OPTIMIZING A SHORT-END ELECTROPHORETICALLY MEDIATED MICRO-ANALYSIS (EMMA) ASSAY FOR CREATININE

In this work electrophoretically mediated micro-analysis (EMMA) is used in conjunction with short end injection to improve the in-capillary Jaffé assay for creatinine. Key advances over prior work include (i) using simulation to ensure intimate overlap of reagent plugs, (ii) using OH- to drive the reaction, (iii) using short-end injection to minimize analysis time and in-line product degradation. The potential-driven overlapping time with the EMMA approach, as well as the borate buffer background electrolyte (BGE) concentration and pH are optimized with the short end approach. The best conditions for short-end analyses would not have been predicted by the prior long end work, owing to a complex interplay of separation time and product degradation rates. Raw peak areas and flow-adjusted peak areas for the Jaffé reaction product (at 505 nm) are used to assess the sensitivity of the short-end EMMA approach. Optimal overlap conditions depend heavily on local conductivity differences within the reagent zone(s), as these differences cause dramatic voltage field differences, which effect reagent overlap dynamics. Simul 5.0, a dynamic simulation program for capillary electrophoresis (CE) systems, is used to understand the ionic boundaries and profiles that give rise to the experimentally obtained data for EMMA analysis. Overall, fast migration of hydroxide ions from the picrate zone makes difficult reagent overlap. In addition, the challenges associated with the simultaneous overlapping of three reagent zones are considered, and experimental results validate the predictions made by the simulation. With one set of “optimized” conditions including OH- (253 mM) as the third reagent zone the response was linear with creatinine concentration (R2 = 0.998) and reproducible over the clinically relevant range (0.08 to 0.1 mM) of standard creatinine concentrations. An LOD (S/N = 3) of 0.02 mM and LOQ (S/N=10) of 0.08 mM were determined. A significant improvement (43%) in assay sensitivity was obtained compared to prior work that considered only two reagents in the overlap.

Evaluation of the Design of Komendant's Cycloidal, Thin Shell Roofs At the Kimbell Art Museum Using Finite Element Analysis

The analysis of Komendant's design of the Kimbell Art Museum was carried out in order to determine the effectiveness of the ring beams, edge beams and prestressing in the shells of the roof system. Finite element analysis was not available to Komendant or other engineers of the time to aid them in the design and analysis. Thus, the use of this tool helped to form a new perspective on the Kimbell Art Museum and analyze the engineer's work. In order to carry out the finite element analysis of Kimbell Art Museum, ADINA finite element analysis software was utilized. Eight finite element models (FEM-1 through FEM-8) of increasing complexity were created. The results of the most realistic model, FEM-8, which included ring beams, edge beams and prestressing, were compared to Komendant's calculations. The maximum deflection at the crown of the mid-span surface of -0.1739 in. in FEM-8 was found to be larger than Komendant's deflection in the design documents before the loss in prestressing force (-0.152 in.) but smaller than his prediction after the loss in prestressing force (-0.3814 in.). Komendant predicted a larger longitudinal stress of -903 psi at the crown (vs. -797 psi in FEM-8) and 37 psi at the edge (vs. -347 psi in FEM-8). Considering the strength of concrete of 5000 psi, the difference in results is not significant. From the analysis it was determined that both FEM-5, which included prestressing and fixed rings, and FEM-8 can be successfully and effectively implemented in practice. Prestressing was used in both models and thus served as the main contribution to efficiency. FEM-5 showed that ring and edge beams can be avoided, however an architect might find them more aesthetically appropriate than rigid walls.

Periodic breathing during ascent to extreme altitude quantified by spectral analysis of the respiratory volume signal

High altitude periodic breathing (PB) shares some common pathophysiologic aspects with sleep apnea, Cheyne-Stokes respiration and PB in heart failure patients. Methods that allow quantifying instabilities of respiratory control provide valuable insights in physiologic mechanisms and help to identify therapeutic targets. Under the hypothesis that high altitude PB appears even during physical activity and can be identified in comparison to visual analysis in conditions of low SNR, this study aims to identify PB by characterizing the respiratory pattern through the respiratory volume signal. A number of spectral parameters are extracted from the power spectral density (PSD) of the volume signal, derived from respiratory inductive plethysmography and evaluated through a linear discriminant analysis. A dataset of 34 healthy mountaineers ascending to Mt. Muztagh Ata, China (7,546 m) visually labeled as PB and non periodic breathing (nPB) is analyzed. All climbing periods within all the ascents are considered (total climbing periods: 371 nPB and 40 PB). The best crossvalidated result classifying PB and nPB is obtained with Pm (power of the modulation frequency band) and R (ratio between modulation and respiration power) with an accuracy of 80.3% and area under the receiver operating characteristic curve of 84.5%. Comparing the subjects from 1(st) and 2(nd) ascents (at the same altitudes but the latter more acclimatized) the effect of acclimatization is evaluated. SaO(2) and periodic breathing cycles significantly increased with acclimatization (p-value < 0.05). Higher Pm and higher respiratory frequencies are observed at lower SaO(2), through a significant negative correlation (p-value < 0.01). Higher Pm is observed at climbing periods visually labeled as PB with > 5 periodic breathing cycles through a significant positive correlation (p-value < 0.01). Our data demonstrate that quantification of the respiratory volume signal using spectral analysis is suitable to identify effects of hypobaric hypoxia on control of breathing.

A unified approach to modeling multivariate binary data using copulas over partitions

Many seemingly disparate approaches for marginal modeling have been developed in recent years. We demonstrate that many current approaches for marginal modeling of correlated binary outcomes produce likelihoods that are equivalent to the proposed copula-based models herein. These general copula models of underlying latent threshold random variables yield likelihood based models for marginal fixed effects estimation and interpretation in the analysis of correlated binary data. Moreover, we propose a nomenclature and set of model relationships that substantially elucidates the complex area of marginalized models for binary data. A diverse collection of didactic mathematical and numerical examples are given to illustrate concepts.

Substitutions due to antiretroviral toxicity or contraindication in the first 3 years of antiretroviral therapy in a large South African cohort

INTRODUCTION: The patterns and reasons for antiretroviral therapy (ART) drug substitutions are poorly described in resource-limited settings. METHODS: Time to and reason for drug substitution were recorded in treatment-naive adults receiving ART in two primary care treatment programmes in Cape Town. The cumulative proportion of patients having therapy changed because of toxicity was described for each drug, and associations with these changes were explored in multivariate models. RESULTS: Analysis included 2,679 individuals followed for a median of 11 months. Median CD4+ T-cell count at baseline was 85 cells/microl. Mean weight was 59 kg, mean age was 32 years and 71% were women. All started non-nucleoside reverse transcriptase inhibitor-based ART (60% on efavrienz) and 75% started on stavudine (d4T). After 3 years, 75% remained in care on-site, of whom 72% remained on their initial regimen. Substitutions due to toxicity of nevirapine (8% by 3 years), efavirenz (2%) and zidovudine (8%) occurred early. Substitutions on d4T occurred in 21% of patients by 3 years, due to symptomatic hyperlactataemia (5%), lipodystrophy (9%) or peripheral neuropathy (6%), and continued to accumulate over time. Those at greatest risk of hyperlactataemia or lipodystrophy were women on ART > or =6 months, weighing > or =75 kg at baseline. DISCUSSION: A high proportion of adult patients are able to tolerate their initial ART regimen for up to 3 years. In most instances treatment-limiting toxicities occur early, but continue to accumulate over time in patients on d4T. Whilst awaiting other treatment options, the risks of known toxicities could be minimized through early identification of patients at the highest risk.

Meta-analysis: chondroitin for osteoarthritis of the knee or hip

BACKGROUND: Previous meta-analyses described moderate to large benefits of chondroitin in patients with osteoarthritis. However, recent large-scale trials did not find evidence of an effect. PURPOSE: To determine the effects of chondroitin on pain in patients with osteoarthritis. DATA SOURCES: The authors searched the Cochrane Central Register of Controlled Trials (1970 to 2006), MEDLINE (1966 to 2006), EMBASE (1980 to 2006), CINAHL (1970 to 2006), and conference proceedings; checked reference lists; and contacted authors. The last update of searches was performed on 30 November 2006. STUDY SELECTION: Studies were included if they were randomized or quasi-randomized, controlled trials that compared chondroitin with placebo or with no treatment in patients with osteoarthritis of the knee or hip. There were no language restrictions. DATA EXTRACTION: The authors extracted data in duplicate. Effect sizes were calculated from the differences in means of pain-related outcomes between treatment and control groups at the end of the trial, divided by the pooled SD. Trials were combined by using random-effects meta-analysis. DATA SYNTHESIS: 20 trials (3846 patients) contributed to the meta-analysis, which revealed a high degree of heterogeneity among the trials (I2 = 92%). Small trials, trials with unclear concealment of allocation, and trials that were not analyzed according to the intention-to-treat principle showed larger effects in favor of chondroitin than did the remaining trials. When the authors restricted the analysis to the 3 trials with large sample sizes and an intention-to-treat analysis, 40% of patients were included. This resulted in an effect size of -0.03 (95% CI, -0.13 to 0.07; I2 = 0%) and corresponded to a difference of 0.6 mm on a 10-cm visual analogue scale. A meta-analysis of 12 trials showed a pooled relative risk of 0.99 (CI, 0.76 to 1.31) for any adverse event. LIMITATIONS: For 9 trials, the authors had to use approximations to calculate effect sizes. Trial quality was generally low, heterogeneity among the trials made initial interpretation of results difficult, and exploring sources of heterogeneity in meta-regression and stratified analyses may be unreliable. CONCLUSIONS: Large-scale, methodologically sound trials indicate that the symptomatic benefit of chondroitin is minimal or nonexistent. Use of chondroitin in routine clinical practice should therefore be discouraged.

Differences in the EEG profiles of early and late responders to antipsychotic treatment in first-episode, drug-naive psychotic patients

The aim of this study was to search for differences in the EEG of first-episode, drug-naive patients having a schizophrenic syndrome which presented different time courses in response to antipsychotic treatment. Thirteen patients who fulfilled DSM-IV diagnosis for schizophrenia or schizophreniform disorder participated in this study. Before beginning antipsychotic treatment, the EEG was recorded. On the same day psychopathological ratings were assessed using the ADMDP system, and again after 7 and 28 days of treatment. The resting EEG (19 leads) was subject to spectral analysis involving power values for six frequency bands. The score for the schizophrenic syndrome was used to divide the patients into two groups: those who displayed a clinically meaningful improvement of this syndrome (reduction of more than 30%) after 7 days of treatment (early responders, ER) and those who showed this improvement after 28 days (late responders. LR). Analysis of variance for repeated measures between ER, LR and their matched controls with the 19 EEG leads yielded highly significant differences for the factor group in the alpha2 and beta2 frequency band. No difference was found between the slow-wave frequency bands. Compared to controls the LR group showed significantly higher alpha2 and beta2 power and, in comparison to the ER group, significantly higher alpha2 power. There were no significant differences between the ER and the control group. These findings point to differences in brain physiology between ER and LR. The implications for diagnosis and treatment are discussed.

Dosimetric impact of geometric errors due to respiratory motion prediction on dynamic multileaf collimator-based four-dimensional radiation delivery

The synchronization of dynamic multileaf collimator (DMLC) response with respiratory motion is critical to ensure the accuracy of DMLC-based four dimensional (4D) radiation delivery. In practice, however, a finite time delay (response time) between the acquisition of tumor position and multileaf collimator response necessitates predictive models of respiratory tumor motion to synchronize radiation delivery. Predicting a complex process such as respiratory motion introduces geometric errors, which have been reported in several publications. However, the dosimetric effect of such errors on 4D radiation delivery has not yet been investigated. Thus, our aim in this work was to quantify the dosimetric effects of geometric error due to prediction under several different conditions. Conformal and intensity modulated radiation therapy (IMRT) plans for a lung patient were generated for anterior-posterior/posterior-anterior (AP/PA) beam arrangements at 6 and 18 MV energies to provide planned dose distributions. Respiratory motion data was obtained from 60 diaphragm-motion fluoroscopy recordings from five patients. A linear adaptive filter was employed to predict the tumor position. The geometric error of prediction was defined as the absolute difference between predicted and actual positions at each diaphragm position. Distributions of geometric error of prediction were obtained for all of the respiratory motion data. Planned dose distributions were then convolved with distributions for the geometric error of prediction to obtain convolved dose distributions. The dosimetric effect of such geometric errors was determined as a function of several variables: response time (0-0.6 s), beam energy (6/18 MV), treatment delivery (3D/4D), treatment type (conformal/IMRT), beam direction (AP/PA), and breathing training type (free breathing/audio instruction/visual feedback). Dose difference and distance-to-agreement analysis was employed to quantify results. Based on our data, the dosimetric impact of prediction (a) increased with response time, (b) was larger for 3D radiation therapy as compared with 4D radiation therapy, (c) was relatively insensitive to change in beam energy and beam direction, (d) was greater for IMRT distributions as compared with conformal distributions, (e) was smaller than the dosimetric impact of latency, and (f) was greatest for respiration motion with audio instructions, followed by visual feedback and free breathing. Geometric errors of prediction that occur during 4D radiation delivery introduce dosimetric errors that are dependent on several factors, such as response time, treatment-delivery type, and beam energy. Even for relatively small response times of 0.6 s into the future, dosimetric errors due to prediction could approach delivery errors when respiratory motion is not accounted for at all. To reduce the dosimetric impact, better predictive models and/or shorter response times are required.

Predictors of optimal viral suppression in patients switched to abacavir, lamivudine, and zidovudine: the Swiss HIV Cohort Study

OBJECTIVE: To investigate predictors of continued HIV RNA viral load suppression in individuals switched to abacavir (ABC), lamivudine (3TC) and zidovudine (ZDV) after successful previous treatment with a protease inhibitor or non-nucleoside reverse transcriptase inhibitor-based combination antiretroviral therapy. DESIGN AND METHODS: An observational cohort study, which included individuals in the Swiss HIV Cohort Study switching to ABC/3TC/ZDV following successful suppression of viral load. The primary endpoint was time to treatment failure defined as the first of the following events: two consecutiveviral load measurements > 400 copies/ml under ABC/3TC/ZDV, one viral load measurement > 400 copies/ml and subsequent discontinuation of ABC/3TC/ZDV within 3 months, AIDS or death. RESULTS: We included 495 individuals; 47 experienced treatment failure in 1459 person-years of follow-up [rate = 3.22 events/100 person-years; 95% confidence interval (95% CI), 2.30-4.14]. Of all failures, 62% occurred in the first year after switching to ABC/3TC/ZDV. In a Cox regression analysis, treatment failure was independently associated with earlier exposure to nucleoside reverse transcriptase inhibitor (NRTI) mono or dual therapy [hazard ratio (HR), 8.02; 95% CI, 4.19-15.35) and low CD4 cell count at the time of the switch (HR, 0.66; 95% CI, 0.51-0.87 by +100 cells/microl up to 500 cells/microl). In patients without earlier exposure to mono or dual therapy, AIDS prior to switch to simplified maintenance therapy was an additional risk factor. CONCLUSIONS: The failure rate was low in patients with suppressed viral load and switch to ABC/3TC/ZDV treatment. Patients with earlier exposure to mono or dual NRTI therapy, low CD4 cell count at time of switch, or AIDS are at increased risk of treatment failure, limiting the use of ABC/3TC/ZDV in these patient groups.

Somatic CEBPA mutations are a frequent second event in families with germline CEBPA mutations and familial acute myeloid leukemia

PURPOSE: The transcription factor CCAAT/enhancer binding protein-alpha (CEBPA) is crucial for normal myeloid differentiation. Mutations in the CEBPA gene are found in subsets of patients with acute myeloid leukemia (AML). Recently, three families were reported in whom several family members had germline CEBPA mutations and subsequently developed AML. Whereas familial AML is considered a rare event, the frequency of CEBPA germline mutations in AML is not known. PATIENTS AND METHODS: In this study, we screened 187 consecutive AML patients for CEBPA mutations at diagnosis. We detected 18 patients (9.6%) with CEBPA mutations. We then analyzed remission samples and constitutive DNA from these patients. RESULTS: We found that two (11.1%) of 18 AML patients with CEBPA mutations carried a germline N-terminal frameshift CEBPA mutation. Interestingly, additional members in the families of both of these patients have been affected by AML, and the germline CEBPA mutations were also observed in these patients. Additional somatic mutations in AML patients with germline CEBPA mutations in the two families comprised in-frame C-terminal CEBPA mutations in two patients, two nonsilent CEBPA point mutations in one patient, and monosomy 7 in one patient. CONCLUSION: This study shows, for the first time to our knowledge, that germline CEBPA mutations are frequently observed among AML patients with CEBPA mutations. Including the families with germline CEBPA mutations reported previously, additional somatic CEBPA mutations represent a frequent second event in AML with germline CEBPA mutations. Our data strongly indicate that germline CEBPA mutations predispose to AML and that additional somatic CEBPA mutations contribute to the development of the disease.

Characterization of legacy organic carbon in a culturally eutrophic lake : the role of the historic carbon deposition in the time course and extent of lake recovery

The time course of lake recovery after a reduction in external loading of nutrients is often controlled by conditions in the sediment. Remediation of eutrophication is hindered by the presence of legacy organic carbon deposits, that exert a demand on the terminal electron acceptors of the lake and contribute to problems such as internal nutrient recycling, absence of sediment macrofauna, and flux of toxic metal species into the water column. Being able to quantify the timing of a lake’s response requires determination of the magnitude and lability, i.e., the susceptibility to biodegradation, of the organic carbon within the legacy deposit. This characterization is problematic for organic carbon in sediments because of the presence of different fractions of carbon, which vary from highly labile to refractory. The lability of carbon under varied conditions was tested with a bioassay approach. It was found that the majority of the organic material found in the sediments is conditionally-labile, where mineralization potential is dependent on prevailing conditions. High labilities were noted under oxygenated conditions and a favorable temperature of 30 °C. Lability decreased when oxygen was removed, and was further reduced when the temperature was dropped to the hypolimnetic average of 8° C . These results indicate that reversible preservation mechanisms exist in the sediment, and are able to protect otherwise labile material from being mineralized under in situ conditions. The concept of an active sediment layer, a region in the sediments in which diagenetic reactions occur (with nothing occurring below it), was examined through three lines of evidence. Initially, porewater profiles of oxygen, nitrate, sulfate/total sulfide, ETSA (Electron Transport System Activity- the activity of oxygen, nitrate, iron/manganese, and sulfate), and methane were considered. It was found through examination of the porewater profiles that the edge of diagenesis occurred around 15-20 cm. Secondly, historical and contemporary TOC profiles were compared to find the point at which the profiles were coincident, indicating the depth at which no change has occurred over the (13 year) interval between core collections. This analysis suggested that no diagenesis has occurred in Onondaga Lake sediment below a depth of 15 cm. Finally, the time to 99% mineralization, the t99, was viewed by using a literature estimate of the kinetic rate constant for diagenesis. A t99 of 34 years, or approximately 30 cm of sediment depth, resulted for the slowly decaying carbon fraction. Based on these three lines of evidence , an active sediment layer of 15-20 cm is proposed for Onondaga Lake, corresponding to a time since deposition of 15-20 years. While a large legacy deposit of conditionally-labile organic material remains in the sediments of Onondaga Lake, it becomes clear that preservation, mechanisms that act to shield labile organic carbon from being degraded, protects this material from being mineralized and exerting a demand on the terminal electron acceptors of the lake. This has major implications for management of the lake, as it defines the time course of lake recovery following a reduction in nutrient loading.

DOUBLE VAULT COMPOSTING LATRINES IN RURAL PARAGUAY : FEASIBLE CONSTRUCTION AND OPTIMAL USE

Water resource depletion and sanitation are growing problems around the world. A solution to both of these problems is the use of composting latrines, as it requires no water and has been recommended by the World Health Organization as an improved sanitation technology. However, little analysis has been done on the decomposition process occurring inside the latrine, including what temperatures are reached and what variables most affect the composting process. Having better knowledge of how outside variables affect composting latrines can aid development workers on the choice of implementing such technology, and to better educate the users on the appropriate methods of maintenance. This report presents a full, detailed construction manual and temperature data analysis of a double vault composting latrine. During the author’s two year Peace Corps service in rural Paraguay he was involved with building twenty one composting latrines, and took detailed temperature readings and visual observations of his personal latrine for ten months. The author also took limited temperature readings of fourteen community member’s latrines over a three month period. These data points were analyzed to find correlations between compost temperatures and several variables. The two main variables found to affect the compost temperatures were the seasonal trends of the outside temperatures, and the mixing and addition of moisture to the compost. Outside seasonal temperature changes were compared to those of the compost and a linear regression was performed resulting in a R2-value of 0.89. Mixing the compost and adding water, or a water/urine mixture, resulted in temperature increases of the compost 100% of the time, with seasonal temperatures determining the rate and duration of the temperature increases. The temperature readings were also used to find events when certain temperatures were held for sufficient amounts of time to reach total pathogen destruction in the compost. Four different events were recorded when a temperature of 122°F (50°C) was held for at least 24 hours, ensuring total pathogen destruction in that area of the compost. One event of 114.8°F (46°C) held for one week was also recorded, again ensuring total pathogen destruction. Through the analysis of the temperature data, however, it was found that the compost only reached total pathogen destruction levels during ten percent of the data points. Because of this the storage time recommendation outlined by the World Health Organization should be complied with. The WHO recommends storing compost for 1.5-2 years in climates with ambient temperatures of 2-20°C (35-68°F), and for at least 1 year with ambient temperatures of 20-35°C (68-95°F). If these storage durations are obtainable the use of the double vault composting latrine is an economical and achievable solution to sanitation while conserving water resources.

The pharmacokinetic profile of fesoterodine: similarities and differences to tolterodine

BACKGROUND: Fesoterodine is a new antimuscarinic agent developed for the treatment of overactive bladder. Fesoterodine itself is inactive and is rapidly and extensively converted by ubiquitous esterases to its principal active moiety, 5-hydroxymethyl tolterodine (5-HMT). 5-HMT is formed via biotransformation of both fesoterodine and tolterodine, albeit by different metabolising enzymes, viz. esterases and CYP2D6 respectively. Tolterodine is a potent muscarinic receptor antagonist and has been used for the treatment of overactive bladder for over ten years. The objective of this study was to establish the pharmacokinetic profile of fesoterodine and to highlight ist potential pharmacokinetic advantages over tolterodine. DESIGN: Single-centre, open-label, randomised, 4-way crossover study in a total of 24 healthy male volunteers. Single oral doses of 4, 8, or 12 mg fesoterodine were administered after an overnight fast. In addition, the 8 mg dose was also administered after a standard high-fat and high-calorie breakfast. Blood and urine samples for the analysis of 5-HMT were collected before and multiple times after drug administration for pharmacokinetic analysis. RESULTS: The mean peak plasma concentration (Cmax) of 5-HMT and the mean area under the time versus concentration curve (AUC) increased proportionally with the fesoterodine dose. These two parameters were some 2-fold higher in CYP2D6 poor metabolisers, whereas the time to peak plasma concentration (tmax) and half life (t1/2) were not influenced by the dose or the CYP2D6 metaboliser status. If fesoterodine was taken following a high-fat breakfast, we observed small increases in Cmax and AUC. In spite of these modest genetic influences and food effects on the pharmacokinetics of fesoterodine, the overall interindividual variability in Cmax levels was relatively little compared to previously published reports using tolterodine. CONCLUSIONS: Due to the esterase-mediated cytochrome P450-independent formation of 5-HMT and involvement of multiple metabolic and renal excretion pathways in the elimination of 5-HMT, the effects of patient-intrinsic and -extrinsic factors on the pharmacokinetics of fesoterodine are only modest, with some 2-fold higher 5-HMT exposure. Therefore, in contrast to tolterodine, no reduction of fesoterodine dosage is required under conditions of reduced elimination. In most cases of drug interaction or renal/hepatic impairment, the fesoterodine dose may be increased to 8 mg/day based on individual patients' response, or patients may be required to remain at the initial recommended dose of 4 mg/day.

AccessMod 3.0: computing geographic coverage and accessibility to health care services using anisotropic movement of patients

Background Access to health care can be described along four dimensions: geographic accessibility, availability, financial accessibility and acceptability. Geographic accessibility measures how physically accessible resources are for the population, while availability reflects what resources are available and in what amount. Combining these two types of measure into a single index provides a measure of geographic (or spatial) coverage, which is an important measure for assessing the degree of accessibility of a health care network. Results This paper describes the latest version of AccessMod, an extension to the Geographical Information System ArcView 3.×, and provides an example of application of this tool. AccessMod 3 allows one to compute geographic coverage to health care using terrain information and population distribution. Four major types of analysis are available in AccessMod: (1) modeling the coverage of catchment areas linked to an existing health facility network based on travel time, to provide a measure of physical accessibility to health care; (2) modeling geographic coverage according to the availability of services; (3) projecting the coverage of a scaling-up of an existing network; (4) providing information for cost effectiveness analysis when little information about the existing network is available. In addition to integrating travelling time, population distribution and the population coverage capacity specific to each health facility in the network, AccessMod can incorporate the influence of landscape components (e.g. topography, river and road networks, vegetation) that impact travelling time to and from facilities. Topographical constraints can be taken into account through an anisotropic analysis that considers the direction of movement. We provide an example of the application of AccessMod in the southern part of Malawi that shows the influences of the landscape constraints and of the modes of transportation on geographic coverage. Conclusion By incorporating the demand (population) and the supply (capacities of heath care centers), AccessMod provides a unifying tool to efficiently assess the geographic coverage of a network of health care facilities. This tool should be of particular interest to developing countries that have a relatively good geographic information on population distribution, terrain, and health facility locations.