The present and future disease burden of hepatitis C virus infections with today's treatment paradigm - volume 3.

The total number, morbidity and mortality attributed to viraemic hepatitis C virus (HCV) infections change over time making it difficult to compare reported estimates from different years. Models were developed for 15 countries to quantify and characterize the viraemic population and forecast the changes in the infected population and the corresponding disease burden from 2014 to 2030. With the exception of Iceland, Iran, Latvia and Pakistan, the total number of viraemic HCV infections is expected to decline from 2014 to 2030, but the associated morbidity and mortality are expected to increase in all countries except for Japan and South Korea. In the latter two countries, mortality due to an ageing population will drive down prevalence, morbidity and mortality. On the other hand, both countries have already experienced a rapid increase in HCV-related mortality and morbidity. HCV-related morbidity and mortality are projected to increase between 2014 and 2030 in all other countries as result of an ageing HCV-infected population. Thus, although the total number of HCV countries is expected to decline in most countries studied, the associated disease burden is expected to increase. The current treatment paradigm is inadequate if large reductions in HCV-related morbidity and mortality are to be achieved.

Strategies to manage hepatitis C virus infection disease burden - volume 3.

The hepatitis C virus (HCV) epidemic was forecasted through 2030 for 15 countries in Europe, the Middle East and Asia, and the relative impact of two scenarios was considered: increased treatment efficacy while holding the annual number of treated patients constant and increased treatment efficacy and an increased annual number of treated patients. Increasing levels of diagnosis and treatment, in combination with improved treatment efficacy, were critical for achieving substantial reductions in disease burden. A 90% reduction in total HCV infections within 15 years is feasible in most countries studied, but it required a coordinated effort to introduce harm reduction programmes to reduce new infections, screening to identify those already infected and treatment with high cure rate therapies. This suggests that increased capacity for screening and treatment will be critical in many countries. Birth cohort screening is a helpful tool for maximizing resources. Among European countries, the majority of patients were born between 1940 and 1985. A wider range of birth cohorts was seen in the Middle East and Asia (between 1925 and 1995).

Historical epidemiology of hepatitis C virus (HCV) in select countries - volume 3.

Detailed, country-specific epidemiological data are needed to characterize the burden of chronic hepatitis C virus (HCV) infection around the world. With new treatment options available, policy makers and public health officials must reconsider national strategies for infection control. In this study of 15 countries, published and unpublished data on HCV prevalence, viraemia, genotype, age and gender distribution, liver transplants and diagnosis and treatment rates were gathered from the literature and validated by expert consensus in each country. Viraemic prevalence in this study ranged from 0.2% in Iran and Lebanon to 4.2% in Pakistan. The largest viraemic populations were in Pakistan (7 001 000 cases) and Indonesia (3 187 000 cases). Injection drug use (IDU) and a historically unsafe blood supply were major risk factors in most countries. Diagnosis, treatment and liver transplant rates varied widely between countries. However, comparison across countries was difficult as the number of cases changes over time. Access to reliable data on measures such as these is critical for the development of future strategies to manage the disease burden.

Glucose excursions and glycaemic control during Ramadan fasting in diabetic patients: insights from continuous glucose monitoring (CGM).

AIM: Ramadan fasting represents a major shift in meal timing and content for practicing Muslims. This study used continuous glucose monitoring (CGM) to assess changes in markers of glycaemic excursions during Ramadan fasting to investigate the short-term safety of this practice in different groups of patients with diabetes. METHODS: A total of 63 subjects (56 with diabetes, seven healthy volunteers; 39 male, 24 female) had CGM performed during, before and after Ramadan fasting. Mean CGM curves were constructed for each group for these periods that were then used to calculate indicators of glucose control and excursions. Post hoc data analyses included comparisons of different medication categories (metformin/no medication, gliptin, sulphonylurea and insulin). Medication changes during Ramadan followed American Diabetes Association guidelines. RESULT: Among patients with diabetes, there was a significant difference in mean CGM curve during Ramadan, with a slow fall during fasting hours followed by a rapid rise in glucose level after the sunset meal (iftar). The magnitude of this excursion was greatest in the insulin-treated group, followed by the sulphonylurea-treated group. Markers of control deteriorated in a small number (n=3) of patients. Overall, whether fasting or non-fasting, subjects showed no statistically significant changes in mean interstitial glucose (IG), mean amplitude of glycaemic excursion (MAGE), high and low blood glucose indices (HBGI/LBGI), and number of glucose excursions and rate of hypoglycaemia. CONCLUSION: The main change in glycaemic control with Ramadan fasting in patients with diabetes is in the pattern of excursions. Ramadan fasting caused neither overall deterioration nor improvement in the majority of patients with good baseline glucose control.

Neuroendocrine tumours.

Neuroendocrine tumours are a heterogeneous group including, for example, carcinoid, gastroenteropancreatic neuroendocrine tumours, pituitary tumours, medullary carcinoma of the thyroid and phaeochromocytomas. They have attracted much attention in recent years, both because they are relatively easy to palliate and because they have indicated the chronic effect of the particular hormone elevated. As neuroendocrine phenotypes became better understood, the definition of neuroendocrine cells changed and is now accepted as referring to cells with neurotransmitter, neuromodulator or neuropeptide hormone production, dense-core secretory granules, and the absence of axons and synapses. Neuroendocrine markers, particularly chromogranin A, are invaluable diagnostically. Study of several neuroendocrine tumours has revealed a genetic etiology, and techniques such as genetic screening have allowed risk stratification and prevention of morbidity in patients carrying the particular mutation. Pharmacological therapy for these often slow-growing tumours, e.g. with somatostatin analogues, has dramatically improved symptom control, and radiolabelled somatostatin analogues offer targeted therapy for metastatic or inoperable disease. In this review, the diagnosis and management of patients with carcinoid, gut neuroendocrine tumours, multiple endocrine neoplasia types 1 and 2, and isolated phaeochromocytoma are evaluated.

Molecular structure matching by simulated annealing. I. A comparison between different cooling schedules.

This paper outlines an application of the theory of simulated annealing to molecular matching problems. Three cooling schedules are examined: linear, exponential and dynamic cooling. The objective function is the sum of the elements of the difference distance matrix between the two molecules generated by continual reordering of one molecule. Extensive tests of the algorithms have been performed on random coordinate data together with two related protein structures. Combinatorial problems, inherent in the assignment of atom correspondences, are effectively overcome by simulated annealing. The algorithms outlined here can readily optimize molecular matching problems with 150 atoms.

Molecular structure matching by simulated annealing. II. An exploration of the evolution of configuration landscape problems.

This paper considers some of the landscape problems encountered in matching molecules by simulated annealing. Although the method is in theory ergodic, the global minimum in the objective function is not always encountered. Factors inherent in the molecular data that lead the trajectory of the minimization away from its optimal route are analysed. Segments comprised of the C alpha atoms of dihydrofolate reductase are used as test data. The evolution of a reverse ordering landscape problem is examined in detail. Where such patterns in the data could lead to incorrect matches, the problem can in part be circumvented by assigning an initial random ordering to the molecules.

Molecular structure matching by simulated annealing. III. The incorporation of null correspondences into the matching problem.

This paper extends an application of the method of simulated annealing for molecular matching so that the best common subsets of atom positions can be identified. Null correspondences are introduced into the difference distance matrix to enable poorly matched positions to be ignored in minimizing the objective function. The efficiency of the algorithm in finding correct subsets is rigorously tested.

The atom assignment problem in automated de novo drug design. 1. Transferability of molecular fragment properties.

This paper is the first of a series which examines the problems of atom assignment in automated de novo drug design. In subsequent papers, a combinatoric optimization method for fragment placement onto 3D molecular graphs is provided. Molecules are built from molecular graphs by placing fragments onto the graph. Here we examine the transferability of atomic residual charge, by fragment placement, with respect to the electrostatic potential. This transferability has been tested on 478 molecular structures extracted from the Cambridge Structural Database. The correlation found between the electrostatic potential computed from composite fragments and that computed for the whole molecule was encouraging, except for extended conjugated systems.

The atom assignment problem in automated de novo drug design. 2. A method for molecular graph and fragment perception.

If atom assignment onto 3D molecular graphs is to be optimized, an efficient scheme for placement must be developed. The strategy adopted in this paper is to analyze the molecular graphs in terms of cyclical and non-cyclical nodes; the latter are further divided into terminal and non-terminal nodes. Molecular fragments, from a fragments database, are described in a similar way. A canonical numbering scheme for the fragments and the local subgraph of the molecular graph enables fragments to be placed efficiently onto the molecular graph. Further optimization is achieved by placing similar fragments into bins using a hashing scheme based on the canonical numbering. The graph perception algorithm is illustrated in detail.

The atom assignment problem in automated de novo drug design. 3. Algorithms for optimization of fragment placement onto 3D molecular graphs.

Atom assignment onto 3D molecular graphs is a combinatoric problem in discrete space. If atoms are to be placed efficiently on molecular graphs produced in drug binding sites, the assignment must be optimized. An algorithm, based on simulated annealing, is presented for efficient optimization of fragment placement. Extensive tests of the method have been performed on five ligands taken from the Protein Data Bank. The algorithm is presented with the ligand graph and the electrostatic potential as input. Self placement of molecular fragments was monitored as an objective test. A hydrogen-bond option was also included, to enable the user to highlight specific needs. The algorithm performed well in the optimization, with successful replications. In some cases, a modification was necessary to reduce the tendency to give multiple halogenated structures. This optimization procedure should prove useful for automated de novo drug design.

The atom assignment problem in automated de novo drug design. 5. Tests for envelope-directed fragment placement based on molecular similarity.

The fragment placement method has been successfully extended to the problem of envelope-directed design. The atom assignment paradigm was based on molecular similarity between two molecular structures. A composite supersurface is defined to form the surface onto which the molecular fields are projected. The assignment process is then determined by using molecular similarity in the objective function to be optimized. In principle, this procedure is closely similar to that outlined in the previous paper for site-directed design. The rationale has been extensively tested on two benzodiazepine antagonists believed to bind to the same site.

The atom assignment problem in automated de novo drug design. 4. Tests for site-directed fragment placement based on molecular complementarity.

Three previous papers in this series have outlined an optimization method for atom assignment in drug design using fragment placement. In this paper the procedure is rigorously tested on a selection of five ligand-protein co-crystals. The algorithm is presented with the molecular graph of the ligand, and the electrostatic/hydrophobic potential of the site, with the aim of creating a placement on the molecular graph which is as electrostatically complementary or hydrophobically similar to the site as possible. Various designer options were tested, including, where appropriate, hydrogen bonding and a restricted number of halogens. In most cases, the placement obtained was at least as good as the native ligand, if not significantly better.

The scope for cardiovascular disease risk factor intervention among people with diabetes mellitus in England: a population-based analysis from the Health Surveys for England 1991-94.

AIMS: To examine the scope for cardiovascular disease risk factor intervention among diabetic patients in England was examined using data from the Health Surveys for England 1991-94. This evaluation included calculating the proportion who require lipid lowering therapy according to the Standing Medical Advisory Committee (SMAC) guidelines. METHODS: The Health Survey for England is an annual, nationwide household-based in which anthropomorphic data, blood pressure, lipids and details of cardiovascular risk factors are collected from households after random stratification for geographical and socio-economic factors within a population sample of 39639 adults, 970 (2.3%) diabetic subjects were identified. RESULTS: Overall, 51% of those with diabetes had hypertension (systolic blood pressure > or = 160 mmHg or a diastolic BP > or = 95 mmHg or being on antihypertensive therapy), 27% were obese (body mass index > or = 30 kg/m2) and 19% were current smokers. One-third of those with hypertension were untreated and less than one-half of those on treatment had their hypertension controlled to below 160/ 95 mmHg. More than one-quarter had poor glycaemic control (glycated Hb>11% or an HbA1c>7.5%). Of those aged <70 years, 29% required lipid lowering therapy according to the SMAC guidelines and almost all (94%) of these were not on treatment. An analysis showed that, because the SMAC guidelines do not require high density lipoprotein (HDL) cholesterol to be measured, their use is likely to result in substantial underestimation of the need for lipid lowering, particularly in diabetic women. CONCLUSION: In England, among those with diabetes there is considerable unmet need for cardiovascular risk factor intervention, particularly for hypertension and raised cholesterol. With this baseline established, future improvements can be monitored.