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For group A streptococcus cheap dapoxetine online visa erectile dysfunction treatment pdf, the combination of clindamycin and pen- icillin should be used purchase dapoxetine 60mg visa erectile dysfunction at the age of 17. Antibiotic therapy alone should not be used as necrotizing fasciitis is rapidly fatal without surgical intervention discount dapoxetine 60mg otc erectile dysfunction injections. Vancomycin is not a first-line antibiotic in necrotizing fasciitis and should be considered only for those with penicillin allergy. Although mucormycosis is a relatively uncommon invasive fungal infection, patients with poorly controlled diabetes, patients receiving glucocorticoids, immunocompro- mised patients, or patients with iron overload syndromes receiving desferrioxamine have an enhanced susceptibility to this devastating infection. The “gold standard” diagnosis is tissue culture, but a common hallmark is the black eschar noted on the palate, which rep- resents invasion of the fungus into tissue, with necrosis. The black eschar in this scenario should prompt the clinician to do more than prescribe treatment for sinusitis. Black es- chars on the extremities can be found with anthrax infection or spider bites. Successful therapy requires reversal of the underlying predisposition (glu- cose control in this case), aggressive surgical debridement, and early initiation of antifun- gal therapy. Posaconazole, an experimental azole antifungal, has been shown to be effective in mouse models of the disease and has been used in patients unable to tolerate amphotericin. Extrapulmonary disease should always be treated, especially if the patient is immunocompromised. Itraconazole is indicated for non-central nervous system extra- pulmonary disease in mild to moderate cases. Otherwise, amphotericin B is the treat- ment of choice, especially if there has been treatment failure with itraconazole. The triazole antifungals have not been studied extensively in human cases of blastomycosis. Fluoroquinolones have activity against many mycobacterial species, but do not have activity against fungi, including B. She asks you about her likelihood of develop- following are true about the patient’s diagnosis except ing complications of hypertension, including renal failure A. She currently is taking hydrochlorothiazide 25 because of the size of the aneurysm. Infrarenal endovascular stent placement is an op- alcohol no more than once per week. Her family history is tion if the aneurysm experiences continued growth significant for hypertension in both parents. Surgical or endovascular intervention is warranted has coronary artery disease and is on hemodialysis. Her point of maximal cardiac impulse is not dis- if the aneurysm expands beyond 5. A 45-year-old woman presents to the emergency room electrocardiogram reveals an axis of –30 degrees with complaining of progressive dyspnea on exertion and borderline voltage criteria for left ventricular hypertrophy. The dyspnea her history and physical examination is a risk factor for a has progressed such that she is only able to walk about 1 poor prognosis in a patient with hypertension? Family history of renal failure and cerebrovascular ticed a cough that occasionally produces thin, pink- disease tinged sputum. She sleeps on three pillows but awakens ation of therapy with dyspnea once or twice nightly. A 68-year-old male presents to your office for routine history of chest pain, heart disease, or heart murmurs. He reports that he is feeling well and has She has been in good health until the past 3 months. He is taking chlorthali- Vital signs: blood pressure of 145/92 mmHg, heart rate of done 25 mg daily, atenolol 25 mg daily, and pravastatin 40 95 beats/min, respiratory rate of 24 breaths/min, temper- mg nightly. The jugular venous 175 Copyright © 2008, 2005, 2001, 1998, 1994, 1991, 1987 by The McGraw-Hill Companies, Inc. Obtain blood cultures and initiate therapy based is an area of erythema with central ulceration covered by upon results. Perform left heart catheterization and consider sur- is the most appropriate plan of care for this patient? Diffusion capacity of the lung and commencing an exercise regimen, he has lost weight and improved his blood pressure control. In the tracing below, what type of conduction abnor- eterization 1 month ago showed two nonobstructive cor- mality is present and where in the conduction pathway is onary lesions in the left circumflex artery. Ventricular septal defect tion murmur that extends to S2 with radiation to the ca- rotids. Improved blood pressure control the base of the heart with a crescendo-decrescendo pat- E. Which noticed shortness of breath with exertion about 12 of the following echocardiographic findings is most months ago. Eccentric mitral regurgitant jet being told when he was younger that he had a heart mur- B. His cardiac examination reveals a harsh ma- valve chinery-like murmur that is continuous throughout sys- D. Systolic anterior motion of the aortic (anterior) mi- tole and diastole with a palpable thrill. There is late tral valve systolic accentuation of the murmur at the upper left ster- E. Intravenous nitroprusside and esmolol and cardiac complaining of severe chest pain. Physical examination and is usually able to exercise at the gym without chest reveals an elevated jugular venous pressure, clear lungs, a pain. In addition to hypertension, he also has a history of third heart sound, a pulsatile liver, ascites, and dependent hypercholesterolemia. Chest radiography reveals no cardiomegaly and clear dipine, 10 mg once daily, and rosuvastatin, 10 mg once lung fields. An echocardiogram demonstrates normal to daily, but says that he only takes them intermittently. The initial smokes 1 pack of cigarettes daily and has done so since diagnostic workup should include all the following except the age of 20. His cardiac examination reveals a hyper- with rhabdomyolysis due to compartment syndrome of dynamic precordium. What is the most ap- tion of the ascending aorta with a small amount of peri- propriate course of action at this point? Reduced serum endothelin level tricular ejection fraction is 15%, and she has New York E. A 45-year-old man is admitted to the intensive care unit pressure and pulse allow for the addition of a calcium with symptoms of congestive heart failure. Which calcium channel– heroin and cocaine and uses both drugs daily via injection.

Using genome-wide associations in millions of patient medical records cheap dapoxetine amex erectile dysfunction treatment for diabetes, a study demonstrated that common variants associated with complex diseases are enriched in the genes indicated by the “Mendelian code” – a phenotypic code that links each complex disorder to a unique collection of Mendelian loci (Blair et al order 60 mg dapoxetine with amex erectile dysfunction protocol free copy. The study identified widespread comorbidity between Mendelian-Mendelian and Mendelian-complex disease pairs dapoxetine 60 mg visa erectile dysfunction patient.co.uk doctor. Pathomechanism of many neurological and psychiatric disorders is poorly understood and genomic studies will not only contribute to better understanding but also improve molecular diagnostics. The current diagnostic process is often long and complex with most patients undergoing multiple invasive and costly investiga- tions without ever reaching a conclusive diagnosis. Genetic disorders can involve multiple systems and with predominant involve- ment of the nervous system, they are referred to as neurogenetic disorders. Some of the disorders described in the following sections have a significant neurogenetic com- ponent. However, even in cases with simple patterns of inheritance, the relationship between disease phenotypes and their corresponding genetic changes can be complicated. The high number of rare, heteroge- neous mutations present in all humans and the paucity of known functional variants in >90 % of annotated genes make this challenge particularly difficult. Role of neurogenomics in the development of personalized neurology is shown schematically in Fig. Role of neurogenomics will be described in the following sections along with the personalized management of various disorders. Many other factors besides genomics are taken into consideration in tailoring the treatment to an individual patient. Universal Free E-Book Store 412 12 Personalized Management of Neurological Disorders Impact of Neurogenomics on the Development of Personalized Neurology Genomics is improving our understanding of neurologic diseases. This will be an important basis for the development of rational therapies in integrated healthcare of the future. Genomics will have the following impact on healthcare: • Increase in the range of diseases that can be treated with drugs. With the sequencing of the genome and genetic redefinition of neurologic dis- eases, pathomechanism will be better understood and will facilitate early detection by molecular methods and effective strategies for management. Availability of low- cost genomic sequencing will expand the use of genomic information in the practice of neurology. Drugs will be targeted better to diseases in particular patients based on genotype information. The epigenome is involved in regulation of gene expression, development, and tissue differentia- tion. Unlike the underlying the genome which is largely static within an individual, the epigenome can be altered by environmental conditions. Whereas epigenetics often refers to the study of single genes or sets of genes, epigenomics refers to more global analyses of epigenetic changes across the entire genome. Neurological disorder are not only associated with genomic mutations and tran- scriptomic dysregulations, but with changes in the epigenome. Universal Free E-Book Store Neuroproteomics 413 Targeting the complete mitochondrial exome provides a greater potential to identify rare variants that disrupt normal mitochondrial function, enabling an exact diagnosis in a large proportion of patients that remain undiagnosed by other meth- ods. Over 95 % of the target bases can be sequenced to an average coverage of 400×, providing highly accurate and sensitive results. Neuroproteomics The role of proteomics in personalized medicine has been described in Chap. Neuroproteomics is the term used for application of proteomics to the study of the nervous system and its disorders with the aim of developing diagnostics and thera- peutics (Jain 2002). Proteomics tools offer new ways to analyze networks of pro- teins that control important neurobiological phenomena. Neuroproteomics, combined with bioinformatics, can be used to study the organization of functional protein networks and molecular structures that underlie physiological, anatomical, and behavioral processes (Bayés and Grant 2009 ). Applications of Neuroproteomics for Study of the Nervous System Proteomics technologies are used for the study of neurotransmitters and neuronal receptors. A brief description of these is as follows (Jain 2013): Neurotransmitters Capillary electrophoresis has been combined with highly sen- sitive micro-electrospray-tandem mass spectrometry to simultaneously detect classi- cal small molecule neurotransmitters as well as neuropeptides from discrete regions of the brain. Endogenous glutamate, gamma-aminobutyric acid, acetylcholine, and dopamine as well as the neuropeptides methionine-enkephalin and substance P 1–7 could be detected in the striatum using only a minute amount of brain tissue. Neuroprotection Use of neuroproteomics, systems biology, and bioinformatics aim to study and establish a global assessment of the entire neuronal proteome (Raad et al. Neuroproteomics aids in the understanding of molecular mecha- nisms of neurogenesis. Potential neuroprotective pharmacological strategies can be targeted at Rho and Rho kinases, which constitute key integral points in the pathway that is known to be disrupted in multiple neuropathologies, such as spinal cord injury and traumatic brain injury (Jain 2011 ). Universal Free E-Book Store 414 12 Personalized Management of Neurological Disorders Regeneration and Degeneration of the Nervous System Neuroproteomic tech- nologies have been designed to uncover the mechanisms and molecules involved in neuronal regeneration and degeneration (Sun and Cavalli 2010). Most proteins mediating regeneration are found to be either malfunctioning or reduced in degeneration. These studies are further facilitated by the availability of 2D maps of brain-specific proteins. Role of neuroproteomics in the management of individual disorders will be described in sections dealing with these disorders. Some disease-specific proteins identified in the cerebrospinal fluid of patients with neurologic disorders are shown in Table 12. Concentrations of the S-100 protein, an acidic calcium-binding protein found in the gray matter of the brain, are elevated in serum after brain damage. However, this test does not replace brain biopsy for definitive diagnosis of Creutzfeldt-Jakob disease. Undetectable S-100 in the blood of patients with head injury can rule out brain damage, and S-100 levels correlate with the extent of brain damage in severe head injury. Peak levels of serum S-100 correlate with neu- rologic deficit resulting from either stroke or traumatic brain injury, and the patterns can be used to differentiate between the two conditions. Elevated serum levels of S-100 in patients with liver cirrhosis indicate early and subclinical portal-systemic encephalopathy. It seems to be a promising biochemical sur- rogate marker for mild cognitive impairments due to portal-systemic encephalopathy. Neuron-Specific Enolase This is a glycolytic enzyme found in the neurons and neuroendocrine cells. Increased levels of neuron-specific enolase have been measured as a result of ischemic stroke in cerebral spinal fluid as well as in blood. Universal Free E-Book Store 416 12 Personalized Management of Neurological Disorders Table 12. Peak levels of both neuron-specific enolase and S-100 are statistically significant and correlate with clinical measures of stroke size and outcome. Myelin Basic Protein This is localized in the myelin sheath and constitutes approximately one third of the total protein of myelin from the human brain.

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The patient described above has only one major risk—intraperitoneal surgery—on the six-point revised cardiac risk index (see Table V-53) purchase dapoxetine 30 mg otc xylitol erectile dysfunction. This puts the patient into an intermediate-risk classication by this scale; however generic 90 mg dapoxetine mastercard erectile dysfunction after age 50, further testing is indicated only if the patient is undergoing vascular surgery order dapoxetine 60 mg on-line erectile dysfunction meds online. In addition, the patient has excellent functional status and can achieve greater than four metabolic equivalents with ease. The risk of postoperative cardiovascular complications does not appear to be influenced by stable hypertension, elevated cholesterol, obesity, cigarette smoking, or bundle branch block. Perioperative beta blockade has been shown to decrease rates of postoperative myo- cardial infarction and cardiac death by at least 50% and is recommended for any patient who has cardiac risk factors or is at intermediate risk of cardiovascular complications after surgery. The patient’s prior adverse reaction to beta blockade should not preclude its use in the perioperative period, as it consisted of only mild fatigue and decreased sexual func- tioning. Finally, the patient’s pulmonary risk is likely to be low as he quit smoking more than 8 weeks before surgery and has good functional status without dyspnea. Other settings where acute mitral regurgita- tion may occur include rupture of chordae tendineae in the setting of myxomatous mitral valve disease, infective endocarditis, or chest wall trauma. The regurgitation into a normal- sized noncompliant left atrium results in an early systolic descrescendo murmur heard best near the apical impulse. The decrescendo nature contrasts with chronic mitral regurgita- tion due to the rapid pressure rise in the left atrium during systole. Ventricular septal rupture also causes a holosystolic murmur and is associated with a systolic thrill at the left sternal border. Severe aortic steno- sis and hypertrophic cardiomyopathy both present with a mid-systolic murmur. Gram-negative sepsis will generally have a normal or in- creased cardiac index with normal filling pressures and low blood pressure. The experience of the surgeon and the likelihood of success- ful mitral valve repair are also an important consideration. The management strategy for chronic severe mitral regurgitation depends on the presence of symptoms, left-ventricu- lar function, left-ventricular dimensions, and the presence of complicating factors such V. With very depressed left-ventricular function (<30% or end-systolic dimension > 55 mm), the risk of surgery increases, left- ventricular recovery is often incomplete, and long-term survival is reduced. However, since medical therapy offers little for these patients, surgical repair should be considered if there is a high likelihood of success (>90%). When ejection fraction is between 30 and 60% and end-systolic dimension rises above 40 mm, surgical repair is indicated even in the absence of symptoms, owing to the excellent long-term results achieved in this group. Waiting for worsening left-ventricular function leads to irreversible left-ventricular re- modeling. Pulmonary hypertension and atrial fibrillation are important to consider as markers for worsening regurgitation. The International Diabetes Foundation also has criteria that further subdivide the cut-offs of waist circumference based on ethnicity. Patients with the metabolic syndrome are at greater risk than patients without the syndrome for developing conditions such as athero- sclerotic cardiovascular disease, type 2 diabetes mellitus, peripheral vascular disease, sleep apnea, and polycystic ovary syndrome. The presence of one of the criteria should prompt the clinician to search for other criteria and treat the conditions as necessary. Risk factors for developing the disease are African ancestry, age >30 years, and multiparity. Counseling patients with peripartum cardiomyopathy who are consider- ing becoming pregnant in the future is important as it directly impacts maternal and fetal mortality. Some of these patients may become pregnant again; however, women whose ventricular function has not returned to normal usually are advised against pregnancy since the mortality can be as high as 50% during subsequent pregnancies in this popula- tion. Among all-comers, there is a 25–67% chance of having another bout of peripartum cardiomyopathy during future pregnancies. Sex of the child during the incident episode of peripartum cardiomyopathy, maternal age, or nadir ejection fraction is not known to be associated with future events. African ancestry is a risk for developing peripartum cardio- myopathy but subsequent risk of mortality depends on the resolution of the first episode. In severe left ventricular dilatation, the jugular venous pressure is elevated, murmurs of mitral and tricuspid regurgitation are common, and third or fourth heart sounds may be heard. Owing to the depressed cardiac output, systemic vascular re- sistance increases, and with it, diastolic blood pressure. Systolic blood pressure may de- crease as a result of decreased cardiac output leading to a narrow pulse pressure. Conditions in which S2 becomes absent include severe aortic stenosis and severe aortic in- sufficiency when the insufficiency murmur is louder than S2. Paradoxical splitting occurs when P2 and A2 become closer during inspiration and can be seen in patients with left bundle branch block. Pulsus bisferiens (double-impulse pulse) is classically detected when aortic insufficiency exists in association with aortic stenosis, but it may also be found in isolated but severe aortic insufficiency and hypertrophic obstructive cardiomyopathy. The benefit of statins ap- pears to be related to stabilization of plaques, long-term egress of lipids, and/or improved vasodilatory tone. The improved vasodilatory tone appears to be mediated by modula- tion of endothelial-dependent vasodilators such as nitric oxide. Thus, the beneficial effect of the statins probably consists of an early effect on vasomotion (or other mechanisms) and a long-term effect on serum and plaque lipids. Where there is significant obstructive coronary disease, there is a pressure gra- dient between prestenotic and poststenotic segments, and the poststenotic vascular bed di- lates to allow for preserved coronary blood flow. Dipyridamole, by disproportionately dilating nonobstructed areas of myo- cardium, is useful as a pharmacologic agent to differentiate ischemic from nonischemic tissue. Where there is high-grade, three-vessel disease, the usefulness of dipyridamole or adenosine infusion is limited by (1) baseline maximal vasodilation, and (2) lack of ability to differentiate affected from nonaffected regions of myocardium. Dipyridamole testing is helpful in identifying ischemic tissue in a single-vessel territory. Intraventricular conduc- tion abnormalities limit the use of electrocardiography or echocardiography as a stress- imaging technique. Dipyridamole, as a pharmacologic stressor, is not affected by heart rate and may be particularly useful for patients who are unable to exercise. Therefore, in this patient a new elevation of myoglobin would be helpful in distinguish- ing new myocardial necrosis. Troponin-I and troponin-T are more specific markers of myocardial necrosis but have a long half-life in the circulation. Serial echocardiograms may detect new wall motion abnormalities that suggest new ischemia or infarction, but in the absence of a prior study a single echocardiogram would have limited utility in this patient. Malaise and weight loss may also occur in association with underlying rheumatic disease. Acute pericarditis can be due to infec- tious, neoplastic, autoimmune, cardiac, metabolic, or pharmacologic events. The echocardiogram will show a small to moderate amount of pericardial ef- fusion with normal left ventricular function.

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Persons offered and completing multiplex genetic susceptibility testing used more physician visits before testing buy dapoxetine 90 mg cheap drugs for erectile dysfunction ppt, but testing was not associated with subsequent changes in use discount 30mg dapoxetine otc erectile dysfunction pills canada. This study supports the supposition that multiplex genetic testing offers can be pro- vided directly to the patients in such a way that use of health services is not inap- propriately increased order discount dapoxetine online erectile dysfunction diabetes causes. Reducing Healthcare Costs by Combining Diagnostics with Therapeutics Cost-effective diagnostics are but a prelude to an era of cost-effective personalized medicine. The real potential is in better targeting expensive drugs to those who will benefit from them, thereby both cutting wasteful expenditure and decreasing adverse events associated with treating non-responders. The anticancer drug Avastin (Genentech/Roche) costs $50,000–$100,000 per year of treatment but works in fewer than 50 % of patients. Avastin may be useful in a targeted group of breast cancer patients but there is no available test that can identify such patients. Given that Avastin may generate $12 billion in peak sales, the low rate of efficacy translates into billions of dollars in misdirected health- care spending. Assuming that a test of this sort is introduced at the beginning of 2015 and is 100 % adopted, cumulative savings of $40 billion could be realized by 2020. Universal Free E-Book Store 688 23 Economics of Personalized Medicine Oncotype Dx (Genomic Health) is a test with compelling cost-saving potential. By averting unnecessary che- motherapy, the test has been shown to save about $2,000 per patient. The total potential cost savings is estimated at roughly $20 million per year (about $12 million for payers as well as~$8 million for hospitals and transplant centers). This scenario, in which a drug with high sales but low efficacy is targeted by diagnostics companies, may become a pattern in the near future, multiplying cost savings. Costs of Pharmacogenetic Testing Among direct to consumer personal genetic testing companies, the cost of 23and- Me’s service, at $399, is the least expensive. Pharmacogenetics to Reduce the Cost Incurred by Adverse Drug Reactions Increase in treatment efficacy by individualize treatment is difficult to measure in financial terms but the savings from reduction of adverse reactions would be consid- erable. Even if personalized medicine reduces adverse reactions by a small percentage, the resulting savings to the health- care industry would be considerable. This is of clin- ical importance mainly in patients having two non-functional alleles, phenotypically Universal Free E-Book Store Commercial Aspects of Pharmacogenomics 689 characterized as “poor metabolizers” (1–10 % of Caucasians). Studies have shown that pharmacogenetic analyses will significantly contribute to reducing treatment costs for drug-induced adverse reactions and costs of sick leave, by predicting the best drug and the most effective and safest dosage. The question has been raised: are pharmacogenetic analyses coming to the point where they drive down costs incurred by illness? There was a trend toward a decrease in drug costs in the genotyping arm, the greatest reduction being in the decreased use of protease inhibi- tors in the genotyping arm. The additional expense of genotyping appeared to be offset by the savings obtained in drug costs. It is concluded that genotypic antiretroviral resistance testing following antiretroviral failure is cost-effective. Primary resistance testing also seems to be reasonably cost-effective and will become more so as the prevalence of primary resistance increases. Universal Free E-Book Store 690 23 Economics of Personalized Medicine Cost-Effectiveness of Warfarin Pharmacogenomics Review of studies incorporating clinical efficacy data of genotype-guided dosing algorithm had shown that warfarin pharmacogenomics would improve quality- adjusted life-years gained (You 2011). Important factors for improving the cost-effectiveness include low genotyping cost, high effectiveness in improving anticoagulation con- trol and lowering adverse events. Application of warfarin pharmacogenomics could possibly be cost-effective in selected patient groups with high bleeding risk or prac- tice sites with suboptimal management of anticoagulation control. Molecular testing is as much about generating cost savings by identifying nonre- sponders as it is about improving survival by identifying responders, and that good modeling must account for the fact that community practice (as opposed to clinical trials) is messy. This study of an unusually accurate test raises important issues that should be considered for other molecular tests in other settings. Universal Free E-Book Store Concluding Remarks on the Economics of Personalized Medicine 691 Lowering the High Costs of Cancer Chemotherapy Pharmacogenomics for cancer is being driven by the fact that treatment costs are so high and getting higher. The costs will be reduced significantly as more genetic variants come into play, which are important in terms of drug response. There might be gene chips that are specifically tailored toward different types of therapy, and one could look at many different genotypes at the same time in a single patient sample. Another contributor to high costs of care of cancer patients are adverse effects from chemotherapy. Identification of patients who might react adversely to a treat- ment could help in saving costs by avoiding administration of drugs to patients at risk of adverse reactions. Researchers are looking at sensitivity to chemotherapies within families and identifying candidate genes that contribute to susceptibility to anticancer drug toxicity. With the help of gene expression profiling, it is possible to identify the genes responsible for conferring drug susceptibility. A clinical trial by research- ers at the University of Chicago has demonstrated the predictive significance of genotyping for variants that affect drug pharmacodynamics. The toxic effects were found only in patients who possessed at least one allele of that polymorphism. Concluding Remarks on the Economics of Personalized Medicine Several studies point to benefits of personalized medicine by improving efficacy and safety. From an ethical point of view, a physician is required to recommend the best available treatment. The pharmaceutical indus- try is adapting to development of trend in personalized medicine, but some contro- versies need to be resolved. Although case studies of application of personalized medicine have shown benefit for patients and cost-effectiveness, the barrier to large-scale real-world adoption of this approach requires a change in health policy. Universal Free E-Book Store 692 23 Economics of Personalized Medicine At point-of-care, the case studies personalized medicine will need to measure outcomes, which are important for policy-makers, as evidence of clinical utility (van Rooij et al. Personalized medicine and the role of health economics and outcomes research: issues, applications, emerging trends, and future research. Personalized medicine policy challenges: measuring clinical utility at point of care. Universal Free E-Book Store Chapter 24 Future of Personalized Medicine Introduction Several studies of the human genome are still going on and some are planned. Ongoing Studies Personal Genome Project Achieving personalized medicine will require extensive research on highly re- identifiable, integrated datasets of genomic and health information. These resources were planned to include full (46-chromosome) genome sequences, digital medical records and other medical information that would become a part of personal health profile. Human cell lines representing each subject are deposited in a repository at the National Institute of Genome Medical Sciences. To that end the team developed a peer production system for recording and organizing variant evaluations according to standard evidence guidelines, creating a public forum for reaching consensus on interpretation of clinically relevant variants. Genome analysis becomes a two-step process: using a prioritized list to record vari- ant evaluations, then automatically sorting reviewed variants using these annota- tions. Genome data, health and trait information, participant samples, and variant interpretations are all shared in the public domain. There is an open invitation to others to review the results using participant samples and contribute to interpreta- tions.