An extended minimal model of OGTT: estimation of α- and ß-cell dysfunction, insulin resistance, and the incretin effect.

Loss of insulin sensitivity, α- and ß-cell dysfunction, and impairment in incretin effect have all been implicated in the pathophysiology of type 2 diabetes (T2D). Parsimonious mathematical models are useful in quantifying parameters related to the pathophysiology of T2D. Here, we extend the minimum model developed to describe the glucose-insulin-glucagon dynamics in the isoglycemic intravenous glucose infusion (IIGI) experiment to the oral glucose tolerance test (OGTT). The extended model describes glucose and hormone dynamics in OGTT including the contribution of the incretin hormones, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide-1 (GLP-1), to insulin secretion. A new function describing glucose arrival from the gut is introduced. The model is fitted to OGTT data from eight individuals with T2D and eight weight-matched controls (CS) without diabetes to obtain parameters related to insulin sensitivity, ß- and α-cell function. The parameters, i.e., measures of insulin sensitivity, a1, suppression of glucagon secretion, k1, magnitude of glucagon secretion, γ2, and incretin-dependent insulin secretion, γ3, were found to be different between CS and T2D with P values < 0.002, <0.017, <0.009, <0.004, respectively. A new rubric for estimating the incretin effect directly from modeling the OGTT is presented. The average incretin effect correlated well with the experimentally determined incretin effect with a Spearman rank test correlation coefficient of 0.67 (P < 0.012). The average incretin effect was found to be different between CS and T2D (P < 0.032). The developed model is shown to be effective in quantifying the factors relevant to T2D pathophysiology.NEW & NOTEWORTHY A new extended model of oral glucose tolerance test (OGTT) has been developed that includes glucagon dynamics and incretin contribution to insulin secretion. The model allows the estimation of parameters related to α- and ß-cell dysfunction, insulin sensitivity, and incretin action. A new function describing the influx of glucose from the gut has been introduced. A new rubric for estimating the incretin effect directly from the OGTT experiment has been developed. The effect of glucose dose was also investigated.

A glucose-insulin-glucagon coupled model of the isoglycemic intravenous glucose infusion experiment.

Type 2 diabetes (T2D) is a pathophysiology that is characterized by insulin resistance, beta- and alpha-cell dysfunction. Mathematical models of various glucose challenge experiments have been developed to quantify the contribution of insulin and beta-cell dysfunction to the pathophysiology of T2D. There is a need for effective extended models that also capture the impact of alpha-cell dysregulation on T2D. In this paper a delay differential equation-based model is developed to describe the coupled glucose-insulin-glucagon dynamics in the isoglycemic intravenous glucose infusion (IIGI) experiment. As the glucose profile in IIGI is tailored to match that of a corresponding oral glucose tolerance test (OGTT), it provides a perfect method for studying hormone responses that are in the normal physiological domain and without the confounding effect of incretins and other gut mediated factors. The model was fit to IIGI data from individuals with and without T2D. Parameters related to glucagon action, suppression, and secretion as well as measures of insulin sensitivity, and glucose stimulated response were determined simultaneously. Significant impairment in glucose dependent glucagon suppression was observed in patients with T2D (duration of T2D: 8 (6-36) months) relative to weight matched control subjects (CS) without diabetes (k1 (mM)-1: 0.16 ± 0.015 (T2D, n = 7); 0.26 ± 0.047 (CS, n = 7)). Insulin action was significantly lower in patients with T2D (a1 (10 pM min)-1: 0.000084 ± 0.0000075 (T2D); 0.00052 ± 0.00015 (CS)) and the Hill coefficient in the equation for glucose dependent insulin response was found to be significantly different in T2D patients relative to CS (h: 1.4 ± 0.15; 1.9 ± 0.14). Trends in parameters with respect to fasting plasma glucose, HbA1c and 2-h glucose values are also presented. Significantly, a negative linear relationship is observed between the glucagon suppression parameter, k1, and the three markers for diabetes and is thus indicative of the role of glucagon in exacerbating the pathophysiology of diabetes (Spearman Rank Correlation: (n = 12; (-0.79, 0.002), (-0.73,.007), (-0.86,.0003)) respectively).

Essential medicine shortages, procurement process and supplier response: A normative study across Indian states.

Efficient public-procurement systems are critical for ensuring Access to Medicines (ATM) and enabling universal healthcare delivery. This is especially true of India where public healthcare caters to the underprivileged population who have limited access to medicines. However, essential medicine shortage in the Indian public-healthcare system is significant and is exacerbated by inefficiencies in the procurement system. Healthcare policy makers have to constantly contend with delays and non-fulfillment of medicine orders leading to shortages. Pharmaceutical companies supplying orders argue that the current system is not business-viable or fair. To explore these issues in-depth, we distill insights from structured interviews with a Policy Maker and interactions with the pharmaceutical industry to identify supply side issues which lead to medicine shortages. We build a normative model and utilize public medicine procurement data to study how pharmaceutical supplier response and order fulfillment is impacted by orders from multiple Indian states with different procurement conditions. We then employ standard supply chain theory to propose solutions to mitigate some of these issues. We find that the current system can be significantly improved by increased capacity allocation at suppliers for state orders, staggered ordering at the state level, stricter but gradual implementation of penalties and blacklisting and sourcing from suppliers located closer to the state.

A time motion study of community mental health workers in rural India.

BACKGROUND: Community Health Workers (CHWs) are critical to providing healthcare services in countries such as India which face a severe shortage of skilled healthcare personnel especially in rural areas. The aim of this study is to understand the work flow of CHWs in a rural Community Mental Health Project (CMHP) in India and identify inefficiencies which impede their service delivery. This will aid in formulating a targeted policy approach, improving efficiency and supporting appropriate work allocation as the roles and responsibilities of the CHWs evolve. METHODS: A continuous observation Time Motion study was conducted on Community Health Workers selected through purposive sampling. The CHWs were observed for the duration of an entire working day (9 am- 3 pm) for 5 days each, staggered during a period of 1 month. The 14 different activities performed by the CHWs were identified and the time duration was recorded. Activities were then classified as value added, non-value added but necessary and non-value-added to determine their time allocation. RESULTS: Home visits occupied the CHWs for the maximum number of hours followed by Documentation, and Traveling. Documentation, Administrative work and Review of work process are the non-value-added but necessary activities which consumed a significant proportion of their time. The CHWs spent approximately 40% of their time on value added, 58.5% of their time on non-value added but necessary and 1.5% of their time on non-value added activities. The CHWs worked for 0.7 h beyond the stipulated time daily. CONCLUSION: The CHW's are "dedicated" mental health workers as opposed to being "generalists" and their activities involve a significant investment of their time due to the specialized nature of the services offered such as counselling, screening and home visits. The CHWs are stretched beyond their standard work hours. Non-value added but necessary activities consumed a significant proportion of their time at the expense of value-added activities. Work flow redesign and implementation of Health Management Information Systems (HMIS) can mitigate inefficiencies.

Which is Superior, Doppler Velocimetry or Non-stress Test or Both in Predicting the Perinatal Outcome of High-Risk Pregnancies.

AIM AND OBJECTIVES: To analyze which is superior, Doppler velocimetry or non-stress test or both by means of categorization into four groups and comparing the prediction of perinatal outcome in high-risk pregnancies like anemia, hypertensive disorders of pregnancies. MATERIALS AND METHODS: This was a prospective study conducted at the Department of Obstetrics and Gynaecology, ISO KGH, Madras Medical College, Chennai, in the year 2014. Two hundred high-risk pregnancies like anemia, hypertensive disorders of pregnancy were included in the study. They were examined systematically, and Doppler velocimetry and non-stress test were done. The main vessels studied by Doppler were umbilical artery and middle cerebral artery, and the indices were calculated. The results of the non-stress test were interpreted as reactive and non-reactive. Based on the results of Doppler and non-stress test, the 200 cases were categorized into four groups and the results were analyzed. RESULTS: Among the 200 cases of high-risk pregnancies, those with a normal Doppler study and a reactive non-stress test had good perinatal outcome. When both were abnormal, there was a higher percentage of adverse outcome as compared to that of either Doppler alone being abnormal or non-stress test alone being non-reactive. It was also found that abnormal Doppler but with a reactive non-stress test had the advantage of prolonging the pregnancy and bringing a better outcome indicating that non-stress test is surely a good test of well-being. When Doppler was normal, but non-stress test was non-reactive, there was an increase in the rate of cesarean section. CONCLUSION: Each method of fetal surveillance reflects different aspect of maternal and fetal pathophysiology. Hence, combining these will help to bring out better perinatal outcome.

Self-Assembled Light-Harvesting System from Chromophores in Lipid Vesicles.

Lipid vesicles are used as the organizational structure of self-assembled light-harvesting systems. Following analysis of 17 chromophores, six were selected for inclusion in vesicle-based antennas. The complementary absorption features of the chromophores span the near-ultraviolet, visible, and near-infrared region. Although the overall concentration of the pigments is low (~1 µM for quantitative spectroscopic studies) in a cuvette, the lipid-vesicle system affords high concentration (≥10 mM) in the bilayer for efficient energy flow from donor to acceptor. Energy transfer was characterized in 13 representative binary mixtures using static techniques (fluorescence-excitation versus absorptance spectra, quenching of donor fluorescence, modeling emission spectra of a mixture versus components) and time-resolved spectroscopy (fluorescence, ultrafast absorption). Binary donor-acceptor systems that employ a boron-dipyrrin donor (S0 ↔ S1 absorption/emission in the blue-green) and a chlorin or bacteriochlorin acceptor (S0 ↔ S1 absorption/emission in the red or near-infrared) have an average excitation-energy-transfer efficiency (ΦEET) of ~50%. Binary systems with a chlorin donor and a chlorin or bacteriochlorin acceptor have ΦEET ∼ 85%. The differences in ΦEET generally track the donor-fluorescence/acceptor-absorption spectral overlap within a dipole-dipole coupling (Förster) mechanism. Substantial deviation from single-exponential decay of the excited donor (due to the dispersion of donor-acceptor distances) is expected and observed. The time profiles and resulting ΦEET are modeled on the basis of (Förster) energy transfer between chromophores relatively densely packed in a two-dimensional compartment. Initial studies of two ternary and one quaternary combination of chromophores show the enhanced spectral coverage and energy-transfer efficacy expected on the basis of the binary systems. Collectively, this approach may provide one of the simplest designs for self-assembled light-harvesting systems that afford broad solar collection and efficient energy transfer.

Diblock copolymer micelles and supported films with noncovalently incorporated chromophores: a modular platform for efficient energy transfer.

We report generation of modular, artificial light-harvesting assemblies where an amphiphilic diblock copolymer, poly(ethylene oxide)-block-poly(butadiene), serves as the framework for noncovalent organization of BODIPY-based energy donor and bacteriochlorin-based energy acceptor chromophores. The assemblies are adaptive and form well-defined micelles in aqueous solution and high-quality monolayer and bilayer films on solid supports, with the latter showing greater than 90% energy transfer efficiency. This study lays the groundwork for further development of modular, polymer-based materials for light harvesting and other photonic applications.

A molecular dynamics and computational study of ligand docking and electron transfer in ferritins.

The mechanism of the reductive release of iron from the cavity of the iron storage protein, ferritin, has been difficult to confirm on the molecular level using experimental studies. In this paper, we use a variety of computational tools to study the binding of flavin redox agents to the protein surface, and the subsequent electron transfer (ET) through the protein coat. Flavin binding sites are identified that represent efficient routes to reduction of Fe(III) across the protein coat in human and bacterial ferritins. Using the pathways model and Dutton's packing density model, we show that ET across the protein coat to nucleation sites is feasible. Different protein configurations for human heavy and light chain ferritin were obtained along classical molecular dynamics trajectories and used for flavin binding and ET studies. We find that protein configuration affects both the binding and ET rate constants significantly. We show that the maximum possible ET rate constants to the nucleation site GLU-61 in human heavy chain ferritin for protein configurations along a MD simulation trajectory can differ by about 8 orders of magnitude compared to the crystal structure and in human light-chain ferritin rate constants vary by about 4 orders of magnitude.