Tenofovir-containing nucleoside/nucleotide-only antiretroviral maintenance therapy: decision making and virological outcome

OBJECTIVE: To assess the virological outcome of patients with undetectable human immunodeficiency (HI) viremia switched to tenofovir (TDF)-containing nucleosideonly (NUKE-only) treatments and to investigate the factors influencing the physicians' decision for application of a nonestablished therapy. METHOD: Patients' characteristics and history were taken from the cohort database. To study the decision-making process, questionnaires were sent to all treating physicians. RESULTS: 49 patients were changed to TDF-containing NUKE-only treatment and 46 had a follow-up measurement of HI viremia. Virological failure occurred in 16 (35%) patients. Virological failure was associated with previous mono or dual therapy and with a regimen including didanosine or abacavir. No failure occurred in 15 patients without these predisposing factors. The main reasons for change to TDF-containing NUKE-only treatment were side effects and presumed favorable toxicity profile. The rationale behind this decision was mainly analogy to the zidovudine/lamivudine/abacavir maintenance therapy. CONCLUSION: TDF-containing NUKE-only treatment is associated with high early failure rates in patients with previous nucleoside reverse transcriptase inhibitor mono or dual therapy and in drug combinations containing didanosine or abacavir but not in patients without these predisposing factors. In HIV medicine, treatment strategies that are not evidence-based are followed by a minority of experienced physicians and are driven by patients' needs, mainly to minimize treatment side effects.

Effectiveness, safety and cost-effectiveness of homeopathy in general practice - summarized health technology assessment

Introduction: The Health Technology Assessment report on effectiveness, cost-effectiveness and appropriateness of homeopathy was compiled on behalf of the Swiss Federal Office for Public Health (BAG) within the framework of the 'Program of Evaluation of Complementary Medicine (PEK)'. Materials and Methods: Databases accessible by Internet were systematically searched, complemented by manual search and contacts with experts, and evaluated according to internal and external validity criteria. Results: Many high-quality investigations of pre-clinical basic research proved homeopathic high-potencies inducing regulative and specific changes in cells or living organisms. 20 of 22 systematic reviews detected at least a trend in favor of homeopathy. In our estimation 5 studies yielded results indicating clear evidence for homeopathic therapy. The evaluation of 29 studies in the domain 'Upper Respiratory Tract Infections/Allergic Reactions' showed a positive overall result in favor of homeopathy. 6 out of 7 controlled studies were at least equivalent to conventional medical interventions. 8 out of 16 placebocontrolled studies were significant in favor of homeopathy. Swiss regulations grant a high degree of safety due to product and training requirements for homeopathic physicians. Applied properly, classical homeopathy has few side-effects and the use of high-potencies is free of toxic effects. A general health-economic statement about homeopathy cannot be made from the available data. Conclusion: Taking internal and external validity criteria into account, effectiveness of homeopathy can be supported by clinical evidence and professional and adequate application be regarded as safe. Reliable statements of cost-effectiveness are not available at the moment. External and model validity will have to be taken more strongly into consideration in future studies.

Diagnostic efficacy of SonoVue, a second generation contrast agent, in the assessment of extracranial carotid or peripheral arteries using colour and spectral Doppler ultrasound: a multicentre study

The purpose of this study was to demonstrate the improvement in diagnostic quality and diagnostic accuracy of SonoVue microbubble contrast-enhanced ultrasound (CE-US) versus unenhanced ultrasound imaging during the investigation of extracranial carotid or peripheral arteries. 82 patients with suspected extracranial carotid or peripheral arterial disease received four SonoVue doses (0.3 ml, 0.6 ml, 1.2 ml and 2.4 ml) with Doppler ultrasound performed before and following each dose. Diagnostic quality of the CE-US examinations was evaluated off-site for duration of clinically useful contrast enhancement, artefact effects and percentage of examinations converted from non-diagnostic to diagnostic. Accuracy, sensitivity and specificity were assessed as agreement of CE-US diagnosis evaluated by an independent panel of experts with reference standard modality. The median duration of clinically useful signal enhancement significantly increased with increasing SonoVue doses (p< or =0.002). At the dose of 2.4 ml of SonoVue, diagnostic quality evaluated as number of inconclusive examinations significantly improved, falling from 40.7% at baseline down to 5.1%. Furthermore, SonoVue significantly (p<0.01) increased the accuracy, sensitivity and specificity of assessment of disease compared with baseline ultrasound. SonoVue increases the diagnostic quality of Doppler images and improves the accuracy of both spectral and colour Doppler examinations of extracranial carotid or peripheral arterial disease.

The role of stress hormones in the relationship between resting blood pressure and coagulation activity

BACKGROUND: Systemic hypertension confers a hypercoagulable state. We hypothesized that resting mean blood pressure (MBP) interacts with stress hormones in predicting coagulation activity at rest and with acute mental stress. METHODS: We measured plasma clotting factor VII activity (FVII:C), FVIII:C, fibrinogen, D-dimer, epinephrine and norepinephrine, and saliva cortisol in 42 otherwise healthy normotensive and hypertensive medication-free men (mean age 43 +/- 14 years) at rest, immediately after stress, and twice during 60 min of recovery from stress. RESULTS: At rest, the MBP-by-epinephrine interaction predicted FVII:C (beta = -0.33, P < 0.04) and D-dimer (beta = 0.26, P < 0.05), and the MBP-by-cortisol interaction predicted D-dimer (beta = 0.43, P = 0.001), all independent of age and body mass index (BMI). Resting norepinephrine predicted fibrinogen (beta = 0.42, P < 0.01) and D-dimer (beta = 0.37, P < 0.03), both independent of MBP. MBP predicted FVIII:C change from rest to immediately post-stress independent of epinephrine (beta = -0.37, P < 0.03) and norepinephrine (beta = -0.38, P < 0.02). Cortisol change predicted FVIII:C change (beta = -0.30, P < 0.05) independent of age, BMI and MBP. Integrated norepinephrine change from rest to recovery (area under the curve, AUC) predicted D-dimer AUC (beta = 0.34, P = 0.04) independent of MBP. The MBP-by-epinephrine AUC interaction predicted FVII:C AUC (beta = 0.28) and fibrinogen AUC (beta = -0.30), and the MBP-by-norepinephrine AUC interaction predicted FVIII:C AUC (beta = -0.28), all with borderline significance (Ps < 0.09) and independent of age and BMI. CONCLUSIONS: MBP significantly altered the association between stress hormones and coagulation activity at rest and, with borderline significance, across the entire stress and recovery interval. Independent of MBP, catecholamines were associated with procoagulant effects and cortisol reactivity dampened the acute procoagulant stress response.

The feasibility, efficacy and functional outcome of local anaesthetic repair of anterior and posterior vaginal wall prolapse

INTRODUCTION: Urogenital prolapse is a very common condition in women with a prevalence of 30%. If conservative therapy fails or is not desired by the patient, prolapse repair is usually performed under general or regional anaesthetic. The aim of the study was to evaluate feasibility, efficacy and functional outcome after fascial prolapse repairs under local anaesthetic (LA). PATIENTS AND METHODS: Between November 1999 and December 2000, 130 consecutive patients presenting with anterior or posterior prolapse or both were invited to have their procedure performed under LA. All patients with a symptomatic minimum stage II prolapse were included. Prior to surgery all women completed a standardized questionnaire examining the specific and non-specific symptoms of prolapse and their situation was classified using the ICS Pelvic Organ Prolapse (POP-Q) system. Follow up was 30 months. Objective success was defined as a stage 1 or less and no symptoms of bulge, subjective success was defined as lack of specific or non-specific symptoms of prolapse. RESULTS: There were 128 patients who agreed to have their operations performed under LA: 68 in the anterior group, 52 in the posterior group and 8 with a combined anterior and posterior repair. Objective cure rate was 88% for posterior repair, 87% for anterior repair and 63% for combined repair. Success rates were no different in primary from recurrent cases. There were no intraoperative complications and operating time was 21 min (anterior repair) or 23 min (posterior repair). There was no de novo postoperative urinary or stool incontinence and all patients but two would have the operation performed again under the same circumstances. The two remaining refused due to embarrassment but for no other reason. CONCLUSION: Local anaesthetic prolapse repair is feasible and effective in middle term results. It is well accepted by the patients who benefit from less side effects and short hospital stay.

Platelet receptors for adhesion and activation. Variability as a factor in susceptibility to cardiovascular diseases

Polymorphisms in coagulation factors leading to altered susceptibility to cardiovascular diseases have been known for some time and some are now well-established risk factors. More recently, an increasing number of polymorphisms have been identified in platelet receptors and a series of studies indicate that these too may play a role as individual risk factors for stroke and myocardial infarction. The effect of these platelet polymorphisms appears less clear-cut than some of the coagulation factor effects and other, associated, risk factors may be important in defining their role. In this review platelet receptor polymorphisms and their role as risk factors are surveyed and their possible relevance discussed.

[Parent satisfaction with a child and family-centered treatment program for primary headache in childhood and adolescence]

Patient satisfaction represents a significant outcome criterion in the context of systemic psychotherapeutic therapy research. This study investigated parent satisfaction with a psychosocial treatment program (comprising three components: child group therapy, parents' evenings, systemic family sessions) for pediatric primary headache (diagnosed according to IHS criteria). 10 weeks after the end of the treatment program, the parents were sent a questionnaire containing open questions and ten-point numerical rating scales. The sample comprised n=48 families. The return rate was 89%. The qualitative content analysis showed a hierarchical category system consisting of 3 major categories, 7 main groups and 69 sub-categories. The parents stated that they were satisfied with (1.) the effects of the treatment program, (2.) the specific treatment techniques and the medical and psychosocial headache-related information provided, and (3.) the therapeutic relationship. The mean satisfaction for all three therapy components on the ten-point numerical rating scale was 8.1 with a standard deviation of 2.0 (child headache group: 8.5; parents' evenings: 8.2; family sessions: 7.5). The results are discussed with reference to methodological aspects: avoidance of ceiling effects and social desirability in measuring customer satisfaction, order effects of items, weighting of the significance of satisfaction levels as an outcome criterion.

Monte Carlo simulation of a dynamic MLC: implementation and applications

PURPOSE: Study of behavior and influence of a multileaf collimator (MLC) on dose calculation, verification, and portal energy spectra in the case of intensity-modulated fields obtained with a step-and-shoot or a dynamic technique. METHODS: The 80-leaf MLC for the Varian Clinac 2300 C/D was implemented in a previously developed Monte Carlo (MC) based multiple source model (MSM) for a 6 MV photon beam. Using this model and the MC program GEANT, dose distributions, energy fluence maps and energy spectra at different portal planes were calculated for three different MLC applications. RESULTS: The comparison of MC-calculated dose distributions in the phantom and portal plane, with those measured with films showed an agreement within 3% and 1.5 mm for all cases studied. The deviations mainly occur in the extremes of the intensity modulation. The MC method allows to investigate, among other aspects, dose components, energy fluence maps, tongue-and-groove effects and energy spectra at portal planes. CONCLUSION: The MSM together with the implementation of the MLC is appropriate for a number of investigations in intensity-modulated radiation therapy (IMRT).

Nuclear localization of epidermal growth factor and epidermal growth factor receptors in human thyroid tissues

Epidermal growth factor (EGF) has widespread growth effects, and in some tissues proliferation is associated with the nuclear localization of EGF and epidermal growth factor receptor (EGFR). In the thyroid, EGF promotes growth but differs from thyrotropin (TSH) in inhibiting rather than stimulating functional parameters. We have therefore studied the occurrence and cellular distribution of EGF and EGFR in normal thyroid, in Graves' disease, where growth is mediated through the thyrotropin receptor (TSHR), and in a variety of human thyroid tumors. In the normal gland the staining was variable, but largely cytoplasmic, for both EGF and EGFR. In Graves' disease there was strong cytoplasmic staining for both EGF and EGFR, with frequent positive nuclei. Nuclear positivity for EGF and particularly for EGFR was also a feature of both follicular adenomas and follicular carcinomas. Interestingly, nuclear staining was almost absent in papillary carcinomas. These findings document for the first time the presence of nuclear EGF and EGFR in thyroid. Their predominant occurrence in tissues with increased growth (Graves' disease, follicular adenoma, and carcinoma) may indicate that nuclear EGF and EGFR play a role in growth regulation in these conditions. The absence of nuclear EGF and EGFR in papillary carcinomas would suggest that the role played by EGF in growth control differs between papillary carcinoma and follicular adenomas/carcinomas of the thyroid.

Patient satisfaction of primary care for musculoskeletal diseases: A comparison between Neural Therapy and conventional medicine

Background The main objective of this study was to assess and compare patient satisfaction with Neural Therapy (NT) and conventional medicine (COM) in primary care for musculoskeletal diseases. Methods A cross-sectional study in primary care for musculoskeletal disorders covering 77 conventional primary care providers and 18 physicians certified in NT with 241 and 164 patients respectively. Patients and physicians documented consultations and patients completed questionnaires at a one-month follow-up. Physicians documented duration and severity of symptoms, diagnosis, and procedures. The main outcomes in the evaluation of patients were: fulfillment of expectations, perceived treatment effects, and patient satisfaction. Results The most frequent diagnoses belonged to the group of dorsopathies (39% in COM, 46% in NT). We found significant differences between NT and COM with regard to patient evaluations. NT patients documented better fulfilment of treatment expectations and higher overall treatment satisfaction. More patients in NT reported positive side effects and less frequent negative effects than patients in COM. Also, significant differences between NT and COM patients were seen in the quality of the patient-physician interaction (relation and communication, medical care, information and support, continuity and cooperation, facilities availability, and accessibility), where NT patients showed higher satisfaction. Differences were also found with regard to the physicians' management of disease, with fewer work incapacity attestations issued and longer consultation times in NT. Conclusion Our findings show a significantly higher treatment and care-related patient satisfaction with primary care for musculoskeletal diseases provided by physicians practising Neural Therapy.

Long-term followup results of 1 cycle of adjuvant bleomycin, etoposide and cisplatin chemotherapy for high risk clinical stage I nonseminomatous germ cell tumors of the testis

PURPOSE: We evaluated the long-term outcome after 1 cycle of adjuvant modified bleomycin, etoposide and cisplatin chemotherapy in patients who underwent orchiectomy for high risk clinical stage I nonseminomatous germ cell tumor of the testis. MATERIALS AND METHODS: Between 1995 and 1999 a consecutive series of 44 patients underwent orchiectomy for clinical stage I nonseminomatous germ cell tumor of the testis, followed by a single postoperative cycle of adjuvant modified bleomycin, etoposide and cisplatin for vascular or lymphatic tumor invasion, and/or a predominance (50% or greater) of embryonal carcinoma. RESULTS: Four of the 44 patients were excluded from analysis. Of the patients 35 had no evidence of disease at a median followup of 99 months (range 60 to 134). One patient with progression after 13 months showed complete remission after 3 cycles of salvage bleomycin, etoposide and cisplatin chemotherapy but he died of pneumonia 4 weeks after the third course. Two patients underwent orchiectomy for contralateral testis cancer at 18 and 42 months, respectively, followed by an additional 3 cycles of adjuvant chemotherapy. They remained relapse-free for 4 and 92 months, respectively. The former patient was lost to followup after 4 months. Two other patients were disease-free at 10 and 31 months, respectively, and were lost to followup thereafter. Late side effects were tinnitus in 3 patients and involuntary childlessness in 3, of whom 2 had cryptorchidism of the contralateral testis. Nine patients fathered children. CONCLUSIONS: One cycle of bleomycin, etoposide and cisplatin effectively decreases the risk of relapse in patients with high risk stage I nonseminomatous germ cell tumor of the testis. It has minimal side effects and can be a valuable alternative to retroperitoneal lymph node dissection.

Androgen deprivation therapy for the treatment of prostate cancer: consider both benefits and risks

CONTEXT: Androgen deprivation therapy (ADT) is increasingly used for the treatment of prostate cancer (PCa), even in clinical settings in which there is no evidence-based proof of prolonged overall survival (OS). ADT, however, may be associated with numerous side effects, including an increased therapy-related cardiovascular mortality. OBJECTIVE: To discuss different clinical settings in which ADT is currently used and to critically weigh the benefits of ADT against its possible side effects. EVIDENCE ACQUISITION: A MEDLINE search was conducted to identify original articles and review articles addressing the efficacy and side effects of ADT for the treatment of PCa. Keywords consisted of prostate cancer, hormonal therapy, adverse effects, radical prostatectomy, and radiotherapy. The articles with the highest level of evidence for the various examined end points were identified with the consensus of all authors and were reviewed. EVIDENCE SYNTHESIS: Even short-term use of ADT may lead to numerous side effects, such as osteoporosis, obesity, sarcopenia, lipid alterations, insulin resistance, and increased risk for diabetes and cardiovascular morbidity. Despite these side effects, ADT is commonly used in various clinical settings in which a clear effect on improved OS has not been shown. CONCLUSIONS: ADT is associated with an increased risk of multiple side effects that may reduce quality of life and/or OS. Consequently, these issues should be discussed in detail with patients and their families before initiation of ADT. ADT should be used with knowledge of its potential long-term side effects and with possible lifestyle interventions, especially in settings with the highest risk-benefit ratio, to alleviate comorbidities.

Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials

BACKGROUND: Erythropoiesis-stimulating agents reduce anaemia in patients with cancer and could improve their quality of life, but these drugs might increase mortality. We therefore did a meta-analysis of randomised controlled trials in which these drugs plus red blood cell transfusions were compared with transfusion alone for prophylaxis or treatment of anaemia in patients with cancer. METHODS: Data for patients treated with epoetin alfa, epoetin beta, or darbepoetin alfa were obtained and analysed by independent statisticians using fixed-effects and random-effects meta-analysis. Analyses were by intention to treat. Primary endpoints were mortality during the active study period and overall survival during the longest available follow-up, irrespective of anticancer treatment, and in patients given chemotherapy. Tests for interactions were used to identify differences in effects of erythropoiesis-stimulating agents on mortality across prespecified subgroups. FINDINGS: Data from a total of 13 933 patients with cancer in 53 trials were analysed. 1530 patients died during the active study period and 4993 overall. Erythropoiesis-stimulating agents increased mortality during the active study period (combined hazard ratio [cHR] 1.17, 95% CI 1.06-1.30) and worsened overall survival (1.06, 1.00-1.12), with little heterogeneity between trials (I(2) 0%, p=0.87 for mortality during the active study period, and I(2) 7.1%, p=0.33 for overall survival). 10 441 patients on chemotherapy were enrolled in 38 trials. The cHR for mortality during the active study period was 1.10 (0.98-1.24), and 1.04 (0.97-1.11) for overall survival. There was little evidence for a difference between trials of patients given different anticancer treatments (p for interaction=0.42). INTERPRETATION: Treatment with erythropoiesis-stimulating agents in patients with cancer increased mortality during active study periods and worsened overall survival. The increased risk of death associated with treatment with these drugs should be balanced against their benefits. FUNDING: German Federal Ministry of Education and Research, Medical Faculty of University of Cologne, and Oncosuisse (Switzerland).

The effects of excluding patients from the analysis in randomised controlled trials: meta-epidemiological study

OBJECTIVE: To examine whether excluding patients from the analysis of randomised trials are associated with biased estimates of treatment effects and higher heterogeneity between trials. DESIGN: Meta-epidemiological study based on a collection of meta-analyses of randomised trials. DATA SOURCES: 14 meta-analyses including 167 trials that compared therapeutic interventions with placebo or non-intervention control in patients with osteoarthritis of the hip or knee and used patient reported pain as an outcome. METHODS: Effect sizes were calculated from differences in means of pain intensity between groups at the end of follow-up, divided by the pooled standard deviation. Trials were combined by using random effects meta-analysis. Estimates of treatment effects were compared between trials with and trials without exclusions from the analysis, and the impact of restricting meta-analyses to trials without exclusions was assessed. RESULTS: 39 trials (23%) had included all patients in the analysis. In 128 trials (77%) some patients were excluded from the analysis. Effect sizes from trials with exclusions tended to be more beneficial than those from trials without exclusions (difference -0.13, 95% confidence interval -0.29 to 0.04). However, estimates of bias between individual meta-analyses varied considerably (tau(2)=0.07). Tests of interaction between exclusions from the analysis and estimates of treatment effects were positive in five meta-analyses. Stratified analyses indicated that differences in effect sizes between trials with and trials without exclusions were more pronounced in meta-analyses with high between trial heterogeneity, in meta-analyses with large estimated treatment benefits, and in meta-analyses of complementary medicine. Restriction of meta-analyses to trials without exclusions resulted in smaller estimated treatment benefits, larger P values, and considerable decreases in between trial heterogeneity. CONCLUSION: Excluding patients from the analysis in randomised trials often results in biased estimates of treatment effects, but the extent and direction of bias is unpredictable. Results from intention to treat analyses should always be described in reports of randomised trials. In systematic reviews, the influence of exclusions from the analysis on estimated treatment effects should routinely be assessed.

The effectiveness and safety of proton radiation therapy for indications of the eye : a systematic review

BACKGROUND AND PURPOSE: : Proton radiation has been used for the treatment of uveal melanoma since 1975, but few studies have been conducted to assess its efficacy and safety. This paper aims to systematically review the effects and side effects of proton therapy for any indication of the eye. MATERIAL AND METHODS: : A range of databases were searched from inception to 2007. All studies that included at least ten patients and that assessed the efficacy or safety of proton therapy for any indication of the eye were included. RESULTS: : The search generated 2,385 references, of which 37 met the inclusion criteria. Five controlled trials, two comparative studies and 30 case series were found, most often reporting on uveal melanoma, choroidal melanoma and age-related macular degeneration (AMD). Methodological quality of these studies was poor. Studies were characterized by large differences in radiation techniques applied within the studies, and by variation in patient characteristics within and between studies. Results for uveal melanoma and choroidal melanoma suggest favorable survival, with, however, significant rates of side effects. Results for choroidal hemangioma and AMD did not reveal beneficial effects from proton radiation. CONCLUSION: : There is limited evidence on the effectiveness and safety of proton radiation due to the lack of well-designed and well-reported studies. There is a need to lift evidence on proton therapy to a higher level by performing dose-finding randomized controlled trials (RCTs), comparative studies of proton radiation versus standard given alternatives and prospective case studies enrolling only patients treated with up-to-date techniques, allowing extrapolation of results to similar patient groups.