pancreatic insufficiency by replacement of missing digestive enzymes allows the duodenum to properly absorb nutrients and vitamins that would otherwise be lost in the feces. however, the best dosage and form of pancreatic enzyme replacement is unclear, as are the risks and long-term effectiveness of this treatment. so far, no large-scale research involving the incidence of atherosclerosis and coronary heart disease in adults with cystic fibrosis has been conducted. this is likely because the vast majority of people with cystic fibrosis do not live long enough to develop clinically significant atherosclerosis or coronary heart disease. diabetes is the most common nonpulmonary complication of cf. it mixes features of type 1 and type 2 diabetes, and is recognized as a distinct entity, cystic fibrosis-related diabetes. while oral antidiabetic drugs are sometimes used, the recommended treatment is the use of insulin injections or an insulin pump, and, unlike in type 1 and 2 diabetes, dietary restrictions are not recommended. while stenotrophomonas maltophilia is relatively common in people with cystic fibrosis, the evidence about the effectiveness of antibiotics for s. maltophilia is uncertain. bisphosphonates taken by mouth or intravenously can be used to improve the bone mineral density in people with cystic fibrosis, but there are no proof that this reduces fractures or increases survival rates. when taking bisphosphates intravenously, adverse effects such as pain and flu-like symptoms can be an issue. the adverse effects of bisphosphates taken by mouth on the gastrointestinal tract are not known. poor growth may be avoided by insertion of a feeding tube for increasing food energy through supplemental feeds or by administration of injected growth hormone. sinus infections are treated by prolonged courses of antibiotics. the development of nasal polyps or other chronic changes within the nasal passages may severely limit airflow through the nose, and over time reduce the person's sense of smell. sinus surgery is often used to alleviate nasal obstruction and to limit further infections. nasal steroids such as fluticasone propionate are used to decrease nasal inflammation. female infertility may be overcome by assisted reproduction technology, particularly embryo transfer techniques. male infertility caused by absence of the vas deferens may be overcome with testicular sperm extraction, collecting sperm cells directly from the testicles. if the collected sample contains too few sperm cells to likely have a spontaneous fertilization, intracytoplasmic sperm injection can be performed. third party reproduction is also a possibility for women with cf. whether taking antioxidants affects outcomes is unclear. physical exercise is usually part of outpatient care for people with cystic fibrosis. aerobic exercise seems to be beneficial for aerobic exercise capacity, lung function and health-related quality of life; however, the quality of the evidence was poor. due to the use of aminoglycoside antibiotics, ototoxicity is common. symptoms may include "tinnitus, hearing loss, hyperacusis, aural fullness, dizziness, and vertigo". gastrointestinal problems with the gastrointestinal system including constipation and obstruction of the gastrointestinal tract including distal intestinal obstruction syndrome are frequent complications for people with cystic fibrosis. treatment of gastrointestinal problems is required in order to prevent a complete obstruction, reduce other cf symptoms, and improve the quality of life. while stool softeners, laxatives, and prokinetics (gi-focused treatments) are often suggested, there is no clear consensus from experts at to which approach is the best and comes with the least risks. mucolytics or systemic treatments aimed at dysfunctional cftr are also sometimes suggested to improve symptoms. prognosis the prognosis for cystic fibrosis has improved due to earlier diagnosis through screening and better treatment and access to health care. in 1959, the median age of survival of children with cf in the united states was six months. in 2010, survival is estimated to be 37 years for women and 40 for men. in canada, median survival increased from 24 years in 1982 to 47.7 in 2007. in the united states those born with cf in 2016 have a predicted life expectancy of 47.7 when cared for in specialty clinics. in the us, of those with cf who are more than 18 years old as of 2009, 92% had graduated from high school, 67% had at least some college education, 15% were disabled, 9% were unemployed, 56% were single, and 39% were married or living with a partner. quality of life chronic illnesses can be difficult to manage. cf is a chronic illness that affects the "digestive and respiratory tracts resulting in generalized malnutrition and chronic respiratory infections". the thick secretions clog the airways in the lungs, which often cause inflammation and severe lung infections. if it is compromised, it affects the quality of life of someone with cf and their ability to complete such tasks as everyday chores. according to schmitz and goldbeck (2006), cf significantly increases emotional stress on both the individual and the family, "and the necessary time-consuming daily treatment routine may have further negative effects on quality of life". however, havermans and colleagues (2006) have established that young outpatients with cf who have participated in the cystic fibrosis questionnaire-revised "rated some quality of life domains higher than did their parents". consequently, outpatients with cf have a more positive outlook for themselves. as merck manual notes, "with appropriate support, most patients can make an age-appropriate adjustment at home and school. despite myriad problems, the educational, occupational, and marital successes of patients are impressive." furthermore, there are many ways to enhance the quality of life in cf patients. exercise is promoted to increase lung function. integrating an exercise regimen into the cf patient's daily routine can significantly improve quality of life. no definitive cure for cf is known, but diverse medications are used, such as mucolytics, bronchodilators, steroids, and antibiotics, that have the purpose of loosening mucus, expanding airways, decreasing inflammation, and fighting lung infections, respectively. epidemiology mutation frequencyworldwide δf508 66–70% g542x 2.4% g551d 1.6% n1303k 1.3% w1282x 1.2% all others 27.5% cystic fibrosis is the most common life-limiting autosomal recessive disease among people of european heritage. in the united states, about 30,000 individuals have cf; most are diagnosed by six months of age. in canada, about 4,000 people have cf. around 1 in 25 people of european descent, and one in 30 of white americans, is a carrier of a cf mutation. although cf is less common in these groups, roughly one in 46 hispanics, one in 65 africans, and one in 90 asians carry at least one abnormal cftr gene. ireland has the world's highest prevalence of cf, at one in 1353. although technically a rare disease, cf is ranked as one of the most widespread life-shortening genetic diseases. it is most common among nations in the western world. an exception is finland, where only one in 80 people carries a cf mutation. the world health organization states, "in the european union, one in 2000–3000 newborns is found to be affected by cf". in the united states, one in 3,500 children is born with cf. in 1997, about one in 3,300 white children in the united states was born with cf. in contrast, only one in 15,000 african american children have it, and in asian americans, the rate was even lower at one in 32,000. cystic fibrosis is diagnosed equally in males and females. for reasons that remain unclear, data have shown that males tend to have a longer life expectancy than females, though recent studies suggest this gender gap may no longer exist, perhaps due to improvements in health care facilities. a recent study from ireland identified a link between the female hormone estrogen and worse outcomes in cf. the distribution of cf alleles varies among populations. the frequency of δf508 carriers has been estimated at one in 200 in northern sweden, one in 143 in lithuanians, and one in 38 in denmark. no δf508 carriers were found among 171 finns and 151 saami people. δf508 does occur in finland, but it is a minority allele there. cf is known to occur in only 20 families (pedigrees) in finland. evolution the δf508 mutation is estimated to be up to 52,000 years old. numerous hypotheses have been advanced as to why such a lethal mutation has persisted and spread in the human population. other common autosomal recessive diseases such as sickle-cell anemia have been found to protect carriers from other diseases, an evolutionary trade-off known as heterozygote advantage. resistance to the following have all been proposed as possible sources of heterozygote advantage: cholera: with the discovery that cholera toxin requires normal host cftr proteins to function properly, it was hypothesized that carriers of mutant cftr genes benefited from resistance to cholera and other causes of diarrhea. further studies have not confirmed this hypothesis. typhoid: normal cftr proteins are also essential for the entry of salmonella typhi into cells, suggesting that carriers of mutant cftr genes might be resistant to typhoid fever. no in vivo study has yet confirmed this. in both cases, the low level of cystic fibrosis outside of europe, in places where both cholera and typhoid fever are endemic, is not immediately explicable. diarrhea: the prevalence of cf in europe might be connected with the development of cattle domestication. in this hypothesis, carriers of a single mutant cftr had some protection from diarrhea caused by lactose intolerance, before the mutations that created lactose tolerance appeared. tuberculosis: another possible explanation is that carriers of the gene could have some resistance to tuberculosis. this hypothesis is based on the thesis that cftr gene mutation carriers have insufficient action in one of their enzymes – arylsulphatase - which is necessary for mycobacterium tuberculosis virulence. as m. tuberculosis would use its host's sources to affect the individual, and due to the lack of enzyme it could not presents its virulence, being a carrier of cftr mutation could provide resistance against tuberculosis. history dorothy hansine andersen first described cystic fibrosis in 1938. cf is supposed to have appeared about 3,000 bc because of migration of peoples, gene mutations, and new conditions in nourishment. although the entire clinical spectrum of cf was not recognized until the 1930s, certain aspects of cf were identified much earlier. indeed, literature from germany and switzerland in the 18th century warned "wehe dem kind, das beim kuß auf die stirn salzig schmeckt, es ist verhext und muss bald sterben" ("woe to the child who tastes salty from a kiss on the brow, for he is cursed and soon must die"), recognizing the association between the salt loss in cf and illness. in the 19th century, carl von rokitansky described a case of fetal death with meconium peritonitis, a complication of meconium ileus associated with cf. meconium ileus was first described in 1905 by karl landsteiner. in 1936, guido fanconi described a connection between celiac disease, cystic fibrosis of the pancreas, and bronchiectasis. in 1938, dorothy hansine andersen published an article, "cystic fibrosis of the pancreas and its relation to celiac disease: a clinical and pathological study", in the american journal of diseases of children. she was the first to describe the characteristic cystic fibrosis of the pancreas and to correlate it with the lung and intestinal disease prominent in cf. she also first hypothesized that cf was a recessive disease and first used pancreatic enzyme replacement to treat affected children. in 1952, paul di sant'agnese discovered abnormalities in sweat electrolytes; a sweat test was developed and improved over the next decade. the first linkage between cf and another marker (paraoxonase) was found in 1985 by hans eiberg, indicating that only one locus exists for cf. in 1988, the first mutation for cf, δf508, was discovered by francis collins, lap-chee tsui, and john r. riordan on the seventh chromosome. subsequent research has found over 1,000 different mutations that cause cf. because mutations in the cftr gene are typically small, classical genetics techniques had been unable to accurately pinpoint the mutated gene. using protein markers, gene-linkage studies were able to map the mutation to chromosome 7. chromosome walking and chromosome jumping techniques were then used to identify and sequence the gene. in 1989, lap-chee tsui led a team of researchers at the hospital for sick children in toronto that discovered the gene responsible for cf. cf represents a classic example of how a human genetic disorder was elucidated strictly by the process of forward genetics. research people with cf may be listed in a disease registry that allows researchers