Remote Blood Glucose Monitoring in mHealth Scenarios: A Review <s> Introduction <s> OBJECTIVES ::: The objectives of this study were to determine the prevalence of hyperglycemia in extremely low birth-weight infants and to determine whether hyperglycemia increases the risk of early adverse outcomes (death or intraventricular hemorrhage of grade 3 or 4) and/or affects the length of hospital stay among survivors without intraventricular hemorrhage. ::: ::: ::: METHODS ::: The charts of all extremely low birth-weight infants (n = 93) admitted to Texas Children's Hospital (Houston, TX) during 2001 were reviewed. The highest daily blood glucose concentrations, highest dopamine infusion rates, highest daily percentage of inspired oxygen, and mean blood sodium concentrations were averaged over the first week of life or before death or occurrence of grade 3 or 4 intraventricular hemorrhage. Among survivors without severe intraventricular hemorrhage, the time ratio for blood glucose concentrations of >150 mg/dL was calculated. ::: ::: ::: RESULTS ::: More than 50% of the infants had persistent blood glucose concentrations of >150 mg/dL during their first week of life. Early adverse outcomes were associated with the average highest daily blood glucose concentration through interaction with the Clinical Risk Index for Babies score and with the average highest daily percentage of inspired oxygen. The length of hospital stay was associated with the time ratio for blood glucose concentrations of >150 mg/dL through interaction with birth weight and the average highest daily percentage of inspired oxygen. ::: ::: ::: CONCLUSION ::: These data confirm the high prevalence of hyperglycemia among parenterally fed, extremely low birth-weight infants and show that high blood glucose concentrations increase the risk of early death and grade 3 or 4 intraventricular hemorrhage and the length of hospital stay among survivors without intraventricular hemorrhage, which suggests that prevention and treatment of hyperglycemia may improve the outcomes of extremely low birth-weight infants. <s> BIB001 </s> Remote Blood Glucose Monitoring in mHealth Scenarios: A Review <s> Introduction <s> Type 2 diabetes mellitus (T2DM) affects a large population worldwide. T2DM is a complex heterogeneous group of metabolic disorders including hyperglycemia and impaired insulin action and/or insulin secretion. T2DM causes dysfunctions in multiple organs or tissues. Current theories of T2DM include a defect in insulin-mediated glucose uptake in muscle, a dysfunction of the pancreatic β-cells, a disruption of secretory function of adipocytes, and an impaired insulin action in liver. The etiology of human T2DM is multifactorial, with genetic background and physical inactivity as two critical components. The pathogenesis of T2DM is not fully understood. Animal models of T2DM have been proved to be useful to study the pathogenesis of, and to find a new therapy for, the disease. Although different animal models share similar characteristics, each mimics a specific aspect of genetic, endocrine, metabolic, and morphologic changes that occur in human T2DM. The purpose of this review is to provide the recent progress and current theories in T2DM and to summarize animal models for studying the pathogenesis of the disease. <s> BIB002 </s> Remote Blood Glucose Monitoring in mHealth Scenarios: A Review <s> Introduction <s> OBJECTIVE ::: The objective of this study was to determine whether hyperglycemia during the first week of life in extremely preterm (EPT) infants was associated with increased mortality rates and with cerebral injury, as assessed with MRI of the brain, at term-equivalent age. ::: ::: ::: METHODS ::: All 143 EPT infants (gestational ages of <27 weeks) who were born at Karolinska University Hospital between January 2004 and December 2006 and were alive at 24 hours were eligible. Of the 118 surviving infants, 24 were excluded for various reasons. MRI was performed for the 94 included survivors at term age, with a 1.5-T system, and scans were scored for gray matter/white matter (WM) abnormalities. Of the 25 infants who died before term age, 6 were excluded because of missing glucose documentation and the remaining 19 were included. Hyperglycemia was defined as plasma glucose levels of >8.3 mmol/L. ::: ::: ::: RESULTS ::: Hyperglycemia occurring on the first day of life was identified as an independent risk factor for death (adjusted odds ratio: 3.7 [95% confidence interval: 1.3-10.6]; P = .01). Hyperglycemia occurring on the first day of life also was a risk factor for WM reduction, as determined through MRI, at term-equivalent age (adjusted odds ratio: 3.1 [95% confidence interval: 1.0-9.2]; P = .04). ::: ::: ::: CONCLUSION ::: In this population-based cohort of EPT infants, hyperglycemia on the first day of life was associated with increased mortality rates and brain damage, as reflected by WM reduction at term age. <s> BIB003 </s> Remote Blood Glucose Monitoring in mHealth Scenarios: A Review <s> Introduction <s> Type 1 diabetes (T1D) is a chronic autoimmune disease in which destruction or damaging of the beta-cells in the islets of Langerhans results in insulin deficiency and hyperglycemia. We only know fo... <s> BIB004 </s> Remote Blood Glucose Monitoring in mHealth Scenarios: A Review <s> Introduction <s> BACKGROUND ::: Gestational diabetes mellitus is a potentially serious condition that affects many pregnancies and its prevalence is increasing. Evidence suggests early detection and treatment improves outcomes, but this is hampered by continued disagreement and inconsistency regarding many aspects of its diagnosis. ::: ::: ::: METHODS ::: The Vitamin D and Lifestyle Intervention for Gestational Diabetes Mellitus Prevention (DALI) research programme aims to promote pan-European standards in the detection and diagnosis of gestational diabetes and to develop effective preventive interventions. To provide an overview of the context within which the programme will be conducted and its findings interpreted, systematic searching and narrative synthesis have been used to identify and review the best available European evidence relating to the prevalence of gestational diabetes, current screening practices and barriers to screening. ::: ::: ::: RESULTS ::: Prevalence is most often reported as 2-6% of pregnancies. Prevalence may be lower towards the Northern Atlantic seaboard of Europe and higher in the Southern Mediterranean seaboard. Screening practice and policy is inconsistent across Europe, hampered by lack of consensus on testing methods, diagnostic glycaemic thresholds and the value of routine screening. Poor clinician awareness of gestational diabetes, its diagnosis and local clinical guidelines further undermine detection of gestational diabetes. ::: ::: ::: CONCLUSIONS ::: Europe-wide agreement on screening approaches and diagnostic standards for gestational diabetes could lead to better detection and treatment, improved outcomes for women and children and a strengthened evidence base. There is an urgent need for well-designed research that can inform decisions on best practice in gestational diabetes mellitus screening and diagnosis. <s> BIB005 </s> Remote Blood Glucose Monitoring in mHealth Scenarios: A Review <s> Introduction <s> Monitoring glucose concentration in the blood is essential in the therapy of diabetes, a pathology which affects about 350 million people around the World (three million in Italy), causes more than four million deaths per year and consumes a significant portion of the budget of national health systems (10% in Italy). In the last 15 years, several sensors with different degree of invasiveness have been proposed to monitor glycemia in a quasi-continuous way (up to 1 sample/min rate) for relatively long intervals (up to 7 consecutive days). These continuous glucose monitoring (CGM) sensors have opened new scenarios to assess, off-line, the effectiveness of individual patient therapeutic plans from the retrospective analysis of glucose time-series, but have also stimulated the development of innovative on-line applications, such as hypo/hyper-glycemia alert systems and artificial pancreas closed-loop control algorithms. In this review, we illustrate some significant Italian contributions, both from industry and academia, to the growth of the CGM sensors research area. In particular, technological, algorithmic and clinical developments performed in Italy will be discussed and put in relation with the advances obtained in the field in the wider international research community. <s> BIB006 </s> Remote Blood Glucose Monitoring in mHealth Scenarios: A Review <s> Introduction <s> AIM ::: Despite recent advances in diabetes therapy including the new long- and rapid-insulin analogs, insulin intensification strategies such as basal/bolus or pump therapy and sophisticated methods for insulin titration derived from the principles of functional insulin therapy, many patients fail to reach or maintain target glycosylated hemoglobin (HbA1c) values, putting them at increased risk for vascular complications. Continuous glucose monitoring (CGM) systems represent an important advance in diabetes technology that can facilitate optimal glucose control in type 1 diabetes. ::: ::: ::: METHOD ::: This review focuses on the efficacy and safety of CGM systems in diabetes management. The different CGM devices available are also described, as the way to use them and the educational approach to the patient in a step-by-step progression toward optimal glycemic control. ::: ::: ::: RESULTS ::: In type 1 diabetes, CGM systems are associated with 0.5-1% reduction in HbA1c without increased risk of hypoglycemia. CGM efficacy correlates with compliance to sensor wear, whatever the patient's age range. ::: ::: ::: CONCLUSION ::: Efficacy of CGM systems is now proven but indications, terms of use and educational issues of this new technology still need to be specified. <s> BIB007 </s> Remote Blood Glucose Monitoring in mHealth Scenarios: A Review <s> Introduction <s> BACKGROUND ::: Neonatal hypoglycemia is common and can cause neurologic impairment, but evidence supporting thresholds for intervention is limited. ::: ::: ::: METHODS ::: We performed a prospective cohort study involving 528 neonates with a gestational age of at least 35 weeks who were considered to be at risk for hypoglycemia; all were treated to maintain a blood glucose concentration of at least 47 mg per deciliter (2.6 mmol per liter). We intermittently measured blood glucose for up to 7 days. We continuously monitored interstitial glucose concentrations, which were masked to clinical staff. Assessment at 2 years included Bayley Scales of Infant Development III and tests of executive and visual function. ::: ::: ::: RESULTS ::: Of 614 children, 528 were eligible, and 404 (77% of eligible children) were assessed; 216 children (53%) had neonatal hypoglycemia (blood glucose concentration, <47 mg per deciliter). Hypoglycemia, when treated to maintain a blood glucose concentration of at least 47 mg per deciliter, was not associated with an increased risk of the primary outcomes of neurosensory impairment (risk ratio, 0.95; 95% confidence interval [CI], 0.75 to 1.20; P=0.67) and processing difficulty, defined as an executive-function score or motion coherence threshold that was more than 1.5 SD from the mean (risk ratio, 0.92; 95% CI, 0.56 to 1.51; P=0.74). Risks were not increased among children with unrecognized hypoglycemia (a low interstitial glucose concentration only). The lowest blood glucose concentration, number of hypoglycemic episodes and events, and negative interstitial increment (area above the interstitial glucose concentration curve and below 47 mg per deciliter) also did not predict the outcome. ::: ::: ::: CONCLUSIONS ::: In this cohort, neonatal hypoglycemia was not associated with an adverse neurologic outcome when treatment was provided to maintain a blood glucose concentration of at least 47 mg per deciliter. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others.). <s> BIB008
Tight monitoring of blood glucose levels is of capital importance for keeping this key physiological parameter under control, and is needed in a number of medical applications encompassing the treatment of diabetes and the management of intensive care therapy, which are briefly described in the following. Diabetes is a family of chronic diseases affecting an ever increasing number of patients. According to the World Health Organization, the worldwide prevalence of diabetes was 422 million adults in 2014, increasing from 108 million in 1980 [1] . It is classified into three major disease types [2] as follows: Type 1 Diabetes (T1D) BIB004 is caused by the destruction of the beta-cells in the pancreatic islets of Langerhans where insulin is produced and secreted; Type 2 Diabetes (T2D) is caused either by a decreased insulin secretion by the pancreas or by some kind of "resistance" to insulin developed by the body BIB002 ; and finally, Gestational Diabetes (GD) may arise during pregnancy in 2%-6% of cases and increase the risk of complications for both mother and child before and after childbirth BIB005 . All diabetes types cause an abnormal increase in Blood Glucose Level (BGL). In particular, prolonged hyper-glycemia leads to metabolic unbalance and is associated with long-term macro-vascular complications such as stroke or coronaropathy and micro-vascular ones such as nephropathy, neuropathy or retinopathy. Despite the lack of a definitive healing treatment for diabetes, new drugs and devices are helping patients in the challenging task of maintaining an adequate glucose control, easing the disease management, and improving their quality of life. Moreover, a tighter glucose monitoring results in a more effective therapeutic strategy that eventually yields a more significant reduction in the complications associated with diabetes  . Therefore, in the past few decades, the development of glucose sensors saw an impressive boost, whose most prominent achievement is given by the commercial availability of subcutaneous sensors for Continuous Glucose Monitoring (CGM) that are becoming a realistic option for home-monitoring and might soon replace the traditional point-of-care BGL measurement BIB006 BIB007 . For instance, recently, the U.S. Food and Drug Administration panel expressed a positive opinion about the use of the Dexcom G5 CGM sensor as a substitute for glucometers based on fingerstick tests [9] . Avoiding hyper-and hypo-glycemia is very important also in critically ill patients, such as those admitted in intensive care units. In these cases, the need arises to adopt a suitable algorithm for the regulation of glucose infusion based on CGM to improve glycemia control and prevent large BGL oscillations as well as hypo-or hyper-glycemia episodes. For example, failure to achieve a proper glucose control in preterm newborns is associated with an impaired neurological development only observed during the second year of life BIB008 , while in the short-term, there is a worsening of clinical outcomes in terms of mortality, infections and brain hemorrhage BIB001 BIB003 . Thus, CGM represents an improvement in the standard therapy in which the actual detection of hypo-and hyper-glycemia episodes is difficult, as they may happen between readings. Effective sensing technology and advanced signal processing techniques are certainly of capital importance to attain an effective blood glucose monitoring. Nevertheless, collecting measurements only represents part of the process, since other essential tasks are delivering these measures and/or any related alerts to the several actors involved in the blood-glucose management process. Those actors include the clinical staff responsible for planning and administering the therapy, the parents of pediatric patients or the significant others of adult ones. Despite being located far from the monitored patient, these people need to be kept up to date with his/her conditions in order to undertake the most appropriate actions. A remote monitoring system, by taking care of the delivery of any relevant information to the right players, becomes an important part of the sensing architecture. In this paper, we emphasize the advantages of remote monitoring, illustrating the technological components required to implement it. We start recalling the evolution that occurred within the Information and Communication Technology (ICT) architectures for acquiring data from patients and sending them remotely for perusal or analysis. Although we provide examples mainly concerning glucose monitoring or diabetes management, the applicability is rather general as they may be effectively exploited in different clinical contexts as well. We also illustrate some projects carried on by the authors where glucose sensors and insulin pumps have been integrated into a remote monitoring architecture operating in real time. Differences will be highlighted among systems addressing various patient populations, such as adults, children and newborns. The paper ends with a discussion on the lessons learned by the authors and the current trends for deploying remote monitoring solutions on a large scale.