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A blood film will demonstrate stitution valine for glutamine at the sixth codon on the the spherocytes discount 16mg medrol otc, but this cell morphology is not diagnos- β globin chain to form haemoglobin (Hb)S medrol 16 mg cheap. Thediagnosiscanbeconfirmedbydemonstratingthe dehydration discount medrol 4mg amex, hypoxia and cold may precipitate a sickle osmotic fragility of the red blood cells. Patients are given Pathophysiology pneumococcal vaccinations and prophylactic antibiotics HbS molecules, when deoxygenated tend to aggregate post splenectomy. The red blood cells become inflex- ible and sickle shaped and become trapped in the mi- Haemoglobinopathies crocirculation, especially within bones, resulting in mi- Haemoglobinopathies are abnormalities in the nor- crovessel occlusion. Normal haemoglobin is made up of four polypeptide chains Clinical features each containing a haem group. HbA is the main adult Sickle cell trait (the carrier state) is asymptomatic, but form comprising two α chains and two β chains. Sickle cell also have a minor haemoglobin HbA2,which makes up anaemia is a clinical spectrum ranging from asymp- around 2% of the circulating haemoglobin and con- tomatic to severe haemolytic anaemia and recurrent sists of two α chains and two δ chains. Painful vascular occlusive crises typically haemoglobins result from: produce symptoms of bone pain and pleuritic chest pain r Abnormal globin chain production such as thalas- with a low-grade fever. Other patterns of crisis: r Acute sequestration (pooling of blood in liver and Sickle cell anaemia spleen) requires transfusion for apparent hypo- Definition volaemia. Autosomal recessive condition in which there is abnor- r Pulmonary infarction may occur in association with mal structure of the globin chain. Chapter 12: Haemoglobin disorders and anaemia 475 Complications syndrome or cerebral infarction require exchange blood Patients have a susceptibility to infections including transfusionstoremovesicklecells. Transfusionsmayalso streptococcal infections and osteomyelitis often due be indicated in patients with regular severe crises and to salmonella. Prognosis Retinal detachment and proliferative retinopathy may Thereismarkedvariationintheseverityofthecondition, result in blindness. See also complications of haemolytic some patients have a relatively normal life span with few anaemia (page 473). Blood film shows a α-Thalassaemia high reticulocyte count and sickle shaped red blood cells. Definition r Sickle screening tests use a reducing solution, which Inherited haemoglobinopathy with defective synthesis causes HbS to precipitate. Aetiology r X-ray of the tubular bones may show destruction and α-Thalassaemia is caused by gene deletions. There are medullary sclerosis together with periosteal bone for- four copies of the α gene, two on each chromosome 16. Management Clinical features Treatment is largely symptomatic with prophylactic an- r Deletion of all four copies of the α gene (–/–) prevents tibiotics,folicacidandpneumococcalvaccination. This disorder agement of a painful crisis includes oxygenation, ade- is also termed haemoglobin Bart’s (γ4)hydrops syn- quate hydration and analgesia. Acute se- r Deletion of three genes (–/α-) causes HbH disease (a questration requires blood transfusion, as patients be- moderate anaemia with splenomegaly and the pro- comeshocked. Normal Investigations Full blood count shows microcytosis with or without Sickle Trait anaemia. These mutations may result in no β chain production Investigations (β0)orveryreducedproduction (β+). The reticulocyte count is noproductionofβ globinandhavetheclinicalpicture raised and there are nucleated red cells. Management Excess α chains precipitate in the red blood cells r Thalassaemiaminordoesnotrequiretreatment;how- or combine with δ resulting in increased HbA2, and ever, iron supplements should be avoided unless γ resulting in increased levels of fetal haemoglobin co-existent iron deficiency has been demonstrated. The partners of women with thalassaemia minor r If there are defects in both β and δ genes, patients shouldbescreenedtoallowappropriategeneticcoun- have thalassaemia intermedia (homozygous) or tha- selling. Homozygous combined β, γ and δ are in- r Thalassaemia major and symptomatic thalassaemia compatible with life. This Clinical features aims to suppress ineffective erythropoesis and pre- r Thalassaemia minor/trait is asymptomatic with a vent bony deformity, while allowing normal growth mild hypochromic microcytic anaemia. Iron overload is prevented by the r Thalassaemia intermedia causes symptomatic mod- use of the chelating agent desferrioxamine, which is erate anaemia with splenomegaly. Splenectomy should be considered in patients ure to thrive and recurrent infections. Bone the production of fetal haemoglobin ceases and the marrow transplantation has been used successfully patient becomes symptomatic with a severe anae- in young patients with severe β-thalassaemia major. Extramedullary haemopoesis causes hepato- Other treatments under investigation include gene splenomegaly, maxillary overgrowth and trabecula- therapy and drugs to maintain the production of fetal tion on bone X-rays. Random X inacti- vation (Lyonisation) means that some heterozygous fe- Glucose-6-phosphate dehydrogenase males may also have symptoms. Clinical features With such a wide variety of genes and enzymatic activity, Aetiology aspectrum of clinical conditions occur. Investigations Pathophysiology During an attack the blood film may show irregularly IgMorIgG antibodies are produced, which bind to red contracted cells, bite cells (indented membrane), blister cells. Autoimmune haemolytic anaemia Definition Clinical features Acquired disorders resulting in haemolysis due to red The clinical features, specific investigations and manage- cell autoantibodies. IgM anti human globulin Red cells coated in antibodies Agglutination (visible) Figure 12. Splenectomy may be indicated if lymphatic leukaemia, haemolysis is severe and carcinoma and drugs such refractory. Cold haemagglutinin May be primary or secondary IgM antibodies agglutinate best Treat any underlying cause and disease to Mycoplasma at 4◦C, often against minor avoid extremes of temperature. Definition A pancytopenia due to a loss of haematopoetic precur- Investigations sors from the bone marrow. Full blood count and blood film will demonstrate a pan- cytopenia with absence of reticulocytes. A bone marrow Aetiology/pathophysiology aspirate and trephine shows a hypocellular marrow with Aplastic anaemia can be either congenital or much more no increased reticulin (fibrosis). This agents, supportive care (blood and platelet transfusions) is an autosomal recessive aplastic anaemia with limb and some form of definitive therapy. Otherdrugsmaycauseaplasticanaemia Immunosuppressive therapy is used as first line treat- through dose dependent (e. Prognosis Clinical features The course is dependent on the severity of the dis- Patients present with the features of pancytopenia: ease and the age of the patient. In the United Kingdom, travellers to these ar- 3year survival but there is a significant risk of developing eas who do not take adequate precautions are at greatest paroxysmal nocturnal haemoglobinuria, myelodysplas- risk. Transmission occurs predominantly by the bite of the female Anophe- Definition les mosquito although transmission may occur by blood Malaria is an infection caused by one of the four species transfusion or transplacentally. Incidence Worldwide there are 300–500 million cases of malaria Pathophysiology peryear with a mortality rate of up to 1%. In the United Parasites consume red cell proteins, glucose and Kingdom there are 1500–2000 cases per year, most of haemoglobin. They affect the red cell membrane making which are caused by Plasmodium falciparum. The inci- the cell less deformable and ultimately causing cell ly- dence in the United Kingdom is rising. Falciparum induces cell surface adhesion molecules on red cells causing adhesion to small vessels and un- Geography infected red cells. This leads to occlusion within the Endemic malaria is found in parts of Asia, Africa, Cen- microcirculation and organ dysfunction. Resistance to tral and South America, Oceania and certain Caribbean malaria is conferred by genetic variation: 1. Fertilisation occurs forming sporozites Sporozoites which migrate to the salivary glands. Sporozoites develop within hepatocytes over weeks before being released as merozoites. In vivax and ovale some remain in liver as a latent infection Release as merozoites Erythrocytic phase 3. Merozoites enter red blood cells, and pass through several stages of development finally resulting in multiple 4. The red blood cells rupture phase a few merozoites releasing merozoites into the circulation. Chapter 12: Myelodysplastic and myeloproliferative disorders 481 r The Duffy red cell antigen is necessary for invasion and blood cultures.

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A scattered red rash that is often most marked in the creases of the joints and over the stomach cheap 4 mg medrol free shipping. The skin may feel rough to the touch best 16mg medrol, sometimes described as feeling like sandpaper medrol 4 mg overnight delivery. Someone with scarlet fever will have evidence of a streptococcal infection somewhere, usually in the throat or sometimes in the skin. Your child can return to school when he/she is well and has fnished one full day of antibiotic treatment. The bacteria are spread through contact with nose and mouth secretions so: • Wash hands thoroughly after wiping nose. The ill child typically has a ‘slapped-cheek’ rash on the face and a lacy red rash on the trunk and limbs. An ill child may feel unwell and have a low-grade fever or a ‘cold’ a few days before the rash breaks out. An adult who is not immune can be infected with parvovirus B19 and either have no symptoms or develop the typical rash of slapped cheek syndrome, joint pain or swelling, or both. The joint pain and swelling usually resolve in a week or two, but may last longer. However, most adults have previously been infected with parvovirus B19 and have developed life-long immunity to the virus and cannot become infected again. A person infected with parvovirus B19 is infectious during the early part of the illness, before the rash appears. By the time a child has the characteristic ‘slapped cheek’ rash he/she is probably no longer contagious. The virus is probably spread from person to person by direct contact with those secretions, such as sharing cutlery, cups, drinks, drinking glasses etc. Parvovirus B19 infection may cause a serious illness in persons with chronic red blood cell disorders (e. Rarely, serious complications may develop from parvovirus B19 infection during early pregnancy. Excluding pupils with slapped cheek syndrome from school is not likely to prevent the spread of the virus. People are infectious before they develop the rash and it becomes clear that they have slapped cheek syndrome. Cases of slapped cheek syndrome in a school most commonly happen when the infection is spreading in the community. Usually, there is no serious complication for a pregnant woman or her baby if exposed to a person with slapped cheek syndrome. Most women are already immune to parvovirus B19, and these women and their babies are protected from infection and illness. Even if a woman is susceptible and gets infected with parvovirus B19, she usually experiences only a mild illness. Likewise, her unborn baby usually does not develop any problems due to parvovirus B19 infection. However, sometimes parvovirus B19 infection may cause miscar- riage or severe anaemia in the unborn baby. There is no evidence that parvovirus B19 infection causes birth defects or developmental delay. The infection has caused many outbreaks in the community and in health care settings in recent years. Symptoms can include: • Nausea (often sudden onset) • Vomiting (often projectile) • Crampy abdominal pain • Watery diarrhoea • High temperature chills and muscle aches. However, illness may be prolonged in some people (usually the very young or elderly). People can become infected with the virus in several ways, including: • Contact with an infected person, especially contact with vomit or faeces. It is often impossible to prevent infection; however, taking good hygiene measures around someone who is infected can decrease your chance of getting infected. People infected with norovirus are contagious from the moment they begin feeling ill to two to three days after recovery. It is important for people to use good hand washing and other hygienic practices after they have recently recovered from a norovirus infection. In addition, noroviruses are very resilient and can survive in the environment (on surfaces etc. Therefore it is important that surfaces and objects that may have become contaminated are cleaned thoroughly. It is extremely important that people who have been ill with vomiting or diarrhoea should remain off school or work while symptomatic and for two full days after their last episode of vomiting or diarrhoea. They are far away from major markets, often with small populations spread across many islands and vast distances, and are at the forefront of climate change and its impacts. Because of this, much research has focused on the challenges and constraints faced by Pacifc Island countries, and fnding ways to respond to these. This paper is one part of the Pacifc Possible series, which takes a positive focus, looking at genuinely transformative opportunities that exist for Pacifc Island countries over the next 25 years and identifes the region’s biggest challenges that require urgent action. Realizing these opportunities will often require collaboration not only between Pacifc Island Governments, but also with neighbouring countries on the Pacifc Rim. The fndings presented in Pacifc Possible will provide governments and policy-makers with specifc insights into what each area could mean for the economy, for employment, for government income and spending. At the macroeconomic level, good health increases worker productivity and reduces absenteeism; increases educational learning and the returns from investing in education; and reduces or postpones the use of medical resources freeing up financial space for other purposes (D. Bloom & Williamson, 1998; McCarthy, Wolf, & Wu, 1999; Ranis, Stewart, & Ramirez, 2000). At the household level, good health – and good health systems – helps individuals maximize their human potential; avoid financial distress and impoverishment; and break the inter-generational cycle of maternal ill health, stunting and impaired productivity of children, and consequential poverty (Barker, 1990; Bhutta, 2013; Black et al. For example, global life expectancy for both sexes increased from around 65 years in 1990 to 71 years in 2013. As shown in table 1, the Pacific contains seven of the top ten diabetes-prevalent countries in the world. Table 1 Prevalence Rates of Diabetes: Top Ten Countries in the World Ranking Country Prevalence of diabetes, as percentage of 20‐79 year olds, in 2015 (age adjusted) 1 Tokelau 30 2 Nauru 24. The first is the interaction between two major demographic trends, as illustrated in figure 2. Most Pacific countries have relatively high total fertility rates and low contraceptive prevalence rates that are more akin to the global average for least developed countries. In figure 2, the absolute population growth is largely driven by Papua New Guinea, but the trends are similar for most Pacific countries. In addition, the share of those aged 60 and older 2 has begun to increase and is expected to grow very rapidly in the coming years. Population and Vital Statistics Report (various years), (3) Census reports and other statistical publications from national statistical offices, (4) Eurostat: Demographic Statistics, (5) Secretariat of the Pacific Community: Statistics and Demography Programme, and (6) U. Dietary risk factors also constitute the highest behavioral risk factors for death due to diabetes. Low physical activity imposes significant risk of death caused by cardiovascular diseases, diabetes, and cancer. Tobacco smokers lose at least one decade of life expectancy compared to those who never smoked (Jha et al. Prevalence of tobacco consumption in the Pacific is much higher than the global average of 21 percent (figure 4). Tobacco consumption among males in Tonga, Solomon Islands, and Vanuatu is also quite high; 43 percent, 45 percent, and 43 percent respectively. Figure 4 Prevalence of Tobacco Consumption in the Pacific 4 80% 67% 70% 60% 52% 55% 50% 45% 43% 43% 41% 37% 36% 37% 36. Tonga and Samoa have the highest obesity rates (58 percent and 54 percent, respectively). School age obesity and overweight percentages are also high in many countries (Anderson, 2013a). Other trends and risk factors also point to a substantial worsening of the situation. The share of public health expenditure is growing for most countries in the Pacific, raising questions about long-term financial sustainability. This pattern is consistent with the global trend in which most countries increase public health expenditure as their economies and financial resources 6 grow. All of this raises the question as to whether the expansion of public health expenditure as a share of the economy is financially sustainable.

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By contrast buy 4mg medrol mastercard, the resources on which consumers drew to frame their encounter with the physician were not terribly rich purchase 4 mg medrol. What one could learn from one’s family purchase medrol 4mg without prescription, friends, neighbors, schools, cul- ture, and the popular press (for decades, Reader’s Digest has been a widely read resource for consumer health information) essentially exhausted the available sources of medical knowledge. As late as The Consumer 97 1998, women were more likely to get their medical information from media sources such as television, newspapers, and magazines than from physicians. Because it is difficult or impossible to reach most physicians by telephone or e-mail, most people must make an ap- pointment to communicate with their physician. The gap between wanting medical knowledge and actually seeing the physician may range from days to weeks. For reasons explored in Chapter 4, this time lag could increase rather than diminish in the next decade as physicians of all specialties become increasingly scarce and difficult to see. To see the physician, the consumer must take time off work, as physicians typically see patients during working hours. If the problem is with a child, the parent must take time off work and take the child out of school to meet the appointment. The time taken off work or out of school is a significant cost to the patient or family member, as well as to employers, that is not entered into account in the national health expenditures. If the physician practices in an urban or suburban setting, the consumer then may get stuck in traffic and may need to allow time for parking. Then they wait, often for minutes, but sometimes for hours, in the physician’s office. Depending in major part on the consumer’s educational level, the actual question that brought him or her to the physician in the first place may or may not get asked; if asked, the answer may or may not be understood. In a 1997 New York Times consumer survey, 51 percent of women left the physician’s office with unanswered questions. For women with less than a high school degree, fully 65 98 Digital Medicine percent left the office with unanswered questions. Some 56 percent felt that physicians talked down to them some or most of the time. In a couple of weeks, a bill arrives, which is frequently incorrect, requiring further interaction with the physician’s office or the health plan. Shortly before he died of cancer, Avedis Donebedian, an eminent academic physician who pioneered the study of quality of healthcare, commented on his care experience at a large, distinguished academic health center:. Often, I couldn’t tell whether I was dealing with a nurse, a technician, an attending physician or an attendant. He went on to say, “The idea that patients should be involved in their care is not really practiced in a responsible way. Today people talk about patient autonomy, but it often gets translated into patient abandonment. Donald Berwick, compared the breakdown in teamwork (and the consequent shifting of the crushing responsibility for ensuring continuity of care to family members) to the Norman MacLean The Consumer 99 story, “Young Men and Fire. According to MacLean, the young smoke jumpers died because they could not function as a team under the pressure of a sudden cataclysmic firestorm. In Berwick’s narrative, his wife, who suffered from a mysteri- ous and potentially lethal spinal cord infection, was exposed to repeated mortal risk in the care process because crucial informa- tion on her health was not available to the clinical team taking care of her and because of continuous shifting of responsibility for making lifesaving care decisions. Berwick’s repeated intervention was needed to provide the continuity and common sense the care system lacked,8 despite the hospital’s state-of-the-art, computerized electronic patient record system. The not-surprising result of these problems is that consumer satisfaction with the health system experience is on a downward trend, as it is for notoriously customer-unfriendly sectors such as the airlines and insurance. The reality is that the logistics of medical care do not work for many American consumers, whether they simply need information about their health or require lifesaving care. The failure to manage the complexity of medicine and to care for people in a thoughtful and compassionate way has contributed to an emerging consumer revolt against medical institutions. The “shot heard round the world” in women’s health was fired in 1970, when the Women’s Health Book Collective of Boston published a “user’s manual” for a woman’s body entitled Our Bodies, Ourselves. Since its initial publication, it has been trans- lated into 20 languages and has sold more than 4. In strident and confident tones, Our Bodies urges women to take responsibility for their own health and to confront what was then (but is no longer) a largely male cadre of obstetricians/gynecologists and other physicians in determining how medical care is defined and delivered. This was at a time when only 7 percent of practic- ing obstetricians/gynecologists in the United States were women, according to the American Medical Association. It encouraged women to reject the surgical trappings of hospital-based childbirth in favor of a more natural ap- proach. Many older, male obstetricians bridled at the large numbers of demanding “new women” who came to their appointment with typed lists of exactly how they wanted their care (and their babies! In a major feat of twentieth century engineering, the Internet reversed the centuries-old flow of health information. Thanks to the Internet, health information now flows “backward” from consumers to physicians. The Internet has enabled those people who are newly diagnosed with complex health problems to reach the scientific sources of information about their condition before their own time-famished physicians can (Figure 5. Little did the visionary Department of Defense planners who conceived the Internet in the late 1960s understand that they were also creating a powerful weapon for women in their struggle with the The Consumer 101 Figure 5. Indeed, few in Congress understood that by opening the Internet to public use in the Telecommunications Act of 1993, accessing health information would quickly become one of the most important uses of this powerful new tool. Seeking health information is one of the most prevalent rea- sons why consumers log on to the Internet. On any given day, six million Americans can be found on the World Wide Web search- ing for health information. More Internet users have sought health information (62 percent) than have shopped online (61 percent), looked up stock quotes (42 percent), or checked sports scores (44 percent). It is helping consumers select physi- 102 Digital Medicine cians based on feedback from their existing patients. Eventually, it will also help patients select hospital-based clinical programs and specialists based on their performance (morbidity and complica- tion rates, infections, clinical volumes, years in practice, credentials, malpractice history, etc. Most importantly, it helps give consumers and their families access to the collective wisdom and experience of others who are coping with and learning about a particular medical problem. As Howard Rheingold has written, the Internet enables “virtual communities” to convene around issues of common inter- est. A recent New York Times article documented that the Inter- net has contributed to a remarkable improvement in the recovery rate for missing children. The improvement is more astounding in those cases where the child is kidnapped by a non- family member. Before 1990, the recovery rate for these cases was around 35 percent; it increased to about 90 percent in 2002. Some take the “Just the facts, Ma’am” ap- proach and use the Internet to gather facts about their condition and what to do about it. Others are searching for referral information, answering questions such as, “Where is the best place for me to go to resolve my problem? However consumers may use it, the advent of the Internet has shifted power in medi- cine from one-on-one relationships controlled by professionals to spontaneous, geographically dispersed networks that may include as many as 100,000 participants. Still shell-shocked from his interaction, this Yale-trained internist related that he had diagnosed a long-time patient with a dread- ful rare, systemic, and fatal autoimmune disease that he had never encountered in his practice and had scheduled a treatment plan- ning session with the now-terrified patient to begin addressing her problem. The patient came to the meeting with a two-inch thick binder of articles she had downloaded via the Internet from national and international medical journals. It also contained a basic science section on the potential genetic and molecular basis of the illness. The patient placed the binder on the internist’s desk and said, “Why don’t we start here? When I related this story at one of my presentations, a physician posed the following rhetorical question about the exchange: “Why should I read it [the binder]? As I have subsequently learned, however, this response from physicians is not an unusual one. The “why should I read it” response reflects at least two kernels of truth wrapped in a thick layer of barely examined and ugly emotions. True enough, many physicians do not feel they have enough time to do their jobs properly; and certainly, a lot of the material in the binder may not have been directly relevant to the treatment 104 Digital Medicine planning task at hand.

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The current biomedical training system separates researchers and physicians from the earliest stages of their education and creates silos of specialized buy medrol 16 mg with mastercard, but limited knowledge buy cheap medrol 16 mg on-line. The insular nature of the current biomedical system does not encourage interdisciplinary collaborations and has significant negative effects on training generic 16mg medrol overnight delivery, study design, prioritization of research efforts, and translation of new research findings. Long-term follow-up was not required to conduct the first generation of genotype-phenotype studies. However, questions such as “Do cystic fibrosis patients with particular genotypes do better over a period of decades with particular treatments? Toward Precision Medicine: Building a Knowledge Network for Biomedical Research and a New Taxonomy of Disease 31 the results were generated, and whether the laboratory work was performed under protocols that permit results feedback. These limiting factors mean that most research results are not integrated into clinical care. Expert opinion on the “duty to inform” research participants of clinically relevant results vary widely. Indeed, many researchers are reluctant to contribute data to a common resource as it may expose them to questions about whether feedback to participants is necessary or desirable. For these, and many other reasons, the project of developing an Information Commons, a Knowledge Network of disease, and a New Taxonomy requires a long-term perspective. In a sense, this challenge has parallels with the building of Europe’s great cathedrals–studies started by one generation will be completed by another, and plans will change over time as new techniques are developed and knowledge evolves. As costs in the health-care system are increasingly dominated by the health problems of a long-lived, aging population, one can imagine that studies that last 5, 10, or even 50 years can answer many of the key questions on which clinicians will look to researchers for guidance. Many patients are already put on powerful drugs in their 40’s, 50’s, and 60’s that they will take for the rest of their lives. The very success of some cancer treatments is shifting attention from short-term survival to the long-term sequelae of treatment. For all these reasons, the era during which a genetic researcher simply needed a blood sample and a reliable diagnosis is passing. Outcomes research is also creating new opportunities for a close integration of medicine and data-intensive biology. Cost constraints on health-care services—as well as an increasing appreciation of how often conventional medical wisdom is wrong—has led to a growing outcomes-research enterprise that barely existed a few decades ago. The requirements of outcomes researchers for access to uniform medical records of large patient populations are remarkably similar to those of molecularly oriented researchers. Multiple Stakeholders Are Ready for Change The tremendous recent progress in genetics, molecular biology, and information technology has been projected to lead to novel therapeutics and improved health-care outcomes with reduced overall health-care costs. This situation has created a “perfect storm” for a wide variety of stakeholders, including health-care providers, payers, regulators, patients, and drug developers. Clinical and basic researchers have learned that for their collective efforts to provide affordable improvements in health care, increased collaboration and coordination are required. Public-private collaborations are needed to combine longitudinal health outcomes data with new advances in technology and basic research. Such initiatives are essential to gain and apply the specific biological knowledge required to develop new approaches to treat and prevent disease. A dynamically evolving Knowledge Network of Disease would provide a framework in which a closer, more effective, relationship between clinical and basic researchers could thrive. Nowhere is the need for change more evident and urgent than in the pharmaceutical and biotechnology industries. Despite a massive increase in the amount of genomic and molecular information available over the past decade, the number of effective new therapies developed each year has remained stable, while the cost of developing each successful therapy has increased dramatically (Munos 2009). Toward Precision Medicine: Building a Knowledge Network for Biomedical Research and a New Taxonomy of Disease 32 large number of novel drug targets, an inadequate biological understanding of these targets has resulted in an ever-increasing failure rate of expensive clinical trials (Arrowsmith 2011a,b). The pharmaceutical and biotechnology industries are now leading proponents for developing public-private collaborations and consortia in which longitudinal clinical outcomes data can be combined with new molecular technology to develop the deep biological understanding needed to re-define disease based on biological mechanisms. Given the time scale on which private entities must seek return on investment, there is an increased willingness to regard much of this information as pre-competitive. Hence, the information itself, and the costs of acquiring it, must be widely shared. A major beneficiary of the proposed Knowledge Network of disease and New Taxonomy would be what has been termed “precision medicine. Today, researchers look for relatively small differences between treated and untreated patients in trials that involve unselected patients, with little insight into the biological heterogeneity among the patients or their diseases. This approach requires a much larger number of patients, more time, and greater costs to assess the effectiveness of new therapies than would more targeted study designs. By using a precision-medicine approach to focus on those patients early in the drug-development process who are most likely to be helped, fewer side effects and reduced costs are likely to ensue. In such studies, compliance will likely be better, treatment duration longer, and therapeutic benefits more obvious than is the case with traditional designs. Greater therapeutic differences could also result in more efficient regulatory approval, and faster adoption by physicians and payers. Access to this knowledge allowed the pharmaceutical industry scientists to modify their clinical trial to look specifically at a cohort of patients with this translocation, and the results were dramatic. For those patients who had the translocation, the median disease-free survival with Crizotinib was a year, compared to just a few months with the standard of care. Thus, even in a trial that involved only a small number of patients that were compared to historical controls, it was obvious that the drug was active. In contrast, in an unselected patient population, most patients did not benefit from this drug and it was unclear whether the drug had any activity. Data sharing needs to occur across companies and across academic institutions to ensure that everyone benefits from fundamental biological knowledge. Toward Precision Medicine: Building a Knowledge Network for Biomedical Research and a New Taxonomy of Disease 33 government, and perhaps most importantly the public at large, will be required to support and sustain the changes required for development of innovative new therapies that improve health outcomes based on the proposed Knowledge Network of Disease and associated New Taxonomy. Public Attitudes Toward Information and Privacy Are in Flux Genetic privacy was a central preoccupation during the early years of genomics, which led to implementation of stringent regulatory procedures to limit the use of genetic data in patient oriented research (Andrews and Jaeger 1991). During the ensuing years, the diffusion of the internet into every corner of our lives is driving massive changes in public attitudes toward privacy. Research studies of public attitudes reveal deep ambivalence about informational privacy. In the particular arena of genetic information and health records, members of focus groups typically grasp the broad social benefits of sharing data. A consistent theme is that people who contribute their own information to public databases want to be asked for permission, to have a clear explanation of how the data will be used, and to be treated as true partners in the research process (Damschroder et al. Although privacy concerns remain, there is little evidence that the public has the extreme sensitivity toward genetic data that many researchers anticipated 25 years ago. The Proposed Knowledge Network of Disease Could Catalyze Changes in Biology, Information Technology, Medicine, and Society The powerful forces affecting basic biological research, information technology, clinical medicine, and public attitudes toward the privacy of health records and personal genetic information create an unprecedented opportunity to change how biomedical research is conducted and to improve health outcomes. The development of the proposed Knowledge Network of Disease and its associated New Taxonomy could take advantage of these forces to inspire revolutionary change. This Committee regards commitment to the development of these resources as a powerful unifying idea that could harness—and, to an appropriate degree, redirect—the creative energies of the key constituencies to achieve the full potential of biology to improve health outcomes. Toward Precision Medicine: Building a Knowledge Network for Biomedical Research and a New Taxonomy of Disease 3 What Would a Knowledge Network and New Taxonomy Look Like? In the previous chapter, the Committee outlined the reasons it concluded that the time is right to develop a Knowledge Network of Disease and New Taxonomy. But what would these resources look like and what implications would they have for disease classification, basic research, clinical care and the health-care system? This chapter describes the Committee’s vision of a comprehensive Knowledge Network of Disease and New Taxonomy that would unite the biomedical-research, public-health, and health-care-delivery communities around the related goals of advancing our understanding of disease pathogenesis and improving health. The Committee envisions that the proposed resources would have several key features: x They would drive development of a disease taxonomy that describes and defines diseases based on their intrinsic biology in addition to traditional physical “signs and symptoms”. The Knowledge Network of Disease Would Incorporate Multiple Parameters and Enable a Taxonomy Heavily Rooted in the Intrinsic Biology of Disease Physical signs and symptoms are the overt manifestations of disease observed by physicians and patients. Physical signs and symptoms are generally also difficult to measure quantitatively. Indeed, in a strict sense, all diseases are presumably asymptomatic for some “latent period” following the initiation of pathological processes. As a consequence, diagnosis based on traditional “signs and symptoms” alone carries the risk of missing opportunities for prevention, or early intervention can readily misdiagnose patients altogether.

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