Continuous Glucose, Insulin and Lifestyle Data Augmentation in Artificial Pancreas Using Adaptive Generative and Discriminative Models.

Artificial pancreas requires data from multiple sources for accurate insulin dose estimation. These include data from continuous glucose sensors, past insulin dosage information, meal quantity and time and physical activity data. The effectiveness of closed-loop diabetes management systems might be hampered by the absence of these data caused by device error or lack of compliance by patients. In this study, we demonstrate the effect of output sequence length-driven generative and discriminative model selection in high quality data generation and augmentation. This novel generative adversarial network (GAN) based architecture automatically selects the generator and discriminator architecture based on the desired output sequence length. The proposed model is able to generate glucose, physical activity, meal information data for individual patients. The discriminative scores for Ohio T1DM (2018) dataset were 0.17 ±0.03 (Inputs: CGM, CHO, Insulin) and 0.15 ±0.02 (Inputs: CGM, CHO, Insulin, Heart Rate, Steps) and for Ohio T1D (2020) dataset was 0.16 ±0.02 (Inputs: CGM, CHO, Insulin) and 0.15 ±0.02 (Inputs: CGM, CHO, Insulin, acceleration). A mixture of generated and real data was used to test predictive scores for glucose forecasting models. The best RMSE and MARD achieved for OhioT1DM patients were 17.19 ±3.22 and 7.14 ±1.76 for PH=30 min with CGM, CHO, Insulin, heartrate and steps as inputs. Similarly, the RMSE and MARD for real+synthetic data were 15.63 ±2.57 and 5.86 ±1.69 respectively. Compared to existing generative models, we demonstrate that sequence length based architecture selection leads to better synthetic data generation for multiple output sequences (CGM, CHO, Insulin) and forecasting accuracy.

InsNET: Accurate Basal and Bolus Insulin Dose Prediction for Closed Loop Diabetes Management.

It has been demonstrated that closed-loop diabetes management results in better glycemic control and greater compliance than open-loop diabetes management. Deep learning models have been used to implement different components of artifical pancreas. In this work, a novel deep learning model InsNET has been proposed to estimate the basal and bolus insulin level and insulin bolus in patients with type I diabetes utilizing subcutaneous insulin infusion pumps for closed loop diabetes management system. The proposed InsNET is formed with a Wide-Deep combination of LSTM and GRU layers. Additionally, physical activity level has been included as an input in comparison to previous models where only past glucose levels (CGM), meal intake (CHO) and past insulin dosage were used as inputs. The proposed model was tested on In-silico data, and it achieved a Mean Absolute Error (MAE) of 0.002 and Root Mean Squared Error (RMSE) of 0.007 for UVA/Padova Dataset and MAE of 0.001 and RMSE OF 0.003 for mGIPsim Dataset.Clinical relevance- Insulin dose determination is an important as aspect of artificial pancreas. This work describes a deep learning model to determine accurate basal and bolus insulin dosage.

Glucose Prediction using Wide-Deep LSTM Network for Accurate Insulin Dosing in Artificial Pancreas.

Closed-loop diabetes management has been shown to indicate improved glycaemic control and better compliance over open loop diabetes management. Currently, commercially available diabetes management devices rely on continuous glucose monitoring (CGM) sensors which monitor glucose levels from the interstitial fluid (ISF). As there exists a physiological delay between the blood glucose levels compared to the ISF glucose levels, it is crucial to predict or forecast glucose levels, in order to prevent hyperglycaemic events due to delayed insulin dosing. Accuracy of the forecast also needs to be optimum such that overdosing on insulin does not lead to hypoglycaemia. In this paper, we describe a novel Long Short Term Memory (LSTM) network which follows a wide and deep approach for different features to deliver an accurate glucose prediction output. It achieved a Mean Absolute Relative Difference (MARD) of 2.61 and Root Mean Squared Error (MSE) of 5.04. Clinical relevance- This work is relevant for closed-loop diabetes management devices, which are currently being used to manage Type 1 Diabetes (T1D).

A Point-of-Care Device for Fully Automated, Fast and Sensitive Protein Quantification via qPCR.

This paper presents a fully automated point-of-care device for protein quantification using short-DNA aptamers, where no manual sample preparation is needed. The device is based on our novel aptamer-based methodology combined with real-time polymerase chain reaction (qPCR), which we employ for very sensitive protein quantification. DNA amplification through qPCR, sensing and real-time data processing are seamlessly integrated into a point-of-care device equipped with a disposable cartridge for automated sample preparation. The system's modular nature allows for easy assembly, adjustment and expansion towards a variety of biomarkers for applications in disease diagnostics and personalised medicine. Alongside the device description, we also present a new algorithm, which we named PeakFluo, to perform automated and real-time quantification of proteins. PeakFluo achieves better linearity than proprietary software from a commercially available qPCR machine, and it allows for early detection of the amplification signal. Additionally, we propose an alternative way to use the proposed device beyond the quantitative reading, which can provide clinically relevant advice. We demonstrate how a convolutional neural network algorithm trained on qPCR images can classify samples into high/low concentration classes. This method can help classify obese patients from their leptin values to optimise weight loss therapies in clinical settings.

Aptasensor for Quantification of Leptin Through PCR Amplification of Short DNA-Aptamers.

Protein quantification is traditionally performed through enzyme-linked immunosorbent assay (ELISA), which involves long preparation times. To overcome this, new approaches use aptamers as an alternative to antibodies. In this paper, we present a new approach to quantify proteins with short DNA aptamers through polymerase chain reaction (PCR) resulting in shorter protocol times with comparatively improved limits of detection. The proposed method includes a novel way to quantify both the target protein and the corresponding short DNA-aptamers simultaneously, which also allows us to fully characterize the performance of aptasensors. Human leptin is used as a target protein to validate this technique, because it is considered an important biomarker for obesity-related studies. In our experiments, we achieved the lowest limit of detection of 100 pg/mL within less than 2 h, a limit affected by the dissociation constant of the leptin aptamer, which could be improved by selecting a more specific aptamer. Because of the simple and inexpensive approach, this technique can be employed for Lab-On-Chip implementations and for rapid "on-site" quantification of proteins.

Aesthetic Evaluation Of The Lower Third Of The Face Comparing Cephalometric And Photographic Analysis Considering Nasolabial And Labiomental Angles In Young Adult Pakistani Population.

BACKGROUND: Although the results derived from orthodontic treatment are focused at attaining an aesthetically pleasing soft tissue profile as directed by Angle's paradigm, however hard tissue including bone and tooth dimensions also play a pivotal role in attaining the set goal. This study was focused on evaluating the comparison of photographs and cephalometric radiographic images to dictate the differences that might occur when the same aesthetic evaluation technique is applied. A cross sectional comparative study was carried out at Frontier college of dentistry, Abbottabad and Sharif Medical and Dental College, Lahore from June to November 2020. METHODS: In this cross-sectional study, 60 subjects were incorporated as part of the study amongst which lateral cephalometric radiographic images and photographs, other diagnostic records such as dental casts were procured. The same analysis was applied to assess the lower third of the face in both the photographs and the radiographs with focus on the Labiomental and nasolabial angles for comparison. RESULTS: The normal value of Nasolabial angle 102.10°±3.126° (NLA2) indicates the relationship of nose and upper lip which is within the normal range for the age group selected. No significant difference was found between the nasolabial angles measured by two separate methods (p-value is 0.67). Mean labiomental angle was found to be 120.70°±6.46°(LNA1) and 121.60°±5.386 degrees °(LMA2) respectively, which was within the normal range for the age group selected. CONCLUSIONS: There is no significant difference in the assessment of lower facial height and aesthetics between lateral cephalometric radiographic images and photographs taken from the camera.

Coronavirus Disease 2019 (COVID-19): Forecast of an Emerging Urgency in Pakistan.

Background/Aims Novel coronavirus disease 2019 (COVID-19) is a global challenge due to little available knowledge and treatment protocols. Thus, there is a great need for collecting data related to COVID-19 from all around the world. Hence, we conducted this study, collecting daily data on COVID-19, to map the epidemiology outbreak and forecast its trajectory for May 2020. Methodology The data was collected from the officially released reports of the National Institute of Health (NIH), Pakistan, and the World Health Organization (WHO). The analysis was done using Statistical Package for the Social Sciences (SPSS) version 23 (IBM Corp., Armonk, NY), and forecasting was done using a simple moving average in time series modeler/expert modeler. Results The purpose of this study is to draw the attention of international, as well as national, governing bodies to the rapidly rising number of COVID-19 cases in Pakistan, and the urgency of evaluating the efficacy of the currently implemented strategy against COVID-19. According to this study, there is now an alarming increase in the number of COVID-19 patients in Pakistan, despite a contained spread in the beginning. The predicted number of COVID-19 cases can go over 35,000 by the end of May 2020. Conclusion It is crucial for governing bodies, administrators, and researchers to re-evaluate the current situation, designed policies, and implemented strategies.

Closed-Loop Implantable Therapeutic Neuromodulation Systems Based on Neurochemical Monitoring.

Closed-loop or intelligent neuromodulation allows adjustable, personalized neuromodulation which usually incorporates the recording of a biomarker, followed by implementation of an algorithm which decides the timing (when?) and strength (how much?) of stimulation. Closed-loop neuromodulation has been shown to have greater benefits compared to open-loop neuromodulation, particularly for therapeutic applications such as pharmacoresistant epilepsy, movement disorders and potentially for psychological disorders such as depression or drug addiction. However, an important aspect of the technique is selection of an appropriate, preferably neural biomarker. Neurochemical sensing can provide high resolution biomarker monitoring for various neurological disorders as well as offer deeper insight into neurological mechanisms. The chemicals of interest being measured, could be ions such as potassium (K+), sodium (Na+), calcium (Ca2+), chloride (Cl-), hydrogen (H+) or neurotransmitters such as dopamine, serotonin and glutamate. This review focusses on the different building blocks necessary for a neurochemical, closed-loop neuromodulation system including biomarkers, sensors and data processing algorithms. Furthermore, it also highlights the merits and drawbacks of using this biomarker modality.

Influence of Cholecystokinin-8 on Compound Nerve Action Potentials from Ventral Gastric Vagus in Rats.

OBJECTIVE: Vagus Nerve Stimulation (VNS) has shown great promise as a potential therapy for a number of conditions, such as epilepsy, depression and for Neurometabolic Therapies, especially for treating obesity. The objective of this study was to characterize the left ventral subdiaphragmatic gastric trunk of vagus nerve (SubDiaGVN) and to analyze the influence of intravenous injection of gut hormone cholecystokinin octapeptide (CCK-8) on compound nerve action potential (CNAP) observed on the same branch, with the aim of understanding the impact of hormones on VNS and incorporating the methods and results into closed loop implant design. METHODS: The cervical region of the left vagus nerve (CerVN) of male Wistar rats was stimulated with electric current and the elicited CNAPs were recorded on the SubDiaGVN under four different conditions: Control (no injection), Saline, CCK1 (100[Formula: see text]pmol/kg) and CCK2 (1000[Formula: see text]pmol/kg) injections. RESULTS: We identified the presence of A[Formula: see text], B, C1, C2, C3 and C4 fibers with their respective velocity ranges. Intravenous administration of CCK in vivo results in selective, statistically significant reduction of CNAP components originating from A and B fibers, but with no discernible effect on the C fibers in [Formula: see text] animals. The affected CNAP components exhibit statistically significant ([Formula: see text] and [Formula: see text]) higher normalized stimulation thresholds. CONCLUSION: This approach of characterizing the vagus nerve can be used in closed loop systems to determine when to initiate VNS and also to tune the stimulation dose, which is patient-specific and changes over time.

Extracellular pH monitoring for use in closed-loop vagus nerve stimulation.

OBJECTIVE: Vagal nerve stimulation (VNS) has shown potential benefits for obesity treatment; however, current devices lack physiological feedback, which limit their efficacy. Changes in extracellular pH (pHe) have shown to be correlated with neural activity, but have traditionally been measured with glass microelectrodes, which limit their in vivo applicability. APPROACH: Iridium oxide has previously been shown to be sensitive to fluctuations in pH and is biocompatible. Iridium oxide microelectrodes were inserted into the subdiaphragmatic vagus nerve of anaesthetised rats. Introduction of the gut hormone cholecystokinin (CCK) or distension of the stomach was used to elicit vagal nerve activity. MAIN RESULTS: Iridium oxide microelectrodes have sufficient pH sensitivity to readily detect changes in pHe associated with both CCK and gastric distension. Furthermore, a custom-made Matlab script was able to use these changes in pHe to automatically trigger an implanted VNS device. SIGNIFICANCE: This is the first study to show pHe changes in peripheral nerves in vivo. In addition, the demonstration that iridium oxide microelectrodes are sufficiently pH sensitive as to measure changes in pHe associated with physiological stimuli means they have the potential to be integrated into closed-loop neurostimulating devices.

A randomized study on a 3-month versus a 7-month prednisolone regimen for the initial episode of childhood idiopathic nephrotic syndrome at a large Saudi center.

BACKGROUND AND OBJECTIVES: The standard International Study of Kidney Disease in Children (ISKDC) regimen of prednisolone of 2 months duration for the treatment of the initial episode of Idiopathic Nephrotic Syndrome (INS) was associated with a high relapse rate. The long prednisolone protocols were introduced in order to reduce the relapse rate and steroid toxicities. The main objective of this study was to assess the efficacy and safety of a 3 months protocol of prednisolone versus a 7 months protocol for the first episode of idiopathic nephrotic syndrome. DESIGN AND SETTING: The study took place in the Pediatric Nephrology Department of King Saud Medical City, Riyadh which is a large referral center all over Saudi Arabia. The study was a randomized control trial using 2 groups. Group A received the 3 months protocol and Group B received the 7 months protocol. PATIENTS AND METHODS: All children with a confirmed diagnosis of Idiopathic Nephrotic Syndrome were included. The patients were randomized by simple randomization using sealed envelopes into two groups; group A comprised of 60 children using the daily regimen prednisolone 60 mg/m2 OD X 1 ½ months then 40mg/m2 on alternate day for 1 ½ months (total = 3 months) and group B also comprised of 60 children using the 7 months protocol, Prednisolone 60mg/m2 OD x 1 month then 40mg/m2 EOD x 2 months then 30mg/m2 EOD for 2 months then 20mg/m2 EOD for 2 months. The efficacy and safety of these two prednisolone regimens were recorded. The follow-up period was two years. Statistical analysis was done using the SPSS progress version 16 (Chicago, USA) P < .05 was taken as a significant result. Consort guidelines for randomized controlled trials (RCTs) were followed. The hospital ethical committee approved the study. The parents gave an informed consent. RESULTS: Group B protocol was found to be significantly better than the group A protocol in both years of follow-up. The mean time of first relapse was significantly better in group B than in group A (P < .0001). The relapse rate reduced significantly in group B vs group A in both the first year (P = .0031) as well as in the second year (P = .00002). The cumulative dose of steroids was significantly less in group B vs group A both in the first year of follow-up (P = .0039) as well as in the second year (P = .0026). The incidence of frequently relapsers was significantly less (P = .049) in group B as compared to group A. The risk of relapse was better in group B as compared to group A (RR 0.8039; 95% CI 0.6566 to 0.9843 significance (P = .0346). The side effects of corticosteroids were significantly less in group B protocol as compared to group A. CONCLUSION: We concluded that the long 7 months protocol was significantly better than the 3 months prednisolone regimen in both efficacy and safety for the initial episode of childhood INS.

Injection moulded microneedle sensor for real-time wireless pH monitoring.

This paper describes the development of an array of individually addressable pH sensitive microneedles using injection moulding and their integration within a portable device for real-time wireless recording of pH distributions in biological samples. The fabricated microneedles are subjected to gold patterning followed by electrodeposition of iridium oxide to sensitize them to 0.07 units of pH change. Miniaturised electronics suitable for the sensors readout, analog-to-digital conversion and wireless transmission of the potentiometric data are embodied within the device, enabling it to measure real-time pH of soft biological samples such as muscles. In this paper, real-time recording of the cardiac pH distribution, during ischemia followed by reperfusion cycles in cardiac muscles of male Wistar rats has been demonstrated by using the microneedle array.

Experience with second line drugs in frequently relapsing and steroid dependent childhood nephrotic syndrome in a large Saudi center.

BACKGROUND AND OBJECTIVES: To assess the efficacy and safety of second line drugs used at our center in frequently relapsing and steroid dependant (FR/SD) childhood nephrotic syndrome. PATIENTS AND METHODS: This was a retrospective study over a period of 3 years (July 2012 to July 2015) on the use of 4 second line drugs in FR/SD nephrotic syndrome in children treated at our center. These drugs were Levamisole, Mycophenolate Mofetil (MMF), Cyclophosphamide, and Cyclosporine. We studied the relapse rate per year, cumulative dose of steroids, success, failure, and side effects of these drugs. Statistical analyses were done with the help of a statistician using the T-test and the "N-1"Chi-Square test. RESULTS: We reviewed the charts of 60 children. All had FR/SD nephrotic syndrome and received a 3 month protocol of prednisolone. 20 received Levamisole (33%), 12 received Cyclophosphamide (20%), 20 received MMF (25%), and 13 received Cyclosporine (22%).All the four drugs significantly reduced the relapse rate and the cumulative dose of steroids (P < .0001). Treatment success was best with Cyclosporine (69.2%), and treatment failure was the least with Cyclosporine (7.6%). However, treatment success and failure with Cyclosporine when compared to other three drugs was not statistically significant. No dangerous side effects were seen with any of the 4 drugs in the observation period. CONCLUSION: All the second line drugs in our study were equally effective. However, we recommend that the initial treatment of FR/SD nephrotic syndrome should be chosen with the least toxic yet equally efficacious drug Levamisole.

Optimization of the Ugi reaction using parallel synthesis and automated liquid handling.

The optimization of a Ugi reaction involving the mixing of furfurylamine, benzaldehyde, boc-glycine and t-butylisocyanide is described. Triplicate runs of 48 parallel experiments are reported, varying concentration, solvent and the excess of some of the reagents. The isolation of the product was achieved by a simple filtration and wash procedure. The highest yield obtained was 66% from 0.4 M methanol with 1.2 eq. of imine. This is significantly above the 49% yield obtained from the initial reaction under equimolar concentration at 0.4 M in methanol. Methanol solutions with reagent concentrations of 0.4M or 0.2M gave superior yields while all solvent systems at 0.07M performed poorly. At 0.2M, methanol and ethanol/methanol (60/40) mixtures were statistically equally good while THF/methanol (60/40) was poor and acetonitrile/methanol (60/40) was intermediate. Good reproducibility of the precipitate yields was obtained in these replicate experiments, allowing for subtle interaction effects to be positively identified.

Gingival fine needle aspiration cytology in acute leukemia.

BACKGROUND: Oral findings in acute leukemia (AL) are common and could be the presenting feature of the disease, namely, gingival enlargement, ulceration, bleeding, and infection. Gingival enlargement in AL is either due to leukemic infiltration, or due to reactive hyperplasia. To differentiate between them a biopsy is required, but being highly contraindicated, biopsy has been substituted in this study by fine needle aspiration cytology (FNAC). METHOD: Gingival FNAC was performed on different sites in the upper and lower gingiva. Each site represents an interdental papilla, which was selected according to the clinical presentation, i.e., being enlarged or not. Seventy-two adult AL patients received a cytological and clinical examination in this study, and the cases were classified and categorized according to the French-American-British (FAB) criteria. RESULTS: Twenty-one cases were diagnosed as being infiltrated, 16 with gingival enlargement, 4 with no evidence of enlargement. In one case the infiltration affected the alveolar mucosa of an edentulous patient. In six cases the ginigva was enlarged without being infiltrated (reactive hyperplasia). Leukemic gingival enlargement was seen mostly in patients with acute myeloid leukemia, particularly M4 and M5 subtypes; however, two patients with acute mixed lineage leukemia (AMLL) were both affected with leukemic infiltration. CONCLUSION: FNAC was shown to be a simple, non-traumatic and useful diagnostic procedure for screening leukemic infiltration in gingival tissues in AL patients.