy, cataplexy, sleep paralysis, hypnogogic and hypnopompic hallucination g47.48 other forms of narcolepsy and cataplexy g47.8 other sleep disorders excl: other sudden death, cause unknown (r96-) sleep apnoea (g47.3) newborn (r96.-) sudden infant death syndrome (r95) g47.80 other rem sleep related parasomnias excl. nightmares (f51.5), sleep paralysis (g47.42 ) g47.800 rem sleep related behavior disorder (phantasmagorias) g47.801 impaired rem sleep related non painful penile erection g47.802 rem sleep related painful penile erection g47.803 rem sleep related cardiac sinus arrest g47.804 rem sleep related headache (use additional code if required to indicate type of

headache) g47.81 other non rem sleep related parasomnias excl: benign neonatal sleep syndrome (g25.37) g47.810 sleep related bruxism g47.811 sleep related enuresis g47.812 non-rem-sleep related abnormal swallowing syndrome g47.813 nocturnal paroxysmal dystonia g47.82 sleep arousal disorders, confusional arousal, sleep drunkenness g47.83 sleep-wake transition disorders excl. nocturnal leg cramps (r25.20) g47.830 sleep related rhythmic movement disorder, head-banging (jactatio capitis noctunus) g47.831 sleep starts g47.832 sleepwalking g47.84 kleine-levin syndrome, recurrent hypersomnia g47.88 other specified sleep disorders f51 nonorganic sleep disorders excl.: sleep disorders (organic) (g47.-) f51.2 nonorganic disorder of the sleep-wake schedule psychogenic inversion of: circadian nyctohemeral sleep rhythm excl.: disorders of the sleep-wake schedule (organic) (g47.2) p28.3 primary sleep apnoea of newborn sleep apnoea of newborn: central nos obstructive p28.4 other apnoea of newborn apnoea (of): newborn, obstructive prematurity excl.: obstructive sleep apnoea of newborn (p28.3) g47.0 insomnia g47.00 ...... unspecified g47.01 ...... due to medical condition g47.09 other insomnia g47.1 hypersomnia g47.10 ...... unspecified g47.11 idiopathic hypersomnia with long sleep time g47.12 idiopathic hypersomnia without long sleep time g47.13 recurrent hypersomnia g47.14 ...... due to medical condition g47.19 other hypersomnia g47.2 circadian rhythm sleep disorders g47.20 circadian rhythm sleep disorder, unspecified type g47.21 circadian rhythm sleep disorder, delayed sleep phase type g47.22 circadian rhythm sleep disorder, advanced sleep phase type g47.23 circadian rhythm sleep disorder, irregular sleep wake type g47.24 circadian rhythm sleep disorder, free running type g47.25 circadian rhythm sleep disorder, jet lag type g47.26 circadian rhythm sleep disorder, shift work type g47.27 circadian rhythm sleep disorder in conditions classified elsewhere g47.29 other circadian rhythm sleep disorder g47.3 sleep apnea g47.30 ...... unspecified g47.31 primary central sleep apnea g47.32 high altitude periodic breathing g47.33 obstructive sleep apnea (adult) (pediatric) g47.34 idiopathic sleep related nonobstructive alveolar hypoventilation g47.35 congenital central alveolar hypoventilation syndrome g47.36 sleep related hypoventilation in conditions classified elsewhere g47.37 central sleep apnea in conditions classified elsewhere g47.39 other sleep apnea g47.4 narcolepsy and cataplexy g47.41 narcolepsy g47.411 ...... with cataplexy g47.419 ...... without cataplexy g47.42 narcolepsy in conditions classified elsewhere g47.421 ...... with cataplexy g47.429 ...... without cataplexy g47.5 parasomnia g47.50 ...... unspecified g47.51 confusional arousals g47.52 rem sleep behavior disorder g47.53 recurrent isolated sleep paralysis g47.54 ...... in conditions classified elsewhere g47.59 other parasomnia g47.6 sleep related movement disorders g47.61 periodic limb movement disorder g47.62 sleep related leg cramps g47.63 sleep related bruxism g47.69 other sleep related movement disorders f51.0 insomnia not due to a substance or known physiological condition f51.01 primary insomnia f51.02 adjustment insomnia f51.03 paradoxical insomnia f51.04 psychophysiologic insomnia f51.05 insomnia due to other mental disorder f51.09 other insomnia not due to a substance or known physiological condition f51.1 hypersomnia not due to a substance or known physiological condition f51.11 primary hypersomnia f51.12 insufficient sleep syndrome f51.13 hypersomnia due to other mental disorder f51.19 other hypersomnia not due to a substance or known physiological condition p28.3 applicable to central sleep apnea of newborn obstructive sleep apnea of newborn sleep apnea of newborn nos approximate synonyms neonatal primary apnea primary apnea in the newborn sleep apnea, primary, neonatal insomnia disorders 8a00 chronic insomnia 8a01 short-term insomnia 8a02 disorders of initiating and maintaining sleep 8a0y other specified insomnia disorders 8a0z insomnia disorders, unspecified sleep-related movement disorders 8a10 restless legs syndrome 8a11 secondary restless legs syndrome 8a12 periodic limb movements disorder 8a13 sleep-related bruxism 8a14 sleep-related leg cramps 8a15 sleep-related rhythmic movement disorder 8a16 benign sleep myoclonus of infancy 8a1y other specified sleep-related movement disorders 8a1z sleep-related movement disorders, unspecified 8a20 hypersomnolence disorders 8a20.1 narcolepsy, type 1 8a20.2 narcolepsy, type 2 8a20.3 idiopathic hypersomnolence disorder 8a20.4 kleine-levin syndrome 8a20.5 behaviourally induced hypersomnolence 8a20.6 hypersomnolence due to substances including medications 8a20.y other specified hypersomnolence disorders 8a20.z hypersomnolence disorders, unspecified sleep-related breathing disorders 8a30 central sleep apnoeas 8a31 obstructive sleep apnoea 8a32 sleep-related hypoventilation or hypoxemia disorders 8a3y other specified sleep-related breathing disorders 8a3z sleep-related breathing disorders, unspecified circadian rhythm sleep-wake disorders 8a40 circadian rhythm sleep-wake disorder, delayed type 8a41 circadian rhythm sleep-wake disorder, advanced type 8a42 circadian rhythm sleep-wake disorder, irregular sleep-wake rhythm type 8a43 circadian rhythm sleep-wake disorder, non-24 hour type 8a44 circadian rhythm sleep-wake disorder, shift work type 8a45 circadian rhythm sleep-wake disorder, jet lag type 8a4y other specified circadian rhythm sleep-wake disorders 8a4z circadian rhythm sleep-wake disorders, unspecified disorders of arousal in non-rem sleep 8a50 confusional arousals 8a51 sleepwalking disorder 8a52 sleep terrors 8a5y other specified disorders of arousal in non-rem sleep 8a5z disorders of arousal in non-rem sleep, unspecified 8a60 sleep-related eating disorder 8a61 rem sleep behavior disorder 8a62 recurrent isolated sleep paralysis 8a63 nightmare disorder 8a63 nightmare disorder 8a64 hypnogogic exploding head syndrome 8a65 recurrent isolated sleep-related hallucinations 8a66 parasomnia disorder due to substances including medications 8a6y other specified parasomnia disorders 8a6z parasomnia disorders, unspecified 7b60.1 nocturnal enuresis 8a70 disorders of the sleep-wake schedule 8a71 parasomnia 8a72 sleeptalking 8a7y other specified sleep-wake disorders 8a7z sleep-wake disorders, unspecified me21 dyssomnia dsm classification of sleep disorders diagnostic and statistical manual (dsm) classification of sleep disorder was first introduced in 1968. dsm ii - 1968 disorders of sleep dsm iii - 1980 other disorders with physical manifestation sleep walking sleep terror dysomnias (disorders of amount, quality or time of sleep) insomnia hypersomnia sleep wake schedule disorder parasomnia (abnormal event during sleep) nightmare disorder sleep terror sleep walking dsm iv tr sleep disorders icd-9 sleep disorders primary sleep disorders dyssomnias 307.42 primary insomnia 307.44 primary hypersomnia specify if recurrent 347.00 narcolepsy 780.59 breathing-related sleep disorder 307.45 circadian rhythm sleep disorder 327.31 circadian rhythm sleep disorder, delayed sleep phase type 327.35 circadian rhythm sleep disorder, jet lag type 327.36 circadian rhythm sleep disorder, shift work type 327.30 circadian rhythm sleep disorder, unspecified type 307.47 dyssomnia nos parasomnias 307.47 nightmare disorder 307.46 sleep terror disorder 307.46 sleepwalking disorder 307.47 parasomnia nos sleep disorders related to another mental disorder 307.42 insomnia related to ... 307.44 hypersomnia related to ... other sleep disorders 327.14 sleep disorder due to ... , hypersomnia type 327.01 sleep disorder due to ... , insomnia type 327.8 sleep disorder due to ... , mixed type 327.44 sleep disorder due to ... , parasomnia type 291.82 alcohol-induced sleep disorder 292.85 amphetamine-induced sleep disorder 292.85 caffeine-induced sleep disorder 292.85 cocaine-induced sleep disorder 292.85 opioid-induced sleep disorder 292.85 other (or unknown) substance-induced sleep disorder major changes from dsm iv sleep-wake disorders comprise 11 diagnostic groups:" m00 insomnia disorder m01 hypersomnolence disorder m02 narcolepsy/hypocretin deficiency m03 obstructive sleep apnea hypopnea syndrome m04 central sleep apnea m05 sleep-related hypoventilation m06 circadian rhythm sleep-wake disorder m07 disorder of arousal m08 nightmare disorder m09 rapid eye movement sleep behavior disorder m10 restless legs syndrome m11 substance-induced sleep disorder sleep-wake disorders not elsewhere classified insomnia disorder not elsewhere classified major somnolence disorder (hypersomnia not elsewhere classified) the following specifiers apply to sleep-wake disorders where indicated: specify if: episodic, persistent, recurrent specify if: acute, subacute, persistent specify current severity: mild, moderate, severe icd9-cm icd10-cm dsm 5 insomnia disorder 780.52 g47.00 insomnia disorder specify if: with non-sleep disorder mental comorbidity. with other medical comorbidity. with other sleep disorder 780.52 g47.09 other specified insomnia disorder 780.52 g47.00 unspecified insomnia disorder 780.54 g47.10 hypersomnolence disorder specify if: with mental disorder. with medical condition. with another sleep disorder 780.54 g47.19 other specified hypersomnolence disorder 780.54 g47.10 unspecified hypersomnolence disorder narcolepsy 347.00 g47.419 autosomal dominant cerebellar ataxia, deafness, and narcolepsy 347.00 g47.419 autosomal dominant narcolepsy, obesity, and type 2 diabetes 347.00 g47.419 narcolepsy without cataplexy but with hypocretin deficiency 347.01 g47.411 narcolepsy with cataplexy but without hypocretin deficiency 347.10 g47.429 narcolepsy secondary to another medical condition breathing-related sleep disorders 327.23 g47.33 obstructive sleep apnea hypopnea central sleep apnea 780.57 g47.37 central sleep apnea comorbid with opioid use 327.21 g47.31 idiopathic central sleep apnea: 786.04 r06.3 cheyne-stokes breathing 780.57 g47.37 central sleep apnea comorbid with opioid use note: first code opioid use disorder, if present. specify current severity sleep-related hypoventilation 327.24 g47.34 idiopathic hypoventilation 327.25 g47.35 congenital central alveolar hypoventilation 327.26 g47.36 comorbid sleep-related hypoventilation primary alveolar hypoventilation circadian rhythm sleep-wake disorders 307.45 g47.22 circadian rhythm sleep-wake disorders, advanced sleep phase type 307.45 g47.21 circadian rhythm sleep-wake disorders, delayed sleep phase type 307.45 g47.23 circadian rhythm sleep-wake disorders, irregular sleep-wake type 307.45 g47.24 circadian rhythm sleep-wake disorders, non-24-hour sleep-wake type 307.45 g47.26 circadian rhythm sleep-wake disorders, shift work type 307.45 g47.20 circadian rhythm sleep-wake disorders, unspecified type non–rapid eye movement (nrem) sleep arousal disorders 307.46 f51.4 non-rapid eye movement sleep arousal disorders, sleep terror type 307.46 f51.3 non-rapid eye movement sleep arousal disorders, sleepwalking type nightmare disorder 307.47 f51.5 nightmare disorder 327.42 g47.52 rapid eye movement (rem) sleep behavior disorder 333.94 g25.81 restless legs syndrome medication-induced sleep disorder 291.82 alcohol-induced sleep disorder 292.85 amphetamine (or other stimulant)-induced sleep disorder 292.85 caffeine-induced sleep disorder 292.85 cannabis-induced sleep disorder 292.85 cocaine-induced sleep disorder 292.85 opioid-induced sleep disorder 292.85 other (or unknown) substance-induced sleep disorder 292.85 sedative-, hypnotic-, or anxiolytic-induced sleep disorder 292.85 tobacco-induced sleep disorder 780.54 g47.19 other specified hypersomnolence disorder 780.54 g47.10 unspecified hypersomnolence disorder disorder of arousal confusional arousals sleepwalking sleep terrors 780.59 g47.8 other specified sleep-wake disorder 780.59 g47.9 unspecified sleep-wake disorder

college of health and sport sciences college of health and sport sciences the college of health and sport sciences (arabic: كلية العلوم الصحية والرياضية) is a public higher education institution situated in the kingdom of bahrain. established in 1976, it is a constituent college of the university of bahrain. college of health and sport sciencesكلية العلوم الصحية والرياضيةlogo of the collegetypepublic universityestablished1976 (1976)deandr. amal aklehlocationmanama, bahrainwebsiteofficial website chs campus. history the college was established in 1976 by the bahraini ministry of health, in partnership with the american university of beirut and the university of illinois at chicago. the institution has been a driving force of bahrainization of the healthcare workforce in the country. in 2011, a royal decree by the king of bahrain hamad bin isa al khalifa led to a merger of the previously-independent college with the university of bahrain as a constituent college. courses the college offers bsc degrees programme in nursing , six allied health subjects: dental hygiene, medical laboratory technology, pharmacy, public health, radiography and physiotherapy and physical education. in 2018, the college started their msc program in nursing, and physiotherapy. campus the college's campus is in the neighborhood of salmaniya, in manama, the capital of bahrain. it is located within the salmaniya medical complex (smc), together with the arabian gulf university and salmaniya hospital. the campus includes an administration and student affairs building, and multiple nursing and laboratory blocks. additionally, facilities include a three floor building which hosts multiple offices, classrooms, laboratories and the ahmed al-farsi library. it also features the 'al ma'arif auditorium' which provides a venue for special classes, workshops, meetings, seminars and conferences. a computer laboratory was installed in 1988.

thioalkalimicrobium thioalkalimicrobium thioalkalimicrobium is a defunct bacterial genus within the gammaproteobacteria. all 4 species in the genus were reclassified to the genus thiomicrospira in 2017. thioalkalimicrobium scientific classification domain: bacteria phylum: pseudomonadota class: gammaproteobacteria order: thiotrichales family: piscirickettsiaceae genus: thioalkalimicrobiumsorokin et al. 2001 type species thioalkalimicrobium aerophilum (now thiomicrospira aerophila) species t. aerophilum t. cyclicum t. microaerophilum t. sibiricum synonyms thioalcalomicrobium, thialkalimicrobium

catatonia catatonia catatonia is a complex neuropsychiatric behavioral syndrome that is characterized by abnormal movements, immobility, abnormal behaviors, and withdrawal. the onset of catatonia can be acute or subtle and symptoms can wax, wane, or change during episodes. it has historically been related to schizophrenia (catatonic schizophrenia), catatonia is most often seen in mood disorders. it is now known that catatonic symptoms are nonspecific and may be observed in other mental, neurological, and medical conditions. catatonia is not a stand-alone diagnosis (although some experts disagree), and the term is used to describe a feature of the underlying disorder. not to be confused with katatonia, cataplexy, catalepsy, catalonia, or cataonia. catatoniaother namescatatonic syndromea patient in catatonic stuporspecialtypsychiatry, neurologysymptomsimmobility, mutism, staring, posturing, rigidity, low consciousness, etc.complicationsphysical trauma, malignant catatonia (autonomic instability, life-threatening), dehydration, pneumonia, pressure ulcers due to immobility, muscle contractions, dvt, pecausesunderlying illness (psychiatric, neurologic, or medical), brain injury/damage, certain drugs/medicationsdiagnostic methodclinical, lorazepam challengetreatmentbenzodiazepines (lorazepam challenge), ect there are several subtypes of catatonia: akinetic catatonia, excited catatonia, malignant catatonia, delirious mania, and self-injurious behaviors in autism. recognizing and treating catatonia is very important as failure to do so can lead to poor outcomes and can be potentially fatal. treatment with benzodiazepines or ect can lead to remission of catatonia. there is growing evidence of the effectiveness of the nmda receptor antagonists amantadine and memantine for benzodiazepine-resistant catatonia. antipsychotics are sometimes employed, but they can worsen symptoms and have serious adverse effects. signs and symptoms the presentation of a patient with catatonia varies greatly depending on the subtype and underlying cause, and can be acute or subtle. because most patients with catatonia have an underlying psychiatric illness, the majority will present with worsening depression, mania, or psychosis followed by catatonia symptoms. catatonia presents as a motor disturbance in which patients will display marked reduction in movement, marked agitation, or a mixture of both despite having the physical capacity to move normally. these patients may be unable to start an action or stop one. movements and mannerisms may be repetitive, or purposeless. the most common signs of catatonia are immobility, mutism, withdrawal and refusal to eat, staring, negativism, posturing (rigidity), rigidity, waxy flexibility/catalepsy, stereotypy (purposeless, repetitive movements), echolalia or echopraxia, verbigeration (repeat meaningless phrases). it should not be assumed that patients presenting with catatonia are unaware of their surroundings as some patients can recall in detail their catatonic state and their actions. there are several subtypes of catatonia and they are characterized by the specific movement disturbance and associated features. although catatonia can be divided into various subtypes, the natural history of catatonia is often fluctuant and different states can exist within the same individual. subtypes withdrawn catatonia: this form of catatonia is characterized by decreased response to external stimuli, immobility or inhibited movement, mutism, staring, posturing, and negativism. patients may sit or stand in the same position for hours, may hold odd positions, and may resist movement of their extremities. excited catatonia: excited catatonia is characterized by odd mannerisms/gestures, performing purposeless or inappropriate actions, excessive motor activity, restlessness, stereotypy, impulsivity, agitation, and combativeness. speech and actions may be repetitive or mimic another person's. people in this state are extremely hyperactive and may have delusions and hallucinations. catatonic excitement is commonly cited as one of the most dangerous mental states in psychiatry. malignant catatonia: malignant catatonia is a life-threatening condition that may progress rapidly within a few days. it is characterized by fever, abnormalities in blood pressure, heart rate, respiratory rate, diaphoresis (sweating), and delirium. certain lab findings are common with this presentation; however, they are nonspecific, which means that they are also present in other conditions and do not diagnose catatonia. these lab findings include: leukocytosis, elevated creatine kinase, low serum iron. the signs and symptoms of malignant catatonia overlap significantly with neuroleptic malignant syndrome (nms) and so a careful history, review of medications, and physical exam are critical to properly differentiate these conditions. for example, if the patient has waxy flexibility and holds a position against gravity when passively moved into that position, then it is likely catatonia. if the patient has a "lead-pipe rigidity" then nms should be the prime suspect. other forms: periodic catatonia is an inconsistently defined entity. in the wernicke-kleist-leonhard school, it is a distinct form of "non-system schizophrenia" characterized by recurrent acute phases with hyperkinetic and akinetic features and often psychotic symptoms, and the build-up of a residual state in between these acute phases, which is characterized by low-level catatonic features and aboulia of varying severity. the condition has a strong hereditary component. according to modern classifications, this may be diagnosed as a form of bipolar disorder, schizoaffective disorder or schizophrenia. independently, the term periodic catatonia is sometimes used in modern literature to describe a syndrome of recurrent phases of acute catatonia (excited or inhibited type) with full remission between episodes, which resembles the description of "motility psychosis" in the wernicke-kleist-leonhard school. system catatonias or systematic catatonias are only defined in the wernicke-kleist-leonhard school. these are chronic-progressive conditions characterized by specific disturbances of volition and psychomotricity, leading to a dramatic decline of executive and adaptive functioning and ability to communicate. they are considered forms of schizophrenia but distinct from other schizophrenic conditions. affective flattening and apparent loss of interests are common but may be related to reduced emotional expression rather than lack of emotion. heredity is low. of the 21 different forms (6 "simple" and 15 "combined" forms) that have been described, most overlap only partially - if at all - with current definitions of either catatonia or schizophrenia, and thus are difficult to classify according to modern diagnostic manuals. early childhood catatonias are also a diagnosis exclusive to the wernicke-kleist-leonhard school, and refers to system catatonias that manifest in young children. clinically, these conditions resemble severe regressive forms of autism. chronic catatonia-like breakdown or autistic catatonia refers to a functional decline seen in some patients with pre-existing autism spectrum disorder and/or intellectual disability which usually runs a chronic-progressive course and encompasses attenuated catatonic symptoms as well as mood and anxiety symptoms that increasingly interfere with adaptive functioning. onset is typically insidious and often mistaken for background autistic symptoms. slowing of voluntary movement, reduced speech, aboulia, increased prompt dependency and obsessive-compulsive symptoms are frequently seen; negativism, (auto-)aggressive behaviors and ill-defined hallucinations have also been reported. both the causes of this disorder as well as its prognosis appear to be heterogenous, with most patients showing partial recovery upon treatment. it seems to be related to chronic stress as a result of life transitions, loss of external time structuring, sensory sensitivities and/or traumatic experiences, co-morbid mental disorders, or other unknown causes. since clinical catatonia can not always be diagnosed, this condition has also been renamed to the more general term "late regression". complications patients may experience several complications from being in a catatonic state. the nature of these complications will depend on the type of catatonia being experienced by the patient. for example, patients presenting with withdrawn catatonia may have refusal to eat which will in turn lead to malnutrition and dehydration. furthermore, if immobility is a symptom the patient is presenting with, then they may develop pressure ulcers, muscle contractions, and are at risk of developing deep vein thrombosis (dvt) and pulmonary embolus (pe). patients with excited catatonia may be aggressive and violent, and physical trauma may result from this. catatonia may progress to the malignant type which will present with autonomic instability and may be life-threatening. other complications also include the development of pneumonia and neuroleptic malignant syndrome. causes catatonia is almost always secondary to another underlying illness, often a psychiatric disorder. mood disorders such as a bipolar disorder and depression are the most common etiologies to progress to catatonia. other psychiatric associations include schizophrenia and other primary psychotic disorders. it also is related to autism spectrum disorders. psychodynamic theorists have interpreted catatonia as a defense against the potentially destructive consequences of responsibility, and the passivity of the disorder provides relief. catatonia is also seen in many medical disorders, including infections (such as encephalitis), autoimmune disorders, meningitis, focal neurological lesions (including strokes), alcohol withdrawal, abrupt or overly rapid benzodiazepine withdrawal, cerebrovascular disease, neoplasms, head injury, and some metabolic conditions (homocystinuria, diabetic ketoacidosis, hepatic encephalopathy, and hypercalcaemia). pathogenesis the pathophysiology that leads to catatonia is still poorly understood and a definite mechanism remains unknown. neurologic studies have implicated several pathways; however, it remains unclear whether these findings are the cause or the consequence of the disorder. abnormalities in gaba, glutamate signaling, serotonin, and dopamine transmission are believed to be implicated in catatonia. furthermore, it has also been hypothesized that pathways that connect the basal ganglia with the cortex and thalamus is involved in the development of catatonia. diagnosis there is not yet a definitive consensus regarding diagnostic criteria of catatonia. in the american diagnostic and statistical manual of mental disorders, fifth edition (dsm-5) and the world health organization's eleventh edition of the international classification of disease (icd-11) the classification is more homogeneous than in earlier editions. prominent researchers in the field have other suggestions for diagnostic criteria. dsm-5 classification the dsm-5 does not classify catatonia as an independent disorder, but rather it classifies it as catatonia associated with another mental disorder, due to another medical condition, or as unspecified catatonia. catatonia is diagnosed by the presence of three or more of the following 12 psychomotor symptoms in association with a mental disorder, medical condition, or unspecified: stupor: no psycho-motor activity; not actively relating to the environment catalepsy: passive induction of a posture held against gravity waxy flexibility: allowing positioning by an examiner and maintaining that position mutism: no, or very little, verbal response (exclude if known aphasia) negativism: opposition or no response to instructions or external stimuli posturing: spontaneous and active maintenance of a posture against gravity mannerisms that are odd, circumstantial caricatures of normal actions stereotypy: repetitive, abnormally frequent, non-goal-directed movements agitation, not influenced by external stimuli grimacing: keeping a fixed facial expression echolalia: mimicking another's speech echopraxia: mimicking another's movements. other disorders (additional code 293.89 to indicate the presence of the co-morbid catatonia): catatonia associated with autism spectrum disorder catatonia associated with schizophrenia spectrum and other psychotic disorders catatonia associated with brief psychotic disorder catatonia associated with schizophreniform disorder catatonia associated with schizoaffective disorder catatonia associated with a substance-induced psychotic disorder catatonia associated with bipolar and related disorders catatonia associated with major depressive disorder catatonic disorder due to another medical condition if catatonic symptoms are present but do not form the catatonic syndrome, a medication- or substance-induced aetiology should first be considered. icd-11 classification in icd-11 catatonia is defined as a syndrome of primarily psychomotor disturbances that is characterized by the simultaneous occurrence of several symptoms such as stupor; catalepsy; waxy flexibility; mutism; negativism; posturing; mannerisms; stereotypies; psychomotor agitation; grimacing; echolalia and echopraxia. catatonia may occur in the context of specific mental disorders, including mood disorders, schizophrenia or other primary psychotic disorders, and neurodevelopmental disorders, and may be induced by psychoactive substances, including medications. catatonia may also be caused by a medical condition not classified under mental, behavioral, or neurodevelopmental disorders. assessment/physical catatonia is often overlooked and under-diagnosed. patients with catatonia most commonly have an underlying psychiatric disorder, for this reason, physicians may overlook signs of catatonia due to the severity of the psychosis the patient is presenting with. furthermore, the patient may not be presenting with the common signs of catatonia such as mutism and posturing. additionally, the motor abnormalities seen in catatonia are also present in psychiatric disorders. for example, a patient with mania will show increased motor activity that may progress to exciting catatonia. one way in which physicians can differentiate between the two is to observe the motor abnormality. patients with mania present with increased goal-directed activity. on the other hand, the increased activity in catatonia is not goal-directed and often repetitive. catatonia is a clinical diagnosis and there is no specific laboratory test to diagnose it. however, certain testing can help determine what is causing the catatonia. an eeg will likely show diffuse slowing. if seizure activity is driving the syndrome, then an eeg would also be helpful in detecting this. ct or mri will not show catatonia; however, they might reveal abnormalities that might be leading to the syndrome. metabolic screens, inflammatory markers, or autoantibodies may reveal

reversible medical causes of catatonia. vital signs should be frequently monitored as catatonia can progress to malignant catatonia which is life-threatening. malignant catatonia is characterized by fever, hypertension, tachycardia, and tachypnea. rating scale various rating scales for catatonia have been developed, however, their utility for clinical care has not been well established. the most commonly used scale is the bush-francis catatonia rating scale (bfcrs) (external link is provided below). the scale is composed of 23 items with the first 14 items being used as the screening tool. if 2 of the 14 are positive, this prompts for further evaluation and completion of the remaining 9 items. a diagnosis can be supported by the lorazepam challenge or the zolpidem challenge. while proven useful in the past, barbiturates are no longer commonly used in psychiatry; thus the option of either benzodiazepines or ect. differential diagnosis the differential diagnosis of catatonia is extensive as signs and symptoms of catatonia may overlap significantly with those of other conditions. therefore, a careful and detailed history, medication review, and physical exam are key to diagnosing catatonia and differentiating it from other conditions. furthermore, some of these conditions can themselves lead to catatonia. the differential diagnosis is as follows: neuroleptic malignant syndrome (nms) and catatonia are both life-threatening conditions that share many of the same characteristics including fever, autonomic instability, rigidity, and delirium. lab values of low serum iron, elevated creatine kinase, and white blood cell count are also shared by the two disorders further complicating the diagnosis. there are features of malignant catatonia (posturing, impulsivity, etc.) that are absent from nms and the lab results are not as consistent in malignant catatonia as they are in nms. some experts consider nms to be a drug-induced condition associated with antipsychotics, particularly, first generation antipsychotics, but it has not been established as a subtype. therefore, discontinuing antipsychotics and starting benzodiazepines is a treatment for this condition, and similarly it is helpful in catatonia as well. anti-nmda receptor encephalitis is an autoimmune disorder characterized by neuropsychiatric features and the presence of igg antibodies. the presentation of anti-nmdar encephalitis has been categorized into 5 phases: prodromal phase, psychotic phase, unresponsive phase, hyperkinetic phase, and recovery phase. the psychotic phase progresses into the unresponsive phase characterized by mutism, decreased motor activity, and catatonia. both serotonin syndrome and malignant catatonia may present with signs and symptoms of delirium, autonomic instability, hyperthermia, and rigidity. again, similar to the presentation in nsm. however, patients with serotonin syndrome have a history of ingestion of serotonergic drugs (ex: ssri). these patients will also present with hyperreflexia, myoclonus, nausea, vomiting, and diarrhea. malignant hyperthermia and malignant catatonia share features of autonomic instability, hyperthermia, and rigidity. however, malignant hyperthermia is a hereditary disorder of skeletal muscle that makes these patients susceptible to exposure to halogenated anesthetics and/or depolarizing muscle relaxants like succinylcholine. malignant hyperthermia most commonly occurs in the intraoperative or postoperative periods. other signs and symptoms of malignant hyperthermia include metabolic and respiratory acidosis, hyperkalemia, and cardiac arrhythmias. akinetic mutism is a neurological disorder characterized by a decrease in goal-directed behavior and motivation; however, the patient has an intact level of consciousness. patients may present with apathy, and may seem indifferent to pain, hunger, or thirst. akinetic mutism has been associated with structural damage in a variety of brain areas. akinetic mutism and catatonia may both manifest with immobility, mutism, and waxy flexibility. differentiating both disorders is the fact that akinetic mutism does not present with echolalia, echopraxia, or posturing. furthermore, it is not responsive to benzodiazepines as is the case for catatonia. elective mutism has an anxious etiology but has also been associated with personality disorders. patients with this disorder fail to speak with some individuals but will speak with others. likewise, they may refuse to speak in certain situations; for example, a child who refuses to speak at school but is conversational at home. this disorder is distinguished from catatonia by the absence of any other signs/symptoms. nonconvulsive status epilepticus is seizure activity with no accompanying tonic-clonic movements. it can present with stupor, similar to catatonia, and they both respond to benzodiazepines. nonconvulsive status epilepticus is diagnosed by the presence of seizure activity seen on electroencephalogram (eeg). catatonia on the other hand, is associated with normal eeg or diffuse slowing. delirium is characterized by fluctuating disturbed perception and consciousness in the ill individual. it has hypoactive and hyperactive or mixed forms. people with hyperactive delirium present similarly to those with excited catatonia and have symptoms of restlessness, agitation, and aggression. those with hypoactive delirium present with similarly to retarded catatonia, withdrawn and quiet. however, catatonia also includes other distinguishing features including posturing and rigidity as well as a positive response to benzodiazepines. patients with locked-in syndrome present with immobility and mutism; however, unlike patients with catatonia who are unmotivated to communicate, patients with locked-in syndrome try to communicate with eye movements and blinking. furthermore, locked-in syndrome is caused by damage to the brainstem. stiff-person syndrome and catatonia are similar in that they may both present with rigidity, autonomic instability and a positive response to benzodiazepines. however, stiff-person syndrome may be associated with anti-glutamic acid decarboxylase (anti-gad) antibodies and other catatonic signs such as mutism and posturing are not part of the syndrome. untreated late-stage parkinson's disease may present similarly to retarded catatonia with symptoms of immobility, rigidity, and difficulty speaking. further complicating the diagnosis is the fact that many patients with parkinson's disease will have major depressive disorder, which may be the underlying cause of catatonia. parkinson's disease can be distinguished from catatonia by a positive response to levodopa. catatonia on the other hand will show a positive response to benzodiazepines. extrapyramidal side effects of antipsychotic medication, especially dystonia and akathisia, can be difficult to distinguish from catatonic symptoms, or may confound them in the psychiatric setting. extrapyramidal motor disorders usually do not involve social symptoms like negativism, while individuals with catatonic excitement typically do not have the physically painful compulsion to move that is seen in akathisia. certain stimming behaviors and stress responses in individuals with autism spectrum disorders can present similarly to catatonia. in autism spectrum disorders, chronic catatonia is distinguished by a lasting deterioration of adaptive skills from the background of pre-existing autistic symptomatology that cannot be easily explained. acute catatonia is usually clearly distinguishable from autistic symptoms. the diagnostic entities of obsessional slowness and psychogenic parkinsonism show overlapping features with catatonia, such as motor slowness, gegenhalten (oppositional paratonia), mannerisms, and reduced or absent speech. however, psychogenic parkinsonism involves tremor which is unusual in catatonia. obsessional slowness is a controversial diagnosis, with presentations ranging from severe but common manifestations of obsessive compulsive disorder to catatonia. treatment the initial treatment of catatonia is to stop medication that could be potentially leading to the syndrome. these may include steroids, stimulants, anticonvulsants, neuroleptics, dopamine blockers, etc. the next step is to provide a "lorazepam challenge," in which patients are given 2 mg of iv lorazepam (or another benzodiazepine). most patients with catatonia will respond significantly to this within the first 15–30 minutes. if no change is observed during the first dose, then a second dose is given and the patient is re-examined. if the patient responds to the lorazepam challenge, then lorazepam can be scheduled at interval doses until the catatonia resolves. the lorazepam must be tapered slowly, otherwise, the catatonia symptoms may return. the underlying cause of the catatonia should also be treated during this time. if within a week the catatonia is not resolved, then ect can be used to reverse the symptoms. ect in combination with benzodiazepines is used to treat malignant catatonia. in france, zolpidem has also been used in diagnosis, and response may occur within the same time period. ultimately the underlying cause needs to be treated. electroconvulsive therapy (ect) is an effective treatment for catatonia that is well acknowledged. ect has also shown favorable outcomes in patients with chronic catatonia. however, it has been pointed out that further high quality randomized controlled trials are needed to evaluate the efficacy, tolerance, and protocols of ect in catatonia. antipsychotics should be used with care as they can worsen catatonia and are the cause of neuroleptic malignant syndrome, a dangerous condition that can mimic catatonia and requires immediate discontinuation of the antipsychotic. there is evidence clozapine works better than other antipsychotics to treat catatonia, following a recent systematic review. excessive glutamate activity is believed to be involved in catatonia; when first-line treatment options fail, nmda antagonists such as amantadine or memantine may be used. amantadine may have an increased incidence of tolerance with prolonged use and can cause psychosis, due to its additional effects on the dopamine system. memantine has a more targeted pharmacological profile for the glutamate system, reduced incidence of psychosis and may therefore be preferred for individuals who cannot tolerate amantadine. topiramate is another treatment option for resistant catatonia; it produces its therapeutic effects by producing glutamate antagonism via modulation of ampa receptors. prognosis patients who experience an episode of catatonia are more likely to recur. treatment response for patients with catatonia is 50–70% and these patients have a good prognosis. however, failure to respond to medication is a very poor prognosis. many of these patients will require long-term and continuous mental health care. for patients with catatonia with underlying schizophrenia, the prognosis is much poorer. epidemiology catatonia has been mostly studied in acutely ill psychiatric patients. catatonia frequently goes unrecognized, leading to the belief that the syndrome is rare; however, this is not true and prevalence has been reported to be as high as 10% in patients with acute psychiatric illnesses. one large population estimate has suggested that the incidence of catatonia is 10.6 episodes per 100 000 person-years. it occurs in males and females in approximately equal numbers. 21-46% of all catatonia cases can be attributed to a general medical condition. history reports of stupor-like and catatonia-like states abound in the history of psychiatry. after the middle of the 19th century there was an increase of interest in the motor disorders accompanying madness, culminating in the publication by karl ludwig kahlbaum in 1874 of die katatonie oder das spannungsirresein (catatonia or tension insanity).

artificial cardiac pacemaker artificial cardiac pacemaker an artificial cardiac pacemaker (artificial pacemaker, and sometimes just pacemaker, although the term is also used to refer to the body's natural cardiac pacemaker) is a medical device, nowadays always implanted, that generates electrical pulses delivered by electrodes to the chambers of the heart, either the upper atria or lower ventricles. each pulse causes the targeted chambers to contract and pump blood, thus regulating the function of the electrical conduction system of the heart. this article is about the medical device that simulates the function. for the natural pacemaker in the heart, see cardiac pacemaker. artificial cardiac pacemakerst. jude single-lead pacemaker with ruler in cm (released in 2005)specialtycardiology, electrophysiology the primary purpose of a pacemaker is to maintain an adequate heart rate, either because the heart's natural pacemaker is not fast enough, or because there is a block in the heart's electrical conduction system. modern pacemakers are externally programmable and allow a cardiologist, particularly a cardiac electrophysiologist, to select the optimal pacing modes for individual patients. most pacemakers are on demand, in which the stimulation of the heart is based on the dynamic demand of the circulatory system. others send out a fixed rate of impulses. a specific type of pacemaker called an implantable cardioverter-defibrillator combines pacemaker and defibrillator functions in a single implantable device. others, called biventricular pacemakers, have multiple electrodes stimulating different positions within the ventricles (the lower heart chambers) to improve their synchronization. methods of pacing an ecg in a person with a single-chamber pacemaker to the atrium. note the circle around one of the sharp electrical spikes in the position where the p wave would be expected. an ecg of a person with a dual-chamber pacemaker percussive pacing percussive pacing, also known as transthoracic mechanical pacing, is the use of the closed fist, usually on the left lower edge of the sternum over the right ventricle in the vena cava, striking from a distance of 20 – 30 cm to induce a ventricular beat (the british journal of anaesthesia suggests this must be done to raise the ventricular pressure to 10–15 mmhg to induce electrical activity). this is an old procedure used only as a life-saving means until an electrical pacemaker is brought to the patient. transcutaneous pacing main article: transcutaneous pacing transcutaneous pacing (tcp), also called external pacing, is recommended for the initial stabilization of hemodynamically significant bradycardias of all types. the procedure is performed by placing two pacing pads on the patient's chest, either in the anterior/lateral position or the anterior/posterior position. the rescuer selects the pacing rate, and gradually increases the pacing current (measured in ma) until electrical capture (characterized by a wide qrs complex with a tall, broad t wave on the ecg) is achieved, with a corresponding pulse. pacing artifact on the ecg and severe muscle twitching may make this determination difficult. external pacing should not be relied upon for an extended period of time. it is an emergency procedure that acts as a bridge until transvenous pacing or other therapies can be applied. epicardial pacing (temporary) main article: epicardial ecg rhythm strip of a threshold determination in a patient with a temporary (epicardial) ventricular pacemaker. the epicardial pacemaker leads were placed after the patient collapsed during aortic valve surgery. in the first half of the tracing, pacemaker stimuli at 60 beats per minute result in a wide qrs complex with a right bundle branch block pattern. progressively weaker pacing stimuli are administered, which results in asystole in the second half of the tracing. at the end of the tracing, distortion results from muscle contractions due to a (short) hypoxic seizure. because decreased pacemaker stimuli do not result in a ventricular escape rhythm, the patient can be said to be pacemaker-dependent and needs a definitive pacemaker. temporary epicardial pacing is used during open heart surgery should the surgical procedure create atrio-ventricular block. the electrodes are placed in contact with the outer wall of the ventricle (epicardium) to maintain satisfactory cardiac output until a temporary transvenous electrode has been inserted. transvenous pacing (temporary) main article: transvenous pacing transvenous pacing, when used for temporary pacing, is an alternative to transcutaneous pacing. a pacemaker wire is placed into a vein, under sterile conditions, and then passed into either the right atrium or right ventricle. the pacing wire is then connected to an external pacemaker outside the body. transvenous pacing is often used as a bridge to permanent pacemaker placement. it can be kept in place until a permanent pacemaker is implanted or until there is no longer a need for a pacemaker and then it is removed. right atrial and right ventricular leads as visualized under x-ray during a pacemaker implant procedure. the atrial lead is the curved one making a u shape in the upper left part of the figure. permanent transvenous pacing permanent pacing with an implantable pacemaker involves transvenous placement of one or more pacing electrodes within a chamber, or chambers, of the heart, while the pacemaker is implanted inside the skin under the clavicle. the procedure is performed by incision of a suitable vein into which the electrode lead is inserted and passed along the vein, through the valve of the heart, until positioned in the chamber. the procedure is facilitated by fluoroscopy which enables the physician to view the passage of the electrode lead. after satisfactory lodgement of the electrode is confirmed, the opposite end of the electrode lead is connected to the pacemaker generator. there are three basic types of permanent pacemakers, classified according to the number of chambers involved and their basic operating mechanism: single-chamber pacemaker. in this type, only one pacing lead is placed into a chamber of the heart, either the atrium or the ventricle. dual-chamber pacemaker. here, wires are placed in two chambers of the heart. one lead paces the atrium and one paces the ventricle. this type more closely resembles the natural pacing of the heart by assisting the heart in coordinating the function between the atria and ventricles. biventricular pacemaker. this pacemaker has three wires placed in three chambers of the heart. one in the atrium and two in either ventricle. it is more complicated to implant. rate-responsive pacemaker. this pacemaker has sensors that detect changes in the patient's physical activity and automatically adjust the pacing rate to fulfill the body's metabolic needs. the pacemaker generator is a hermetically sealed device containing a power source, usually a lithium battery, a sensing amplifier which processes the electrical manifestation of naturally occurring heart beats as sensed by the heart electrodes, the computer logic for the pacemaker and the output circuitry which delivers the pacing impulse to the electrodes. most commonly, the generator is placed below the subcutaneous fat of the chest wall, above the muscles and bones of the chest. however, the placement may vary on a case-by-case basis. the outer casing of pacemakers is so designed that it will rarely be rejected by the body's immune system. it is usually made of titanium, which is inert in the body. leadless pacing leadless pacemakers are devices that are small enough to allow the generator to be placed within the heart, therefore avoiding the need for pacing leads. as pacemaker leads can fail over time, a pacing system that avoids these components offers theoretical advantages. leadless pacemakers can be implanted into the heart using a steerable catheter fed into the femoral vein via an incision in the groin. basic function single-chamber vvir/aair pacemaker dual-chamber dddr pacemaker modern pacemakers usually have multiple functions. the most basic form monitors the heart's native electrical rhythm. when the pacemaker wire or "lead" does not detect heart electrical activity in the chamber – atrium or ventricle – within a normal beat-to-beat time period – most commonly one second – it will stimulate either the atrium or the ventricle with a short low voltage pulse. if it does sense electrical activity, it will hold off stimulating. this sensing and stimulating activity continues on a beat by beat basis and is called "demand pacing". in the case of a dual-chamber device, when the upper chambers have a spontaneous or stimulated activation, the device starts a countdown to ensure that in an acceptable – and programmable – interval, there is an activation of the ventricle, otherwise again an impulse will be delivered. the more complex forms include the ability to sense and/or stimulate both the atrial and ventricular chambers. the revised naspe/bpeg generic code for antibradycardia pacing iiiiiiivv chamber(s) pacedchamber(s) sensedresponse to sensingrate modulationmultisite pacing o = noneo = noneo = noneo = noneo = none a = atriuma = atriumt = triggeredr = rate modulationa = atrium v = ventriclev = ventriclei = inhibitedv = ventricle d = dual (a+v)d = dual (a+v)d = dual (t+i)d = dual (a+v) from this the basic ventricular "on demand" pacing mode is vvi or with automatic rate adjustment for exercise vvir – this mode is suitable when no synchronization with the atrial beat is required, as in atrial fibrillation. the equivalent atrial pacing mode is aai or aair which is the mode of choice when atrioventricular conduction is intact but the sinoatrial node of the natural pacemaker is unreliable – sinus node disease (snd) or sick sinus syndrome. where the problem is atrioventricular block (avb) the pacemaker is required to detect (sense) the atrial beat and after a normal delay (0.1–0.2 seconds) trigger a ventricular beat, unless it has already happened – this is vdd mode and can be achieved with a single pacing lead with electrodes in the right atrium (to sense) and ventricle (to sense and pace). these modes aair and vdd are unusual in the us but widely used in latin america and europe. the dddr mode is most commonly used as it covers all the options though the pacemakers require separate atrial and ventricular leads and are more complex, requiring careful programming of their functions for optimal results. automatic pacemakers are designed to be over-ridden by the heart's natural rate at any moment that it gets back to a non-pathologic normal sinus rhythm and can reinitiate influencing the electric activity in the heart when the pathologic event happens again. a "ventricular-demand pacemaker" produces a narrow vertical spike on the ecg, just before a wide qrs. the spike of an "atrial-demand pacemaker" appears just before the p wave. comparably, a triggered pacemaker is activated immediately after an electrical activity is commenced in the heart tissue by itself. a "ventricular triggered pacemaker" produces the impulse just after a pulse is created in the ventricular tissue and it appears as a simultaneous spike with qrs. an "atrial triggered pacemaker" is the mode in which an impulse is produced immediately after an electrical event in the atrium. it appears as a discharge following the p wave but prior to the qrs which is commonly widened. biventricular pacing three leads can be seen in this example of a cardiac resynchronization device: a right atrial lead (solid black arrow), a right ventricular lead (dashed black arrow), and a coronary sinus lead (red arrow). the coronary sinus lead wraps around the outside of the left ventricle, enabling pacing of the left ventricle. note that the right ventricular lead in this case has two thickened aspects that represent conduction coils and that the generator is larger than typical pacemaker generators, demonstrating that this device is both a pacemaker and a cardioverter-defibrillator, capable of delivering electrical shocks for dangerously fast abnormal ventricular rhythms. main article: cardiac resynchronization therapy cardiac resynchronization therapy (crt) is used for people with heart failure in whom the left and right ventricles do not contract simultaneously (ventricular dyssynchrony), which occurs in approximately 25–50% of heart failure patients. to achieve crt, a biventricular pacemaker (bvp) is used, which can pace both the septal and lateral walls of the left ventricle. by pacing both sides of the left ventricle, the pacemaker can resynchronize the ventricular contractions. crt devices have at least two leads, one passing through the vena cava and the right atrium into the right ventricle to stimulate the septum, and another passing through the vena cava and the right atrium and inserted through the coronary sinus to pace the epicardial wall of the left ventricle. often, for patients in normal sinus rhythm, there is also a lead in

the right atrium to facilitate synchrony with the atrial contraction. thus, the timing between the atrial and ventricular contractions, as well as between the septal and lateral walls of the left ventricle can be adjusted to achieve optimal cardiac function. crt devices have been shown to reduce mortality and improve quality of life in patients with heart failure symptoms; a lv ejection fraction less than or equal to 35% and qrs duration on ekg of 120 ms or greater. biventricular pacing alone is referred to as crt-p (for pacing). for selected patients at risk of arrhythmias, crt can be combined with an implantable cardioverter-defibrillator (icd): such devices, known as crt-d (for defibrillation), also provide effective protection against life-threatening arrhythmias. conduction system pacing conventional placement of ventricular leads in or around the tip or apex of the right ventricle, or rv apical pacing, can have negative effects on heart function. it has been associated with increased risk of atrial fibrillation, heart failure, weakening of the heart muscle and potentially shorter life expectancy. his bundle pacing (hbp) leads to a more natural or perfectly natural ventricular activation and has generated strong research and clinical interest. by stimulating the his–purkinje fiber network directly with a special lead and placement technique, hbp causes a synchronized and therefore more effective ventricular activation and avoids long-term heart muscle disease. hbp in some cases can also correct bundle branch block patterns. advancements in function posteroanterior and lateral chest radiographs of a pacemaker with normally located leads in the right atrium (white arrow) and right ventricle (black arrowhead), respectively. a major step forward in pacemaker function has been to attempt to mimic nature by utilizing various inputs to produce a rate-responsive pacemaker using parameters such as the qt interval, po2 – pco2 (dissolved oxygen or carbon dioxide levels) in the arterial-venous system, physical activity as determined by an accelerometer, body temperature, atp levels, adrenaline, etc. instead of producing a static, predetermined heart rate, or intermittent control, such a pacemaker, a 'dynamic pacemaker', could compensate for both actual respiratory loading and potentially anticipated respiratory loading. the first dynamic pacemaker was invented by anthony rickards of the national heart hospital, london, uk, in 1982. dynamic pacemaking technology could also be applied to future artificial hearts. advances in transitional tissue welding would support this and other artificial organ/joint/tissue replacement efforts. stem cells may be of interest in transitional tissue welding. many advancements have been made to improve the control of the pacemaker once implanted. many of these have been made possible by the transition to microprocessor controlled pacemakers. pacemakers that control not only the ventricles but the atria as well have become common. pacemakers that control both the atria and ventricles are called dual-chamber pacemakers. although these dual-chamber models are usually more expensive, timing the contractions of the atria to precede that of the ventricles improves the pumping efficiency of the heart and can be useful in congestive heart failure. rate responsive pacing allows the device to sense the physical activity of the patient and respond appropriately by increasing or decreasing the base pacing rate via rate response algorithms. the david trials have shown that unnecessary pacing of the right ventricle can exacerbate heart failure and increases the incidence of atrial fibrillation. the newer dual-chamber devices can keep the amount of right ventricle pacing to a minimum and thus prevent worsening of the heart disease. considerations insertion a pacemaker may be implanted whilst a person is awake using local anesthetic to numb the skin with or without sedation, or asleep using a general anesthetic. an antibiotic is usually given to reduce the risk of infection. pacemakers are generally implanted in the front of the chest in the region of the left or right shoulder. the skin is prepared by clipping or shaving any hair over the implant site before cleaning the skin with a disinfectant such as chlorhexidine. an incision is made below the collar bone and a space or pocket is created under the skin to house the pacemaker generator. this pocket is usually created just above the pectoralis major muscle (prepectoral), but in some cases the device may be inserted beneath the muscle (submuscular). the lead or leads are fed into the heart through a large vein guided by x-ray imaging (fluoroscopy). the tips of the leads may be positioned within the right ventricle, the right atrium, or the coronary sinus, depending on the type of pacemaker required. surgery is typically completed within 30 to 90 minutes. following implantation, the surgical wound should be kept clean and dry until it has healed. some movements of the shoulder within a few weeks of insertion carry a risk of dislodging the pacemaker leads. the batteries within a pacemaker generator typically last 5 to 10 years. when the batteries are nearing the end of life, the generator is replaced in a procedure that is usually simpler than a new implant. replacement involves making an incision to remove the existing device, disconnecting the leads from the old device and reconnecting them to a new generator, reinserting the new device and closing the skin. periodic pacemaker checkups two types of remote monitoring devices used by pacemaker patients once the pacemaker is implanted, it is periodically checked to ensure the device is operational and performing appropriately; the device can be checked as often as is deemed necessary. routine pacemaker checks are typically done in-office every six months, though will vary depending upon patient/device status and remote monitoring availability. newer pacemaker models can also be interrogated remotely, with the patient transmitting their pacemaker data using a transmitter at home connected to a cellular telephone network. during in-office follow-up, diagnostic tests may include: sensing: the ability of the device to "see" intrinsic cardiac activity (atrial and ventricular depolarization). impedance: a test to measure lead integrity. large and/or sudden increases in impedance can indicate a lead fracture, while large and/or sudden decreases in impedance can be caused by insulation failure. threshold amplitude: the minimum voltage (generally in hundredths of volts) required in order to pace the atrium or ventricle connected to the lead. threshold duration: the time that the device requires at the preset amplitude to reliably pace the atrium or ventricle connected to the lead. percentage of pacing: the percentage of time that the pacemaker has been actively pacing since the previous device interrogation, which shows how dependent the patient is on the device. estimated battery life at current rate: as modern pacemakers are "on-demand" and only pace when necessary, battery lifespan is affected by how much the pacemaker is utilized. other factors affecting battery life include programmed output and algorithms (features) that use battery power. any events that were stored since the last follow-up, in particular arrhythmias such as atrial fibrillation. these are typically stored based on specific criteria set by the physician and specific to the patient. some devices have the availability to display intracardiac electrograms showing the onset of an event as well as the event itself, which helps to diagnose its cause or origin. magnetic fields, mris, and other lifestyle issues a patient's lifestyle is usually not modified to any great degree after the insertion of a pacemaker. there are a few activities that are unwise, such as full-contact sports and exposure of the pacemaker to intense magnetic fields. the pacemaker patient may find that some types of everyday actions need to be modified. for instance, the shoulder harness of a vehicle seatbelt may be uncomfortable if it falls across the pacemaker insertion site. women will not be able to wear bras for a while after the operation, and later might have to wear bras with wide shoulder straps. for some sports and physical activities, special pacemaker protection can be worn to prevent possible injuries, or damage to the pacemaker leads. pacemakers may be affected by magnetic or electromagnetic fields, and ionising and acoustic radiation. however, a 2013 study found that "the overall risk of clinically significant adverse events related to emi (electromagnetic interference) in recipients of cieds (cardiovascular implantable electronic devices) is very low. therefore, no special precautions are needed when household appliances are used. environmental and industrial sources of emi are relatively safe when the exposure time is limited and distance from the cieds is maximized. the risk of emi-induced events is highest within the hospital environment." the study lists and tabulates (in table 2) many sources of interference, and many different potential effects: damage to circuitry, asynchronous pacing, etc. some sources of hazard in older devices have been eliminated in newer ones. activities involving strong magnetic fields should be avoided. this includes activities such as arc welding with certain types of equipment, and maintaining heavy equipment that may generate strong magnetic fields. some medical procedures, particularly magnetic resonance imaging (mri), involve very strong magnetic fields or other conditions that may damage pacemakers. however, many modern pacemakers are specified to be mr conditional or mri conditional, safe to use during mri subject to certain conditions. the first to be so specified was the medtronic revo mri surescan, approved by the us fda in february 2011, which was the first to be specified as mr conditional. there are several conditions to use of mr conditional pacemakers, including certain patients' qualifications and scan settings. an mri conditional device has to have mri settings enabled before a scan, and disabled afterwards. as of 2014 the five most commonly used cardiac pacing device manufacturers (covering more than 99% of the us market) made fda-approved mr-conditional pacemakers. the use of mri may be ruled out by the patient having an older, non-mri conditional pacemaker, or by having old pacing wires inside the heart, no longer connected to a pacemaker. a 2008 us study found that the magnetic field created by some headphones used with portable music players or cellphones may cause interference if placed very close to some pacemakers. in addition, according to the american heart association, some home devices have the potential to occasionally inhibit a single beat. cellphones do not seem to damage pulse generators or affect how the pacemaker works. it is recommended that objects containing magnets, or generating a significant magnetic field, should not be in close proximity to a pacemaker. induction cooktops, in particular, can pose a risk. before medical procedures, the patient should inform all medical personnel that they have a pacemaker. having a pacemaker does not imply that a patient requires the use of antibiotics to be administered before procedures such as dental work. end-of-life care and pacemaker deactivation a panel of the heart rhythm society, a us specialist organization based in washington, dc, deemed that it was legal and ethical to honor requests by patients, or by those with legal authority to make decisions for patients, to deactivate implanted cardiac devices. lawyers say that the legal situation is similar to removing a feeding tube, though as of 2010 there was no legal precedent involving pacemakers in the united states. a patient in many jurisdictions (including the us) is deemed to have a right to refuse or discontinue treatment, including a pacemaker that keeps them alive. physicians have a right to refuse to turn it off, but are advised by the hrs panel that they should refer the patient to a physician who will. some patients consider that hopeless, debilitating conditions, such as severe strokes or late-stage dementia, can cause so much suffering that they would prefer not to prolong their lives with supportive measures. privacy and security security and privacy concerns have been raised with pacemakers that allow wireless communication. unauthorized third parties may be able to read patient records contained in the pacemaker, or reprogram the devices, as has been demonstrated by a team of researchers. the demonstration worked at short range; they did not attempt to develop a long range antenna. the proof of concept exploit helps demonstrate the need for better security and patient alerting measures in remotely accessible medical implants. in response to this threat, purdue university and princeton university researchers have developed a prototype firewall device, called medmon, which is designed to protect wireless medical devices such as pacemakers and insulin pumps from attackers. complications complications from having surgery to implant a pacemaker are uncommon (each 1-3% approximately), but could include: infection where the pacemaker is implanted or in the bloodstream;

allergic reaction to the dye or anesthesia used during the procedure; swelling, bruising or bleeding at the generator site, or around the heart, especially if the patient is taking blood thinners, elderly, of thin frame or otherwise on chronic steroid use. a possible complication of dual-chamber artificial pacemakers is 'pacemaker-mediated tachycardia' (pmt), a form of reentrant tachycardia. in pmt, the artificial pacemaker forms the anterograde (atrium to ventricle) limb of the circuit and the atrioventricular (av) node forms the retrograde limb (ventricle to atrium) of the circuit. treatment of pmt typically involves reprogramming the pacemaker. another possible complication is "pacemaker-tracked tachycardia," where a supraventricular tachycardia such as atrial fibrillation or atrial flutter is tracked by the pacemaker and produces beats from a ventricular lead. this is becoming exceedingly rare as newer devices are often programmed to recognize supraventricular tachycardias and switch to non-tracking modes. sometimes the leads, which are small diameter wires from the pacemaker to the implantation site in the heart muscle, will need to be removed. the most common reason for lead removal is infection; however, over time, leads can degrade due to a number of reasons such as lead flexing. changes to the programming of the pacemaker may overcome lead degradation to some extent. however, a patient who has several pacemaker replacements over a decade or two in which the leads were reused may require lead replacement surgery. lead replacement may be done in one of two ways. insert a new set of leads without removing the current leads (not recommended as it provides additional obstruction to blood flow and heart valve function) or remove the current leads and then insert replacements. the lead removal technique will vary depending on the surgeon's estimation of the probability that simple traction will suffice to more complex procedures. leads can normally be disconnected from the pacemaker easily, which is why device replacement usually entails simple surgery to access the device and replace it by simply unhooking the leads from the device to replace and hooking the leads to the new device. the possible complications, such as perforation of the heart wall, come from removing the lead from the patient's body. the free end of a pacemaker lead is actually implanted into the heart muscle with a miniature screw or anchored with small plastic hooks called tines. the longer the leads have been implanted (starting from a year or two), the more likely that they will have additional attachments to the patient's body at various places in the pathway from device to heart muscle, since the body tends to incorporate foreign devices into tissue. in some cases, for a lead that has been inserted for a short amount of time, removal may involve simple traction to pull the lead from the body. removal in other cases is typically done with a laser or cutting device which threads like a cannula with a cutting edge over the lead and is moved down the lead to remove any organic attachments with tiny cutting lasers or similar device. pacemaker lead malposition in various locations has been described in the literature. treatment varies, depending on the location of the pacer lead and symptoms. another possible complication called twiddler's syndrome occurs when a patient manipulates the pacemaker and causes the leads to be removed from their intended location and causes possible stimulation of other nerves. overall life expectancy with pacemakers is excellent, and mostly depends upon underlying diseases, presence of atrial fibrillation, age and sex at the time of first implantation. other devices sometimes devices resembling pacemakers, called implantable cardioverter-defibrillators (icds) are implanted. these devices are often used in the treatment of patients at risk from sudden cardiac death. an icd has the ability to treat many types of heart rhythm disturbances by means of pacing, cardioversion, or defibrillation. some icd devices can distinguish between ventricular fibrillation and ventricular tachycardia (vt), and may try to pace the heart faster than its intrinsic rate in the case of vt, to try to break the tachycardia before it progresses to ventricular fibrillation. this is known as fast-pacing, overdrive pacing, or anti-tachycardia pacing (atp). atp is only effective if the underlying rhythm is ventricular tachycardia, and is never effective if the rhythm is ventricular fibrillation. naspe / bpeg defibrillator (nbd) code – 1993 iiiiiiiv shock chamberantitachycardia pacing chambertachycardia detectionantibradycardia pacing chamber o = noneo = nonee = electrogramo = none a = atriuma = atriumh = hemodynamica = atrium v = ventriclev = ventriclev = ventricle d = dual (a+v)d = dual (a+v)d = dual (a+v) short form of the naspe/bpeg defibrillator (nbd) code icd-sicd with shock capability only icd-bicd with bradycardia pacing as well as shock icd-ticd with tachycardia (and bradycardia) pacing as well as shock history in 1958, arne larsson (1915–2001) became the first to receive an implantable pacemaker. he had 26 devices during his life and campaigned for other patients needing pacemakers. origin in 1889, john alexander macwilliam reported in the british medical journal (bmj) of his experiments in which application of an electrical impulse to the human heart in asystole caused a ventricular contraction and that a heart rhythm of 60–70 beats per minute could be evoked by impulses applied at spacings equal to 60–70/minute. in 1926, mark c lidwill of the royal prince alfred hospital of sydney, supported by physicist edgar h. booth of the university of sydney, devised a portable apparatus which "plugged into a lighting point" and in which "one pole was applied to a skin pad soaked in strong salt solution" while the other pole "consisted of a needle insulated except at its point, and was plunged into the appropriate cardiac chamber". "the pacemaker rate was variable from about 80 to 120 pulses per minute, and likewise the voltage variable from 1.5 to 120 volts". in 1928, the apparatus was used to revive a stillborn infant at crown street women's hospital in sydney, whose heart continued "to beat on its own accord", "at the end of 10 minutes" of stimulation. in 1932, american physiologist albert hyman, with the help of his brother, described an electro-mechanical instrument of his own, powered by a spring-wound hand-cranked motor. hyman himself referred to his invention as an "artificial pacemaker", the term continuing in use to this day. an apparent hiatus in the publication of research conducted between the early 1930s and world war ii may be attributed to the public perception of interfering with nature by "reviving the dead". for example, "hyman did not publish data on the use of his pacemaker in humans because of adverse publicity, both among his fellow physicians, and due to newspaper reporting at the time. lidwell may have been aware of this and did not proceed with his experiments in humans". transcutaneous in 1950, canadian electrical engineer john hopps designed and built the first external pacemaker based upon observations by cardio-thoracic surgeons wilfred gordon bigelow and john callaghan at toronto general hospital. the device was first tested on a dog at the university of toronto's banting institute. a substantial external device using vacuum tube technology to provide transcutaneous pacing, it was somewhat crude and painful to the patient in use and, being powered from an ac wall socket, carried a potential hazard of electrocution of the patient and inducing ventricular fibrillation. a number of innovators, including paul zoll, made smaller but still bulky transcutaneous pacing devices from 1952 using a large rechargeable battery as the power supply. in 1957, william l. weirich published the results of research performed at the university of minnesota. these studies demonstrated the restoration of heart rate, cardiac output and mean aortic pressures in animal subjects with complete heart block through the use of a myocardial electrode. in 1958 colombian doctor alberto vejarano laverde and colombian electrical engineer jorge reynolds pombo constructed an external pacemaker, similar to those of hopps and zoll, weighing 45 kg and powered by a 12 volt car lead–acid battery, but connected to electrodes attached to the heart. this apparatus was successfully used to sustain a 70-year-old priest, gerardo florez. the development of the silicon transistor and its first commercial availability in 1956 was the pivotal event that led to the rapid development of practical cardiac pacemaking. wearable in 1958, engineer earl bakken of minneapolis, minnesota, produced the first wearable external pacemaker for a patient of c. walton lillehei. this transistorized pacemaker, housed in a small plastic box, had controls to permit adjustment of pacing heart rate and output voltage and was connected to electrode leads which passed through the skin of the patient to terminate in electrodes attached to the surface of the myocardium of the heart. in the uk in the 1960s, lucas engineering in birmingham was asked by mr abrams of the queen elizabeth hospital to produce a prototype for a transistorised replacement for the electro-mechanical product. the team was headed by roger nolan, an engineer with the lucas group research centre. nolan designed and created the first blocking oscillator and transistor-powered pacemaker. this pacemaker was worn on a belt and powered by a rechargeable sealed battery, enabling users to live a more-normal life. one of the earliest patients to receive this lucas pacemaker device was a woman in her early 30s. the operation was carried out in 1964 by south african cardiac surgeon alf gunning, a student of christiaan barnard. this pioneering operation took place under the guidance of cardiac consultant peter sleight at the radcliffe infirmary in oxford and his cardiac research team at st george's hospital in london. implantable illustration of implanted cardiac pacemaker showing locations of cardiac pacemaker leads the first clinical implantation into a human of a fully implantable pacemaker was on october 8, 1958, at the karolinska institute in solna, sweden, using a pacemaker designed by inventor rune elmqvist and surgeon åke senning (in collaboration with elema-schönander ab, later siemens-elema ab), connected to electrodes attached to the myocardium of the heart by thoracotomy. the device failed after three hours. a second device was then implanted which lasted for two days. the world's first implantable pacemaker patient, arne larsson, went on to receive 26 different pacemakers during his lifetime. he died in 2001, at the age of 86, outliving the inventor and the surgeon. in 1959, temporary transvenous pacing was first demonstrated by seymour furman and john schwedel, whereby the catheter electrode was inserted via the patient's basilic vein. in february 1960, an improved version of the swedish elmqvist design was implanted by doctors orestes fiandra and roberto rubio in the casmu 1 hospital of montevideo, uruguay. this pacemaker, the first implanted in the americas, lasted until the patient died of other ailments, nine months later. the early swedish-designed devices used batteries recharged by an induction coil from the outside. implantable pacemakers constructed by engineer wilson greatbatch entered use in humans from april 1960 following extensive animal testing. the greatbatch innovation varied from the earlier swedish devices in using primary cells (a mercury battery) as the energy source. the first patient lived for a further 18 months. the first use of transvenous pacing in conjunction with an implanted pacemaker was by parsonnet in the united states, lagergren in sweden and jean-jacques welti in france in 1962–63. the transvenous, or pervenous, procedure involved incision of a vein into which was inserted the catheter electrode lead under fluoroscopic guidance, until it was lodged within the trabeculae of the right ventricle. this became the method of choice by the mid-1960s. cardiothoracic surgeon leon abrams and medical engineer ray lightwood developed and implanted the first patient-controlled variable-rate heart pacemaker in 1960 at birmingham university. the first implant took place in march 1960, with two further implants the following month. these three patients made good recoveries and returned to a high quality of life. by 1966, 56 patients had undergone implantation with one surviving for over 5+1⁄2 years. lithium battery the first lithium-iodide cell-powered pacemaker. invented by anthony adducci and art schwalm. cardiac pacemakers inc. 1972 the preceding implantable devices all suffered from the unreliability and short lifetime of the available primary cell technology, mainly the mercury battery. in the late 1960s, several companies, including arco in the us, developed isotope-powered pacemakers, but this development was overtaken by the development in 1971 of the lithium iodide cell by wilson greatbatch. lithium-iodide or lithium anode cells became

the standard for pacemaker designs. a further impediment to the reliability of the early devices was the diffusion of water vapor from body fluids through the epoxy resin encapsulation, affecting the electronic circuitry. this phenomenon was overcome by encasing the pacemaker generator in a hermetically sealed metal case, initially by telectronics of australia in 1969, followed by cardiac pacemakers, inc. of st. paul, minnesota in 1972. this technology, using titanium as the encasing metal, became the standard by the mid-1970s. on july 9, 1974, manuel a. villafaña and anthony adducci, the founders of cardiac pacemakers, inc. (guidant), manufactured the world's first pacemaker with a lithium anode and a lithium-iodide electrolyte solid-state battery. lithium-iodide or lithium anode cells increased the life of pacemakers from one year to as long as eleven years, and has become the standard for pacemaker designs. they began designing and testing their implantable cardiac pacemaker powered by a new longer-life lithium battery in 1971. the first patient to receive a cpi pacemaker emerged from surgery in june 1973. intra-cardial in 2013, several firms announced devices that could be inserted via a leg catheter rather than invasive surgery. the devices are roughly the size and shape of a pill, much smaller than the size of a traditional pacemaker. once implanted, the device's prongs contact the muscle and stabilize heartbeats. development of this type of device was continuing. in november 2014, bill pike of fairbanks, alaska, received a medtronic micra pacemaker in providence st vincent hospital in portland, oregon. d. randolph jones was the ep doctor. also in 2014, st. jude medical inc. announced the first enrollments in the company's leadless pacemaker observational study evaluating the nanostim leadless pacing technology. the nanostim pacemaker received european ce marking in 2013. post-approval implant trials were carried out in europe. the european study was stopped after reports of six perforations that led to two patient deaths. after investigations, st jude medical restarted the study. in the united states, this therapy had not been approved by the fda as of 2014. while the st jude nanostim and the medtronic micra are single-chamber pacemakers, it was anticipated that leadless dual-chamber pacing for patients with atrioventricular block would become possible with further development. reusable pacemakers worldwide each year, in a simple procedure to avoid explosions, thousands of pacemakers are removed from bodies to be cremated. pacemakers with significant remaining battery life are potentially life-saving devices for people in low- and middle-income countries (lmics). the institute of medicine, a us non-governmental organization, has reported that inadequate access to advanced cardiovascular technologies is a major contributor to cardiovascular disease morbidity and mortality in lmics. ever since the 1970s, multiple studies worldwide have reported on the safety and efficacy of pacemaker reuse. as of 2016, widely acceptable standards for safe pacemaker and icd reuse had not been developed, and there continued to be legal and regulatory barriers to widespread adoption of medical device reuse. manufacturers current and prior manufacturers of implantable pacemakers biotronik (germany) boston scientific (usa) cardiac pacemaker inc. ; guidant (usa) (now owned by boston scientific) intermedics (usa) lepu medical (china) medico (italy) medtronic (usa) sorin group (italy) (merged with cyberonics to form livanova; in 2018, livanova sold its cardiac rhythm management business unit to microport for $190m ) st. jude medical (usa) (now owned by abbott laboratories)

eremothecium gossypii eremothecium gossypii eremothecium gossypii (also known as ashbya gossypii) is a filamentous fungus or mold closely related to yeast, but growing exclusively in a filamentous way. it was originally isolated from cotton as a pathogen causing stigmatomycosis by ashby and nowell in 1926. this disease affects the development of hair cells in cotton bolls and can be transmitted to citrus fruits, which thereupon dry out and collapse (dry rot disease). in the first part of the 20th century, e. gossypii and two other fungi causing stigmatomycosis (eremothecium coryli, aureobasidium pullulans) made it virtually impossible to grow cotton in certain regions of the subtropics, causing severe economical losses. control of the spore-transmitting insects - cotton stainer (dysdercus suturellus) and antestiopsis (antestia bugs) - permitted full eradication of infections. e. gossypii was recognized as a natural overproducer of riboflavin (vitamin b2), which protects its spores against ultraviolet light. this made it an interesting organism for industries, where genetically modified strains are still used to produce this vitamin. eremothecium gossypii fluorescent micrograph of eremothecium gossypii mycelium. scientific classification kingdom: fungi phylum: ascomycota subphylum: saccharomycotina class: saccharomycetes order: saccharomycetales family: saccharomycetaceae genus: eremothecium species: e. gossypii subspecies: atcc 10895, fdag binomial name eremothecium gossypii(s.f. ashby & w. nowell) kurtzman, 1995 synonyms nematospora gossypii (s.f. ashby & w. nowell, 1926) ashbya gossypii guillierm., 1928 e. gossypii as a model organism a few years ago, e. gossypii became recognized as an attractive model to study the growth of long and multinucleate fungal cells (hyphae) because of its small genome, haploid nuclei, and efficient gene targeting methods. it is generally assumed that a better understanding of filamentous fungal growth will greatly stimulate the development of novel fungicides. its use as a model organism is particularly promising because of the high level of gene order conservation (synteny) between the genomes of e. gossypii and the yeast saccharomyces cerevisiae. genome the complete sequencing and annotation of the entire e. gossypii genome, as published in 2004, was initiated when a significant degree of gene synteny was observed in preliminary studies in comparison to the genome of budding yeast, saccharomyces cerevisiae. this not only helped to improve gene annotation of s. cerevisiae, but also allowed the reconstruction of the evolutionary history of both organisms. e. gossypii and s. cerevisiae originated from a common ancestor which carried about 5000 genes. divergence of these two close relatives started some 100 million years ago. one branch of evolution involving up to 100 viable genome rearrangements (translocations and inversions), a few million base pair changes, and a limited number of gene deletions, duplications and additions lead to modern e. gossypii with its 4718 protein-coding genes and 9.2 million base pairs (smallest genome of a free-living eukaryote yet characterized) spread over seven chromosomes. the genome of s. cerevisiae underwent a more eventful evolution, which includes a whole-genome duplication. despite the long evolutionary history of the two organisms and fundamentally different ways of growth and development, the complete synteny map of both genomes reveals 95% of e. gossypii genes are orthologs of s. cerevisiae genes, and 90% map within blocks of synteny (syntenic homologs). growth, development and morphology development from a spore to a mature mycelium in e. gossypii (kindly provided by dr. philipp knechtle) a) ungerminated spore b) isotropic growth phase in the germ bubble c) unipolar germling d) emergence of a second germ tube e) emergence of lateral branches and septum generation f) apical branching in mature hypha the e. gossypii life cycle starts with the only known phase of isotropic growth in wild type: germination of the haploid spore to form a germ bubble. this is followed by apical growth, extending two germ tubes in succession on opposing sites of the germ bubble. more axes of polarity are established with lateral branch formation in young mycelium. maturation is characterized by apical branching (tip splitting) and a dramatic increase of growth speed (up to 200 μm/h at 30 °c), which enables it to cover an 8 cm petri dish of full medium in about seven days. sporulation is thought to be induced by nutrient deprivation, leading to contraction at the septa, cytokinesis and subsequent abscission of sporangia which contain up to eight haploid spores. hyphae are compartmentalized by septa, which in young parts appear as rings that allow transfer of nuclei and in older parts may appear as closed discs. compartments typically contain around eight nuclei.

american health care act of 2017 american health care act of 2017 the american health care act of 2017 (often shortened to the ahca or nicknamed ryancare) was a bill in the 115th united states congress. the bill, which was passed by the united states house of representatives but not by the united states senate, would have partially repealed the affordable care act (aca). american health care act of 2017long titlean act to provide for reconciliation pursuant to title ii of the concurrent resolution on the budget for fiscal year 2017acronyms (colloquial)ahcanicknamestrumpcare, ryancare, obamacare lite, wealthcareannounced inthe 115th united states congresscodificationacts affectedaffordable care act, medicare access and chip reauthorization act of 2015, social security act, balanced budget and emergency deficit control act of 1985, public health service actlegislative historyintroduced in the house as h.r. 1628 by diane black (r-tn) on march 20, 2017committee consideration by house energy and commerce committee: passed as "budget reconciliation legislative recommendations relating to repeal and replace of the patient protection and affordable care act" on march 9, 2017 (31–23); house ways and means committee: passed on march 9, 2017 as "budget reconciliation legislative recommendations relating to repeal and replace of health-related tax policy" (23–16), "repeal of certain consumer taxes" (24–16), "repeal of tanning tax" (24–15), "remuneration from certain insurers"(23–16), and "repeal of net investment income tax" (24–15); house budget committee: passed as "american health care act of 2017" on march 16, 2017 (19–17); house rules committee: passed with amendments on march 24, 2017 (9–3) and with further amendments on may 3, 2017 (8–3)passed the house on may 4, 2017 (217–213) the house bill passed by a 217–213 vote with twenty republican representatives voting no. republican "aye" republican "no" democratic "no" republican "abstain" this article is part of a series onhealthcare reform in theunited states history debate legislation preceding social security amendments of 1965 emtala (1986) hipaa (1996) medicare modernization act (2003) psqia (2005) superseded affordable health care for america (h.r. 3962) america's affordable health choices (h.r. 3200) baucus health bill (s. 1796) proposed american health care act (2017) medicare for all act (2021, h.r. 1976) healthy americans act (2007, 2009) health security act (h.r. 3600) latest enacted affordable care act (h.r. 3590) health care and education reconciliation act (h.r. 4872) reforms obama administration proposals public opinion reform advocacy groups rationing insurance coverage systems free market health insurance exchange nationalized insurance publicly-funded single-payer canadian vs. american two-tier universal third-party payment models all-payer rate setting capitation fee-for-service global payment united states portal health care portal republican party leaders had campaigned on the repeal of the aca since its passage in 2010, and the 2016 elections gave republicans unified control of congress and the presidency for the first time since the aca came into effect. upon the start of the 115th congress, congressional republicans sought to pass a partial repeal of the aca using the reconciliation process, which allows legislation to bypass the senate filibuster and pass with a simple majority in the senate. with the support of president donald trump, house republicans introduced the ahca in early 2017, and the bill passed the house in a close vote on may 4, 2017. all house democrats, along with several members of the centrist tuesday group and some other house republicans, voted against the ahca. the bill would have repealed the individual mandate and the employer mandate, dramatically cut medicaid spending and eligibility, eliminated tax credits for healthcare costs, abolished some taxes on high earners, and altered rules concerning pre-existing conditions and essential health benefits. senate republicans initially sought to pass the better care reconciliation act of 2017 (bcra), a healthcare bill containing provisions largely similar to those of the ahca. the bcra was never voted on in its original form due to opposition from several republican senators. senate majority leader mitch mcconnell instead sought to pass the health care freedom act (hcfa), which was colloquially referred to as a "skinny repeal" by republicans since it would only repeal the individual mandate and the employer mandate. on july 27, the senate rejected the hcfa in a 51-to-49 vote, with republican senators susan collins, lisa murkowski, and john mccain joining with all senate democrats in voting against it. in september 2017, some republican senators pushed a renewed effort to repeal the aca, but their bill never received a vote in the senate. the 115th congress ultimately did not pass an aca repeal bill, though it did pass the tax cuts and jobs act of 2017, which repealed the individual mandate. the ahca was a significant issue in the midterm elections the following year, which saw the election of a democratic house majority and defeat of several of the bill's supporters for re-election. members of congress who voted for the ahca were more likely to lose their re-election bids. the nonpartisan congressional budget office projected that the ahca would have increased the number of uninsured people by 23 million over 10 years, but would have decreased the federal budget deficit by $119 billion over the same period. polling consistently showed that the ahca was deeply unpopular with the american population during and after its evaluations in congress. business insider stated that the ahca was "the least popular major bill in decades", and major medical organizations, including the american medical association and the american academy of pediatrics, strongly condemned the bill and excoriated its supporters in congress. background the aca (colloquially called "obamacare"), a major reform of health care in the united states, was passed in 2010 by the 111th congress and signed by president barack obama in 2010 after nearly a year of bipartisan debate. the aca draws from many conservative ideas proposed by the heritage foundation in the 1980s and 1990s, which included a mandate that all have coverage (to prevent "free riders"), subsidy tax credits, and medicaid reform. heritage proposed funding program costs by taxing health insurance premiums paid by employers on behalf of workers (presently exempt from income), which would have affected all workers covered by employers, while aca primarily relied on tax rate increases on roughly the top 5% of households. from obama's inauguration in january 2009 until the november 2010 elections, both houses of congress and the presidency were controlled by the democratic party. during the 2012 presidential election, republican nominee mitt romney, running against obama, promised to repeal the aca, despite its similarity to romneycare. after romney's defeat, the aca remained in effect for the duration of obama's presidency despite republican efforts to repeal it. in the 114th congress, republicans passed a bill that would have repealed much of the aca, but the bill was vetoed by obama. after winning the 2016 presidential election, president donald trump promised to "repeal and replace" the aca with a new law. the 2016 elections left republicans in control of the executive and legislative branches of the u.s. government, but with 52 seats in the 100-member senate, republicans would still have to rely on at least some senate democrats to overcome a filibuster. however, senate rules provide for a special budget rule called reconciliation, which allows certain budget-related bills to bypass the filibuster and be enacted with a simple majority vote. republican leaders were seeking to pass the ahca through the senate by using the reconciliation rule. in 2015, u.s. health care costs were approximately $3.2 trillion, or nearly $10,000 per person on average. major categories of expense include hospital care (32%), physician and clinical services (20%), and prescription drugs (10%). u.s. costs in 2016 were substantially higher than other oecd countries, at 17.2% gdp versus 12.4% gdp for the next most expensive country (switzerland). for scale, a 5% gdp difference represents about $1 trillion or $3,000 per person. some of the many reasons cited for the cost differential with other countries include: higher administrative costs of a private system with multiple payment processes; higher costs for the same products and services; more expensive volume/mix of services with higher usage of more expensive specialists; aggressive treatment of very sick elderly versus palliative care; less use of government intervention in pricing; and higher income levels driving greater demand for health care. healthcare costs are a fundamental driver of health insurance costs, which leads to coverage affordability challenges for millions of families. there is ongoing debate whether the current law (aca/obamacare) and the republican alternatives (ahca and bcra) do enough to address the cost challenge. overview both the republican house ahca and senate bcra bills have proposed major reforms relative to current law (aca) that would substantially reduce the number of persons covered, moderately lower the budget deficit over a decade, reverse the tax increases on the top 5% (mainly the top 1%), dramatically cut medicaid payments (25-35%) that benefit lower-income persons, and expand choice by allowing lower quality insurance to be purchased at lower prices for the young and middle-aged. key provisions of the republican senate bcra take effect over several years and include: eliminate employer and individual mandates and related penalties, substituting a one-time premium increase of 30% for persons that were without coverage previously for a specified time period (63 days). states would be allowed more flexibility in establishing essential health benefits (i.e., insurance policy content). change tax credit/subsidy formulas used to help pay for insurance premiums (initially age-based, later modified to income-based) and eliminate a "cost-sharing subsidy" that reduced out-of-pocket costs. provide funding to health insurers to stabilize premiums and promote marketplace participation, via a "long-term state stability and innovation program" with features analogous to a high-risk pool. reduce income ceiling used for medicaid eligibility and substitute a tax credit for those below 100% of the poverty line. reduce medicaid payments relative to current law, by capping the growth in per-enrollee payments for non-disabled children and non-disabled adults, by using a lower inflation index. repeal taxes on high-income earners established under aca/obamacare, repeal the annual fee on health insurance providers, and delay the excise tax on high premium health plans (the so-called "cadillac tax"). allow insurers to charge premiums up to five times as much to older people vs. young people, instead of three times, unless the state sets a different limit. remove federal cap on the share of premiums that may go to insurers' administrative costs and profits (the "minimum medical loss ratio"). public opinion regarding the republican house (ahca) and senate (bcra) bills was very negative (i.e., opposed), with approval ratings between 12 and 38%, and disapproval ratings between 41% and 62%, measured between march and june 2017 (refer to "specific poll results" table below for sources). views were split along party lines. for example, the monthly kaiser family foundation health tracking poll for may 2017 indicated that: more view the republican ahca unfavorably (55%) than favorably (31%). views are split along party lines, with % in favor of ahca: democrats 8%, independents 30%, republicans 67%. although historically more people viewed the current law (aca/"obamacare") unfavorably than favorably, in may 2017 more had a favorable view (49%) than unfavorable (42%). more favorably view the aca/obamacare (49%) than the republican ahca (31%). health care experts from across the political spectrum – liberal, moderate, and conservative – agreed that the house republican health care bill was unworkable and suffered from fatal flaws, although specific objections varied depending on ideological perspective. experts agreed that the bill fell far short of the goals laid forth by president donald trump during his 2016 campaign – "affordable coverage for everyone; lower deductibles and health care costs; better care; and zero cuts to medicaid" – because the bill was (1) "almost certain" to reduce overall health care coverage and increase deductibles and (2) would phase out the medicaid expansion. among the key concerns identified by health-care experts were that (1) the tax credits funded at the level proposed in the bill are insufficient to pay for individual insurance, and could lead to americans dropping out of the health care market; (2) the bill's elimination of the aca's community rating provision (barring insurance companies from charging older people more than three times what they charge younger people) would increase cost disparities between age groups and would increase premiums for americans more prone to illness; (3) the dropping of healthy people from the health insurance market (adverse selection) could lead to insurer "death spirals" that would decrease choice; and (4) the phaseout

of the medicaid expansion was likely to result in a loss of healthcare for poorer americans. estimated impact of the republican ahca and bcra cbo estimated in may 2017 that under the republican ahca, about 23 million fewer people would have health insurance in 2026, compared with current law. ahca (republican healthcare bill) impact on income distribution, as of the year 2022. net benefits would go to families with over $50,000 income on average, with net costs to those below $50,000. impact on the budget deficit of the republican healthcare bills (ahca and bcra). cuts to medicaid more than offset tax cuts, resulting in moderate deficit reduction. changes in medicaid spending under the better care reconciliation act compared with cbo's extended baseline share of nonelderly adults without health insurance coverage under current law and the better care reconciliation act, by age and income category, 2026 cbo projections of persons without health insurance under 65 years of age (%) under various legislative proposals and current law. the nonpartisan congressional budget office has evaluated ("scored") the ahca (initial and revised) and bcra with respect to health insurance coverage, impact on the annual budget deficit, cost of insurance, and quality of insurance (i.e., the actuarial value, or percent of costs a given policy is expected to cover). other groups have evaluated some of these elements, as well as the distributional impact of the tax changes by income level and impact on job creation. the results of these analyses are as follows: health insurance coverage according to each of the cbo scores, passage of the republican bills would result in a dramatic reduction in the number of persons with health insurance, relative to current law. persons with healthcare insurance coverage would be reduced by 14 million in 2018, 21 million in 2020, and 24 million in 2026 relative to current law. in 2018, most of the reduction would be caused by the elimination of the penalties for the individual mandate, both directly and indirectly. later reductions would be due to reductions in medicaid enrollment, elimination of the individual mandate penalty, subsidy reduction, and higher costs for some persons. by 2026, an estimated 49 million people would be uninsured under the senate bcra, versus 28 million under current law. non-cbo coverage estimates according to a report viewed by politico, the white house office of management and budget's own analysis of the ahca estimated that 26 million people would under ahca lose coverage over the next decade. according to white house communications director michael dubke, the analysis tried to use similar methodology as the cbo. other individuals and organizations such as the brookings institution and s&p estimated sizable coverage losses due to the ahca. according to a report published by the center on budget and policy priorities, the legislation would lead to 3 million more children (defined as persons under 18 years old) losing healthcare coverage. budget deficit cbo has evaluated the impact on the budget deficit in each of its scores, generally finding a moderate reduction relative to current law: cbo ahca march 13: the ahca would reduce the deficit relative to current law by $337 billion over a decade. approximately $1.2 trillion less would be spent over that time, while $900 billion less in tax revenue would be collected. medicaid spending would be cut considerably. taxes on the roughly top 5% of income-earners under current law would considerably drop. cbo ahca revised march 24: in negotiations after the initial report, the law was modified such that the cbo estimated the deficit reduction would total about $150 billion over a decade. cbo bcra june 26: a reduction of $321 billion over a decade. for scale, cbo has estimated that the u.s. will add approximately $9.4 trillion to the debt total over the 2018-2027 period, based on laws in place as of january 2017. the $321 billion therefore represents a reduction of about 3.5% of the total debt increase over the decade, while the $150 billion is about 1.6%. insurance costs and quality there are many variables that affect premiums, deductibles, and out-of-pocket amounts, including (among others) age and health of plan participants, availability of subsidies, funding for high-risk pools, required insurance coverage elements, lifetime limits, maximum ratio of prices charged to older persons versus younger, and the quality of insurance offered. regarding quality, the "actuarial value" is an estimate of the percentage of total cost that a particular insurance plan is expected to cover. cbo reported that: cbo ahca march 13: insurance premiums would rise initially relative to current law, but would be reduced in the future moderately: "starting in 2020, the increase in average premiums from repealing the individual mandate penalties would be more than offset by the combination of several factors that would decrease those premiums: grants to states from the patient and state stability fund (which cbo and jct expect to largely be used by states to limit the costs to insurers of enrollees with very high claims); the elimination of the requirement for insurers to offer plans covering certain percentages of the cost of covered benefits; and a younger mix of enrollees. by 2026, average premiums for single policyholders in the nongroup market under the legislation would be roughly 10 percent lower than under current law..." cbo ahca march 13: premium changes would vary significantly by age: "under the legislation, insurers would be allowed to generally charge five times more for older enrollees than younger ones rather than three times more as under current law, substantially reducing premiums for young adults and substantially raising premiums for older people." this would lead to a mix of younger enrollees, one of the reasons for the lower overall premiums over the longer-term. cbo bcra june 26: "in 2020, average premiums for benchmark plans for single individuals would be about 30 percent lower than under current law. a combination of factors would lead to that decrease—most important, the smaller share of benefits paid for by the benchmark plans and federal funds provided to directly reduce premiums. that share of services covered by insurance would be smaller because the benchmark plan under this legislation would have an actuarial value of 58 percent beginning in 2020. that value is slightly below the actuarial value of 60 percent for "bronze" plans currently offered in the marketplaces." cbo bcra june 26: "under this legislation, starting in 2020, the premium for a silver plan would typically be a relatively high percentage of income for low-income people. the deductible for a plan with an actuarial value of 58 percent would be a significantly higher percentage of income—also making such a plan unattractive, but for a different reason. as a result, despite being eligible for premium tax credits, few low-income people would purchase any plan..." cbo bcra june 26: cbo has provided a summary (table #5 on page 48) that compares premiums under current law (aca) with the bcra, for different ages and income levels, for bronze and silver plans. for example, a single individual 40 years old with annual income of $56,800 (375% of poverty level) would pay $5,000 for a bronze plan under bcra vs. $5,500 under current law, but receives a lower actuarial value plan of 58 versus 60. for that person, silver plans would be basically identical in terms of cost and quality. relative to current law, persons aged 64 years old would pay considerably more for either a bronze or silver plan under bcra, while a 21 year old would pay considerably less under bcra, due in part to relaxing the rules on how much more older persons can be charged relative to younger. non-cbo cost estimates the chief actuary of centers for medicare and medicaid services of the department of health and human services released a report on june 13, 2017 providing their estimates of the legislation's impact. they estimated that gross premiums would decrease by 13%, but net premiums, the amount paid by consumers after federal subsidies, would increase by 5% by 2026. taxation and income inequality the current law (aca) established two taxes on high-income individuals (defined as income over $200,000 for individuals or $250,000 for couples, roughly the top 6% of earners), via a 0.9% medicare payroll surtax on earnings over that threshold and a 3.8% tax on net investment income. the latter tax is steeply progressive, with the top 1% paying 90% of the tax, as investment income is highly concentrated with the wealthy. the aca also established a penalty tax (related to the individual mandate) for individuals without adequate insurance, an excise tax on employers with 50 or more workers who offer insufficient coverage, annual fees on health insurance providers, and the "cadillac tax" (yet to be implemented as of 2017) on generous employer-sponsored health plans. combined with subsidies that primarily benefit low-income households, the law significantly reduced income inequality after taxes and transfers. the republican bills (ahca and bcra) essentially repeal all of the taxes, penalties and fees and postpone the "cadillac tax" further. the tax policy center estimated in march 2017 that the ahca would significantly reduce taxes for the wealthy, with those irs tax units (an approximation for families) earning over $200,000 per year (the top 6%) receiving 70.6% of the benefit or a reduction of $5,680 in annual taxes on average. those with incomes over $1 million (the top 0.4%) would see a tax decrease of $51,410 on average, receiving 46% of the benefit. in general, those with incomes over $50,000 would see a tax cut, while those with income below $50,000 would see a tax increase. those with income below $10,000 would see a tax cut as well, but this benefit would be offset overall by reductions in medicaid availability. the effects overall would worsen income inequality. the center on budget and policy priorities (cbpp) reported that "the house bill would represent the largest transfer in modern u.s. history from low- and moderate-income people to the very wealthy." cbpp also wrote: "millionaires would gain roughly $40 billion in tax cuts annually...roughly equivalent to the $38 billion that 32 million households in poverty would lose from cuts to their tax credits and medicaid." medicaid medicaid is the u.s. program for low-income children, adults, seniors and people with disabilities, covering one in five americans. it is the primary payer of nursing home care. the aca (current law) expanded medicaid eligibility; 31 states and the district of columbia implemented the expansion. approximately 41% of medicaid enrollees are white, 25% are hispanic, and 22% are black. the proportion of white recipients in key swing states are 67% in ohio, 59% in michigan, and 58% in pennsylvania. about 48% of recipients are children (18 or under). most of the cost savings (deficit reduction) under ahca and bcra is due to reductions in medicaid spending and coverage relative to current law. cbo estimated that there would be 15 million fewer medicaid enrollees relative to current law by 2026, the largest component of the reduced coverage discussed above. cbo estimated that medicaid spending under bcra would be 26% lower in 2026 and 35% lower in 2036 relative to current law. this would reduce medicaid spending in 2036 from 2.4% gdp under current law to 1.6% gdp. the reductions are driven by reduced funding to states for those who became covered under the medicaid expansion in the current law (aca), reducing the inflation index used to compute per-enrollee payments to states, and eliminating coverage mandates. while the nominal spending amounts continue to rise but at a slower pace, adjusted for inflation the amounts are actually cut moderately relative to 2017 levels. jobs according to researchers at the milken institute school of public health at george washington university, the ahca legislation would lead to a loss of 924,000 jobs by 2026. the group also studied the bcra, which would cost an estimated 1.45 million jobs by 2026, including over 900,000 in healthcare. the stimulus effects from tax cuts would initially create jobs, but would be offset by the larger declines in spending as the various parts of the law take effect. further, gross state products would be $162 billion lower in 2026. states that expanded medicaid would bear the brunt of the economic impact, as government funds would be reduced more significantly. exchange stability under both the aca (current law) and the ahca,

cbo reported that the health exchange marketplaces would remain stable (i.e., no "death spiral"). yale law school professor abbe r. gluck, the director of the solomon center for health law and policy, writes that republican elected officials have taken a variety of steps to "sabotage" the aca, creating uncertainty that has likely adversely impacted enrollment and insurer participation, and then insisting that the exchanges are in difficulty as an argument for repealing the aca. the washington post columnist dana milbank has made the same argument. health insurance writer louise norris states that republicans sabotaged the aca through: lawsuits, both successful (medicaid expansion limited) and unsuccessful (mandates and insurance subsidies upheld). lawsuits pending, such as whether cost-sharing subsidies must be paid. president trump is threatening not to pay these subsidies. prevention of appropriations for transitional financing ("risk corridors") to steady insurance markets, resulting in the bankruptcy of many co-ops offering insurance. weakening of the individual mandate through irs-related executive orders to limit penalty collection. reduction to funding for advertising for the 2017 exchange enrollment period. ongoing insistence, despite cbo assertions to the contrary, that the exchanges are unstable or in a "death spiral". other impact social security expenditures would decrease due to earlier mortality: "cbo also estimates that outlays for social security benefits would decrease by about $3 billion over the 2017–2026 period." medicaid expenditures would increase due to reduced access to birth control. "by cbo's estimates, in the one-year period in which federal funds for planned parenthood would be prohibited under the legislation, the number of births in the medicaid program would increase by several thousand, increasing direct spending for medicaid by $21 million in 2017 and by $77 million over the 2017–2026 period." two reports from the center for budget and policy priorities concluded that the acha would have shifted $370 billion in medicaid costs to the states, which would have then been forced to cut coverage and services, and would make health insurance far less affordable in high-cost states, particularly 11 states in which tax credit would have been more the halved. every year one in 830 uninsured americans die in a way which could have been prevented with better health care. a congressional budget office report suggests an extra 16 million people would be left uninsured leading to 19,277 preventable deaths. other uninsured people would develop painful chronic conditions or permanent disabilities which could have been prevented with health insurance. other provisions the bills would allow states to continue to enroll persons in the aca medicaid expansion through january 1, 2020, and would disallow further enrollment after that date. the ahca will include age-based tax credits for those who earn less than $75,000, or $150,000 for joint filers. the bill would have required insurance companies to cover pre-existing conditions. the ahca used a standard of 'continuous coverage', defined by a 63-day coverage gap, where an individual who currently has insurance and is changing insurers will not pay a higher rate with their new insurer. individuals who wished to buy insurance but were outside of the coverage gap would have paid a 30 percent premium surcharge for one year and then return to standard rates. both healthy and the sick were required to pay the surcharge, which may have caused healthier persons to remain outside of the market, causing overall health care costs to rise (see adverse selection, high-risk pool). accuracy of cbo coverage forecasts in general, cbo has been more accurate than other significant forecasting entities regarding the coverage impact of the aca/obamacare. it has been very accurate with respect to forecasting the number of uninsured and change in uninsured, but off significantly in forecasting the number of persons who would enroll in the exchanges. instead, many more persons retained their employer-based plan than cbo had anticipated. cbo revises its forecasts for health insurance coverage due to current law (aca/obamacare) annually. cbo forecast in february 2010 that there would be 31 million fewer uninsured in 2017 due to aca; the 2016 forecast for 2017 was 24 million (7 million or 23% difference). the kaiser family foundation estimated in october 2015 that 3.1 million additional people were not covered because of 19 states that rejected the medicaid expansion in the wake of a 2012 supreme court decision that preserved their existing medicaid funding whether or not they expanded coverage. this 2012 event accounts for much of the difference; cbo reduced its medicaid coverage expansion forecast for the year 2017 by 5 million between 2010 and 2013. cbo forecast in february 2013 that there would be 29 million uninsured in 2017; the 2017 forecast is 27 million (2 million or 7% difference). cbo forecast in february 2013 that there would be 11 million additional persons covered by medicaid in 2017; the 2017 forecast is 12 million (1 million or 9% difference). cbo forecast in february 2013 that there would be 26 million additional persons covered under the exchanges in 2017; the 2017 forecast is 10 million (16 million or 62% difference). regarding the inaccuracy of their exchange forecast, cbo explained that one of their assumptions was that more employers would choose to drop their coverage in favor of the exchanges than has actually occurred. cbo wrote in march 2017 that: "...most of the people who are no longer projected to obtain insurance through the marketplaces will instead be covered by employment-based insurance." history trump discussing with lawmakers on replacing the aca at the white house, march 2017. initial version the two bills that constituted the ahca were introduced into the house energy and commerce committee and the house ways and means committee on march 8, 2017 and passed both committees the next day. both committees approved the ahca on a party-line vote without a cbo report, prompting criticism from democrats. house minority leader nancy pelosi argued that the bill should not proceed through congress until the cbo completed its analysis of the bill. representative richard neal, the ranking democratic member of the house ways and means committee, stated: "to consider a bill of this magnitude without a cbo score is not only puzzling and concerning, but also irresponsible." trump administration officials, including budget director mick mulvaney and economic adviser gary cohn, preemptively attacked the cbo, with cohn saying that the cbo's score would be "meaningless". these criticisms from the white house are unusual: prior administrations of both parties had refrained from questioning the cbo's credibility, and many members of congress respect the cbo as a neutral body. the bill next went to the house budget committee, which passed it on march 16 by 19 to 17 votes, with three republicans from the conservative freedom caucus joining democrats in opposition. it next went to the rules committee, which sets the terms of the debate before a bill comes to the full house. a house vote was initially scheduled for march 23, but was delayed for at least a day after republican leaders were unable to find enough votes for passage. on march 24, with both moderate and far-right republican lawmakers opposing the bill, speaker paul ryan and president trump chose to withdraw the bill from consideration rather than go through with a full house vote that would have failed. the comparatively "lightning fast" legislative movement for the ahca through the house was in contrast to the affordable care act, which took months of negotiations, committee markup, and debate before passage in 2010. the quick process prompted complaints from democrats "that the republicans were rushing to approve a repeal bill without hearing from consumers, health care providers, insurance companies or state officials – and without having estimates of the cost or the impact on coverage from the congressional budget office". in house committees, democratic representatives offered more than 100 amendments to the legislation, including amendments that "would have required the law to guarantee no one would lose insurance, hospitals would not see an increase in uncompensated care, the deficit would not increase, taxes would not go up on people making less than $250,000, and that people over 55 years old would not lose benefits or pay higher out-of-pocket costs." democratic representative joe crowley of new york offered an amendment that during the 2010 affordable care act debate had been proposed by republican representative kevin brady of texas, requiring "that the bill be posted online for 72 hours before any votes were taken on it, and that every member put a statement in the congressional record stating he or she had read the bill." all of these democratic amendments were rejected, as brady (the chairman of the house ways and means committee) ruled that the amendments were "not germane" to the bill, and the republican majority repeatedly upheld these rulings. division among house republicans in the days leading up to the vote, which was originally scheduled for march 23, 2017, there was increased division among house republicans over the replacement, causing concerns among republican party leadership over having the votes needed to pass the bill. among republican defectors from the bill, the largest opposition came from members of the house freedom caucus, which consists of some of the most conservative members in the house. the freedom caucus members, among their primary objections to the bill, were not convinced that the healthcare replacement effectively abolished some elements of the affordable care act, most prominently the essential health benefits. to achieve success in the house, republicans could not afford more than twenty-one members of their own party voting against the bill, and several days before the vote, dissent within the party, largely from the freedom caucus, was a significant threat to its passage. beyond the conservative members of the freedom caucus, there was continued opposition to the bill from more moderate republicans in the house, such as from members of the center-right tuesday group, where there were concerns about loss of coverage and the potential of rising insurance costs. amid the division between the republicans, the party leadership, which was led by house speaker paul ryan, attempted to ease concerns among the freedom caucus and others. president trump also held numerous meetings with republicans in the house leading up to the vote, though after negotiations with the freedom caucus over the aca's essential health benefits, there was still a considerable amount of opposition from moderates and members of the freedom caucus alike. on the day of the scheduled vote, which coincided with the seven-year anniversary of the aca's signing into law, party leadership continued to struggle with getting the required votes for the bill, and the vote was rescheduled for the following day, march 24, 2017, as requested by the white house. withdrawal ahead of vote the night before the rescheduled vote, trump, in a final effort to negotiate with those opposing the bill, announced to the house republicans that the vote the following day would be their only chance to repeal the affordable care act, a goal long sought after by republicans in congress. the following morning the bill was brought to the house floor after being approved by the house rules committee for four hours of debate preceding the vote, which was expected in the afternoon. it was reported that a couple hours before the expected vote, ryan made a sudden visit to the white house to meet with trump, in which ryan told trump that the bill did not have enough votes to pass in the house. shortly after the time of the expected vote it was announced that the republicans were withdrawing the ahca from consideration, a decision made after ryan met with trump. following the withdrawal, ryan stated in a press conference that the country is "going to be living with obamacare for the foreseeable future", while trump said that it was tough to pass the bill without support from democrats; ryan and trump both said they were going to move forward on other policy issues. revised version through the various iterations of bill it has been nicknamed variously as trumpcare, ryancare, republicare, and pejoratively as obamacare-lite, and wealthcare. map of the house of representatives' vote on h.r. 1628, the "american health care act of 2017", on may 4, 2017 (sorted by whoever represents each congressional district): 217 yes (republican) 20 no (republican) 1 not voting (republican) 4 vacant seat 193 no (democrat) macarthur amendment in april

2017, house republicans tried to reconcile their divisions with the proposed macarthur amendment. the macarthur amendment, developed by representative tom macarthur of the tuesday group (representing more moderate republicans) and representative mark meadows of the house freedom caucus (representing the hard-line right). the language of the proposed amendment became available on april 25, 2017. the amendment allows insurers to charge enrollees in their 50s and early 60s more than younger enrollees. it also allows states to waive essential health benefits and certain sections of the community rating program. as revised by the macarthur amendment, the acha weakens protections for patients with preexisting conditions; under this version of the bill, insurers would be able to charge people significantly more if they had a pre-existing condition. passage in house on may 3, house republicans announced that they had enough votes to pass the bill, after amending it to include an additional $8 billion over five years to subsidize insurance for people with pre-existing conditions. on may 4, 2017, the house of representatives voted in favor of repealing the patient protection and affordable care act and passing the american health care act with a narrow vote of 217 to 213. upon the bill's passing, congressional republicans rushed to the white house for a televised celebration. 217 republican congressmen voted for the bill, while all 193 democrats and 20 republicans voted against it. most of the republicans who voted against the bill are members of the centrist tuesday group, and only one member of the freedom caucus voted against the bill. senate bills the senate developed several amendments / bills to modify the ahca bill that had passed in the house, but none had received enough votes in the senate to pass as of july 28, 2017. these included the: better care reconciliation act of 2017 (bcra), which was not voted on in its initial form, but as modified based on changes led by senator ted cruz, was defeated in a 43–57 vote. obamacare repeal reconciliation act of 2017 (orra), which would have essentially repealed obamacare, and was defeated in a 45–55 vote. health care freedom act of 2017 (hcfa) or "skinny repeal", which would have repealed the individual mandate but not the medicaid expansion, and was defeated in a 49–51 vote. under the various senate bills, the cbo estimated that relative to current law, millions more would be without health insurance and the budget deficit would be reduced moderately (roughly 5% or less over a decade). the effect on insurance premiums would vary widely in the exchange marketplaces (the non-employer market created by obamacare) depending on the specific legislation. better care reconciliation act of 2017 (bcra) in the senate, majority leader mitch mcconnell appointed a group of 13 republican senators to prepare a bill. democrats, independents, and other republicans were excluded from the process and given no information until the new bill was released on june 22, 2017. the senate bill is called the better care reconciliation act of 2017. the bill's differences from the house bill reflected divergent opinions within the republican caucus. the phase-out of the medicaid expansion would be made more gradual, but funding for medicaid as it stood before the aca would be reduced. eligibility for premium subsidies would be tightened for middle-class recipients, but some aid would be extended to enrollees below the poverty level in states that did not expand medicaid. the ahca would have replaced the individual mandate with a provision that would allow an insurer to add a 30 percent surcharge to the premium if an individual goes without coverage for 63 days or more. the original draft of the bcra would have repealed the aca's individual mandate but it did not include the ahca's continuous coverage provision. a few days after the draft's release, it was amended to provide that someone who went without coverage for 63 days or more would have to wait six months to obtain new coverage. obamacare repeal reconciliation act of 2017 (orra) the cbo evaluated the bill, concluding that relative to current law it would reduce the budget deficit by $473 billion over 10 years (roughly 5%), increase the number of uninsured by 17 million in 2018 and 27 million in 2020, and increase average premiums in the marketplaces (non-group/non-employer-based) by roughly 25% in 2018 and by 50% in 2020. roughly half the u.s. population would live in areas with no insurers participating in the marketplaces. health care freedom act of 2017 (hcfa) on july 14, senator john mccain had surgery to remove a blood clot. the next day, mcconnell announced that the vote on proceeding to consider the bill would be deferred until mccain returned from his recuperation period. senate democrats urged the republican leadership to "use this additional time to hold public hearings ... on the policies in the bill, especially the radically conservative cruz/lee proposal released to the public only five days ago." on july 17, senators mike lee (r-ut) and jerry moran (r-ks) came out against the bill, joining rand paul and susan collins who already opposed it, making it impossible for republicans alone to pass it through. it was later revealed that john mccain was diagnosed with brain cancer, which was discovered during his surgery. on july 25, senate republicans released a significantly stripped-down version of the healthcare bill, containing only fundamental provisions of the repeal that all republicans agreed on, designed to only pass the motion to proceed to floor debate, still allowing further amendments to be added on the floor before final passage. the motion to proceed on this version of the bill passed in a 51–50 vote, with a tie-breaking vote cast by vice president mike pence; senators susan collins and lisa murkowski diverged from their party and voted against the measure. senator john mccain traveled to washington for the vote, returning to senate for the first time since his cancer diagnosis. sen. mitch mcconnell amendment called the health care freedom act; also known as "skinny repeal" cbo score of the "skinny bill" after several failed votes within 24 hours of the bill being passed to floor debate, including a repeal without replace bill, the republican senate leadership attempted to pass the health care freedom act (hcfa), referred to as a "skinny repeal." the skinny repeal, which was still being drafted on july 27, only repeals some provisions of the aca, among them the individual mandate, requiring that all americans buy insurance or pay a tax penalty, and parts of the employer mandate, which requires employers with greater than 50 employees to pay for health care for their employees. the bill was brought to the floor vote and the vote reached the predicted 49–50, majority being in favor of keeping the aca as is. a tie would have allowed vice president mike pence to cast a final tie breaking vote. the final vote was to be mccain, who walked to the floor in near silence and held out his hand. in a very climactic moment, he gave a thumbs down and the bill was rejected 49–51, with two other republican senators, susan collins and lisa murkowski, siding with all democrats and independents. graham-cassidy on september 13, 2017, senators graham, cassidy, heller, and johnson released a draft amendment to the bill that "repeals the structure and architecture of obamacare and replaces it with a block grant given annually to states". however, it was not voted upon due to lack of support. on october 12, 2017, due to this failure of congress to pass a repeal, president donald trump issued executive order 13813, titled an executive order to promote healthcare choice and competition. reaction initial version president trump endorsed the bill after its release, calling it "our wonderful new healthcare bill" on twitter. speaker of the house paul ryan referred to the bill as a "conservative wish list" that would provide for "monumental, exciting conservative reform". conservative economist douglas holtz-eakin described the ahca as "a good start". but conservative members of the republican party quickly raised skepticism about the proposed reform as they would prefer a complete repeal of the ppaca. the white house sent mick mulvaney, executive of the office of management and budget, to convince members of the house freedom caucus to support the legislation. according to numerous reports, mulvaney was unsuccessful. shortly after the meeting caucus chairman mark meadows said, "no new position tonight. our position is the same. we believe we need to do a clean repeal bill." a number of conservative groups have also criticized the bill for not being enough of a repeal, calling it "obamacare 2.0". the koch brother-supported organizations americans for prosperity and freedom partners have indicated their intention to put together a multimillion-dollar fund in support of re-election campaigns for conservative lawmakers who take a stand against the bill. the aarp released a statement opposing the bill. stating, "on top of the hefty premium increase for consumers, big drug companies and other special interests get a sweetheart deal". the american medical association released a statement opposing the bill. america's essential hospitals, american hospital association, association of american medical colleges, catholic health association of the united states, children's hospital association, federation of american hospitals, and national association of psychiatric health systems also stated their opposition in a joint letter. conservative groups, including heritage action, the cato institute, americans for prosperity, freedomworks, and the tea party patriots all oppose the bill. progressive groups, including moveon.org, american bridge, the center for american progress, and our revolution, were resolutely opposed to the bill, as expected. economist and the new york times columnist paul krugman stated that the bill's "awfulness is almost surreal", writing that what republican congressional leadership "came up with instead was a dog's breakfast that conservatives are, with some justice, calling obamacare 2.0. but a better designation would be obamacare 0.5, because it's a half-baked plan that accepts the logic and broad outline of the affordable care act while catastrophically weakening key provisions." on march 23, 2017 (the seventh anniversary of aca and one day prior to the vote on the american health care act), former president obama hailed the successes of the affordable care act, including 20 million more americans insured, preexisting conditions covered, young people staying on their parents' plans until 26, lowered costs for women's health care and free preventive care. later versions president trump celebrating the house passage of the american health care act with vice president mike pence and a number of key republicans in the rose garden after the house passed the ahca, but before any legislation passed the senate, republican congressmen gathered with trump to celebrate in the rose garden. in his speech, trump described the bill as "very incredibly well-crafted." republican senators expressed less enthusiasm about the bill and opted to draft their own bill instead of taking up the house's version. congressional democrats and interest groups, such as the aarp, american medical association, aclu, and planned parenthood, expressed their opposition to the bill. at a lunch with senate republicans in june 2017, trump reportedly called the ahca "mean, mean, mean" and a "son of a bitch". he reportedly implored the senators to make their version of the bill "more generous, more kind." later that month, trump confirmed that he had used the term "mean" to describe the bill. on june 16, 2017, a bipartisan group of seven current governors sent a letter to senate majority and minority leaders mitch mcconnell and chuck schumer criticizing the house's legislation and requesting a bipartisan effort in the senate to reform healthcare. the signatories include governors john kasich (ohio), steve bullock (montana), brian sandoval (nevada), john bel edwards (louisiana), john hickenlooper (colorado), charlie baker (massachusetts), and tom wolf (pennsylvania). when the senate bill text (bcra) was released, four conservative republican senators – ted cruz, ron johnson, mike lee, and rand paul – released a joint statement saying that they would not vote for the bill in that form. this was seen as an attempt to move the bill to the right by bringing pressure on mcconnell. the next day, senator dean heller of nevada announced his opposition. he emphasized the effect on medicaid, noting that the bill's cuts to medicaid would "pull the rug" out from under many nevada residents. public opinion an analysis of national polls by mit

political scientist christopher warshaw and stanford political economist david broockman showed that the ahca "is the most unpopular piece of major legislation congress has considered in decades" more so than troubled asset relief program legislation ("the bank bailout") and much more unpopular than the aca. their estimates of survey results indicate that there is not majority support for the bill in any state. public opinion polls show high levels of public opposition to the republican health-care proposals (the ahca in the house and the bcra in the senate). approval ratings vary between 12 and 38%, and disapproval ratings between 41% and 62%, measured between march and june 2017 (refer to "specific poll results" table below for sources). views were split along party lines. for example, the monthly kaiser family foundation health tracking poll for may 2017 indicated that: more view the republican ahca unfavorably (55%) than favorably (31%). views are split along party lines, with % in favor of ahca: democrats 8%, independents 30%, republicans 67%. although historically more people viewed the current law (aca/"obamacare") unfavorably than favorably, in may 2017 more had a favorable view (49%) than unfavorable (42%). more favorably view the aca/obamacare (49%) than the republican ahca (31%). specific poll results the following are the results of polls of public opinion regarding the ahca. poll source fieldwork support/approve oppose/disapprove start end cbs news september 21 september 24 20% 20 52% 52 public policy polling september 20 september 21 24% 24 50% 50 public policy polling august 18 august 21 25% 25 57% 57 the economist/yougov july 31 august 1 23% 23 53% 53 quinnipiac university july 27 august 1 25% 25 64% 64 cbs news/yougov july 26 july 28 11% 11 41% 41 fox news july 16 july 18 25% 25 55% 55 the economist/yougov july 15 july 18 28% 28 48% 48 public policy polling july 14 july 17 20% 20 57% 57 associated press-norc july 13 july 17 22% 22 51% 51 monmouth university july 13 july 16 27% 27 56% 56 huffpost/yougov july 12 july 14 18% 18 44% 44 huffpost/yougov july 12 july 14 16% 16 45% 45 morning consult/politico july 7 july 9 40% 40 47% 47 kaiser family foundation july 5 july 10 28% 28 61% 61 the economist/yougov june 25 june 27 28% 28 48% 48 fox news june 25 june 27 27% 27 54% 54 usa today/suffolk university june 24 june 27 12% 12 45% 45 investor's business daily/tipp june 23 june 29 33% 33 62% 62 quinnipiac university june 22 june 27 16% 16 58% 58 morning consult/politico june 22 june 24 38% 38 45% 45 npr/pbs newshour/marist june 21 june 25 17% 17 55% 55 the economist/yougov june 18 june 20 28% 28 45% 45 nbc news/wall street journal june 17 june 20 16% 16 48% 48 morning consult/politico june 15 june 19 35% 35 50% 50 cbs news june 15 june 18 32% 32 59% 59 kaiser family foundation june 14 june 19 30% 30 55% 55 huffpost/yougov june 13 june 13 24% 24 45% 45 reuters/ipsos june 9 june 13 30% 30 41% 41 public policy polling june 9 june 11 24% 24 55% 55 the economist/yougov june 4 june 6 29% 29 47% 47 quinnipiac university may 31 june 6 17% 17 62% 62 the economist/yougov may 27 may 30 28% 28 48% 48 quinnipiac university may 17 may 23 20% 20 57% 57 kaiser family foundation may 16 may 22 31% 31 55% 55 the economist/yougov may 13 may 16 31% 31 47% 47 public policy polling may 12 may 14 25% 25 52% 52 nbc news/wall street journal may 11 may 13 23% 23 48% 48 the economist/yougov may 6 may 9 31% 31 47% 47 huffpost/yougov may 6 may 6 31% 31 44% 44 quinnipiac university may 4 may 9 21% 21 56% 56 morning consult/politico may 4 may 6 38% 38 42% 42 huffpost/yougov march 25 march 25 22% 22 52% 52 the economist/yougov march 19 march 21 31% 31 45% 45 quinnipiac university march 16 march 21 17% 17 56% 56 morning consult/politico march 16 march 19 40% 40 37% 37 huffpost/yougov march 16 march 17 24% 24 45% 45 cbs news/yougov march 15 march 17 12% 12 41% 41 fox news march 12 march 14 34% 34 54% 54 surveymonkey march 10 march 13 42% 42 55% 55 public policy polling march 10 march 12 24% 24 49% 49 morning consult/politico march 9 march 13 46% 46 35% 35 2018 elections the niskanen center stated that the gop's support for ahca in 2017 was a major factor in the party's heavy house losses in the 2018 midterm elections, costing the party its majority in the house, and snopes publicly identified 33 house republicans who were voted out of office largely due to their votes in favor of the ahca, including in states where republicans control most house seats, such as kansas and utah. comparison between versions this table describes major differences and similarities between the aca, the ahca as considered in the house in march 2017, the ahca as passed by the house on may 4, 2017, and the bcra. the kaiser family foundation has also summarized the differences in a comprehensive table. differences and similarities between the aca, ahca, bcra, and the hcfa aca ahca (march 2017) ahca (may 2017) bcra (june 2017) bcra (july 2017) hcfa (july 2017) insurance mandates individual mandate and an income tax penalty for not having insurance employer mandate on larger companies no individual or employer mandateinsurers can impose a one-year 30% surcharge on consumers with a lapse in coverage of more than 63 days no individual or employer mandatean individual with a lapse in coverage of more than 63 days can be required to wait six months before obtaining new coverage no individual mandate but incentives and subsidies for those who keep coverage employer mandate on larger companies but smaller companies who optionally comply will get little to no small business taxes no individual or employer mandate, but employers must still report aid for premiums income-based subsidies for premiums that limit after-subsidy cost to a percent of income age-based refundable tax credits for premiums, phased out for higher incomes income based refundable tax credits for premiums that limit after-subsidy cost to a percent of income income based subsidies for premiums that limit after-subsidy cost to a percent of income aid for out-of-pocket expenses tax credits for out-of-pocket expenses no tax credits for out-of-pocket expenses no tax credits for out-of-pocket expenses after 2019 tax credits for out-of-pocket expenses medicaid matching federal funds to states for anyone who qualifies expanded eligibility to 138% of poverty level income federal funds granted to states based on a capped, per-capita basis starting in 2020states can choose to expand medicaid eligibility, but would receive less federal support for those additional persons lets state impose work requirements on medicaid recipients federal funds granted to states based on a capped, per-capita basis or block grant starting in 2021federal government would pay smaller portion of cost in 2021 matching federal funds to states for anyone who qualifies expanded eligibility to 138% of poverty level income with continuous funding and incentives to expand coverage by state no changes premium age differences insurers can charge older customers up to three times as much as younger customers insurers can charge older customers up to five times as much as younger customers insurers can charge older customers up to five times as much as younger customers; states can apply for waivers exempting insurers from this limit insurers can charge older customers up to five times as much as younger customers; states can change this ratio insurers can charge older customers up to four times as much as younger customers; states can apply for waivers to reduce ratio health savings accounts individuals can put $3,400 and families can put $6,750 into a tax-free health savings account individuals can put $6,550 and families can put $13,100 into a tax-free health savings account individuals can put up to the maximum allowed for out-of-pocket costs and spouses can make additional contributions individuals with incomes below $100,000 a year can save up to $7000 for individuals and $14000 for families in a tax-free health savings account; incomes above that limit will be subject to taxes on a sliding scale individuals can put $6,550 and families can put $13,100 in hsa-eligible high-deductible health plans for three years, 2018 to 2020 "cadillac" tax cadillac tax on high-cost employer plans implemented in 2020 cadillac tax on high-cost employer plans implemented in 2025 cadillac tax on high-cost employer plans implemented in 2026 cadillac tax on high-cost employer plans implemented in 2023 other taxes 3.8% tax on investment income0.9% tax on individuals with an income higher than $200,000 or families with an income higher than $250,000 fee on health insurance providers firms based on plans 2.3% tax on medical devices repeal of all four taxes 3% tax on investment income for companies that don't buy or hire american0.7% tax on individuals and families with incomes higher than $275,000 moratorium on the medical device tax extended from december 31, 2017 to december 31, 2020 essential health benefits insurers are required to offer ten essential health benefits private plans are required to offer the ten essential health benefits.some medicaid plans are not required to offer mental health and substance abuse benefits states can apply for waivers exempting insurers from the essential health benefits requirement states could determine what qualifies as an essential health benefitsunset of essential health benefits on december 31, 2019 insurers are required to offer ten essential health benefits pre-existing conditions insurers are banned from denying coverage or charging more for pre-existing conditions each state can allow insurers to increase premiums based on pre-existing conditions after a lapse in coverage, if the state sets up a high-risk pool insurers are banned from denying coverage or charging more for pre-existing conditions insurers are banned from denying coverage or charging more for pre-existing conditions but will receive funding for unexpected losses due to this requirement dependents staying on plan dependents can stay on health insurance plan until age 26 annual and lifetime limits insurers are prohibited from setting annual and lifetime limits on individual coverage insurers may be able to place annual and lifetime limits on individual coverage insurers are prohibited for setting annual or lifetime limits on individual coverage treatment of planned parenthood and similar organizations no provisions federal payments blocked for one year no provisions federal payments blocked for one year

mumoli's sign mumoli's sign mumoli's sign (also known as a "playboy rabbit" sign) is a radiologic sign seen in the normal liver. it appears as a rabbit-shaped image caused by the confluence of the middle and right hepatic veins as they merge with the inferior vena cava. it can be seen on ultrasound images of the liver with a transverse subcostal view during deep inspiration. the image was named after nicola mumoli of the department of internal medicine, livorno hospital, livorno, italy.

cryptolepine cryptolepine cryptolepine is an alkaloid with antimalarial and cytotoxic properties, in vitro and in mice. it is able to intercalate into dna at the cytosine-cytosine sites. because of its toxicity, cryptolepine is not considered appropriate for use as an anti-malarial drug in humans. cryptolepine names preferred iupac name 5-methyl-5h-indoloquinoline identifiers cas number 480-26-2 y 3d model (jsmol) interactive image chebi chebi:3930 chembl chembl92129 chemspider 74137 kegg c09142 pubchem cid 82143 unii of1uit4rdh y comptox dashboard (epa) dtxsid6037645 inchi inchi=1s/c16h12n2/c1-18-15-9-5-2-6-11(15)10-14-16(18)12-7-3-4-8-13(12)17-14/h2-10h,1h3key: kurwkddwcjelsv-uhfffaoysa-n smiles n2=c1c(c=cc=c1)=c4c2=cc3ccccc3n4c properties chemical formula c16h12n2 molar mass 232.286 g·mol−1 except where otherwise noted, data are given for materials in their standard state (at 25 °c , 100 kpa). infobox references cryptolepine can be found in the roots of the west african plant, cryptolepis sanguinolenta.

pharmasave pharmasave pharmasave is a canadian independent pharmacy and drugstore retailer with over 800 stores across canada. pharmasave produces a line of over 700 private-label pharmasave brand products. pharmasave drugs (national) ltd.industrypharmacy, retailfounded1981 (1981)headquarterslangley, british columbiaproductsdrugs, healthcare productswebsitepharmasave.com history pharmasave was created in august 1981 through the merger of two british columbia-based pharmacy chains, united pharmacy and western drug mart. locations pharmasave's national office is located in langley, british columbia. its stores are located in nine provinces and territories across canada and are organized into 2 regions with each region having their own regional offices: west (british columbia, alberta, saskatchewan, manitoba, and yukon), and east (ontario, newfoundland and labrador, new brunswick, nova scotia, and prince edward island). management each of pharmasave's stores operates independently and they range in size from small dispensaries to large-format home healthcare pharmacies. each region has a board of directors as well as representation on the national board of directors. pharmasave's business model is one of self-governance, where pharmacy owners are elected to serve on its regional boards of directors. this way, the needs of the owners are served by other owners, and not by a separate corporate entity. the success of this model has played an important part in the attracting of new members and its growing store count across the country.

net acid excretion net acid excretion in renal physiology, net acid excretion (nae) is the net amount of acid excreted in the urine per unit time. its value depends on urine flow rate, urine acid concentration, and the concentration of bicarbonate in the urine (the loss of bicarbonate, a buffering agent, is physiologically equivalent to a gain in acid). nae is commonly expressed in units of milliliters per minute (ml/min) and is given by the following equation: n a e = v ( u n h 4 + u t a − u h c o 3 ) +u_-u_)} where variablemeaning naenet acid excretion vvolume of urine produced per unit time unh4urine concentration of ammonium utaurine concentration of titratable acid (e.g., phosphoric acid, sulfuric acid) uhco3urine concentration of bicarbonate pathology increased net acid excretion is a compensation for respiratory acidosis, while decreased net acid excretion is a compensation for respiratory alkalosis.

prauserella coralliicola prauserella coralliicola prauserella coralliicola is a gram-positive bacterium from the genus prauserella which has been isolated from the coral galaxea fascicularis from the luhuitou fringing reef in china. prauserella coralliicola scientific classification domain: bacteria phylum: actinomycetota class: actinomycetia order: pseudonocardiales family: pseudonocardiaceae genus: prauserella species: p. coralliicola binomial name prauserella coralliicolawu et al. 2014 type strain dsm 45821nbrc 109418scsio 11529 synonyms prauserella endophytica liu et al. 2015

eplerenone eplerenone eplerenone, sold under the brand name inspra, is an aldosterone antagonist type of potassium-sparing diuretic that is used to treat chronic heart failure and high blood pressure, particularly for patients with resistant hypertension due to elevated aldosterone. it is a steroidal antimineralocorticoid of the spirolactone group and a selective aldosterone receptor antagonist (sara). eplerenone is more selective than spironolactone at the mineralocorticoid receptor relative to binding at androgen, progestogen, glucocorticoid, or estrogen receptors. eplerenoneclinical datapronunciation/ɛpˈlɛrənoʊn/ trade namesinspra, epnone, dosterepother namessc-66110; cgp-30083; 9-11α-epoxymexrenone; 9,11α-epoxy-7α-methoxycarbonyl-3-oxo-17α-pregn-4-ene-21,17-carbolactoneahfs/drugs.commonographmedlineplusa603004pregnancycategory au: b3 routes ofadministrationby mouth (tablets)atc codec03da04 (who) legal statuslegal status au: s4 (prescription only) us: ℞-only pharmacokinetic databioavailability~70%protein binding~50% (33–60%) (primarily to α1-acid glycoprotein)metabolismliver (cyp3a4)metabolites6β-oh-epl, 6β,21-oh-epl, 21-oh-epl, 3α,6β-oh-epl (all inactive)elimination half-life4–6 hoursexcretionurine (67%), feces (32%)identifiers iupac name methyl (4as,4br,5ar,6as,7r,9as,9br,10r)-4a,6a-dimethyl-2,5'-dioxo-2,4,4',4a,5',5a,6,6a,8,9,9a,9b,10,11-tetradecahydro-3h,3'h-spirophenanthrooxirene-7,2'-furan]-10-carboxylate cas number107724-20-9 ypubchem cid5282131iuphar/bps2876drugbankdb00700 ychemspider10203511 yunii6995v82d0bkeggd01115 ychebichebi:31547 ychemblchembl1095097 ypdb ligandynu (pdbe, rcsb pdb)comptox dashboard (epa)dtxsid2046094 echa infocard100.106.615 chemical and physical dataformulac24h30o6molar mass414.498 g·mol−13d model (jsmol)interactive image smiles coc(=o)4c\c1=c\c(=o)cc1(c)65o6c3(c)(cc23ccc(=o)o2)45 inchi inchi=1s/c24h30o6/c1-21-7-4-14(25)10-13(21)11-15(20(27)28-3)19-16-5-8-23(9-6-18(26)30-23)22(16,2)12-17-24(19,21)29-17/h10,15-17,19h,4-9,11-12h2,1-3h3/t15-,16+,17-,19+,21+,22+,23-,24-/m1/s1 ykey:jukpwjgbannwmw-vwbfhtrksa-n y (verify) medical uses heart failure eplerenone reduces risk of death in patients with heart failure, particularly in patients with recent myocardial infarction (heart attack). hypertension eplerenone lowers blood pressure in patients with primary hypertension. eplerenone also reduces arterial stiffness and vascular endothelial dysfunction. for persons with resistant hypertension, eplerenone is safe and effective for reducing blood pressure, particularly in persons with resistant hypertension due to hyperaldosteronism. central serous chorioretinopathy eplerenone is often prescribed for people with central serous chorioretinopathy (csc). however, the most recent and largest randomized controlled trial showed that eplerenone has no significant effect on chronic csc that has been untreated for four months. adverse effects common adverse drug reactions (adrs) associated with the use of eplerenone include: hyperkalaemia, hypotension, dizziness, and reduced renal clearance. eplerenone may have a lower incidence than spironolactone of sexual side effects such as feminization, gynecomastia, impotence, low sex drive and reduction of size of male genitalia. this is because other antimineralocorticoids have structural elements of the progesterone molecule, causing progestogenic and antiandrogenic outcomes. when considering taking these medicines, it is important to note the variations in their ability to offset the nongenomic effects of aldosterone. currently, there is not enough evidence available from the randomized controlled trials on side effects of eplerenone to do a benefit versus risk assessment in people with primary hypertension. interactions eplerenone is primarily metabolized by the cytochrome p450 enzyme cyp3a4. thus the potential exists for adverse drug interactions with other drugs that induce or inhibit cyp3a4. specifically, the concomitant use of the cyp3a4 potent inhibitors ketoconazole and itraconazole is contraindicated. other cyp3a4 inhibitors including erythromycin, saquinavir, and verapamil should be used with caution. other drugs that increase potassium concentrations may increase the risk of hyperkalemia associated with eplerenone therapy, including salt substitutes, potassium supplements and other potassium-sparing diuretics. pharmacology eplerenone is an antimineralocorticoid, or an antagonist of the mineralocorticoid receptor (mr). eplerenone is also known chemically as 9,11α-epoxy-7α-methoxycarbonyl-3-oxo-17α-pregn-4-ene-21,17-carbolactone and "was derived from spironolactone by the introduction of a 9α,11α-epoxy bridge and by substitution of the 17α-thoacetyl group of spironolactone with a carbomethoxy group." the drug controls high blood pressure by blocking the binding of aldosterone to the mineralocorticoid receptor (mr) in epithelial tissues, such as the kidney. blocking the action of aldosterone decreases blood volume and lowers blood pressure. it has 10- to 20-fold lower affinity for the mr relative to spironolactone, and is less potent in vivo as an antimineralocorticoid. however, in contrast to spironolactone, eplerenone has little affinity for the androgen, progesterone, and glucocorticoid receptors. it also has more consistently observed non-genomic antimineralocorticoid effects relative to spironolactone (see membrane mineralocorticoid receptor). eplerenone differs from spironolactone in its extensive metabolism, with a short half-life and inactive metabolites. eplerenone seems to be about 50 to 75% as potent as spironolactone as an antimineralocorticoid. hence, 25 mg/day spironolactone may be equivalent to approximately 50 mg/day eplerenone. regulatory and patent history eplerenone was patented in 1983 and approved for medical use in the united states in 2002. eplerenone is currently approved for sale in canada, the us, eu, netherlands and japan. eplerenone costs an estimated $2.93 per day when treating congestive heart failure and $5.86 per day when treating hypertension.

geobacter anodireducens geobacter anodireducens geobacter anodireducens is a gram-negative, aerotolerant, exoelectrogenic, anaerobic, non-spore-forming and non-motile bacterium from the genus of geobacter like others in its genus, it is commonly found in soil and uses iron as its electron acceptor. due to its ability to generate current, it is an organism of note for microbial fuel cell research. g. anodireducens was first isolated in 2014, and characterized in 2019, both by dan sun. geobacter anodireducens scientific classification domain: bacteria phylum: thermodesulfobacteriota class: desulfuromonadia order: geobacterales family: geobacteraceae genus: geobacter species: g. anodireducens binomial name geobacter anodireducenssun et al. 2014 type strain cgmcc 1.12536, sd-1, kctc 4672 synonyms geobacter anodereducens characteristics g. anodireducens is curved bacillus, most easily distinguished from its cousins geobacter metallireducens and geobacter sulfurreducens by its osmotolerance: it is able to withstand nearly twice the salt concentration in solution. genome the genome of g. anodireducens is 3,555,507 base pairs long. the bacteria also contains a plasmid at 110,507 base pairs long. both are circular. a total of 3,564 genes have been located on the plasmid and genome combined.

caenibius tardaugens caenibius tardaugens caenibius tardaugens is an oestradiol-degrading bacterium from the family hyphomicrobiaceae which has been isolated from activated sludge from a sewage treatment plant in japan. caenibius tardaugens scientific classification domain: bacteria phylum: pseudomonadota class: alphaproteobacteria order: hyphomicrobiales family: hyphomicrobiaceae genus: caenibiushördt et al. 2020 species: c. tardaugens binomial name caenibius tardaugens(fujii et al. 2003) hördt et al. 2020 type strain atcc baa-531, ifo 16725, jcm 11434, nbrc 16725, ari-1 synonyms novosphingobium tardaugens fujii et al. 2003

evergreening evergreening evergreening is any of various legal, business, and technological strategies by which producers (often pharmaceutical companies) extend the lifetime of their patents that are about to expire in order to retain revenues from them. often the practice includes taking out new patents (for example over associated delivery systems or new pharmaceutical mixtures), or by buying out or frustrating competitors, for longer periods of time than would normally be permissible under the law. robin feldman, a law professor at uc law sf and a leading researcher in intellectual property and patents, defines evergreening as "artificially extending the life of a patent or other exclusivity by obtaining additional protections to extend the monopoly period." part of a series oncapitalism concepts austerity business business cycle businessperson capital capital accumulation capital markets company corporation competitive markets economic interventionism economic liberalism economic surplus entrepreneurship fictitious capital financial market free price system free market goods and services investor invisible hand visible hand liberalization marginalism money private property privatization profit rent seeking supply and demand surplus value value wage labour economic systems anglo-saxon authoritarian corporate dirigist free-market humanistic laissez-faire liberal libertarian market mercantilist mixed monopoly state national neoliberal nordic private raw regulated market regulatory rhine social state state-sponsored welfare economic theories american austrian chartalism mmt chicago classical institutional keynesian neo- new post- market monetarism critique of political economy critique of work marxist monetarist neoclassical new institutional supply-side origins age of enlightenment capitalism and islam commercial revolution feudalism industrial revolution mercantilism primitive accumulation physiocracy simple commodity production development advanced consumer community corporate crony finance global illiberal late marxist merchant progressive rentier state monopoly technological people adam smith john stuart mill david ricardo thomas robert malthus jean-baptiste say karl marx milton friedman friedrich hayek john maynard keynes alfred marshall vilfredo pareto leon walras ludwig von mises ayn rand murray rothbard joseph schumpeter thorstein veblen max weber ronald coase related topics anti-capitalism capitalist realism capitalist state consumerism crisis theory criticism of capitalism critique of political economy critique of work cronyism culture of capitalism evergreening exploitation of labour globalization history history of theory market economy periodizations of capitalism perspectives on capitalism post-capitalism speculation spontaneous order venture philanthropy wage slavery ideologies anarcho authoritarian classical liberalism democratic dirigisme eco humanistic inclusive liberal liberalism libertarian neo neoliberalism objectivism ordoliberalism privatism right-libertarianism third way capitalism portal business portal overview evergreening is not a formal concept of patent law; it is best understood as a social idea used to refer to the myriad ways in which pharmaceutical patent owners use the law and related regulatory processes to extend their high-earning intellectual property rights, particularly over highly profitable (either in total sales volume or price per unit) "blockbuster" drugs. thus, while the courts are an instrument frequently used by pharmaceutical brand name manufacturers to prolong their patent royalties, evergreening is rarely mentioned explicitly by judges in patent protection cases. the term usually refers to threats made to competitors about a brand-name manufacturer's tactical use of pharmaceutical patents (including over uses, delivery systems and even packaging), not to extension of any particular patent over an active product ingredient. robin feldman has documented several types of patent tactics commonly used in the u.s. by pharmaceutical companies, including evergreening, pay-for-delay, gaming the citizen petition process, and the misuse of trade secrets, among others. in one study of the prescription drug market, feldman found that 78% of new patents associated with prescription drugs were for existing drugs. controversy the evergreening process has caused some controversy in the pharmaceutical industry. in this context, evergreening may be used by manufacturers of a particular drug to restrict or prevent competition from manufacturers of generic equivalents to that drug. in 2002, an extensive and lengthy inquiry by the us federal trade commission (ftc) found, in the wake of the hatch-waxman legislation or drug price competition and patent term restoration act (which was instrumental in establishing the us generic pharmaceuticals industry), as many as 75% of new drug applications by generic drug manufacturers had been contested with legal actions under patent laws by the original brand name patent owner. these were driving up us drug costs by keeping the cheaper generic versions off the market. the ftc recommended only one evergreening injunction against a potential generic market entrant be permitted per product, and an expedited process of resolving such claims. linkage evergreening and international trade law the process of evergreening may involve specific aspects of patent law and international trade law. linkage evergreening is the process whereby pharmaceutical safety, quality and efficacy regulators are required to 'link' their normal evaluation with an assessment of whether an impending generic product may infringe an existing patent. by country australia a requirement for the ausfta to come into force was fulfilment of the article 17.10.4 linkage obligation; done by amendments to the therapeutic goods act 1989 (cth). the amendments inserted a new section 26b which required applicants for marketing approval to certify their product would not infringe a valid patent claim, or that the patent holder had been notified of the application. in response, the australian government passed anti-evergreening amendments in sections 26c and 26d of the therapeutic goods act 1989 (cth) designed to prevent patent holders from manipulating the court system to lengthen the term of the patent and delay the entry of generic pharmaceuticals into the market. they are a strong statement of australia's legitimate expectations of benefit (that is of freedom from pharmaceutical price rises due to evergreening) in this area. the chief australian negotiator of this aspect of the ausfta stated: we are not importing the hatch-waxman legislation into australian law as a result of the free trade agreement... will not extend the time of the marketing approval process, and it does not add or provide any additional rights to the patent holders in that process...there is no injunction that can be applied under this article...it will be clear in the legislation tomorrow....we are establishing a measure in the marketing approval process that will fully meet the commitments under this article." in november 2004, the us expressly signalled their disapproval of australia's implementation of article 17.10.4 in an exchange of letters between the australian minister for trade and the us trade representative on the implementation of the ausfta, in which the ustr stated: if australia's law is not sufficient to prevent the marketing of a product, or a product for an approved use, where the produce or use is covered by a patent, australia will have acted inconsistently with the agreement. we will be monitoring the matter closely, and reserve all rights and remedies as discussed below. we also remain concerned about recent amendments to sections 26b(1)(a), 26c and 26d of the therapeutic goods act of 1989. under these amendments, pharmaceutical patents owners risk incurring significant penalties when they seek to enforce their patent rights. these provisions impose a potentially significant, unjustifiable, and discriminatory burden on the enjoyment of patent rights, specifically on owners of pharmaceutical patents. i urge the australian government to review this matter, particularly in light of australia's international legal obligations. the united states reserves its rights to challenge the consistency of these amendments with such obligations. the capacity of the us to make such threats is arguably facilitated by the linkage of article 17.10.4 of the ausfta to a non-violation nullification of benefits provision. canada in 1993, under the nafta-induced canadian notice of compliance (noc) regulations, drug safety, quality and efficacy regulators at health canada were prevented from issuing an authorization for market entry, until all of the relevant patents on a brand name product had been proven to have expired. as a result, when a canadian generic company (such as apotex) submits its application to get a product approved, it also sends a notice of allegation (noa) to the patent holder claiming that no patents are being infringed. the patent holder then has 45 days in which to initiate an application in the federal court of canada, seeking an order to prohibit the relevant minister from issuing a notice of compliance to the generic manufacturer for a period of 24 months, or upon resolution of the court application, whichever is sooner. the problems with this were analysed in the royal commission on the future of health care in canada or romanow report. in 2006, the supreme court of canada ruled against an instance of drug patent evergreening, two days before the food and drug regulations extended data protection on brand-name drugs from 5 to 8.5 years. india indian patent act was amended in 2005 under obligations to trips. novartis v. union of india & others is a landmark decision, in which indian supreme court upheld rejection of novartis patent by indian patent office. the key basis for the rejection was the part of indian patent law that was created by amendment in 2005, describing the patentability of new uses for known drugs and modifications of known drugs. that section, paragraph 3d, specified that such inventions are patentable only if "they differ significantly in properties with regard to efficacy." south korea the us has achieved a similar provision to article 17.10.4 of the ausfta in article 18.9.4 of the republic of korea-united states free trade agreement (korusfta). such provisions are sometimes referred to as trips-plus meaning that they are in addition to the patent requirements of the world trade organization multilateral agreement on trade-related aspects of intellectual property rights agreement. some academics prefer to refer to them as trips-minus due to their potential, but controversial and still largely unproven, deleterious impact on public health. united states various laws have provisions to limit the practice, but as of 2018 the issue remains a concern among legislators. according to one study, 12 top-selling drugs attempted an average 38 years of patent protection, above the granted 20 years. another study found that nearly 80% of the top 100 drugs extended the duration of patent protection with a new patent. issues which prevent generics from reaching the market include: lack of availability of samples to do testing; the creates act is a bill, intended to address issues in getting samples, was passed on december 20, 2019 risk evaluation and mitigation system (rems) requirements reverse payment settlements, which involve payment to delay; these are required to be reported to the ftc for generics since 2004 and biosimilars since 2018 “citizen petitions”: citizen petitions and petitions for stay of action subject to section 505(q) of the federal food, drug, and cosmetic act allow the food and drug administration to delay action on a pending generic drug application. by law, the fda is required to prioritize these petitions. however, the citizens filing concerns are not individuals, they’re corporations. the fda recently said branded drug manufacturers submitted 92% of all citizen petitions. many of these petitions are filed near the date of patent expiration, effectively limiting potential competition for another 150 days. “authorized generics": an authorized generic is exactly the same as the brand name drug, but marketed without the brand name on the label. by law, the first generic company to market a drug gets an exclusivity period of 180 days. during this time, no other companies can market a generic product. but the company with the expiring patent is not barred from launching an “authorized generic.” by selling a drug they are already making under a different name, pharmaceutical firms are effectively extending their monopoly for another six months. regulation the main arguments in favor of governments regulating against evergreening are that rapid entry of multiple generic competitors after patent expiry is likely to lower prices and facilitate competition, and that eventual loss of monopoly was part of the trade-off for the initial award of patent (or intellectual monopoly privilege) protection in the first place. in canada, the office of patented medicines and liaison under health canada has become an important regulatory mechanism for policing "linkage" evergreening. no attempt has been made to create a similar multidisciplinary regulatory agency in australia. yet, it appears that article 18.9.4 of the republic of korea-united states free trade agreement (korusfta) has been specifically drafted to permit the establishment of such a pharmaceutical patent "anti-evergreening" oversight agency. the office of patented medicines and liaison is located in the therapeutic products directorate, health products and foods branch, health canada. the notice of compliance regulations it administers require the

minister of health to maintain a patent register. this consists of patent lists submitted in respect of eligible noc-issued drugs. the minister responsible for health canada may refuse to add, or may delete, information from this patent register. each patent list is audited (for example as to whether potential inclusions are mere 'evergreening' attempts) by the office of patented medicines and liaison. reports produced by that body outline statistics relating to the maintenance of the patent register, including the number of patents filed, the number of patents accepted and rejected, and litigation resulting from the acceptance or rejection of patents for listing on the patent register. in october 2006, the canadian federal government recognized that some brand-name companies had been abusing the noc regulations. it limited their use of 'evergreening' follow-on patents by promulgating regulations that prevented any new patents they filed after a generic company had submitted an application for approval of its product from being considered in the noc regulations process. moreover, the new regulations made it clear that patents covering areas without direct therapeutic application, such as processes or intermediates, could not be used to delay generic approval. in australia, anti-evergreening amendments to the therapeutic goods act 1983 (cth)were part of the package of legislation required to be passed by the australian government as a precondition to entry into force of the australia-united states free trade agreement (ausfta). they provide that where a certificate has been given under s26b by a generic manufacturer and the patent holder wishes to claim a patent and institute infringement proceedings, he or she must first certify that the proceedings are being commenced in good faith, have reasonable prospects of success (as defined in s26c(4)) and will be conducted without unreasonable delay. if the certificate is found to be false or misleading, fines of up to $10 million apply and the cth attorney general is permitted to join the action to recoup losses to the pbs. section 26d provides that a patent holder who seeks an interlocutory injunction to prevent the marketing of the generic pharmaceutical must obtain leave from the government to do so. trips both the international federation of pharmaceutical manufacturing associations (ifpma) and the us phrma have stated that the australian anti-evergreening provisions are inconsistent with obligations under the world trade organization agreement on trade-related aspects of intellectual property rights trips article 27 which prohibits discrimination in an area of technology (in this case pharmaceuticals). the argument is that the australian anti-"linkage evergreening" legislation affects only pharmaceutical patents and is therefore discriminatory under trips. on the other hand, international trade law recognises that where a unique problem arises specifically referable only to a particular field of technology, a solution applying sui generis only to that field of technology cannot be said to be discriminatory according to the ordinary meaning and purpose of the trips agreement or the ausfta as required by article ausfta 21.9.2 (incorporating articles 31 and 32 of the vienna convention on the law of treaties (vclt). the decision of the world trade organization dispute resolution panel in canada – patent protection of pharmaceutical products case, for example, accepted that it was not inconsistent with trips to provide for distinct patent rules that responded to practical consequences of differences between fields of technology. almost all nations including the united states now have anti-evergreening legislation as part of their public health policy and none of this legislation (which is clearly targeted at a problem particular to the pharmaceutical industry) has been argued to be contrary to trips. further, there are a number of obligations imposed by the ausfta that relate to the enjoyment of patent rights for pharmaceuticals alone, including extension of the terms of a pharmaceutical patent to compensate the patent owner for unreasonable curtailment of the effective patent term as a result of the marketing approval process(17.9.8(b)). this is clearly not discriminatory because the issue of delays in enjoyment of patent rights due to the marketing approval process arises only in the context of pharmaceutical patents. future in terms of future evergreening strategies, patent holders may: seek to make incremental patentable innovations to existing products with soon-to-expire patents through the generic arm of their own company and launch early to secure market share (supragenerics), attempt to make separately patentable nanotechnology or biologic versions of such pharmaceuticals through the generic arm of their own company and launch early to secure market share, seek to exclude generic companies from the safety, quality and efficacy data they need to prepare for springboarding (early market launch after patent expiry) using trips-plus data exclusivity protections and seek to extend exclusivity on a soon-to-patent-expire-pharmaceutical by patenting a genetic test to establish potential toxicity or efficacy (pharmacogenomics).

descending branch of occipital artery descending branch of occipital artery the descending branch of occipital artery, the largest branch of the occipital, descends on the back of the neck, and divides into a superficial and deep portion. the superficial portion runs beneath the splenius, giving off branches which pierce that muscle to supply the trapezius and anastomose with the ascending branch of the transverse cervical. the deep portion runs down between the semispinales capitis and colli, and anastomoses with the vertebral and with the a. profunda cervicalis, a branch of the costocervical trunk. descending branch of occipital arterysuperficial dissection of the right side of the neck, showing the carotid and subclavian arteries.detailssourceoccipital arteryidentifierslatinramus descendens arteriae occipitalista98a12.2.05.036ta24404fma49608anatomical terminology the anastomosis between these vessels assists in establishing the collateral circulation after ligature of the common carotid or subclavian artery.

waiting in healthcare waiting in healthcare waiting for healthcare refers to any waiting period experienced by a patient before or during medical treatment. waiting to get an appointment with a physician, staying in a waiting room before an appointment, and being observed during a physician's watchful waiting are different concepts in waiting for healthcare. when a patient is waiting, their family and friends may also be waiting for an outcome. waiting time influences patient satisfaction. patients can spend longer waiting for treatment than actually receiving treatment. some experts have suggested that patient waiting rooms in hospitals be integrated with the other rooms providing patient care so that information updates can come freely to anyone waiting. time in the waiting room has been used to experiment with giving patient health education. in 2014 the patient-centered outcomes research institute began funding a study for improving the waiting room experience. patients who are waiting for surgery depend on the availability of the operating theater, and if any patient getting treatment in that room takes longer than scheduled, all patients who are waiting to be next must wait beyond their appointed time. it can be difficult to maximize efficient use of the operating room when unexpected delays can happen and lead to patients waiting.

nesfatin-1 nesfatin-1 nesfatin-1 is a neuropeptide produced in the hypothalamus of mammals. it participates in the regulation of hunger and fat storage. increased nesfatin-1 in the hypothalamus contributes to diminished hunger, a 'sense of fullness', and a potential loss of body fat and weight. a study of metabolic effects of nesfatin-1 in rats have been done in which subjects administered nesfatin-1 ate less, used more stored fat and became more active. nesfatin-1-induced inhibition of feeding may be mediated through the inhibition of orexigenic neurons. in addition, the protein stimulated insulin secretion from the pancreatic beta cells of both rats and mice. biochemistry nesfatin-1 is a polypeptide encoded in the n-terminal region of the protein precursor, nucleobindin-2 (nucb2). recombinant human nesfatin-1 is a 9.7 kda protein containing 82 amino acid residues. nesfatin-1 is expressed in the hypothalamus, in other areas of the brain, and in pancreatic islets, gastric endocrine cells and adipocytes. satiety nesfatin/nucb2 is expressed in the appetite-control hypothalamic nuclei such as paraventricular nucleus (pvn), arcuate nucleus (arc), supraoptic nucleus (son) of hypothalamus, lateral hypothalamic area (lha), and zona incerta in rats. nesfatin-1 immunoreactivity was also found in the brainstem nuclei such as nucleus of the solitary tract (nts) and dorsal nucleus of vagus nerve. brain nesfatin-1 can cross the blood–brain barrier without saturation. the receptors within the brain are in the hypothalamus and the solitary nucleus, where nesfatin-1 is believed to be produced via peroxisome proliferator-activated receptors (ppars). it appears there is a relationship between nesfatin-1 and cannabinoid receptors. nesfatin-1-induced inhibition of feeding may be mediated through the inhibition of orexigenic npy neurons. nesfatin/nucb2 expression has been reported to be modulated by starvation and re-feeding in the paraventricular nucleus (pvn) and supraoptic nucleus (son) of the brain. nesfatin-1 influences the excitability of a large proportion of different subpopulations of neurons located in the pvn. it is also reported that magnocellular oxytocin neurons are activated during feeding, and icv infusion of oxytocin antagonist increases food intake, indicating a possible role of oxytocin in the regulation of feeding behavior. in addition, it is proposed that feeding-activated nesfatin-1 neurons in the pvn and son could play an important role in the postprandial regulation of feeding behavior and energy homeostasis. nesfatin-1 immunopositive neurons are also located in the arcuate nucleus (arc). nesfatin-1 immunoreactive neurons in the arc are activated by simultaneous injection of ghrelin and desacyl ghrelin, nesfatin-1 may be involved in the desacyl ghrelin-induced inhibition of the orexigenic effect of peripherally administered ghrelin in freely fed rat. nesfatin-1 was co-expressed with melanin concentrating hormone (mch) in tuberal hypothalamic neurons. nesfatin-1 co-expressed in mch neurons may play a complex role not only in the regulation of food intake, but also in other essential integrative brain functions involving mch signaling, ranging from autonomic regulation, stress, mood, cognition to sleep. metabolism there is growing evidence that nesfatin-1 may play an important role in the regulation of food intake and glucose homeostasis. for instance, continuous infusion of nesfatin-1 into the third brain ventricle significantly decreased food intake and body weight gain in rats. in previous studies, it was demonstrated that plasma nesfatin-1 levels were elevated in patients with type 2 diabetes mellitus (t2dm) and associated with bmi, plasma insulin, and the homeostasis model assessment of insulin resistance. it was found that central nesfatin-1 resulted in a marked suppression of hepatic pepck mrna and protein levels in both standard diet (sd) and high fat diet (hfd) rats but failed to alter glucose 6-phosphatase (g-6-pase) activity and protein expression. central nesfatin-1 appeared to antagonize the effect of hfd on increasing pepck gene expression in vivo. in agreement with decreasing pepck gene expression, central nesfatin-1 also resulted in a reduced pepck enzyme activity, further confirming that it affected pepck rather than g-6-pase. the part of the glucose entering the liver is phosphorylated by glucokinase and then dephosphorylated by g-6-pase. this futile cycle between glucokinase and g-6-pase is named glucose cycling, and it accounts for the difference between the total flux through g-6-pase and glucose production. g-6-pase catalyzes the last step in both gluconeogenesis and glycogenolysis, and pepck is responsible only for gluconeogenesis. in this study, central nesfatin-1 led to a marked suppression of hepatic pepck protein and activity, but failed to alter hepatic g-6-pase activity, suggesting that pepck may be more sensitive to short-term central nesfatin-1 exposure than g-6-pase. in addition, suppression of hgp by central nesfatin-1 was dependent on an inhibition of the substrate flux through g-6-pase and not on a decrease in the amount of g-6-pase enzyme. thus, in sd and hfd rats, central nesfatin-1 may have decreased glucose production mainly via decreasing gluconeogenesis and pepck activity. recently, it has been reported that icv nesfatin-1 produced a dose-dependent delay of gastric emptying. to further delineate the mechanism by which central nesfatin-1 modulates glucose homeostasis, we assessed the effects of central nesfatin-1 on the phosphorylation of several proteins in the insr → irs-1 → ampk → akt signaling cascade in the liver. we found that central nesfatin-1 significantly augmented insr and irs-1 tyrosine phosphorylation. these results demonstrated that central nesfatin-1 in both sd and hfd rats resulted in a stimulation of liver insulin signaling that could account for the increased insulin sensitivity and improving glucose metabolism. ampk is a key regulator of both lipid and glucose metabolism. it has been referred to as a metabolic master switch, because its activity is regulated by the energy status of the cell. in this study, we demonstrate that central nesfatin-1 resulted in increased phosphorylation of ampk accompanied by a marked suppression of hepatic pepck activity, mrna, and protein levels in both sd and hfd rats. notably, central nesfatin-1 appears to prevent the obesity-driven decrease in phospho-ampk levels in hfd-fed rats. because hepatic ampk controls glucose homeostasis mainly through the inhibition of gluconeogenic gene expression and glucose production, the suppressive effect of central nesfatin-1 on the hgp (hepatic glucose production) can be attributed partly to its ability to suppress the expression of pepck mrna and protein through ampk activation. furthermore, the activation of ampk has been shown to enhance glucose uptake in skeletal muscle. therefore, increased ampk phosphorylation by central nesfatin-1 may also have been responsible for the improved glucose uptake in muscle. akt is a key effector of insulin-induced inhibition of hgp and stimulation of muscle glucose uptake. we therefore examined the effects of central nesfatin-1 on akt phosphorylation in vivo. we found that central nesfatin-1 produced a pronounced increase in insulin-mediated phosphorylation of akt in the liver of hfd-fed rats. this increase was paralleled by an increase in muscle glucose uptake and inhibition of hgp. this provided correlative evidence that akt activation may be involved in nesfatin-1 signaling and its effects on glucose homeostasis and insulin sensitivity. the mtor pathway has emerged as a molecular mediator of insulin resistance, which can be activated by both insulin and nutrients. it is needed to fully activate akt and consists of two discrete protein complexes, torc1 and torc2, only one of which, torc1, binds rapamycin. in addition to mtor, the torc2 complex contains rictor, mlst8, and sin1 and regulates insulin action and akt phosphorylation. thus, mtor sits at a critical juncture between insulin and nutrient signaling, making it important both for insulin signaling downstream from akt and for nutrient sensing. until now, it has not been known whether nesfatin-1 affects activation of mtor. to gain further insight into the mechanism underlying the insulin-sensitizing effects of icv nesfatin-1, we assessed mtor and torc2 phosphorylation in liver samples of sd- and hfd-fed animals. both mtor and torc2 phosphorylations were increased in livers from these rats, demonstrating activation of mtor and torc2 by central nesfatin-1 in vivo. as mtor kinase activity is required for akt phosphorylation, the observed increased akt phosphorylation may have been caused by the concomitant activation of the mtor/torc2. thus, it's postulated that the mtor/torc2 plays a role as a negative-feedback mechanism in the regulation of metabolism and insulin sensitivity mediated by central nesfatin-1.

timeline of the covid-19 pandemic in south africa timeline of the covid-19 pandemic in south africa this article is about the timeline of events during the covid-19 pandemic in south africa which was part of the ongoing pandemic of coronavirus disease 2019 (covid-19) that was first recorded in south africa on 1 march 2020. since that date the pandemic has hit the country in four waves. covid-19 cases in south africa (click for all data) () deaths recoveries active cases20202020202120212022202220232023marmarapraprmaymayjunjunjuljulaugaugsepsepoctoctnovnovdecdecjanjanfebfebmarmarapraprmaymayjunjunjuljulaugaugsepsepoctoctnovnovdecdecjanjanfebfebmarmarapraprmaymayjunjunjuljulaugaugsepsepoctoctnovnovdecdecjanjanfebfeblast 15 dayslast 15 days date# of cases# of deaths 2020-03-051(n.a.) 2020-03-061(=) 2020-03-072(+1) 2020-03-083(+1) 2020-03-097(+4) 2020-03-107(=) 2020-03-1113(+6) 2020-03-1216(+3) 2020-03-1324(+8) 2020-03-1438(+14) 2020-03-1561(+23) 2020-03-1662(+1) 2020-03-1785(+23) 2020-03-18116(+31) 2020-03-19150(+34) 2020-03-20202(+52) 2020-03-21240(+38) 2020-03-22274(+34) 2020-03-23402(+128) 2020-03-24554(+152) 2020-03-25709(+155) 2020-03-26927(+218) 2020-03-271,170(+243)1(n.a.) 2020-03-281,187(+17)1(=) 2020-03-291,280(+93)2(+1) 2020-03-301,326(+46)3(+1) 2020-03-311,372(+46)5(+2) 2020-04-011,380(+8)5(=) 2020-04-021,462(+82)5(=) 2020-04-031,505(+43)7(+2) 2020-04-041,585(+80)9(+2) 2020-04-051,655(+70)11(+2) 2020-04-061,686(+31)12(+1) 2020-04-071,749(+63)13(+1) 2020-04-081,845(+96)18(+5) 2020-04-091,934(+89)18(=) 2020-04-102,003(+69)24(+6) 2020-04-112,028(+25)25(+1) 2020-04-122,173(+145)25(=) 2020-04-132,272(+99)27(+2) 2020-04-142,415(+143)27(=) 2020-04-152,506(+91)34(+7) 2020-04-162,605(+99)48(+14) 2020-04-172,783(+178)50(+2) 2020-04-183,034(+251)52(+2) 2020-04-193,158(+124)54(+2) 2020-04-203,300(+142)58(+4) 2020-04-213,465(+165)58(=) 2020-04-223,635(+170)65(+7) 2020-04-233,953(+318)75(+10) 2020-04-244,220(+267)79(+4) 2020-04-254,361(+141)86(+7) 2020-04-264,546(+185)87(+1) 2020-04-274,793(+247)90(+3) 2020-04-284,996(+203)93(+3) 2020-04-295,350(+354)103(+10) 2020-04-305,647(+297)103(=) 2020-05-015,951(+304)116(+13) 2020-05-026,336(+385)123(+7) 2020-05-036,783(+447)131(+8) 2020-05-047,220(+437)138(+7) 2020-05-057,572(+352)148(+10) 2020-05-067,808(+236)153(+5) 2020-05-078,232(+424)161(+8) 2020-05-088,895(+663)178(+17) 2020-05-099,420(+525)186(+8) 2020-05-1010,015(+595)194(+8) 2020-05-1110,652(+637)206(+12) 2020-05-1211,350(+698)206(=) 2020-05-1312,074(+724)219(+13) 2020-05-1412,739(+665)238(+19) 2020-05-1513,524(+785)247(+9) 2020-05-1614,355(+831)261(+14) 2020-05-1715,515(+1,160)264(+3) 2020-05-1816,433(+918)286(+22) 2020-05-1917,200(+767)312(+26) 2020-05-2018,003(+803)339(+27) 2020-05-2119,137(+1,134)369(+30) 2020-05-2220,125(+988)397(+28) 2020-05-2321,343(+1,218)407(+10) 2020-05-2422,583(+1,240)429(+22) 2020-05-2523,615(+1,032)481(+52) 2020-05-2624,264(+649)524(+43) 2020-05-2725,937(+1,673)552(+28) 2020-05-2827,403(+1,466)577(+25) 2020-05-2929,240(+1,837)611(+34) 2020-05-3030,967(+1,727)643(+32) 2020-05-3132,683(+1,716)683(+40) 2020-06-0134,357(+1,674)705(+22) 2020-06-0235,812(+1,455)755(+50) 2020-06-0337,525(+1,713)792(+37) 2020-06-0440,792(+3,267)848(+56) 2020-06-0543,434(+2,642)908(+60) 2020-06-0645,973(+2,539)952(+44) 2020-06-0748,285(+2,312)998(+46) 2020-06-0850,879(+2,594)1,080(+82) 2020-06-0952,991(+2,112)1,162(+82) 2020-06-1055,421(+2,430)1,210(+48) 2020-06-1158,568(+3,147)1,284(+74) 2020-06-1261,927(+3,359)1,354(+70) 2020-06-1365,736(+3,809)1,423(+69) 2020-06-1470,038(+4,302)1,480(+57) 2020-06-1573,533(+3,495)1,568(+88) 2020-06-1676,334(+2,801)1,625(+57) 2020-06-1780,412(+4,078)1,674(+49) 2020-06-1883,890(+3,478)1,737(+63) 2020-06-1987,715(+3,825)1,831(+94) 2020-06-2092,681(+4,966)1,877(+46) 2020-06-2197,302(+4,621)1,930(+53) 2020-06-22101,590(+4,288)1,991(+61) 2020-06-23106,108(+4,518)2,102(+111) 2020-06-24111,796(+5,688)2,205(+103) 2020-06-25118,375(+6,579)2,292(+87) 2020-06-26124,590(+6,215)2,340(+48) 2020-06-27131,800(+7,210)2,413(+73) 2020-06-28138,134(+6,334)2,456(+43) 2020-06-29144,264(+6,130)2,529(+73) 2020-06-30151,209(+6,945)2,657(+128) 2020-07-01159,333(+8,124)2,749(+92) 2020-07-02168,061(+8,728)2,844(+95) 2020-07-03177,124(+9,063)2,952(+108) 2020-07-04187,977(+10,853)3,026(+74) 2020-07-05196,750(+8,773)3,199(+173) 2020-07-06205,721(+8,971)3,310(+111) 2020-07-07215,855(+10,134)3,502(+192) 2020-07-08224,665(+8,810)3,600(+98) 2020-07-09238,399(+13,734)3,720(+120) 2020-07-10250,687(+12,288)3,860(+140) 2020-07-11264,184(+13,497)3,971(+111) 2020-07-12276,242(+12,058)4,079(+108) 2020-07-13287,796(+11,554)4,172(+93) 2020-07-14298,292(+10,496)4,346(+174) 2020-07-15311,049(+12,757)4,453(+107) 2020-07-16324,221(+13,172)4,669(+216) 2020-07-17337,594(+13,373)4,804(+135) 2020-07-18350,879(+13,285)4,948(+144) 2020-07-19364,328(+13,449)5,033(+85) 2020-07-20373,628(+9,300)5,173(+140) 2020-07-21381,798(+8,170)5,368(+195) 2020-07-22394,948(+13,150)5,940(+572) 2020-07-23408,052(+13,104)6,093(+153) 2020-07-24421,996(+13,944)6,343(+250) 2020-07-25434,200(+12,204)6,655(+312) 2020-07-26445,433(+11,233)6,769(+114) 2020-07-27452,529(+7,096)7,067(+298) 2020-07-28459,761(+7,232)7,257(+190) 2020-07-29471,123(+11,362)7,497(+240) 2020-07-30482,169(+11,046)7,812(+315) 2020-07-31493,183(+11,014)8,005(+193) 2020-08-01503,290(+10,107)8,153(+148) 2020-08-02511,485(+8,195)8,366(+213) 2020-08-03516,862(+5,377)8,539(+173) 2020-08-04521,318(+4,456)8,884(+345) 2020-08-05529,877(+8,559)9,298(+414) 2020-08-06538,184(+8,307)9,604(+306) 2020-08-07545,476(+7,292)9,909(+305) 2020-08-08553,188(+7,712)10,210(+301) 2020-08-09559,858(+6,670)10,408(+198) 2020-08-10563,598(+3,740)10,621(+213) 2020-08-11566,109(+2,511)10,751(+130) 2020-08-12568,919(+2,810)11,010(+259) 2020-08-13572,865(+3,946)11,270(+260) 2020-08-14579,140(+6,275)11,556(+286) 2020-08-15583,653(+4,513)11,677(+121) 2020-08-16587,345(+3,692)11,839(+162) 2020-08-17589,886(+2,541)11,982(+143) 2020-08-18592,144(+2,258)12,264(+282) 2020-08-19596,060(+3,916)12,423(+159) 2020-08-20599,940(+3,880)12,618(+195) 2020-08-21603,338(+3,398)12,843(+225) 2020-08-22607,045(+3,707)12,987(+144) 2020-08-23609,773(+2,728)13,059(+72) 2020-08-24611,450(+1,677)13,159(+100) 2020-08-25613,017(+1,567)13,308(+149) 2020-08-26615,701(+2,684)13,502(+194) 2020-08-27618,286(+2,585)13,628(+126) 2020-08-28620,132(+1,846)13,743(+115) 2020-08-29622,551(+2,419)13,981(+238) 2020-08-30625,056(+2,505)14,028(+47) 2020-08-31627,041(+1,985)14,149(+121) 2020-09-01628,259(+1,218)14,263(+114) 2020-09-02630,595(+2,336)14,389(+126) 2020-09-03633,015(+2,420)14,563(+174) 2020-09-04635,078(+2,063)14,678(+115) 2020-09-05636,884(+1,806)14,779(+101) 2020-09-06638,517(+1,633)14,889(+110) 2020-09-07639,362(+845)15,004(+115) 2020-09-08640,441(+1,079)15,086(+82) 2020-09-09642,431(+1,990)15,168(+82) 2020-09-10644,438(+2,007)15,265(+97) 2020-09-11646,398(+1,960)15,378(+113) 2020-09-12648,214(+1,816)15,427(+49) 2020-09-13649,793(+1,579)15,447(+20) 2020-09-14650,749(+956)15,499(+52) 2020-09-15651,521(+772)15,641(+142) 2020-09-16653,444(+1,923)15,705(+64) 2020-09-17655,572(+2,128)15,772(+67) 2020-09-18657,627(+2,055)15,857(+85) 2020-09-19659,626(+1,999)15,940(+83) 2020-09-20661,211(+1,585)15,953(+13) 2020-09-21661,936(+725)15,992(+39) 2020-09-22663,282(+1,346)16,118(+126) 2020-09-23665,188(+1,906)16,206(+88) 2020-09-24667,049(+1,861)16,283(+77) 2020-09-25668,529(+1,480)16,312(+29) 2020-09-26669,498(+969)16,376(+64) 2020-09-27670,766(+1,268)16,398(+22) 2020-09-28671,669(+903)16,586(+188) 2020-09-29672,572(+903)16,667(+81) 2020-09-30674,339(+1,767)16,734(+67) 2020-10-01676,084(+1,745)16,866(+132) 2020-10-02677,833(+1,749)16,909(+43) 2020-10-03679,716(+1,883)16,938(+29) 2020-10-04681,289(+1,573)16,976(+38) 2020-10-05682,215(+926)17,016(+40) 2020-10-06683,242(+1,027)17,103(+87) 2020-10-07685,155(+1,913)17,248(+145) 2020-10-08686,891(+1,736)17,408(+160) 2020-10-09688,352(+1,461)17,547(+139) 2020-10-10690,896(+2,544)17,673(+126) 2020-10-11692,471(+1,575)17,780(+107) 2020-10-12693,359(+888)17,863(+83) 2020-10-13694,537(+1,178)18,028(+165) 2020-10-14696,414(+1,877)18,151(+123) 2020-10-15698,184(+1,770)18,309(+158) 2020-10-16700,203(+2,019)18,370(+61) 2020-10-17702,131(+1,928)18,408(+38) 2020-10-18703,793(+1,662)18,471(+63) 2020-10-19705,254(+1,461)18,492(+21) 2020-10-20706,304(+1,050)18,656(+164) 2020-10-21708,359(+2,055)18,741(+85) 2020-10-22710,515(+2,156)18,843(+102) 2020-10-23712,412(+1,897)18,891(+48) 2020-10-24714,246(+1,834)18,944(+53) 2020-10-25715,868(+1,622)18,968(+24) 2020-10-26716,759(+891)19,008(+40) 2020-10-27717,851(+1,092)19,053(+45) 2020-10-28719,714(+1,863)19,111(+58) 2020-10-29721,770(+2,056)19,164(+53) 2020-10-30723,682(+1,912)19,230(+66) 2020-10-31725,452(+1,770)19,276(+46) 2020-11-01726,823(+1,371)19,411(+135) 2020-11-02727,595(+772)19,465(+54) 2020-11-03728,836(+1,241)19,539(+74) 2020-11-04730,548(+1,712)19,585(+46) 2020-11-05732,414(+1,866)19,677(+92) 2020-11-06734,175(+1,761)19,749(+72) 2020-11-07735,906(+1,731)19,789(+40) 2020-11-08737,278(+1,372)19,809(+20) 2020-11-09738,525(+1,247)19,845(+36) 2020-11-10740,254(+1,729)19,951(+106) 2020-11-11742,394(+2,140)20,011(+60) 2020-11-12744,732(+2,338)20,076(+65) 2020-11-13746,945(+2,213)20,153(+77) 2020-11-14749,182(+2,237)20,206(+53) 2020-11-15751,024(+1,842)20,241(+35) 2020-11-16752,269(+1,245)20,314(+73) 2020-11-17754,256(+1,987)20,432(+118) 2020-11-18757,144(+2,888)20,556(+124) 2020-11-19759,658(+2,514)20,671(+115) 2020-11-20762,763(+3,105)20,759(+88) 2020-11-21765,409(+2,646)20,845(+86) 2020-11-22767,679(+2,270)20,903(+58) 2020-11-23769,759(+2,080)20,968(+65) 2020-11-24772,252(+2,493)21,083(+115) 2020-11-25775,502(+3,250)21,201(+118) 2020-11-26778,571(+3,069)21,289(+88) 2020-11-27781,941(+3,370)21,378(+89) 2020-11-28785,139(+3,198)21,439(+61) 2020-11-29787,702(+2,563)21,477(+38) 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2022-01-053,494,696(+11,106)91,561(+110) 2022-01-063,504,554(+9,858)92,112(+551) 2022-01-073,513,813(+9,259)92,252(+140) 2022-01-083,521,572(+7,759)92,371(+119) 2022-01-093,526,054(+4,482)92,453(+82) 2022-01-103,528,463(+2,409)92,530(+77) 2022-01-113,534,131(+5,668)92,649(+119) 2022-01-123,540,891(+6,760)92,830(+181) 2022-01-133,546,808(+5,917)92,989(+159) 2022-01-143,552,043(+5,235)93,117(+128) 2022-01-153,556,633(+4,590)93,278(+161) 2022-01-163,559,230(+2,597)93,364(+86) 2022-01-173,560,921(+1,691)93,451(+87) 2022-01-183,564,578(+3,657)93,551(+100) 2022-01-193,568,900(+4,322)93,707(+156) 2022-01-203,572,860(+3,960)93,846(+139) 2022-01-213,576,379(+3,519)93,949(+103) 2022-01-223,579,428(+3,049)94,063(+114) 2022-01-233,581,359(+1,931)94,177(+114) 2022-01-243,582,691(+1,332)94,265(+88) 2022-01-253,585,888(+3,197)94,397(+132) 2022-01-263,590,399(+4,511)94,491(+94) 2022-01-273,594,499(+4,100)94,651(+160) 2022-01-283,598,288(+3,789)94,784(+133) 2022-01-293,601,630(+3,342)94,905(+121) 2022-01-303,603,856(+2,226)95,022(+117) 2022-01-313,605,222(+1,366)95,093(+71) 2022-02-013,608,307(+3,085)95,288(+195) 2022-02-023,612,809(+4,502)95,463(+175) 2022-02-033,616,075(+3,266)95,545(+82) 2022-02-043,618,853(+2,778)95,766(+221) 2022-02-053,622,210(+3,357)95,817(+51) 2022-02-063,623,962(+1,752)95,835(+18) 2022-02-073,625,190(+1,228)96,021(+186) 2022-02-083,626,014(+824)96,289(+268) 2022-02-093,631,642(+5,628)96,502(+213) 2022-02-103,634,811(+3,169)96,705(+203) 2022-02-113,637,673(+2,862)96,851(+146) 2022-02-123,640,162(+2,489)96,985(+134) 2022-02-133,641,811(+1,649)96,993(+8) 2022-02-143,642,905(+1,094)97,250(+257) 2022-02-153,645,269(+2,364)97,431(+181) 2022-02-163,648,968(+3,699)97,520(+89) 2022-02-173,652,024(+3,056)97,955(+435) 2022-02-183,654,824(+2,800)98,298(+343) 2022-02-193,657,091(+2,267)98,617(+319) 2022-02-203,658,547(+1,456)98,667(+50) 2022-02-213,659,698(+1,151)98,804(+137) 2022-02-223,662,032(+2,334)98,868(+64) 2022-02-233,665,149(+3,117)98,978(+110) 2022-02-243,667,560(+2,411)99,018(+40) 2022-02-253,669,671(+2,111)99,145(+127) 2022-02-263,671,991(+2,320)99,191(+46) 2022-02-273,673,257(+1,266)99,229(+38) 2022-02-283,674,042(+785)99,412(+183) 2022-03-013,675,691(+1,649)99,430(+18) 2022-03-023,677,686(+1,995)99,458(+28) 2022-03-033,679,539(+1,853)99,499(+41) 2022-03-043,681,437(+1,898)99,517(+18) 2022-03-053,683,172(+1,735)99,543(+26) 2022-03-063,684,319(+1,147)99,543(=) 2022-03-073,685,120(+801)99,609(+66) 2022-03-083,685,556(+436)99,625(+16) 2022-03-093,688,423(+2,867)99,656(+31) 2022-03-103,690,291(+1,868)99,681(+25) 2022-03-113,691,962(+1,671)99,709(+28) 2022-03-123,693,532(+1,570)99,712(+3) 2022-03-133,694,504(+972)99,725(+13) 2022-03-143,695,175(+671)99,725(=) 2022-03-153,696,823(+1,648)99,727(+2) 2022-03-163,698,803(+1,980)99,767(+40) 2022-03-173,700,484(+1,681)99,829(+62) 2022-03-183,700,484(=)99,829(=) 2022-03-193,703,329(+2,845)99,879(+50) 2022-03-203,704,218(+889)99,881(+2) 2022-03-213,704,784(+566)99,890(+9) 2022-03-223,705,696(+912)99,893(+3) 2022-03-233,707,089(+1,393)99,899(+6) 2022-03-243,709,209(+2,120)99,932(+33) 2022-03-253,710,766(+1,557)99,939(+7) 2022-03-263,712,263(+1,497)99,965(+26) 2022-03-273,713,252(+989)99,966(+1) 2022-03-283,713,833(+581)99,970(+4) 2022-03-293,715,390(+1,557)99,976(+6) 2022-03-303,717,067(+1,677)100,020(+44) 2022-03-313,718,953(+1,886)100,032(+12) 2022-04-013,720,645(+1,692)100,042(+10) 2022-04-023,722,065(+1,420)100,046(+4) 2022-04-033,722,954(+889)100,050(+4) 2022-04-043,723,639(+685)100,052(+2) 2022-04-053,725,177(+1,538)100,067(+15) 2022-04-063,727,208(+2,031)100,070(+3) 2022-04-073,728,689(+1,481)100,075(+5) 2022-04-083,730,066(+1,377)100,084(+9) 2022-04-093,731,247(+1,181)100,096(+12) 2022-04-103,732,075(+828)100,096(=) 2022-04-113,732,628(+553)100,098(+2) 2022-04-123,733,919(+1,291)100,116(+18) 2022-04-133,735,578(+1,659)100,132(+16) 2022-04-143,737,346(+1,768)100,138(+6) 2022-04-153,739,192(+1,846)100,142(+4) 2022-04-163,740,398(+1,206)100,144(+2) 2022-04-173,741,230(+832)100,147(+3) 2022-04-183,742,107(+877)100,181(+34) 2022-04-193,743,582(+1,475)100,195(+14) 2022-04-203,746,424(+2,842)100,211(+16) 2022-04-213,750,830(+4,406)100,276(+65) 2022-04-223,755,459(+4,629)100,286(+10) 2022-04-233,759,689(+4,230)100,298(+12) 2022-04-243,762,911(+3,222)100,303(+5) 2022-04-253,764,865(+1,954)100,333(+30) 2022-04-263,769,927(+5,062)100,348(+15) 2022-04-273,776,298(+6,371)100,351(+3) 2022-04-283,780,444(+4,146)100,355(+4) 2022-04-293,785,398(+4,954)100,360(+5) 2022-04-303,791,925(+6,527)100,363(+3) 2022-05-013,795,763(+3,838)100,363(=) 2022-05-023,798,413(+2,650)100,370(+7) 2022-05-033,802,198(+3,785)100,377(+7) 2022-05-043,808,368(+6,170)100,407(+30) 2022-05-053,818,125(+9,757)100,471(+64) 2022-05-063,827,378(+9,253)100,505(+34) 2022-05-073,835,902(+8,524)100,516(+11) 2022-05-083,841,388(+5,486)100,523(+7) 2022-05-093,844,625(+3,237)100,533(+10) 2022-05-103,852,148(+7,523)100,559(+26) 2022-05-113,862,165(+10,017)100,609(+50) 2022-05-123,871,085(+8,920)100,630(+21) 2022-05-133,879,434(+8,349)100,744(+114) 2022-05-143,887,449(+8,015)100,753(+9) 2022-05-153,891,793(+4,344)100,755(+2) 2022-05-163,894,745(+2,952)100,771(+16) 2022-05-173,899,841(+5,096)100,812(+41) 2022-05-183,908,020(+8,179)100,867(+55) 2022-05-193,915,258(+7,238)100,898(+31) 2022-05-203,921,633(+6,375)100,916(+18) 2022-05-213,926,652(+5,019)100,931(+15) 2022-05-223,929,872(+3,220)100,933(+2) 2022-05-233,931,534(+1,662)100,962(+29) 2022-05-243,935,761(+4,227)101,002(+40) 2022-05-253,941,045(+5,284)101,043(+41) 2022-05-263,944,845(+3,800)101,092(+49) 2022-05-273,948,119(+3,274)101,128(+36) 2022-05-283,952,193(+4,074)101,142(+14) 2022-05-293,953,967(+1,774)101,146(+4) 2022-05-303,954,971(+1,004)101,162(+16) 2022-05-313,957,777(+2,806)101,190(+28) 2022-06-013,960,424(+2,647)101,219(+29) 2022-06-023,963,394(+2,970)101,250(+31) 2022-06-033,965,422(+2,028)101,285(+35) 2022-06-043,967,078(+1,656)101,313(+28) 2022-06-053,968,205(+1,127)101,317(+4) 2022-06-063,968,931(+726)101,350(+33) 2022-06-073,970,993(+2,062)101,397(+47) 2022-06-083,973,086(+2,093)101,424(+27) 2022-06-093,975,062(+1,976)101,448(+24) 2022-06-103,976,653(+1,591)101,468(+20) 2022-06-113,977,628(+975)101,477(+9) 2022-06-123,978,590(+962)101,484(+7) 2022-06-133,979,126(+536)101,509(+25) 2022-06-143,979,836(+710)101,550(+41) 2022-06-153,981,739(+1,903)101,576(+26) 2022-06-163,983,675(+1,936)101,584(+8) 2022-06-173,984,646(+971)101,589(+5) 2022-06-183,985,606(+960)101,598(+9) 2022-06-193,986,601(+995)101,604(+6) 2022-06-203,986,892(+291)101,620(+16) 2022-06-213,986,892(=)101,640(+20) 2022-06-223,989,007(+2,115)101,697(+57) 2022-06-233,989,007(=)101,697(=) 2022-06-243,991,003(+1,996)101,717(+20) 2022-06-253,991,944(+941)101,727(+10) 2022-06-263,992,449(+505)101,731(+4) 2022-06-273,992,661(+212)101,740(+9) 2022-06-283,993,004(+343)101,745(+5) 2022-06-293,993,444(+440)101,764(+19) 2022-06-303,993,843(+399)101,793(+29) 2022-07-013,994,223(+380)101,809(+16) 2022-07-023,995,065(+842)101,811(+2) 2022-07-033,995,291(+226)101,812(+1) 2022-07-043,995,400(+109)101,815(+3) 2022-07-053,995,784(+384)101,847(+32) 2022-07-063,996,441(+657)101,859(+12) 2022-07-073,996,904(+463)101,868(+9) 2022-07-083,997,269(+365)101,876(+8) 2022-07-093,997,269(=)101,876(=) 2022-07-103,997,269(=)101,876(=) 2022-07-113,997,269(=)101,876(=) 2022-07-123,998,466(+1,197)101,895(+19) 2022-07-133,998,863(+397)101,907(+12) 2022-07-143,999,345(+482)101,915(+8) 2022-07-153,999,751(+406)101,918(+3) 2022-07-163,999,751(=)101,918(=) 2022-07-173,999,751(=)101,918(=) 2022-07-184,000,631(+880)101,922(+4) 2022-07-194,000,894(+263)101,935(+13) 2022-07-204,001,444(+550)101,939(+4) 2022-07-214,001,816(+372)101,942(+3) 2022-07-224,002,133(+317)101,943(+1) 2022-07-234,002,133(=)101,943(=) 2022-07-244,002,133(=)101,943(=) 2022-07-254,002,981(+848)101,955(+12) 2022-07-264,003,502(+521)101,962(+7) 2022-07-274,003,883(+381)101,967(+5) 2022-07-284,004,201(+318)101,977(+10) 2022-07-294,004,555(+354)101,982(+5) ⋮ 2022-08-174,008,697(n.a.)102,066(n.a.) ⋮ 2022-08-244,010,206(n.a.)102,084(n.a.) ⋮ 2022-08-314,011,385(n.a.)102,108(n.a.) ⋮ 2022-09-074,012,860(n.a.)102,129(n.a.) ⋮ 2022-09-144,014,442(n.a.)102,146(n.a.) ⋮ 2022-09-214,016,081(n.a.)102,169(n.a.) ⋮ 2022-09-294,017,700(n.a.)102,185(n.a.) ⋮ 2022-10-054,019,365(n.a.)102,194(n.a.) ⋮ 2022-10-124,021,297(n.a.)102,246(n.a.) ⋮ 2022-10-194,023,655(n.a.)102,257(n.a.) ⋮ 2022-11-024,028,198(n.a.)102,363(n.a.) ⋮ 2022-11-184,034,234(n.a.)102,395(n.a.) ⋮ 2022-11-244,038,051(n.a.)102,428(n.a.) ⋮ 2022-11-304,040,939(n.a.)102,464(n.a.) ⋮ 2022-12-074,042,912(n.a.)102,550(n.a.) ⋮ 2022-12-144,045,262(n.a.)102,568(n.a.) ⋮ 2023-01-254,054,206(n.a.)102,595(n.a.) ⋮ 2023-02-014,055,656(n.a.)102,595(n.a.) source: covid-19 online resource & news portal notes: positive antigen tests are included from 23 november 2021 including 17 718 retrospective cases. includes 19 840 retrospective cases. includes 506 retrospective deaths. the health department announced on 1 august 2022 that daily figures would no longer be reported. first wave: march 2020 – november 2020 march 2020 on 1 march 2020, the first patient later confirmed with covid-19 in south africa, returned with his wife and 8 others from the milan, italy, travelling via dubai, o. r. tambo international airport in kempton park, gauteng and king shaka international airport in durban to hilton. on 3 march, the patient reported with symptoms to a private general practitioner and isolated himself; the doctor isolated herself as well. on 5 march the minister of health, zweli mkhize, announced the first confirmed case, epidemiologists and clinicians from the national institute for communicable diseases (nicd) were deployed to kwazulu-natal in response on 15 march 2020, the president of south africa, cyril ramaphosa, declared a national state of disaster, and the patient went to grey's hospital in pietermaritzburg. on 7 march, it was announced that a woman from the same travel group from italy, returning to gauteng, also tested positive. on 11 march 6 new cases were reported, with 1 case from the same travel group from italy, while the other 5 cases appear unrelated having travel histories to other european countries. the first case was confirmed in the western cape province. 3 new cases were announced on 12 march, including the first case in mpumalanga province. the first local transmission and first case in the free state province was also announced, but withdrawn later in the day by the nicd who confirmed that the case's test result was in fact negative. this brought the total cases to 16. on 15 march, the first local transmissions, not yet confirmed by government labs, were announced by president cyril ramaphosa and the following day, the first confirmed case from limpopo province was announced. the day thereafter, on 17 march, the first confirmed cases of local transmission were announced by government labs, 4 in gauteng, 3 in kwazulu-natal, and 1 in the western cape. on the next day, 18 march, the first confirmed case of local transmission in mpumalanga was announced by government labs. on 19 march, the health minister suggested that two-thirds of the south african population could contract the virus, a prediction in line with europe's estimates on population infection. on 20 march, the free state province recorded seven cases, becoming the sixth of south africa's nine provinces to be infected. of the seven cases, five were from abroad (israel, france and texas) who had congregated in bloemfontein for a prayer breakfast attended by 859 people. the eastern cape reported its first case one day later. o. r. tambo international airport instituted isolation of foreigners on arrival and returning them to their countries of origin. following a funeral on 21 march in kwadwesi attended by 1200 mourners, at least 45 persons (31 women and 14 men) contracted covid-19 and at least one person died. on 23 march, a national 21-day lockdown was announced by president ramaphosa to begin on 27 march to 16 april. the first local death from the disease was reported on 27 march 2020. on 21 april, a 500 billion rand stimulus was announced in response to the pandemic. by 24 march all nine provinces had confirmed cases, with the first cases in the northern cape and north west announced. the country's first death was announced on 27 march. there were 1,353 confirmed cases in march. five patients died and 31 recovered, while 1,317 remained active cases at the end of the month. april 2020 on 1 april, researchers from the nicd and south african national bioinformatics institute at the university of western cape released the genetic sequence of the sars-cov-2 from a south african covid-19 patient. pick-up trucks dispensed free hand sanitizer in alexandra in early april. following a funeral in zwide on 4 april, at least nine mourners contracted covid-19. on 9 april, it was announced that south africa's cabinet members, which include the president, deputy president, ministers and deputy ministers would donate one-third of their salaries for three months to a solidarity fund. on 9 april, the st augustine's hospital in durban was shut down following a localised outbreak of over 60 confirmed cases and four covid-19 related deaths; by then 1,845 had tested positive for the virus nationally with total 18 deaths. on 10 april, mkhize recommended that the general public use cloth facemasks when going out in public. on 13 april, chair of the ministerial advisory committee on covid-19 salim abdool karim indicated that the lockdown had been effective in delaying transmissions. he also described the country's 8-stage plan to combat the coronavirus. this included criteria for extending or easing the lockdown. by 23 april, when president ramaphosa again addressed the nation the total number of cases had increased to 3953. detailed figures released by the nicd showed that in april that the number of cases had taken distinct trajectories in different provinces. the number of daily tests increased: for the first 14 days of april the daily average number of tests was 3394; for the next 9 days the daily average was 6283. the rate of positive tests versus total tests remained less than 3%. the minister of health released figures that showed that of all the tests done up to 23 april 62% had been done in the private sector and 38% in the public sector. however, that ratio was changing as the public sector increased capacity. the public sector performed 63% of the new tests reported on 23 april 2020. in the two weeks from 9 to 23 april, the cases in the coastal provinces had a very high increase – eastern cape cases rose 583% from a low base, kwazulu-natal rose 108% and western cape 148%. north west (67%) and gauteng (57%) had high increases, while the other provinces had much lower increases from 6% in the northern cape to 23% in limpopo (all with low absolute numbers – 106 in the free state and under 30 in each of the other provinces). as of 27 april 2020 23:59, the median age

of laboratory-confirmed cases was 38 years (interquartile range 29–51 years), and children aged <10 years accounted for 3% (156/4996). on 30 april 2020, ramaphosa received a consignment of personal protective equipment (ppe) donated by global internet group naspers on 30 april. there were 4,294 new cases in april, raising the total number of confirmed cases to 5,647. the death toll rose to 103. the number of recovered patients increased to 2,073, leaving 3,471 active cases at the end of the month. may 2020 on 19 may 2020, scientists advising the government estimated 475 confirmed covid-19 deaths by the end of that month, and more than forty-thousand deaths by november. they also estimated that there could be insufficient icu beds by june or july. the scientists stated that these estimates were subject to deviations and were based on simple and pessimistic assumptions. by the end of the month, there had been 683 deaths, with 27,036 new cases and 16,809 recoveries. june 2020 police patrolling in shopping mall areas to see if citizens are following safety measures (pretoria, june 2020). testing of 330 pupils and staff at makaula senior secondary school in kwabhaca resulted in 204 positive tests. in june, there were 118,526 new cases, raising the total number of confirmed cases to 151,209. the death toll rose to 2,657. the number of recovered patients increased by 56,734 to 73,543. at the end of the month there were 75,009 active cases. july 2020 as of 3 july 2020, the median age of those who had died was 61 years and males had a 1.5 times greater death rate compared to females. on 12 july, in an address to the nation, president ramaphosa announced that the anticipated surge in covid-19 cases had arrived. the state of disaster was extended until 15 august 2020 and the alcohol ban was reintroduced along with a new curfew from 21:00 until 4:00. resumption of alcohol sale and distribution had led to increased pressure on hospitals from road traffic accidents, trauma and violence which happened mostly at night. on 22 july, the south african medical research council (samrc) and the university of cape town's centre for actuarial research estimated that 17,090 excess natural deaths had taken place between 6 may and 14 july 2020 in south africa. these represented, by the second week of july, a 59% increase in natural deaths compared to the same time period in previous years 11,175 (65%) of these excess estimated natural deaths were in those above age 60 years. excess natural deaths were covid-19 related either directly or indirectly through delayed diagnosis and treatment of other conditions. unnatural deaths, from car accidents and murders, were 20% lower than expected. on 23 july, president ramaphosa announced the re-closure of all public schools for four-weeks from 27 july to 24 august 2020 and the extension of the academic year into 2021. in july, there were 341,974 new cases, raising the total number of confirmed cases to 493,183. the death toll tripled to 8,005. the number of recovered patients increased by 252,628 to 326,171. at the end of the month, there were 159,007 active cases. august 2020 on 15 august, president ramaphosa addressed the nation announcing the passing of the covid-19 peak, the lowering of restrictions to level 2 and the extension of the national state of disaster by another month. there were 285,067 new cases in august, raising the total number of confirmed cases to 627,041. the death toll increased to 14,149. at the end of the month there were 71,969 active cases. an initial non-representative seroprevalence survey indicated that approximately 40% of some cape town residents had been infected with sars-cov-2. september 2020 on 16 september, the president made a national address where he announced the further lowering of restrictions to level 1, beginning from 21 september 2020. the national state of disaster was extended by one more month. there were 45,531 new cases in september, bringing the total number of confirmed cases to 672,572. the death toll rose to 16,667. the number of recovered patients increased to 606,520, leaving 49,655 active cases at the end of the month. october 2020 on 18 october, minister of health zweli mkhize announced that he had tested positive for the covid-19. the national state of disaster was extended by another month. for two consecutive weeks, excess natural deaths were above the normal expected rate. these excess deaths were far below the july excess death peak. there were 52,880 new cases in october, raising the total number of confirmed cases to 725,452. the death toll rose to 19,276. the number of recovered patients increased to 654,182, leaving 51,994 active cases at the end of the month. november 2020 on 11 november, president ramaphosa addressed the nation where he announced extension of the state of disaster by another month until 15 december 2020. relaxation of international travel, shop trading hours restrictions along with continued covid unemployment support were announced. there were 64,552 new cases in november, raising the total number of confirmed cases to 790,004. the death toll rose to 21,535. the number of recovered patients increased to 731,242, leaving 37,227 active cases at the end of the month. second wave: december 2020 – april 2021 december 2020 on 3 december, the president addressed the nation. he noted a resurgence of covid-19 in some districts of the eastern and western cape provinces. nelson mandela bay metropolitan municipality was identified as a coronavirus hotspot; restrictions were tightened for this area. the national state of disaster was extended until 15 january 2021. on 7 december, the government said that end-of-school parties known as "rage parties" are super spreader events. on 9 december, the minister of health announced that the country had entered the second wave of infections. the country was now recording over 6000 cases per day from fewer than 1000 cases per day at the end of september. the average proportion of positive covid-19 tests had risen from 10% to 18%. on 14 december, the president announced in an address to the nation, the closure of some beaches, lowering of the number of people that can attend gatherings and the tightening of other measures to curb the second wave. on 18 december, minister of health zweli mkhize said scientists had discovered a new variant of coronavirus, called 501.v2 variant. on 27 december, the number of confirmed cases reached 1 million. on 28 december 2020, president cyril ramaphosa addressed the nation again and announced that the country would go back into a partial lockdown level 3 for 14 days to reduce the speed of the second wave during the festive season. this introduced a curfew from 9 pm to 6 am, the ban on sale and transport of alcohol, closure of public amenities like beaches, lakes and dams and the compulsory wearing of masks in public. there were 267,157 new cases in december, raising the total number of confirmed cases to 1,057,161. the death toll rose to 28,469. the number of recovered patients increased to 879,671, leaving 149,021 active cases at the end of the month. modelling by who's regional office for africa suggests that due to under-reporting, the true number of infections in 2020 was around 17 million. january 2021 a vaccine rollout strategy was announced on 3 january 2021, with doses for 10% of the population already secured and more on the way. during the first phase, frontline healthcare workers would be vaccinated. on 11 january, president ramaphosa addressed the nation. he announced the continuation of current pandemic alleviation measures, vaccine rollout developments and the extension of the state of disaster on 13 january the government said it had arrested 7,000 people since the end of december for not wearing face masks. in the week ending 17 january 130,000 new cases and 4,000 deaths cause public and private hospitals to be overrun. the 501.v2 variant has been found in all nine provinces as well as in foreign countries, but experts are unsure if the rise in cases is related to the new variant or to a lack of compliance with health guidelines during the holiday period. several countries have banned flights from south africa, and all 20 of the country's land entry points have been closed until february. south africa lost 2.2 million jobs in the second quarter of 2020, and gdp is expected to show a 6.1% decrease for the year. in total, south africa has registered more than 1.3 million coronavirus confirmed infections and at least 36,851 related deaths. on 27 january the department of health announced the emergency use approval of the astrazeneca vaccine and that the transportation of one million doses would be delivered from india on 1 february with a further half a million doses in late february. they also announced a full vaccination plan as well as a platform to manage the mass vaccination of the country. there were 396,600 new cases in january, raising the total number of confirmed cases to 1,453,761. the death toll rose to 44,164. the number of recovered patients increased to 1,299,620, leaving 109,977 active cases at the end of the month. february 2021 on 1 february, president ramaphosa announced the arrival at o. r. tambo international airport of the first batch of covid-19 vaccines produced by the serum institute of india. although south africa would remain at alert level 3, easing of restrictions effective the next day was announced because the peak of the second wave had passed. in his address to the nation, ramaphosa also mentioned that the south african cabinet had approved the proposal to nominate the cuban medical brigade for the 2021 nobel peace prize for its role in sending over 3 700 members around the world to help fight covid-19. on 7 february, it was announced that the oxford–astrazeneca covid-19 vaccine did not work well in protecting clinical trial participants from mild or moderate illness caused by the 501.v2 variant severe acute respiratory syndrome coronavirus 2, also known as b.1.351 lineage. the vaccination programme was announced to be put on hold. on 17 february, the national covid vaccination program was officially rolled out, beginning at khayelitsha district hospital in the western cape province where healthcare workers, the president and minister of health were given shots of the janssen vaccine. on 17 february 2021, the national covid-19 vaccination program was officially rolled out. on 28 february, the president addressed the nation, announcing relaxation of restrictions with a move from adjusted alert level 3 to adjusted alert level 1. there were 59,632 new cases in february, taking the total number of confirmed cases to 1,513,393. the death toll rose to 49,993. the number of recovered patients increased to 1,430,259, leaving 33,141 active cases at the end of the month. march 2021 on 5 march 2021, the number of people fully vaccinated against covid-19 surpassed 100,000 in the country. the south african medical research council estimated more than 150 000 excess deaths during the pandemic by 20 march 2021, with 85–95% of these excess natural deaths attributable to covid-19, and the remaining 5–15% probably mainly due to overwhelming of the health services. on 30 march 2021, president ramaphosa, addressed the nation ahead of the easter holiday. he gave information on covid-19 vaccination progress, announced temporary restrictions on offsite holiday alcohol sales and the easing of measures around religious gatherings. there were 34,764 new cases in march, taking the total number of confirmed cases to 1,548,157. the death toll rose to 52,846. the number of recovered patients increased to 1,474,319, leaving 20,992 active cases at the end of the month. april 2021 on 13 april 2021, minister of health zweli mkhize announced the suspension of janssen covid-19 vaccine (johnson & johnson) use following health concerns raised by the food and drug administration (fda). on 28 april 2021, the janssen vaccines suspension was lifted, and given the full approval for use by saprah. there were 33,053 new cases in april, taking the total number of confirmed cases to 1,581,210. the death toll rose to 54,350. the number of recovered patients increased to 1,505,620, leaving 21,240 active cases at the end of the month. third wave: may 2021 – october 2021 may 2021 by 1 may there were 157542 excess deaths of persons older than 1 years from natural causes since the start of the pandemic,

with 85–95% of these excess deaths attributable to covid-19, and the remaining 5–15% probably mainly due to overwhelming of the health services. on 8 may, the national institute for communicable diseases confirmed that they had sequenced covid-19 specimens from individuals who had recently travelled to india. this resulted in that four of the specimens tested positive for b.1.617.2 (two cases from gauteng and two from kwazulu-natal). eleven cases were also detected of the b.1.1.7 variant of concern, which has a higher transmissibility and is more lethal than south africa's dominant b.1.351. on 30 may, president ramaphosa, due to a surge in covid-19 infections, addressed the nation announcing the tightening of restrictions from adjusted level lockdown 1 to 2, beginning on 31 may 2021. the third covid-19 wave had taken hold. june 2021 on 15 june 2021 president cyril ramaphosa announced that the country was moved to alert level 3 due to the third wave. on 28 june 2021, the country was moved to adjusted level 4, with the delta variant fast becoming the dominant strain in the country. on 9 july 2021, sixteen months into the pandemic, doctors in johannesburg described the system there as beyond its breaking point, with insufficient beds and barely enough oxygen. on 27 june 2021, in a national address, the president announced the tightening of restrictions with a move to adjusted level 4 beginning on 28 june 2021. july 2021 the us delivers pfizer covid-19 vaccines to south africa as part of the covax initiative in 2021 on 9 july, sixteen months into the pandemic, doctors in johannesburg described the system there as beyond its breaking point, with insufficient beds and barely enough oxygen. on the 11th, the president cyril ramaphosa addressed the nation. he announced the continuation of adjusted level 4 restrictions, with some modifications to better tackle the third wave. on the 12th, the president announced that because of the 2021 south african unrest some covid-19 vaccination sites and clinics had been closed in gauteng and kwazulu-natal provinces. on the 25th the president announced moving the country to adjusted level 3 restrictions. august 2021 the highly mutated c.1.2 lineage variant, first detected in may, is reported to be of potential interest. september 2021 on 12 september 2021, the president announced the lowering of restrictions to adjusted alert level 2 taking effect on 13 september. on 13 september 2021 an adjusted alert level 2 took effect, and on 1 october 2021 more restrictions were eased by moving to adjusted alert level 1. october 2021 on 1 october 2021 more restrictions were eased by moving to adjusted alert level 1. november 2021 on 25 november 2021, a new heavily mutated coronavirus variant, b.1.1.529, later called omicron which spread from neighboring botswana, was announced. several countries announced travel bans from south africa, including: australia, canada, france, germany, hungary, indonesia, italy, malaysia, mauritius, singapore, south korea, sri lanka, thailand, the united kingdom, and the united states. countries that banned entry to all foreign travelers include israel, japan, and morocco (also banning moroccan citizens). on 28 november 2021, president cyril ramaphosa addressed the nation. he stated that there would be no immediate change in the country's coronavirus alert level because of the recently discovered omicron variant. he also asked countries that had imposed travel bans on south africa and its sister countries to reverse their decision. fourth wave: december 2021 – april 2022 december 2021 on 8 december, the national institute for communicable diseases (nicd) reported nearly 20,000 new covid-19 cases - a record since the omicron variant was detected. it was not immediately clear how many of the infections were caused by omicron. on 12 december, president ramaphosa tested positive for covid-19. on 30 december, government lifted more lockdown restrictions including curfew. modelling by who's regional office for africa suggests that due to under-reporting, the true cumulative number of infections by the end of 2021 was around 30 million while the true number of covid-19 deaths was around 92 thousand. january 2022 on the 31st, the adjusted alert level 1 was changed by not requiring isolation for those who tested positive but have no symptoms. those who tested positive but had symptoms, had to isolate for only 7 days (instead of the previous 10 days). contacts did not have to isolate unless they developed symptoms. primary, secondary, and special schools returned to daily attendance; and the requirement of social distancing of 1 meter in schools, was removed. april 2022 on midnight 4 april 2022, the national state of disaster was ended although some transitional provisions remained in place for a period of 30 days. fifth wave: may 2022 – present may 2022 in may 2022, the country entered a fifth wave. samples taken between may and october showed that the rapidly spreading ba.5.2.1.7 variant was present in south africa. june 2022 on 22 june, in a notification published in the government gazette, health minister joe phaahla repealed the country's covid-19 laws, which abolished covid restrictions such as the use of face masks.

forensic toxicology forensic toxicology forensic toxicology is the use of toxicology and disciplines such as analytical chemistry, pharmacology and clinical chemistry to aid medical or legal investigation of death, poisoning, and drug use. the primary concern for forensic toxicology is not the legal outcome of the toxicological investigation or the technology utilized, but rather the obtention and interpretation of results. a toxicological analysis can be done to various kinds of samples. a forensic toxicologist must consider the context of an investigation, in particular any physical symptoms recorded, and any evidence collected at a crime scene that may narrow the search, such as pill bottles, powders, trace residue, and any available chemicals. provided with this information and samples with which to work, the forensic toxicologist must determine which toxic substances are present, in what concentrations, and the probable effect of those chemicals on the person. in the united states, forensic toxicology can be separated into 3 disciplines: postmortem toxicology, human performance toxicology, and forensic drug testing (fdt). postmortem toxicology includes the analysis of biological specimens taken from an autopsy to identify the effect of drugs, alcohol, and poisons. a wide range of biological specimens may be analyzed including blood, urine, gastric contents, oral fluids, hair, tissues, and more. the forensic toxicologist works with pathologists, medical examiners, and coroners to help determine the cause and manner of death. in human performance toxicology, a dose-response relationship between a drug(s) present in the body and the effects on the body are examined. this field of forensic toxicology is responsible for building and implementing laws such as driving under the influence of alcohol or drugs. lastly, forensic drug testing (fdt) is the detection of drug use among individuals in the workplace, sport doping, drug-related probation, and new job applicant screenings. determining the substance ingested is often complicated by the body's natural processes (see adme), as it is rare for a chemical to remain in its original form once in the body. for example: heroin is almost immediately metabolised into another substance and further to morphine, making detailed investigation into factors such as injection marks and chemical purity necessary to confirm diagnosis. the substance may also have been diluted by its dispersal through the body; while a pill or other regulated dose of a drug may have grams or milligrams of the active constituent, an individual sample under investigation may only contain micrograms or nanograms. drug's location in the body how certain substances affect your body alcohol alcohol enters your central nervous system through the blood stream through the lining within your stomach and your small intestine. once it is in your blood stream, is passes through your blood brain barrier via blood circulation. the alcohol absorbed will reduce your reflexes, interfere with nerve impulses, prolong muscle responses, and affect other parts of your body as well. marijuana marijuana, like alcohol, is also absorbed into the blood stream and passed through the blood brain barrier. however, the thc that is released from marijuana attaches to the cb-1 cannabinoid receptors which causes all of the effects experienced. these effects include, but are not limited to, mood changes, altered perception of time, and increased sensitivity. cocaine cocaine is a stimulant unlike marijuana or alcohol. as soon as cocaine enters the bloodstream it reaches the brain in minutes. dopamine levels are increased intensely and the effects can last up to about 30 minutes. the most common way to use cocaine is by snorting it through the nose but other methods could be by smoking it in a crystal rock form. but because dopamine levels are increased at such a rate this leads to an even worse come down leading to needing a higher dose to get the same effect as the time before if taken again. this is how some addictions begin. some effects when taken are an increase of energy and happiness, paranoia, rapid heart rate, anxiety, etc... examples drugs in body urine a urine sample is urine that has come from the bladder and can be provided or taken post-mortem. urine is less likely to be infected with viruses such as hiv or hepatitis b than blood samples. many drugs have a higher concentration and can remain for much longer in urine than blood. collection of urine samples can be taken in a non-invasive way which does not require professionals for collection. urine is used for qualitative analysis as it cannot give any indication of impairment due to the fact that drug presence in urine only indicates prior exposure. different drugs can also stay in your urine for different amounts of time. for example, alcohol will stay within your urine for 7–12 hours, cocaine metabolites will stay for 2–4 days, and morphine will stay for 48–74 hours. one drug that will stay in your urine for a varying amount of time (dependent on the usage and frequency) is marijuana. for a single use, it will stay for 3 days, moderate use (4 times per week) will stay for 5–7 days, daily use of the drug will cause it to stay for 10–15 days, and a long-term heavy smoker will have it stay within their urine for less than 30 days. blood a blood sample of approximately 10 ml (0.35 imp fl oz; 0.34 us fl oz) is usually sufficient to screen and confirm most common toxic substances. a blood sample provides the toxicologist with a profile of the substance that the subject was influenced by at the time of collection; for this reason, it is the sample of choice for measuring blood alcohol content in drunk driving cases. hair hair is capable of recording medium to long-term or high dosage substance abuse. chemicals in the bloodstream may be transferred to the growing hair and stored in the follicle, providing a rough timeline of drug intake events. head hair grows at rate of approximately 1 to 1.5 cm a month, and so cross sections from different sections of the follicle can give estimates as to when a substance was ingested. testing for drugs in hair is not standard throughout the population. the darker and coarser the hair the more drug that will be found in the hair. if two people consumed the same amount of drugs, the person with the darker and coarser hair will have more drug in their hair than the lighter haired person when tested. this raises issues of possible racial bias in substance tests with hair samples. hair samples are analyzed using enzyme-linked immunosorbent assay (elisa). in elisa, an antigen must be immobilized to a solid surface and then complexed with an antibody that is linked to an enzyme. bone marrow bone marrow can be used for testing but that depends on the quality and availability of the bones. so far there is no proof that says that certain bones are better than others when it comes to testing. extracting bone marrow from larger bones is easier than smaller bones. forensic toxicologists use bone marrow to find what type poisons used. these poisons can include cocaine or ethanol.this diagram was created using google drawings, it was intended to model how and why a hair strand is useful in forensic investigation. other other bodily fluids and organs may provide samples, particularly samples collected during an autopsy. a common autopsy sample is the gastric contents of the deceased, which can be useful for detecting undigested pills or liquids that were ingested prior to death. in highly decomposed bodies, traditional samples may no longer be available. the vitreous humour from the eye may be used, as the fibrous layer of the eyeball and the eye socket of the skull protects the sample from trauma and adulteration. other common organs used for toxicology are the brain, liver, and spleen. detection and classification detection of drugs and pharmaceuticals in biological samples is usually done by an initial screening and then a confirmation of the compound(s), which may include a quantitation of the compound(s). the screening and confirmation are usually, but not necessarily, done with different analytical methods. every analytical method used in forensic toxicology should be carefully tested by performing a validation of the method to ensure correct and indisputable results at all times. the choice of method for testing is highly dependent on what kind of substance one expects to find and the material on which the testing is performed. customarily, a classification scheme is utilized that places poisons in categories such as: corrosive agents, gases and volatile agents, metallic poisons, non-volatile organic agents, and miscellaneous. immunoassays immunoassays requires you to draw blood and use the antibodies to find a reaction with substances such as drugs. the substances must be specific. it is the most common drug screening technique. using the targeted drug the test will tell you if it is positive or negative to that drug. there can be 4 results when taking the test. those results can be a true-positive, a false-negative, a false-positive, and a true-negative. gas chromatography-mass spectrometry gas chromatography-mass spectrometry (gc-ms) is a widely used analytical technique for the detection of volatile compounds. ionization techniques most frequently used in forensic toxicology include electron ionization (ei) or chemical ionization (ci), with ei being preferred in forensic analysis due to its detailed mass spectra and its large library of spectra. however, chemical ionization can provide greater sensitivity for certain compounds that have high electron affinity functional groups. liquid chromatography-mass spectrometry liquid chromatography-mass spectrometry (lc-ms) has the capability to analyze compounds that are polar and less volatile. derivatization is not required for these analytes as it would be in gc-ms, which simplifies sample preparation. as an alternative to immunoassay screening which generally requires confirmation with another technique, lc-ms offers greater selectivity and sensitivity. this subsequently reduces the possibility of a false negative result that has been recorded in immunoassay drug screening with synthetic cathinones and cannabinoids. a disadvantage of lc-ms on comparison to other analytical techniques such as gc-ms, is the high instrumentation cost. however, recent advances in lc-ms have led to higher resolution and sensitivity which assists in the evaluation of spectra to identify forensic analytes. detection of metals the compounds suspected of containing a metal are traditionally analyzed by the destruction of the organic matrix by chemical or thermal oxidation. this leaves the metal to be identified and quantified in the inorganic residue, and it can be detected using such methods as the reinsch test, emission spectroscopy or x-ray diffraction. unfortunately, while this identifies the metals present it removes the original compound, and so hinders efforts to determine what may have been ingested. the toxic effects of various metallic compounds can vary considerably.

vania (foram) vania (foram) vania is a genus of benthic forams from the upper paleocene of turkey with a large discoidal test up to 6.5mm in diameter. the microspheric test begins with a short planispiral stage, later chambers spreading successively from flabelliform (fan-shaped) to reniform (kidney-shaped) and finally annular. the interior is subdivided by radial primary beams intercalated with secondary beams. the wall finely agglutinated, imperforate; aperture, two alternating rows of pores on the periphery. vaniatemporal range: late paleocene scientific classification domain: eukaryota (unranked): sar (unranked): rhizaria phylum: retaria subphylum: foraminifera subclass: textulariia order: loftusiida family: spirocyclinidae genus: vaniasirel and gûndûz, 1985

hair follicle nevus hair follicle nevus hair follicle nevus is a cutaneous condition that presents as a small papule from which fine hairs protrude evenly from the surface. hair follicle nevusother namesvellus hamartomaspecialtydermatology

mammary gland mammary gland a mammary gland is an exocrine gland in humans and other mammals that produces milk to feed young offspring. mammals get their name from the latin word mamma, "breast". the mammary glands are arranged in organs such as the breasts in primates (for example, humans and chimpanzees), the udder in ruminants (for example, cows, goats, sheep, and deer), and the dugs of other animals (for example, dogs and cats). lactorrhea, the occasional production of milk by the glands, can occur in any mammal, but in most mammals, lactation, the production of enough milk for nursing, occurs only in phenotypic females who have gestated in recent months or years. it is directed by hormonal guidance from sex steroids. in a few mammalian species, male lactation can occur. with humans, male lactation can occur only under specific circumstances. mammary glandcross-section of the human mammary gland. chest wallpectoralis muscleslobulesnippleareolamilk ductfatty tissueskindetailsprecursormesoderm (blood vessels and connective tissue)ectoderm (cellular elements)arteryinternal thoracic arterylateral thoracic arteryveininternal thoracic veinaxillary veinnervesupraclavicular nervesintercostal nerves (lateral and medial branches)lymphpectoral axillary lymph nodesidentifiersta98a16.0.02.006ta27099fma60088anatomical terminology mammals are divided into 3 groups: prototherians, metatherians, and eutherians. in the case of prototherians, both males and females have functional mammary glands, but their mammary glands are without nipples. these mammary glands are modified sebaceous glands. concerning metatherians and eutherians, only females have functional mammary glands. their mammary glands can be termed as breasts or udders. in the case of breasts, each mammary gland has its own nipple (e.g., human mammary glands). in the case of udders, pairs of mammary glands comprise a single mass, with more than one nipple (or teat) hanging from it. for instance, cows and buffalo each have one udder with four teats, whereas sheep and goats each have two teats protruding from the udder. these mammary glands are modified sweat glands. structure

penicillium rasile penicillium rasile penicillium rasile is a species of fungus in the genus penicillium. penicillium rasile scientific classification kingdom: fungi division: ascomycota class: eurotiomycetes order: eurotiales family: trichocomaceae genus: penicillium species: p. rasile binomial name penicillium rasilepitt, j.i. 1979 type strain atcc 10464, cbs 345.48, frr 0705, ifo 6101, ifo 8849, imi 039735, mucl 38759, nbrc 6101, nbrc 8849, nrrl 705, qm 1877, thom 5521

breast cancer now breast cancer now breast cancer now is a charity in the united kingdom which was formed in 2015 by the merger of breast cancer campaign and breakthrough breast cancer. it is the united kingdom's largest breast cancer charity. its declared "action plan" is "by 2050, everyone who develops breast cancer will live". a truck owned by the mcgee engineering company advertising breast cancer now's 'wear it pink' campaign in 2015 among other projects the charity provides most of the funding for the breast cancer now toby robins research centre at the institute of cancer research, london, which employs 120 scientists and clinicians. the charity's chief executive is delyth morgan, baroness morgan of drefelin, and prince charles is its patron. in november 2018 research-focused breast cancer now and support-focused breast cancer care announced that they would merge on 1 april 2019, creating a charity with an income of about £45 million. the merged charity is chaired by jill thompson, formerly a trustee of breast cancer care, and the chief executive is delyth morgan, formerly chief executive of breast cancer now. the combined headquarters are at breast cancer now offices at aldgate, london. the charity said that it would operate using both names for about a year, when a new logo and name was expected to be introduced. as of january 2020 the charity's formal name is "breast cancer care and breast cancer now" and it uses the working name "breast cancer now". breast cancer now's flagship fundraising event is their 'wear it pink' campaign. this is one of the uk's biggest fundraising events having raised over £33 million since it launched in 2002. in 2019, the date for the 'wear it pink' campaign was 18 october.

hereditary diffuse gastric cancer hereditary diffuse gastric cancer hereditary diffuse gastric cancer (hdgc) is an inherited genetic syndrome most often caused by an inactivating mutation in the e-cadherin gene (cdh1) located on chromosome 16. individuals who inherit an inactive copy of the cdh1 gene are at significantly elevated risk for developing stomach cancer. for this reason, individuals with these mutations will often elect to undergo prophylactic gastrectomy, or a complete removal of the stomach to prevent this cancer. mutations in cdh1 are also associated with high risk of lobular breast cancers, and may be associated with a mildly elevated risk of colon cancer. hereditary diffuse gastric cancerother nameshdgcdiagram demonstrating the end result of a total gastrectomy, the most common prophylactic treatment of hdgc. in the procedure the esophagus is directly connected to the small intestine.specialtyoncology, gastroenterologycomplicationslobular breast cancerusual onset38 years of age (median)causesmutation of the e-cadherin gene (cdh1)risk factorsstomach cancertreatmenttotal gastrectomyfrequency1-3% of gastric cancers the most common form of stomach cancer associated with cdh1 mutations is diffuse type adenocarcinoma. an estimated 70% of males and 56% of females who inherit an inactivating cdh1 mutation will develop this form of cancer by age 80. female patients are also estimated to have a 42% lifetime risk of developing lobular breast cancer. the median age of gastric cancer diagnosis in individuals with a cdh1 inactivating mutation is 38 years of age, but cases have been reported as young as 14 years of age. genetics hdgc is inherited in an autosomal dominant fashion. hereditary diffuse gastric cancer is inherited as an autosomal dominant mutation of the e-cadherin gene (cdh1), which is located on chromosome 16q22.1. because the condition only conveys significantly increased risk of cancer, it can be described as having incomplete penetrance. the autosomal dominant nature of the mutations implies that inheriting just one mutated copy of the cdh1 gene is sufficient to induce a disease state. however, in order for cancer to arise in these individuals, both copies of the cdh1 gene must be inactive. therefore, hdgc is developed through a loss of heterozygosity, in which the one unmutated copy of the cdh1 gene undergoes mutation or inactivation in some cells during the lifetime of the individual. this explains why the majority of individuals with cdh1 mutations will develop clinical apparent cancer, but some do not. the gene mutated in hdgc, cdh1, codes for the e-cadherin protein. this protein serves numerous functions in cell to cell interactions, as well as intracellular signaling. development of cancerous cells and malignancy may be related to several of these functions. one major function includes cell-cell adhesion facilitated by e-cadherin binding. loss of this function may lead to dedifferentiation of cells and/or unregulated cell growth and replication. another major function includes binding and sequestering of the beta-catenin transcription factor, keeping it inactive. loss of this function may lead to overactivity of the transcription factor. genetic counseling and testing for cdh1 mutations are advised for families meeting the following criteria: families with two or more documented cases of diffuse gastric cancer among first or second degree relatives, with at least one case diagnosed before age 50. families with two or more documented cases of lobular breast cancers among first or second degree relatives, with or without diffuse gastric cancer in a first or second degree relative. any individual diagnosed with diffuse gastric cancer before 35 years of age from a low incidence population. non-cdh1 forms although cdh1 is by far the most common gene associated with hdgc, around 11% of cases arise in individuals who are negative for mutations in this gene. no other gene has been proven to cause hdgc, but possible associated genes include ctnna1, brca2, stk11, sdhb, prss1, atm, msr1, and palb2. treatment surgical removal of the stomach (gastrectomy) is typically recommended for people after 20 years of age, and before 40 years of age in order to prevent development of diffuse gastric adenocarcinoma. however, individuals discovering cdh1 mutations after the age of 40 may still be considered for gastrectomy. the physical and psychological health of each individual should be considered in determining the optimal time to perform this operation. younger individuals may wish to delay this procedure, and are often monitored with endoscopies and random biopsies. in addition, all individuals testing positive receive an initial endoscopy, at which any lesion is biopsied, as gastric cancer frequently begins without symptoms. females with cdh1 mutations also have an elevated risk of lobular breast carcinoma. frequent screening for breast cancer with both mammography and breast mri is common and recommended for these individuals. the risk of colon cancer in those with cdh1 mutations is still unclear. due to the mild risk that may be associated, individuals often receive screening colonoscopies at age 40, five years prior to the recommendation in the general population. epidemiology the median age at diagnosis is 38 years. an estimated 1-3% of gastric cancers are associated with hereditary cancer syndromes. hdgc is the most common hereditary cancer syndrome of the stomach. hdgc was originally discovered through studies of maori families in new zealand that were noted to have increased incidences of gastric cancer. detection of cdh1 mutations causing hdgc is highest in countries with low incidences of gastric cancer, such as the united states and canada. conversely, detection of cdh1 mutations is lowest in countries with high rates of gastric cancer, such as portugal, italy, and japan. for this reason, some have pushed for increased genetic screening in countries with high rates of gastric cancer, as the rates may mask the incidence of cdh1 mutations.

glucagon-like peptide-1 receptor agonist glucagon-like peptide-1 receptor agonist glucagon-like peptide-1 receptor agonists, also known as glp-1 receptor agonists (glp-1-ra), incretin mimetics, or glp-1 analogs, are agonists of the glp-1 receptor. this class of medications is used for the treatment of type 2 diabetes. one of their advantages over older insulin secretagogues, such as sulfonylureas or meglitinides, is that they have a lower risk of causing hypoglycemia. glp-1 has a short duration of action, so to overcome this limitation several modifications in either the drugs or the formulations are being developed. the 2022 ada standards of medical care in diabetes include glp-1-ra as a first line pharmacological therapy for type 2 diabetes, specifically in patients with atherosclerotic cardiovascular disease or obesity. some glp-1 receptor agonists have been used off-label for obesity and impulse control. health effects a 2021 meta-analysis found a 12% reduction in all-cause mortality when glp-1 analogs are used in the treatment of type 2 diabetes, as well as significant improvements in cardiovascular and renal outcomes. a jama article meta-analysis in 2018 (covering studies concerning glp-1 agonists, dpp-4 inhibitors, and sglt2 inhibitors) showed glp-1 agonists were associated with lower stroke risk than controls. preclinical research has suggested the possibility that the drugs may increase the risk of pancreatitis and pancreatic cancer. analyses of human trials have not found an increased risk of pancreatitis but are insufficiently powered to rule out an effect on pancreatic cancer. studies in rodents have shown glp1 mediated thyroid c-cell hyperplasia. approved exenatide (brand names byetta and bydureon, manufactured by astrazeneca), approved in 2005/2012 liraglutide (victoza for diabetes, saxenda for obesity, manufactured by novo nordisk), approved in 2010 albiglutide (tanzeum, manufactured by gsk), approved in 2014 dulaglutide (trulicity, manufactured by eli lilly), approved in 2014 lixisenatide (lyxumia in europe, adlyxin in the united states, manufactured by sanofi), approved in 2016 semaglutide (ozempic and rybelsus for diabetes, wegovy for obesity, manufactured by novo nordisk), approved in 2017 tirzepatide (mounjaro, manufactured by eli lilly), approved in 2022 under investigation taspoglutide, phase iii halted sept 2010 efpeglenatide mechanism these agents work by activating the glp-1r, rather than inhibiting the breakdown of glp-1 as do dpp-4 inhibitors, and are generally considered more potent.

diplomonad diplomonad the diplomonads (greek for "two units") are a group of flagellates, most of which are parasitic. they include giardia duodenalis, which causes giardiasis in humans. they are placed among the metamonads, and appear to be particularly close relatives of the retortamonads. diplomonad giardia lamblia scientific classification domain: eukaryota (unranked): excavata phylum: metamonada order: diplomonadida families, subfamilies, and genera enteromonadidae enteromonas trimitus hexamitidae giardiinae giardia octomitus hexamitinae hexamita spironucleus trepomonas most diplomonads are double cells: they have two nuclei, each with four associated flagella, arranged symmetrically about the body's main axis. like the retortamonads, they lack both mitochondria and golgi apparatuses. however, they are now known to possess modified mitochondria, in the case of g. duodenalis, called mitosomes. these are not used in atp synthesis the way mitochondria are, but are involved in the maturation of iron-sulfur proteins. possible sexual reproduction in giardia the common intestinal parasite giardia duodenalis (synonyms giardia lamblia, g. intestinalis) was once considered to be a descendant of a protist lineage that predated the emergence of meiosis and sex. however, researchers found g. duodenalis to have a core set of genes that function in meiosis and that are widely present among sexual eukaryotes. these results suggested that giardia duodenalis is capable of meiosis and thus sexual reproduction. furthermore, cooper et al. found direct evidence in giardia duodenalis for infrequent meiotic recombination, indicative of sexual reproduction between individuals. lasek-nesselquist et al. also detected molecular signatures consistent with meiotic sex. the possibility of sexual reproduction is still debated. giardia duodenalis contains two functionally equivalent nuclei that are inherited independently during mitosis. in the giardial cyst these nuclei fuse (karyogamy) and undergo homologous recombination facilitated by meiosis gene homologs. the recombination associated with karyogamy may primarily function to repair dna damage. giardia duodenalis is divided into eight assemblages based on host specificities and genetic divergence of marker genes. although recombination can occur infrequently within assemblages, xu et al. found that recombination between individuals from different assemblages is very rare. they suggested that the assemblages are genetically isolated lineages, and thus could be viewed as separated giardia species.

domoxin domoxin domoxin (inn) is a hydrazine derivative monoamine oxidase inhibitor (maoi) antidepressant which was never marketed. domoxinclinical dataatc codenoneidentifiers iupac name 1-benzyl-1-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)hydrazine cas number61-74-5pubchem cid208853chemspider180960unii5c0k1gqb2lchemblchembl2105038chemical and physical dataformulac16h18n2o2molar mass270.332 g·mol−13d model (jsmol)interactive image smiles o1c3c(oc(c1)cn(n)cc2ccccc2)cccc3 inchi inchi=1s/c16h18n2o2/c17-18(10-13-6-2-1-3-7-13)11-14-12-19-15-8-4-5-9-16(15)20-14/h1-9,14h,10-12,17h2key:ixtxysawzicapv-uhfffaoysa-n

ibrolipim ibrolipim ibrolipim (no-1886) is a cholesterol lowering drug from the statin family, which acts as a lipoprotein lipase activator. the discovery of the "statin" mevalonic acid synthesis inhibitors focused new attention on control of blood lipid levels as a measure to stave off heart disease. a number of compounds have been found that treat elevated lipid levels by other diverse mechanisms. the phosphonic acid derivative ibrolipim is believed to lower those levels by accelerating fatty acid oxidation. ibrolipim names preferred iupac name diethyl (methyl)phosphonate identifiers cas number 133208-93-2 y 3d model (jsmol) interactive image chemspider 116297 y echa infocard 100.162.319 kegg d03747 y pubchem cid 131601 unii 07h1561618 y comptox dashboard (epa) dtxsid20157989 inchi inchi=1s/c19h20brn2o4p/c1-3-25-27(24,26-4-2)13-14-5-7-15(8-6-14)19(23)22-18-10-9-17(20)11-16(18)12-21/h5-11h,3-4,13h2,1-2h3,(h,22,23) ykey: kprturmjvwxurq-uhfffaoysa-n yinchi=1s/c19h20brn2o4p/c1-3-25-27(24,26-4-2)13-14-5-7-15(8-6-14)19(23)22-18-10-9-17(20)11-16(18)12-21/h5-11h,3-4,13h2,1-2h3,(h,22,23)inchi=1s/c19h20brn2o4p/c1-3-25-27(24,26-4-2)13-14-5-7-15(8-6-14)19(23)22-18-10-9-17(20)11-16(18)12-21/h5-11h,3-4,13h2,1-2h3,(h,22,23)key: kprturmjvwxurq-uhfffaoysa-n smiles brc2cc(c#n)c(nc(=o)c1ccc(cc1)cp(=o)(occ)occ)cc2 properties chemical formula c19h20brn2o4p molar mass 451.25 except where otherwise noted, data are given for materials in their standard state (at 25 °c , 100 kpa). n verify (what is yn ?) infobox references

united states health care reform: progress to date and next steps united states health care reform: progress to date and next steps "united states health care reform: progress to date and next steps" is a review article by then-president of the united states barack obama in which he reviews the effects of the affordable care act (aca), a major health care law he signed in 2010, and recommends health care policy changes that he thinks would build on its successes. the article was published in the journal of the american medical association (jama) as a "special communication" online on july 11, 2016, and in print on august 2, 2016. with the article's publication, obama became the first sitting u.s. president to publish an article in a peer-reviewed academic journal. the article was named the most popular paper published in an academic journal in 2016 by altmetric, which gave it a score of 8,063, the highest such score ever recorded. background white house deputy chief of staff for implementation kristie canegallo told npr that the idea for obama to write the article originated when he requested a "comprehensive review" of the affordable care act from his staff in late 2015. canegallo also said that after he received this review, he decided he wanted to share its findings publicly, and that the purpose of obama's article was to inform future policy makers. peer review according to bloomberg news, the article was not peer-reviewed, but did undergo multiple rounds of editing and fact-checking. a spokesman for jama said that "the article by president obama was treated in the same fashion as other special communication articles, including undergoing rigorous internal review, two revisions of the manuscript, and subsequent modifications during the editing process as the revised manuscript was reviewed again by the editor-in-chief and executive editor". the editor-in-chief of jama, howard bauchner, said that the article underwent two months of fact-checking and revisions before being published. accompanying editorials four editorials were also published alongside the article critiquing its conclusions. one editorial was written by peter orszag, the former director of the office of management and budget earlier in the obama administration, and a major architect of the aca. orszag argued that the aca had generally succeeded in its objectives, in line with what obama argued in his article, while the other three editorials (one by stuart butler, one by jonathan skinner and amitabh chandra, and one by howard bauchner) were more critical of obama's conclusions. for example, the editorial by skinner and chandra criticized obama's claim that the aca was limiting the growth of health care spending, and butler's editorial argued that the savings produced by the aca may not have benefited consumers. conclusions regarding the affordable care act in the article, obama reviews the effects of his signature health care reform law, the patient protection and affordable care act, widely known as "obamacare". he concludes that since the law took effect, 20 million more americans have gained health insurance under it, and the uninsurance rate has dropped to 9.1% (as of 2015). he also acknowledges that more work remains to be done to improve america's health care system, noting that many americans still cannot afford many of their medical treatments and visits, or have no health insurance at all. recommendations in the article, obama recommends that after he leaves office, the next president should introduce a "public option" for health insurance in parts of the united states where there are few insurers in the marketplace. he also calls on his successor to try to reduce prices of prescription drugs.

ferb 033 ferb 033 ferb 033 is a synthetic, nonsteroidal estrogen that was synthesized in 2009 and is used in scientific research. it is a potent and selective erβ agonist (ki = 7.1 nm, ec50 = 4.8 nm), with 62-fold selectivity for the erβ over the erα. ferb 033identifiers iupac name 2-chloro-3′-fluoro-3,4′-dihydroxy--4-carboxaldehyde oxime cas number1111084-78-6 ychemspider24606020unii9fut9fh3exchemical and physical dataformulac13h9clfno3molar mass281.67 g·mol−13d model (jsmol)interactive image smiles c1cc(c(cc1c2ccc(c(c2cl)o)/c=n/o)f)o inchi inchi=1s/c13h9clfno3/c14-12-9(3-1-8(6-16-19)13(12)18)7-2-4-11(17)10(15)5-7/h1-6,17-19h/b16-6+key:lrrmqngsyouany-omciszlksa-n

fingersmith (slang) fingersmith (slang) fingersmith or finger-smith is slang for a midwife or pickpocket. look up fingersmith in wiktionary, the free dictionary. used in a 1977 short story, "the hitchhiker" by roald dahl and as the title of sarah waters's 2002 novel: "fingersmith".

gallium nitrate gallium nitrate gallium nitrate (brand name ganite) is the gallium salt of nitric acid with the chemical formula ga(no3)3. it is a drug used to treat symptomatic hypercalcemia secondary to cancer. it works by preventing the breakdown of bone through the inhibition of osteoclast activity, thus lowering the amount of free calcium in the blood. gallium nitrate is also used to synthesize other gallium compounds. gallium nitrate names iupac name gallium trinitrate other names gallium(iii) nitratenitric acid, gallium salt identifiers cas number 13494-90-1 n 3d model (jsmol) interactive image chembl chembl1200983 y drugbank db05260 echa infocard 100.033.453 ec number 236-815-5 pubchem cid 61635 unii y2v2r4w9tq y un number 1477 comptox dashboard (epa) dtxsid0043923 inchi inchi=1s/ga.3no3/c;3*2-1(3)4/q+3;3*-1key: chpzknuldcncbw-uhfffaoysa-n smiles (=o)().(=o)().(=o)(). properties chemical formula ga(no3)3 molar mass 255.7377 g/mol hazards ghs labelling: pictograms signal word danger hazard statements h272, h314, h315, h319, h335 precautionary statements p210, p220, p221, p260, p261, p264, p271, p280, p301+p330+p331, p302+p352, p303+p361+p353, p304+p340, p305+p351+p338, p310, p312, p321, p332+p313, p337+p313, p362, p363, p370+p378, p403+p233, p405, p501 except where otherwise noted, data are given for materials in their standard state (at 25 °c , 100 kpa). n verify (what is yn ?) infobox references history gallium (ga) was discovered in 1875 by p.é. lecoq de boisbaudran. in most of its compounds, gallium is found with an oxidation number of 3+. gallium chemically behaves similarly to iron 3+ when forming a coordination complex. that means gallium(iii) and iron(iii) are similar in similar coordination number, electrical charge, ion diameter and electron configuration. biological activity gallium atoms are bound to the phosphates of dna at low gallium concentrations, forming a stable complex. gallium competes with magnesium in dna binding, since its dna affinity is 100 times higher than that of magnesium. no interactions have been found between the metal and dna bases. according to hedley et al., gallium inhibits replicative dna synthesis, the major gallium-specific target probably being ribonucleotide reductase. in addition to that, it was reported by chitambar that gallium binds to transferrin more strongly than iron. the transferrin gallium complex inhibits dna synthesis by acting on the m2 subunit of ribonucleotide reductase. gallium(iii) seems to act as an antagonist to the actions of several ions (ca2+, mg2+, fe2+ and zn2+) in processes of cellular metabolism. the action of gallium on bone metabolism decreases hypercalcemia associated with cancer. however, gallium is mostly found within the cell as a salt in lysosomes. preparation gallium nitrate is commercially available as the hydrate. the nonahydrate may also be prepared by dissolving gallium in nitric acid, followed by recrystallization. the structure of gallium nitrate nonahydrate has been determined by x-ray crystallography. use and manufacturing preparation of gallium nitride from gallium nitrate gan powder was synthesized using a direct current (dc) non-transferred arc plasma. medication information gallium nitrate injection is a clear, colorless, odorless, sterile solution of gallium nitrate, a hydrated nitrate salt of the group iiia element, gallium. the stable, nonahydrate, ga(no3)3•9h2o is a white, slightly hygroscopic, crystalline powder of molecular weight 417.87, that is readily soluble in water. each ml of ganite (gallium nitrate injection) contains gallium nitrate 25 mg (on an anhydrous basis) and sodium citrate dihydrate 28.75 mg. the solution may contain sodium hydroxide or hydrochloric acid for ph adjustment to 6.0-7.0. overdose use of higher doses of gallium nitrate than recommended may cause nausea, vomiting and increases risk of chronic kidney disease. in the case of overdose, serum calcium should be monitored, patients should receive vigorous hydration for 2–3 days and any further drug administrations should be discontinued. treatment the action of gallium in gallium nitrate on bone metabolism decreases the hypercalcemia associated with cancer. gallium inhibits osteoclastic activity and therefore decreases hydroxyapatite crystal formation, with adsorption of gallium onto the surfaces of hydroxyapatite crystals. also, the increased concentration of gallium in the bone leads to increasing the synthesis of collagen as well as the formation of the bone tissue inside the cell. it has been reported that a protracted infusion was effective against cancer-associated hypercalcemia. preliminary studies in bladder carcinoma, carcinoma of the urothelium and lymphomas are also promising. another interesting schedule of subcutaneous injection with low doses of gallium nitrate has been proposed, especially for the treatment of bone metastases, but the definitive results have not yet been published. chemical reactivity gallium nitrate can react with reducing agents to generate heat and products that may be gaseous. the products may themselves be capable of further reactions (such as combustion in the air). the chemical reduction of materials in this group can be rapid, but often requires initiation of heat, catalyst and addition of a solvent. explosive mixtures of gallium nitrate with reducing agents often persist unchanged for long periods if initiation is prevented. some inorganic oxidizing agents such as gallium nitrate are salts of metals that are soluble in water; dissolution dilutes but does not nullify the oxidizing power of such materials. generally, inorganic oxidizing agents can react violently with active metals, cyanides, esters, and thiocyanates. adverse reaction kidney adverse renal effects have been reported in about 12.5% of patients treated with gallium nitrate. two patients receiving gallium nitrate and one patient receiving calcitonin developed acute renal failure in a controlled trial of patients with cancer-related hypercalcemia. also, it was reported that gallium nitrate should not be administered to patients with serum creatinine >2.5 mg/dl. blood pressure in a controlled trial of patients, it was noticed a decrease in mean systolic and diastolic blood pressure after the treatment with gallium nitrate. the decrease in blood pressure was asymptomatic and did not require specific treatment. hematologic high doses of gallium nitrate were associated with anemia when used in treating patients for advanced cancer. in results, several patients have received red blood cell transfusions.

100,000 genomes project 100,000 genomes project the 100,000 genomes project is a now-completed uk government project managed by genomics england that is sequencing whole genomes from national health service patients. the project is focusing on rare diseases, some common types of cancer, and infectious diseases. participants give consent for their genome data to be linked to information about their medical condition and health records. the medical and genomic data is shared with researchers to improve knowledge of the causes, treatment, and care of diseases. not to be confused with 100k pathogen genome project or 1000 genomes project. 100,000 genomes projectproject typegovernmentfunding agencynational institute for health and care researchnhs englandreferencedoi:10.3389/fpubh.2019.00079project coordinatorgenomics englandpartnersscottish genomes partnershipnorthern ireland genomic medicine centrenhs walesthe wellcome trustcancer research ukmedical research councildurationjuly 2013 – december 2018websitewww.genomicsengland.co.uk/about-genomics-england/the-100000-genomes-project/ history the project was first announced by uk prime minister david cameron in december 2012. the government set up a new company genomics england to oversee the project with the plan to focus on rare diseases, cancer, and infectious diseases announced by health secretary jeremy hunt in july 2013. the project was also made possible by the national institute for health and care research (nihr), nhs england, public health england, and health education england. in 2015, northern ireland and scotland also joined the project with plans to start work the following year. in 2016, the welsh government issued a statement of intent and is considering participating in the 100,000 genomes project. the initial participants were recruited from cambridge university hospitals, university college london partners, and newcastle upon tyne nhs foundation trust. the following medical centres joined the project a short time later: central manchester university hospitals nhs foundation trust, great ormond street hospital, guy's and st thomas' nhs foundation trust, moorfields eye hospital nhs foundation trust and oxford university hospitals nhs trust. in september 2015, genomics england announced it had contracted with interpretation partners congenica and omicia. this is in addition to ongoing work with sequencing partner illumina. as of 1 october 2018, the 100,000 genomes project had completed the sequencing of 87,231 whole genomes in england and results are in the process of being returned to nhs genomic medicine centres and ultimately back to participants; the first diagnoses from the project were returned to patients in spring 2015 and over 2,000 families' results have been returned to the nhs in the rare disease programme to date (july 2017). in december 2018, the full 100,000 genomes milestone was reached. in july 2019, genomics england announced data release 7, which included the 100,000th whole genome made available to researchers. a 2019 review identified the initiative as an 'exemplar' in involving the public in genomic research. in june 2020, lifebit, a uk-based biotechnology company, was announced as the provider of the trusted research environment that will link the genomic data gathered as part of the 100,000 genome project with academic research institutions. nhs genomic medicine centres main article: genomics_england § nhs_genomic_medicine_centres research the genomics england clinical interpretation partnership (gecip) includes 2,500 uk and international clinicians and scientists from approximately 300 institutions in 24 countries. there are plans to increase this number. researchers are organised in "domains" formed around particular conditions, cancer types and research areas such as machine learning and health economics. the partnership is integrated with the nhs and the aims include improving the use of genotype and phenotype data in healthcare, and providing a platform for genomic research collaborations to add to the knowledge base for genetic disorders. genomicc study on covid-19 the 100,000 genomes project provided a pre-covid reference set in the genomicc study on covid-19. genomics england worked in partnership with the genomicc consortium, led by the university of edinburgh, to analyse the whole genome sequences of approximately 20,000 people who have been severely affected by covid-19. this data was compared with 15,000 other genomes from people who were only mildly affected. it was combined with data set which now includes more than 120,000 genomes (from the "100,000 genomes" project). the 100,000 genomes project was referred to as the "incredibly important" pre-covid reference set. industrial partnerships from 2015 to 2017, 13 companies joined to form a pre-competitive industry trial, named the genomics expert network for enterprises (gene) consortium. this trial aimed to bring industry expertise into the 100,000 genomes project to identify potential benefits for patients, as the private sector is involved in developing new medicines and diagnostics for the nhs.

hypermobility (joints) hypermobility (joints) hypermobility, also known as double-jointedness, describes joints that stretch farther than normal. for example, some hypermobile people can bend their thumbs backwards to their wrists, bend their knee joints backwards, put their leg behind the head or perform other contortionist "tricks". it can affect one or more joints throughout the body. hypermobilityother nameshyperlaxity, benign joints hypermobility syndrome (bjhs), hypermobility syndrome (hms)hypermobile fingers and thumbspecialtyrheumatology, medical genetics hypermobile joints are common and occur in about 10 to 25% of the population, but in a minority of people, pain and other symptoms are present. this may be a sign of what is known as joint hypermobility syndrome (jms) or, more recently, hypermobility spectrum disorder (hsd). hypermobile joints are a feature of genetic connective tissue disorders such as hypermobility spectrum disorder (hsd) or ehlers–danlos syndromes (eds). until new diagnostic criteria were introduced, hypermobility syndrome was sometimes considered identical to hypermobile ehlers–danlos syndrome (heds), formerly called eds type 3. as no genetic test can distinguish the two conditions and because of the similarity of the diagnostic criteria and recommended treatments, many experts recommend they be recognized as the same condition until further research is undertaken. in 2016 the diagnostic criteria for heds were re-written to be more restrictive, with the intent of narrowing the pool of heds patients in the hope of making it easier to identify a common genetic mutation, heds being the only eds variant without a diagnostic dna test. at the same time, joint hypermobility syndrome was renamed as hypermobility spectrum disorder and redefined as a hypermobility disorder that does not meet the diagnostic criteria for heds, other types of ehlers-danlos syndrome, or other heritable connective tissue disorder (such as marfan's, loeys-dietz, or osteogenesis imperfecta). signs and symptoms people with joint hypermobility syndrome may develop other conditions caused by their unstable joints. these conditions include: joint instability causing frequent sprains, tendinitis, or bursitis when doing activities that would not affect others joint pain early-onset osteoarthritis (as early as during teen years) subluxations or dislocations, especially in the shoulder (severe limits on one's ability to push, pull, grasp, finger, reach, etc., is considered a disability by the us social security administration) knee pain fatigue, even after short periods of exercise back pain, prolapsed discs or spondylolisthesis joints that make clicking noises (also a symptom of osteoarthritis) susceptibility to whiplash temporomandibular joint dysfunction, also known as tmd increased nerve compression disorders (such as carpal tunnel syndrome) the ability of finger locking poor response to anaesthetic or pain medication "growing pains" as described in children in late afternoon or night associated conditions those with hypermobile joints are more likely to have fibromyalgia, mitral valve prolapse, and anxiety disorders such as panic disorder. causes hypermobile thumbs a hypermobile thumb (also called hitchhiker's thumb) hypermobility generally results from one or more of the following: abnormally shaped ends of one or more bones at a joint a defect of type 1 collagen (as found in ehlers–danlos syndrome) or other connective tissue (as found in loeys–dietz syndrome and marfan syndrome) resulting in weakened ligaments/ligamentous laxity, muscles and tendons. this same defect also results in weakened bones, which may result in osteoporosis and fractures. abnormal joint proprioception (an impaired ability to locate body parts in space and/or monitor an extended joint) these abnormalities cause abnormal joint stress, meaning that the joints can wear out, leading to osteoarthritis. the condition tends to run in families, suggesting a genetic basis for at least some forms of hypermobility. the term double jointed is often used to describe hypermobility; however, the name is a misnomer and should not be taken literally, as hypermobile joints are not doubled/extra in any sense. most people have hypermobility with no other symptoms. approximately 5% of the healthy population have one or more hypermobile joints. however, people with "joint hypermobility syndrome" are subject to many difficulties. for example, their joints may be easily injured, be more prone to complete dislocation due to the weakly stabilized joint and they may develop problems from muscle fatigue (as muscles must work harder to compensate for weakness in the ligaments that support the joints). hypermobility syndrome can lead to chronic pain or even disability in severe cases. musical instrumentalists with hypermobile fingers may have difficulties when fingers collapse into the finger locking position. or, conversely, they may display superior abilities due to their increased range of motion for fingering, such as in playing a violin or cello. hypermobility may be symptomatic of a serious medical condition, such as stickler syndrome, ehlers–danlos syndrome, marfan syndrome, loeys–dietz syndrome, rheumatoid arthritis, osteogenesis imperfecta, lupus, polio, fragile x syndrome, down syndrome, morquio syndrome, cleidocranial dysostosis or myotonia congenita. hypermobility has been associated with chronic fatigue syndrome and fibromyalgia. hypermobility causes physical trauma (in the form of joint dislocations, joint subluxations, joint instability, sprains, etc.). these conditions often, in turn, cause physical and/or emotional trauma and are possible triggers for conditions such as fibromyalgia. women with hypermobility may experience particular difficulties when pregnant. during pregnancy, the body releases relaxin and certain hormones that alter ligament physiology, easing the stretching needed to accommodate fetal growth as well as the birthing process. the combination of hypermobility and pregnancy-related pelvic girdle during pregnancy can be debilitating. the pregnant woman with hypermobile joints will often be in significant pain as muscles and joints adapt to the pregnancy. pain often inhibits such women from standing or walking during pregnancy. the pregnant patient may be forced to use a bedpan and/or a wheelchair during pregnancy and may experience permanent disability. symptoms of hypermobility include a dull but intense pain around the knee and ankle joints and the soles of the feet. the pain and discomfort affecting these body parts can be alleviated by using custom orthoses. syndromes hypermobile metacarpo-phalangeal joints hyperextension of the thumb hyperextension of the hand hypermobility syndrome is generally considered to comprise hypermobility together with other symptoms, such as myalgia and arthralgia. it is relatively common among children and affects more females than males. current thinking suggests four causative factors: the shape of the ends of the bones—some joints normally have a large range of movement, such as the shoulder and hip. both are ball-and-socket joints. if a shallow rather than a deep socket is inherited, a relatively large range of movement will be possible. if the socket is particularly shallow, then the joint may dislocate easily. protein deficiency or hormone problems—ligaments are made up of several types of protein fibre. these proteins include elastin, which gives elasticity and which may be altered in some people. female sex hormones alter collagen proteins. women are generally more supple just before a period and even more so in the latter stages of pregnancy, because of a hormone called relaxin that allows the pelvis to expand so the head of the baby can pass. joint mobility differs by race, which may reflect differences in collagen protein structure. people from the indian sub-continent, for example, often have more supple hands than caucasians. muscle tone—the tone of muscles is controlled by the nervous system, and influences range of movement. special techniques can change muscle tone and increase flexibility. yoga, for example, can help to relax muscles and make the joints more supple. however, yoga is not recommended by most medical professionals for people with joint hypermobility syndrome, due to the likelihood of damage to the joints. gymnasts and athletes can sometimes acquire hypermobility in some joints through activity. proprioception—compromised ability to detect exact joint/body position with closed eyes, may lead to overstretching and hypermobile joints. hypermobility can also be caused by connective tissue disorders, such as ehlers–danlos syndrome (eds) and marfan syndrome. joint hypermobility is a common symptom for both. eds has numerous sub-types; most include hypermobility in some degree. when hypermobility is the main symptom, then eds/hypermobility type is likely. people with eds-ht experience frequent joint dislocations and subluxations (partial/incomplete dislocations), with or without trauma, sometimes spontaneously. commonly, hypermobility is dismissed by medical professionals as nonsignificant. ehlers–danlos syndrome hypermobility type joint hypermobility is often correlated with hypermobile ehlers–danlos syndrome (heds, known also by eds type iii or ehlers–danlos syndrome hypermobility type (eds-ht)). ehlers–danlos syndrome is a genetic disorder caused by mutations or hereditary genes, but the genetic defect that produced heds is largely unknown. in conjunction with joint hypermobility, a common symptom for heds is smooth, velvety, and stretchy skin; a symptom largely unique to the syndrome. when diagnosing heds, the beighton criteria are used, but are not always able to distinguish between generalized hypermobility and heds. ehlers–danlos hypermobility type can have severe musculoskeletal effects, including: jaw laxity that may make an individual's jaw open and close like a hinge, as well as open further than the average. neck pain that can lead to chronic headaches and is usually associated with a crackling or grinding sensation (crepitus). the spine may end up in a "round back" or inversely may extend too much into hyperlordosis. individuals may also experience scoliosis. joints commonly associated with hypermobility (wrists, knees, ankles, elbows, shoulders) may be at more severe risk to dislocate or strain. diagnosis joint hypermobility syndrome shares symptoms with other conditions such as marfan syndrome, ehlers-danlos syndrome, and osteogenesis imperfecta. experts in connective tissue disorders formally agreed that severe forms of hypermobility syndrome and mild forms of ehlers-danlos syndrome hypermobility type are the same disorder. generalized hypermobility is a common feature in all these hereditary connective tissue disorders and many features overlap, but often features are present that enable differentiating these disorders. the inheritance pattern of ehlers-danlos syndrome varies by type. the arthrochalasia, classic, hypermobility and vascular forms usually have an autosomal dominant pattern of inheritance. autosomal dominant inheritance occurs when one copy of a gene in each cell is sufficient to cause a disorder. in some cases, an affected person inherits the mutation from one affected parent. other cases result from new (sporadic) gene mutations. such cases can occur in people with no history of the disorder in their family. the dermatosparaxis and kyphoscoliosis types of eds and some cases of the classic and hypermobility forms, are inherited in an autosomal recessive pattern. in autosomal recessive inheritance, two copies of the gene in each cell are altered. most often, both parents of an individual with an autosomal recessive disorder are carriers of one copy of the altered gene but do not show signs and symptoms of the disorder. beighton criteria beighton score criteria: one point for each elbow and knee that hyperextends by 10 degrees or more (4 points), one for each little finger that bends back by 90 degrees (2 points), one for each thumb which can be touched to the forearm (2 points), and one for touching the floor with the palms. as of july 2000, hypermobility was diagnosed using the beighton criteria. in 2017, the criteria changed, but still involve the beighton score. the beighton criteria do not replace the beighton score but instead use the previous score in conjunction with other symptoms and criteria. hms is diagnosed in the presence of either two major criteria, one major and two minor criteria, or four minor criteria. the criteria are: major criteria a beighton score of 5/9 or more (either current or historic) arthralgia for more than three months in four or more joints minor criteria a beighton score of 1, 2 or 3/9 (0, 1, 2 or 3 if aged 50+) arthralgia (> 3 months) in one to three joints or back pain (> 3 months), spondylosis, spondylolysis/spondylolisthesis. dislocation/subluxation in more than one joint, or in one joint on more than one occasion. soft tissue rheumatism. > 3 lesions (e.g. epicondylitis, tenosynovitis, bursitis). marfanoid habitus (tall, slim, span/height ratio >1.03, upper: lower segment ratio less than 0.89, arachnodactyly; positive steinberg finger / walker wrist signs). abnormal skin: striae, hyperextensibility, thin skin, papyraceous scarring. beighton score the beighton score is an edited version of the carter/wilkinson scoring system which was used for many years as an indicator of widespread hyper-mobility. medical professionals varied in their interpretations of the results; some accepting as low as 1/9 and some 4/9 as a diagnosis of hms. therefore, it was incorporated, with clearer guidelines, into the beighton criteria. the beighton score is measured by adding 1 point for each of the following: placing flat hands on the floor with straight legs left

knee bending backward right knee bending backward left elbow bending backward right elbow bending backward left thumb touching the forearm right thumb touching the forearm left little finger bending backward past 90 degrees right little finger bending backward past 90 degrees beighton test in a person with a 9/9 score treatments physical therapy it is important that hypermobile individuals remain fit – even more so than the average individual – to prevent recurrent injuries. regular exercise and exercise that is supervised by a physician and physical therapist can reduce symptoms because strong muscles increase dynamic joint stability. low-impact exercise such as closed kinetic chain exercises are usually recommended as they are less likely to cause injury when compared to high-impact exercise or contact sports. heat and cold treatment can help temporarily to relieve the pain of aching joints and muscles but does not address the underlying problems. medication medication is not the primary treatment for hypermobility, but can be used as an adjunct treatment for related joint pain. nonsteroidal anti-inflammatory drugs are the primary medications of choice. narcotics are not recommended for primary or long-term treatment and are reserved for short-term use after acute injury. lifestyle modification for some people with hypermobility, lifestyle changes decrease symptom severity. in general, activity that increases pain is to be avoided. for example: typing can reduce pain from writing. voice control software or a more ergonomic keyboard can reduce pain from typing. bent knees or sitting can reduce pain from standing. unwanted symptoms are frequently reduced by some forms of yoga and weightlifting. use of low impact elliptical trainer machines can replace high-impact running. pain-free swimming may require a kickboard or extra care to avoid hyperextending elbow and other joints. weakened ligaments and muscles contribute to poor posture, which may contribute to other medical conditions. isometric exercise avoids hyperextension and contributes to strength. other treatments bracing can be helpful for temporarily protecting unstable joints. epidemiology hypermobile joints occur in about 10 to 25% of the population.

maxillary first premolar maxillary first premolar the maxillary first premolar is one of two teeth located in the upper jaw, laterally (away from the midline of the face) from both the maxillary canines of the mouth but mesial (toward the midline of the face) from both maxillary second premolars. the function of this premolar is similar to that of canines in regard to tearing being the principal action during mastication, commonly known as chewing. there are two cusps on maxillary first premolars, and the buccal (closest to the cheek) cusp is sharp enough to resemble the prehensile teeth found in carnivorous animals. there are no deciduous maxillary premolars. around 10-11 years of age, the primary molars are shed and the permanent premolars erupt in their place. it takes about 3 years for the adult premolar and its root to fully calcify. due to its long buccal root with narrow root canal and short palatal root with wide root canal, the upper 1st premolar is very prone to fracture during exodontia, hence, it is sometimes referred to some dentists as the "king of fracture". in the universal system of notation, the permanent maxillary premolars are designated by a number. the right permanent maxillary first premolar is known as "5", and the left one is known as "12". in the palmer notation, a number is used in conjunction with a symbol designating in which quadrant the tooth is found. for this tooth, the left and right first premolars would have the same number, "4", but the right one would have the symbol, "┘", underneath it, while the left one would have, "└". the international notation has a different numbering system than the previous two, and the right permanent maxillary first premolar is known as "14", and the left one is known as "24". maxillary first premolarmaxillary first premolarmaxillary first premolaridentifiersfma55801anatomical terminology

streptomyces griseus streptomyces griseus streptomyces griseus is a species of bacteria in the genus streptomyces commonly found in soil. a few strains have been also reported from deep-sea sediments. it is a gram-positive bacterium with high gc content. along with most other streptomycetes, s. griseus strains are well known producers of antibiotics and other such commercially significant secondary metabolites. these strains are known to be producers of 32 different structural types of bioactive compounds. streptomycin, the first antibiotic ever reported from a bacterium, comes from strains of s. griseus. recently, the whole genome sequence of one of its strains had been completed. streptomyces griseus spore arrangement in streptomyces griseus. grey spores arranged in straight chains, as is typical of these strains. scientific classification domain: bacteria phylum: actinomycetota class: actinomycetia order: streptomycetales family: streptomycetaceae genus: streptomyces species: s. griseus binomial name streptomyces griseus(krainsky 1914)waksman and henrici 1948 synonyms "actinomyces acrimycini" preobrazhenskaya et al. 1957 "actinomyces fimicarius" duché 1934 "actinomyces globisporus subsp. flavofuscus" kudrina 1957 "actinomyces griseus" krainsky 1914 "actinomyces setonii" millard and burr 1926 streptomyces acrimycini (preobrazhenskaya et al. 1957) pridham et al. 1958 (approved lists 1980) streptomyces argenteolus tresner et al. 1961 (approved lists 1980) streptomyces baarnensis pridham et al. 1958 (approved lists 1980) streptomyces caviscabies goyer et al. 1996 streptomyces erumpens calot and cercós 1963 (approved lists 1980) streptomyces fimicarius (duché 1934) waksman and henrici 1948 (approved lists 1980) streptomyces flavofuscus (kudrina 1957) preobrazhenskaya 1986 streptomyces globisporus subsp. flavofuscus (kudrina 1957) pridham et al. 1958 (approved lists 1980) streptomyces setonii (millard and burr 1926) waksman 1953 (approved lists 1980) the taxonomic history of s. griseus and its phylogenetically related strains has been turbulent. s. griseus was first described in 1914 by krainsky, who called the species actinomyces griseus. the name was changed in 1948 by waksman and henrici to streptomyces griseus. the interest in these strains stems from their ability to produce streptomycin, a compound which demonstrated significant bactericidal activity against organisms such as yersinia pestis (the causative agent of plague) and mycobacterium tuberculosis (the causative agent of tuberculosis). streptomycin was discovered in the laboratory of selman waksman, although his phd student albert schatz probably did most of the work on these strains of bacteria and the antibiotic they produce. taxonomy main article: streptomyces streptomyces is the largest genus of the actinomycetota and is the type genus of the family streptomycetaceae. these are gram-positive bacteria with high gc content and are characterised by a complex secondary metabolism. they produce over two-thirds of the clinically useful antibiotics of natural origin. streptomycetes are found predominantly in soil and in decaying vegetation, and most produce spores. streptomycetes are noted for their distinct "earthy" odor which results from production of a volatile metabolite, geosmin. like other streptomycetes, s. griseus has a high gc content in its genome, with an average of 72.2%. the species was first classified within the genus streptomyces by waksman and henrici in 1948. the taxonomy of s. griseus and its evolutionarily related strains have been a considerable source of confusion for microbial systematists. 16s rrna gene sequence data have been used to recognise the related strains, and are called s. griseus 16s rrna gene clade. the strains of this clade have homogeneous phenotypic properties but show substantial genotypic heterogenecity based on genomic data. several attempts are still made to solve this issue using techniques such as dna:dna homology and multilocus sequence typing. a whole genome sequence was carried out on the ifo 13350 strain of s. griseus. physiology and morphology s. griseus and its related strains have recently been shown to be alkaliphilic, i.e., they grow best at alkaline ph values. although these organisms grow in a wide ph range (from 5 to 11), they show a growth optimum at ph 9. they produce grey spore masses and grey-yellow reverse pigments when they grow as colonies. the spores have smooth surfaces and are arranged as straight chains. ecology s. griseus strains have been isolated from various ecologies, including stell waste tips, rhizosphere, deep sea sediments and coastal beach and dune sand systems. recent studies have indicated the strains of s. griseus might be undergoing ecology-specific evolution, giving rise to genetic variation with the specific ecology, termed ecovars. antibiotic production interest in the genus streptomyces for antibiotics came after the discovery of the antibiotic streptomycin in a s. griseus strain in 1943. the discovery of streptomycin, an antituberculosis antibiotic, earned selman waksman the nobel prize in 1952. the award was not without controversy, since it excluded the nomination of albert schatz, who is now recognized as one of the major co-inventors of streptomycin. the strains of this species are now known to be rich sources of antibiotics and to produce 32 different structural types of commercially significant secondary metabolites. furthermore, the genomic studies have revealed a single strain of s. griseus ifo 13350 has the capacity to produce 34 different secondary metabolites. etymology by 1943, albert schatz, a phd student working in selman waksman’s laboratory, had isolated streptomycin from streptomyces griseus (from the greek strepto- ("twisted") + mykēs and the latin griseus, “gray”). the official new jersey state microbe s. griseus was designated the official new jersey state microbe in legislation submitted by senator sam thompson (r-12) in may 2017 and assemblywoman annette quijano (d-20) in june 2017. the organism was chosen because it is a new jersey native that made unique contributions to healthcare and scientific research worldwide. a strain of s. griseus that produced the antibiotic streptomycin was discovered in new jersey in “heavily manured field soil” from the new jersey agricultural experimental station by albert schatz in 1943. streptomycin is noteworthy because it is the first significant antibiotic discovered after penicillin, the first systemic antibiotic discovered in america, the first antibiotic active against tuberculosis, and the first-line treatment for plague. moreover, new jersey was the home of selman waksman, who was awarded the nobel prize in physiology or medicine for his systematic studies of antibiotic production by s. griseus and other soil microbes. the bill, s1729, was signed into law by nj governor phil murphy may 2019.

oscillatoria willei oscillatoria willei oscillatoria willei is a species of bacteria that is able to photosynthesize to make food, similarly to plants. oscillatoria willei scientific classification domain: bacteria phylum: cyanobacteria class: cyanophyceae order: oscillatoriales family: oscillatoriaceae genus: oscillatoria species: o. willei binomial name oscillatoria willein. l. gardner anatomy bacteria of the genus oscillatoria occur in rows of cells of similar size. they form filaments called trichomes. many trichomes are enveloped in a firm casing, but in this genus the casing is almost non-existent. this gives the filaments easier mobility in all directions. nitrogen fixing ability this species of oscillatoria is able to fix nitrogen, but unlike other bacteria, it is uncertain whether or not it has cells specialized for that particular purpose. hormogonia fragments of filaments of oscillatoria willei are called hormogonia. they consist of dozens of cells, which sometimes break off to reproduce by establishing new colonies. danger to humans like all species of oscillatoria, this species can cause skin irritation in humans who come in close contact with them in the tropics.

hypohidrotic ectodermal dysplasia hypohidrotic ectodermal dysplasia hypohidrotic ectodermal dysplasia is one of about 150 types of ectodermal dysplasia in humans. before birth, these disorders result in the abnormal development of structures including the skin, hair, nails, teeth, and sweat glands. hypohidrotic ectodermal dysplasiaother namesanhidrotic ectodermal dysplasia, christ-siemens-touraine syndrome: 570 this condition is inherited in an x-linked recessive manner.specialtymedical genetics presentation actor michael berryman displays outward symptoms of the condition most people with hypohidrotic ectodermal dysplasia have a reduced ability to sweat (hypohidrosis) because they have fewer sweat glands than normal or their sweat glands do not function properly. sweating is a major way that the body controls its temperature; as sweat evaporates from the skin, it cools the body. an inability to sweat can lead to a dangerously high body temperature (hyperthermia) particularly in hot weather. in some cases, hyperthermia can cause life-threatening medical problems. affected individuals tend to have sparse scalp and body hair (hypotrichosis). the hair is often light-coloured, brittle, and slow-growing. this condition is also characterized by absent teeth (hypodontia) or teeth that are malformed. the teeth that are present are frequently small and pointed. hypohidrotic ectodermal dysplasia is associated with distinctive facial features including a prominent forehead, thin lips, and a flattened bridge of the nose. additional features of this condition include thin, wrinkled, and dark-colored skin around the eyes; chronic skin problems such as eczema; and a foul-smelling discharge from the nose (ozena). hypohidrotic ectodermal dysplasia is the most common form of ectodermal dysplasia in humans. it is estimated to affect at least 1 in 17,000 people worldwide. genetics mutations in the eda, edar, and edaradd genes cause hypohidrotic ectodermal dysplasia. the eda, edar, and edaradd genes provide instructions for making proteins that work together during embryonic development. these proteins form part of a signaling pathway that is critical for the interaction between two cell layers, the ectoderm and the mesoderm. in the early embryo, these cell layers form the basis for many of the body's organs and tissues. ectoderm-mesoderm interactions are essential for the formation of several structures that arise from the ectoderm, including the skin, hair, nails, teeth, and sweat glands. hypohidrotic ectodermal dysplasia has several different inheritance patterns. eda (x-linked) most cases are caused by mutations in the eda gene, which are inherited in an x-linked recessive pattern, called x-linked hypohidrotic ectodermal dysplasia (xlhed). a condition is considered x-linked if the mutated gene that causes the disorder is located on the x chromosome, one of the two sex chromosomes. in males (who have only one x chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. in females (who have two x chromosomes), a mutation must be present in both copies of the gene to cause the disorder. males are affected by x-linked recessive disorders much more frequently than females. a striking characteristic of x-linked inheritance is that fathers cannot pass x-linked traits to their sons. in x-linked recessive inheritance, a female with one altered copy of the gene in each cell is called a carrier. since females operate on only one of their two x chromosomes (x inactivation) a female carrier may or may not manifest symptoms of the disease. if a female carrier is operating on her normal x she will not show symptoms. if a female is operating on her carrier x she will show symptoms. in about 70 percent of cases, carriers of hypohidrotic ectodermal dysplasia experience some features of the condition. these signs and symptoms are usually mild and include a few missing or abnormal teeth, sparse hair, and some problems with sweat gland function. some carriers, however, have more severe features of this disorder. treatments in january 2013, edimer pharmaceuticals, a biotechnology company based in cambridge, ma, usa, initiated a phase i, open-label, safety and pharmacokinetic clinical study of edi200, a drug aimed at the treatment of xlhed. during development in mice and dogs edi200 has been shown to substitute for the altered or missing protein resulting from the eda mutation which causes xlhed. a second trial in newborn infants with xlhed tested the synthetic protein in 10 subjects between 2013 and 2016 at 6 sites in the us and europe. as the treated group "didn’t see significant changes in sweat gland function and other early markers of biologic activity", prenatal administration of the drug was considered. following the edimer trials, dr. holm schneider, the principal investigator of these trials which indicated sufficient safety of the replacement protein, injected edi200 via amniocentesis with better development of tooth buds and sweat glands than in the postnatal trial and persistent sweating ability in all three treated boys. edar or edaradd (autosomal) less commonly, hypohidrotic ectodermal dysplasia results from mutations in the edar or edaradd gene. both edar and edaradd mutations can have an autosomal dominant or autosomal recessive pattern of inheritance. autosomal dominant inheritance means one copy of the altered gene in each cell is sufficient to cause the disorder. autosomal recessive inheritance means two copies of the gene in each cell are altered. most often, the parents of an individual with an autosomal recessive disorder are carriers of one copy of the altered gene but do not show signs and symptoms of the disorder. terminology the eponym christ-siemens-touraine syndrome was named after its discoverers: josef christ (1871–1948), a german dentist and physician from wiesbaden, who was the first physician to identify the condition, hermann werner siemens (1891–1969), a pioneering german dermatologist from charlottenburg, who clearly identified its pathological characteristics in the early 1930s, and albert touraine (1883–1961), a french dermatologist who likewise noted and identified additional characteristics of the disease in the late 1930s. notable individuals michael berryman, saturn award-nominated character actor

roseovarius azorensis roseovarius azorensis roseovarius azorensis is a gram-negative, aerobic, non-spore-forming, rod-shaped and motile bacterium from the genus of roseovarius which has been isolated from seawater from espalamaca from the azores. roseovarius azorensis scientific classification domain: bacteria phylum: pseudomonadota class: alphaproteobacteria order: rhodobacterales family: rhodobacteraceae genus: roseovarius species: r. azorensis binomial name roseovarius azorensisrajasabapathy et al. 2014 type strain kctc 32421, mtcc 11812, strain ssw084

water resources management in el salvador water resources management in el salvador water resources management in el salvador is characterized by difficulties in addressing severe water pollution throughout much of the country's surface waters due to untreated discharges of agricultural, domestic and industrial run off. the river that drains the capital city of san salvador is considered to be polluted beyond the capability of most treatment procedures. not to be confused with water supply and sanitation in el salvador. water resources management in el salvadorwithdrawals by sector 2000 domestic: 25% agriculture: 59.4% industry: 15.6% renewable water resources17.75 km3surface water produced internally25 km3groundwater recharge6.15 km3overlap shared by surface water and groundwater6 km3renewable water resources per capita2,755 m3/yearwetland designated as ramsar sites1,333 km2 (2010)hydropower generation36% el salvador has ample groundwater and partly relies on these supplies for domestic purposes. deforestation has ravaged the country to the point that very little primary forest remains. this has led to substantial difficulties in managing stormwater when hurricanes and tropical storms make landfall. torrential rain leads to deadly floods and mudslides that have claimed many lives in el salvador. a growing urban population coupled with high levels of water losses in urban centers is also challenging water institutions that are not well coordinated. this leads to inefficient water resources management. water management challenges water pollution the acelhuate river is an important drainage system for el salvador's capital, san salvador, and is severely contaminated with heavy metals along with domestic and industrial waste. this water is considered a biohazard, and the contamination is so severe that it is rendered untreatable by treatment methods such as reverse osmosis. contaminated water from the acelhuate river flows directly into the cerron grande reservoir. the cerrón grande reservoir is overloaded with sewage and industrial waste. in a 2004 study, the el salvador ministry of environment found that the waste is coming from 54 industrial plants, 55 coffee processing plants, seven sugar mills, and 29 sewer systems discharging directly into the reservoir. cerrón grande dam was built in 1974 to drive el salvador's largest hydroelectric project, and the 135 km2 reservoir collects some 3,800 tones of excrement each year from the sewage pipes, as well as factory effluents consisting of heavy metals such as chromium and lead. the sedimentation volumes in the cerron grande reservoir are dangerously high also and estimated to be as high as 7 million m3 per year which gravely impacts the health of the reservoir. many shallow aquifers are becoming contaminated from the severe surface pollution, and this is critically challenging as deeper wells are more relied upon to provide potable water. in el salvador, rivers and streams in the principal agricultural areas are highly polluted by pesticides, particularly by ddt in cotton cultivations in the south-eastern coastal plains. concentrations of 3.15 mg of ddt per litre of water have been discovered in the río grande de san miguel. flooding and stormwater el salvador sits directly in the path of tropical storms and hurricanes as evidenced by hurricane mitch in 1998 causing us$400 million in damage. hurricane stan in 2005 caused considerable flooding throughout el salvador, resulted in 67 deaths, and displaced more than 50,000 people. damages from stan were estimated at us$355 million. there was a tropical storm in 2008 that also led to major flooding and mudslides and killed 199. another determining factor in the severe flood waters that plague el salvador is deforestation. el salvador is the second most deforested country in latin america after haiti. much of el salvador's tree cover has been removed, leaving the country vulnerable to flash flooding. only an estimated 2 per cent of the tree cover that existed before the 10-year civil war remains. almost 85 percent of its forested cover has disappeared since the 1960s and less than 6,000 hectares are classified as primary forest. urbanization the urbanized population in el salvador was 61% in 2008 with an increase of 2% each year. in the case of san salvador, the urbanized surface of the metropolitan area has increased almost exponentially, from 6.8 km2 in 1935 to 91.5 km2 in 2000. this has mainly taken place in the largest aquifer recharge areas. because of this, the areas with the highest rate of infiltration have been reduced, whereas the areas with a low infiltration rate of 0.05 mm/hour have increased by the same proportion. water resource base lempa riversunset over the lempa riverphysical characteristicssource • locationsierra madre, guatemala • elevation1,200 m (3,900 ft) mouthpacific ocean • locationel playón, tecoluca, el salvadorlength422 km (262 mi)basin size18,246 km2 (7,045 sq mi)discharge • average362 m3/s (12,800 cu ft/s) it is estimated that el salvador has 17.3 km3 of water resources per year. approximately 67% or 11.6 km3 of this water is surface water. the remaining 5.7 km3 are found in groundwater which is heavily relied upon because surface water is generally severely polluted. precipitation levels are the most significant in the higher elevations varying from about 2, 286 mm in the mountain ranges down to 1,448 mm in coastal plains. about 95% of the rainfall occurs from may to october with frequent and severe droughts occurring during the drier months. around 84% of the surface runoff takes place during the rainy season (may–october) while the remaining 16% will run off during the dry season. groundwater and surface water resources el salvador counts nearly 360 rivers that connect to form ten hydrographic regions. there are four primary lakes in el salvador including the llopango (70 km2), guija (44 km2), coatepeque (24.8 km2), , olomega ( 24.2 km2) and four reservoirs created by hydroelectric dams discussed in more detail below. el salvador also obtains about 7.5 km3 of surface water per year from neighboring honduras and guatemala. the cerrón grande reservoir, known locally as lake suchitlán, is the largest body of fresh water in el salvador. the lempa river watershed dominates el salvador covering half of the country at 10, 255 km2 and draining 6, 214 million m3. the lempa is 422 km long and originates in the sierra madre and the sierra del merendón in southern guatemala. the river flows in honduras for 31 km before entering el salvador in northwest. groundwater is heavily relied upon for water supply as a result of polluted surface water, and sufficient supplies of fresh groundwater are available throughout most of the country. groundwater recharge from infiltration is estimated at 6.15 km3 per year whereby 5.97 km3 is considered base flow that serves to recharge surface waters and therefore has the possibility of being extracted. the remaining unused water passes down through the river system and discharges into the pacific ocean. the best aquifers are located in coastal areas and valleys of the central plateau where substantial groundwater aquifers are located at depths of 10–100 meters. table: principal characteristics in hydrological regions of el salvador. hydrographic region primary rivers surface area (km2) annual runoff (million m3) rainy season annual runoff (million m3) dry season annual runoff (million m3) a lempa 10, 255 6, 214 5, 217 836 b paz 929 466 358 107 c sacramento, sunza 659 369 317 51 d san pedro, sonsonate, banderas 875 776 654 123 e maridinga, tihuapa 1,146 359 310 50 f comalapa, guayabo 1,717 886 804 95 g afluentes de la bahia de jiquilisco 958 618 502 115 h grande de san miguel 2, 250 1,161 985 175 i afluentes del golfo de fonseca 804 299 296 33 j sirama y guascorán 1,348 479 423 56 subtotal 20,941 11,627 9.867 1,642 total with guatemala and honduras runoff totals added (regions a, b, j) 31,841 17,768 15,017 2,632 source: fao 2000 water resources management by sector the average per capita availability of water in el salvador is less than 2,800 m3/year. per capita annual extraction is 118 m3 representing about 4.3% of available supplies. agriculture uses about 60%, domestic needs are around 24%, and industrial usage is 16%. water coverage and usage main article: water supply and sanitation in el salvador access to an improved water source in el salvador was estimated at 76% in 2006. urban access was 90%, including about 13% lacking a piped connection to the house. access in rural areas in 2006 was 50%, however only 38% of this total had a piped connection to the house. most water in rural areas is drawn from groundwater wells. irrigation and drainage potential surface area for irrigation if only considering soil type is around 676,000 acres (2,740 km2); however, when adequate availability of water is also considered, the potential surface area for irrigation is about 500,000 acres (2,000 km2). approximately 56% of water available for irrigation is drawn from surface water while the rest is supplied from groundwater. the highest potential for irrigation is located in the coastal plains where the best groundwater is located. about 24% of the total potential area is classified as having "good" potential, while 60% is classified as having a "moderate" potential, and finally about 15% is classified as having potential with substantial limitations. the private sector for irrigation has grown substantially since 1950 when only 4,000 acres (16 km2) were under irrigation by the private sector. by 1960, there were 40,000 acres (160 km2) irrigated by the private sector and in 1995, 57,000 acres (230 km2) were being irrigated under private control. a concerted effort to develop the irrigation sector between 1966 and 1991 was put forth by the ministry of agriculture (mag) through their general directorate of irrigation and drainage. mag enacted irrigation districts in zapotitán (7,400 acres), and atiocoyo (9,760 acres) with an investment of us $24.7 million and later developed the lempa-acahuapa district at a cost of us $21.2 million. since 1975, growth in private sector irrigation has stabilized where grass crops have been replaced with higher value crops with a larger profit margin. the distribution of publicly managed irrigation are located mostly in the sonsonate, sensunapán, banderas, and san pedro watersheds. public irrigation projects are also prevalent in other areas where good water and soil are located such as the lempa river, titihuapa, sucio, torola, grande, and suquiapa basins. the beneficiaries of public irrigation are organized into 36 associations. total surface area with irrigation drainage problems was estimated at 370,658 acres (1,500.00 km2) where most of this land is located in coastal plains. these coastal regions are home to many mangroves and marshes, therefore land remains saturated. there have been successful past efforts to pump off or convey excess water left behind after the rainy season. while drainage is a problem, salinity problems have not been widely detected in the soil. hydroelectricity hydroelectric potential is estimated at 1,889 mw where 1,409 mw of this potential is on the lempa river. however, only 21% of the potential of the lempa river is utilized. cel (comisión hidroeléctrica del río lempa) is a public entity that generates over 90% of the hydroelectric output of el salvador. four projects on the lempa river constitute all of the hydroelectricity generation in el salvador and account for 41% of the total electricity produced in the country. projects include: 5 de noviembre with 81.4 mw installed generation capacity guajoyo with 15mw of installed generation capacity cerrón grande hydroelectric dam with 135 mw of installed generation capacity. the dam's reservoir has a surface area of 135 km2 and a capacity of 2,180 million m3. 15 de septiembre with 156.3 mw installed generation capacity including and upgrade to 24 mw of new installed capacity new hydroelectric projects include: cimarron hydroelectric power project is a project whose construction is expected to begin in 2010 and will also be on the lempa river within the upper river basin in the santa ana department. water will be diverted from the lempa river to a power generation site near the town of agua caliente. installed capacity will be 261 mw and will generate an average of 686 gwh per year. the dam will be 165 meters high and 660 meters long and create a reservoir holding 592 million m3 of water. el chaparral will have 66 mw of installed generation capacity legal and institutional framework twenty-five agencies share responsibility for overseeing the water resources of el salvador. there is currently no mechanism for coordinating their efforts, which creates duplication and inefficient use of resources. the el salvador congress charged the secretaria ejecutiva

del medio ambiente (sema) with the responsibility of setting the national environmental regulatory policy and to also enforce its compliance. as of 1998, land use regulations rested with the administracion nacional de acueductos y alcantarillados (anda) but these regulations were lacking the necessary enforcement tools. although there is a general lack of enforcement, laws for regulating discharge of domestic and industrial wastes exist, but only for new industries. legal framework 1961: law of the national administration for water supply and sanitation (anda) was passed to create anda. 2007: approval procedure by act 2095 for the revision of technical plans to introduce a certification process for feasible drinking water projects. institutional framework anda (administración nacional de acueductos y alcantarillados) is the national administration for water supply and sanitation. the mission of anda is to provide adequate supplies of water for human consumption in quantities demanded by consumers and to treat sewage. dgfcr (general directorate of forestry, river basin and irrigation management) is under the ministry of farming and agriculture and is in charge of generating and distributing information, providing technical and legal assistance about water resources, and implementing programs contributing to the sustainable development of water resources in el salvador. the irrigation and drainage division of dgfcr is in charge of administrating and regulating the irrigation systems. cel (comisión ejecutiva hidroeléctrica del río lempa) is the lempa river executive hydroelectric commission whose role is to develop and utilize the hydroelectric potential of the country. snet (servicio nacional de estudios territoriales) conducts national studies on many sectors. specific to water resources, their focus is on the following: monitoring and evaluation of contaminated waters and related health risks, vulnerability to aquifers and contamination due to over-exploitation, and analysis of floods, water availability, equity of water supplies, and the effects of climate change on water resources. marn is the ministry of environment and natural resources created in 1997, is the environmental authority in the country. among other functions it oversees el salvador's commitments to the united nations framework convention on climate change (unfccc) and other climate change related actions. fisdl (fondo de inversion social de el salvador) is the social investment fund of el salvador and supplies the materials and expertise needed for the development and construction of ground and surface water supply projects for rural areas. mspas (ministerio de salud pública y asistencia social) is the public health and social assistance ministry and is responsible for financing small infrastructure projects and the provision of equipment for health, potable water, sanitation, and other programs. their mission is to reduce the negative effects of failing infrastructures, namely those existing in communities experiencing extreme poverty. cooperation with guatemala and honduras the upper watershed of the lempa river is shared by guatemala, el salvador, and honduras, as outlined in the trifinio plan, which was established and signed by the aforementioned countries to address economic and environmental problems in the lempa river basin, and foster cooperation and regional integration. the trifinio plan or treaty sought to provide a more viable and effective alternative to unilateral development thereby concentrating on greater multinational integration. the trifinio region covers an area of about 7,500 km2 in the border areas of honduras, guatemala, and el salvador. the region is made up of 45 municipalities whereby 22 belong to honduras within the departments of ocotepeque and copán, 15 are situated in guatemala corresponding to the departments of chiquimula and jutiapa, and 8 are in the departments of santa ana and chalatenango in el salvador. in the early stages of the trifinio plan's development, the commission studied three international river basins, and in 1987 they developed a new plan involving the lempa river basin, the ulúa river, and the motagua river. however, the motagua and ulúa rivers were eventually dropped, leaving the lempa river as the trifinio plan's primary focus. in 1996, the governments of el salvador, honduras, and guatemala signed an agreement to cooperate on formulating a development plan for their shared boundary region. in 1998, the signatories completed the central american action plan for integrated development of water resources to combat water pollution and promote the sustainable development of central america's shared water resources by jointly developing watershed management plans. these plans included reforestation efforts which concluded in the second phase of the trifinio plan in 1997. by 2000 new efforts were initiated to begin managing the upper lempa river basin. ramsar wetland sites in el salvador lake olomegalake olomegashow map of el salvadorlake olomegashow map of central americalocationsouth-eastern el salvadorcoordinates13°19′n 88°04′wprimary inflowsrío grande de san miguelbasin countriesel salvador wetlands in el salvador serve many crucial water management services such as flood control, groundwater replenishment, natural water purification, and are also productive fish and shrimp ecosystems. the wetlands within the bahía de jiquilisco for example are primarily mangrove forests that serve to protect against tidal surges when hurricanes and tropical storms strike. without these forests, tidal surges would lead to the salination of fresh groundwater further inland which would contaminate supplies for domestic and agricultural uses. the ramsar convention wetland sites: complejo bahía de jiquilisco in the state of usulután (63,500 ha, 156,911 acres) embalse cerrón grande in chalatenango, san salvador, cuscatlán, cabañas (60,698 ha, 150,000 acres) laguna de olomega in the states of san miguel and la unión (7,557 ha, 18,673 acres) area natural protegida laguna del jocotal (1,571 ha, 3,882 acres) potential climate change impacts the global climate risk index constructed for the period between 1997 and 2006 and covering both human and economic impacts, ranks el salvador the 30th most at risk country in the world. according to climate scenarios developed by researchers for el salvador, the following (below) climate changes are likely to occur between 2070 and 2099 and adversely impact groundwater, hydropower output, and flood control management efforts. average temperatures will rise be between 1.9-3.4 °c increasing likelihood of drought significant temperature increases will occur in june and july precipitation decreases early in rainy season reducing infiltration to groundwater supplies greatest decrease in precipitation in may–july average inflows to the major reservoirs will decline by 13-24% the greatest declines in reservoir inflow will be between july–august and be around 21 to 41% affecting hydropower output and irrigation supplies drop in hydropower generation capability may range from 33% to 53% near the end of the 21st century sea level increase: it is probable that the sea level will increase 20 cm by 2030, 40 cm by 2040, and up to 70 cm by 2100. this will contaminate coastal groundwater with high concentrations of saline water and greatly reduce supply for domestic and agricultural uses. the drought response and mitigation project in el salvador, implemented by the red cross in 2002 helped to mitigate the effects of droughts affecting the country. the objective of this initiative was to increase the capacity of subsistence farmers in the east of the country to better respond to adverse effects of climate conditions, by providing technical assistance to diversify and market crops, reforestation using fruit trees, use of organic fertilizers and small scale irrigation systems.

superficial palmar branch of radial artery superficial palmar branch of radial artery the superficial palmar branch of the radial artery arises from the radial artery, just where this vessel is about to wind around the lateral side of the wrist. superficial palmar branch of radial arterypalm of left hand, showing position of skin creases and bones, and surface markings for the volar arches.detailssourceradial arterybranchessuperficial palmar archidentifierslatinramus palmaris superficialis arteriae radialista98a12.2.09.031ta24645fma22752anatomical terminology running forward, it passes through, occasionally over, the thenar muscles, which it supplies, and sometimes anastomoses with the terminal portion of the ulnar artery, completing the superficial palmar arch. this vessel varies considerably in size: usually it is very small, and ends in the muscles of the thumb; sometimes it is as large as the continuation of the radial artery itself.

atherosclerosis atherosclerosis atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. these lesions may lead to narrowing due to the buildup of atheromatous plaque. at onset there are usually no symptoms, but if they develop, symptoms generally begin around middle age. when severe, it can result in coronary artery disease, stroke, peripheral artery disease, or kidney problems, depending on which arteries are affected. not to be confused with arteriosclerosis. atherosclerosisother namesarteriosclerotic vascular disease (asvd)the progression of atherosclerosis (narrowing exaggerated)specialtycardiology, angiologysymptomsnonecomplicationscoronary artery disease, stroke, peripheral artery disease, kidney problemsusual onsetyouth (worsens with age)causesunknownrisk factorshigh blood pressure, diabetes, smoking, obesity, family history, unhealthy diet (notably trans fat), chronic vitamin c deficiencypreventionhealthy diet, exercise, not smoking, maintaining a normal weightmedicationstatins, blood pressure medication, aspirinfrequency≈100% (>65 years old) the exact cause is not known and is proposed to be multifactorial. risk factors include abnormal cholesterol levels, elevated levels of inflammatory markers, high blood pressure, diabetes, smoking, obesity, family history, genetic, and an unhealthy diet. plaque is made up of fat, cholesterol, calcium, and other substances found in the blood. the narrowing of arteries limits the flow of oxygen-rich blood to parts of the body. diagnosis is based upon a physical exam, electrocardiogram, and exercise stress test, among others. prevention is generally by eating a healthy diet, exercising, not smoking, and maintaining a normal weight. treatment of established disease may include medications to lower cholesterol such as statins, blood pressure medication, or medications that decrease clotting, such as aspirin. a number of procedures may also be carried out such as percutaneous coronary intervention, coronary artery bypass graft, or carotid endarterectomy. atherosclerosis generally starts when a person is young and worsens with age. almost all people are affected to some degree by the age of 65. it is the number one cause of death and disability in the developed world. though it was first described in 1575, there is evidence that the condition occurred in people more than 5,000 years ago. signs and symptoms atherosclerosis is asymptomatic for decades because the arteries enlarge at all plaque locations, thus there is no effect on blood flow. even most plaque ruptures do not produce symptoms until enough narrowing or closure of an artery, due to clots, occurs. signs and symptoms only occur after severe narrowing or closure impedes blood flow to different organs enough to induce symptoms. most of the time, patients realize that they have the disease only when they experience other cardiovascular disorders such as stroke or heart attack. these symptoms, however, still vary depending on which artery or organ is affected. abnormalities associated with atherosclerosis begin in childhood. fibrous and gelatinous lesions have been observed in the coronary arteries of children aged 6–10. fatty streaks have been observed in the coronary arteries of juveniles aged 11–15, though they appear at a much younger age within the aorta. clinically, given enlargement of the arteries for decades, symptomatic atherosclerosis is typically associated with men in their 40s and women in their 50s to 60s. sub-clinically, the disease begins to appear in childhood and rarely is already present at birth. noticeable signs can begin developing at puberty. though symptoms are rarely exhibited in children, early screening of children for cardiovascular diseases could be beneficial to both the child and his/her relatives. while coronary artery disease is more prevalent in men than women, atherosclerosis of the cerebral arteries and strokes equally affect both sexes. marked narrowing in the coronary arteries, which are responsible for bringing oxygenated blood to the heart, can produce symptoms such as chest pain of angina and shortness of breath, sweating, nausea, dizziness or light-headedness, breathlessness or palpitations. abnormal heart rhythms called arrhythmias—the heart beating either too slowly or too quickly—are another consequence of ischemia. carotid arteries supply blood to the brain and neck. marked narrowing of the carotid arteries can present with symptoms such as: a feeling of weakness; being unable to think straight; difficulty speaking; dizziness; difficulty in walking or standing up straight; blurred vision; numbness of the face, arms and legs; severe headache; and loss of consciousness. these symptoms are also related to stroke (death of brain cells). stroke is caused by marked narrowing or closure of arteries going to the brain; lack of adequate blood supply leads to the death of the cells of the affected tissue. peripheral arteries, which supply blood to the legs, arms and pelvis, also experience marked narrowing due to plaque rupture and clots. symptoms of the narrowing are numbness within the arms or legs, as well as pain. another significant location for plaque formation is the renal arteries, which supply blood to the kidneys. plaque occurrence and accumulation lead to decreased kidney blood flow and chronic kidney disease, which, like in all other areas, is typically asymptomatic until late stages. according to united states data for 2004, in about 66% of men and 47% of women, the first symptom of atherosclerotic cardiovascular disease is a heart attack or sudden cardiac death (death within one hour of onset of the symptom). cardiac stress testing, traditionally the most commonly performed non-invasive testing method for blood flow limitations, in general, detects only lumen narrowing of ≈75% or greater, although some physicians claim that nuclear stress methods can detect as little as 50%. case studies have included autopsies of u.s. soldiers killed in world war ii and the korean war. a much-cited report involved the autopsies of 300 u.s. soldiers killed in korea. although the average age of the men was 22.1 years, 77.3 percent had "gross evidence of coronary arteriosclerosis". other studies done of soldiers in the vietnam war showed similar results, although often worse than the ones from the earlier wars. theories include high rates of tobacco use and (in the case of the vietnam soldiers) the advent of processed foods after world war ii. risk factors

terutroban terutroban terutroban is an antiplatelet agent developed by servier laboratories. it is a selective thromboxane prostanoid (tp) antagonist and is an orally active drug in clinical development for the secondary prevention of acute thrombotic complications. terutrobanclinical dataroutes ofadministrationoralatc codenonelegal statuslegal status investigational pharmacokinetic dataelimination half-life6–10 hoursidentifiers iupac name 3-((6r)-6--2-methyl-5,6,7,8-tetrahydronaphthalen-1-yl]propanoic acid cas number165538-40-9 n 609340-89-8 (sodium salt)pubchem cid9938840chemspider8114465 nuniia6wx9391d8echa infocard100.107.361 chemical and physical dataformulac20h22clno4smolar mass407.91 g·mol−13d model (jsmol)interactive image smiles cc1=c(c2=c(cc(cc2)ns(=o)(=o)c3=cc=c(c=c3)cl)c=c1)ccc(=o)o inchi inchi=1s/c20h22clno4s/c1-13-2-3-14-12-16(6-9-19(14)18(13)10-11-20(23)24)22-27(25,26)17-7-4-15(21)5-8-17/h2-5,7-8,16,22h,6,9-12h2,1h3,(h,23,24)/t16-/m1/s1 nkey:hweoxfsbsqiwsy-mrxnpfedsa-n n ny (what is this?) (verify) it has been tested in the phase iii clinical trial perform (prevention of cerebrovascular and cardiovascular events of ischemic origin with terutroban in patients with a history of ischemic stroke or transient ischemic attack). the study was prematurely stopped and it could not be determined whether terutroban has a better effect than aspirin. the 2011 clinical trial that studied the antiplatelet agent versus aspirin found that it was not superior in the prevention of cerebral and cardiovascular ischaemic events, although it was significantly better in patients who already suffered previous stroke to the qualifying event. researchers from the university of milan also found in a new research that terutroban can prevent the development of aorta hyperplasia and has beneficial effects on fibrotic processes, leading to the conclusion that it has beneficial effects in preventing or retarding atherogenesis. method of action aside from its anti-inflammatory effect, terutroban is a selective antagonist of the thromboxane receptor. it blocks thromboxane induced platelet aggregation and vasoconstriction.

respiratory sounds respiratory sounds respiratory sounds, also known as lung sounds or breath sounds, refer to the specific sounds generated by the movement of air through the respiratory system. these may be easily audible or identified through auscultation of the respiratory system through the lung fields with a stethoscope as well as from the spectral characteristics of lung sounds. these include normal breath sounds and adventitious or "added" sounds such as crackles, wheezes, pleural friction rubs, stertor, and stridor. respiratory soundsother namesbreath sounds, lung soundsspecialtyrespirology description and classification of the sounds usually involve auscultation of the inspiratory and expiratory phases of the breath cycle, noting both the pitch (typically described as low (≤200 hz), medium or high (≥400 hz)) and intensity (soft, medium, loud or very loud) of the sounds heard. normal breath sounds normal breath sounds are classified as vesicular, bronchovesicular, bronchial or tracheal based on the anatomical location of auscultation. normal breath sounds can also be identified by patterns of sound duration and the quality of the sound as described in the table below: name location where heard normally quality of sound sound duration example tracheal over the trachea very loud expiratory sound duration is equivalent to inspiratory sound bronchial over the manubrium loud, high pitched expiratory sound duration is longer than inspiratory sound bronchovesicular anteriorly between the 1st and 2nd intercostal space; posteriorly in-between the scapulae intermediate expiratory sound duration is about equivalent to inspiratory sound vesicular over most of both lungs soft, low pitched expiratory sound duration is shorter than inspiratory sound abnormal breath sounds common types of abnormal breath sounds include the following: name continuous/discontinuous frequency/pitch inspiratory/expiratory quality common causes example wheeze or rhonchi continuous high (wheeze) or lower (rhonchi) expiratory or inspiratory whistling/sibilant caused by narrowing of airways, such as in asthma, chronic obstructive pulmonary disease, foreign body. stridor continuous high inspiratory, expiratory, or both whistling/sibilant epiglottitis, foreign body, laryngeal edema, croup inspiratory gasp continuous high inspiratory whoop pertussis (whooping cough) see new england journal of medicine, classic whooping cough sound file, supplement to the n engl j med 2004; 350:2023-2026 crackles (rales) continuous high (fine) or low (coarse) inspiratory cracking/clicking/rattling pneumonia, pulmonary edema, tuberculosis, bronchitis, heart failure pleural friction rub discontinuous low inspiratory and expiratory many repeated rhythmic sounds inflammation of lung linings, lung tumors not available hamman's sign (or mediastinal crunch) discontinuous neither (heartbeat) crunching, rasping pneumomediastinum, pneumopericardium not available grunting continuous low expiratory snoring surfactant deficiency, pneumonia, cardiac abnormalities continued rales: small clicking, bubbling, or rattling sounds in the lungs. they are heard when a person breathes inhales. they are believed to occur when air opens alveoli. rales can also be described as moist, dry, fine, and coarse. rhonchi are coarse rattling respiratory sounds, usually caused by secretions in bronchial airways. the sounds resemble snoring. "rhonchi" is the plural form of the singular word "rhonchus". stridor: wheeze-like sound heard when a person breathes. usually it is due to a blockage of airflow in the windpipe (trachea) or in the back of the throat. wheezing: high-pitched sounds produced by narrowed airways. they are most often heard when a person breathes out (exhales). wheezing and other abnormal sounds can sometimes be heard without a stethoscope. other tests of auscultation a clinician auscultating the posterior lung of a patient.pectoriloquy, egophony and bronchophony are tests of auscultation that utilize the phenomenon of vocal resonance. clinicians can utilize these tests during a physical exam to screen for pathological lung disease. for example, in whispered pectoriloquy, the person being examined whispers a two syllable number as the clinician listens over the lung fields. the whisper is not normally heard over the lungs, but if heard may be indicative of pulmonary consolidation in that area. this is because sound travels differently through denser (fluid or solid) media than the air that should normally be predominant in lung tissue. in egophony, the person being examined continually speaks the english long-sound "e" (/i/). the lungs are usually air filled, but if there is an abnormal solid component due to infection, fluid, or tumor, the higher frequencies of the "e" sound will be diminished. this changes the sound produced, from a long "e" sound to a long "a" sound (/eɪ/). history in 1957, robertson and coope proposed the two main categories of adventitious (added) lung sounds. those categories were "continuous" and "interrupted" (or non-continuous). in 1976, the international lung sound association simplified the sub-categories as follows: continuous wheezes (>400 hz) rhonchi (<200 hz) discontinuous fine crackles coarse crackles several sources will also refer to "medium" crackles, as a crackling sound that seems to fall between the coarse and fine crackles. crackles are defined as discrete sounds that last less than 250 ms, while the continuous sounds (rhonchi and wheezes) last approximately 250 ms. rhonchi are usually caused by a stricture or blockage in the upper airway. these are different from stridor.

single ventricle single ventricle single ventricle is a rare congenital heart defect, which constitute just over 1% of congenital cardiovascular diseases. the single functional ventricle could be morphologically right or left with the second ventricle usually hypoplastic and/or insufficiently functional. therefore, there are several subtypes of the disease, depending on which ventricle is underdeveloped. single ventricle with functional left ventricle: pulmonal atresia tricuspidal atresia double inlet left ventricle double outlet left ventricle single ventricle with functional right ventricle: hypoplastic left heart syndrome double inlet right ventricle double outlet right ventricle single ventricle heterotaxy syndrome is also included to this category. physiology in neonates with single ventricle, the systemic and pulmonary blood flow mix with each other in the single functioning ventricle with consequent lower systemic oxygen saturations (75–85%). the single ventricle then provides both the systemic and pulmonary blood flow. treatment due to the different types of a single ventricle heart disease, treatment should be individualized. usually it requires open-heart surgery. the goal is to allow the functioning ventricle to supply the systemic circulation and to connect the systemic veins to the pulmonary arteries. the deoxygenated blood from the systemic veins flows directly into the lungs without passing the heart. the oxygenated blood then returns to the heart and enters the systemic circulation. although surgical intervention depends on the type of single ventricular disease, any combination of three general procedures are utilized to address those defects: stage i – norwood procedure stage ii – glenn procedure stage iii – fontan procedure prognosis prenatal diagnosis is associated with higher survival in neonates with single ventricle physiology. outcome and life expectancy are highly depending on the underlying morpho-functional subtype and individual characteristics. more than half survive two years with the average length of up to 30 to 40 years.

casualty notification casualty notification casualty notification is the process of notifying relatives of people who have been killed or seriously injured unexpectedly (for example, in a car crash). the notification may be done over the phone or in person, but is normally done by a police officer in person when possible, at least for the next of kin. in the case of the united states armed forces, the notification is done by a specialist known as a casualty notification officer (cno), normally within four hours of learning of the casualty (but only from 6:00 a.m. to 10:00 p.m. local time) or, for the navy, by a casualty assistance calls officer (caco). denny hayes, who spent fifteen years as a chaplain for the fbi’s critical response team, says: always deliver bad news in person. always bring a partner (“95 percent of them defer to me to do the actual speaking of the words—nobody wants to experience sad”). skip the euphemisms—they comfort no one except the person speaking them. never abandon anyone until they have someone else to hold on to. "you can’t make it better," said dr. nancy davis, former chief of counseling services for the fbi. "but you can definitely make it worse."

promestriene promestriene promestriene (inn) (brand names colpotrofin, colpotrophine, delipoderm), also known as estradiol 3-propyl 17β-methyl diether, is a synthetic estrogen which is used topically in a 1% cream formulation for the treatment of vaginal atrophy in women. it is the 3-propyl and 17β-methyl diether of estradiol and does not appear to convert into estradiol in the body. promestriene is minimally absorbed and appears to have negligible systemic estrogenic effect. the drug has been described as a tropic agent and antiseborrheic. it has not been found to be effective in the treatment of pattern hair loss or other conditions of cutaneous androgenization. promestriene was first introduced in france in 1974 and has been marketed in 34 countries worldwide. it has been used in millions of women. promestrieneclinical datatrade namescolpotrofin, colpotrophine, delipodermother namesestradiol 3-propyl 17β-methyl diether; 17β-methoxy-3-propoxyestra-1,3,5(10)-trieneroutes ofadministrationtopicaldrug classestrogen; estrogen esteratc codeg03ca09 (who) identifiers iupac name (8r,9s,13s,14s)-17-methoxy-13-methyl-3-propoxy-6,7,8,9,11,12,14,15,16,17-decahydrocyclopentaphenanthrene cas number39219-28-8pubchem cid71717chemspider64767 yuniigxm4per6wzcomptox dashboard (epa)dtxsid2057730 echa infocard100.049.401 chemical and physical dataformulac22h32o2molar mass328.496 g·mol−13d model (jsmol)interactive image smiles cccoc1ccc2c(c1)cc32cc4(3ccc4oc)c inchi inchi=1s/c22h32o2/c1-4-13-24-16-6-8-17-15(14-16)5-7-19-18(17)11-12-22(2)20(19)9-10-21(22)23-3/h6,8,14,18-21h,4-5,7,9-13h2,1-3h3/t18-,19-,20+,21?,22+/m1/s1 nkey:iuwknlftjbhtsd-qikjaygvsa-n n (verify)

parental alienation syndrome parental alienation syndrome parental alienation syndrome (pas) is a term introduced by child psychiatrist richard gardner in 1985 to describe signs and symptoms he believed to be exhibited by children who have been alienated from one parent through manipulation by the other parent. proposed symptoms included extreme but unwarranted fear, and disrespect or hostility towards a parent. gardner believed that a set of behaviors that he observed in some families involved in child custody litigation could be used to diagnose psychological manipulation or undue influence of a child by a parent, typically by the other parent who may be attempting to prevent an ongoing relationship between a child and other family members after family separation or divorce. use of the term "syndrome" has not been accepted by either the medical or legal communities and gardner's research has been broadly criticized by legal and mental health scholars for lacking scientific validity and reliability. initial description parental alienation syndrome is a term coined by child psychiatrist richard a. gardner drawing upon his clinical experiences in the early 1980s. the concept of one parent attempting to separate their child from the other parent as punishment or part of a divorce have been described since at least the 1940s, but gardner was the first to define a specific syndrome. in his 1985 paper, he defined pas as...a disorder that arises primarily in the context of child-custody disputes. its primary manifestation is the child's campaign of denigration against the parent, a campaign that has no justification. the disorder results from the combination of indoctrinations by the alienating parent and the child's own contributions to the vilification of the alienated parent.he also stated that the indoctrination may be deliberate or unconscious on the part of the alienating parent. gardner initially believed that parents (usually mothers) made false accusations of child abuse and sexual abuse against the other parent (usually fathers) in order to prevent further contact between them. while gardner initially described the mother as the alienator in 90% of pas cases, he later stated both parents were equally likely to alienate. he also later stated that in his experience accusations of sexual abuse were not present in the vast majority of cases of pas. characteristics gardner described pas as a preoccupation by the child with criticism and deprecation of a parent. gardner stated that pas occurs when, in the context of child custody disputes, one parent deliberately or unconsciously attempts to alienate a child from the other parent. according to gardner, pas is characterized by a cluster of eight symptoms that appear in the child. these include a campaign of denigration and hatred against the targeted parent; weak, absurd, or frivolous rationalizations for this deprecation and hatred; lack of the usual ambivalence about the targeted parent; strong assertions that the decision to reject the parent is theirs alone (the "independent-thinker phenomenon"); reflexive support of the favored parent in the conflict; lack of guilt over the treatment of the alienated parent; use of borrowed scenarios and phrases from the alienating parent; and the denigration not just of the targeted parent but also to that parent's extended family and friends. despite frequent citations of these factors in scientific literature, the value ascribed to these factors has not been explored with professionals in the field. gardner and others divided pas into mild, moderate and severe levels. the number and severity of the eight symptoms included in the syndrome were hypothesized to increase through the different levels. recommendations for management differed according to the severity level of the child's symptoms. while a diagnosis of pas is made based on the child's symptoms, gardner stated that any change in custody should be based primarily on the symptom level of the alienating parent. in mild cases, it was alleged that there was some parental programming against the targeted parent, but little or no disruption of visitation, and gardner did not recommend court-ordered visitation. in moderate cases, it was alleged that more parental programming occurred resulting in greater resistance to visits with the targeted parent. gardner recommended that primary custody remain with the programming parent if the brainwashing was expected to be discontinued, but if not, that custody should be transferred to the targeted parent. in addition, therapy with the child to stop alienation and remediate the damaged relationship with the targeted parent was recommended. in severe cases, in which children were found to display most or all of the eight symptoms and refused to visit the targeted parent, possibly threatening to run away or engage in self-harm if forced to visit the other parent, gardner recommended that the child be removed from the alienating parent's home into a transition home before moving into the home of the targeted parent. in addition to modification of custody, gardner recommended therapy for the child. gardner's proposed intervention for moderate and severe pas, which include court-ordered transfer to the alienated parent, fines, house arrest, and incarceration, have been critiqued for their punitive nature towards the alienating parent and alienated child, and for the risk of abuse of power and violation of their civil rights. with time, gardner revised his views and expressed less support for the most aggressive management strategies. reception gardner's original formulation, which labeled mothers almost exclusively as the alienating parent, was endorsed by fathers' rights groups, as it allowed fathers to explain the reluctance of their children to visit them and assign blame to their former wives. in contrast, women's groups criticized the syndrome, concerned that it permitted abusers to claim that allegations of abuse by mother or child were reflective of brainwashing. gardner himself emphasized that pas only applied in situations where there was no actual abuse or neglect had not occurred, but by 1998, noted an increase in the awareness of pas had led to an increase in its misapplication as an exculpatory legal maneuver. pas has been cited in high-conflict divorce and child custody cases, particularly as a defense against accusations of domestic violence or sexual abuse. the status of the syndrome, and thus its admissibility in the testimony of experts, has been the subject of dispute, with challenges raised about its acceptance by professionals in the field, whether it follows a scientific methodology that is testable, whether it has been tested and has a known error rate, and the extent to which the theory has been published and peer-reviewed. pas has not been accepted by experts in psychology, child advocacy or the study of child abuse or legal scholars. pas has been extensively criticized by members of the legal and mental health community, who state that pas should not be admissible in child custody hearings based on both science and law. no professional association has recognized pas as a relevant medical syndrome or mental disorder. pas is not listed in the international statistical classification of diseases and related health problems of the who. it is not recognized by the american medical association or the american psychiatric association. the american psychological association declined to give a position on pas, but raised concerns over its lack of supporting data and how the term is used. the apa's 1996 presidential task force on violence and the family expressed concern that custody evaluators use pas as a means of giving custody to fathers despite a history of violence, a concern shared by other commentators. the united states national council of juvenile and family court judges rejected pas, recommending it not be used for the consideration of child-custody issues. the admissibility of pas was rejected by an expert review panel and the court of appeal of england and wales in the united kingdom and canada's department of justice recommends against its use. pas has been mentioned in some family court cases in the united states. gardner portrayed pas as well accepted by the judiciary and having set a variety of precedents, but legal analysis of the actual cases indicates that as of 2006 this claim was incorrect. exclusion from the dsm pas is not included in the american psychiatric association's diagnostic and statistical manual of mental disorders (dsm-iv). gardner and others lobbied for its inclusion in the dsm-v revision. in 2001, gardner argued that when the dsm-iv was released, there was insufficient research to include pas, but since then, there have been enough scientific articles and attention to pas that it merited being taken seriously. a survey of american custody evaluators, published in 2007, found that half of the respondents disagreed with its inclusion, while a third thought it should be. a related formulation, named parental alienation disorder, has been proposed, suggesting that inclusion of pas in the dsm-5 would promote research and appropriate treatment, as well as reduce misuse of a valid and reliable construct. in december 2012, the american psychiatric association announced that pas would not be included in the dsm-v revision. however, there are now diagnoses included in dsm-v that reflect the impact of parental behavior upon children, in particular parent-child relational problem and child affected by parental relationship distress. the key distinction is that the diagnoses listed in the dsm relate to the mental health of the diagnosed individual, as opposed to attempting to describe a disorder of the relationship between different people, whether parent-child or parent-parent. scientific status gardner's formulation of pas is critiqued as lacking a scientific basis, and as a hypothesis whose proponents have failed to meet the scientific burden of proof to merit acceptance. the first publications about pas were self-published and not peer reviewed, and though subsequent articles have been published in peer reviewed journals, most have consisted of anecdotal evidence in the form of case studies; in addition, the limited research into pas has lacked evidence of its validity and reliability. the lack of objective research and replication, falsifiability, and independent publication has led to claims that pas is pseudoscience or junk science. proponents of pas concur that large scale systematic controlled studies into pas's validity and reliability are required, supplementing a single small study in 2004 which suggested practitioners could come to a consensus based on written reports. the theoretical foundation of pas has been described as incomplete, simplistic and erroneous for ignoring the multiple factors (including the behaviors of the child, parents and other family members) that may contribute to parental alienation, family dysfunction and a breakdown in attachment between a parent and a child. in this view, pas confuses a child's developmental reaction to a divorce with psychosis, vastly overstates the number of false allegations of child sexual abuse, ignores the scientific literature suggesting most allegations of child sexual abuse are well founded and thus well-meaning efforts to protect a child from an abusive parent, exaggerates the damaging effects of parental alienation on children and proposes an unsupported and endangering remedy for pas. concern has been expressed that pas lacks adequate scientific support to be considered a syndrome and that gardner has promoted pas as a syndrome based on a vague clustering of behaviors. despite concerns about the validity of testimony regarding pas, it has been inappropriately viewed as reliable by family court judges. proponents of pas and others agree that using the designation of syndrome may be inappropriate as it implies more scientific legitimacy than it currently deserves. while pas is not accepted as scientifically valid, the concept of parental alienation has been advanced based upon theories of the "alienated child" and the dynamics that may have contributed to the child's alienation from a parent. like pas, parental alienation is not recognized as a diagnosable mental condition. clinical status pas has been criticized for making clinical work with children who are alienated more confusing and for labeling children with a mental diagnosis who may react angrily to their parents' separation or divorce. gardner's analysis has been criticized for inappropriately assigning all responsibility of the child's behavior to one parent when the child's behavior is oftentimes, but not always, the result of a dynamic in which both parents and the child play a role. gardner disagreed with criticism of pas as overly simplistic, stating that while there are a wide variety of causes on why a child may become alienated from a parent, the primary etiological factor in cases of pas is the brainwashing parent, and that otherwise, there is no pas. gardner also stated

that those initially critical of pas for being a caricature were not directly involved with families in custody disputes and that criticisms of this nature faded by the late 1980s because the disorder was widespread. however, no scientific study has yet demonstrated that the elements of pas are unique to alleged parental alienation such that they are useful for diagnosis. pas has been criticized by for being sexist, being used by fathers to marginalize legitimate fears and concerns about abuse, and women's groups and others oppose the legitimacy of pas as a danger to children. after his initial publications, gardner revised his theory to make fathers and mothers equally likely to alienate or be indoctrinators and disagreed that recognition of pas is sexist. gardner later indicated he believed men were equally likely to be pas indoctrinators. studies of children and adults labelled with pas have suggested that mothers were more likely than fathers to be the alienator. in courts canada early canadian court cases accepted expert opinions about pas, used the term "syndrome" and concurred with gardner's theory that only one parent was fully responsible for it. gardner testified in one case (fortin v. major, 1996) but the court did not accept his opinion, concluding that the child was not alienated based on the evaluation of a court-appointed expert who, unlike gardner, had met with the family members. more recent cases, while accepting the concept of alienation, have noted the lack of recognition in the dsm-iv, and have generally avoided "syndrome" terminology, emphasizing that changes in custody are stressful for the child and should only occur in the most severe cases. a 2006 research report by the canadian department of justice described pas as "empirically unsupported" and favored a different framework for dealing with issues of alienation that has more research support. decisions about possible parental alienation are considered a legal decision, to be determined by the judge based on the facts of the case, rather than a diagnosis made by a mental health professional. there is recognition that rejection of a parent is a complex issue, and that a distinction must be made between pathological alienation and reasonable estrangement. united kingdom in the united kingdom, the admissibility concerning the evaluation of pas was rejected both in an expert review, and by the court of appeal. united states on occasion, pas has been cited as part of the child custody determination process in the united states, and some courts have awarded sole custody to fathers based upon findings of pas. in some cases a custody court's acceptance of allegations of parental alienation have resulted in children being placed in the custody of an abusive parent. the admissibility of testimony alleging pas has been challenged under the frye test and daubert standard, to evaluate if it has sufficient scientific basis and acceptance within the scientific community. richard gardner's claims although gardner claimed that pas was generally accepted by the scholarly community and had passed the frye test in two states, a 2006 analysis of court cases involving pas and cited by gardner concluded that these decisions did not set legal precedent, that pas is viewed negatively in most legal scholarship, and that gardner's writings do not support the existence of pas. of sixty-four precedent-bearing cases reviewed at that time, only two decisions, both in new york state and both in criminal courts actually set precedents. both held that the theory of pas was inadmissible. one of the cases, subsequently upheld on appeal, found that pas failed the frye test as the appropriate professional community did not generally accept. at the time, gardner listed fifty cases on his website that he claimed set precedents that made pas admissible. upon review it was determined that none of the cases set precedents for the admissibility of pas. forty-six set no precedents or did not discuss admissibility and the remaining four were problematic. in the first the trial court found that pas passed the frye test, but that finding was not reviewed on appeal so as to become precedential as the trial court " out the words 'parental alienation syndrome'" and focused instead on the "willingness and ability of each parent to facilitate and encourage a close and continuing relationship between the parents and the child" under the state's child custody best interest factors. in the second case, the appellate court did not discuss pas. the third case specifically chose not to discuss the admissibility of pas and the fourth made no decision on pas. case law in one new york case, matter of robert coull v. pamela rottman, 15 n.y.s.3d 834, 131 ad 3d 964 (2015), child support was suspended based upon a trial court's finding of a parent's alienating behaviors. the court found that the father was prevented from seeing his son by the child's mother through a "pattern of alienation", and child support was suspended on that basis. the decision was not based upon a psychological diagnosis, but was instead based upon a pattern of alienation actions and behaviors by the mother and her conduct during court proceedings. a focus on parental behavior allows a court to base its decision "upon accepted psychological concepts and diagnoses... without mention of the controversial and potentially inflammatory concept of pas"; new york has followed this approach, with a court explaining, pas, essentially dismissed as "junk science", is not generally accepted in the scientific community, as it is not an approved term or diagnosis in the field of psychiatry and no new york court has allowed the admission of testimony concerning pas.... however, new york courts have embraced parental alienation as a concept. in recognizing that parental alienation can exist, some courts have loosely defined it as a custodial parent's active interference with or deliberate and unjustified frustration of the non-custodial parents' reasonable right of access to the child. that approach treats parental alienation as a descriptive concept, allowing a court to consider parental behavior without the need to determine whether parental alienation is a valid psychological construct.

accommodative excess accommodative excess in ophthalmology, accommodative excess (also known as excessive accommodation or accommodation excess) occurs when an individual uses more than normal accommodation (focusing on close objects) for performing certain near work. accommodative excess has traditionally been defined as accommodation that is persistently higher than expected for the patient's age. modern definitions simply regard it as an inability to relax accommodation readily. excessive accommodation is seen in association with excessive convergence also. accommodative excessaccommodationspecialtyophthalmologysymptomsasthenopia, blurring of vision symptoms and signs blurring of vision due to pseudomyopia headache eye strain asthenopia trouble concentrating when reading causes causes related to refractive errors accommodative excess may be seen in the following conditions: hypermetropia: young hypermetropes use excessive accommodation as a physiological adaptation in the interest of clear vision. myopia: young myopes performing excessive near work may also use excessive accommodation in association with excessive convergence. astigmatism: astigmatic eye may also be associated with accommodative excess. presbyopia: early presbyopic eye may also induce excessive accommodation. improper or ill fitting spectacles: use of improper or ill fitting spectacles may also cause use of excessive accommodation. causes related to systemic drugs use of systemic drugs like morphine, digitalis, sulfonamides, carbonic anhydrase inhibitors may cause accommodative excess. causes related to diseases unilateral excessive accommodation-trigeminal neuralgia, and head trauma may cause ciliary spasm and may cause accommodative excess. bilateral excessive accommodation-diseases like encephalitis, syphilis, head trauma, influenza, meningitis may cause ciliary spasm and bilateral excessive accommodation. secondary to convergence insufficiency accommodative excess may occur secondary to convergence insufficiency also. in convergence insufficiency near point of convergence will recede, and positive fusional vergence (pfv) will reduce. so, the patient uses excessive accommodation to stimulate accommodative convergence to overcome reduced pfv. risk factors a large amount of near work is the main precipitating factor of accommodative excess. pseudomyopia pseudomyopia also known as artificial myopia refers to an intermittent and temporary shift in refractive error of the eye towards myopia. it may occur due to excessive accommodation or spasm of accommodation. diagnosis differential diagnosis parinaud’s syndrome, which can mimic some aspects of spasm of the near reflex, such as excessive accommodation and convergence; however, pupillary near-light dissociation, not miosis, is a feature of parinaud’s syndrome. treatment optical: cycloplegic refraction, and correction of refractive errors if any vision therapy general: relax from near work

vinayaga mission medical college vinayaga mission medical college vinayaka mission medical college (popularly called as vmmc in karaikal: french: collège médical de la mission vinayaka) is a medical college in karaikal approved by the medical council of india, government of puducherry & india. this institution established medical college and hospitals in karaikal in the year 1996. highlights this college is situated in keezhakasakudy , karaikal. it has a 150-acre campus. it has well equipped laboratories, class rooms, museums demonstration rooms and pre & paramedicals. free medical services to poor patients. has an experienced team of doctors.

five wishes five wishes five wishes is a united states advance directive created by the non-profit organization aging with dignity. it has been described as the "living will with a heart and soul". cover of five wishes history five wishes was originally introduced in 1996 as a florida-only document, combining a living will and health care power of attorney in addition to addressing matters of comfort care and spirituality. with help from the american bar association's commission on law and aging and leading medical experts, a national version of five wishes was introduced in 1998. it was originally distributed with support from a grant by the robert wood johnson foundation. with assistance from the united health foundation, five wishes is now available in 28 languages and in braille. more than 40 million documents have been distributed by a network of over 40,000 partner organizations worldwide. an online version called five wishes online was introduced in april 2011 allowing users to complete the document using an online interface or print out a blank version to complete by hand. an updated version, renamed five wishes digital, debuted in 2022, including options for all 50 states, and fully digital signing and witnessing options. the five wishes wishes 1 and 2 are both legal documents. once signed, they meet the legal requirements for an advance directive in the states listed below. wishes 3, 4, and 5 are unique to five wishes, in that they address matters of comfort care, spirituality, forgiveness, and final wishes. wish 1: the person i want to make care decisions for me when i can't this section is an assignment of a health care agent (also called proxy, surrogate, representative, or health care power of attorney). this person makes medical decisions on your behalf if you are unable to speak for yourself. wish 2: the kind of medical treatment i want or don't want this section is a living will—a definition of what life support treatment means to you, and when you would and would not want it. wish 3: how comfortable i want to be this section addresses matters of comfort care—what type of pain management you would like, personal grooming and bathing instructions, and whether you would like to know about options for hospice care, among others. wish 4: how i want people to treat me this section speaks to personal matters, such as whether you would like to be at home and whether you would like someone to pray at your bedside. wish 5: what i want my loved ones to know this section deals with matters of forgiveness, how you wish to be remembered, and final wishes regarding funeral or memorial plans. signing and witnessing requirements the last portion of the document contains a section for signing the document and having it witnessed. the document indicates which states require notarization. legal requirements according to analysis by the american bar association's commission on law and aging, five wishes currently meets the legal requirements for an advance directive in the following 46 states and the district of columbia. in the remaining 4 states, (kansas, new hampshire, ohio, texas) a statutory form is required, and one must attach the state document if one wishes to use the five wishes document as a guide. alaska alabama arizona arkansas california colorado connecticut delaware florida georgia hawaii idaho illinois indiana iowa kentucky louisiana maine maryland massachusetts michigan minnesota mississippi missouri montana nebraska nevada new jersey new mexico new york north carolina north dakota oklahoma oregon pennsylvania rhode island south carolina south dakota tennessee utah vermont virginia washington west virginia wisconsin wyoming translations five wishes has been translated from english into 29 other languages: albanian; arabic; armenian; bengali; chinese traditional; chinese simplified; croatian; farsi; french; german; gujarati; haitian creole; hebrew; hindi; hmong; ilocano; italian; japanese; khmer; korean; polish; portuguese; punjabi; russian; somali; spanish; tagalog; urdu; vietnamese.

biochemical cascade biochemical cascade a biochemical cascade, also known as a signaling cascade or signaling pathway, is a series of chemical reactions that occur within a biological cell when initiated by a stimulus. this stimulus, known as a first messenger, acts on a receptor that is transduced to the cell interior through second messengers which amplify the signal and transfer it to effector molecules, causing the cell to respond to the initial stimulus. most biochemical cascades are series of events, in which one event triggers the next, in a linear fashion. at each step of the signaling cascade, various controlling factors are involved to regulate cellular actions, in order to respond effectively to cues about their changing internal and external environments. an example would be the coagulation cascade of secondary hemostasis which leads to fibrin formation, and thus, the initiation of blood coagulation. another example, sonic hedgehog signaling pathway, is one of the key regulators of embryonic development and is present in all bilaterians. signaling proteins give cells information to make the embryo develop properly. when the pathway malfunctions, it can result in diseases like basal cell carcinoma. recent studies point to the role of hedgehog signaling in regulating adult stem cells involved in maintenance and regeneration of adult tissues. the pathway has also been implicated in the development of some cancers. drugs that specifically target hedgehog signaling to fight diseases are being actively developed by a number of pharmaceutical companies. introduction signaling cascades cells require a full and functional cellular machinery to live. when they belong to complex multicellular organisms, they need to communicate among themselves and work for symbiosis in order to give life to the organism. these communications between cells triggers intracellular signaling cascades, termed signal transduction pathways, that regulate specific cellular functions. each signal transduction occurs with a primary extracellular messenger that binds to a transmembrane or nuclear receptor, initiating intracellular signals. the complex formed produces or releases second messengers that integrate and adapt the signal, amplifying it, by activating molecular targets, which in turn trigger effectors that will lead to the desired cellular response. transductors and effectors signal transduction is realized by activation of specific receptors and consequent production/delivery of second messengers, such as ca2+ or camp. these molecules operate as signal transducers, triggering intracellular cascades and in turn amplifying the initial signal. two main signal transduction mechanisms have been identified, via nuclear receptors, or via transmembrane receptors. in the first one, first messenger cross through the cell membrane, binding and activating intracellular receptors localized at nucleus or cytosol, which then act as transcriptional factors regulating directly gene expression. this is possible due to the lipophilic nature of those ligands, mainly hormones. in the signal transduction via transmembrane receptors, the first messenger binds to the extracellular domain of transmembrane receptor, activating it. these receptors may have intrinsic catalytic activity or may be coupled to effector enzymes, or may also be associated to ionic channels. therefore, there are four main transmembrane receptor types: g protein coupled receptors (gpcrs), tyrosine kinase receptors (rtks), serine/threonine kinase receptors (rstks), and ligand-gated ion channels (lgics). second messengers can be classified into three classes: hydrophilic/cytosolic – are soluble in water and are localized at the cytosol, including camp, cgmp, ip3, ca2+, cadpr and s1p. their main targets are protein kinases as pka and pkg, being then involved in phosphorylation mediated responses. hydrophobic/membrane-associated – are insoluble in water and membrane-associated, being localized at intermembrane spaces, where they can bind to membrane-associated effector proteins. examples: pip3, dag, phosphatidic acid, arachidonic acid and ceramide. they are involved in regulation of kinases and phosphatases, g protein associated factors and transcriptional factors. gaseous – can be widespread through cell membrane and cytosol, including nitric oxide and carbon monoxide. both of them can activate cgmp and, besides of being capable of mediating independent activities, they also can operate in a coordinated mode. cellular response the cellular response in signal transduction cascades involves alteration of the expression of effector genes or activation/inhibition of targeted proteins. regulation of protein activity mainly involves phosphorylation/dephosphorylation events, leading to its activation or inhibition. it is the case for the vast majority of responses as a consequence of the binding of the primary messengers to membrane receptors. this response is quick, as it involves regulation of molecules that are already present in the cell. on the other hand, the induction or repression of the expression of genes requires the binding of transcriptional factors to the regulatory sequences of these genes. the transcriptional factors are activated by the primary messengers, in most cases, due to their function as nuclear receptors for these messengers. the secondary messengers like dag or ca2+ could also induce or repress gene expression, via transcriptional factors. this response is slower than the first because it involves more steps, like transcription of genes and then the effect of newly formed proteins in a specific target. the target could be a protein or another gene. examples of biochemical cascades in biochemistry, several important enzymatic cascades and signal transduction cascades participate in metabolic pathways or signaling networks, in which enzymes are usually involved to catalyze the reactions. for example, the tissue factor pathway in the coagulation cascade of secondary hemostasis is the primary pathway leading to fibrin formation, and thus, the initiation of blood coagulation. the pathways are a series of reactions, in which a zymogen (inactive enzyme precursor) of a serine protease and its glycoprotein co-factors are activated to become active components that then catalyze the next reaction in the cascade, ultimately resulting in cross-linked fibrin. another example, sonic hedgehog signaling pathway, is one of the key regulators of embryonic development and is present in all bilaterians. different parts of the embryo have different concentrations of hedgehog signaling proteins, which give cells information to make the embryo develop properly and correctly into a head or a tail. when the pathway malfunctions, it can result in diseases like basal cell carcinoma. recent studies point to the role of hedgehog signaling in regulating adult stem cells involved in maintenance and regeneration of adult tissues. the pathway has also been implicated in the development of some cancers. drugs that specifically target hedgehog signaling to fight diseases are being actively developed by a number of pharmaceutical companies. most biochemical cascades are series of events, in which one event triggers the next, in a linear fashion. biochemical cascades include: the complement system the insulin signaling pathway the sonic hedgehog signaling pathway the wnt signaling pathway the jak-stat signaling pathway the adrenergic receptor pathways the acetylcholine receptor pathways the mitogen-activated protein kinase cascade conversely, negative cascades include events that are in a circular fashion, or can cause or be caused by multiple events. negative cascades include: ischemic cascade cell-specific biochemical cascades epithelial cells adhesion is an essential process to epithelial cells so that epithelium can be formed and cells can be in permanent contact with extracellular matrix and other cells. several pathways exist to accomplish this communication and adhesion with environment. but the main signalling pathways are the cadherin and integrin pathways. the cadherin pathway is present in adhesion junctions or in desmosomes and it is responsible for epithelial adhesion and communication with adjacent cells. cadherin is a transmembrane glycoprotein receptor that establishes contact with another cadherin present in the surface of a neighbour cell forming an adhesion complex. this adhesion complex is formed by β-catenin and α-catenin, and p120cas is essential for its stabilization and regulation. this complex then binds to actin, leading to polymerization. for actin polymerization through the cadherin pathway, proteins of the rho gtpases family are also involved. this complex is regulated by phosphorylation, which leads to downregulation of adhesion. several factors can induce the phosphorylation, like egf, hgf or v-src. the cadherin pathway also has an important function in survival and proliferation because it regulates the concentration of cytoplasmic β-catenin. when β-catenin is free in the cytoplasm, normally it is degraded, however if the wnt signalling is activated, β-catenin degradation is inhibited and it is translocated to the nucleus where it forms a complex with transcription factors. this leads to activation of genes responsible for cell proliferation and survival. so the cadherin-catenin complex is essential for cell fate regulation. integrins are heterodimeric glycoprotein receptors that recognize proteins present in the extracellular matrix, like fibronectin and laminin. in order to function, integrins have to form complexes with ilk and fak proteins. for adhesion to the extracellular matrix, ilk activate the rac and cdc42 proteins and leading to actin polymerization. erk also leads to actin polymerization through activation of cpla2. recruitment of fak by integrin leads to akt activation and this inhibits pro-apoptotic factors like bad and bax. when adhesion through integrins do not occur the pro-apoptotic factors are not inhibited and resulting in apoptosis. hepatocytes the hepatocyte is a complex and multifunctional differentiated cell whose cell response will be influenced by the zone in hepatic lobule, because concentrations of oxygen and toxic substances present in the hepatic sinusoids change from periportal zone to centrilobular zone10. the hepatocytes of the intermediate zone have the appropriate morphological and functional features since they have the environment with average concentrations of oxygen and other substances. this specialized cell is capable of: regulate glucose metabolism via camp/pka/torc (transducers of regulated creb)/cre, pip3 /pkb and plc /ip3 expression of enzymes for synthesis, storage and distribution of glucose synthesis of acute phase proteins via jak /stat /apre (acute phase response element) expression of c-reactive protein, globulin protease inhibitors, complement, coagulation and fibrinolytic systems and iron homeostasis regulate iron homeostasis (acute phase independent) via smads /hamp hepcidin expression regulate lipid metabolism via lxr /lxre (lxr response element) expression of apoe cetp, fas and lpl exocrine production of bile salts and other compounds via lxr /lxre expression of cyp7a1 and abc transporters degradate of toxic substances via lxr /lxre expression of abc transporters endocrine production via jak/stat /ghre (growth hormone response element) igf-1 and igfbp-3 expression via thr/thre (thyroid hormone response element) angiotensinogen expression regenerate itself by hepatocyte mitosis via stat and gab1: ras/mapk, plc/ip3 and pi3k/fak cell growth, proliferation, survival, invasion and motility the hepatocyte also regulates other functions for constitutive synthesis of proteins (albumin, alt and ast) that influences the synthesis or activation of other molecules (synthesis of urea and essential amino acids), activate vitamin d, utilization of vitamin k, transporter expression of vitamin a and conversion of thyroxine. neurons purinergic signalling has an essential role at interactions between neurons and glia cells, allowing these to detect action potentials and modulate neuronal activity, contributing for intra and extracellular homeostasis regulation. besides purinergic neurotransmitter, atp acts as a trophic factor at cellular development and growth, being involved on microglia activation and migration, and also on axonal myelination by oligodendrocytes. there are two main types of purinergic receptors, p1 binding to adenosine, and p2 binding to atp or adp, presenting different signalling cascades. the nrf2/are signalling pathway has a fundamental role at fighting against oxidative stress, to which neurons are especially vulnerable due to its high oxygen consumption and high lipid content. this neuroprotective pathway involves control of neuronal activity by perisynaptic astrocytes and neuronal glutamate release, with the establishment of tripartite synapses. the nrf2/are activation leads to a higher expression of enzymes involved in glutathione syntheses and metabolism, that have a key role in antioxidant response. the lkb1/nuak1 signalling pathway regulates terminal axon branching at cortical neurons, via local immobilized mitochondria capture. besides nuak1, lkb1 kinase acts under other effectors enzymes as sad-a/b and mark, therefore regulating neuronal polarization and axonal growth, respectively. these kinase cascades implicates also tau and others map. an extended knowledge of these and others neuronal pathways could provide new potential therapeutic targets for several neurodegenerative chronic diseases as alzheimer's, parkinson's and huntington's disease, and also amyotrophic lateral sclerosis. blood cells the blood cells (erythrocytes, leukocytes and platelets) are produced by hematopoiesis. the erythrocytes have as main function the o2 delivery to the tissues, and this transfer occurs by diffusion and is determined by the o2 tension (po2). the erythrocyte is able to feel the tissue need for o2 and cause a change in vascular caliber, through the pathway of atp release, which requires an increase in camp, and are regulated by the phosphodiesterase (pde). this pathway can be triggered via two mechanisms: physiological stimulus (like

reduced o2 tension) and activation of the prostacyclin receptor (ipr). this pathway includes heterotrimeric g proteins, adenylyl cyclase (ac), protein kinase a (pka), cystic fibrosis transmembrane conductance regulator (cftr), and a final conduit that transport atp to vascular lumen (pannexin 1 or voltage-dependent anion channel (vdac)). the released atp acts on purinergic receptors on endothelial cells, triggering the synthesis and release of several vasodilators, like nitric oxide (no) and prostacyclin (pgi2). the current model of leukocyte adhesion cascade includes many steps mentioned in table 1. the integrin-mediated adhesion of leukocytes to endothelial cells is related with morphological changes in both leukocytes and endothelial cells, which together support leukocyte migration through the venular walls. rho and ras small gtpases are involved in the principal leukocyte signaling pathways underlying chemokine-stimulated integrin-dependent adhesion, and have important roles in regulating cell shape, adhesion and motility. the leukocyte adhesion cascade steps and the key molecules involved in each step after a vascular injury occurs, platelets are activated by locally exposed collagen (glycoprotein (gp) vi receptor), locally generated thrombin (par1 and par4 receptors), platelet-derived thromboxane a2 (txa2) (tp receptor) and adp (p2y1 and p2y12 receptors) that is either released from damaged cells or secreted from platelet dense granules. the von willebrand factor (vwf) serves as an essential accessory molecule. in general terms, platelet activation initiated by agonist takes to a signaling cascade that leads to an increase of the cytosolic calcium concentration. consequently, the integrin αiibβ3 is activated and the binding to fibrinogen allows the aggregation of platelets to each other. the increase of cytosolic calcium also leads to shape change and txa2 synthesis, leading to signal amplification. lymphocytes the main goal of biochemical cascades in lymphocytes is the secretion of molecules that can suppress altered cells or eliminate pathogenic agents, through proliferation, differentiation and activation of these cells. therefore, the antigenic receptors play a central role in signal transduction in lymphocytes, because when antigens interact with them lead to a cascade of signal events. these receptors, that recognize the antigen soluble (b cells) or linked to a molecule on antigen presenting cells (t cells), do not have long cytoplasm tails, so they are anchored to signal proteins, which contain a long cytoplasmic tails with a motif that can be phosphorylated (itam – immunoreceptor tyrosine-based activation motif) and resulting in different signal pathways. the antigen receptor and signal protein form a stable complex, named bcr or tcr, in b or t cells, respectively. the family src is essential for signal transduction in these cells, because it is responsible for phosphorylation of itams. therefore, lyn and lck, in lymphocytes b and t, respectively, phosphorylate immunoreceptor tyrosine-based activation motifs after the antigen recognition and the conformational change of the receptor, which leads to the binding of syk/zap-70 kinases to itam and its activation. syk kinase is specific of lymphocytes b and zap-70 is present in t cells. after activation of these enzymes, some adaptor proteins are phosphorylated, like blnk (b cells) and lat (t cells). these proteins after phosphorylation become activated and allow binding of others enzymes that continue the biochemical cascade. one example of a protein that binds to adaptor proteins and become activated is plc that is very important in the lymphocyte signal pathways. plc is responsible for pkc activation, via dag and ca2+, which leads to phosphorylation of carma1 molecule, and formation of cbm complex. this complex activates iκκ kinase, which phosphorylates i-κb, and then allows the translocation of nf-κb to the nucleus and transcription of genes encoding cytokines, for example. others transcriptional factors like nfat and ap1 complex are also important for transcription of cytokines. the differentiation of b cells to plasma cells is also an example of a signal mechanism in lymphocytes, induced by a cytokine receptor. in this case, some interleukins bind to a specific receptor, which leads to activation of mapk/erk pathway. consequently, the blimp1 protein is translated and inhibits pax5, allowing immunoglobulin genes transcription and activation of xbp1 (important for the secretory apparatus formation and enhancing of protein synthesis). also, the coreceptors (cd28/cd19) play an important role because they can improve the antigen/receptor binding and initiate parallel cascade events, like activation o pi3 kinase. pip3 then is responsible for activation of several proteins, like vav (leads to activation of jnk pathway, which consequently leads to activation of c-jun) and btk (can also activate plc). wnt signaling pathway the wnt signaling pathway can be divided in canonical and non-canonical. the canonical signaling involves binding of wnt to frizzled and lrp5 co-receptor, leading to gsk3 phosphorylation and inhibition of β-catenin degradation, resulting in its accumulation and translocation to the nucleus, where it acts as a transcription factor. the non-canonical wnt signaling can be divided in planar cell polarity (pcp) pathway and wnt/calcium pathway. it is characterized by binding of wnt to frizzled and activation of g proteins and to an increase of intracellular levels of calcium through mechanisms involving pkc 50. the wnt signaling pathway plays a significative role in osteoblastogenesis and bone formation, inducing the differentiation of mesenquimal pluripotent cells in osteoblasts and inhibiting the rankl/rank pathway and osteoclastogenesis. rankl/rank signaling pathway rankl is a member of the tnf superfamily of ligands. through binding to the rank receptor it activates various molecules, like nf-kappa b, mapk, nfat and pi3k52. the rankl/rank signaling pathway regulates osteoclastogenesis, as well as, the survival and activation of osteoclasts. adenosine signaling pathway adenosine is very relevant in bone metabolism, as it plays a role in formation and activation of both osteoclasts and osteoblasts. adenosine acts by binding to purinergic receptors and influencing adenylyl cyclase activity and the formation of camp and pka 54. adenosine may have opposite effects on bone metabolism, because while certain purinergic receptors stimulate adenylyl cyclase activity, others have the opposite effect. under certain circumstances adenosine stimulates bone destruction and in other situations it promotes bone formation, depending on the purinergic receptor that is being activated. stem cells self-renewal and differentiation abilities are exceptional properties of stem cells. these cells can be classified by their differentiation capacity, which progressively decrease with development, in totipotents, pluripotents, multipotents and unipotents. self-renewal process is highly regulated from cell cycle and genetic transcription control. there are some signaling pathways, such as lif/jak/stat3 (leukemia inhibitory factor/janus kinase/signal transducer and activator of transcription 3) and bmp/smads/id (bone morphogenetic proteins/ mothers against decapentaplegic/ inhibitor of differentiation), mediated by transcription factors, epigenetic regulators and others components, and they are responsible for self-renewal genes expression and inhibition of differentiation genes expression, respectively. at cell cycle level there is an increase of complexity of the mechanisms in somatic stem cells. however, it is observed a decrease of self-renewal potential with age. these mechanisms are regulated by p16ink4a-cdk4/6-rb and p19arf-p53-p21cip1 signaling pathways. embryonic stem cells have constitutive cyclin e-cdk2 activity, which hyperphosphorylates and inactivates rb. this leads to a short g1 phase of the cell cycle with rapid g1-s transition and little dependence on mitogenic signals or d cyclins for s phase entry. in fetal stem cells, mitogens promote a relatively rapid g1-s transition through cooperative action of cyclin d-cdk4/6 and cyclin e-cdk2 to inactivate rb family proteins. p16ink4a and p19arf expression are inhibited by hmga2-dependent chromatin regulation. many young adult stem cells are quiescent most of the time. in the absence of mitogenic signals, cyclin-cdks and the g1-s transition are suppressed by cell cycle inhibitors including ink4 and cip/kip family proteins. as a result, rb is hypophosphorylated and inhibits e2f, promoting quiescence in g0-phase of the cell cycle. mitogen stimulation mobilizes these cells into cycle by activating cyclin d expression. in old adult stem cells, let-7 microrna expression increases, reducing hmga2 levels and increasing p16ink4a and p19arf levels. this reduces the sensitivity of stem cells to mitogenic signals by inhibiting cyclin-cdk complexes. as a result, either stem cells cannot enter the cell cycle, or cell division slows in many tissues. extrinsic regulation is made by signals from the niche, where stem cells are found, which is able to promote quiescent state and cell cycle activation in somatic stem cells. asymmetric division is characteristic of somatic stem cells, maintaining the reservoir of stem cells in the tissue and production of specialized cells of the same. stem cells show an elevated therapeutic potential, mainly in hemato-oncologic pathologies, such as leukemia and lymphomas. little groups of stem cells were found into tumours, calling cancer stem cells. there are evidences that these cells promote tumor growth and metastasis. oocytes the oocyte is the female cell involved in reproduction. there is a close relationship between the oocyte and the surrounding follicular cells which is crucial to the development of both. gdf9 and bmp15 produced by the oocyte bind to bmpr2 receptors on follicular cells activating smads 2/3, ensuring follicular development. concomitantly, oocyte growth is initiated by binding of kitl to its receptor kit in the oocyte, leading to the activation of pi3k/akt pathway, allowing oocyte survival and development. during embryogenesis, oocytes initiate meiosis and stop in prophase i. this arrest is maintained by elevated levels of camp within the oocyte. it was recently suggested that cgmp cooperates with camp to maintain the cell cycle arrest. during meiotic maturation, the lh peak that precedes ovulation activates mapk pathway leading to gap junction disruption and breakdown of communication between the oocyte and the follicular cells. pde3a is activated and degrades camp, leading to cell cycle progression and oocyte maturation. the lh surge also leads to the production of progesterone and prostaglandins that induce the expression of adamts1 and other proteases, as well as their inhibitors. this will lead to degradation of the follicular wall, but limiting the damage and ensuring that the rupture occurs in the appropriate location, releasing the oocyte into the fallopian tubes. oocyte activation depends on fertilization by sperm. it is initiated with sperm's attraction induced by prostaglandins produced by the oocyte, which will create a gradient that will influence the sperm's direction and velocity. after fusion with the oocyte, plc ζ of the spermatozoa is released into the oocyte leading to an increase in ca2+ levels that will activate camkii which will degrade mpf, leading to the resumption of meiosis. the increased ca2+ levels will induce the exocytosis of cortical granules that degrade zp receptors, used by sperm to penetrate the oocyte, blocking polyspermy. deregulation of these pathways will lead to several diseases like, oocyte maturation failure syndrome which results in infertility. increasing our molecular knowledge of oocyte development mechanisms could improve the outcome of assisted reproduction procedures, facilitating conception. spermatozoon spermatozoon is the male gamete. after ejaculation this cell is not mature, so it can not fertilize the oocyte. to have the ability to fertilize the female gamete, this cell suffers capacitation and acrosome reaction in female reproductive tract. the signaling pathways best described for spermatozoon involve these processes. the camp/pka signaling pathway leads to sperm cells capacitation; however, adenylyl cyclase in sperm cells is different from the somatic cells. adenylyl cyclase in spermatozoon does not recognize g proteins, so it is stimulated by bicarbonate and ca2+ ions. then, it converts adenosine triphosphate into cyclic amp, which activates protein kinase a. pka leads to protein tyrosine phosphorylation. phospholipase c (plc) is involved in acrosome reaction. zp3 is a glycoprotein present in zona pelucida and it interacts with receptors in spermatozoon. so, zp3 can activate g protein coupled receptors and tyrosine kinase receptors, that leads to production of plc. plc cleaves the phospholipid phosphatidylinositol 4,5-bisphosphate (pip2) into diacyl glycerol (dag) and inositol 1,4,5-trisphosphate. ip3 is released as a soluble structure into the cytosol and dag remains bound to the membrane. ip3 binds to ip3 receptors, present in acrosome membrane. in addition, calcium and dag together work to activate protein kinase c, which goes on to phosphorylate other molecules, leading to altered cellular activity. these actions cause an increase in cytosolic concentration of ca2+ that leads to dispersion of actin and consequently promotes plasmatic membrane and outer acrosome membrane fusion. progesterone is a steroid hormone produced in cumulus oophorus. in somatic cells it binds to receptors in nucleus; however, in spermatozoon its receptors are present in plasmatic membrane. this hormone activates akt that leads to activation of other protein kinases, involved in capacitation and acrosome reaction. when ros (reactive oxygen species) are present in high concentration, they can affect the physiology of cells, but when

they are present in moderated concentration they are important for acrosome reaction and capacitation. ros can interact with camp/pka and progesterone pathway, stimulating them. ros also interacts with erk pathway that leads to activation of ras, mek and mek-like proteins. these proteins activate protein tyrosine kinase (ptk) that phosphorylates various proteins important for capacitation and acrosome reaction. embryos various signalling pathways, as fgf, wnt and tgf-β pathways, regulate the processes involved in embryogenesis. fgf (fibroblast growth factor) ligands bind to receptors tyrosine kinase, fgfr (fibroblast growth factor receptors), and form a stable complex with co-receptors hspg (heparan sulphate proteoglycans) that will promote autophosphorylation of the intracellular domain of fgfr and consequent activation of four main pathways: mapk/erk, pi3k, plcγ and jak/stat. mapk/erk (mitogen-activated protein kinase/extracellular signal-regulated kinase) regulates gene transcription through successive kinase phosphorylation and in human embryonic stem cells it helps maintaining pluripotency. however, in the presence of activin a, a tgf-β ligand, it causes the formation of mesoderm and neuroectoderm. phosphorylation of membrane phospholipids by pi3k (phosphatidylinositol 3-kinase) results in activation of akt/pkb (protein kinase b). this kinase is involved in cell survival and inhibition of apoptosis, cellular growth and maintenance of pluripotency, in embryonic stem cells. plcγ (phosphoinositide phospholipase c γ) hydrolyzes membrane phospholipids to form ip3 (inositoltriphosphate) and dag (diacylglycerol), leading to activation of kinases and regulating morphogenic movements during gastrulation and neurulation. stat (signal trandsducer and activator of transcription) is phosphorylated by jak (janus kinase) and regulates gene transcription, determining cell fates. in mouse embryonic stem cells, this pathway helps maintaining pluripotency. the wnt pathway allows β-catenin function in gene transcription, once the interaction between wnt ligand and g protein-coupled receptor frizzled inhibits gsk-3 (glycogen synthase kinase-3) and thus formation of β-catenin destruction complex. although there is some controversy about the effects of this pathway in embryogenesis, it is thought that wnt signalling induces primitive streak, mesoderm and endoderm formation. in tgf-β (transforming growth factor β) pathway, bmp (bone morphogenic protein), activin and nodal ligands bind to their receptors and activate smads that bind to dna and promote gene transcription. activin is necessary for mesoderm and specially endoderm differentiation, and nodal and bmp are involved in embryo patterning. bmp is also responsible for formation of extra-embryonic tissues before and during gastrulation, and for early mesoderm differentiation, when activin and fgf pathways are activated. pathway construction pathway building has been performed by individual groups studying a network of interest (e.g., immune signaling pathway) as well as by large bioinformatics consortia (e.g., the reactome project) and commercial entities (e.g., ingenuity systems). pathway building is the process of identifying and integrating the entities, interactions, and associated annotations, and populating the knowledge base. pathway construction can have either a data-driven objective (ddo) or a knowledge-driven objective (kdo). data-driven pathway construction is used to generate relationship information of genes or proteins identified in a specific experiment such as a microarray study. knowledge-driven pathway construction entails development of a detailed pathway knowledge base for particular domains of interest, such as a cell type, disease, or system. the curation process of a biological pathway entails identifying and structuring content, mining information manually and/or computationally, and assembling a knowledgebase using appropriate software tools. a schematic illustrating the major steps involved in the data-driven and knowledge-driven construction processes. for either ddo or kdo pathway construction, the first step is to mine pertinent information from relevant information sources about the entities and interactions. the information retrieved is assembled using appropriate formats, information standards, and pathway building tools to obtain a pathway prototype. the pathway is further refined to include context-specific annotations such as species, cell/tissue type, or disease type. the pathway can then be verified by the domain experts and updated by the curators based on appropriate feedback. recent attempts to improve knowledge integration have led to refined classifications of cellular entities, such as go, and to the assembly of structured knowledge repositories. data repositories, which contain information regarding sequence data, metabolism, signaling, reactions, and interactions are a major source of information for pathway building. a few useful databases are described in the following table. databasecuration typego annotation (y/n)description 1. protein-protein interactions databases bindmanual curationn200,000 documented biomolecular interactions and complexes mintmanual curationnexperimentally verified interactions hprdmanual curationnelegant and comprehensive presentation of the interactions, entities and evidences mpactmanual and automated curationnyeast interactions. a part of mips dipmanual and automated curationyexperimentally determined interactions intactmanual curationydatabase and analysis system of binary and multi-protein interactions pdzbasemanual curationnpdz domain containing proteins gnpvmanual and automated curationybased on specific experiments and literature biogridmanual curationyphysical and genetic interactions unihimanual and automated curationycomprehensive human protein interactions ophidmanual curationycombines ppi from bind, hprd, and mint 2. metabolic pathway databases ecocycmanual and automated curationyentire genome and biochemical machinery of e. coli metacycmanual curationnpathways of over 165 species humancycmanual and automated curationnhuman metabolic pathways and the human genome biocycmanual and automated curationncollection of databases for several organism 3. signaling pathway databases keggmanual curationycomprehensive collection of pathways such as human disease, signaling, genetic information processing pathways. links to several useful databases panthermanual curationncompendium of metabolic and signaling pathways built using celldesigner. pathways can be downloaded in sbml format reactomemanual curationyhierarchical layout. extensive links to relevant databases such as ncbi, ensembl, uniprot, hapmap, kegg, chebi, pubmed, go. follows psi-mi standards biomodelsmanual curationydomain experts curated biological connection maps and associated mathematical models stkemanual curationnrepository of canonical pathways ingenuity systemsmanual curationycommercial mammalian biological knowledgebase about genes, drugs, chemical, cellular and disease processes, and signaling and metabolic pathways human signaling networkmanual curationyliterature-curated human signaling network, the largest human signaling network database pidmanual curationycompendium of several highly structured, assembled signaling pathways bioppmanual and automated curationyrepository of biological pathways built using celldesigner legend: y – yes, n – no; bind – biomolecular interaction network database, dip – database of interacting proteins, gnpv – genome network platform viewer, hprd = human protein reference database, mint – molecular interaction database, mips – munich information center for protein sequences, unihi – unified human interactome, ophid – online predicted human interaction database, ecocyc – encyclopaedia of e. coli genes and metabolism, metacyc – ametabolic pathway database, kegg – kyoto encyclopedia of genes and genomes, panther – protein analysis through evolutionary relationship database, stke – signal transduction knowledge environment, pid – the pathway interaction database, biopp – biological pathway publisher. a comprehensive list of resources can be found at http://www.pathguide.org. pathway-related databases and tools kegg the increasing amount of genomic and molecular information is the basis for understanding higher-order biological systems, such as the cell and the organism, and their interactions with the environment, as well as for medical, industrial and other practical applications. the kegg resource provides a reference knowledge base for linking genomes to biological systems, categorized as building blocks in the genomic space (kegg genes), the chemical space (kegg ligand), wiring diagrams of interaction networks and reaction networks (kegg pathway), and ontologies for pathway reconstruction (brite database). the kegg pathway database is a collection of manually drawn pathway maps for metabolism, genetic information processing, environmental information processing such as signal transduction, ligand–receptor interaction and cell communication, various other cellular processes and human diseases, all based on extensive survey of published literature. genmapp gene map annotator and pathway profiler (genmapp) a free, open-source, stand-alone computer program is designed for organizing, analyzing, and sharing genome scale data in the context of biological pathways. genmapp database support multiple gene annotations and species as well as custom species database creation for a potentially unlimited number of species. pathway resources are expanded by utilizing homology information to translate pathway content between species and extending existing pathways with data derived from conserved protein interactions and coexpression. a new mode of data visualization including time-course, single nucleotide polymorphism (snp), and splicing, has been implemented with genmapp database to support analysis of complex data. genmapp also offers innovative ways to display and share data by incorporating html export of analyses for entire sets of pathways as organized web pages. in short, genmapp provides a means to rapidly interrogate complex experimental data for pathway-level changes in a diverse range of organisms. reactome given the genetic makeup of an organism, the complete set of possible reactions constitutes its reactome. reactome, located at http://www.reactome.org is a curated, peer-reviewed resource of human biological processes/pathway data. the basic unit of the reactome database is a reaction; reactions are then grouped into causal chains to form pathways the reactome data model allows us to represent many diverse processes in the human system, including the pathways of intermediary metabolism, regulatory pathways, and signal transduction, and high-level processes, such as the cell cycle. reactome provides a qualitative framework, on which quantitative data can be superimposed. tools have been developed to facilitate custom data entry and annotation by expert biologists, and to allow visualization and exploration of the finished dataset as an interactive process map. although the primary curational domain is pathways from homo sapiens, electronic projections of human pathways onto other organisms are regularly created via putative orthologs, thus making reactome relevant to model organism research communities. the database is publicly available under open source terms, which allows both its content and its software infrastructure to be freely used and redistributed. studying whole transcriptional profiles and cataloging protein–protein interactions has yielded much valuable biological information, from the genome or proteome to the physiology of an organism, an organ, a tissue or even a single cell. the reactome database containing a framework of possible reactions which, when combined with expression and enzyme kinetic data, provides the infrastructure for quantitative models, therefore, an integrated view of biological processes, which links such gene products and can be systematically mined by using bioinformatics applications. reactome data available in a variety of standard formats, including biopax, sbml and psi-mi, and also enable data exchange with other pathway databases, such as the cycs, kegg and amaze, and molecular interaction databases, such as bind and hprd. the next data release will cover apoptosis, including the death receptor signaling pathways, and the bcl2 pathways, as well as pathways involved in hemostasis. other topics currently under development include several signaling pathways, mitosis, visual phototransduction and hematopoeisis. in summary, reactome provides high-quality curated summaries of fundamental biological processes in humans in a form of biologist-friendly visualization of pathways data, and is an open-source project. pathway-oriented approaches in the post-genomic age, high-throughput sequencing and gene/protein profiling techniques have transformed biological research by enabling comprehensive monitoring of a biological system, yielding a list of differentially expressed genes or proteins, which is useful in identifying genes that may have roles in a given phenomenon or phenotype. with dna microarrays and genome-wide gene engineering, it is possible to screen global gene expression profiles to contribute a wealth of genomic data to the public domain. with rna interference, it is possible to distill the inferences contained in the experimental literature and primary databases into knowledge bases that consist of annotated representations of biological pathways. in this case, individual genes and proteins are known to be involved in biological processes, components, or structures, as well as how and where gene products interact with each other. pathway-oriented approaches for analyzing microarray data, by grouping long lists of individual genes, proteins, and/or other biological molecules according to the pathways they are involved in into smaller sets of related genes or proteins, which reduces the complexity, have proven useful for connecting genomic data to specific biological processes and systems. identifying active pathways that differ between two conditions can have more explanatory power than a simple list of different genes or proteins. in addition, a large number of pathway analytic methods exploit pathway knowledge in public repositories such as gene ontology (go) or kyoto encyclopedia of genes and genomes (kegg), rather than inferring pathways from molecular measurements. furthermore, different research focuses have given the word "pathway" different meanings. for example, 'pathway' can denote a metabolic pathway involving a sequence of enzyme-catalyzed reactions of small molecules, or a signaling pathway involving a set of protein phosphorylation reactions and gene regulation events. therefore, the term "pathway analysis" has a very broad application. for instance, it can refer to the analysis physical interaction networks (e.g., protein–protein interactions), kinetic simulation of pathways, and steady-state pathway analysis (e.g., flux-balance analysis), as well as its usage in the inference of pathways from expression and sequence data. several functional enrichment analysis tools and algorithms have been developed to

enhance data interpretation. the existing knowledge base–driven pathway analysis methods in each generation have been summarized in recent literature. applications of pathway analysis in medicine colorectal cancer (crc) a program package matchminer was used to scan hugo names for cloned genes of interest are scanned, then are input into gominer, which leveraged the go to identify the biological processes, functions and components represented in the gene profile. also, database for annotation, visualization, and integrated discovery (david) and kegg database can be used for the analysis of microarray expression data and the analysis of each go biological process (p), cellular component (c), and molecular function (f) ontology. in addition, david tools can be used to analyze the roles of genes in metabolic pathways and show the biological relationships between genes or gene-products and may represent metabolic pathways. these two databases also provide bioinformatics tools online to combine specific biochemical information on a certain organism and facilitate the interpretation of biological meanings for experimental data. by using a combined approach of microarray-bioinformatic technologies, a potential metabolic mechanism contributing to colorectal cancer (crc) has been demonstrated several environmental factors may be involved in a series of points along the genetic pathway to crc. these include genes associated with bile acid metabolism, glycolysis metabolism and fatty acid metabolism pathways, supporting a hypothesis that some metabolic alternations observed in colon carcinoma may occur in the development of crc. parkinson's disease (pd) cellular models are instrumental in dissecting a complex pathological process into simpler molecular events. parkinson's disease (pd) is multifactorial and clinically heterogeneous; the aetiology of the sporadic (and most common) form is still unclear and only a few molecular mechanisms have been clarified so far in the neurodegenerative cascade. in such a multifaceted picture, it is particularly important to identify experimental models that simplify the study of the different networks of proteins and genes involved. cellular models that reproduce some of the features of the neurons that degenerate in pd have contributed to many advances in our comprehension of the pathogenic flow of the disease. in particular, the pivotal biochemical pathways (i.e. apoptosis and oxidative stress, mitochondrial impairment and dysfunctional mitophagy, unfolded protein stress and improper removal of misfolded proteins) have been widely explored in cell lines, challenged with toxic insults or genetically modified. the central role of a-synuclein has generated many models aiming to elucidate its contribution to the dysregulation of various cellular processes. classical cellular models appear to be the correct choice for preliminary studies on the molecular action of new drugs or potential toxins and for understanding the role of single genetic factors. moreover, the availability of novel cellular systems, such as cybrids or induced pluripotent stem cells, offers the chance to exploit the advantages of an in vitro investigation, although mirroring more closely the cell population being affected. alzheimer's disease (ad) synaptic degeneration and death of nerve cells are defining features of alzheimer's disease (ad), the most prevalent age-related neurodegenerative disorders. in ad, neurons in the hippocampus and basal forebrain (brain regions that subserve learning and memory functions) are selectively vulnerable. studies of postmortem brain tissue from ad people have provided evidence for increased levels of oxidative stress, mitochondrial dysfunction and impaired glucose uptake in vulnerable neuronal populations. studies of animal and cell culture models of ad suggest that increased levels of oxidative stress (membrane lipid peroxidation, in particular) may disrupt neuronal energy metabolism and ion homeostasis, by impairing the function of membrane ion-motive atpases, glucose and glutamate transporters. such oxidative and metabolic compromise may thereby render neurons vulnerable to excitotoxicity and apoptosis. recent studies suggest that ad can manifest systemic alterations in energy metabolism (e.g., increased insulin resistance and dysregulation of glucose metabolism). emerging evidence that dietary restriction can forestall the development of ad is consistent with a major "metabolic" component to these disorders, and provides optimism that these devastating brain disorders of aging may be largely preventable.

glycomyces tritici glycomyces tritici "glycomyces tritici" is a bacterium from the genus of glycomyces which has been isolated from rhizospheric soil from a wheat-plant (triticum aestivum). glycomyces tritici scientific classification domain: bacteria phylum: actinomycetota class: actinomycetia order: glycomycetales family: glycomycetaceae genus: glycomyces species: g. tritici binomial name glycomyces triticili et al. 2018 type strain cgmcc 4.7410dsm 104644neau-c2

list of drugs: an–ap list of drugs: an–ap this multi-page article lists pharmaceutical drugs alphabetically by name. many drugs have more than one name and, therefore, the same drug may be listed more than once. brand names and generic names are differentiated by capitalizing brand names.

national perinatal epidemiology unit national perinatal epidemiology unit the national perinatal epidemiology unit (npeu) is a multi-disciplinary research unit within the nuffield department of population health at oxford university. it is located in the richard doll building on the old road campus, in headington, east oxford, england. the unit's work involves randomized controlled trials, national surveillance programs and surveys and other research on maternal and infant health and care in the perinatal period (before, during and after birth). the early work of the npeu in developing a register of perinatal trials and methods for synthesizing their results lay the foundations for the cochrane collaboration. activities the mission of the npeu is "...to produce methodologically rigorous research evidence to improve the care provided to women and their families during pregnancy, childbirth, the newborn period and early childhood as well as promoting the effective use of resources by perinatal health services.” since its inception, a key area of its activities has been undertaking and supporting randomized controlled trials of the effects of perinatal care, now through the npeu clinical trials unit. the npeu runs the uk obstetric surveillance system (ukoss), which is a national system studying rare disorders of pregnancy. in 2011, the policy research unit in maternal health and care (prumc) was established at the npeu. history the npeu's classified bibliography of controlled trials in perinatal medicine 1940–1984 the npeu was established in 1978 by the department of health at oxford university, following a joint request for a national research institute by the royal college of obstetricians and gynaecologists and the british paediatric association. the department gave the unit the task of providing "information which can promote effective use of resources in the perinatal health services." from the beginning, the first npeu director, iain chalmers, was guided by the principles for evaluating effectiveness of health care described by archie cochrane in his book, effectiveness and efficiency: random reflections on health services. from its early days, the npeu was a leader in both randomized controlled trials to assess the effects of perinatal care, the retrieval of information, and the development and use of systematic reviews and meta-analyses to synthesize research results. the unit developed extensive national and international collaborations which were to form both the basis of its work and lay the foundations for the development of the cochrane collaboration. beginning with a card file of references to perinatal trials and both manual and electronic searching for further trials, the npeu developed first a book, the classified bibliography of controlled trials in perinatal medicine 1940–1984, and then the oxford database of perinatal trials (odpt). this process of developing a register of trials led to others establishing a register of trials in fertility as well as the basis for the development of the cochrane controlled trials register (cctr) when the npeu's director left to establish the uk cochrane centre in 1992, from where the cochrane collaboration evolved in 1993. by 1989, the synthesis of the results of perinatal research led to the publication of major books. by 1990, odpt included electronic syntheses called overviews, which were the precursor for the cochrane collaboration's cochrane database of systematic reviews. in 2013, the npeu was awarded a silver department athena swan award for its commitment to advancing women's careers in science and medicine. directors sir iain chalmers (1978 to 1992) judith lumley (1994 to 1995) peter brocklehurst (2002 to 2011) jenny kurinczuk (2011 to present)

advanced airway advanced airway an advanced airway includes: an endotracheal tube, the most frequently used advanced airway endotracheal tube supraglottic airway laryngeal mask airway combitube king lt

streptomyces kurssanovii streptomyces kurssanovii streptomyces kurssanovii is a bacterium species from the genus of streptomyces which has been isolated from soil in russia. streptomyces kurssanovii produces chitinase, n-(phenylacetyl)-2-butenediamide and fumaramidmycin. streptomyces kurssanovii scientific classification domain: bacteria phylum: actinomycetota class: actinomycetia order: streptomycetales family: streptomycetaceae genus: streptomyces species: s. kurssanovii binomial name streptomyces kurssanovii(preobrazhenskaya et al. 1957) pridham et al. 1958 (approved lists 1980) type strain atcc 15824, atcc 19774, atcc 23629, bcrc 12133, cbs 213.62, cbs 512.68, ccrc 12133, cect 3274, cest 3274, cgmcc 4.1889, dsm 40162, eth 28492, ifo 13192, ina 10294, isp 5162, jcm 4388, kcc s-0388, kccs-0388, kctc 9876, nbrc 13192, ncimb 12787, ncimb 12788, nrrl b-3366, nrrl-isp 5162, preobrazhenskaya 10294, ria 1054, uniqem 160 synonyms "actinomyces kurssanovii" preobrazhenskaya et al. 1957

ventricular system ventricular system the ventricular system is a set of four interconnected cavities known as cerebral ventricles in the brain. within each ventricle is a region of choroid plexus which produces the circulating cerebrospinal fluid (csf). the ventricular system is continuous with the central canal of the spinal cord from the fourth ventricle, allowing for the flow of csf to circulate. ventricular systemthe ventricular system accounts for the production and circulation of cerebrospinal fluid.rotating 3d rendering of the four ventricles and connections. from top to bottom:blue - lateral ventriclescyan - interventricular foramina (monro)yellow - third ventriclered - cerebral aqueduct (sylvius)purple - fourth ventriclegreen - continuous with the central canal(aperture to subarachnoid space are not visible)detailsidentifierslatinventriculi cerebrimeshd002552neuronames2497fma242787anatomical terms of neuroanatomy all of the ventricular system and the central canal of the spinal cord are lined with ependyma, a specialised form of epithelium connected by tight junctions that make up the blood–cerebrospinal fluid barrier. structure size and location of the ventricular system in the human head. the system comprises four ventricles: lateral ventricles right and left (one for each hemisphere) third ventricle fourth ventricle there are several foramina, openings acting as channels, that connect the ventricles. the interventricular foramina (also called the foramina of monro) connect the lateral ventricles to the third ventricle through which the cerebrospinal fluid can flow. namefromto interventricular foramina (monro)lateral ventriclesthird ventricle cerebral aqueduct (sylvius)third ventriclefourth ventricle median aperture (magendie)fourth ventriclesubarachnoid space via the cisterna magna right and left lateral aperture (luschka)fourth ventriclesubarachnoid space via the cistern of great cerebral vein ventricles 3d rendering of ventricles (lateral and anterior views). ventricular system anatomy. the four cavities of the human brain are called ventricles. the two largest are the lateral ventricles in the cerebrum, the third ventricle is in the diencephalon of the forebrain between the right and left thalamus, and the fourth ventricle is located at the back of the pons and upper half of the medulla oblongata of the hindbrain. the ventricles are concerned with the production and circulation of cerebrospinal fluid. development the structures of the ventricular system are embryologically derived from the neural canal, the centre of the neural tube. as the part of the primitive neural tube that will develop into the brainstem, the neural canal expands dorsally and laterally, creating the fourth ventricle, whereas the neural canal that does not expand and remains the same at the level of the midbrain superior to the fourth ventricle forms the cerebral aqueduct. the fourth ventricle narrows at the obex (in the caudal medulla), to become the central canal of the spinal cord. in more detail, around the third week of development, the embryo is a three-layered disc. the embryo is covered on the dorsal surface by a layer of cells called ectoderm. in the middle of the dorsal surface of the embryo is a linear structure called the notochord. as the ectoderm proliferates, the notochord is dragged into the middle of the developing embryo. as the brain develops, by the fourth week of embryological development three swellings known as brain vesicles have formed within the embryo around the canal, near where the head will develop. the three primary brain vesicles represent different components of the central nervous system: the prosencephalon, mesencephalon and rhombencephalon. these in turn divide into five secondary vesicles. as these sections develop around the neural canal, the inner neural canal becomes known as primitive ventricles. these form the ventricular system of the brain: the neural stem cells of the developing brain, principally radial glial cells, line the developing ventricular system in a transient zone called the ventricular zone. the prosencephalon divides into the telencephalon, which forms the cortex of the developed brain, and the diencephalon. the ventricles contained within the telencephalon become the lateral ventricles, and the ventricles within the diencephalon become the third ventricle. the rhombencephalon divides into a metencephalon and myelencephalon. the ventricles contained within the rhombencephalon become the fourth ventricle, and the ventricles contained within the mesencephalon become the aqueduct of sylvius. separating the anterior horns of the lateral ventricles is the septum pellucidum: a thin, triangular, vertical membrane which runs as a sheet from the corpus callosum down to the fornix. during the third month of fetal development, a space forms between two septal laminae, known as the cave of septum pellucidum (csp), which is a marker for fetal neural maldevelopment. during the fifth month of development, the laminae start to close and this closure completes from about three to six months after birth. fusion of the septal laminae is attributed to rapid development of the alvei of the hippocampus, amygdala, septal nuclei, fornix, corpus callosum and other midline structures. lack of such limbic development interrupts this posterior-to-anterior fusion, resulting in the continuation of the csp into adulthood. function flow of cerebrospinal fluid mri showing flow of csf the cerebrospinal fluid passes out through arachnoid villi into the venous sinuses of the skull. a schematic illustration of the venous sinuses surrounding the brain. the ventricles are filled with cerebrospinal fluid (csf) which bathes and cushions the brain and spinal cord within their bony confines. csf is produced by modified ependymal cells of the choroid plexus found in all components of the ventricular system except for the cerebral aqueduct and the posterior and anterior horns of the lateral ventricles. csf flows from the lateral ventricles via the interventricular foramina into the third ventricle, and then the fourth ventricle via the cerebral aqueduct in the midbrain. from the fourth ventricle it can pass into the central canal of the spinal cord or into the subarachnoid cisterns via three small foramina: the central median aperture and the two lateral apertures. according to the traditional understanding of cerebrospinal fluid (csf) physiology, the majority of csf is produced by the choroid plexus, circulates through the ventricles, the cisterns, and the subarachnoid space to be absorbed into the blood by the arachnoid villi the fluid then flows around the superior sagittal sinus to be reabsorbed via the arachnoid granulations (or arachnoid villi) into the venous sinuses, after which it passes through the jugular vein and major venous system. csf within the spinal cord can flow all the way down to the lumbar cistern at the end of the cord around the cauda equina where lumbar punctures are performed. the cerebral aqueduct between the third and fourth ventricles is very small, as are the foramina, which means that they can be easily blocked. protection of the brain the brain and spinal cord are covered by the meninges, the three protective membranes of the tough dura mater, the arachnoid mater and the pia mater. the cerebrospinal fluid (csf) within the skull and spine provides further protection and also buoyancy, and is found in the subarachnoid space between the pia mater and the arachnoid mater. the csf that is produced in the ventricular system is also necessary for chemical stability, and the provision of nutrients needed by the brain. the csf helps to protect the brain from jolts and knocks to the head and also provides buoyancy and support to the brain against gravity. (since the brain and csf are similar in density, the brain floats in neutral buoyancy, suspended in the csf.) this allows the brain to grow in size and weight without resting on the floor of the cranium, which would destroy nervous tissue. clinical significance the narrowness of the cerebral aqueduct and foramina means that they can become blocked, for example, by blood following a hemorrhagic stroke. as cerebrospinal fluid is continually produced by the choroid plexus within the ventricles, a blockage of outflow leads to increasingly high pressure in the lateral ventricles. as a consequence, this commonly leads in turn to hydrocephalus. medically one would call this post-haemorrhagic acquired hydrocephalus, but is often referred to colloquially by the layperson as "water on the brain". this is an extremely serious condition regardless of the cause of blockage. an endoscopic third ventriculostomy is a surgical procedure for the treatment of hydrocephalus in which an opening is created in the floor of the third ventricle using an endoscope placed within the ventricular system through a burr hole. this allows the cerebrospinal fluid to flow directly to the basal cisterns, thereby bypassing any obstruction. a surgical procedure to make an entry hole to access any of the ventricles is called a ventriculostomy. this is done to drain accumulated cerebrospinal fluid either through a temporary catheter or a permanent shunt. other diseases of the ventricular system include inflammation of the membranes (meningitis) or of the ventricles (ventriculitis) caused by infection or the introduction of blood following trauma or haemorrhage (cerebral haemorrhage or subarachnoid haemorrhage). during embryogenesis in the choroid plexus of the ventricles, choroid plexus cysts can form. the scientific study of ct scans of the ventricles in the late 1970s gave new insight into the study of mental disorders. researchers found that individuals with schizophrenia had (in terms of group averages) larger than usual ventricles. this became the first "evidence" that schizophrenia was biological in origin and led to a renewed interest in its study via the use of imaging techniques. magnetic resonance imaging (mri) has superseded the use of ct in research in the role of detecting ventricular abnormalities in psychiatric illness. whether the enlarged ventricles is a cause or a result of schizophrenia has not yet been established. enlarged ventricles are also found in organic dementia and have been explained largely in terms of environmental factors. they have also been found to be extremely diverse between individuals, such that the percentage difference in group averages in schizophrenia studies (+16%) has been described as "not a very profound difference in the context of normal variation" (ranging from 25% to 350% of the mean average). the cave of septum pellucidum has been loosely associated with schizophrenia, post-traumatic stress disorder, traumatic brain injury, as well as with antisocial personality disorder. csp is one of the distinguishing features of individuals displaying symptoms of dementia pugilistica. additional media transverse dissection showing the ventricles of the brain. 3d model of ventricular system scheme showing relations of the ventricles to the surface of the brain. drawing of a cast of the ventricular cavities, viewed from above. view of ventricles and choroid plexus lateral ventricles along with subcortical structures, in glass brain

ulnar notch of the radius ulnar notch of the radius the articular surface for the ulna is called the ulnar notch (sigmoid cavity) of the radius; it is in the distal radius, and is narrow, concave, smooth, and articulates with the head of the ulna forming the distal radioulnar joint. "sigmoid cavity" redirects here. for greater sigmoid cavity, see trochlear notch. ulnar notch of the radiusbones of left forearm. anterior aspect. (ulnar notch visible but not labeled.)detailsidentifierslatinincisura ulnaris radiita98a02.4.05.019ta21228fma75082 23530, 75082anatomical terminology

quality of life index by country quality of life index by country this article charts a quality of life index by country as determined by world population review, an independent organization. quality of life index by country 2022 countries this list includes 87 countries in the world and updated in 2022. a higher number indicates a higher quality of life in the country . rank countries/districts quality of life index by country 1 switzerland195.27 2 denmark192.36 3 netherlands185.38 4 finland184.96 5 poland183.81 6 iceland182.26 7 germany180.27 8 austria179.16 9 new zealand176.81 10 norway176.39 11 sweden175.30 12 estonia174.19 13 oman173.68 14 luxembourg173.63 15 united states170.72 16 japan169.48 17 slovenia169.04 18 spain168.48 19 czech republic162.64 20 portugal162.52 21 lithuania161.84 22 united kingdom161.74 23 canada160.38 24 united arab emirates160.38 25 croatia159.21 26 france156.65 27 qatar154.53 28 ireland154.52 29 belgium151.86 30 singapore151.59 31 slovakia151.16 32 latvia150.81 33 saudi arabia149.54 34 cyprus147.10 35 israel146.06 36 italy141.07 37 taiwan140.15 38 australia140.02 39 hungary137.15 40 south africa136.02 41 puerto rico133.77 42 romania133.38 43 bulgaria130.09 44 bosnia and herzegovina127.07 45 south korea125.04 46 mexico124.90 47 turkey124.05 48 uruguay122.26 49 costa rica122.07 50 georgia121.14 51 ecuador118.84 52 malaysia117.98 53 kuwait117.34 54 serbia117.23 55 tunisia114.56 56 panama114.32 57 greece113.92 58 ukraine111.93 59 india110.99 60 north macedonia109.60 61 malta109.50 62 belarus108.48 63 morocco107.54 64 brazil107.04 65 argentina105.42 66 china105.07 67 azerbaijan104.10 68 colombia103.54 69 russia103.28 70 pakistan102.57 71 thailand100.97 72 chile100.15 73 lebanon99.35 74 hong kong98.42 75 kazakhstan93.77 76 kenya92.54 77 indonesia90.36 78 vietnam89.95 79 egypt89.87 80 philippines83.74 81 peru80.42 82 venezuela77.43 83 sri lanka67.88 84 bangladesh67.59 85 iran64.89 86 jordan52.45

exposure notification exposure notification the (google/apple) exposure notification (gaen) system, originally known as the privacy-preserving contact tracing project, is a framework and protocol specification developed by apple inc. and google to facilitate digital contact tracing during the covid-19 pandemic. when used by health authorities, it augments more traditional contact tracing techniques by automatically logging encounters with other notification system users using their android or ios smartphone. exposure notification is a decentralized reporting based protocol built on a combination of bluetooth low energy technology and privacy-preserving cryptography. it is used as an opt-in feature within covid-19 apps developed and published by authorized health authorities. originally unveiled on april 10, 2020, it was first made available on ios on may 20, 2020 as part of the ios 13.5 update and on december 14, 2020 as part of the ios 12.5 update for older iphones. on android, it was added to devices via a google play services update, supporting all versions since android marshmallow. exposure notificationdeveloped byapple inc.googleintroducedapril 10, 2020 (2020-04-10)industrydigital contact tracingcompatible hardwareandroid & ios smartphonesphysical range~10 m (33 ft) the apple/google protocol is similar to the decentralized privacy-preserving proximity tracing (dp-3t) protocol created by the european dp-3t consortium and the temporary contact number (tcn) protocol by covid watch, but is implemented at the operating system level, which allows for more efficient operation as a background process. since may 2020, a variant of the dp-3t protocol is supported by the exposure notification interface. other protocols are constrained in how they operate as they have no special privilege over normal apps. this leads to issues, particularly on ios devices where digital contact tracing apps running in the background experience significantly degraded performance. the joint approach is also designed to maintain interoperability between android and ios devices, which constitute the sheer majority of the market. the aclu stated the approach "appears to mitigate the worst privacy and centralization risks, but there is still room for improvement". in late april, google and apple shifted the emphasis of the naming of the system, describing it as an "exposure notification service", rather than "contact tracing" system. technical specification typically digital contact tracing protocols have two major responsibilities: encounter logging and infection reporting. exposure notification only defines encounter logging which is a decentralized architecture, with the majority of the infection reporting, currently it is centralized, being delegated to individual app implementations. to handle encounter logging, the system uses bluetooth low energy to send tracking messages to nearby devices running the protocol to discover encounters with other people. the tracking messages contain unique identifiers that are encrypted with a secret daily key held by the sending device. these identifiers change every 15–20 minutes as well as bluetooth mac address in order to prevent tracking of clients by malicious third parties through observing static identifiers over time. the sender's daily encryption keys are generated using a random number generator. devices record received messages, retaining them locally for 14 days. if a user tests positive for infection, the last 14 days of their daily encryption keys can be uploaded to a central server, where it is then broadcast to all devices on the network. the method through which daily encryption keys are transmitted to the central server and broadcast is defined by individual app developers. the google-developed reference implementation calls for a health official to request a one-time verification code (vc) from a verification server, which the user enters into the encounter logging app. this causes the app to obtain a cryptographically signed certificate, which is used to authorize the submission of keys to the central reporting server. the received keys are then provided to the protocol, where each client individually searches for matches in their local encounter history. if a match meeting certain risk parameters is found, the app notifies the user of potential exposure to the infection. google and apple intend to use the received signal strength (rssi) of the beacon messages as a source to infer proximity. rssi and other signal metadata will also be encrypted to resist deanonymization attacks. version 1.0 to generate encounter identifiers, first a persistent 32-byte private tracing key ( t k ) is generated by a client. from this a 16 byte daily tracing key is derived using the algorithm d t k i = h k d f ( t k , n u l l , 'ct-dtk' | | d i , 16 ) =hkdf(tk,null,||d_,16)} , where h k d f ( key, salt, data, outputlength ) )} is a hkdf function using sha-256, and d i is the day number for the 24-hour window the broadcast is in starting from unix epoch time. these generated keys are later sent to the central reporting server should a user become infected. from the daily tracing key a 16-byte temporary rolling proximity identifier is generated every 10 minutes with the algorithm r p i i , j = truncate ( h m a c ( d t k i , 'ct-rpi' | | t i n j ) , 16 ) =(hmac(dtk_,||tin_),16)} , where h m a c ( key, data ) )} is a hmac function using sha-256, and t i n j is the time interval number, representing a unique index for every 10 minute period in a 24-hour day. the truncate function returns the first 16 bytes of the hmac value. when two clients come within proximity of each other they exchange and locally store the current r p i i , j as the encounter identifier. once a registered health authority has confirmed the infection of a user, the user's daily tracing key for the past 14 days is uploaded to the central reporting server. clients then download this report and individually recalculate every rolling proximity identifier used in the report period, matching it against the user's local encounter log. if a matching entry is found, then contact has been established and the app presents a notification to the user warning them of potential infection. version 1.1 unlike version 1.0 of the protocol, version 1.1 does not use a persistent tracing key, rather every day a new random 16-byte temporary exposure key ( t e k i ) is generated. this is analogous to the daily tracing key from version 1.0. here i denotes the time is discretized in 10 minute intervals starting from unix epoch time. from this two 128-bit keys are calculated, the rolling proximity identifier key ( r p i k i ) and the associated encrypted metadata key ( a e m k i ). r p i k i is calculated with the algorithm r p i k i = h k d f ( t e k i , n u l l , 'en-rpik' , 16 ) =hkdf(tek_,null,,16)} , and a e m k i using the algorithm a e m k i = h k d f ( t e k i , n u l l , 'en-aemk' , 16 ) =hkdf(tek_,null,,16)} . from these values a temporary rolling proximity identifier ( r p i i , j ) is generated every time the ble mac address changes, roughly every 15–20 minutes. the following algorithm is used: r p i i , j = a e s 128 ( r p i k i , 'en-rpi' | | 0 x 000000000000 | | e n i n j ) =aes128(rpik_,||||enin_)} , where a e s 128 ( key, data ) )} is an aes cryptography function with a 128-bit key, the data is one 16-byte block, j denotes the unix epoch time at the moment the roll occurs, and e n i n j is the corresponding 10-minute interval number. next, additional associated encrypted metadata is encrypted. what the metadata represents is not specified, likely to allow the later expansion of the protocol. the following algorithm is used: associated encrypted metadata i , j = a e s 128 _ c t r ( a e m k i , r p i i , j , metadata ) _=aes128\_ctr(aemk_,rpi_,)} , where a e s 128 _ c t r ( key, iv, data ) )} denotes aes encryption with a 128-bit key in ctr mode. the rolling proximity identifier and the associated encrypted metadata are then combined and broadcast using ble. clients exchange and log these payloads. once a registered health authority has confirmed the infection of a user, the user's temporary exposure keys t e k i and their respective interval numbers i for the past 14 days are uploaded to the central reporting server. clients then download this report and individually recalculate every rolling proximity identifier starting from interval number i , matching it against the user's local encounter log. if a matching entry is found, then contact has been established and the app presents a notification to the user warning them of potential infection. version 1.2 version 1.2 of the protocol is identical to version 1.1, only introducing minor terminology changes. privacy preservation of privacy was referred to as a major component of the protocol; it is designed so that no personally identifiable information can be obtained about the user or their device. apps implementing exposure notification are only allowed to collect personal information from users on a voluntary basis. consent must be obtained by the user to enable the system or publicize a positive result through the system, and apps using the system are prohibited from collecting location data. as an additional measure, the companies stated that it would sunset the protocol by-region once they determine that it is "no longer needed". the electronic frontier foundation showed concerns the protocol was vulnerable to "linkage attacks", where sufficiently capable third parties who had recorded beacon traffic may retroactively be able to turn this information into tracking information, for only areas in which they had already recorded beacons, for a limited time segment and for only users who have disclosed their covid-19 status, once a device's set of daily encryption keys have been revealed. on april 16, the european union started the process of assessing the proposed system for compatibility with privacy and data protection laws, including the general data protection regulation (gdpr). on april 17, 2020, the uk's information commissioner's office, a supervisory authority for data protection, published an opinion analyzing both exposure notification and the decentralized privacy-preserving proximity tracing protocol, stating that the systems are "aligned with the principles of data protection by design and by default" (as mandated by the gdpr). deployment exposure notification is compatible with android devices supporting bluetooth low energy and running android 6.0 "marshmallow" and newer with google mobile services. it is serviced via updates to google play services, ensuring compatibility with the majority of android devices released outside of mainland china, and not requiring it to be integrated into android firmware updates (which would hinder deployment by relying on individual oems). it is not compatible with devices that do not have gms, such as huawei devices released since may 2019. on ios, en is serviced via operating system updates. it was first introduced as part of ios 13.5 on may 20, 2020. in december 2020, apple released ios 12.5, which backported en support to iphone models that cannot be upgraded to ios 13, including iphone 6 and older. exposure notification apps may only be released by public health authorities. to discourage fragmentation, each country will typically be restricted to one app, although apple and google stated that they would accommodate regionalized approaches if a country elects to do so. apple and google released reference implementations for apps utilizing the system, which can be used as a base. on september 1, 2020, the consortium announced "exposure notifications express" (en express), a system designed to ease adoption of the protocol by health authorities by removing the need to develop an app themselves. under this system, a health authority provides parameters specific to their implementation (such as thresholds, branding, messaging, and key servers), which is then processed to generate the required functionality. on android, this data is used to generate an app, and a configuration profile that can also be deployed to users via google play services without a dedicated app. on ios, the functionality is integrated directly at the system level on ios 13.7 and newer without a dedicated

app. on december 14, 2020, apple released ios 12.5, bringing support for exposure notifications to older iphones. the last information update on the “exposure notification systems” partnership was a year end review issued by google in december 2020: "we plan to keep you updated here with new information again next year". nothing has however been issued on the one year anniversary of the launch of the “exposure notification interface” api in spite of important changes on the pandemic front such as vaccination, variants, digital health passports, app adoption challenges as well as growing interest for tracking qr codes (and notifying from that basis) on a mostly airborne transmitted virus. the frequently asked questions (faq) published document has not been revised since may 2020. basic support remains provided through the apps store released by authorized public health agencies, including enforcement of the personal privacy protection framework as demonstrated on the uk nhs challenge in support of their contact tracers. in june 2021, google faced allegations that it had automatically downloaded massachusetts' "massnotify" app to android devices without user consent. google clarified that it had not actually downloaded the app to user devices, and that google play services was being used to deploy an en express configuration profile that would allow it to be enabled via the google settings app without needing to download a separate app. adoption as of may 21, at least 22 countries had received access to the protocol. switzerland and austria were among the first to back the protocol. on april 26, after initially backing pepp-pt, germany announced it would back exposure notification, followed shortly after by ireland and italy. despite already adopting the centralised bluetrace protocol, australia's department of health and digital transformation agency were investigating whether the protocol could be implemented to overcome limitations of its covidsafe app. on may 25, switzerland became the first country to launch an app leveraging the protocol, swisscovid, beginning with a small pilot group. in england, the national health service (nhs) trialed both an in-house app on a centralized platform developed by its nhsx division, and a second app using exposure notification. on june 18, the nhs announced that it would focus on using exposure notification to complement manual contact tracing, citing tests on the isle of wight showing that it had better cross-device compatibility (and would also be compatible with other european approaches), but that its distance calculations were not as reliable as the centralized version of the app, an issue which was later rectified. later, it was stated that the app would be supplemented by qr codes at venues. a study of the impact of exposure notification in england and wales estimated that it averted 8,700 (95% confidence interval 4,700–13,500) deaths out of the 32,500 recorded from its introduction on 24 september 2020 to 31 december 2020. canada launched its covid alert app, co-developed in partnership with blackberry limited and shopify, on july 31 in ontario. as of february 2022, only around 57,000 positive cases had been reported via the app, leading some critics to dismiss it as a failure. in may 2020, covid watch launched the first calibration and beta testing pilot of the gaen apis in the united states at the university of arizona. in aug 2020, the app launched publicly for a phased roll-out in the state of arizona. the u.s. association of public health laboratories (aphl) stated in july 2020 that it was working with apple, google, and microsoft on a national reporting server for use with the protocol, which it stated would ease adoption and interoperability between states. in august 2020, google stated that at least 20 u.s. states had expressed interest in using the protocol. in alabama, the alabama department of public health, university of alabama at birmingham, and the university of alabama system deployed the "guidesafe" app for university students returning to campus, which includes exposure notification features. on august 5, the virginia department of health released its "covidwise" app — making it the first u.s. state to release an exposure notification-based app for the general public. north dakota and wyoming released an en app known as "care19 alert", developed by proudcrowd and using the aphl server (the app is a spin-off from an existing location logging application it had developed, based on one it had developed primarily for use by students travelling to attend college football away games). maryland, nevada, virginia, and washington, d.c. have announced plans to use en express. in september, delaware, new jersey, new york, and pennsylvania all adopted "covid alert" apps developed by nearform, which are based on its covid tracker ireland app. later that month, the norwegian institute of public health announced that it would lead development of an exposure notification-based app for the country, which replaces a centralized app that had ceased operations in june 2020 after the norwegian data protection authority ruled that it violated privacy laws. in nov 2020, bermuda launched the wehealth bermuda app developed by wehealth, a public benefit corporation, which was based on the covid watch app released in arizona. country region/state name announced/released notes austria stopp corona app june 26, 2020 brazil coronavírus-sus july 31, 2020 bermuda wehealth bermuda nov 24, 2020 belgium coronalert october 1, 2020 (public) september 2, 2020 (pilot phase) canada covid alert july 31, 2020 available in new brunswick, newfoundland and labrador, ontario, manitoba, saskatchewan, quebec, prince edward island, and nova scotia. alberta and british columbia have declined its use. czech republic erouška (emask) september 17, 2020 since version 2.1 denmark smittestop june 18, 2020 estonia hoia august 20, 2020 finland koronavilkku august 31, 2020 germany corona-warn-app june 16, 2020 gibraltar beat covid gibraltar june 18, 2020 based on covid tracker ireland and will interoperate with it. iceland rakning c-19 may 12, 2021 gean implementation activated in may 2021, replaced previous version of app which used gps tracking stored on-device launched in april 2020. ireland covid tracker ireland july 7, 2020 italy immuni june 1, 2020 japan cocoa june 19, 2020 jersey jersey covid alert september 21, 2020 latvia apturi covid may 29, 2020 lebanon ma3an july 16, 2020 netherlands coronamelder october 10, 2020 (full release) new zealand nz covid tracer december 10, 2020 (full release) norway smittestopp december 21, 2020 replaced a version of the app that was suspended earlier in the year due to scrutiny from the local norwegian data protection authority. philippines staysafe.ph march 29, 2021 gaen implementation activated in april 2021 poland protego safe june 9, 2020 update to existing encounter logging app. portugal stayaway covid august 28, 2020 russia gosuslugi. covid tracker november 23, 2020 https://play.google.com/store/apps/details?id=com.minsvyaz.gosuslugi.exposurenotificationdroid south africa covid alert sa september 1, 2020 spain radar covid june 30, 2020 (beta test) switzerland swisscovid may 26, 2020 (pilot phase) taiwan 臺灣社交距離 may 3, 2021 thailand thai covid alert april 26, 2022 united kingdom england wales nhs covid-19 september 24, 2020 northern ireland stopcovid ni july 30, 2020 interoperates with covid tracker ireland. scotland protect scotland september 11, 2020 based on covid tracker ireland and will interoperate with it. united states alabama guidesafe august 3, 2020 targeting university of alabama students as part of a larger program under the same name. alaska alaska covid enx january 20, 2022 arizona covid watch may 28, 2020 (attenuation and dynamic risk testing) august 19, 2020 (released) targeting university of arizona in a phased roll-out for the state of arizona. california ca notify december 10, 2020 colorado co exposure notifications october 25, 2020 connecticut covid alert ct november 12, 2020 delaware covid alert de september 15, 2020 based on covid tracker ireland. guam guam covid alert september 10, 2020 based on the pathcheck foundation's gaen mobile project hawaii aloha safe alert november 11, 2020 based on the pathcheck foundation's gaen mobile project louisiana covid defense january 22, 2021 based on the pathcheck foundation's gaen mobile project maryland md covid alert october 10, 2020 massachusetts massnotify uses en express. michigan mi covid alert october 15, 2020 (michigan state university pilot) november 9, 2020 (statewide) minnesota covidaware mn november 23, 2020 missouri mo/notify july 29, 2021 targeting washington university in st. louis in a phased roll-out for the state of missouri. new jersey covid alert nj september 30, 2020 based on covid tracker ireland. new york covid alert ny september 30, 2020 based on covid tracker ireland. north carolina slowcovidnc september 22, 2020 the app was shut down on or before august 19, 2022. north dakota care19 alert august 13, 2020 pennsylvania covid alert pa september 24, 2020 based on covid tracker ireland. utah ut exposure notifications february 16, 2021 virginia covidwise august 5, 2020 washington wa notify november 30, 2020 wisconsin wi exposure notification december 23, 2020 wyoming care19 alert august 14, 2020 uruguay coronavirus uy june 15, 2020 alternatives some countries, such as france, have pursued centralized approaches to digital contact tracing, in order to maintain records of personal information that can be used to assist in investigating cases. the french government asked apple in april 2020 to allow apps to perform bluetooth operations in the background, which would allow the government to create its own system independent of exposure notification. on august 9, the canadian province of alberta announced plans to migrate to the en-based covid alert from its bluetrace-based abtracetogether app. this did not occur, and on november 6 premier of alberta jason kenney announced that the province would not do so, arguing that abtracetogether was "from our view, simply a better and more effective public health tool", and that they would be required to phase out abtracetogether if they did switch. british columbia has also declined to adopt covid alert, with provincial health officer bonnie henry stating that covid alert was too "non-specific". australia's officials have stated its covidsafe, which is based on singapore's bluetrace, will not be shifting from manual intervention. in the united states, states such as california and massachusetts declined to use the technology, opting for manual contact tracing. california later reversed course and adopted the system in december 2020. chinese vendor huawei (which cannot include google software on its current android products due to u.s. sanctions) added a os-level dp-3t api known as "contact shield" to its huawei mobile services stack in june 2020, which the company states is intended to be interoperable with exposure notification.

halopseudomonas halopseudomonas halopseudomonas is a genus of pseudomonad bacteria. halopseudomonas scientific classification domain: bacteria phylum: pseudomonadota class: gammaproteobacteria order: pseudomonadales family: pseudomonadaceae genus: halopseudomonasrudra and gupta 2021 species see text. synonyms the pseudomonas pertucinogena group neopseudomonas saati-santamaría et al. 2021 species the genus halopseudomonas comprises the following species: halopseudomonas aestusnigri (sánchez et al. 2014) rudra and gupta 2021 halopseudomonas bauzanensis (zhang et al. 2011) rudra and gupta 2021 halopseudomonas formosensis (lin et al. 2013) rudra and gupta 2021 halopseudomonas gallaeciensis (mulet et al. 2018) rudra and gupta 2021 halopseudomonas litoralis (pascual et al. 2012) rudra and gupta 2021 halopseudomonas oceani (wang and sun 2016) rudra and gupta 2021 halopseudomonas pachastrellae (romanenko et al. 2005) rudra and gupta 2021 halopseudomonas pelagia (hwang et al. 2009) rudra and gupta 2021 halopseudomonas pertucinogena (kawai and yabuuchi 1975) rudra and gupta 2021 halopseudomonas sabulinigri (kim et al. 2009) rudra and gupta 2021 halopseudomonas salegens (amoozegar et al. 2014) rudra and gupta 2021 halopseudomonas salina (zhong et al. 2015) rudra and gupta 2021 halopseudomonas xiamenensis (lai and shao 2008) rudra and gupta 2021 halopseudomonas xinjiangensis (liu et al. 2009) rudra and gupta 2021 the following species belong to halopseudomonas but have not formally been transferred, yet: pseudomonas abyssi wei et al. 2018 "pseudomonas jilinensis" wang et al. 2020 "pseudomonas laoshanensis" wang et al. 2021 "pseudomonas nanhaiensis" pang et al. 2021 pseudomonas neustonica jang et al. 2020 pseudomonas phragmitis li et al. 2020 pseudomonas populi anwar et al. 2016 pseudomonas profundi sun et al. 2018 pseudomonas saliphila zhang et al. 2021 "pseudomonas saudimassiliensis" azhar et al. 2017 "pseudomonas yangmingensis" wong and lee 2014

tan syndrome tan syndrome tegumental angiomyxoma-neurothekeoma (tan syndrome) is a syndrome, an acronym, and eponym proposed by malaysian ophthalmologist of chinese descent, tan aik kah (b. june 1975). angiomyxomas are associated with lamb (lentigines, atrial myxomas, muco-cutaneous myxomas, and blue naevi) syndrome, name (nevi, atrial myxoma, myxoid neurofibromas, and ephelides) syndrome and carney syndrome (atrial, cutaneous and mammary myxomas, lentigines, blue naevi, endocrine disorders and testicular tumours). tan syndromespecialtydermatology tan syndrome is characterized by multiple superficial angiomyxoma and neurothekeoma confined only to the skin (tegument). tan syndrome may be used to describe myxomas confined to the skin without visceral involvement. case tan et al. reported a 10-year-old girl with multiple superficial angiomyxoma associated with neurothekeoma palpebrae. there was no evidence of visceral involvement. the lesions were excised with no recurrence during follow up.

saurocytozoon saurocytozoon saurocytozoon is a genus of parasitic alveolates. they infect reptiles and are thought to be transmitted by mosquitoes. only two species have been described to date. their relationship with the other members of this order is not presently clear. saurocytozoon scientific classification domain: eukaryota clade: diaphoretickes clade: tsar clade: sar clade: alveolata phylum: apicomplexa class: aconoidasida order: haemospororida family: plasmodiidae genus: saurocytozoon species saurocytozoon agamidorum saurocytozoon mabuyi saurocytozoon tupinambi description members of this genus infect reptiles. they do not produce pigment nor do they undergo merogony in the blood. schizonts are found in the tissues. gametocytes are found in the peripheral blood. they infect the leukocytes and cause gross distortion of the host cell. the gametocytes are large and round. hosts skinks (mabuya mabouya) tegu (tupinambis teguixin)

basilar plexus basilar plexus the basilar plexus (transverse or basilar sinus) consists of several interlacing venous channels between the layers of the dura mater over the basilar part of the occipital bone (the clivus), and serves to connect the two inferior petrosal sinuses. basilar plexusthe sinuses at the base of the skulldetailsidentifierslatinplexus basilarista98a12.3.05.106ta24866fma50783anatomical terminology it communicates with the anterior vertebral venous plexus.

phyllobacterium loti phyllobacterium loti phyllobacterium loti is a bacterium from the genus of phyllobacterium which was isolated from nodules from the plants lotus corniculatus in uruguay. phyllobacterium loti scientific classification domain: bacteria phylum: pseudomonadota class: alphaproteobacteria order: hyphomicrobiales family: phyllobacteriaceae genus: phyllobacterium species: p. loti binomial name phyllobacterium lotisánchez et al. 2014 type strain cect 8230, lmg 27289, s658t

desquamative interstitial pneumonia desquamative interstitial pneumonia desquamative interstitial pneumonia (dip) is a form of idiopathic interstitial pneumonia featuring elevated numbers of macrophages within the alveoli (air sacs) of the lung. the alveolar macrophages have a characteristic light brown pigmentation and accumulate in the alveolar lumen and septa regions of the lower lobes of the lungs. the typical effects of the macrophage accumulation are inflammation and later fibrosis (thickening and stiffness) of the lung tissue. desquamative interstitial pneumoniaspecialtypulmonology the term dip is a misnomer. its name is derived from the former belief that these macrophages were pneumocytes that had desquamated. it has been suggested that a more accurate term for cases of dip that occur in smokers and feature "ropey" alveolar septal collagen is smoking-related interstitial fibrosis (srif). it is associated with patients with a history of smoking. since more than 80% of cases occur in smokers, it has been suggested that the term dip should be discarded and the subset occurring in smokers should be replaced with more accurate terms such as smoking-related interstitial fibrosis (srif). although smoking is the most common cause, studies have shown a relationship between occupational exposures and the development of dip, including occupational dust, fire-extinguisher powder, diesel fumes, nylon filaments and beryllium and copper dust. additionally, dip has been observed in children where it typically presents as a result of surfactant protein gene mutations, indicating that the disease is not always acquired in adulthood. smoking cessation and avoidance of secondhand smoke exposure are both crucial to preventing disease progression, however, treatment with corticosteroids and immunosuppressive therapy has been reported to be effective pharmacologic intervention. treatment with methylprednisolone has been reported.

tunica albuginea tunica albuginea tunica albuginea may refer to: tunica albuginea (penis), the tough fibrous layer of connective tissue that surrounds the corpora cavernosa of the penis tunica albuginea (testicles), a layer of connective tissue covering the testicles tunica albuginea (ovaries), the connective tissue covering of the ovaries tunica albuginea oculi, the tough fibrous layer that covers most of the eyeball. look up tunica albuginea in wiktionary, the free dictionary.

hemoglobin barts hemoglobin barts hemoglobin barts, abbreviated hb barts, is an abnormal type of hemoglobin that consists of four gamma globins. it is moderately insoluble, and therefore accumulates in the red blood cells. hb barts has an extremely high affinity for oxygen, so it cannot release oxygen to the tissue. therefore, this makes it an inefficient oxygen carrier. as an embryo develops, it begins to produce alpha-globins at weeks 5–6 of development. when both of the hba1 and hba2 genes which code for alpha globins becomes dysfunctional, the affected fetuses will have difficulty in synthesizing a functional hemoglobin. as a result, gamma chains will accumulate and form four gamma globins. these gamma globins bind to form hemoglobin barts. it is produced in the disease alpha-thalassemia and in the most severe of cases, it is the only form of hemoglobin in circulation. in this situation, a fetus will develop hydrops fetalis and normally die before or shortly after birth, unless intrauterine blood transfusion is performed. since hemoglobin barts is elevated in alpha thalassemia, it can be measured, providing a useful screening test for this disease in some populations. the ability to measure hemoglobin barts makes it useful in newborn screening tests. if hemoglobin barts is detected on a newborn screen, the patient is usually referred for further evaluation since detection of hemoglobin barts can indicate either one alpha globin gene deletion, making the baby a silent alpha thalassemia carrier, two alpha globin gene deletions (alpha thalassemia), or hemoglobin h disease (three alpha globin gene deletions). deletion of four alpha globin genes was previously felt to be incompatible with life, but there are currently 69 patients who have survived past infancy. genotypes alpha-globin gene deletions clinical component αα/αα 0 normal -α/αα 1 silent carrier --/αα or -α/-α 2 alpha-thalassemia trait --/-α 3 hb h disease --/-- 4 fetal hydrops table 1: α represents the presence of α-globin gene and- represents the deletion of α-globin gene. the chance of a fetus developing hemoglobin bart's hydrops fetalis is dependent upon if one or both parent carries the alpha-thalassemia trait. due to this disease being incompatible with life, diagnosis for it is done prenatally. early detection of hemoglobin (hb) bart's disease before the development of hydrops fetalis is crucial because fetuses that develop hydrops fetalis will either be stillborn or may die shortly after birth. there can be early pregnancy termination to prevent serious complications for the baby or mother. studies shows that in 11 to 14 weeks of gestation, sonographic markers can associate affected from unaffected pregnancies. it was found that the most sensitive marker was ct ratio and mca‐psv. parents at risk of having a child with fetal hydrops can continue their pregnancy with regular ultrasounds and intrauterine blood transfusion. babies of such parents are born with no edema or major neurological defects, and eventually, this disease can be cured with haematopoietic stem cell transplantation. a newly developed diagnostic test, called immunochromatography (ic) strip tests, uses monoclonal antibodies to detect hemoglobin barts in red blood cells' lysate. this diagnostic test is validated for positive and negative predictive values. it is also cheap and easy, making regular screening for alpha-thalassemia a plausible possibility. anemia is a factor in fetuses with hemoglobin bart's disease as there is an "increased cardiac output" and hypovolemia as the tissues of the fetus require oxygen because of the gamma globulin's high affinity for oxygen. this deprives the tissues of receiving oxygen to function well. the symptoms of anemia occur within the first trimester. this variant of hemoglobin is so called as it was discovered at st bartholomew's hospital in london, often abbreviated to barts. notes al-allawi na, shamdeen my, rasheed ns (2010). "homozygosity for the mediterranean a-thalassemic deletion (hemoglobin barts hydrops fetalis)". annals of saudi medicine. 30 (2): 153–155. doi:10.4103/0256-4947.60523. pmc 2855068. pmid 20220267. "pathophysiology of alpha thalassemia". www.uptodate.com. retrieved 2016-08-30. van der dijs fp, volmer m, van gijssel-wiersma dg, smit jw, van veen r, muskiet fa (september 1999). "predictive value of cord blood hematological indices and hemoglobin barts for the detection of heterozygous alpha-thalassemia-2 in an african-caribbean population". clinical chemistry. 45 (9): 1495–1500. doi:10.1093/clinchem/45.9.1495. pmid 10471652. songdej d, babbs c, higgs dr (march 2017). "an international registry of survivors with hb bart's hydrops fetalis syndrome". blood. 129 (10): 1251–1259. doi:10.1182/blood-2016-08-697110. pmc 5345731. pmid 28057638. "validate user". fogel bn, nguyen hl, smink g, sekhar dl (april 2018). "variability in state-based recommendations for management of alpha thalassemia trait and silent carrier detected on the newborn screen". the journal of pediatrics. 195: 283–287. doi:10.1016/j.jpeds.2017.11.048. pmid 29273175. s2cid 4349631. wu my, xie xm, li j, li dz (october 2015). "neonatal screening for α-thalassemia by cord hemoglobin barts: how effective is it?". international journal of laboratory hematology. 37 (5): 649–653. doi:10.1111/ijlh.12376. pmid 25955662. s2cid 40335193. sirichotiyakul s, luewan s, srisupundit k, tongprasert f, tongsong t (march 2014). "prenatal ultrasound evaluation of fetal hb bart's disease among pregnancies at risk at 11 to 14 weeks of gestation". prenatal diagnosis. 34 (3): 230–234. doi:10.1002/pd.4293. pmid 24318930. s2cid 37146677. hui pw, pang p, tang mh (february 2022). "20 years review of antenatal diagnosis of haemoglobin bart's disease and treatment with intrauterine transfusion". prenatal diagnosis: pd.6125. doi:10.1002/pd.6125. pmid 35226373. s2cid 247157134. pata s, laopajon w, pongpaiboon m, thongkum w, polpong n, munkongdee t, et al. (2019-10-29). "impact of the detection of ζ-globin chains and hemoglobin bart's using immunochromatographic strip tests for α0-thalassemia (--sea) differential diagnosis". plos one. 14 (10): e0223996. bibcode:2019ploso..1423996p. doi:10.1371/journal.pone.0223996. pmc 6818768. pmid 31661492. luewan s, tongprasert f, srisupundit k, tongsong t (april 2015). "fetal cardiac doppler indices in fetuses with hemoglobin bart's disease at 12-14weeks of gestation". international journal of cardiology. 184: 614–616. doi:10.1016/j.ijcard.2015.02.053. pmid 25770840. ager ja, lehmann h (april 1958). "observations on some fast haemoglobins: k, j, n, and bart's". british medical journal. 1 (5076): 929–931. doi:10.1136/bmj.1.5076.929. pmc 2028335. pmid 13523233. proteins that contain heme (hemoproteins)globinshemoglobinsubunitsalpha locus on 16: α hba1 hba2 pseudo ζ hbz θ hbq1 μ hbm beta locus on 11: β hbb δ hbd γ hbg1 hbg2 ε hbe1 tetramersstages of development:embryonic hbe gower 1 (ζ2ε2) hbe gower 2 (α2ε2) hbe portland i (ζ2γ2) hbe portland ii (ζ2β2) fetal hbf/fetal (α2γ2) hba (α2β2) adult hba (α2β2) hba2 (α2δ2) hbf/fetal (α2γ2) pathology: hbh (β4) barts (γ4) hbs (α2βs2) hbc (α2βc2) hbe (α2βe2) hbo (α2βo2) compounds carboxyhemoglobin carbaminohemoglobin oxyhemoglobin/deoxyhemoglobin sulfhemoglobin other human glycated hemoglobin methemoglobin nonhuman chlorocruorin erythrocruorin otherhuman: myoglobin metmyoglobin neuroglobin cytoglobin plant: leghemoglobin other cytochrome cytochrome b cytochrome p450 methemalbumin see also disorders of globin and globulin proteins this article is issued from wikipedia. the text is licensed under creative commons - attribution - sharealike. additional terms may apply for the media files.

7α-methylestradiol 7α-methylestradiol 7α-methylestradiol (7α-me-e2), also known as 7α-methylestra-1,3,5(10)-triene-3,17β-diol, is a synthetic estrogen and an active metabolite of the androgen/anabolic steroid trestolone. it is considered to be responsible for the estrogenic activity of trestolone. the compound shows about the same affinity for the estrogen receptor as estradiol. relative affinities (%) of 7α-methylestradiol and related steroids compoundprarergrmrshbgcbg estradiol2.67.91000.60.138.7<0.1 7α-methylestradiol1–315–25101<1<1 ? ? trestolone50–75100–125 ?<1 ? ? ? values are percentages (%). reference ligands (100%) were progesterone for the pr, testosterone for the ar, e2 for the er, dexa for the gr, aldosterone for the mr, dht for shbg, and cortisol for cbg. not to be confused with methylestradiol. 7α-methylestradiolclinical dataother names7α-methyl-e2; 7α-me-e2; 7α-methylestra-1,3,5(10)-triene-3,17β-dioldrug classestrogenidentifiers iupac name (7r,8r,9s,13s,14s,17s)-7,13-dimethyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopentaphenanthrene-3,17-diol cas number10448-97-2 ypubchem cid10424124uniivd3ug279pschemical and physical dataformulac19h26o2molar mass286.415 g·mol−13d model (jsmol)interactive image smiles 12cc(o)1(c)cc1()c3=cc=c(o)c=c3c(c)21 inchi inchi=1/c19h26o2/c1-11-9-12-10-13(20)3-4-14(12)15-7-8-19(2)16(18(11)15)5-6-17(19)21/h3-4,10-11,15-18,20-21h,5-9h2,1-2h3/t11-,15-,16+,17+,18-,19+/s2key:dxwwyjwufulmap-bqxdhoisna-n

stoccareddo stoccareddo stoccareddo is a village in the comune of gallio, province of vicenza, italy. it is known for its 400 villagers (380 of them with the surname baù) with great health who tend to be able to consume fatty foods without the consequences of strokes and heart attacks. informally, stoccareddo is known as "il paese dei baù", meaning "the country of the baù". stoccareddofrazionestoccareddolocation of stoccareddo in italycoordinates: 45°52′00″n 11°36′00″ecountry italyregionvenetoprovincevincenzacomunegallio (vi)elevation981 m (3,219 ft)population • total400time zoneutc+1 (cet) • summer (dst)utc+2 (cest)postal code36032dialing code(+39) 0424patron saintsan bartolomeowebsiteofficial website history and geography stoccareddo is a secluded village in the italian alps that was, until the late 20th century, very isolated. stoccareddo was first inhabited by a family with the surname baù about 800 years ago. it was destroyed during world war i, but was rebuilt during the early 1920s by its citizens. because of its location, the villagers, mainly baùs, were not able to mingle with any outside citizens. the continuous centuries of seclusion created a gene pool of baùs that had good health. health phenomenon almost all of stoccareddo's villagers have the surname baù (pronounced ), and are all from the same family. most of stoccareddo's villagers have phenomenally good health, despite their diet of fried cheeses and other unhealthy italian delicacies. according to the independent, 38% of stoccareddo's men have high cholesterol, as opposed to the italian average of 21%. however, about 23% of italian men have low levels of hdl cholesterol as opposed to 5.4% of men in stoccareddo. also, hypertension (high blood pressure) affects about 33% of italian men, but only 6.5% of stoccareddo men. inbreeding the villagers of stoccareddo are prominent for inbreeding. although many baùs have children with other baùs, they tend to marry more distant relatives and not first cousins, which can cause genetic defects. there is a local saying, "only a baù can understand a baù." their inbreeding over a period of over eight centuries is likely to be the reason why many citizens of stoccareddo are so healthy, despite their unhealthy diet.

age-related mobility disability age-related mobility disability age-related mobility disability is a self-reported inability to walk due to impairments, limited mobility, dexterity or stamina. it has been found mostly in older adults with decreased strength in lower extremities. history according to the national research council, the population of older adults is expected to increase in the united states by 2030 due to the aging population of the baby boomer generation; this will increase the population of mobility disabled individuals in the community. this raises the importance of being able to predict disability due to inability to walk at an early stage, which will eventually decrease health care costs. aging cause a decrease in physical strength and in lower extremities which ultimately leads to decrease in functional mobility, in turn leading to disability which is shown to be common in women due to differences in distribution of resources and opportunities. the early detection of mobility disabilities will help clinicians and patients in determining the early management of the conditions which could be associated with the future disability. mobility disabilities are not restricted to older and hospitalized individuals; such disabilities have been reported in young and non-hospitalized individuals as well due to decreased functional mobility. the increase in the rate of disability causes loss of functional independence and increases the risk of future chronic diseases. definition mobility is defined as the ability to move around, and mobility disability occurs when a person has problems with activities such as walking, standing up, or balancing. the use of a mobility aid device such as a mobility scooter, wheelchair, crutches or a walker can help with community ambulation. another term that is coined to define mobility disabilities based on performance is “performance based mobility disability”. it is the inability to increase your walking speed more than 0.4 m/s. if an individual is unable to walk at >0.4 m/s, he or she is considered severely disabled and would require a mobility device to walk in community. risk factors there are number of factors that could be associated with mobility disability, but according to the centers for disease control and prevention, “stroke is found to be the leading cause of mobility disability, in turn reducing functional mobility in more than half of the stroke survivors above 65 years of age”. measures there are several measurement scales designed to detect mobility disabilities. the measures that can detect mobility disabilities are classified into two categories, self-reported measures and performance measures. there is a need to differentiate between these measures based on their ability to detect mobility disabilities, such as differences in their reliability and validity. self-reported measures are commonly used to detect mobility disabilities, but recently developed performance measures have been shown to be effective in predicting future mobility disabilities in older adults. self-reported measures several qualitative research studies use survey (human research), questionnaires and self-reported scales to detect a decrease in functional mobility or to predict future mobility disability in older adults. the advantages of these qualitative research scales are easier data acquisition and can be performed on the larger population. although there is difference in perception of condition between subjects (gender difference), type of chronic conditions and age-related changes such as memory and reasoning, all of which can affect the information and scores of the individual, still self-reported measures have been used extensively in behavioral and correlation studies. the commonly used self-reported measures to detect mobility disability are stroke impact scale, rosow- breslau scale, barthel index, tinetti falls efficacy scale. based on reliability and validity of these scales, stroke impact scale has proven to have excellent test-retest reliability and construct validity, however, if it can predict future mobility disability in older adults is yet to be found. in contrast, rosow- breslau scale, barthel index and tinetti falls efficacy scale proved important to predict future mobility disability based on the activities involved in these questionnaire scales. performance-based measures mobility disabilities due to age-related musculoskeletal pain or increase in chronic conditions are easier to detect by performance measures. some commonly used performance measures to detect mobility disabilities are the 400-meter walking test, 5-minute walk test , walking speed, short physical performance battery test. among these measures, 400-meter walk test and short physical performance battery test has been proven to be strong predictors of mobility disability in older adults. in addition to prediction, there is moderate to excellent correlation between these two tests. based on reliability and validity of measurement scales to predict mobility disability, self-reported measures such as barthel index, and performance measures such as 400 m walk test and short physical performance battery test are strongly associated with prediction of mobility disability in older adults.