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By: Joseph St. Geme, MD

  • Chair, Department of Pediatrics, Professor of Pediatrics and Microbiology, Perelman School of Medicine at the University of Pennsylvania
  • Physician-in-Chief, Leonard and Madlyn Abramson Endowed Chair in Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania

https://www.chop.edu/doctors/st-geme-joseph-w

Study quality Type 1 Diabetes Overall Summary For type 1 diabetes we identified eight publications24-27 keratin intensive treatment purchase clozaril from india, 30-32 medicine garden discount generic clozaril canada, 36 of seven studies evaluating six commercially available mobile applications (Glucose Buddy symptoms 3 weeks into pregnancy clozaril 25mg with visa,43 medications on backorder cheap clozaril 50mg overnight delivery, 44, 49 Diabetes Manager,41 Dbees,50 Diabetes Diary,51 Diabetes Interactive Diary,52 and Diabeo Telesage40, 53). Please see Table 1 for detailed descriptions of apps (including app name, platform, cost, what it tracks, what feedback it provides, usability, evidence of effectiveness, and quality of associated studies), and Appendix C, Table C-1 for a detailed description of each study. Of the six apps, three (Dbees,50 Diabetes Diary,51 and Diabetes Interactive Diary52) were free to download, one (Diabetes Manager41) required a download fee, one (Diabeo Telesage40, 53) required a paid subscription, and one (Glucose Buddy) had two tiers of access: one (Glucose Buddy44, 49) is free and the other (Glucose Buddy Pro43) costs $1. One app (Diabetes Diary51) 10 had an additional blood glucose meter module, Diastat, that was examined in the study that is not currently available through the app. Duration of diabetes in the intervention groups ranged from 16 to 25 years, while baseline HbA1c ranged from 7. Study duration and length of time that participants used the apps ranged from 8 weeks to 6 months. Features, usability, and significant outcomes for apps for type 1 diabetes Name of App Platform Cost What does What feedback does Does this app have a the app the app provide to privacy/security policy? Developer has access to records and personally identifiable information and can share information with thirdparty contractors. Apple version of app recently changed to a new developer and they implemented a new policy. Privacy policy has not been updated since 2012, but the developer maintains they have no access to records or personally identifiable information. Developer Unable to · Participants Medication will not sell information but will use assess. Platform Cost What does What feedback does Does this app have a the app the app provide to privacy/security policy? All three apps provide users with the ability to track blood glucose, HbA1c, meals and carbohydrates, medication, and physical activity; provide medication and glucose measurement reminders; and assist with HbA1c calculation. Only Glucose Buddy Pro allows users to track weight and blood pressure and display it graphically, though using the "notes" feature on Glucose Buddy could help to log these changes. The user interfaces of Glucose Buddy and Glucose Buddy Pro are almost identical, and whenever a user of Glucose Buddy chooses an option that is only available on Pro, the app prompts the user to upgrade. This allows for an easy transition from one app to another, if the user chooses to upgrade. The developer of Glucose Buddy and Glucose Buddy Pro (Apple) has a privacy policy that addresses the use of cookies, collection of personal information, and personal information is used. The developer has access to records and personally identifiable information and can share information with third-party contractors. Glucose Buddy (Android) privacy policy has no red flags, and the developer explicitly states that the developer has no access to records or any personally identifiable information. According to the usability scales, Glucose Buddy has "acceptable" usability, and Glucose Buddy Pro has "marginal" acceptability, which are generally consistent with reviews in both app marketplaces. The intervention group used Glucose Buddy, which allowed participants to manually enter data including blood glucose levels, insulin other medication dosages, diet, and physical activity. Participants received personalized feedback on their data from a certified diabetes educator at a minimum of one text message per week. The control group received usual care which included a visit to primary care diabetes health care practitioner every 3 months, and did not have any feedback from the certified diabetes educator. The intervention group demonstrated no statistically significant improvement in quality of life, self-care activities. The interaction effect between the intervention and control group for HbA1c at 9 months (6 months of intervention and 3 months follow-up) was clinically and statistically significant (difference-indifference = -1. The effect of HbA1c should be interpreted with caution because of the significant differences between intervention and control groups at baseline. This study was moderate quality, due to a lack of information on the allocation concealment and a high attrition rate (26 percent). Also, the intervention group received text 14 messages from a certified diabetes educator while the control group did not. Therefore, the results of this study are applicable when Glucose Buddy is used in combination with text messages from a diabetes educator. If this additional support affected some outcomes, the effects of Glucose Buddy by itself are less certain. This app has a generic food database, which allows users to select their meals and automatically import carbohydrate and other nutrition information. Participants had a mean duration of diabetes of nearly 25 years in the intervention group and 22 years in the control group. The intervention group had communication every 7 to 14 days with a provider via email, text, or phone. Participants in the control group did not have regular scheduled communication with providers, but were encouraged to contact providers as needed. The intervention was shown to statistically reduce HbA1c (difference-in-difference = 0. This study was low quality due to inconsistent reporting of outcomes as well as lack of information on randomization and allocation concealment. In addition, providers contacted participants in the intervention group using the app every 7 to 14 days, while the control group did not have regularly scheduled contact with providers. Therefore, the results of this study are applicable when Diabetes Manager is used in addition to scheduled contact with providers every 7 to 14 days. If this additional support affected some outcomes, then the effects of Diabetes Manager by itself are less certain. The Apple app was last updated in 2012, so it is unknown if this function will be fixed in the near future. Users must first create an account online and enter basic information about their diabetes before they are able to use the mobile app. Once users log into the app, they can track their blood glucose, meals and 15 carbohydrates, medication, physical activity, and weight. A privacy policy is available on the Dbees Web site, and there are no clear data security issues. We were only able to evaluate the Android app due to the graphical error on the Apple app. Our "marginal" usability score is consistent with Android marketplace ratings of the app. Participants had a mean duration of diabetes of nearly 17 years and two-thirds (66 percent) were on an insulin pump. Participants had important comorbidities including retinopathy (25 percent) and neuropathy (19 percent). The intervention group used the Dbees app and personal Web portal that allowed manual entry of participant self-care data, including blood glucose, carbohydrate intake, medication, and physical exercise. The study did not demonstrate significant changes in HbA1c, quality of life, or diabetes emotional distress. This study was moderate quality due to a lack of clarity on randomization and insufficient detail about the difference in planned interactions with research staff between the group that used the app and the control group. Like the Diabetes Manager app, this app has a generic food database that allows users to select their meals and automatically import carbohydrate and other nutrition information. This app has a privacy policy that discusses data security and how information will be used, and while there are no clear red flags, this app will request access to photos and Bluetooth connections. The intervention group used the Diabetes Diary with the Diastat feedback module for blood glucose management, while the control group used the Diabetes Diary app without the Diastat feedback module. Out-of-range blood glucose events, defined as blood glucose outside range 72270 mg/dL, were found to be significantly reduced in the Diastat intervention groups (median out-of-range events over 2 weeks: -14. We could not determine the effect of Diastat on HbA1c because the between-group difference-in-differences was not provided. This study was low quality based on incomplete information about randomization and lack of information about allocation concealment. In addition, there were insufficient details about the difference in planned interactions between the research staff and intervention and control groups. Participants had a mean duration of diabetes more than 8 years and nearly one-fifth (19 percent) of both intervention and control groups were on an insulin pump. Participants with all other insulin regimens, including insulin pumps, were excluded.

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This information is often best transmitted in person-given to treatment 5th metatarsal avulsion fracture buy clozaril 50 mg line the young adult to treatment 2nd degree burn buy discount clozaril 25 mg on-line be handed to symptoms 7dp5dt purchase cheap clozaril online the new health-care provider so that there is no delay medications zocor order clozaril 100mg line. When you are planning to go off to college, it helps to spend a visit or two going through all of the details of what it means to re-establish care in another location. You will need to connect with student health; you may need to sign basic disability paperwork so that there is accommodation for tests or assignments postponed due to a diabetes-related issues. Discuss how to safely approach drinking alcohol, and the effects recreational drugs and athletic-performance­enhancing drugs might have on diabetes management. Many college campuses have a van that will pick up sick students and take them to student health. One of the biggest problems for transitioning youth is getting "lost to followup," which means there is a gap in care. This happens far too commonly and when it does, not surprisingly, people do worse. Make use of the resources offered by your pediatrician to ensure that a connection is made with an adult provider before pediatric care ends. The Bottom Line Transition plans must start in the pediatric setting, years before they will actually occur. Ideally there will always be the "right fit" in an adult endocrinologist waiting to care for the young adult patient. However, endocrinologists are in short supply, and it may not always be possible to immediately connect with your adult "diabetes dream team" right off the bat. But young adults can and must continue to receive medical care in some fashion or another. The key to making a successful transition is having a plan and the support to make it happen. Each person with type 1 diabetes needs at least one health-care provider who can write prescriptions for insulin and diabetes-related supplies. In a pinch this can be a primary care provider, a free clinic, or student health center. By the time of the last visit in pediatric care, a new place for care should be clearly identified and an appointment set up. Understandably there are many competing issues as young adults grow up and leave home, but having diabetes necessitates a little extra planning and connection. Young adults are often accustomed to simply following their parents in terms of who is the best doctor to followup with, but as an adult this is a more personal decision. This is especially true if you are settling into a place where you will live for a while. In some health-care settings, you will need to find a primary care provider first to refer you to an endocrinologist. As long as the first connection with a provider is made, you should be safe and able to connect to the help you need. C hapter 14 the Golden Years T ype 1 diabetes is sometimes, mistakenly, thought of as a childhood disease. But the disease can show up in adulthood (it is estimated that half of all new-onset cases develop after the age of 20). Some older adults with type 1 diabetes are running races, while others reside in nursing homes. Make sure all your health-care providers and family members know what type of diabetes you have and how to treat it. Too often, all older individuals are assumed to have type 2 diabetes and thus are treated inappropriately for type 1 diabetes. Several days later he would show up in the diabetes clinic on oral agents with blood glucose levels in the 400­500 mg/dL range. Make sure all your health-care providers, caregivers, and family members know what type of diabetes you have and how to treat it. This information should be in your electronic medical record and recorded on smartphone health information apps. Long-Duration Diabetes the risk of developing complications of diabetes increases over time. People living today who have had type 1 diabetes for 35 or more years were treated before we had tools such as self-monitoring of blood glucose, newer insulins, sensors, and modern pumps. It was much harder to keep blood glucose levels in the normal range and more common to develop some of the complications of diabetes. Some participants have had no significant complications from their diabetes and are living active, healthy lives. And given the fact that outcomes for people with type 1 diabetes are improving with improved treatments, it is hoped that people who live long lives with type 1 diabetes will have even fewer complications in the future. My life would have been different in so many ways and looking back to analyze alternatives is pointless. I am very happy where I am and to the extent diabetes was part of getting me here, it has been good. On top of reproductive issues, earlier menopause may have additional health ramifications. Type 1 diabetes already takes a toll on heart health, and early menopause may exacerbate the damage. In women without diabetes, menopause is associated with an increased risk of cardiovascular disease, plus osteoporosis and premature death. Living Well and Long the goal for most people as they age is maintaining their independence. On top of all the standard life chores of cooking, shopping, and cleaning, you have the additional jobs of counting carbs, checking blood glucose, and taking insulin. On the other hand, by now these diabetes-related tasks may be second nature to you. With the kids grown up and out of the house, you may have more time for self-care and activities such as yoga, meditation, swimming, or walking with peers. We know the benefits of appropriate exercise and engaging the mind in challenging activities. Who knows, maybe calculating insulin doses helps keep the mind young and functional. A fall can set in motion a series of events that can lead to reduced mobility and a loss of functional independence. Hypoglycemia can trigger a loss of balance and lead to a fall, so check 174 the Type 1 Diabetes Self-Care Manual blood glucose regularly. Certain medications, such as those taken for high blood pressure, may cause you to become dizzy when standing (postural hypotension), another fall factor. Other issues that can impact fall risk include peripheral neuropathy-loss of sensation in the feet and/or a loss of balance (known as proprioception). People with type 1 diabetes seem to develop large-joint issues, and this can lead to pain and disability. A fall and fracture due to osteoporosis can lead to a period of forced immobility, which can be difficult to recover from. Sometimes this can be done on your own; other times it requires a caregiver or physical therapist. There are wonderful groups for older folks where physical activity is supervised and is age-appropriate. Pool aerobics can be helpful if walking is difficult due to joint pain or neuropathy. Physical therapists can often make house calls and perform physical therapy at your home. Finally, if you have had a heart attack, cardiac rehab is very helpful and a good way to learn healthy exercise habits in a monitored setting. Not only can physical activity help you maintain balance, it may help slow some of the cognitive decline seen with aging. You may have tooth loss or other dental issues, or trouble with grocery shopping or cooking. Weigh yourself once a week and report any trends of gain or loss to your health-care provider. Meet with a diabetes nutrition expert to learn how to adjust your meal plan, if needed, as you age. Cognitive impairment can make it more difficult to match carbs to insulin doses, leading to fluctuating blood glucose levels.

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Increasingly medications with gluten purchase clozaril 50mg fast delivery, as list prices and overall cost of care continue to treatment medical abbreviation order generic clozaril pills rise symptoms in dogs buy clozaril american express, consumers are shouldering a greater portion in the form of out-of-pocket costs medicine 3604 order 50 mg clozaril amex. A zero out-of-pocket diabetes solution can eliminate cost as a barrier, encouraging people with diabetes to fill their prescriptions and be more adherent, improving health outcomes. Our analysis clearly shows such a solution will not raise, and may even help lower, overall costs for payors without the perceived trade-off with deductibles and premiums. In this white paper, we explore the range of challenges that the diabetes epidemic creates for individuals and payors, and highlight some approaches and solutions that can help address this national crisis. Diabetes causes tremendous morbidity, mortality and suffering for the more than 30 million Americans diagnosed with the condition, and strains the ability of the health care system to shoulder the costs. It is estimated that the number of adults living with diabetes has doubled over the past two decades. From a managed care standpoint, one critical element to improve outcomes for people with diabetes is making sure they can afford their medications. While cost share can range substantially, members who use brand antidiabetic medication spent an average of $467 out-of-pocket annually. As a result, their adherence to the care plan suffers, leading to the development of comorbidities and a worsening of their overall condition. Health services research has shown that in large populations of study subjects, higher out-of-pocket costs lead to lower adherence and poor health outcomes. Such programs could also lead to cost savings for payors - insurers or self-insured employers - because better adherence improves health outcomes and therefore lowers overall medical costs. The first step should always be prevention and counseling, especially regarding diet, exercise, and a healthy lifestyle to help prevent individuals from advancing to diabetes and needing treatment. Once a person progresses to requiring medication therapy, it is important to ensure affordability and accessibility. In the past, the focus of the discussion around affordability for diabetes medication has been on insulin. Of all those diagnosed with diabetes, about 5 percent have type 1 diabetes, and for them, insulin is the cornerstone of therapy. Any discussion of affordability should include the entire range of diabetes treatments. For people living with type 1 diabetes, treatment starts with insulin delivered either through multiple daily injections or continuously through an insulin pump. However, some people with diabetes cannot achieve their target glucose level, measured as hemoglobin A1C, on metformin alone. All three drug classes have several clinically equivalent alternatives that help treat elevated blood sugar levels, and can also prevent further development of heart disease, kidney disease, and congestive heart failure. Our analysis reveals that client pre-rebate spend for members taking antidiabetic medications was just over $2,744 for 2018. They are responsible for the full cost of the medication until their deductible is met, because rebates typically go back to the payor - employer or insurer - not the member. However, a majority of clients opt to keep rebates at the plan level to help lower one of the several other key parameters of affordability for their employees or members: premiums, deductibles and coinsurance/copays. The result of non-adherence is worse health outcomes for members with diabetes, and higher medical costs for the payor from avoidable downstream adverse events. Some choose to adopt higher deductibles in order to offer a lower overall premium. This benefits members who do not have a chronic condition and do not need ongoing medication treatment. But for those with a condition like diabetes - and possible comorbidities - it can lead to higher out-of-pocket costs. This is the central conundrum of plan design - the choice between higher premiums for everyone, or higher costs for a segment of the population. Our solution can help lower out-of-pocket costs for members with diabetes without increasing other costs such as premiums or deductibles for all plan members. As we discussed, the average post-rebate cost of diabetes to a plan is $1,256 per year for every member taking an antidiabetic medication. Research shows that eliminating out-of-pocket costs for members, improves adherence. Based on published findings, this increase in adherence costs the client an additional $51 per member per year. This incremental plan cost can be offset in two steps: 1 Clients can save $170 per member per year by adopting our most cost-conscious, genericsfocused, Value Formulary. Plan sponsors can also save money in overall medical costs because higher adherence - as a result of lower out-of-pocket costs - improves member health. Our Pharmacy Care Economic Model reveals that for each member with diabetes, who goes from non-adherent status to adherent, client health care costs drop by $2,202 per year. Applying these values to the entire member population, we estimate the value to the plan in improved adherence and lower medical costs is $156 per member per year. While this is not a huge amount of savings, it means clients can help their members better afford their medication and improve health outcomes without raising premiums or deductibles. As we noted, average out-of-pocket cost for a member with at least one brand medication is $467 per year, and 12 percent of those spend more than $1,000 annually on all diabetes medication. Many people have much higher out-of-pocket costs - into the thousands of dollars. Some of those people face the quiet desperation of not being able to afford the medications they know they need. One point that deserves reiteration is that this program covers all medications used to treat diabetes, not just insulin. For too long the focus has been on insulin only, ignoring the fact that members may face the same challenge with out-of-pocket costs for other brand diabetes medications. Fewer Trade-Offs for Plans and Members the critical difference between this program and other proposed solutions is its comprehensiveness: there are no member out-of-pocket costs for any diabetes medication, not just insulin. Our solution takes away the need for members with diabetes to make difficult decisions about whether they can afford their medications. As our analysis demonstrates, it can also contain or even lower costs for payors, without the perceived trade-off they had to make before of deductibles and premiums. Plan designs vary from client to client - there is no such thing as an "average" payor. Our zero out-of-pocket solution will work somewhat differently for payors depending on their current plan design and member population. Our research suggests that payors with more lower-income members will see a greater positive impact from this program, simply because for those members out-of-pocket costs for medications are likely to represent a greater portion of their earnings and so pose a greater barrier. In addition, payors with members whose overall adherence is rather low will also see a higher benefit. Alternatively, payors with higher-paid employees, and whose adherence is high, may see a small overall increase in costs. We anticipate that many of our clients will be interested in exploring and using it. To do this, in addition to ensuring members can afford their medications, we also provide holistic clinical support to help members effectively manage their condition. They can also help people living with diabetes - especially type 2 - get started on the appropriate pharmacological regimen, either metformin or insulin, as applicable. Our clinicians have access to electronic health record systems with clinical decision support to assist in diabetes management. Our clinicians can also monitor for potential complications or adverse events, offer annual health check-ups for people with diabetes, including screening for diabetic retinopathy, nephropathy and peripheral neuropathy, and provide targeted support and interventions. They can help people with diabetes better manage their condition with connected blood glucose monitors and interpret the results in partnership with their primary care providers, and train them on how to administer insulin. How Patient Cost-Sharing Trends Affect Adherence and Outcomes: A Literature Review. Medication adherence leads to lower health care use and costs despite increased drug spending. Based on 2018 claims for a representative group of 330 commercial clients who have not adopted a preventive drug list. Adherence results may vary based upon a variety of factors such as plan design, demographics and programs adopted by the plan. Savings will vary based upon a variety of factors including things such as plan design, demographics and programs implemented by the plan.

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Younger age medications online cheap clozaril master card, lower HbA1c levels medications grapefruit interacts with clozaril 100 mg for sale, antecedent exercise and hypoglycemia are associated with a greater frequency of nocturnal hypoglycemia treatment xyy order 100mg clozaril amex. Hence medicine 02 order clozaril 100mg line, extra snacks may be unnecessary145 and enforcing prebed meals may contribute to nocturnal hyperglycemia and/or additional calories contributing to weight gain. The recommendation for inclusion of prebed meals should be individually tailored and not mandatory. Pump therapy is associated with less nocturnal hypoglycemia and this is further reduced with the availability of sensor-augmented pump therapy with control algorithms which suspend basal insulin with sensor-detected8 or sensor-predicted hypoglycemia. In adults, 20 g of carbohydrate in the form of glucose tablets raised glucose levels by approximately 2. Intranasal glucagon is now being developed as a needle-free device that delivers glucagon for the treatment of severe hypoglycemia. A single dose of 3 mg can be used in children and adults with type 1 diabetes, which would potentially simplify prescription across the entire age range (4 years) of patients with type 1 diabetes. Intravenous glucose should be administered by trained personnel over several minutes to reverse hypoglycemia. The recommended dose is glucose 10% to 20%, for a total of 200 to 500 mg/kg of glucose. Rapid administration or excessive concentration (ie, glucose 50%) may result in an excessive rate of osmotic change with risk of hyperosmolar cerebral injury. In the outpatient setting, the predisposing events that led to the severe event should be evaluated to allow for prevention of future events. Caregivers need to be aware that following a severe hypoglycemic event, the child will be at significantly higher risk of a future event and alterations to therapy may be appropriate. In countries where neither glucagon nor glucose gel may be available; a powder form (glucose D 25 or anhydrous glucose) is used. Sugar or any other powdery substance or thin liquids like a glucose solution or honey should not be given forcibly to the semi/unconscious child. The child should be put in a lateral position to prevent aspiration and a thick paste of glucose (glucose powder with a few drops of water or table sugar crushed into powdered sugar with consistency of thick cake icing) smeared onto the dependent cheek pad; the efficacy of this practice is anecdotal. Although an earlier study in healthy adult volunteers demonstrated poor buccal absorption of glucose,160 sublingual glucose was found to be a child-friendly and effective method of raising blood glucose in severely ill children with malaria. In general, the initial therapy with rapidly acting carbohydrate is followed with a serve (eg, 15 g) of slower-acting carbohydrate, such as bread, milk, biscuits, or fruit. However, this is not always required, particularly for those on insulin pump therapy. Essentially, it is important to remember that the amount of carbohydrate required will depend on the size of the child, type of insulin therapy, active insulin on board, the timing and intensity of antecedent exercise, and other factors. Chocolate, milk, and other foods containing fat will cause the glucose to be absorbed more slowly and should be avoided as the initial treatment of hypoglycemia. Commercially available glucagon rescue kits include GlucaGen HypoKit 1 mg (Novo NordiskA/S, Bagsvaerd, Denmark) and Glucagon Emergency Rescue Kit (Eli Lilly and Company, Indianapolis, Indiana). The recommended glucagon dosing is weight based: 1 mg for adults and children >25 kg and 0. Glucagon often induces nausea and vomiting on regaining consciousness and hence it is important to continue close observation and glucose monitoring after treatment. If blood glucose failed to rise over the first 30 minutes, a repeat injection was given using twice the initial dose. The efficacy of glucagon is also dependent on the glycogen stores in the liver and hence would be predicted to be less efficacious in cases of prolonged fasting and parenteral glucose would be the therapy of choice. Although most systems are single-hormone insulin, dualhormone systems (bionic pancreas) that infuse both insulin and glucagon have also been studied in clinical trials. Sensor-augmented pump therapy with low glucose suspension (suspend on low) the incorporation of algorithms in sensor-augmented pump therapy further reduces the time spent in hypoglycemia due to pump suspension. In the absence of patient interference, following pump suspension, the insulin infusion resumes after a maximum suspend period of 2 hours or earlier if the auto-resumption parameters are met. There was also no deterioration of glycemic control with the use of the system in a 6 month randomized controlled home trial. Closed-loop systems Automated insulin delivery, with continuous glucose sensing and insulin delivery without patient intervention, offers the potential to circumvent the significant glycemic excursions associated with conventional therapy. Severe hypoglycemia rates are not associated with HbA1c: a cross-sectional analysis of 3 contemporary pediatric diabetes registry databases. Improved biomedical and psychological outcomes 1 year after structured education in flexible insulin therapy for people with type 1 diabetes: the U. Reduction in hypoglycemia with the predictive low-glucose management system: a long-term randomized controlled trial in adolescents with type 1 diabetes. Prevention of hypoglycemia with predictive low glucose insulin suspension in children with type 1 diabetes: a randomized controlled trial. Effect of sensor-augmented insulin pump therapy and automated insulin suspension vs standard insulin pump therapy on hypoglycemia in patients with type 1 diabetes: a randomized clinical trial. Hypoglycaemia, fear of hypoglycaemia and quality of life in children with type 1 diabetes and their parents. Assessment and monitoring of glycemic control in children and adolescents with diabetes. The Australasian diabetes data network: first national audit of children and adolescents with type 1 diabetes. Hemoglobin A1c levels and risk of severe hypoglycemia in children and young adults with type 1 diabetes from Germany and Austria: a trend analysis in a cohort of 37,539 patients between 1995 and 2012. Reducing rates of severe hypoglycemia in a population-based cohort of children and adolescents with type 1 diabetes over the decade 2000-2009. A population-based study of risk factors for severe hypoglycaemia in a contemporary cohort of childhood-onset type 1 diabetes. Defining relevant hypoglycemia measures in children and adolescents with type 1 diabetes. Effect of intensive insulin therapy on glycemic thresholds for counterregulatory hormone release. Plasma glucose concentrations at the onset of hypoglycemic symptoms in patients with poorly controlled diabetes and in nondiabetics. Hierarchy of glycemic thresholds for counterregulatory hormone secretion, symptoms, and cerebral dysfunction. Glycemic thresholds for activation of glucose counterregulatory systems are higher than the threshold for symptoms. Contemporary rates of severe hypoglycaemia in youth with type 1 diabetes: variability by insulin regimen. Temporal trends in the treatment of pediatric type 1 diabetes and impact on acute outcomes. The impact of a decade of changing treatment on rates of severe hypoglycemia in a population-based cohort of children with type 1 diabetes. Glycated hemoglobin A1c as a risk factor for severe hypoglycemia in pediatric type 1 diabetes. Incidence of severe hypoglycemia in children with type 1 diabetes in the Nordic countries in the period 2008-2012: association with hemoglobin A1c and treatment modality. Prevalence and predictors of severe hypoglycemia in Danish children and adolescents with diabetes. Confirmation of hypoglycemia in the "dead-in-bed" syndrome, as captured by a retrospective continuous glucose monitoring system. Cardiac autonomic regulation and repolarization during acute experimental hypoglycemia in type 2 diabetes. Diurnal differences in risk of cardiac arrhythmias during spontaneous hypoglycemia in young people with type 1 diabetes. Risk of and risk factors for hypoglycemia and associated arrhythmias in patients with type 2 diabetes and cardiovascular disease: a cohort study under real-world conditions. Acute complications and drug misuse are important causes of death for children and young adults with type 1 diabetes: results from the Yorkshire register of diabetes in children and young adults. Long-term mortality in a nationwide cohort of childhood-onset type 1 diabetic patients in Norway. Excess all-cause mortality before age 30 in childhood onset type 1 diabetes: data from the Brecon group cohort in Wales.

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Epidemiological evidence for the association of hyperglycaemia and atherosclerotic vascular disease in 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 81 Part 1 Diabetes in its Historical and Social Context non-insulin-dependent diabetes mellitus medicine dispenser order on line clozaril. Garattini L medications used for adhd cheap 100mg clozaril, Tediosi F medicine 5443 order genuine clozaril, Chiaffarino F medications prolonged qt buy clozaril, Roggeri D, Parazzini F, Coscelli C; Gruppo di Studio R. Expenditure on health care incurred by diabetic subjects in a developing country: a study from southern India. Health insurance status, cost-related medication underuse, and outcomes among diabetes patients in three systems of care. The prevalence and cost of diabetes in metropolitan France: what trends between 1998 and 2000? Reductions in individual work productivity associated with type 2 diabetes mellitus. Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function. Is diabetes associated with cognitive impairment and cognitive decline among older women? Health economic benefits and quality of life during improved glycemic control in patients with type 2 diabetes mellitus: a randomized, controlled, double-blind trial. Addressing the needs of patients with multiple chronic illnesses: the case of diabetes and depression. The burden of mortality attributable to diabetes: realistic estimates for the year 2000. Relationship between diabetes and mortality: a population study using record linkage. Associations of diabetes mellitus with total life expectancy and life 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 82 the Global Burden of Diabetes Chapter 5 expectancy with and without cardiovascular disease. Socioeconomic position and health among persons with diabetes mellitus: a conceptual framework and review of the literature. Excess costs of medical care for patients with diabetes in a managed care population. The Economics of Diabetes and Diabetes Care: a report of Diabetes Health Economics Study Group. Commissioned by the National Changing Diabetes Program, a program of Novo Nordisk, Inc. Paper presented at: Innovation in Health Care: the Economics of Diabetes; in Population Health Management (Mary Ann Liebert Inc. Paper presented at: Proceedings of the Novo Nordisk Diabetes Update, Bangalore, 2000. Graph: Treatment with insulin or oral medication among adults with diagnosed diabetes, United States, National Health Interview Survey, 2004 to 2006. Increasing expenditure on health care incurred by diabetic subjects in a developing country: a study from India. Economic consequences of epidemiological changes in diabetes in middle-income countries: the Mexican case. The obesitydriven rising costs of type 2 diabetes in Australia: projections from the Fremantle Diabetes Study. Introduction the German anatomy student Paul Langerhans first described in 1869 the "islands of clear cells" distributed throughout the pancreas [1] but he did not realize the physiologic significance of these cell clusters, which are today known as islets of Langerhans. We now know that islets are the endocrine compartment of the pancreas, comprising around 2­3% of the total pancreatic volume. Islet structure and function Islet anatomy A typical mammalian islet comprises several thousand endocrine cells including the insulin-expressing -cells (60% of adult human islet cells), glucagon-expressing -cells (20­30%), somatostatin-expressing -cells (10%), pancreatic polypeptideexpressing cells (<5%), and ghrelin-expressing cells (1%). In rodents, the majority -cell population forms a central core surrounded by a mantle of -cells and -cells (Figure 6. Islets are highly vascularized, and receive up to 15% of the pancreatic blood supply despite accounting for only 2­3% of the total pancreatic mass. Each islet is served by an arteriolar blood supply that penetrates the mantle to form a capillary bed in the islet core. Earlier studies using vascular casts of rodent islets suggested that the major route of blood flow through an islet was from the inner -cells to the outer and -cells [3], but more recent studies using optical imaging of fluorescent markers to follow islet blood flow in vivo [4] reveal more complex patterns of both inner-to-outer and top-to-bottom blood flow through the rodent islet. Islets are well supplied by autonomic nerve fibers and terminals containing the classic neurotransmitters acetylcholine and norepinephrine, along with a variety of biologically active neuropeptides [5]. The anatomic organization of the islet has a profound influence on the ability of the -cells to recognize and respond to physio- 87 Part 2 Normal Physiology (a) (b) (c) Figure 6. The figure shows a section through a mouse pancreas in which insulin and glucagon are identified by red and green immunofluorescence, respectively, demonstrating the typical -cell core surrounded by a thin mantle of -cells. The figure shows a section through a human pancreas in which insulin and glucagon are identified by red and green immunofluorescence respectively, demonstrating the less organized structure of the human islet when compared with mouse islets. The figure shows a transmission electron micrograph of several cells within a human islet. The two cells in the top left with the electron dense secretory granules surrounded by a clear halo are -cells. There are a number of mechanisms through which islet cells can communicate, although the relative importance of the different mechanisms is still uncertain [10]. Islet cells are functionally coupled through a network of gap junctions, and gene deletion studies in mice have highlighted the importance of gap-junctional coupling via connexin 36 in the regulation of insulin secretory responses [11,12]. Cell­cell contact through cell surface adhesion molecules offers an alternative communication mechanism, and interactions mediated by E-cadherin [13,14] or ephrins [15] have been implicated in the regulation of -cell function. A further level of control can be exerted via intra-islet paracrine and autocrine effects in which a biologically active substance released by one islet cell can influence the functional status of a neighboring cell (paracrine), or of itself (autocrine). Thus, islet cells can interact with each other via the classic islet hormones ­ insulin, glucagon and somatostatin [16­19]; via other products secreted by the endocrine cells, such as neurotransmitters or adenine nucleotides and divalent cations that are co-released with insulin [20­23]; and via other less well-known mechanisms, including the generation of gaseous signals such as nitric oxide and carbon monoxide [24­27]. The wide range of intra-islet interactions presumably reflects the requirement for fine-tuning and coordinating secretory responses of many individual islet cells to generate the rate and pattern of hormone secretion appropriate to the prevailing physiologic conditions. Insulin biosynthesis and storage the ability to release insulin rapidly in response to metabolic demand, coupled with the relatively slow process of producing polypeptide hormones, means that -cells are highly specialized for the production and storage of insulin, to the extent that insulin comprises approximately 10% (10 pg/cell) of the total -cell protein. Biosynthesis of insulin In humans, the gene encoding preproinsulin, the precursor of insulin, is located on the short arm of chromosome 11 [28]. It is 1355 base pairs in length and its coding region consists of three exons: the first encodes the signal peptide at the N-terminus of preproinsulin, the second the B chain and part of the C (connecting) peptide, and the third the rest of the C peptide and the A chain (Figure 6. The cellular processes and approximate timescales involved in insulin biosynthesis, processing and storage are summarized in Figure 6. Preproinsulin is rapidly (<1 min) discharged into the cisternal space of the rough endoplasmic reticulum, where proteolytic enzymes immediately cleave the signal peptide, generating proinsulin. Proinsulin is a 9-kDa peptide, containing the A and B chains of insulin (21 and 30 amino acid residues, respectively) joined by the C peptide (30­35 amino acids). The heterogeneous nature and complex anatomy of the islet enables numerous interactions between islet cells that are mediated by the release of biologically active molecules. Proinsulin is transported in microvesicles to the Golgi apparatus, where it is packaged into membrane-bound vesicles known as secretory granules. The conversion of proinsulin to insulin is initiated in the Golgi complex and continues within the maturing secretory granule through the sequential action of two endopeptidases (prohormone convertases 2 and 3) and carboxypeptidase H [29], which remove the C peptide chain, liberating two cleavage dipeptides and finally yielding insulin (Figure 6. Insulin and C peptide are stored together in the secretory granules and are ultimately released in equimolar amounts by a process of regulated exocytosis. Under normal conditions, >95% of the secreted product is insulin (and C peptide) and <5% is released as proinsulin. However, the secre- 89 Part 2 Normal Physiology Molecular stages Reduced unfolded preproinsulin S-S bond formation, proinsulin folding Cellular events Preproinsulin synthesis and cleavage to proinsulin (10­20 min) Rough endoplasmic reticulum Organelles Microvesicles Formation of Znproinsulin hexamers Zn-insulin hexamer with released C peptide. Precipitation begins Transfer (20 min) Golgi apparatus Proinsulin conversion begins Conversion completed (30­120 min) Secretory granules Late Early Crystal formation Storage (for hours­days) Mature granules Release by exocytosis Figure 6. The molecular folding of the proinsulin molecule, its conversion to insulin and the subsequent arrangement of the insulin hexamers into a regular pattern are shown at the left. The time course of the various processes, and the organelles involved are also shown. The -cell responds to increases in the circulating concentrations of nutrients by increasing insulin production in addition to increasing insulin secretion, thus maintaining insulin stores [30]. There is a sigmoidal relationship between glucose concentrations and biosynthetic activity, with a threshold glucose level of 2­4 mmol/L. This is slightly lower than the threshold for the stimulation of insulin secretion (5 mmol/L), which ensures an adequate reserve of insulin within the -cell.

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THE BLUEGRASS SPECIAL
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