Continuous glucose monitoring sensors: Past, present and future algorithmic challenges

Continuous glucose monitoring (CGM) sensors are portable devices that allow measuring and visualizing the glucose concentration in real time almost continuously for several days and are provided with hypo/hyperglycemic alerts and glucose trend information. CGM sensors have revolutionized Type 1 diabetes (T1D) management, improving glucose control when used adjunctively to self-monitoring blood glucose systems. Furthermore, CGM devices have stimulated the development of applications that were impossible to create without a continuous-time glucose signal, e.g., real-time predictive alerts of hypo/hyperglycemic episodes based on the prediction of future glucose concentration, automatic basal insulin attenuation methods for hypoglycemia prevention, and the artificial pancreas. However, CGM sensors’ lack of accuracy and reliability limited their usability in the clinical practice, calling upon the academic community for the development of suitable signal processing methods to improve CGM performance. The aim of this paper is to review the past and present algorithmic challenges of CGM sensors, to show how they have been tackled by our research group, and to identify the possible future ones

Combining continuous glucose monitoring and insulin pumps to automatically tune the basal insulin infusion in diabetes therapy: a review

For individuals affected by Type 1 diabetes (T1D), a chronic disease in which the pancreas does not produce any insulin, maintaining the blood glucose (BG) concentration as much as possible within the safety range (70-180\ua0mg/dl) allows avoiding short- and long-term complications. The tuning of exogenous insulin infusion can be difficult, especially because of the inter- and intra-day variability of physiological and behavioral factors. Continuous glucose monitoring (CGM) sensors, which monitor glucose concentration in the subcutaneous tissue almost continuously, allowed improving the detection of critical hypo- and hyper-glycemic episodes. Moreover, their integration with insulin pumps for continuous subcutaneous insulin infusion allowed developing algorithms that automatically tune insulin dosing based on CGM measurements in order to mitigate the incidence of critical episodes. In this work, we aim at reviewing the literature on methods for CGM-based automatic attenuation or suspension of basal insulin with a focus on algorithms, their implementation in commercial devices and clinical evidence of their effectiveness and safety

Wearable continuous glucose monitoring sensors: A revolution in diabetes treatment

Worldwide, the number of people affected by diabetes is rapidly increasing due to aging populations and sedentary lifestyles, with the prospect of exceeding 500 million cases in 2030, resulting in one of the most challenging socio-health emergencies of the third millennium. Daily management of diabetes by patients relies on the capability of correctly measuring glucose concentration levels in the blood by using suitable sensors. In recent years, glucose monitoring has been revolutionized by the development of Continuous Glucose Monitoring (CGM) sensors, wearable non/minimally-invasive devices that measure glucose concentration by exploiting different physical principles, e.g., glucose-oxidase, fluorescence, or skin dielectric properties, and provide real-time measurements every 1–5 min. CGM opened new challenges in different disciplines, e.g., medicine, physics, electronics, chemistry, ergonomics, data/signal processing, and software development to mention but a few. This paper first makes an overview of wearable CGM sensor technologies, covering both commercial devices and research prototypes. Then, the role of CGM in the actual evolution of decision support systems for diabetes therapy is discussed. Finally, the paper presents new possible horizons for wearable CGM sensor applications and perspectives in terms of big data analytics for personalized and proactive medicine

Psychiatric Adverse Reactions to Anaplastic Lymphoma Kinase Inhibitors in Non-Small-Cell Lung Cancer: Analysis of Spontaneous Reports Submitted to the FDA Adverse Event Reporting System

open7siBackground The development of anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) has improved the survival outcomes of patients with advanced ALK-rearranged non-small-cell lung cancer (NSCLC). The adverse events (AEs) related to ALK inhibitors are fairly well known; notably, about 20% of patients receiving lorlatinib experienced cognitive effects and behavioral alterations in pivotal trials. Therefore, psychiatric disorders could represent AEs of special interest for all ALK TKIs, deserving careful assessment in the post-marketing setting. Objective We conducted a real-world pharmacovigilance study on psychiatric AEs with marketed ALK inhibitors in subjects with advanced NSCLC. Patients and methods We performed an observational, retrospective analysis of spontaneous reports submitted to the Food and Drug Administration Adverse Events Reporting System (FAERS, as of December 2020), selecting psychiatric AEs to ALK TKIs approved in NSCLC (crizotinib, ceritinib, alectinib, brigatinib, lorlatinib). These AEs were independently scrutinized by three oncologists applying predefined exclusion criteria, described in terms of clinical/demographic features and assessed for drug-related causality according to an adaptation of the WHO–UMC system, a standardized probabilistic algorithm. Results Among 584 reported psychiatric AEs, 95 cases were selected as potentially treatment related, with higher reporting frequency for lorlatinib (26, 2.8%), followed by brigatinib (10, 1.2%), alectinib (18, 0.7%), ceritinib (12, 0.6%), and crizo- tinib (29, 0.3%). Reported psychiatric symptoms were mood disorders (39), psychotic disorders (24), and anxiety, agitation, and irritability (25). In the majority (74%) of cases, psychiatric AEs were serious and required hospitalization in about 32% of patients; 15.8% of retained cases were considered as highly probable and 69.5% as probable. Drug discontinuation was recorded in 31.6% of the reported cases, with the highest proportion for lorlatinib (65.4%). Conclusion Notwithstanding limitations, our study found a higher proportion of psychiatric AEs with lorlatinib, but also raised the hypothesis of psychiatric reactions as a class effect of ALK TKIs.openSisi, Monia; Fusaroli, Michele; De Giglio, Andrea; Facchinetti, Francesco; Ardizzoni, Andrea; Raschi, Emanuel; Gelsomino, FrancescoSisi, Monia; Fusaroli, Michele; De Giglio, Andrea; Facchinetti, Francesco; Ardizzoni, Andrea; Raschi, Emanuel; Gelsomino, Francesc

Regularised Model Identification Improves Accuracy of Multisensor Systems for Noninvasive Continuous Glucose Monitoring in Diabetes Management

Continuous glucose monitoring (CGM) by suitable portable sensors plays a central role in the treatment of diabetes, a disease currently affecting more than 350 million people worldwide. Noninvasive CGM (NI-CGM), in particular, is appealing for reasons related to patient comfort (no needles are used) but challenging. NI-CGM prototypes exploiting multisensor approaches have been recently proposed to deal with physiological and environmental disturbances. In these prototypes, signals measured noninvasively (e.g., skin impedance, temperature, optical skin properties, etc.) are combined through a static multivariate linear model for estimating glucose levels. In this work, by exploiting a dataset of 45 experimental sessions acquired in diabetic subjects, we show that regularisation-based techniques for the identification of the model, such as the least absolute shrinkage and selection operator (better known as LASSO), Ridge regression, and Elastic-Net regression, improve the accuracy of glucose estimates with respect to techniques, such as partial least squares regression, previously used in the literature. More specifically, the Elastic-Net model (i.e., the model identified using a combination of ${l}_{1}$ and ${l}_{2}$ norms) has the best results, according to the metrics widely accepted in the diabetes community. This model represents an important incremental step toward the development of NI-CGM devices effectively usable by patients

Glycaemic variability-based classification of impaired glucose tolerance vs. type 2 diabetes using continuous glucose monitoring data

Many glycaemic variability (GV) indices extracted from continuous glucose monitoring systems data have been proposed for the characterisation of various aspects of glucose concentration profile dynamics in both healthy and non-healthy individuals. However, the inter-index correlations have made it difficult to reach a consensus regarding the best applications or a subset of indices for clinical scenarios, such as distinguishing subjects according to diabetes progression stage. Recently, a logistic regression-based method was used to address the basic problem of differentiating between healthy subjects and those affected by impaired glucose tolerance (IGT) or type 2 diabetes (T2D) in a pool of 25 GV-based indices. Whereas healthy subjects were classified accurately, the distinction between patients with IGT and T2D remained critical. In the present work, by using a dataset of CGM time-series collected in 62 subjects, we developed a polynomial-kernel support vector machine-based approach and demonstrated the ability to distinguish between subjects affected by IGT and T2D based on a pool of 37 GV indices complemented by four basic parameters—age, sex, BMI, and waist circumference—with an accuracy of 87.1%.Peer reviewe

Use of strictureplasty technique for surgical treatment of ileal endometriosis: a case series

Intestinal deep infiltrating endometriosis is the most frequent extragenital localisation and its traditional surgical treatment is segmental resection of the affected tract. The need for implementing alternative techniques in the treatment of intestinal endometriosis arises from those cases of multiple ileal and recto-sigmoidal localisations, in which removing excessive lengths of intestine could lead to a higher rate of adverse events. Ileal endometriosis represents 4.7% of all intestinal localisations, often associated with multiple lesions and yet, to the best of our knowledge, there are no data on techniques other than intestinal resection for its treatment. Since its capacity to solve fibrostenotic lesions without removing centimeters of intestine, strictureplasty is widely implemented in the management of Crohn's disease. We propose the use of strictureplasty for the treatment of ileal endometriosis. We performed surgical treatment for symptomatic deep infiltrating endometriosis in two patients with either ileal and sigmoidal localisations. We approached ileal nodules with strictureplasty technique, while sigmoidal nodules were removed by traditional segmental resection. No complications occurred and both patients are now asymptomatic after a 12 months-follow up. Therefore, strictureplasty could provide a tool to eliminate small bowel endometriosis maintaining a regular caliber of the ileal tract without modifying its length

Characterizing multisegment foot kinematics during gait in diabetic foot patients

<p>Abstract</p> <p>Background</p> <p>The prevalence of diabetes mellitus has reached epidemic proportions, this condition may result in multiple and chronic invalidating long term complications. Among these, the diabetic foot, is determined by the simultaneous presence of both peripheral neuropathy and vasculopathy that alter the biomechanics of the foot with the formation of callosity and ulcerations. To diagnose and treat the diabetic foot is crucial to understand the foot complex kinematics. Most of gait analysis protocols represent the entire foot as a rigid body connected to the shank. Nevertheless the existing multisegment models cannot completely decipher the impairments associated with the diabetic foot.</p> <p>Methods</p> <p>A four segment foot and ankle model for assessing the kinematics of the diabetic foot was developed. Ten normal subjects and 10 diabetics gait patterns were collected and major sources of variability were tested. Repeatability analysis was performed both on a normal and on a diabetic subject. Direct skin marker placement was chosen in correspondence of 13 anatomical landmarks and an optoelectronic system was used to collect the data.</p> <p>Results</p> <p>Joint rotation normative bands (mean plus/minus one standard deviation) were generated using the data of the control group. Three representative strides per subject were selected. The repeatability analysis on normal and pathological subjects results have been compared with literature and found comparable. Normal and pathological gait have been compared and showed major statistically significant differences in the forefoot and midfoot dorsi-plantarflexion.</p> <p>Conclusion</p> <p>Even though various biomechanical models have been developed so far to study the properties and behaviour of the foot, the present study focuses on developing a methodology for the functional assessment of the foot-ankle complex and for the definition of a functional model of the diabetic neuropathic foot. It is, of course, important to evaluate the major sources of variation (true variation in the subject's gait and artefacts from the measurement procedure). The repeatability of the protocol was therefore examined, and results showed the suitability of this method both on normal and pathological subjects. Comparison between normal and pathological kinematics analysis confirmed the validity of a similar approach in order to assess neuropathics biomechanics impairment.</p

BRCA mutation carriers' perceptions on postmenopausal hormone therapy: An Italian study

Objective To evaluate the actual perceptions of postmenopausal hormone therapy (HT) in BRCA mutation carriers (BRCAmc) in comparison with women from the general population.Methods Questionnaire-based study of 83 BRCAmc and a control group of 89 women without a genetic mutation. Perceptions were evaluated by specific questions and Likert scales (-5-+5).Results Present and past users of HT were more frequent in the control group (p = 0.01), with a longer time of use (p = 0.03). The preferred route of administration of HT was 'oral' (54.6%). The most frequently reported adverse effect of HT was venous thrombosis (0.8), while a protective effect on bone health was reported. No noticeable beneficial effects of HT have been recognised for hot flushes (0.2) and vaginal dryness (0.1). The most frequently perceived beneficial and adverse effects of HT were not significantly different between BRCA mutation carriers and controls. The greatest oncological fear was breast cancer (1.0). The protective role of HT on colorectal cancer was not known (0.1). These oncological impacts were mostly overestimated in BRCAmc, however this was not significant. Few BRCAmc would think of taking HT after risk-reducing surgeries.Conclusions Knowledge of the effects of HT on BRCAmc is relatively poor and they are likely to overstate its negative effects and underestimate its health benefits; however, this is not significant in comparison to the general population. More and better information should be given to BRCAmc to allow them to make informed decisions about the use of HT, especially before undergoing risk-reducing surgeries