Changes In Treatment Efficacy Research Articles

Dynamics of Cardicola spp. Infection in Ranched Southern Bluefin Tuna: First Observation of C. orientalis at Transfer.

Aporocotylid blood flukes Cardicola forsteri and C. orientalis are an ongoing health concern for the Southern Bluefin Tuna (Thunnus maccoyii, SBT) industry, where infections can lead to morbidity and mortality in ranched SBT populations. This study compared blood fluke infection in SBT from two companies during the 2021 ranching season. Both companies administered the same dosage of praziquantel approximately 5 weeks after transfer, feeding with frozen baitfish daily; the only difference in the company's practices was that the pontoons were located 2.5 km apart. Infection severity was measured as prevalence and intensity by quantifying adult C. forsteri in SBT heart and copy numbers of C. forsteri and C. orientalis ITS-2 DNA in SBT heart and gills. Data from the 2018 and 2019 harvests of SBT were used to make comparisons with 2021 harvest data. Cardicola orientalis was detected at transfer and no longer detected after treatment with praziquantel. Cardicola spp. were present in 83% of sampled SBT in 2021. Both companies demonstrated similar patterns of infection, and Company A had higher prevalence and intensity of Cardicola spp. infection. Based on C. forsteri ITS-2 DNA, infection intensity at harvest was significantly greater for both companies in 2021 when compared to 2018 and 2019. Continued monitoring of Cardicola spp. in SBT and improvements in diagnostics contribute to our understanding of Cardicola spp. epizootiology and the detection of changes in treatment efficacy.

A Bayesian zero-inflated beta-binomial model for longitudinal data with group-specific changepoints.

Timeline followback (TLFB) is often used in addiction research to monitor recent substance use, such as the number of abstinent days in the past week. TLFB data usually take the form of binomial counts that exhibit overdispersion and zero inflation. Motivated by a 12-week randomized trial evaluating the efficacy of varenicline tartrate for smoking cessation among adolescents, we propose a Bayesian zero-inflated beta-binomial model for the analysis of longitudinal, bounded TLFB data. The model comprises a mixture of a point mass that accounts for zero inflation and a beta-binomial distribution for the number of days abstinent in the past week. Because treatment effects appear to level off during the study, we introduce random changepoints for each study group to reflect group-specific changes in treatment efficacy over time. The model also includes fixed and random effects that capture group- and subject-level slopes before and after the changepoints. Using the model, we can accurately estimate the mean trend for each study group, test whether the groups experience changepoints simultaneously, and identify critical windows of treatment efficacy. For posterior computation, we propose an efficient Markov chain Monte Carlo algorithm that relies on easily sampled Gibbs and Metropolis-Hastings steps. Our application shows that the varenicline group has a short-term positive effect on abstinence that tapers off after week 9.

Assessing the Cost-effectiveness of a Hypothetical Disease-modifying Therapy With Limited Duration for the Treatment of Early Symptomatic Alzheimer Disease

PurposeClinical trials have produced promising results for disease-modifying therapies (DMTs) for Alzheimer’s disease (AD); however, the evidence on their potential cost-effectiveness is limited. This study assesses the cost-effectiveness of a hypothetical DMT with a limited treatment duration in AD. MethodsWe developed a Markov state–transition model to estimate the cost-effectiveness of a hypothetical DMT plus best supportive care (BSC) versus BSC alone among Americans living with mild cognitive impairment (MCI) due to AD or mild AD. AD states included MCI due to AD, mild AD, moderate AD, severe AD, and death. A hypothetical DMT was assumed to confer a 30% reduction in progression from MCI and mild AD. The base case annual drug acquisition cost was assumed to be $56,000. Other medical and indirect costs were obtained from published literature or list prices. Utilities for patients and caregivers were obtained from the published literature and varied by AD state and care setting (community care or long-term care). We considered 3 DMT treatment strategies: (1) treatment administered until patients reached severe AD (continuous strategy), (2) treatment administered for a maximum duration of 18 months or when patients reached severe AD (fixed-duration strategy), and (3) 40% of patients discontinuing treatment at 6 months because of amyloid plaque clearance and the remaining patients continuing treatment until 18 months or until they reached severe AD (test-and-discontinue strategy). Incremental cost-effectiveness ratios (ICERs) were calculated as the incremental cost per quality-adjusted life-year (QALY) gained. FindingsFrom the health care sector perspective, continuous treatment with a hypothetical DMT versus BSC resulted in an ICER of $612,354 per QALY gained. The ICER decreased to $157,288 per QALY gained in the fixed-duration strategy, driven by large reductions in treatment costs. With 40% of patients discontinuing treatment at 6 months (test-and-discontinue strategy), the ICER was $125,631 per QALY gained. In sensitivity and scenario analyses, the ICER was the most sensitive to changes in treatment efficacy, treatment cost, and the initial population AD state distribution. From the modified societal perspective, ICERs were 6.3%, 20.4%, and 25.1% lower than those from the health care sector perspective for the continuous, fixed-duration, and test-and-discontinue strategies, respectively. ImplicationsUnder a set of assumptions for annual treatment costs and the magnitude and duration of treatment efficacy, DMTs used for a limited duration may deliver value consistent with accepted US cost-effectiveness thresholds.

Salmon lice should be managed before they attach to salmon: Exploring epidemiological factors affecting Lepeophtheirus salmonis abundance on salmon farms

The ectoparasite Lepeophtheirus salmonis has for decades been a serious challenge to the sustainability of salmonid aquaculture and has the potential to disrupt the ecosystem of wild salmonids. To tackle this challenge, efforts have been made to develop effective lice control strategies that deter ectoparasitic infestations on salmon farms. Infestation control can be enhanced by understanding L. salmonis population dynamics that may reveal critical points at which to intervene. Here, we investigate the impact of key parameters affecting L. salmonis population dynamics on salmon farms with a view to informing L. salmonis management. We built a system dynamics model to simulate L. salmonis populations in a hypothetical Atlantic salmon (Salmo salar L.) farm. Our model focused on three key parameters in the life cycle of L. salmonis: external pressure (rate of introduction of planktonic L. salmonis from outside the farm), attachment proportion (proportion of L. salmonis that successfully infest salmon), and treatment efficacy (proportion of L. salmonis that are killed as a result of treatment). By applying various combinations of plausible values for these three parameters, their modelled impacts on L. salmonis management were evaluated in terms of the total number of required treatments and the total infestation burden during a typical production cycle. These two modelled outcomes represent the cost of treatment and a proxy for other likely costs, such as lost growth or mortality caused by the parasite. Our results indicated that overall L. salmonis infestation levels were more sensitive to changes in the proportion of successful attachment, followed by changes in external pressure, and were least affected by changes in treatment efficacy. While attachment proportion and external pressure are involved at the pre-infestation stages in the life cycle of L. salmonis, treatment efficacy is involved in the post-infestation stages. Therefore, these findings suggest that preventing infestation before lice attach to fish is a more effective L. salmonis control strategy than treating already infested salmon. Overall, the presented results provide numerical evidence for the efficiency of prevention and support the development and application of prevention measures that have been on the rise in recent years.

Objective assessment of the effects of tumor motion in radiation therapy

Internal organ motion reduces the accuracy and efficacy of radiation therapy. However, there is a lack of tools to objectively (based on a medical or scientific task) assess the dosimetric consequences of motion, especially on an individual basis. We propose to use therapy operating characteristic (TOC) analysis to quantify the effects of motion on treatment efficacy for individual patients. We demonstrate the application of this tool with pancreatic stereotactic body radiation therapy (SBRT) clinical data and explore the origin of motion sensitivity. The technique is described as follows. (a) Use tumor-motion data measured from patients to calculate the motion-convolved dose of the gross tumor volume (GTV) and the organs at risk (OARs). (b) Calculate tumor control probability (TCP) and normal tissue complication probability (NTCP) from the motion-convolved dose-volume histograms. (c) Construct TOC curves from TCP and NTCP models. (d) Calculate the area under the TOC curve (AUTOC) and use it as a figure of merit for treatment efficacy. We used tumor motion data measured from patients to calculate the relation between AUTOC and motion magnitude for 25 pancreatic SBRT treatment plans. Furthermore, to explore the driving factor of motion sensitivity of a given plan, we compared the dose distribution of motion-sensitive plans and motion-robust plans and studied the dependence of motion sensitivity to motion directions. Our technique is able to recognize treatment plans that are sensitive to motion. Under the presence of motion, the treatment efficacy of some plans changes from providing high tumor control and low risks of complications to providing no tumor control and high risks of side effects. Several treatment plans experience falloffs in AUTOC at a smaller magnitude of motion than other plans. In our dataset, a potential indicator of a motion-sensitive treatment plan is that the duodenum is in proximity to the tumor in the SI direction. The TOC framework can serve as a tool to quantify the effects of internal organ motion in radiation therapy. With pancreatic SBRT clinical data, we applied this tool to study the change in treatment efficacy induced by motion for individual treatment plans. This framework could potentially be used clinically to understand the effects of motion in an individual patient and to design a patient-specific motion management plan. This framework could also be used in research to evaluate different components of the treatment process, such as motion-management techniques, treatment-planning algorithms, and treatment margins.

Clinical outcome of patients with gestational trophoblastic neoplasia receiving primary treatment at Peking Union Medical College Hospital: a 30-year retrospective cohort study

Objective: To summarize and analyze the clinical outcomes of gestational trophoblastic neoplasia (GTN) patients receiving primary treatment at Peking Union Medical College Hospital from 1985 to 2015, and investigate the changes in treatment efficacy between the first and the second 15 years. Methods: Clinical data of GTN patient receiving primary chemotherapy at Peking Union Medical College Hospital from January 1985 to December 2015 were retrospectively analyzed. It further compared the therapeutic results and chemotherapy cycles given to GTN patients, according to International Federation of Gynecology and Obstetrics (FIGO, 2000) prognostic score system, who were classified to different stages and low- or high-risk groups. Results: In total, 1 711 GTN patients were included in this study. Comparing the 1985-2000 group and the 2001-2015 group, the results showed that: (1) while the overall complete remission (CR) rate was 93.7% (1 603/1 711) , the CR rate of 2001-2015 group was significantly higher than that of 1985-2000 group [98.4% (1 155/1 174) vs 83.4% (448/537) , χ(2)=139.353, P<0.01]. This difference was significant between stage Ⅲ and Ⅳ patients, but nonexistent between stage Ⅰ and Ⅱ patients, including low- and high-risk groups. (2) The relapse rate of patients who had been in CR was 2.7% (43/1 603) , with no significant differences between the groups of 1985-2001 and 2001-2015 [3.6% (16/448) vs 2.3% (27/1 155) , χ(2)=6.867, P=0.142]. (3) The overall mortality rate was 2.6% (44/1 711) , which significantly decreased in 2001-2015 group compared to 1985-2000 group [1.6% (19/1 174) vs 4.7% (25/537) , χ(2)=13.830, P<0.01]. This difference appeared only in high-risk patients with stage Ⅲ disease (χ(2)=9.505, P<0.01) . (4) Fluorouracil was gradually replaced by floxridine in chemotherapy regimens. The total cycles of chemotherapy regimens given to low-risk patients with stage Ⅲ disease significantly decreased in 2001-2015 group, but no statistical difference was shown with patients at other stages. Moreover, the cycles of consolidation treatment were significantly reduced in patients with stage Ⅲ patients. Conclusions: GTN patients could obtain satisfactory curative results after appropriate and standard treatment. Peking Union Medical College Hospital has achieved better curative effect in the latest 15 years than before.

How does the pattern of aeroallergen sensitization change over time across all ages?

Identification of aeroallergen sensitization is important for diagnosis and management of allergic diseases. Immunoglobulin E (IgE) sensitization status is known to change over time. However, few studies have explored changes in sensitization patterns across all age groups. The aim of the present study was to evaluate the changing patterns of in vitro IgE sensitization tests in allergic rhinitis patients across all age groups. We recruited all patients who were diagnosed as having rhinitis and who underwent in vitro IgE sensitization testing from 2007 to 2016. Of these, we included 138 who underwent repeat testing. We analyzed epidemiological data and allergen sensitization patterns. Of all patients, 56.5% of exhibited changes in allergen sensitization patterns. The allergens to which all age groups were sensitive were most commonly mites, with the exception of patients aged 40 to 59 years. The age group in which "new sensitization," composed of those with "newly developed sensitization" and "sensitization to more allergens," was most frequent was the 2 to 12 years old group, followed by the 20 to 39 years old group. The age group in which "desensitization," composed of those with "negative conversion" and "desensitization to fewer allergens," was most prevalent was the 20 to 39 years old group followed by the 13 to 19 years old group. Grass pollen was the most common newly-sensitized allergen and also the most common desensitized allergen. IgE sensitization to aeroallergens can change in individuals with allergy. These changes may be different according to the patient's age. If rhinitis symptoms or treatment efficacy changes, repeat IgE sensitization testing is needed to find changes in allergen sensitization patterns.

Priority-Setting for Novel Drug Regimens to Treat Tuberculosis: An Epidemiologic Model.

BackgroundNovel drug regimens are needed for tuberculosis (TB) treatment. New regimens aim to improve on characteristics such as duration, efficacy, and safety profile, but no single regimen is likely to be ideal in all respects. By linking these regimen characteristics to a novel regimen’s ability to reduce TB incidence and mortality, we sought to prioritize regimen characteristics from a population-level perspective.Methods and FindingsWe developed a dynamic transmission model of multi-strain TB epidemics in hypothetical populations reflective of the epidemiological situations in India (primary analysis), South Africa, the Philippines, and Brazil. We modeled the introduction of various novel rifampicin-susceptible (RS) or rifampicin-resistant (RR) TB regimens that differed on six characteristics, identified in consultation with a team of global experts: (1) efficacy, (2) duration, (3) ease of adherence, (4) medical contraindications, (5) barrier to resistance, and (6) baseline prevalence of resistance to the novel regimen. We compared scale-up of these regimens to a baseline reflective of continued standard of care.For our primary analysis situated in India, our model generated baseline TB incidence and mortality of 157 (95% uncertainty range [UR]: 113–187) and 16 (95% UR: 9–23) per 100,000 per year at the time of novel regimen introduction and RR TB incidence and mortality of 6 (95% UR: 4–10) and 0.6 (95% UR: 0.3–1.1) per 100,000 per year. An optimal RS TB regimen was projected to reduce 10-y TB incidence and mortality in the India-like scenario by 12% (95% UR: 6%–20%) and 11% (95% UR: 6%–20%), respectively, compared to current-care projections. An optimal RR TB regimen reduced RR TB incidence by an estimated 32% (95% UR: 18%–46%) and RR TB mortality by 30% (95% UR: 18%–44%). Efficacy was the greatest determinant of impact; compared to a novel regimen meeting all minimal targets only, increasing RS TB treatment efficacy from 94% to 99% reduced TB mortality by 6% (95% UR: 1%–13%, half the impact of a fully optimized regimen), and increasing the efficacy against RR TB from 76% to 94% lowered RR TB mortality by 13% (95% UR: 6%–23%). Reducing treatment duration or improving ease of adherence had smaller but still substantial impact: shortening RS TB treatment duration from 6 to 2 mo lowered TB mortality by 3% (95% UR: 1%–6%), and shortening RR TB treatment from 20 to 6 mo reduced RR TB mortality by 8% (95% UR: 4%–13%), while reducing nonadherence to the corresponding regimens by 50% reduced TB and RR TB mortality by 2% (95% UR: 1%–4%) and 6% (95% UR: 3%–10%), respectively. Limitations include sparse data on key model parameters and necessary simplifications to model structure and outcomes.ConclusionsIn designing clinical trials of novel TB regimens, investigators should consider that even small changes in treatment efficacy may have considerable impact on TB-related incidence and mortality. Other regimen improvements may still have important benefits for resource allocation and outcomes such as patient quality of life.

Cost-Effectiveness Analysis of Atorvastatin versus Rosuvastatin in Primary and Secondary Cardiovascular Prevention Populations in Brazil and Columbia

BackgroundLatin America has witnessed a marked increase in cardiovascular (CV) disease, the leading cause of death in many countries. The benefits of lipid-lowering therapy to reduce CV-related events are widely accepted. Clinical evidence suggests that rosuvastatin is associated with slightly greater reductions in low-density lipoprotein cholesterol levels than is atorvastatin at comparable doses. Rosuvastatin, however, is often priced at a premium. ObjectiveOur objective was to examine the cost-effectiveness of using atorvastatin versus rosuvastatin in reducing CV events in Brazil and Colombia using real-world prices. MethodsA global Markov cohort model of primary and secondary CV prevention was developed and adapted to Brazilian and Colombian settings. The risks and costs of major CV events and efficacy, adherence, and costs of statins were considered. Total gains in life-years, quality-adjusted life-years, major CV events avoided, and costs over the lifetime horizon were estimated. Several dose comparisons were considered. ResultsIn the Colombian analyses, differences in drug costs between therapies were considerable while outcomes were similar. The incremental cost per quality-adjusted life-year gained for rosuvastatin versus atorvastatin was more than $700,000 and $200,000 in primary and secondary prevention, respectively. Brazilian analyses found lower incremental cost-effectiveness ratios for rosuvastatin at some dose comparisons due to similar pricing between statins. Sensitivity analyses revealed that changes in treatment efficacy and adherence had the largest impact on results. ConclusionsIn primary and secondary CV prevention, the efficacy advantage of rosuvastatin was minimal, while its acquisition cost was higher, particularly in Colombia. The incremental cost-effectiveness ratios were, therefore, generally in favor of atorvastatin being the cost-effective option.

Cost-Effectiveness of Truncated Therapy for Hepatitis C Based on Rapid Virologic Response

BackgroundShortened courses of treatment with pegylated interferon alfa and ribavirin for patients with hepatitis C virus infection who experience rapid virologic response can be effective in appropriately selected patients. The cost-effectiveness of truncated therapy is not known. ObjectiveTo assess the cost-effectiveness of response-guided therapy versus standard-duration therapy on the basis of best available evidence. MethodsWe developed a decision model for chronic hepatitis C virus infection representing two treatment strategies: 1) standard-duration therapy with pegylated interferon alfa and ribavirin for 48 weeks in patients with genotype 1 or 4 and for 24 weeks in patients with genotype 2 or 3 and 2) truncated therapy (i.e., 50% decrease in treatment duration) in patients with rapid virologic response. Patients for whom truncated therapy failed began standard-duration therapy guided by genotype. We used a Markov model to estimate lifetime costs and quality-adjusted life-years. ResultsIn the base-case analysis, mean lifetime costs were $46,623 ± $2,483 with standard-duration therapy and $42,354 ± $2,489 with truncated therapy. Mean lifetime quality-adjusted life-years were similar between the groups (17.1 ± 0.7 with standard therapy; 17.2 ± 0.7 with truncated therapy). Across model simulations, the probability of truncated therapy being economically dominant (i.e., both cost saving and more effective) was 78.6%. The results were consistent when we stratified the data by genotype. In one-way sensitivity analyses, the results were sensitive only to changes in treatment efficacy. ConclusionTruncated therapy based on rapid virologic response is likely to be cost saving for treatment-naive patients with chronic hepatitis C virus infection. Cost-effectiveness varied with small changes in relative treatment efficacy.

HIV Drug-resistant Strains as Epidemiologic Sentinels

Observed declines in drug resistance to nucleoside reverse transcriptase inhibitors among persons recently infected with HIV-1 in monitored subpopulations can be interpreted as a positive sign and lead public health officials to decrease efforts towards HIV prevention. By means of a mathematical model, we identified 3 processes that can account for the observed decline: increase in high-risk behavior, decrease in proportion of acutely infected persons whose conditions are treated, and change in treatment efficacy. These processes, singly or in combination, can lead to increases or decreases in disease and drug-resistance prevalence in the general population. We discuss the most appropriate public health response under each scenario and emphasize how further data collection and analyses are required to more reliably evaluate the observed time trends and the relative importance of forces shaping the epidemic. Our study highlights how drug resistance markers can be used as epidemiologic sentinels to devise public health solutions.

Biofilm-control strategies based on enzymic disruption of the extracellular polymeric substance matrix – a modelling study

A kinetic model is proposed to assess the feasibility of strategies for the removal of biofilms by using substances that induce detachment by affecting the cohesiveness of the matrix of extracellular polymeric substances (EPSs). The model uses a two-state description of the EPS (natural EPS and compromised EPS) to provide a unified representation of diverse mechanisms of action of detachment-promoting agents (DPAs), which include enzymes that degrade the EPS and other agents described in the literature. A biofilm-cohesiveness factor describes local increases in detachment rates resultant from losses in cohesive strength. The kinetic model was implemented in an individual-based biofilm-modelling framework, including detachment rates dependent on local cohesiveness. The efficacy of treatments with DPAs was assessed by three-dimensional model simulations. Changes in treatment efficacy were evaluated quantitatively by using a Thiele modulus, which quantifies the relationship between diffusion of the DPA through the biofilm matrix and DPA decay rate, and a Damköhler number relating the rate of EPS reaction with a DPA and the rate of EPS production by the micro-organisms in the biofilm. This study demonstrates the feasibility and limits of implementing biofilm-control strategies based on attacking the EPS.

Respiratory exacerbations in children with cystic fibrosis: Physiotherapy treatment outcomes

Treatment efficacy is crucial in cystic fibrosis (CF) as it impacts directly upon life expectancy, with its evaluation contributing to the evidence base for physiotherapy practice. This study assesses whether respiratory outcomes changed at the Royal Children's Hospital, Brisbane (RCH) over a period when physiotherapy airways clearance techniques altered. All 1998 and 2000 admissions of children over two years of age to RCH for CF related respiratory exacerbations were included, totalling 248 admissions, 125 in 1998 and123 in 2000. Data for respiratory effort, cough quality, sputum volume/weight, sputum colour and sputum stickiness were analysed. Respiratory function test (RFT) results included: forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and forced expiratory flow (FEF25–75%) and % of predicted values.Repeated measures ANOVA and appropriate post hoc tests evaluated changes occurring during the admissions. Independent-samples t-tests allowed comparison of the improvement in the two years. During hospital admission in both 1998 and 2000, a significant improvement in RFT results occurred. Similar improvements in 1998 and 2000 suggested no change in treatment efficacy had occurred. Significant changes during hospitalisation, in cough quality, sputum volume/weight, and sputum colour suggest that these variables are appropriate and simple physiotherapy outcome measures.

Cost-effectiveness analysis of the first-line therapies for nicotine dependence.

Nicotine dependence is the major obstacle for smokers who want to quit. Guidelines have identified five effective first-line therapies, four nicotine replacement therapies (NRTs)--gum, patch, nasal spray and inhaler--and bupropion. Studying the extent to which these various treatments are cost-effective requires additional research. To determine cost-effectiveness (CE) ratios of pharmacotherapies for nicotine dependence provided by general practitioners (GPs) during routine visits as an adjunct to cessation counselling. We used a Markov model to generate two cohorts of one-pack-a-day smokers: (1) the reference cohort received only cessation counselling from a GP during routine office visits; (2) the second cohort received the same counselling plus an offer to use a pharmacological treatment to help them quit smoking. The effectiveness of adjunctive therapy was expressed in terms of the resultant differential in mortality rate between the two cohorts. Data on the effectiveness of therapies came from meta-analyses, and we used odds ratio for quitting as the measure of effectiveness. The costs of pharmacotherapies were based on the cost of the additional time spent by GPs offering, prescribing and following-up treatment, and on the retail prices of the therapies. We used the third-party-payer perspective. Results are expressed as the incremental cost per life-year saved. The cost per life-year saved for only counselling ranged from Euro 385 to Euro 622 for men and from Euro 468 to Euro 796 for women. The CE ratios for the five pharmacological treatments varied from Euro 1768 to Euro 6879 for men, and from Euro 2146 to Euro 8799 for women. Significant variations in CE ratios among the five treatments were primarily due to differences in retail prices. The most cost-effective treatments were bupropion and the patch, and, then, in descending order, the spray, the inhaler and, lastly, gum. Differences in CE between men and women across treatments were due to the shape of their respective mortality curve. The lowest CE ratio in men was for the 45- to 49-year-old group and for women in the 50- to 54-year-old group. Sensitivity analysis showed that changes in treatment efficacy produced effects only for less-well proven treatments (spray, inhaler, and bupropion) and revealed a strong influence of the discount rate and natural quit rate on the CE of pharmacological treatments. The CE of first-line treatments for nicotine dependence varied widely with age and sex and was sensitive to the assumption for the natural quit rate. Bupropion and the nicotine patch were the two most cost-effective treatments.

Survival after pleural malignant mesothelioma: a population-based study in Italy.

The study analyzed survival after malignant mesothelioma in the population-based Registry of Malignant Mesothelioma of Piedmont (NW Italy, 4.5 million total population). It focused on possible differences related to period of diagnosis a proxy of changes in diagnostic or therapeutic procedures. Cases were actively searched in pathology units and files of hospital admissions and discharges. In 1990-1998, 693 incident cases were diagnosed in residents in the region: 590 of them had a histologic diagnosis of pleural mesothelioma in life and were included in the study. Vital status was ascertained at the municipality of residence as of January 1, 2000. Fifty-eight cases were alive (9.8%) and 20 were lost (3.6%) at the end of the follow-up. Median survival was 0.71 years (95% CI, 0.64-0.78). Cumulative survival was 35.9% at 1 year (95% CI, 32.0-39.8) and 14.2% at 2 years (95% CI, 11.2-17.1). Survival was associated to age (longer survival for younger subjects at diagnosis; P <0.0001) and to histology (longer survival for epithelial mesothelioma, shorter for fibrous and intermediate for mixed or unspecified types; P <0.0001). There was no difference in survival for period of diagnosis. The results were confirmed in multivariate analyses. Analyses according to type of hospital (with vs without thoracic surgery) did not show any statistically significant difference. The study on survival after malignant mesothelioma is the second largest of the three population-based studies in the world, which showed results similar to ours. Survival measured in published clinical series ranged between 18.4% and 57.6% at 1 year for pleural and 24.1% and 33.8% for peritoneal mesothelioma. The most striking effect of the present study was the absence of improvement in survival with period of diagnosis. Either there was no change in treatment efficacy or the effect was limited to small subgroups and could not be noticed when the analysis included larger categories.

The evolution of drug-resistant malaria: the role of drug elimination half-life.

This paper seeks to define and quantify the influence of drug elimination half-life on the evolution of antimalarial drug resistance. There are assumed to be three general classes of susceptibility of the malaria parasite Plasmodium falciparum to a drug: Res0, the original, susceptible wildtype; Res1, a group of intermediate levels of susceptibility that are more tolerant of the drug but still cleared by treatment; and Res2, which is completely resistant to the drug. Res1 and Res2 resistance both evolve much faster if the antimalarial drug has a long half-life. We show that previous models have significantly underestimated the rate of evolution of Res2 resistance by omitting the effects of drug half-life. The methodology has been extended to investigate (i) the effects of using drugs in combination, particularly when the components have differing half-lives, and (ii) the specific example of the development of resistance to the antimalarial pyrimethamine-sulphadoxine. An important detail of the model is the development of drug resistance in two separate phases. In phase A, Res1 is spreading and replacing the original sensitive forms while Res2 remains at a low level. Phase B starts once parasites are selected that can escape drug action (Res1 genotypes with borderline chemosensitivity, and Res2): these parasites are rapidly selected, a process that leads to widespread clinical failure. Drug treatment is clinically successful during phase A, and health workers may be unaware of the substantial changes in parasite population genetic structure that predicate the onset of phase B. Surveillance programs are essential, following the introduction of a new drug, to monitor effectively changes in treatment efficacy and thus provide advance warning of drug failure. The model is also applicable to the evolution of antibiotic resistance in bacteria: in particular, the need for these models to incorporate drug pharmacokinetics to avoid potentially large errors in their predictions.

Mortality in treated heterozygous familial hypercholesterolaemia: implications for clinical management

Clinical management of heterozygous familial hypercholesterolaemia is largely based on evidence from a small number of observational studies and extrapolation from the results of clinical trials of lipid-lowering in patients with polygenic hypercholesterolaemia The objectives of this study were (i) to determine the absolute and relative mortality of patients with treated heterozygous familial hypercholesterolaemia, (ii) to estimate the effect of changes in treatment efficacy on mortality trends over time, and (iii) to examine the implications of these findings for patient management. A cohort of 605 men and 580 women aged 20–79 years with heterozyous familial hypercholesterolaemia were recruited from 21 out-patient lipid clinics in the UK. Patients were followed prospectively from 1980 to 1995 for 8770 person-years. Absolute mortality was calculated, and relative risk was expressed as the ratio of the number of observed deaths to the number expected in the general population of England and Wales. Forty six of the 73 deaths were due to coronary heart disease. In women aged 20–39, despite treatment, the relative risk of a fatal coronary event was increased 125-fold (95% confidence intervals 15–451) and the annual coronary mortality was 0.17%. In men aged 20–39 the relative risk was increased 48-fold (17-105) and the annual coronary mortality was 0.46%. The relative risk decreased with age but the absolute risk increased. For men and women aged 60–79, the annual coronary mortality was 1.1% representing a significant excess mortality for women (relative risk 2.6, 1.3–4.5) but not for men (RR 1.1, 0.5–2.3). Non-coronary mortality was not increased at any age (RR for all ages 0.68, 0.45–0.99). There was a decline in the relative risk for coronary mortality in patients aged 20–59 from an eight-fold (4.8–7.2) increased risk before 1992 to 3.7 (1.6–7.2.) thereafter ( P=0.08). The results suggest that the prognosis for patients with heterozygous familial hypercholesterolaemia has improved with the introduction of more effective treatment, and that lipid-lowering therapy is not associated with increased non-coronary mortality. These findings and the excess coronary mortality observed suggest that all affected adult men and post-menopausal women should be treated with HMG-CoA reductase inhibitors.

Effect of a macrolide (spiramycin) on the pharmacokinetics of L-dopa and carbidopa in healthy volunteers.

In one well-equilibrated parkinsonian patient treated with combined L-dopa and carbidopa (Sinemet), we have observed changes in treatment efficacy while receiving spiramycin (Rovamycine) for an intercurrent respiratory infection. A preliminary study of the pharmacokinetics of L-dopa and its main metabolites 3-O-methyldopa (3-OMD) and dihydroxyphenylacetic acid (dopac) in two parkinsonian patients treated with Sinemet has revealed a marked decrease in the AUC0-360 of these two metabolites after a 3-day course of Rovamycine. In order to confirm this interaction, we have studied the modifications of the pharmacokinetics of L-dopa, 3-OMD, dopac, and carbidopa in eight male healthy volunteers after a single dose of Sinemet 250 (L-dopa, 250 mg and carbidopa, 25 mg) before and after a 3-day course of Rovamycine. Our study confirms this interaction. After spiramycin, we observed a marked reduction in AUC0-360 for L-dopa (p less than 0.001), 3-OMD (p less than 0.001), and carbidopa (p less than 0.001), and an increase in AUC0-360 for dopac (p less than 0.01). The L-dopa elimination half-life was increased (p less than 0.012); differences in peak plasma concentrations did not attain statistical significance. We think that these modifications in L-dopa pharmacokinetics after spiramycin are due to nonabsorption of carbidopa secondary to modified gastrointestinal motility.