Cost-effectiveness models for Alzheimer's disease and related dementias: IPECAD modeling workshop cross-comparison challenge.

INTRODUCTION: The credibility of model-based economic evaluations of Alzheimer's disease (AD) interventions is central to appropriate decision-making in a policy context. We report on the International PharmacoEconomic Collaboration on Alzheimer's Disease (IPECAD) Modeling Workshop Challenge. METHODS: Two common benchmark scenarios, for the hypothetical treatment of AD mild cognitive impairment (MCI) and mild dementia, were developed jointly by 29 participants. Model outcomes were summarized, and cross-comparisons were discussed during a structured workshop. RESULTS: A broad concordance was established among participants. Mean 10-year restricted survival and time in MCI in the control group ranged across 10 MCI models from 6.7 to 9.5 years and 3.4 to 5.6 years, respectively; and across 4 mild dementia models from 5.4 to 7.9 years (survival) and 1.5 to 4.2 years (mild dementia). DISCUSSION: The model comparison increased our understanding of methods, data used, and disease progression. We established a collaboration framework to assess cost-effectiveness outcomes, an important step toward transparent and credible AD models.

Cost-Effectiveness of Magnetic Resonance Imaging in Prostate Cancer Screening: A Microsimulation Study.

OBJECTIVE: This study aimed to assess the cost-effectiveness of magnetic resonance imaging (MRI) with combinations of targeted biopsy (TBx) and systematic biopsy (SBx) for early prostate cancer detection in Sweden. METHODS: A cost-utility analysis was conducted from a lifetime societal perspective using a microsimulation model. Five strategies included no screening and quadrennial screening for men aged 55 to 69 years using SBx alone, TBx on positive MRI (MRI + TBx), combined TBx/SBx on positive MRI (MRI + TBx/SBx), and SBx on negative MRI with TBx/SBx on positive MRI (MRI - SBx, MRI + TBx/SBx). Test characteristics were based on a recent Cochrane review. We predicted the number of biopsies, costs, quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios. RESULTS: The screening strategies were classified in Sweden as high costs per QALY gained compared with no screening. Using MRI + TBx and MRI + TBx/SBx reduced the number of biopsy episodes across a lifetime by approximately 40% compared with SBx alone. Both strategies showed strong dominance over SBx alone and MRI - SBx, MRI + TBx. Compared with MRI + TBx, the MRI + TBx/SBx strategy had an incremental cost-effectiveness ratio of more than €200 000 per QALY gained, which was classified in Sweden as a very high cost. These predictions were robust in the probabilistic sensitivity analysis. Limitations included generalizability of the model assumptions and uncertainty regarding the health-state values and study heterogeneity from the Cochrane review. CONCLUSIONS: MRI + TBx and MRI + TBx/SBx showed strong dominance over alternative screening strategies. MRI + TBx resulted in similar or marginally lower gains in QALYs and lower costs than MRI + TBx/SBx. MRI + TBx was considered the optimal choice among the screening strategies.

The cost-effectiveness of prostate cancer screening using the Stockholm3 test.

OBJECTIVES: The European Randomized Study of Screening for Prostate Cancer found that prostate-specific antigen (PSA) screening reduced prostate cancer mortality, however the costs and harms from screening may outweigh any mortality reduction. Compared with screening using the PSA test alone, using the Stockholm3 Model (S3M) as a reflex test for PSA ≥ 1 ng/mL has the same sensitivity for Gleason score ≥ 7 cancers while the relative positive fractions for Gleason score 6 cancers and no cancer were 0.83 and 0.56, respectively. The cost-effectiveness of the S3M test has not previously been assessed. METHODS: We undertook a cost-effectiveness analysis from a lifetime societal perspective. Using a microsimulation model, we simulated for: (i) no prostate cancer screening; (ii) screening using the PSA test; and (iii) screening using the S3M test as a reflex test for PSA values ≥ 1, 1.5 and 2 ng/mL. Screening strategies included quadrennial re-testing for ages 55-69 years performed by a general practitioner. Discounted costs, quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs) were calculated. RESULTS: Comparing S3M with a reflex threshold of 2 ng/mL with screening using the PSA test, S3M had increased effectiveness, reduced lifetime biopsies by 30%, and increased societal costs by 0.4%. Relative to the PSA test, the S3M reflex thresholds of 1, 1.5 and 2 ng/mL had ICERs of 170,000, 60,000 and 6,000 EUR/QALY, respectively. The S3M test was more cost-effective at higher biopsy costs. CONCLUSIONS: Prostate cancer screening using the S3M test for men with an initial PSA ≥ 2.0 ng/mL was cost-effective compared with screening using the PSA test alone.

XRMA analysis and X-ray diffraction analysis of dental enamel from human permanent teeth exposed to hydrogen peroxide of varying pH.

BACKGROUND: This in vitroinvestigation shows how 3.3% H2O2, at different pH-values affects the enamel. MATERIAL AND METHODS: A number of fifteen human premolars were used. The enamel of the coronal half in six of the teeth, were exposed by H2O2. Nine teeth were prepared to enamel powder. The enamel was exposed to 3.3% H2O2, at six different pH-values (pH range 4.5 - 7.0). Analyses of the topography of enamel performed by scanning electron microscope (SEM) and the chemical composition of enamel by X-ray microanalysis (XRMA). X-ray powder diffraction (XRD) analysed the crystallinity in enamel powder. RESULTS: The exposure to H2O2 at pH<5.5 resulted in a rougher topography of the enamel, according to the SEM studies. The XRMA analysis revealed a increase in the ratio of Ca:C. Exposure to H2O2 at pH>5.5 resulted in a decrease of O in the exposed enamel, and changes in C:P, Ca:C, Ca:P and Ca:O were observed. The H2O22 did not affect the unit cell parameters, but the signal-to-noise level was increased for slightly acidic or neutral solutions. The unit cell parameters decreased in the acidic solutions. CONCLUSIONS: The exposure to H2O2 at varying pH values affect the enamel with two different mechanisms. One effect is the oxidation of the organic or bioorganic matter in the hydroxyapatite matrix, due to the use of 3.3% H2O2. The other effect is due to the current pH of the H2O2, since the structure of the hydroxyapatite starts to erode when the pH<5.5. Key words:Dental Enamel, Tooth Bleaching Agents, Hydrogen Peroxide, Scanning Electron Microscopy, X-ray diffraction.

The impact of different prostate-specific antigen (PSA) testing intervals on Gleason score at diagnosis and the risk of experiencing false-positive biopsy recommendations: a population-based cohort study.

OBJECTIVE: Given a man's current prostate- specific antigen (PSA) level, age and family history of prostate cancer, what are the benefits (decreased risk of higher Gleason score [GS] cancer at diagnosis) and harms (increased risk of false-positive biopsy recommendation) of waiting 1, 2, 3, 4 or 5-8 years until the next PSA test? DESIGN: Prospective cohort. SETTING: All PSA tested men in Stockholm, Sweden, between 2003 and 2015. PARTICIPANTS: Men aged 50-74 years with at least two PSA tests between 2003 and 2015 (n=174 636). MAIN OUTCOME MEASURES: Log-binomial regression to calculate the risk ratio (RR) of GS ≥7 and GS 6 versus benign outcome at prostate biopsy and 12-year cumulative probability of experiencing a false-positive biopsy by testing interval, age, PSA level and first-degree family history. RESULTS: Men with PSA ≤1 ng/mL had low risk of GS ≥7 prostate cancer irrespective of testing interval; <3% had a PSA >3 at the next testing occasion, and of the 663 men biopsied after the next PSA test only 32 (5%) had GS ≥7 cancer. Men with PSA >1 ng/mL had increased risk of being diagnosed with GS ≥7 prostate cancer when screened with longer than annual intervals (RRs ranged from 1.4 to 3.2 depending on PSA level and testing interval). The results were consistent across age groups and family history status. This benefit needs to be balanced against the increased risk for false-positive biopsy recommendation with shorter testing intervals (twofold for annual vs biennial and threefold for annual vs triennial). CONCLUSIONS: Men aged 50-74 years with PSA ≤1 ng/mL can wait 3-4 years before having a new PSA test. For men with PSA >1 ng/mL, we observed an increased risk of being diagnosed with GS ≥7 prostate cancer with longer than annual testing intervals. This benefit needs to be balanced against the markedly increased risks for false-positive biopsy recommendations with shorter testing intervals recommendations.

A natural history model for planning prostate cancer testing: Calibration and validation using Swedish registry data.

Recent prostate cancer screening trials have given conflicting results and it is unclear how to reduce prostate cancer mortality while minimising overdiagnosis and overtreatment. Prostate cancer testing is a partially observable process, and planning for testing requires either extrapolation from randomised controlled trials or, more flexibly, modelling of the cancer natural history. An existing US prostate cancer natural history model (Gulati et al, Biostatistics 2010;11:707-719) did not model for differences in survival between Gleason 6 and 7 cancers and predicted too few Gleason 7 cancers for contemporary Sweden. We re-implemented and re-calibrated the US model to Sweden. We extended the model to more finely describe the disease states, their time to biopsy-detectable cancer and prostate cancer survival. We first calibrated the model to the incidence rate ratio observed in the European Randomised Study of Screening for Prostate Cancer (ERSPC) together with age-specific cancer staging observed in the Stockholm PSA (prostate-specific antigen) and Biopsy Register; we then calibrated age-specific survival by disease states under contemporary testing and treatment using the Swedish National Prostate Cancer Register. After calibration, we were able to closely match observed prostate cancer incidence trends in Sweden. Assuming that patients detected at an earlier stage by screening receive a commensurate survival improvement, we find that the calibrated model replicates the observed mortality reduction in a simulation of ERSPC. Using the resulting model, we predicted incidence and mortality following the introduction of regular testing. Compared with a model of the current testing pattern, organised 8 yearly testing for men aged 55-69 years was predicted to reduce prostate cancer incidence by 14% and increase prostate cancer mortality by 2%. The model is open source and suitable for planning for effective prostate cancer screening into the future.

Incorporation of Metals into Calcite in a Deep Anoxic Granite Aquifer.

Understanding metal scavenging by calcite in deep aquifers in granite is of importance for deciphering and modeling hydrochemical fluctuations and water-rock interaction in the upper crust and for retention mechanisms associated with underground repositories for toxic wastes. Metal scavenging into calcite has generally been established in the laboratory or in natural environments that cannot be unreservedly applied to conditions in deep crystalline rocks, an environment of broad interest for nuclear waste repositories. Here, we report a microanalytical study of calcite precipitated over a period of 17 years from anoxic, low-temperature (14 °C), neutral (pH: 7.4-7.7), and brackish (Cl: 1700-7100 mg/L) groundwater flowing in fractures at >400 m depth in granite rock. This enabled assessment of the trace metal uptake by calcite under these deep-seated conditions. Aquatic speciation modeling was carried out to assess influence of metal complexation on the partitioning into calcite. The resulting environment-specific partition coefficients were for several divalent ions in line with values obtained in controlled laboratory experiments, whereas for several other ions they differed substantially. High absolute uptake of rare earth elements and U(IV) suggests that coprecipitation into calcite can be an important sink for these metals and analogousactinides in the vicinity of geological repositories.

Challenges in assessing the health risks of consuming vegetables in metal-contaminated environments.

A great deal of research has been devoted to the characterization of metal exposure due to the consumption of vegetables from urban or industrialized areas. It may seem comforting that concentrations in crops, as well as estimated exposure levels, are often found to be below permissible limits. However, we show that even a moderate increase in metal accumulation in crops may result in a significant increase in exposure. We also highlight the importance of assessing exposure levels in relation to a regional baseline. We have analyzed metal (Pb, Cd, As) concentrations in nearly 700 samples from 23 different vegetables, fruits, berries and mushrooms, collected near 21 highly contaminated industrial sites and from reference sites. Metal concentrations generally complied with permissible levels in commercial food and only Pb showed overall higher concentrations around the contaminated sites. Nevertheless, probabilistic exposure assessments revealed that the exposure to all three metals was significantly higher in the population residing around the contaminated sites, for both low-, median- and high consumers. The exposure was about twice as high for Pb and Cd, and four to six times as high for As. Since vegetable consumption alone did not result in exposure above tolerable intakes, it would have been easy to conclude that there is no risk associated with consuming vegetables grown near the contaminated sites. However, when the increase in exposure is quantified, its potential significance is harder to dismiss - especially when considering that exposure via other routes may be elevated in a similar way.

Do public nursing home care providers deliver higher quality than private providers? Evidence from Sweden.

BACKGROUND: Swedish nursing home care has undergone a transformation, where the previous virtual public monopoly on providing such services has been replaced by a system of mixed provision. This has led to a rapidly growing share of private actors, the majority of which are large, for-profit firms. In the wake of this development, concerns have been voiced regarding the implications for care quality. In this article, we investigate the relationship between ownership and care quality in nursing homes for the elderly by comparing quality levels between public, for-profit, and non-profit nursing home care providers. We also look at a special category of for-profit providers; private equity companies. METHODS: The source of data is a national survey conducted by the Swedish National Board of Health and Welfare in 2011 at 2710 nursing homes. Data from 14 quality indicators are analyzed, including structure and process measures such as staff levels, staff competence, resident participation, and screening for pressure ulcers, nutrition status, and risk of falling. The main statistical method employed is multiple OLS regression analysis. We differentiate in the analysis between structural and processual quality measures. RESULTS: The results indicate that public nursing homes have higher quality than privately operated homes with regard to two structural quality measures: staffing levels and individual accommodation. Privately operated nursing homes, on the other hand, tend to score higher on process-based quality indicators such as medication review and screening for falls and malnutrition. No significant differences were found between different ownership categories of privately operated nursing homes. CONCLUSIONS: Ownership does appear to be related to quality outcomes in Swedish nursing home care, but the results are mixed and inconclusive. That staffing levels, which has been regarded as a key quality indicator in previous research, are higher in publicly operated homes than private is consistent with earlier findings. The fact that privately operated homes, including those operated by for-profit companies, had higher processual quality is more unexpected, given previous research. Finally, no significant quality differences were found between private ownership types, i.e. for-profit, non-profit, and private equity companies, which indicates that profit motives are less important for determining quality in Swedish nursing home care than in other countries where similar studies have been carried out.

E-Science technologies in a workflow for personalized medicine using cancer screening as a case study.

OBJECTIVE: We provide an e-Science perspective on the workflow from risk factor discovery and classification of disease to evaluation of personalized intervention programs. As case studies, we use personalized prostate and breast cancer screenings. MATERIALS AND METHODS: We describe an e-Science initiative in Sweden, e-Science for Cancer Prevention and Control (eCPC), which supports biomarker discovery and offers decision support for personalized intervention strategies. The generic eCPC contribution is a workflow with 4 nodes applied iteratively, and the concept of e-Science signifies systematic use of tools from the mathematical, statistical, data, and computer sciences. RESULTS: The eCPC workflow is illustrated through 2 case studies. For prostate cancer, an in-house personalized screening tool, the Stockholm-3 model (S3M), is presented as an alternative to prostate-specific antigen testing alone. S3M is evaluated in a trial setting and plans for rollout in the population are discussed. For breast cancer, new biomarkers based on breast density and molecular profiles are developed and the US multicenter Women Informed to Screen Depending on Measures (WISDOM) trial is referred to for evaluation. While current eCPC data management uses a traditional data warehouse model, we discuss eCPC-developed features of a coherent data integration platform. DISCUSSION AND CONCLUSION: E-Science tools are a key part of an evidence-based process for personalized medicine. This paper provides a structured workflow from data and models to evaluation of new personalized intervention strategies. The importance of multidisciplinary collaboration is emphasized. Importantly, the generic concepts of the suggested eCPC workflow are transferrable to other disease domains, although each disease will require tailored solutions.

Differential Water Thermodynamics Determine PI3K-Beta/Delta Selectivity for Solvent-Exposed Ligand Modifications.

Phosphoinositide 3-kinases (PI3Ks) are involved in important cellular functions and represent desirable targets for drug discovery efforts, especially related to oncology; however, the four PI3K subtypes (α, ß, γ, and δ) have highly similar binding sites, making the design of selective inhibitors challenging. A series of inhibitors with selectivity toward the ß subtype over δ resulted in compound 3(S), which has entered a phase I/Ib clinical trial for patients with advanced PTEN-deficient cancer. Interestingly, X-ray crystallography revealed that the modifications making inhibitor 3(S) and related compounds selective toward the ß-isoform do not interact directly with either PI3Kß or PI3Kδ, thereby confounding rationalization of the SAR. Here, we apply explicit solvent molecular dynamics and solvent thermodynamic analysis using WaterMap in an effort to understand the unusual affinity and selectivity trends. We find that differences in solvent energetics and water networks, which are modulated upon binding of different ligands, explain the experimental affinity and selectivity trends. This study highlights the critical role of water molecules in molecular recognition and the importance of considering water networks in drug discovery efforts to rationalize and improve selectivity.

Preparation and optimization of new 4-(2-(indolin-1-yl)-2-oxoethyl)-2-morpholinothiazole-5-carboxylic acid and amide derivatives as potent and selective PI3Kß inhibitors.

In our continuous efforts to identify and develop novel targeted cancer treatments, a new morpholino-thiazole scaffold active against PI3Kß has been identified. This Letter reports the optimization of this compound class to develop PI3Kß isoform-selective inhibitors with suitable pharmacological properties.

Discovery and optimization of pyrimidone indoline amide PI3Kß inhibitors for the treatment of phosphatase and tensin homologue (PTEN)-deficient cancers.

Compelling molecular biology publications have reported the implication of phosphoinositide kinase PI3Kß in PTEN-deficient cell line growth and proliferation. These findings supported a scientific rationale for the development of PI3Kß-specific inhibitors for the treatment of PTEN-deficient cancers. This paper describes the discovery of 2-[2-(2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one (7) and the optimization of this new series of active and selective pyrimidone indoline amide PI3Kß inhibitors. 2-[2-(2-Methyl-2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one (28), identified following a carefully designed methyl scan, displayed improved physicochemical and in vitro pharmacokinetic properties. Structural biology efforts enabled the acquisition of the first X-ray cocrystal structure of p110ß with the selective inhibitor compound 28 bound to the ATP site. The nonplanar binding mode described herein is consistent with observed structure-activity relationship for the series. Compound 28 demonstrated significant in vivo activity in a UACC-62 xenograft model in mice, warranting further preclinical investigation. Following successful development, compound 28 entered phase I/Ib clinical trial in patients with advanced cancer.

Psychological factors in genital pain: The role of fear-avoidance, pain catastrophizing and anxiety sensitivity among women living in Sweden.

Objectives One in five women under the age of 30 report recurrent genital pain and pain during sexual intercourse. Female genital pain negatively affects sexual and general health, as well as dyadic function and quality of life. Although the current field of research and clinical expertise in general agree upon a biopsychosocial conceptualization, there is still a lack of theoretical models describing the psychosocial mechanisms involved in the development of genital pain. Originally developed to outline the transition from acute to chronic back pain, the fear avoidance (FA) model has lately been proposed as a possible tool in illustrating the mechanisms involved in genital pain. However, only few studies have empirically tested the components of the FA model empirically. The aim of the present study is to examine fear avoidance beliefs, pain catastrophizing, and symptoms of depression and anxiety among women reporting genital pain, and to relate these concepts to sexual satisfaction/function and the characteristics of pain. Methods The study was a population-based study using a postal questionnaire administered to 4052 women (age 18-35). Of these 944 (response rate: 23%) took part in the study. Results Genital pain of six months duration was reported by 16.1% of the women. Women with pain reported elevated levels of symptoms of anxiety, fear avoidance beliefs, pain catastrophizing and anxiety sensitivity. Symptoms of anxiety also predicted pain in the explanatory model together with vaginal tension and fungal infection. Vaginal tension has previously been described as a fear-response to painful intercourse and the results thereby seem to give further support to viewing genital pain from a fear avoidance perspective. Furthermore, fear avoidance beliefs seem to be of similar importance as lack of desire for the experience of sexual satisfaction and could also predict pain during specific activities among women with pain. The results also indicate that sexual satisfaction is related to a specific pain-related fear, rather than a heightened level of general anxiety. Conclusions The study had a low response rate, but still indicates that genital pain is common and is associated with several aspects of fear and avoidance. In sum, the results support the FA model by giving strong support for fear reactions (vaginal tension) and fear avoidance beliefs, and moderate support for negative affect. In the model negative affect drives pain catastrophizing. Implications It seems that the experience of genital pain among women in the general population is common and could be associated with increased levels of anxiety and fear-avoidance beliefs. However, the associations should not be understood in isolation from physiological mechanisms but seem to indicate interactions between, e.g. fungal infections, negative appraisals of pain and symptoms, lack of sexual function and satisfaction and increased pain experience. It is possible that psychological mechanisms work in the transition from acute physiological pain to chronic psychologically maintained pain in terms of secondary reactions to, e.g. repeated fungal infections by adding emotional distress, fear of pain and avoidance behaviours.

The reliability of cardiogenic impedance and correlation with echocardiographic and plethysmographic parameters for predicting CRT time intervals post implantation.

AIMS: Encouraging data have been reported on the use of cardiogenic impedance (CI) in cardiac resynchronization therapy (CRT) optimization. The purposes of this study were to: evaluate the stability of certain CI vectors 24 h postimplantation, study the correlation between these CI signals and selected echocardiographic parameters, and examine the possibility of non-invasive calibration of the patient-specific impedance-based prediction model. METHODS AND RESULTS: Thirteen patients received a CRT-defibrillator device with monitor capability of the dynamic impedance between several electrodes. At implantation, a patient-specific impedance-based prediction model was created for identification of optimal atrioventricular and interventricular (VV) delays and calibrated on invasive measurements of left ventricular contractility (LV dP/dtmax). Simultaneously, non-invasive measurements of LV dP/dtmax and stroke volume (SV) were obtained using a finger plethysmograph. Patients were re-evaluated with echocardiography and new CI measurements the day after implantation. The hemodynamic benefit achieved by optimal VV setting according to the patient-specific impedance-based prediction model at follow-up was not as large as the one obtained at implantation. In a multivariate partial least square regression analysis, a correlation was found between aortic velocity time integral (VTI) and a generic linear combination of CI features (P < 0,005). No correlation was found between the patient-specific impedance-based prediction models and the non-invasive measurements of LV dP/dtmax and SV. CONCLUSION: Cardiogenic impedance signals can be used to optimize CRT settings but seem less feasible as an ambulatory tool since calibration is required. The positive correlation between aortic VTI and CI measurements seems promising, although a larger cohort is required to create an echocardiography-based patient-specific model.

Preparation and optimization of new 4-(morpholin-4-yl)-(6-oxo-1,6-dihydropyrimidin-2-yl)amide derivatives as PI3Kß inhibitors.

From a HTS campaign, a new series of pyrimidone anilides exemplified by compound 1 has been identified with good inhibitory activity for the PI3Kß isoform. The structure of compound 1 in PI3Kγ was solved revealing a binding mode in agreement with the SAR observed on PI3Kß. These compounds displayed inhibition in the nanomolar range in the biochemical assay and were also potent p-Akt inhibitors in a PTEN-deficient PC3 prostate cancer cell line. Optimization of in vitro pharmocokinetic properties led to compound 25 exhibiting 52% bioavailability in mice and target engagement in an acute PK/PD study.

Discovery and optimization of new benzimidazole- and benzoxazole-pyrimidone selective PI3Kß inhibitors for the treatment of phosphatase and TENsin homologue (PTEN)-deficient cancers.

Most of the phosphoinositide-3 kinase (PI3K) kinase inhibitors currently in clinical trials for cancer treatment exhibit pan PI3K isoform profiles. Single PI3K isoforms differentially control tumorigenesis, and PI3Kß has emerged as the isoform involved in the tumorigenicity of PTEN-deficient tumors. Herein we describe the discovery and optimization of a new series of benzimidazole- and benzoxazole-pyrimidones as small molecular mass PI3Kß-selective inhibitors. Starting with compound 5 obtained from a one-pot reaction via a novel intermediate 1, medicinal chemistry optimization led to the discovery of compound 8, which showed a significant activity and selectivity for PI3Kß and adequate in vitro pharmacokinetic properties. The X-ray costructure of compound 8 in PI3Kδ showed key interactions and structural features supporting the observed PI3Kß isoform selectivity. Compound 8 achieved sustained target modulation and tumor growth delay at well tolerated doses when administered orally to SCID mice implanted with PTEN-deficient human tumor xenografts.

Relationship between intracardiac impedance and left ventricular contractility in patients undergoing cardiac resynchronization therapy.

AIMS: Cardiac resynchronization therapy (CRT) has dramatically improved the symptoms and prognosis of patients with heart failure in large randomized clinical trials. Optimization of device settings may maximize benefit on an individual basis, although the best method for this is not yet established. We evaluated the use of cardiogenic impedance measurements (derived from intracardiac impedance signals) in CRT device optimization, using invasive left ventricular (LV) dP/dtmax as the reference. METHODS AND RESULTS: Seventeen patients underwent invasive haemodynamic assessment using a pressure wire placed in the LV cavity at the time of CRT device implantation. Intracardiac impedance measurements were made at different atrioventricular (AV) and interventricular (VV) delays and compared with LV dP/dtmax. We assessed the performance of patient-specific and generic impedance-based models in predicting acute haemodynamic response to CRT. In two patients, LV catheterization with the pressure wire was unsuccessful and in two patients LV lead delivery was unsuccessful; therefore, data were acquired for 13 out of 17 patients. Left ventricular dP/dtmax was 919±182 mmHg/s at baseline and this increased acutely (by 24%) to 1121±226 mmHg/s as a result of CRT. The patient-specific impedance-based model correctly predicted the optimal haemodynamic response (to within 5% points) for AV and VV delays in 90 and 92% of patients, respectively. CONCLUSION: Cardiogenic impedance measurements are capable of correctly identifying the maximum achievable LV dP/dtmax as measured by invasive haemodynamic assessment. This study suggests that cardiogenic impedance can potentially be used for CRT optimization and may have a role in ambulatory assessment of haemodynamics.

Pharyngeal Chlamydia trachomatis is not uncommon any more.

BACKGROUND: The significance of Chlamydia trachomatis (Ct) infection in the pharynx, and possible symptoms, are under discussion. Most studies have involved only homo/bisexual men. We report findings of pharyngeal Ct (PhCt) infections in patients with long-lasting throat discomfort and the prevalence of PhCt in genitally Ct-infected young people in a Swedish primary care setting. METHOD: Sub-study 1 (SS1) included 48 persons aged 15-35 y, with pharyngeal discomfort for more than 14 days. Sub-study 2 (SS2) included 150 persons, aged 15-35 y, with genital Ct. Questionnaires concerning symptoms, sexual behaviour and sexual identity were completed for both groups. Samples for Ct testing were taken from the pharynx, and in SS1, samples were also collected to ascertain genital Ct. RESULTS: In SS1, 2 of 48 persons (4%) with pharyngeal discomfort had PhCt. In all, 35 of the 48 persons (73%) included in SS1 reported unprotected oral sex during the previous year. In SS2, 11 of 92 women (12%) and 4 of 58 men (7%) tested positive for PhCt. More women (94%) than men (83%) had given unprotected oral sex. Persons with PhCt had more symptoms from the upper respiratory tract (p = 0.04). CONCLUSIONS: Some primary care patients with long-lasting throat discomfort have a PhCt infection. PhCt infection is not uncommon in genitally infected sexually active people. More heterosexual women than heterosexual men had given unprotected oral sex and were infected by Ct in the pharynx. Thus, research on PhCt should not focus on homo/bisexual men only. Information about Ct should include the risk of contracting a PhCt infection as well as a gender perspective.

Internet-versus group-administered cognitive behaviour therapy for panic disorder in a psychiatric setting: a randomised trial.

BACKGROUND: Internet administered cognitive behaviour therapy (CBT) is a promising new way to deliver psychological treatment, but its effectiveness in regular care settings and in relation to more traditional CBT group treatment has not yet been determined. The primary aim of this study was to compare the effectiveness of Internet-and group administered CBT for panic disorder (with or without agoraphobia) in a randomised trial within a regular psychiatric care setting. The second aim of the study was to establish the cost-effectiveness of these interventions. METHODS: Patients referred for treatment by their physician, or self-referred, were telephone-screened by a psychiatric nurse. Patients fulfilling screening criteria underwent an in-person structured clinical interview carried out by a psychiatrist. A total of 113 consecutive patients were then randomly assigned to 10 weeks of either guided Internet delivered CBT (n = 53) or group CBT (n = 60). After treatment, and at a 6-month follow-up, patients were again assessed by the psychiatrist, blind to treatment condition. RESULTS: Immediately after randomization 9 patients dropped out, leaving 104 patients who started treatment. Patients in both treatment conditions showed significant improvement on the main outcome measure, the Panic Disorder Severity Scale (PDSS) after treatment. For the Internet treatment the within-group effect size (pre-post) on the PDSS was Cohen's d = 1.73, and for the group treatment it was d = 1.63. Between group effect sizes were low and treatment effects were maintained at 6-months follow-up. We found no statistically significant differences between the two treatment conditions using a mixed models approach to account for missing data. Group CBT utilised considerably more therapist time than did Internet CBT. Defining effect as proportion of PDSS responders, the cost-effectiveness analysis concerning therapist time showed that Internet treatment had superior cost-effectiveness ratios in relation to group treatment both at post-treatment and follow-up. CONCLUSIONS: This study provides support for the effectiveness of Internet CBT in a psychiatric setting for patients with panic disorder, and suggests that it is equally effective as the more widely used group administered CBT in reducing panic-and agoraphobic symptoms, as well as being more cost effective with respect to therapist time. TRIAL REGISTRATION: ClinicalTrials.gov NCT00845260.