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1.  Effect of a Brief Video Intervention on Incident Infection among Patients Attending Sexually Transmitted Disease Clinics  
PLoS Medicine  2008;5(6):e135.
Background
Sexually transmitted disease (STD) prevention remains a public health priority. Simple, practical interventions to reduce STD incidence that can be easily and inexpensively administered in high-volume clinical settings are needed. We evaluated whether a brief video, which contained STD prevention messages targeted to all patients in the waiting room, reduced acquisition of new infections after that clinic visit.
Methods and Findings
In a controlled trial among patients attending three publicly funded STD clinics (one in each of three US cities) from December 2003 to August 2005, all patients (n = 38,635) were systematically assigned to either a theory-based 23-min video depicting couples overcoming barriers to safer sexual behaviors, or the standard waiting room environment. Condition assignment alternated every 4 wk and was determined by which condition (intervention or control) was in place in the clinic waiting room during the patient's first visit within the study period. An intent-to-treat analysis was used to compare STD incidence between intervention and control patients. The primary endpoint was time to diagnosis of incident laboratory-confirmed infections (gonorrhea, chlamydia, trichomoniasis, syphilis, and HIV), as identified through review of medical records and county STD surveillance registries. During 14.8 mo (average) of follow-up, 2,042 patients (5.3%) were diagnosed with incident STD (4.9%, intervention condition; 5.7%, control condition). In survival analysis, patients assigned to the intervention condition had significantly fewer STDs compared with the control condition (hazard ratio [HR], 0.91; 95% confidence interval [CI], 0.84 to 0.99).
Conclusions
Showing a brief video in STD clinic waiting rooms reduced new infections nearly 10% overall in three clinics. This simple, low-intensity intervention may be appropriate for adoption by clinics that serve similar patient populations.
Trial registration: http://www.ClinicalTrials.gov (#NCT00137670).
In a controlled trial at three urban STD clinics, Lee Warner and colleagues find that showing an educational video in waiting rooms reduced new infections by approximately 10%.
Editors' Summary
Background.
In the US alone there are 19 million new cases of sexually transmitted diseases (STDs) every year. STDs are infections that pass between people during sexual activity (through semen, vaginal fluids, blood, or skin-to-skin contact). Some STDs are caused by bacteria (for example, chlamydia, gonorrhea, and syphilis). Others are caused by parasites (for example, trichomoniasis) or viruses (for example, herpes simplex virus and HIV). Symptoms vary among STDs but may include sores, unusual lumps and itching in the genital region, pain when urinating, and unusual genital discharge. While symptoms are generally more common in men than women, many STDs cause no symptoms. Untreated STDs are more serious for women and may include pelvic inflammatory disease (PID), ectopic pregnancy, infertility, and chronic pain. Bacterial and parasitic STDs can be cured with various drugs; STDs caused by viruses cannot be cured although they can be treated with antiviral drugs.
Why Was This Study Done?
Several interventions have been developed to educate people at risk of infection about risky sexual behavior and to teach them the personal skills needed to avoid unsafe sex (for example, negotiation skills that help them persuade their partner to use a condom). Although these interventions reduce the incidence of STDs, they usually involve several sessions of individual or group counseling and are likely too complex and expensive to implement in busy STD clinics. In this study, the researchers ask whether a short video that contains key STD prevention messages can reduce the acquisition of new infections among patients who watch the video while sitting in the waiting room of an STD clinic (a “teachable moment” when people are likely to be receptive to messages about health risks).
What Did the Researchers Do and Find?
The researchers developed a 23-minute soap-opera style video—“Safe in the City”—that contained three interwoven dramas about young people in various types of relationships negotiating safer sexual behavior, and two animation segments about condoms. The researchers showed this video (and displayed related posters) in the waiting rooms of three US publicly funded STD clinics every alternate month over a 20-month period. Nearly 20,000 patients were exposed to this intervention. Another 20,000 “control” patients who attended the clinics in the months when the video was not shown were exposed to a standard waiting room environment in which only leaflets about STDs and condoms were available. The researchers then reviewed medical records and STD surveillance registries to find out how many patients in each group developed laboratory-confirmed STD after their initial clinic visit. Their statistical analyses show that the intervention reduced the number of new STD diagnoses by nearly 10%. The intervention was most effective among patients who had had an STD at their first visit and among men, but did not appear to reduce the chances of women acquiring an STD.
What Do These Findings Mean?
These findings suggest that showing a brief, carefully designed video in STD clinic waiting rooms might be a simple, effective way to reduce the incidence of STDs. More research is needed to discover which parts of the video—those that increase knowledge and perception of STD risk, those that promote positive attitudes toward condom use, or those that provide the necessary skills to negotiate safe sexual practices—are the most effective and why the video appeared to be more effective for some groups of patients than others. The intervention also needs to be tested in other types of clinics but if it works as well elsewhere as in the three study clinics, the widespread implementation of this low-cost, low-intensity waiting room intervention could produce a meaningful reduction in the incidence of STDs in the US and elsewhere.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050135.
Information is available from Avert, an international AIDS charity, on sexually transmitted diseases
The US Centers for Disease Control and Prevention provides detailed information about sexually transmitted diseases, including information about STD prevention (in English and Spanish)
MedlinePlus also provides a list of links to information about sexually transmitted diseases (in English and Spanish)
The MedlinePlus encyclopedia has a page on safe sex (in English and Spanish)
The Safe in the CIty Study Group has a project-specific Web site that provides additional details about the intervention and a mechanism for ordering the video
doi:10.1371/journal.pmed.0050135
PMCID: PMC2504047  PMID: 18578564
2.  Defective Awakening Response to Nocturnal Hypoglycemia in Patients with Type 1 Diabetes Mellitus 
PLoS Medicine  2007;4(2):e69.
Background
Nocturnal hypoglycemia frequently occurs in patients with type 1 diabetes mellitus (T1DM). It can be fatal and is believed to promote the development of the hypoglycemia-unawareness syndrome. Whether hypoglycemia normally provokes awakening from sleep in individuals who do not have diabetes, and whether this awakening response is impaired in T1DM patients, is unknown.
Methods and Findings
We tested two groups of 16 T1DM patients and 16 healthy control participants, respectively, with comparable distributions of gender, age, and body mass index. In one night, a linear fall in plasma glucose to nadir levels of 2.2 mmol/l was induced by infusing insulin over a 1-h period starting as soon as polysomnographic recordings indicated that stage 2 sleep had been reached. In another night (control), euglycemia was maintained.
Only one of the 16 T1DM patients, as compared to ten healthy control participants, awakened upon hypoglycemia (p = 0.001). In the control nights, none of the study participants in either of the two groups awakened during the corresponding time. Awakening during hypoglycemia was associated with increased hormonal counterregulation. In all the study participants (from both groups) who woke up, and in five of the study participants who did not awaken (three T1DM patients and two healthy control participants), plasma epinephrine concentration increased with hypoglycemia by at least 100% (p < 0.001). A temporal pattern was revealed such that increases in epinephrine in all participants who awakened started always before polysomnographic signs of wakefulness (mean ± standard error of the mean: 7.5 ± 1.6 min).
Conclusions
A fall in plasma glucose to 2.2 mmol/l provokes an awakening response in most healthy control participants, but this response is impaired in T1DM patients. The counterregulatory increase in plasma epinephrine that we observed to precede awakening suggests that awakening forms part of a central nervous system response launched in parallel with hormonal counterregulation. Failure to awaken increases the risk for T1DM patients to suffer prolonged and potentially fatal hypoglycemia.
A study of 16 patients with type 1 diabetes and 16 healthy participants showed that the normal awakening response provoked by a fall in plasma glucose was impaired in diabetic individuals.
Editors' Summary
Background.
Hypoglycemia (low blood sugar) is a frequent complication of insulin-treated diabetes, affecting patients with type 1 diabetes mellitus in particular. In individuals who do not have diabetes, insulin secretion is modified naturally and continuously by the body's own regulatory systems, depending on the blood sugar. However, in diabetes patients there is a lack of natural insulin and so manufactured insulin has to be given by injection after blood sugar testing. Hence, it is not possible for patients with diabetes to modify insulin secretion naturally in response to a change in glucose levels, and so blood glucose levels can rise and fall beyond healthy levels. In individuals who have intensive insulin therapy, hypoglycemia can be a particular problem; each year about 25% of patients on intensive insulin therapy have at least one episode of severe hypoglycemia—which requires the assistance of another person.
When hypoglycemia occurs during the day, diabetes patients can recognize it by a variety of symptoms, e.g., feeling sweaty and lightheaded, and they may either seek help from another person or treat themselves with sugar. Hypoglycemia during sleep may be very common—it has been observed to occur in up to half of the nights when patients with diabetes were monitored. The particular problem with hypoglycemia occurring during sleep is that diabetes patients may not be aware of it and hence may not be able to treat themselves or to seek assistance. It is believed to contribute to some instances of sudden death during sleep in patients with diabetes.
Why Was This Study Done?
It has not been clear whether there is a certain level of blood glucose below which a signal is triggered that provokes awakening from sleep in either diabetes patients or in individuals who do not have diabetes. The authors of this study wanted to compare responses to lowered blood glucose in diabetes patients and in individuals who do not have diabetes and to see whether the responses differed. They also wanted to look at whether there were any other hormonal changes that preceded or followed awakening after hypoglycemia.
What Did the Researchers Do and Find?
They treated two groups; 16 type 1 diabetes mellitus patients and 16 healthy control participants. With careful monitoring, on one night once stage 2 sleep (as measured by a method known as polysomnography) had been reached, they gave insulin to lower the blood glucose to a specific level (2.2 mmol/l), which would when awake give symptoms of hypoglycemia. On another night (the control night) normal blood sugar levels were maintained.
They found that only one of the 16 diabetes patients, as compared to ten healthy control participants, woke when hypoglycemia occurred. In the control nights, none of the study participants in either of the two groups awakened during the corresponding time. Awakening during hypoglycemia was associated with substantial hormonal changes, especially with an increase in one hormone, epinephrine (also known as adrenaline), and the increases in this hormone occurred before polysomnographic signs of wakefulness.
What Do These Findings Mean?
It appears that patients with type 1 diabetes mellitus do not awake at a level of hypoglycemia that triggers waking in normal individuals. The hormonal responses that were seen in individuals who awoke may be part of a crucial response system to hypoglycemia. These results help us to understand how diabetes patients respond to hypoglycemia, but further work will need to be done to determine whether it is possible to improve the response. It should be noted, however, that the results are probably not generalizable to patients with type 2 diabetes mellitus, who represent the majority of patients with diabetes.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040069.
A related PLoS Medicine Perspective article by Ilan Gabriely and Harry Shamoon discusses this study and more about hypoglycemia in T1DM
MedlinePlus, the encyclopedia of health information from the US National Library of Medicine, has a collection of pages on hypoglycemia
Wikipedia pages on hypoglycemia (note that Wikipedia is a free online encyclopedia that anyone can edit)
National Diabetes Information Clearinghouse, a service of the US National Institute of Diabetes and Digestive and Kidney Diseases, has information on hypoglycemia
doi:10.1371/journal.pmed.0040069
PMCID: PMC1808097  PMID: 17326710
3.  Event Rates, Hospital Utilization, and Costs Associated with Major Complications of Diabetes: A Multicountry Comparative Analysis 
PLoS Medicine  2010;7(2):e1000236.
Philip Clarke and colleagues examined patient-level data for over 11,000 participants with type 2 diabetes from 20 countries and find that major complications of diabetes significantly increased hospital use and costs across settings.
Background
Diabetes imposes a substantial burden globally in terms of premature mortality, morbidity, and health care costs. Estimates of economic outcomes associated with diabetes are essential inputs to policy analyses aimed at prevention and treatment of diabetes. Our objective was to estimate and compare event rates, hospital utilization, and costs associated with major diabetes-related complications in high-, middle-, and low-income countries.
Methods and Findings
Incidence and history of diabetes-related complications, hospital admissions, and length of stay were recorded in 11,140 patients with type 2 diabetes participating in the Action in Diabetes and Vascular Disease (ADVANCE) study (mean age at entry 66 y). The probability of hospital utilization and number of days in hospital for major events associated with coronary disease, cerebrovascular disease, congestive heart failure, peripheral vascular disease, and nephropathy were estimated for three regions (Asia, Eastern Europe, and Established Market Economies) using multiple regression analysis. The resulting estimates of days spent in hospital were multiplied by regional estimates of the costs per hospital bed-day from the World Health Organization to compute annual acute and long-term costs associated with the different types of complications. To assist, comparability, costs are reported in international dollars (Int$), which represent a hypothetical currency that allows for the same quantities of goods or services to be purchased regardless of country, standardized on purchasing power in the United States. A cost calculator accompanying this paper enables the estimation of costs for individual countries and translation of these costs into local currency units. The probability of attending a hospital following an event was highest for heart failure (93%–96% across regions) and lowest for nephropathy (15%–26%). The average numbers of days in hospital given at least one admission were greatest for stroke (17–32 d across region) and heart failure (16–31 d) and lowest for nephropathy (12–23 d). Considering regional differences, probabilities of hospitalization were lowest in Asia and highest in Established Market Economies; on the other hand, lengths of stay were highest in Asia and lowest in Established Market Economies. Overall estimated annual hospital costs for patients with none of the specified events or event histories ranged from Int$76 in Asia to Int$296 in Established Market Economies. All complications included in this analysis led to significant increases in hospital costs; coronary events, cerebrovascular events, and heart failure were the most costly, at more than Int$1,800, Int$3,000, and Int$4,000 in Asia, Eastern Europe, and Established Market Economies, respectively.
Conclusions
Major complications of diabetes significantly increase hospital use and costs across various settings and are likely to impose a high economic burden on health care systems.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Worldwide, nearly 250 million people have diabetes, and this number is increasing rapidly. Diabetes is characterized by dangerous amounts of sugar (glucose) in the blood. Blood sugar levels are normally controlled by insulin, a hormone produced by the pancreas. Blood sugar control fails in people with diabetes because they make no insulin (type 1 diabetes) or, more commonly, because the fat and muscle cells that usually respond to insulin by removing excess sugar from the blood have become insulin insensitive (type 2 diabetes). Type 2 diabetes can be prevented and controlled by eating a healthy diet and exercising regularly. It can also be treated with drugs that help the pancreas make more insulin or that increase insulin sensitivity. Major long-term complications of diabetes include kidney failure and an increased risk of cardiovascular problems such as heart attacks, heart failure, stroke, and problems with the blood vessels in the arms and legs. Because of these complications, the life expectancy of people with diabetes is about ten years shorter than that of people without diabetes.
Why Was This Study Done?
Diabetes imposes considerable demands on health care systems but little is known about the direct medical costs associated with treating this chronic disease in low- and middle-income countries where more than three-quarters of affected people live. In particular, although estimates have been made of the overall resources devoted to the treatment of diabetes, very little is known about how the different long-term complications of diabetes contribute to health care costs in different countries. Public-health experts and governments need this information to help them design effective and sustainable policies for the prevention and treatment of diabetes. In this study, the researchers estimate the resource use associated with diabetes-related complications in three economic regions using information collected in the Action in Diabetes and Vascular Disease (ADVANCE) study. This multinational clinical trial is investigating how drugs that control blood pressure and blood sugar levels affect the long-term complications of diabetes.
What Did the Researchers Do and Find?
The researchers recorded diabetes-related complications, hospital admissions for these complications, and length of hospital stays in 11,140 patients with severe diabetes from 20 countries who participated in the ADVANCE study. They used “multiple regression analysis” to estimate the number of days spent in hospital for diabetes-related complications in Asia, Eastern Europe, and the Established Market Economies (Canada, Australia, New Zealand, and several Western European countries). Finally, they calculated the economic costs of each complication using regional estimates of the costs per bed-day from the World Health Organization's CHOICE project (CHOosing Interventions that are Cost Effective). Nearly everyone in the study who developed heart failure attended a hospital, but only 15%–26% of people attended a hospital for kidney problems. The chances of hospitalization for any complication were lowest in Asia and highest in the Established Market Economies; conversely, lengths of stay were longest in Asia and shortest in the Established Market Economies. Finally, the estimated annual hospital costs for patients who had a coronary event, stroke, or heart failure were more than Int$1,800, Int$3,000, and Int$4,000 in Asia, Eastern Europe, and the Established Market Economies, respectively (the international dollar, Int$, is a hypothetical currency that has the same purchasing power in all countries), compared to Int$76, Int$156, and Int$296 for patients who experienced none of these events.
What Do These Findings Mean?
Because the ADVANCE trial had strict entry criteria, the findings of this study may not be generalizable to the broader population of people with diabetes. Nevertheless, given the lack of information about the costs associated with diabetes-related complications in low- and middle-income countries, these findings provide important new information about the patterns of hospital resource use and costs in these countries. Specifically, these findings show that the major complications of diabetes greatly increase hospital use and costs in all three economic regions considered and impose a high economic burden on health care systems that is likely to increase as the diabetes epidemic develops. Importantly, these findings should help policy makers anticipate the future health care costs associated with diabetes and should help them evaluate which therapies aimed at preventing diabetes-related complications will reduce these costs most effectively.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000236.
The International Diabetes Federation provides information about all aspects of diabetes
The US National Diabetes Information Clearinghouse provides detailed information about diabetes for patients, health care professionals, and the general public (in English and Spanish)
The UK National Health Service also provides information for patients and caregivers about type 2 diabetes (in several languages)
Information about the ADVANCE study is available
The World Health Organization's CHOICE Web site provides information about the analysis of the cost effectiveness of health care interventions
doi:10.1371/journal.pmed.1000236
PMCID: PMC2826379  PMID: 20186272
4.  Delay in Seeking Care for Sexually Transmitted Diseases in Young Men and Women Attending a Public STD Clinic 
The Open AIDS Journal  2013;7:7-13.
Background:
Delay in seeking care for sexually transmitted diseases (STDs) has adverse consequences for both the individual and population. We sought to identify factors associated with delay in seeking care for STDs.
Methods:
Subjects included 300 young men and women (aged 15-24) attending an urban STD clinic for a new STD-related problem due to symptoms or referral for an STD screening. Subjects completed a structured interview that evaluated STD history, attitudes and beliefs about STDs, depression, substance use, and other factors possibly associated with delay. Delay was defined as waiting > 7 days to seek and obtain care for STDs.
Results:
Nearly one-third of participants delayed seeking care for > 7 days. Significant predictors for delay included self-referral for symptoms as the reason for visit (OR 5.3, 95% CI: 2.58 – 10.98), and the beliefs “my partner would blame me if I had an STD” (OR 2.44, 95% CI: 1.30 – 4.60) and “it’s hard to find time to get checked for STDs” (OR 3.62, 95% CI: 1.95 – 6.69), after adjusting for age, race, sex, and other factors. Agreeing with the statement “would use a STD test at home if one were available” was associated with a decrease in delay (OR 0.24, 95% CI: 0.09 – 0.60).
Conclusions:
Many young persons delay seeking care for STDs for a number of reasons. Strategies to improve STD care-seeking include encouragement of symptomatic persons to seek medical care more rapidly, reduction of social stigmas, and improved access to testing options.
doi:10.2174/1874613620130614002
PMCID: PMC3785038  PMID: 24078858
Delay; healthcare-seeking behavior; men; sexually transmitted diseases; symptoms; women.
5.  Feasibility of overnight closed-loop therapy in young children with type 1 diabetes aged 3–6 years: comparison between diluted and standard insulin strength 
Objective
To assess feasibility of overnight closed-loop therapy in young children with type 1 diabetes and contrast closed loop using diluted versus standard insulin strength.
Research design and methods
Eleven children (male 6; age range 3.75–6.96 years; glycated hemoglobin 60 (14) mmol/mol; body mass index SD score 1.0 (0.8); diabetes duration 2.2 (1.0) years, mean (SD); total daily dose 12.9 (10.6, 16.5) IU/day, median (IQR)) were studied at a clinical research facility on two occasions. In random order, participants received closed loop with diluted insulin aspart (CL_Dil; 20 IU/mL) or closed loop with standard aspart (CL_Std; 100 IU/mL) from 17:00 until 8:00 the following morning. Children consumed an evening meal at 17:00 (44 (12) gCHO) and an optional bedtime snack (6 (7) gCHO) identical on both occasions. Meal insulin boluses were calculated by standard pump bolus calculators. Basal rates on insulin pump were adjusted every 15 min as directed by a model-predictive-control algorithm informed by a real-time glucose sensor values.
Results
Mean plasma glucose was 122 (24) mg/dL during CL_Dil vs 122 (23) mg/dL during CL_Std (p=0.993). The time spent in the target glucose range 70–145 mg/dL was 83 (70, 100)% vs 72 (54, 81)% (p=0.328). Time above 145 mg/dL was 13 (0, 27)% vs 19 (10, 45)% (p=0.477) and time spent below 70 mg/dL was 0.0 (0.0, 1.4)% vs 1.4 (0.0, 11.6)% (p=0.161). One asymptomatic hypoglycemia below 63 mg/dL occurred in one participant during CL_Dil versus six episodes in five participants during CL_Std (p=0.09). Glucose variability measured by CV of plasma glucose tended to be reduced during CL_Dil (20% (13, 31) vs 32% (24, 42), p=0.075).
Conclusions
In this feasibility study, closed-loop therapy maintained good overnight glucose control with tendency towards reduced hypoglycemia and reduced glucose variability using diluted insulin.
Trial registration number
clinicaltrials.gov Identifier: NCT01557634.
doi:10.1136/bmjdrc-2014-000040
PMCID: PMC4265121  PMID: 25512874
Artificial Pancreas; Type 1; Child
6.  Paraneoplastic hypoglycemia in a patient with a malignant solitary fibrous tumor 
Summary
Hypoglycemia is a common medical emergency. It is the most frequent complication induced by anti-diabetic treatment. However, it can be observed in other conditions unrelated to diabetes such as insulinoma, autoimmune disorders, and neoplasia. Herein, we report the case of a rare cause of severe and recurrent hypoglycemia in a 77-year-old woman with a malignant solitary fibrous tumor (MSFT). A 77-year-old woman was admitted to the emergency department for loss of consciousness induced by severe hypoglycemia. Her standard laboratory findings were unremarkable. HbA1c, albumin, renal, liver, thyroid, and adrenal function tests were normal. Cerebral CT scan was also normal. At the time of confirmed hypoglycemia, the serum level of insulin and C-peptide was low. On the basis of the past medical history and the absence of other comment etiologies, a paraneoplastic cause was suspected. Thus, the diagnosis of a non-islet cell tumor-induced hypoglycemia (NICTH) was established by the presence of incompletely processed precursors of IGF2 (big IGF2) in plasma electrophoresis. However, the IGF1 level was low. Therapy with corticosteroids improved hypoglycemia and clinical symptoms. NICTH is a rare cause of hypoglycemia. It should be considered in patients with mesenchymal or malignant epithelial tumors suffering from recurrent episodes of hypoglycemia. The diagnosis will be established in the case of low serum insulin concentrations and elevated levels of big IGF2. Treatment with corticosteroids, GH, or both can improve hypoglycemic symptoms and restore plasma glucose to normal levels.
Learning points
NICTH is a very rare condition that should be considered in patients known to have mesenchymal or malignant epithelial tumors and suffering from recurrent episodes of hypoglycemia.The diagnosis of an NICTH is established on the basis of the hypoinsulinemic hypoglycemia, the MSFT history, and the presence of paraneoplastic secretion of IGF1 or an immature form of IGF2.Treatment with corticosteroids, GH, or both can improve hypoglycemic symptoms and restore plasma glucose to normal levels in NICTH.
doi:10.1530/EDM-14-0026
PMCID: PMC4031926  PMID: 24891941
7.  Uncovering undetected hypoglycemic events 
Hypoglycemia is the rate-limiting factor that often prevents patients with diabetes from safely and effectively achieving their glycemic goals. Recent studies have reported that severe hypoglycemia is associated with a significant increase in the adjusted risks of major macrovascular events, major microvascular events, and mortality. Minor hypoglycemic episodes can also have serious implications for patient health, psychological well being, and adherence to treatment regimens. Hypoglycemic events can impact the health economics of the patient, their employer, and third-party payers. Insulin treatment is a key predictor of hypoglycemia, with one large population-based study reporting an overall prevalence of 7.1% (type 1 diabetes mellitus) and 7.3% (type 2 diabetes mellitus) in insulin-treated patients, compared with 0.8% in patients with type 2 diabetes treated with an oral sulfonylurea. Patients with type 1 diabetes typically experience symptomatic hypoglycemia on average twice weekly and severe hypoglycemia once annually. The progressive loss of islet cell function in patients with type 2 diabetes results in a higher risk of both symptomatic and unrecognized hypoglycemia over time. Patients with diabetes who become hypoglycemic are also more susceptible to developing defective counter-regulation, also known as hypoglycemia awareness autonomic failure, which is life-threatening and must be aggressively addressed. In patients unable to recognize hypoglycemia symptoms, frequent home monitoring or use of continuous glucose sensors are critical. Primary care physicians play a key role in the prevention and management of hypoglycemia in patients with diabetes, particularly in those requiring intensive insulin therapy, yet physicians are often unaware of the multitude of consequences of hypoglycemia or how to deal with them. Careful monitoring, adherence to guidelines, and use of optimal treatment combinations are all important steps toward improving care in patients with diabetes. The most important goals are for primary care physicians to recognize that every patient treated with antihyperglycemic medications is at risk of iatrogenic hypoglycemia and to ask patients about hypoglycemia at every visit.
doi:10.2147/DMSO.S29367
PMCID: PMC3340111  PMID: 22563248
hypoglycemia; insulin analogs; type 1 diabetes mellitus; type 2 diabetes mellitus
8.  Increased incidence of sexually transmitted diseases in the recent years: data from the ICONA cohort 
Journal of the International AIDS Society  2014;17(4Suppl 3):19653.
Introduction
Sexually transmitted diseases (STDs) data collected in HIV+ patients could be used as indicator of risky sexual behaviour possibly linked to HIV transmission. We described the STDs incidence over time and identified higher incidence factors.
Methodology
All patients in the ICONA Foundation Study enrolled after 1998 were included. STDs considered: any-stage syphilis, human papilloma virus (HPV) diseases, gonococcal and non-gonococcal urethritis, herpes simplex virus (HSV) genital ulcers, vaginitis and acute hepatitis B virus (HBV), hepatitis A virus (HAV), and hepatitis C virus (HCV) infections (only for non-IVDU (intravenous drug user) patients). STDs incidence rate (IR): number of STDs divided by person years of follow-up (PYFU). Calendar periods: 1998–2002, 2003–2007 and 2008–2012. Predictors of STDs occurrence were identified using Poisson regression and sandwich estimates for the standard errors were used for multiple STD events.
Results
Data of 9,168 patients were analyzed (median age 37.3 (SD=9.3), 74% male, 30% MSM). Over 46,736 PYFU, 996 episodes of STDs were observed (crude IR 17.3/1,000 PYFU). Median (IQR) CD4/mmc and HIV-RNA/mL at STD: 433 (251–600) and 10,900 (200–63,000). Highest crude IRs were observed for any-stage syphilis (3.95, 95% CI 3.59–4.35), HPV diseases (1.96, 1.71–2.24) and acute hepatitis (1.72, 1.49–1.99). At multivariable analysis (variables of adjustment shown in Figure 1), age (IRR 0.82 per 10 years younger, 95% CI 0.77–0.89), MSM contacts (IRR 3.03, 95% CI 2.52–3.64 vs heterosexual) and calendar period (IRR 1.67, 95% CI 1.42–1.96, comparing 2008–2012 with 1998–2002) significantly increased the risk of acquiring STDs. Moreover, having a HIV-RNA >50 c/mL (IRR 1.44, 95% CI 1.19–1.74 vs HIV-RNA <50 c/mL) and current CD4+ cell count <100/mmc (IRR 4.66, 95% CI 3.69–5.89, p<0.001 vs CD4+ cell count >500) showed an increased risk of STDs. Being on ARV treatment significantly reduced the risk of developing an STD (IRR 0.37, 95% CI 0.32–0.43) compared to ART-naïve people, even in the situation of temporary interruption of treatment (IRR 0.51, 95% CI 0.39–0.43) (see Figure 1).
Conclusions
The overall incidence of STDs has been increasing in the recent years. Interventions to prevent STDs and potential further spread of HIV infection should target the recently HIV diagnosed, the young population and MSM. Being on ARV treatment (potentially an indicator of whether a person is regularly seen for care) seems to reduce the risk of acquiring STDs independently of its viro-immunological effect.
doi:10.7448/IAS.17.4.19653
PMCID: PMC4224872  PMID: 25394157
9.  Health System and Personal Barriers Resulting in Decreased Utilization of HIV and STD Testing Services among At-Risk Black Men Who Have Sex with Men in Massachusetts 
AIDS Patient Care and STDs  2009;23(10):825-835.
Abstract
Testing for HIV and other sexually transmitted diseases (STD) remains a cornerstone of public health prevention interventions. This analysis was designed to explore the frequency of testing, as well as health system and personal barriers to testing, among a community-recruited sample of Black men who have sex with men (MSM) at risk for HIV and STDs. Black MSM (n = 197) recruited via modified respondent-driven sampling between January and July 2008 completed an interviewer-administered assessment, with optional voluntary HIV counseling and testing. Logistic regression procedures examined factors associated with not having tested in the 2 years prior to study enrollment for: (1) HIV (among HIV-uninfected participants, n = 145) and (2) STDs (among the entire mixed serostatus sample, n = 197). The odds ratios and their 95% confidence intervals obtained from this analysis were converted to relative risks. (1) HIV: Overall, 33% of HIV-uninfected Black MSM had not been tested for HIV in the 2 years prior to study enrollment. Factors uniquely associated with not having a recent HIV test included: being less educated; engaging in serodiscordant unprotected sex; and never having been HIV tested at a community health clinic, STD clinic, or jail. (2) STDs: Sixty percent had not been tested for STDs in the 2 years prior to study enrollment, and 24% of the sample had never been tested for STDs. Factors uniquely associated with not having a recent STD test included: older age; having had a prior STD; and never having been tested at an emergency department or urgent care clinic. Overlapping factors associated with both not having had a recent HIV or STD test included: substance use during sex; feeling that using a condom during sex is “very difficult”; less frequent contact with other MSM; not visiting a health care provider (HCP) in the past 12 months; having a HCP not recommend HIV or STD testing at their last visit; not having a primary care provider (PCP); current PCP never recommending they get tested for HIV or STDs. In multivariable models adjusting for relevant demographic and behavioral factors, Black MSM who reported that a HCP recommended getting an HIV test (adjusted relative risk [ARR] = 0.26; p = 0.01) or STD test (ARR = 0.11; p = 0.0004) at their last visit in the past 12 months were significantly less likely to have not been tested for HIV or STDs in the past 2 years. Many sexually active Black MSM do not regularly test for HIV or STDs. HCPs play a pivotal role in encouraging testing for Black MSM. Additional provider training is warranted to educate HCPs about the specific health care needs of Black MSM, in order to facilitate access to timely, culturally competent HIV and STD testing and treatment services for this population.
doi:10.1089/apc.2009.0086
PMCID: PMC2859760  PMID: 19803696
10.  Motor Vehicle Crashes in Diabetic Patients with Tight Glycemic Control: A Population-based Case Control Analysis 
PLoS Medicine  2009;6(12):e1000192.
Using a population-based case control analysis, Donald Redelmeier and colleagues found that tighter glycemic control, as measured by the HbA1c, is associated with an increased risk of a motor vehicle crash.
Background
Complications from diabetes mellitus can compromise a driver's ability to safely operate a motor vehicle, yet little is known about whether euglycemia predicts normal driving risks among adults with diabetes. We studied the association between glycosylated hemoglobin (HbA1c) and the risk of a motor vehicle crash using a population-based case control analysis.
Methods and Findings
We identified consecutive drivers reported to vehicle licensing authorities between January 1, 2005 to January 1, 2007 who had a diagnosis of diabetes mellitus and a HbA1c documented. The risk of a crash was calculated taking into account potential confounders including blood glucose monitoring, complications, and treatments. A total of 57 patients were involved in a crash and 738 were not involved in a crash. The mean HbA1c was lower for those in a crash than controls (7.4% versus 7.9%, unpaired t-test, p = 0.019), equal to a 26% increase in the relative risk of a crash for each 1% reduction in HbA1c (odds ratio = 1.26, 95% confidence interval 1.03–1.54). The trend was evident across the range of HbA1c values and persisted after adjustment for measured confounders (odds ratio = 1.25, 95% confidence interval 1.02–1.55). The two other significant risk factors for a crash were a history of severe hypoglycemia requiring outside assistance (odds ratio = 4.07, 95% confidence interval 2.35–7.04) and later age at diabetes diagnosis (odds ratio per decade = 1.29, 95% confidence interval 1.07–1.57).
Conclusions
In this selected population, tighter glycemic control, as measured by the HbA1c, is associated with an increased risk of a motor vehicle crash.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Around 8% of the US population has diabetes, a group of diseases in which the body cannot control levels of glucose (sugar) in the blood. It can lead to serious complications and premature death, but suitable treatment can control the disease and lower the risk of complications.
Type 1 diabetes occurs when the body's immune system prevents the production of insulin, the hormone that controls blood glucose. It accounts for 5%–10% of diabetes cases in adults and the vast majority of cases in childhood. Patients with type 1 diabetes need to inject insulin to survive. Type 2 diabetes is associated with older age, obesity, family history of diabetes, lack of physical activity, and race/ethnicity. As obesity rates rise worldwide, it is expected that the prevalence of type 2 diabetes will increase.
Why Was This Study Done?
Some complications of diabetes affect the ability to drive safely. Prolonged periods of high blood sugar levels can damage eyesight and nerves throughout the body, resulting in pain, tingling, and reduction of feeling or muscle control. Over time, some diabetics may become unaware of the early symptoms of an abnormally low blood sugar level (hypoglycemia) that can cause confusion, clumsiness, or fainting. Severe hypoglycemia can result in seizures or a coma.
It is common for driver licensing authorities to require evidence that a diabetic person's condition is well controlled before they issue a driving license. One measure of this is the percentage of hemoglobin in their blood that has joined up with glucose, known as HbA1c. This provides a measure of average blood glucose levels over the previous 8–12 weeks. A lower reading is considered an indicator of good diabetic control, but conversely, a blood glucose level that is too low can cause hypoglycemia. Normal nondiabetic HbA1c is between 3.5% and 5.5%, but 6.5% is considered good for people with diabetes.
In this study the researchers tested whether blood glucose levels, as measured by levels of HbA1c, were statistically associated with the risk of a motor vehicle crash.
What Did the Researchers Do and Find?
The authors studied 795 diabetic adults who had been in contact with the driver licensing authority in Ontario, Canada between January 1, 2005 and January 1, 2007 and for whom HbA1c levels were recorded. HbA1c levels varied between 4.4% and 14.7%.
Of the drivers considered, 57 were involved in a car crash and 738 were not. The authors found that lower HbA1c levels were associated with an increased risk of a motor vehicle crash, even when they took into account other factors such as time since diagnosis, treatment, age, age when diagnosed, and, if taking insulin, age insulin started.
The authors also found that the risk of a crash quadrupled when a driver had a history of severe hypoglycemia that required outside help and that there was an increase in risk when diabetes had first been diagnosed at an older age.
What Do These Findings Mean?
The authors conclude by emphasizing the difficulty in knowing whether someone with diabetes is fit to drive. They suggest that a patient's HbA1c level is neither necessary nor sufficient to determine whether a diabetic person is fit to drive and these results, which agree with some other studies, call into question the current legal framework of the US, UK, Canada, Germany, Holland, and Australia, which single out diabetic drivers for medical review.
The finding that lower HbA1c levels are associated with an increased risk of a crash is surprising, as it suggests that a driver is less safe if they control their diabetes well. However, a statistical link does not prove that one event causes another. Unknown social or medical factors might explain the results. In this case, the authors point out that a major drawback of their study is that it is not randomized and drivers have free will in choosing how tightly to control their diabetes and also how carefully they drive. The authors considered whether time spent driving might explain the results, but discounted this for several reasons. One more plausible explanation is that intensive treatment to attain a lower HbA1c level for better general health raises the risk of hypoglycemic episodes.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000192.
Wikipedia includes an article on diabetes (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The American Diabetes Association publishes information on diabetes in English and Spanish
The American Diabetes Association also publishes information on US states regulation of drivers with diabetes
The World Health Organization of the United Nations Diabetes Programme works to prevent diabetes, minimize complications, and maximize quality of life
doi:10.1371/journal.pmed.1000192
PMCID: PMC2780354  PMID: 19997624
11.  Home screening for sexually transmitted diseases in high‐risk young women: randomised controlled trial 
Sexually Transmitted Infections  2007;83(4):286-291.
Objective
Home screening tests could eliminate several barriers to testing sexually transmitted diseases (STDs).
Aim
To determine whether offering repeated home screening tests would increase the rate of testing for chlamydia and gonorrhoea in a high‐risk sample of young women.
Methods
In this randomised controlled trial, 403 young women (mean age 18.9 years, 70% black) with a recent STD or with STD‐related risk factors were enrolled. Participants were recruited from clinics and high‐prevalence neighbourhoods and then randomly assigned to receive either a home testing kit or an invitation to attend a medical clinic for testing at 6, 12 and 18 months after enrollment. Over 80% of women were followed for 2 years. The trial is registered with ClinicalTrials.gov, number NCT 00177437.
Results
Of 197 women in the intervention group, 140 (71%) returned at least one home test and 25 of 249 (10%) home tests were positive. Women who received home screening tests completed significantly more STD tests overall (1.94 vs 1.41 tests per woman‐year, p<0.001) and more STD tests in the absence of symptoms (1.18 vs 0.75 tests per woman‐year, p<0.001). More women in the intervention group completed at least one test when asymptomatic (162 (82.2%) vs 117 (61.3%), p<0.001). The intervention was most effective among women recruited outside medical clinics. There was no significant difference in the overall rate of STDs detected.
Conclusions
Home screening significantly increased the utilisation of chlamydia and gonorrhoea testing in this sample of high‐risk young women, and thus represents a feasible strategy to facilitate STD testing in young women.
doi:10.1136/sti.2006.023762
PMCID: PMC2598665  PMID: 17301105
12.  Operational performance of an STD control programme in Mwanza Region, Tanzania 
Sexually Transmitted Infections  2000;76(6):426-436.
Objectives: To describe important details of the design and operational features of the Mwanza sexually transmitted diseases (STD) control programme. To assess the feasibility of the intervention, the distribution of STD syndromes observed, the clinical effectiveness of syndromic STD case management, the utilisation of STD services by the population, and the quality of syndromic STD services delivered at rural health units.
Methods: The intervention was integrated into rural primary healthcare (PHC) units. It comprised improved STD case management using the syndromic approach, facilitated by a regional programme office which ensured the training of health workers, a reliable supply of effective drugs, and regular support supervision. Five studies were performed to evaluate operational performance: (i) a survey of register books to collect data on patients presenting with STDs and reproductive tract infections (RTIs) to rural health units with improved STD services, (ii) a survey of register books from health units in communities without improved services, (iii) a survey of register books from referral clinics, (iv) a home based cross sectional study of STD patients who did not return to the intervention health units for follow up, (v) a cross sectional survey of reported STD treatment seeking behaviour in a random cohort of 8845 adults served by rural health units.
Results: During the 2 years of the Mwanza trial, 12 895 STD syndromes were treated at the 25 intervention health units. The most common syndromes were urethral discharge (67%) and genital ulcers (26%) in men and vaginal discharge (50%), lower abdominal tenderness (33%), and genital ulcers (13%) in women. Clinical treatment effectiveness was high in patients from whom complete follow up data were available, reaching between 81% and 98% after first line treatment and 97%–99% after first, second, and third line treatment. Only 26% of patients referred to higher levels of health care had presented to their referral institutions. During the trial period, data from the cohort showed that 12.8% of men and 8.6% of women in the intervention communities experienced at least one STD syndrome. Based on various approaches, utilisation of the improved health units by symptomatic STD patients in these communities was estimated at between 50% and 75%. During the first 6 months of intervention attendance at intervention units increased by 53%. Thereafter, the average attendance rate was about 25% higher than in comparison communities. Home visits to 367 non-returners revealed that 89% had been free of symptoms after treatment, but 28% became symptomatic again within 3 months of treatment. 100% of these patients reported that they had received treatment, but only 74% had been examined, only 57% had been given health education, and only 30% were offered condoms. Patients did not fully recall which treatment they had been given, but possibly only 63% had been treated exactly according to guidelines.
Conclusions: This study demonstrated that it is feasible to integrate effective STD services into the existing PHC structure of a developing country. Improved services attract more patients, but additional educational efforts are needed to further improve treatment seeking behaviour. Furthermore, clear treatment guidelines, a reliable drug supply system, and regular supervision are critical. All efforts should be made to treat patients on the spot, without delay, as referral to higher levels of care led to a high number of dropouts. The syndromic approach to STD control should be supported by at least one reference clinic and laboratory per country to ensure monitoring of prevalent aetiologies, of the development of bacterial resistance, and of the effectiveness of the syndromic algorithms in use.
Key Words: sexually transmitted infections; syndromic treatment; programme performance; Tanzania
doi:10.1136/sti.76.6.426
PMCID: PMC1744245  PMID: 11221123
13.  Value of Continuous Glucose Monitoring For Minimizing Severe Hypoglycemia during Tight Glycemic Control 
Objective
Tight glycemic control (TGC) can potentially reduce morbidity and mortality in the ICU but increases the risk of hypoglycemia. The most effective means to avoid hypoglycemia is to obtain frequent blood glucose (BG) samples, but this increases the burden to nursing staff. The objective of this study was to assess the ability of a real-time continuous glucose monitor (CGM-RT) to reduce hypoglycemia (BG<60 mg/dL [3.3 mmol/L]) during standard care (STD) or TGC effected with a proportional integral derivative (PID) insulin titration algorithm.
Design
CGM-RT profiles obtained from an ongoing prospective randomized trial of TGC were retrospectively analyzed to determine if the continuous glucose measure had prevented instances of hypoglycemia.
Setting
Cardiac ICU.
Patients
Children 3 years of age or less undergoing cardiac surgery were studied.
Interventions
Intravenous insulin infusion and rescue glucose with guided by CGM-RT and the PID algorithm in the TGC arm (N=155; target glucose 80–110 mg/dL [4.4–6.1 mmol/L); CGM-RT in the STD care arm (N=156).
Measurements and Main Results
No reduction in hypoglycemia was observed with CGM-RT alarms set at 60 mg/dL [3.3 mmol/L] (0 of 19 occurrences of BG<60 mg/dL [3.3 mmol/L] detected); 18 of 40 subsequent incidences of hypoglycemia were detected after increasing the alarm threshold to 70 mg/dL [3.9 mmol/L]. In the TGC arm, 8 incidences were reduced in duration and an additional 8 events were prevented with intravenous glucose. In the STD arm, 3 of 9 occurrences of hypoglycemia were detected with the duration reduced in all cases. On average, one to two false hypoglycemia alarms were observed in each patient.
Conclusions
CGM-RT in combination with PID control can reduce hypoglycemia during TGC. CGM-RT can also reduce hypoglycemia during STD. However, false alarms increase the overall nursing workload.
doi:10.1097/PCC.0b013e31821926a5
PMCID: PMC3705721  PMID: 21499183
tight glycemic control; continuous glucose monitoring; intensive care unit
14.  Relationships Between Perceived STD-Related Stigma, STD-Related Shame and STD Screening Among a Household Sample of Adolescents 
Context
Important barriers to STD testing for an individual may include STD-related stigma, defined as personal fears about negative societal attitudes toward STD infection, and STD-related shame, defined as anticipated negative personal feelings resulting from a positive STD test. Obtaining a clear understanding of the relationship between STD-related stigma, STD-related shame, and STD testing may help inform programs and policies to reduce STD transmission.
Methods
Measures derived from previously published scales were used to assess an urban, household sample of 594 15–24 year olds’ perceptions of STD-related stigma (Cronbach’s alpha 0.92), STD-related shame (Crobach’s alpha = 0.89), and receipt of an STD test in the past year. Logistic regression was used to examine the associations between STD testing and perceptions of stigma, shame, and other participant characteristics.
Results
Thirty-seven percent of males and 70% of females reporting receiving an STD test in the past year, the majority of which occurred in the context of a routine health care visit. For both males and females, perceiving higher levels of STD-related stigma was independently associated with decreased odds of having been STD tested (OR = 0.54 and 0.48, respectively). STD-related shame was not related to STD testing.
Conclusions
STD-related stigma may be an important barrier to STD screening for adolescents and young adults. Given the fact that most participants reported receiving an STD test during a routine health visit, it is unclear whether STD-related stigma may be associated with care seeking versus acceptance of STD screening at a routine health visit.
doi:10.1363/4122509
PMCID: PMC4334654  PMID: 20444177
15.  Impaired Awareness of Hypoglycemia in a Population-Based Sample of Children and Adolescents With Type 1 Diabetes 
Diabetes Care  2009;32(10):1802-1806.
OBJECTIVE
To determine the prevalence and clinical associations of impaired awareness of hypoglycemia in a population-based sample of children and adolescents with type 1 diabetes.
RESEARCH DESIGN AND METHODS
A validated questionnaire was administered to 656 patients with type 1 diabetes over a 6-month period to determine hypoglycemia awareness status. Case ascertainment was 79% of the clinic population. The rate of severe hypoglycemia was determined by data collected prospectively in the preceding year.
RESULTS
Impaired awareness of hypoglycemia was present in 29% of patients. Patients with impaired awareness of hypoglycemia had an earlier onset of diabetes (P < 0.001), were younger (P < 0.001), and had lower mean levels of A1C since diabetes onset (P = 0.006) and at their last visit (P = 0.001). The overall rate of severe hypoglycemia was 24.5 episodes per 100 patient-years in the preceding year. The severe hypoglycemia rate was higher in those with impaired awareness of hypoglycemia (37.1 vs. 19.3 episodes per 100 patient-years, P < 0.001). Among patients aged <6 years (n = 46), 59% of care providers reported impaired awareness of hypoglycemia, and the rate of severe hypoglycemia was significantly higher in those reporting impaired awareness (33.3 vs. 52 episodes per 100 patient-years, P = 0.02). More patients with recurrent hypoglycemia reported impaired awareness of hypoglycemia (47 vs. 28%, P = 0.03).
CONCLUSIONS
A significant proportion of children and adolescents with type 1 diabetes have impaired awareness of hypoglycemia. Screening for impaired awareness is an important component of routine diabetes care and can identify patients at increased risk of a severe hypoglycemic event.
doi:10.2337/dc09-0541
PMCID: PMC2752917  PMID: 19587370
16.  The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study at 30 Years: Overview 
Diabetes Care  2013;37(1):9-16.
OBJECTIVE
The Diabetes Control and Complications Trial (DCCT) was designed to test the glucose hypothesis and determine whether the complications of type 1 diabetes (T1DM) could be prevented or delayed. The Epidemiology of Diabetes Interventions and Complications (EDIC) observational follow-up determined the durability of the DCCT effects on the more-advanced stages of diabetes complications including cardiovascular disease (CVD).
RESEARCH DESIGN AND METHODS
The DCCT (1982–1993) was a controlled clinical trial in 1,441 subjects with T1DM comparing intensive therapy (INT), aimed at achieving levels of glycemia as close to the nondiabetic range as safely possible, with conventional therapy (CON), which aimed to maintain safe asymptomatic glucose control. INT utilized three or more daily insulin injections or insulin pump therapy guided by self-monitored glucose. EDIC (1994–present) is an observational study of the DCCT cohort.
RESULTS
The DCCT followed >99% of the cohort for a mean of 6.5 years and demonstrated a 35–76% reduction in the early stages of microvascular disease with INT, with a median HbA1c of 7%, compared with CONV, with a median HbA1c of 9%. The major adverse effect of INT was a threefold increased risk of hypoglycemia, which was not associated with a decline in cognitive function or quality of life. EDIC showed a durable effect of initial assigned therapies despite a loss of the glycemic separation (metabolic memory) and demonstrated that the reduction in early-stage complications during the DCCT translated into substantial reductions in severe complications and CVD.
CONCLUSIONS
DCCT/EDIC has demonstrated the effectiveness of INT in reducing the long-term complications of T1DM and improving the prospects for a healthy life span.
doi:10.2337/dc13-2112
PMCID: PMC3867999  PMID: 24356592
17.  The Risks and Benefits of Implementing Glycemic Control Guidelines in Frail Elders with Diabetes 
BACKGROUND/OBJECTIVES
To determine the hypo- and hyper-glycemic outcomes associated with implementing the American Geriatrics Society (AGS) guideline for Hemoglobin A1c (HbA1c)<8% in frail older patients with diabets.
DESIGN/SETTING
Guideline Implementation in PACE (Program of All-Inclusive Care for the Elderly)
PARTICIPANTS
All patients in the Before (10/02–12/04, n=338), Early (1/05–6/06, n=289) and Late phases of guideline implementation (7/06–12/08, n=385) with a diagnosis of diabetes mellitus and at least one HbA1c measurement.
INTERVENTION
Clinician education in 2005 with annual monitoring of the proportion of each clinician’s patients with diabetes with HbA1c<8%.
MEASUREMENTS
Hypoglycemia (Blood sugar or BS<50), hyperglycemia (BS>400) and severe hypoglycemia (Emergency room or ER visit for hypoglycemia)
RESULTS
Before, Early and Late groups were similar in mean age, race/ethnicity, comorbidity and functional dependency. Antihyperglycemic medication use increased with more patients using metformin (28% Before versus 42% Late, p<0.001) and insulin (23% Before versus 34% Late, p<0.001), with more patients achieving the AGS glycemic target of HbA1c<8% (74% Before versus 84% Late, p<0.001). Episodes of hyperglycemia (per 100 person-years) decreased dramatically (159 Before versus 46 Late, p<0.001) and episodes of hypoglycemia were unchanged (10.1 versus 9.3, p=0.50). Episodes of severe hypoglycemia were increased in the Early period (1.1 Before versus 2.9 Early, p=0.03).
CONCLUSION
Implementing the AGS glycemic control guideline for frail elders led to fewer hyperglycemic episodes, but more severe hypoglycemic episodes requiring ER visits in the Early implementation period. Future glycemic control guideline implementation efforts should be coupled with close monitoring for severe hypoglycemia in the early implementation period.
doi:10.1111/j.1532-5415.2011.03362.x
PMCID: PMC3764989  PMID: 21480838
glycemic control; guideline; hypoglycemia; PACE; diabetes mellitus
18.  Overnight Closed-Loop Insulin Delivery with Model Predictive Control: Assessment of Hypoglycemia and Hyperglycemia Risk Using Simulation Studies 
Background
Hypoglycemia and hyperglycemia during closed-loop insulin delivery based on subcutaneous (SC) glucose sensing may arise due to (1) overdosing and underdosing of insulin by control algorithm and (2) difference between plasma glucose (PG) and sensor glucose, which may be transient (kinetics origin and sensor artifacts) or persistent (calibration error [CE]). Using in silico testing, we assessed hypoglycemia and hyperglycemia incidence during over-night closed loop. Additionally, a comparison was made against incidence observed experimentally during open-loop single-night in-clinic studies in young people with type 1 diabetes mellitus (T1DM) treated by continuous SC insulin infusion.
Methods
Simulation environment comprising 18 virtual subjects with T1DM was used to simulate overnight closed-loop study with a model predictive control (MPC) algorithm. A 15 h experiment started at 17:00 and ended at 08:00 the next day. Closed loop commenced at 21:00 and continued for 11 h. At 18:00, protocol included meal (50 g carbo-hydrates) accompanied by prandial insulin. The MPC algorithm advised on insulin infusion every 15 min. Sensor glucose was obtained by combining model-calculated noise-free interstitial glucose with experimentally derived tran-sient and persistent sensor artifacts associated with FreeStyle Navigator® (FSN). Transient artifacts were obtained from FSN sensor pairs worn by 58 subjects with T1DM over 194 nighttime periods. Persistent difference due to FSN CE was quantified from 585 FSN sensor insertions, yielding 1421 calibration sessions from 248 subjects with diabetes.
Results
Episodes of severe (PG ≤ 36 mg/dl) and significant (PG ≤ 45 mg/dl) hypoglycemia and significant hy-perglycemia (PG ≥ 300 mg/dl) were extracted from 18,000 simulated closed-loop nights. Severe hypoglycemia was not observed when FSN CE was less than 45%. Hypoglycemia and hyperglycemia incidence during open loop was assessed from 21 overnight studies in 17 young subjects with T1DM (8 males; 13.5 ± 3.6 years of age; body mass index 21.0 ± 4.0 kg/m2; duration diabetes 6.4 ± 4.1 years; hemoglobin A1c 8.5% ± 1.8%; mean ± standard deviation) participating in the Artificial Pancreas Project at Cambridge. Severe and significant hypoglycemia during simulated closed loop occurred 0.75 and 17.11 times per 100 person years compared to 1739 and 3479 times per 100 person years during experimental open loop, respectively. Signifi-cant hyperglycemia during closed loop and open loop occurred 75 and 15,654 times per 100 person years, respec-tively.
Conclusions
The incidence of severe and significant hypoglycemia reduced 2300- and 200-fold, respectively, during simu-lated overnight closed loop with MPC compared to that observed during open-loop overnight clinical studies in young subjects with T1DM. Hyperglycemia was 200 times less likely. Overnight closed loop with the FSN and the MPC algorithm is expected to reduce substantially the risk of hypoglycemia and hyperglycemia.
PMCID: PMC2769888  PMID: 20144424
artificial pancreas; computer simulation; glucose regulation; risk analysis
19.  Hypoglycemia-associated autonomic failure in insulin-dependent diabetes mellitus. Recent antecedent hypoglycemia reduces autonomic responses to, symptoms of, and defense against subsequent hypoglycemia. 
Journal of Clinical Investigation  1993;91(3):819-828.
We hypothesize that in patients with insulin-dependent diabetes mellitus (IDDM), recent antecedent iatrogenic hypoglycemia is a major cause of hypoglycemia-associated autonomic failure, a disorder distinct from classical diabetic autonomic neuropathy (CDAN), and that hypoglycemia-associated autonomic failure, by reducing both symptoms of and defense against developing hypoglycemia, results in recurrent iatrogenic hypoglycemia, thus creating a vicious cycle. We used the hyperinsulinemic (12.0 pmol.kg-1.min-1) stepped hypoglycemic clamp technique to assess autonomic and symptomatic responses to hypoglycemia and the insulin infusion test (4.0 pmol.kg-1.min-1) to assess defense against hypoglycemia on mornings before and after clamped afternoon hypoglycemia (approximately 2.8 mmol/liter) and hyperglycemia (approximately 11.1 mmol/liter) in patients with IDDM. Compared with nondiabetic subjects, IDDM with or without CDAN exhibited reduced epinephrine (P = 0.0222 and 0.0040) and pancreatic polypeptide (P = 0.0083 and 0.0056) responses to hypoglycemia. After afternoon hypoglycemia, lower plasma glucose concentrations were required to elicit autonomic and symptomatic responses during morning hypoglycemic clamps in patients without CDAN. At the 2.8 mmol/liter step, mean (+/- SE) epinephrine levels were 1,160 +/- 270 and 2,040 +/- 270 pmol/liter (P = 0.0060), pancreatic and total symptom scores were 22 +/- 3 and 41 +/- 7 (P = 0.0475) after afternoon hypoglycemia and hyperglycemia, respectively. During morning insulin infusion tests after afternoon hypoglycemia, nadir plasma glucose concentrations were 2.6 +/- 0.2 mmol/liter compared with 3.3 +/- 0.3 mmol/liter (P < 0.001) at the corresponding time points after afternoon hyperglycemia. Thus, we conclude: (a) elevated glycemic thresholds for autonomic responses to hypoglycemia are a feature of IDDM per se, not classical diabetic autonomic neuropathy; and (b) a single episode of afternoon hypoglycemia results in both elevated glycemic thresholds for autonomic and symptomatic responses to hypoglycemia and impaired physiological defense against hypoglycemia the next morning in IDDM.
PMCID: PMC288033  PMID: 8450063
20.  Impact of hypoglycemia on patients with type 2 diabetes mellitus and their quality of life, work productivity, and medication adherence 
Background
The purpose of this study was to determine the characteristics of adults with type 2 diabetes mellitus (T2DM) that correlate with greater risk of hypoglycemia and determine the impact of hypoglycemia on health-related quality of life, work productivity, and medication adherence from a patient perspective.
Methods
Data from a large web-based survey were retrospectively analyzed. Adults with a diagnosis of T2DM taking antihyperglycemic agents were included in the analysis. Participants with knowledge of their hypoglycemic history were divided into three groups: those experiencing recent hypoglycemia (previous 3 months), those experiencing nonrecent hypoglycemia, and those never experiencing hypoglycemia.
Results
Of the participants with T2DM taking antihyperglycemic agents who were knowledgeable of their hypoglycemia history, 55.7% had ever experienced hypoglycemia. Of those, 52.7% had recent hypoglycemia. Compared with those who never experienced hypoglycemia, those who experienced hypoglycemia tended to: be younger; be more aware of their glycated hemoglobin (HbA1c) levels; have higher HbA1c levels; have a higher body mass index; have higher Charlson Comorbidity Index scores; be on insulin, sulfonylureas, and/or glucagon-like peptide-1 agonists; and be less adherent to their antihyperglycemic agents. Hypoglycemia interfered with social activities, caused more missed work (absenteeism), more impairment while at work (presenteeism), and decreased overall work productivity compared with patients who had never experienced hypoglycemia. Overall health-related quality of life, as determined by the Short Form-36 health questionnaire, was negatively impacted by hypoglycemia. Both Physical and Mental Summary scores were significantly lower for the recent hypoglycemia and nonrecent hypoglycemia groups compared with the never hypoglycemia group.
Conclusion
Hypoglycemia can negatively impact many aspects of life. Greater awareness of those who are at risk for developing hypoglycemia can lead to the development of measures (eg, patient and physician education) to prevent future hypoglycemia episodes.
doi:10.2147/PPA.S58813
PMCID: PMC4020884  PMID: 24855344
adherence; survey; patient preference; burden; antihyperglycemic; low glucose effect; hemoglobin A1C
21.  HbA1c and Risk of Severe Hypoglycemia in Type 2 Diabetes 
Diabetes Care  2013;36(11):3535-3542.
OBJECTIVE
We examined the association between HbA1c level and self-reported severe hypoglycemia in patients with type 2 diabetes.
RESEARCH DESIGN AND METHODS
Type 2 diabetic patients in a large, integrated healthcare system, who were 30–77 years of age and treated with glucose-lowering therapy, were asked about severe hypoglycemia requiring assistance in the year prior to the Diabetes Study of Northern California survey conducted in 2005–2006 (62% response rate). The main exposure of interest was the last HbA1c level collected in the year preceding the observation period. Poisson regression models adjusted for selected demographic and clinical variables were specified to evaluate the relative risk (RR) of severe hypoglycemia across HbA1c levels. We also tested whether the HbA1c-hypoglycemia association differed across potential effect modifiers (age, diabetes duration, and category of diabetes medication).
RESULTS
Among 9,094 eligible survey respondents (mean age 59.5 ± 9.8 years, mean HbA1c 7.5 ± 1.5%), 985 (10.8%) reported experiencing severe hypoglycemia. Across HbA1c levels, rates of hypoglycemia were 9.3–13.8%. Compared with those with HbA1c of 7–7.9%, the RR of hypoglycemia was 1.25 (95% CI 0.99–1.57), 1.01 (0.87–1.18), 0.99 (0.82–1.20), and 1.16 (0.97–1.38) among those with HbA1c <6, 6–6.9, 8–8.9, and ≥9%, respectively, in a fully adjusted model. Age, diabetes duration, and category of diabetes medication did not significantly modify the HbA1c-hypoglycemia relationship.
CONCLUSIONS
Severe hypoglycemia was common among patients with type 2 diabetes across all levels of glycemic control. Risk tended to be higher in patients with either near-normal glycemia or very poor glycemic control.
doi:10.2337/dc13-0610
PMCID: PMC3816866  PMID: 23900589
22.  Effect of Prior Intensive Therapy in Type 1 Diabetes on 10-Year Progression of Retinopathy in the DCCT/EDIC: Comparison of Adults and Adolescents 
Diabetes  2010;59(5):1244-1253.
OBJECTIVE
The aim of this study was to examine differences between adolescents and adults in persistence of the benefits of intensive therapy 10 years after completion of the Diabetes Control and Complications Trial (DCCT).
RESEARCH DESIGN AND METHODS
During the Epidemiology of Diabetes Interventions and Complications (EDIC) study, progression of retinopathy from DCCT closeout to EDIC year 10 was evaluated in 1,055 adults and 156 adolescents.
RESULTS
During 10 years of follow-up, HbA1c (A1C) was similar between original intensive (INT) and conventional (CON) groups and between former adolescents and adults. At EDIC year 10, adults in the former INT group continued to show slower progression of diabetic retinopathy than those in the CON group (adjusted hazard reduction 56%, P < 0.0001), whereas in adolescents this beneficial effect had disappeared (32%, P = 0.13). Seventy-nine percent of observed differences in the prolonged treatment effect between adults and adolescents at year 10 were explained by differences in mean A1C during DCCT between adolescents and adults (8.9 vs. 8.1%), particularly between INT adolescents and adults (8.1 vs. 7.2%).
CONCLUSIONS
Prior glycemic control during DCCT is vital for the persistence of the beneficial effects of INT therapy 10 years later. Lowering A1C to as close to normal as safely possible without severe hypoglycemia and starting as early as possible should be attempted for all subjects with type 1 diabetes. These results underscore the importance of maintaining A1C at target values for as long as possible because the benefits of former INT treatment wane over time if A1C levels rise.
doi:10.2337/db09-1216
PMCID: PMC2857905  PMID: 20150283
23.  Usefulness of Quantitative Assessment of Electrocardiographic ST Depression for Predicting New-Onset Heart Failure in American Indians (From the Strong Heart Study) 
The qualitative ECG strain pattern of ST depression (STD) and T-wave inversion is strongly associated with coronary heart disease and left ventricular (LV) hypertrophy and is an independent predictor of new-onset heart failure in hypertensive patients. However, whether quantitative measures of STD in the lateral precordial predict new heart failure is unclear. Digital ECGs were examined in 2,059 American Indian participants in the second Strong Heart Study examination with no history of heart failure. The absolute magnitude of ST segment deviation was measured by computer to the nearest 5 μV in leads V5 and V6. During 5.7±1.4 years follow-up, heart failure developed in 77 participants (3.7%). Participants who developed heart failure had greater STD in leads V5 or V6 (−11±35 vs 12±27 μV, p<0.001) than those who did not. In univariate Cox analyses, STD was a significant predictor of new heart failure, with each 10 μV greater STD associated with a 31% greater risk of heart failure (hazard ratio [HR] 1.31, 95% CI 1.24-1.39). Increasing STD grouped according to quartiles was strongly associated with the development of heart failure, with step-wise increasing risk of heart failure compared with the lowest quartile of STD for the second (HR 2.39, 95% CI 0.77-7.40), third (HR 3.01, 95% CI 1.00-9.08) and fourth quartile of STD (HR 9.06, 95% CI 3.26-25.16). In Cox multivariate analyses controlling for age, gender, diabetes, coronary heart disease, albuminuria and for other baseline risk factors, STD remained a significant predictor of incident heart failure (HR 1.22, 95% CI 1.13-1.32, per 10 μV increment in STD, p<0.001). In conclusion, increasing STD in the lateral precordial leads is strongly associated with an increased risk of developing heart failure, independent of other risk factors for new heart failure.
doi:10.1016/j.amjcard.2007.02.059
PMCID: PMC2556507  PMID: 17599448
electrocardiogram; heart failure; hypertrophy
24.  Severe Hypoglycemia–Induced Lethal Cardiac Arrhythmias Are Mediated by Sympathoadrenal Activation 
Diabetes  2013;62(10):3570-3581.
For people with insulin-treated diabetes, severe hypoglycemia can be lethal, though potential mechanisms involved are poorly understood. To investigate how severe hypoglycemia can be fatal, hyperinsulinemic, severe hypoglycemic (10–15 mg/dL) clamps were performed in Sprague-Dawley rats with simultaneous electrocardiogram monitoring. With goals of reducing hypoglycemia-induced mortality, the hypotheses tested were that: 1) antecedent glycemic control impacts mortality associated with severe hypoglycemia; 2) with limitation of hypokalemia, potassium supplementation could limit hypoglycemia-associated deaths; 3) with prevention of central neuroglycopenia, brain glucose infusion could prevent hypoglycemia-associated arrhythmias and deaths; and 4) with limitation of sympathoadrenal activation, adrenergic blockers could prevent hypoglycemia-induced arrhythmic deaths. Severe hypoglycemia–induced mortality was noted to be worsened by diabetes, but recurrent antecedent hypoglycemia markedly improved the ability to survive an episode of severe hypoglycemia. Potassium supplementation tended to reduce mortality. Severe hypoglycemia caused numerous cardiac arrhythmias including premature ventricular contractions, tachycardia, and high-degree heart block. Intracerebroventricular glucose infusion reduced severe hypoglycemia–induced arrhythmias and overall mortality. β-Adrenergic blockade markedly reduced cardiac arrhythmias and completely abrogated deaths due to severe hypoglycemia. Under conditions studied, sudden deaths caused by insulin-induced severe hypoglycemia were mediated by lethal cardiac arrhythmias triggered by brain neuroglycopenia and the marked sympathoadrenal response.
doi:10.2337/db13-0216
PMCID: PMC3781452  PMID: 23835337
25.  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 
PLoS Medicine  2014;11(10):e1001742.
In a cohort study, Beate Karges and colleagues find that the association between low hemoglobin A1C and severe hypoglycemia in children and young adults with type 1 diabetes has decreased over the period between 1995 and 2012.
Please see later in the article for the Editors' Summary
Background
Severe hypoglycemia is a major complication of insulin treatment in patients with type 1 diabetes, limiting full realization of glycemic control. It has been shown in the past that low levels of hemoglobin A1c (HbA1c), a marker of average plasma glucose, predict a high risk of severe hypoglycemia, but it is uncertain whether this association still exists. Based on advances in diabetes technology and pharmacotherapy, we hypothesized that the inverse association between severe hypoglycemia and HbA1c has decreased in recent years.
Methods and Findings
We analyzed data of 37,539 patients with type 1 diabetes (mean age ± standard deviation 14.4±3.8 y, range 1–20 y) from the DPV (Diabetes Patienten Verlaufsdokumentation) Initiative diabetes cohort prospectively documented between January 1, 1995, and December 31, 2012. The DPV cohort covers an estimated proportion of >80% of all pediatric diabetes patients in Germany and Austria. Associations of severe hypoglycemia, hypoglycemic coma, and HbA1c levels were assessed by multivariable regression analysis. From 1995 to 2012, the relative risk (RR) for severe hypoglycemia and coma per 1% HbA1c decrease declined from 1.28 (95% CI 1.19–1.37) to 1.05 (1.00–1.09) and from 1.39 (1.23–1.56) to 1.01 (0.93–1.10), respectively, corresponding to a risk reduction of 1.2% (95% CI 0.6–1.7, p<0.001) and 1.9% (0.8–2.9, p<0.001) each year, respectively. Risk reduction of severe hypoglycemia and coma was strongest in patients with HbA1c levels of 6.0%–6.9% (RR 0.96 and 0.90 each year) and 7.0%–7.9% (RR 0.96 and 0.89 each year). From 1995 to 2012, glucose monitoring frequency and the use of insulin analogs and insulin pumps increased (p<0.001). Our study was not designed to investigate the effects of different treatment modalities on hypoglycemia risk. Limitations are that associations between diabetes education and physical activity and severe hypoglycemia were not addressed in this study.
Conclusions
The previously strong association of low HbA1c with severe hypoglycemia and coma in young individuals with type 1 diabetes has substantially decreased in the last decade, allowing achievement of near-normal glycemic control in these patients.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Worldwide, more than 380 million people have diabetes, a chronic disorder characterized by high levels of glucose (sugar) in the blood. Blood sugar levels are usually controlled by insulin, a hormone produced by the pancreas. In people with diabetes, blood sugar control fails because they make no insulin (type 1 diabetes) or because the cells that normally respond to insulin by removing sugar from the blood have become insulin-resistant (type 2 diabetes). Type 1 diabetes, which tends to develop in childhood or early adulthood, is responsible for about 10% of cases of diabetes in adults and is treated with injections of insulin. Type 2 diabetes can usually be treated with diet, exercise, and antidiabetic drugs. With both types of diabetes, it is important to keep blood sugar levels within the normal range (good glycemic control) to reduce the long-term complications of diabetes, which include kidney failure, blindness, and an increased risk of cardiovascular disease.
Why Was This Study Done?
Patients with type 1 diabetes can achieve strict glycemic control using intensive insulin therapy, but such treatment is associated with a risk of severe or fatal hypoglycemia (low blood sugar). Past studies have found an association between low levels of hemoglobin A1c (HbA1c, a marker of average blood sugar levels over the past 2–3 months; a low HbA1c percentage indicates good glycemic control) and a high risk of severe hypoglycemia. Because of this inverse association, people at risk of severe hypoglycemia are advised to aim for an HbA1c of 7.5% or less, which puts them at risk of diabetic complications (most adults with diabetes aim for an HbA1c of 6.5% or less; people without diabetes have Hb1Ac readings below 6.05%). With recent improvements in insulin therapy, it is not clear whether the inverse association between the incidence of severe hypoglycemia and HbA1c levels still exists. In this trend analysis, the researchers investigate the association over time between HbA1C levels and the risk of severe hypoglycemia in a large cohort (group) of Austrian and German children and young adults with type 1 diabetes.
What Did the Researchers Do and Find?
The researchers analyzed data on Hb1Ac levels and on incidents of severe hypoglycemia and hypoglycemic coma collected from 37,539 children and young adults with type 1 diabetes between 1995 and 2012 by the DPV (Diabetes Patienten Verlaufsdokumentation) Initiative for diabetes care. The DPV cohort includes around 80% of all children and young adults with type 1 diabetes in Germany and Austria. Over the study period, the use of insulin analogs (compounds related to insulin that keep blood sugar levels steadier than regular insulin injections) and of insulin pumps (which deliver constant amounts of short-acting insulin analogs to the body) increased, and there was an increase in how often patients monitored their blood sugar level. Notably, between 1995 and 2012, the relative risk for severe hypoglycemia per 1% decrease in Hb1Ac declined from 1.28 to 1.05, and the relative risk for hypoglycemic coma per 1% decrease in Hb1Ac declined from 1.39 to 1.01. That is, the strength of the inverse association between severe hypoglycemia or coma and HbA1c decreased during the study period. Expressed another way, between 1995 and 2012, the relative risk for severe hypoglycemia and coma per 1% HbA1c decrease dropped by 1.2% and 1.9%, respectively, each year.
What Do These Findings Mean?
These findings reveal a substantial decrease since 1995 in the previously strong inverse association between low HbA1c levels and severe hypoglycemia and hypoglycemic coma in this cohort of young Germans and Austrians with type 1 diabetes. This decrease mainly occurred because of substantial reductions in the risk of hypoglycemia in patients with HbA1c levels between 6.0% and 7.9%, but the study provides no information about the drivers of this reduction. Moreover, these findings may apply only to young type 1 diabetes patients of European descent, and their accuracy may be limited by other aspects of the study design. However, by showing that HbA1c has become a minor predictor for severe hypoglycemia in this group of patients, these findings suggest that strict glycemic control in young patients with type 1 diabetes has become safer in recent years. Thus, it should now be possible to reduce the risk of long-term diabetic complications in such patients through achievement of near-normal glycemic control without increasing patients' risk of severe hypoglycemia.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001742.
The US National Diabetes Information Clearinghouse provides information about diabetes for patients, health care professionals, and the general public (in English and Spanish), including information on the HbA1c test and a description of a trial that compared the effects of intensive versus conventional treatment of blood glucose levels on the development of diabetic complications in patients with type 1 diabetes
The UK National Health Service Choices website provides information for patients and carers about type 1 diabetes, including a video that describes parents' experiences caring for a child with type 1 diabetes, and information about treating type 1 diabetes that includes a short video about HbA1c
The charity Diabetes UK provides detailed information about type 1 diabetes for patients and carers
The UK-based non-profit organization Healthtalkonline provides information about type 1 diabetes and young people, including interviews with young people about their experiences of the condition
MedlinePlus provides links to further resources and advice about type 1 diabetes (in English and Spanish)
Information about the DPV Initiative is available (mainly in German)
doi:10.1371/journal.pmed.1001742
PMCID: PMC4188517  PMID: 25289645

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