In Vitro Biodegradation of Resorbable Magnesium Alloys Promising for Implant Development.

The aim of the investigation was to study the biodegradation characteristics and rate of magnesium alloys in vitro. MATERIALS AND METHODS: We studied the biodegradation of magnesium alloys Mg-Zn-Ca and WE43 (Mg-Y-Nd-Zr) in homogenized (initial) condition and after strengthening by mechanical processing using equal channel angular pressing (ECAP). The samples were incubated in a model system based on reference fetal calf serum (FCS) in the static and dynamic modes. The morphology of alloy surfaces was analyzed using light microscopy and computed tomography. Biodegradation was assessed by calculating weight loss within a certain incubation period. Cell adhesion and colonization stimulation were quantified in terms of a cell index (CI) using an analyzer xCELLigence RTCA Systems (ACEA Biosciences, Inc., USA) during the incubation of HEK 293 cells on WE43 specimens. RESULTS: Strengthening of magnesium alloys Mg-Zn-Ca and WE43 using ECAP and, consequently, the changed structure resulted in the biodegradation acceleration as high as eightfold. Among the specimens incubated in FCS in different modes, those incubated in liquid flow exhibited the biodegradation rate twice as high as that of the specimens tested under static conditions. The biodegradation process was accompanied by local corrosion, although the degradation was primarily concentrated along the specimen margins stimulating cell adhesion and colonization. Such nature of degradation, as a rule, does not lead to anisotropy of the strength characteristics, that is important for medical materials. Superficial degradation of the alloys with no X-ray density changes in the bulk of the specimens was confirmed by computed tomography. CONCLUSION: The study of the biodegradation rate and further characteristics of magnesium alloys Mg-Zn-Ca and WE43 showed that the materials in both structural conditions are suitable for implants and can be used in bone implants and surgical fasteners.

Mortality differences and inequalities within and between 'protected characteristics' groups, in a Scottish Cohort 1991-2009.

BACKGROUND: Little is known about the interaction between socio-economic status and 'protected characteristics' in Scotland. This study aimed to examine whether differences in mortality were moderated by interactions with social class or deprivation. The practical value was to pinpoint population groups for priority action on health inequality reduction and health improvement rather than a sole focus on the most deprived socioeconomic groups. METHODS: We used data from the Scottish Longitudinal Study which captures a 5.3 % sample of Scotland and links the censuses of 1991, 2001 and 2011. Hazard ratios for mortality were estimated for those protected characteristics with sufficient deaths using Cox proportional hazards models and through the calculation of European age-standardised mortality rates. Inequality was measured by calculating the Relative Index of Inequality (RII). RESULTS: The Asian population had a polarised distribution across deprivation deciles and was more likely to be in social class I and II. Those reporting disablement were more likely to live in deprived areas, as were those raised Roman Catholic, whilst those raised as Church of Scotland or as 'other Christian' were less likely to. Those aged 35-54 years were the least likely to live in deprived areas and were most likely to be in social class I and II. Males had higher mortality than females, and disabled people had higher mortality than non-disabled people, across all deprivation deciles and social classes. Asian males and females had generally lower mortality hazards than majority ethnic ('White') males and females although the estimates for Asian males and females were imprecise in some social classes and deprivation deciles. Males and females who reported their raised religion as Roman Catholic or reported 'No religion' had generally higher mortality than other groups, although the estimates for 'Other religion' and 'Other Christian' were less precise.Using both the area deprivation and social class distributions for the whole population, relative mortality inequalities were usually greater amongst those who did not report being disabled, Asians and females aged 35-44 years, males by age, and people aged <75 years. The RIIs for the raised religious groups were generally similar or too imprecise to comment on differences. CONCLUSIONS: Mortality in Scotland is higher in the majority population, disabled people, males, those reporting being raised as Roman Catholics or with 'no religion' and lower in Asians, females and other religious groups. Relative inequalities in mortality were lower in disabled than nondisabled people, the majority population, females, and greatest in young adults. From the perspective of intersectionality theory, our results clearly demonstrate the importance of representing multiple identities in research on health inequalities.

Multicentre randomised controlled trial of the clinical and cost-effectiveness of a bypass-surgery-first versus a balloon-angioplasty-first revascularisation strategy for severe limb ischaemia due to infrainguinal disease. The Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial.

OBJECTIVE: To compare a 'bypass-surgery-first' with a 'balloon-angioplasty-first' revascularisation strategy in patients with severe limb ischaemia (SLI) due to infrainguinal disease requiring immediate/early revascularisation. DESIGN: A stratified randomised controlled trial. A Delphi consensus study of vascular surgeons' and interventional radiologists' views on SLI treatment was performed before the trial. SETTING: Twenty-seven UK hospitals. PARTICIPANTS: Patients presenting with SLI as the result of infrainguinal atherosclerosis and who, in the opinion of the responsible consultant vascular surgeon and interventional radiologist, required and were suitable for both surgery and angioplasty. INTERVENTIONS: Patients were randomised to either 'bypass-surgery-first' or 'balloon-angioplasty-first' revascularisation strategies. MAIN OUTCOME MEASURES: The primary end point was amputation-free survival (AFS); secondary end points were overall survival (OS), health-related quality of life (HRQoL) and cost-effective use of hospital resources. RESULTS: AFS at 1 and 3 years was not significantly different for surgery and angioplasty. Interim analysis showed that surgery was associated with significantly lower immediate failure, higher 30-day morbidity and lower 12-month reintervention rates than angioplasty; 30-day mortality was similar. Beyond 2 years from randomisation, hazard ratios (HRs) were significantly reduced for both AFS (adjusted HR 0.37; 95% CI 0.17 to 0.77; p = 0.008) and OS (HR 0.34; 95% CI 0.17 to 0.71; p = 0.004) for surgery relative to angioplasty. By 2008 all but four patients had been followed for 3 years, some for over 7 years: 250 (56%) were dead, 168 (38%) were alive without amputation and 30 (7%) were alive with amputation. Considering the follow-up period as a whole, AFS and OS did not differ between treatments but for patients surviving beyond 2 years from randomisation, bypass was associated with reduced HRs for AFS (HR 0.85; 95% CI 0.50 to 1.07; p = 0.108) and OS (HR 0.61; 95% CI 0.50 to 0.75; p = 0.009), equating to an increase in restricted mean OS of 7.3 months (p = 0.02) and AFS of 5.9 months (p = 0.06) during the subsequent follow-up period. Vein bypasses and angioplasties performed better than prosthetic bypasses. HRQoL was non-significantly better in the surgery group; amputation was associated with a significant reduction in HRQoL. Over the first year, hospital costs for bypass were significantly higher (difference 5420 pounds; 95% CI 1547 pounds to 9294 pounds) than for angioplasty. However, by 3 and at 7 years the differences in cost between the two strategies were no longer significant. Patients randomised to surgery lived, on average, 29 days longer at an additional average cost of 2310 pounds. A 36-month perspective showed not significantly different mean quality-adjusted life times for angioplasty and surgery. The Delphi study revealed substantial disagreement between and among surgeons and radiologists on the appropriateness of bypass surgery or balloon angioplasty. CONCLUSIONS: The findings of our study suggest that in patients with SLI due to infrainguinal disease the decision whether to perform bypass surgery or balloon angioplasty first appears to depend upon anticipated life expectancy. Patients expected to live less than 2 years should usually be offered balloon angioplasty first as it is associated with less morbidity and cost, and such patients are unlikely to enjoy the longer-term benefits of surgery. By contrast, those patients expected to live beyond 2 years should usually be offered bypass surgery first, especially where a vein is available as a conduit. Many patients who could not undergo a vein bypass would probably have been better served by a first attempt at balloon angioplasty than prosthetic bypass. The failure rate of angioplasty in SLI is high (c. 25%) and patients who underwent bypass after failed angioplasty fared significantly worse than those who underwent surgery as their first procedure. The interests of a significant proportion of BASIL patients may have been best served by primary amputation followed by high-quality rehabilitation. Further research is required to confirm or refute the BASIL findings and recommendations; validate the BASIL survival prediction model in a separate cohort of patients with SLI; examine the clinical and cost-effectiveness of new endovascular techniques and devices; and compare revascularisation with primary amputation and with best medical and nursing care in those SLI patients with the poorest survival prospects. TRIAL REGISTRATION: Current Controlled Trials ISRCTN45398889.

When are summary ROC curves appropriate for diagnostic meta-analyses?

Diagnostic tests are increasingly evaluated with systematic reviews and this has lead to the recent developments of statistical methods to analyse such data. The most commonly used method is the summary receiver operating characteristic (SROC) curve, which can be fitted with a non-linear bivariate random-effects model. This paper focuses on the practical problems of interpreting and presenting data from such analyses. First, many meta-analyses may be underpowered to obtain reliable estimates of the SROC parameters. Second, the SROC model may be inappropriate. In these situations, a summary with two univariate meta-analyses of the true and false positive rates (TPRs and FPRs) may be more appropriate. We characterize the type of problems that can occur in fitting these models and present an algorithm to guide the analyst of such studies, with illustrations from analyses of published data. A set of R functions, freely available to perform these analyses, can be downloaded from (www.diagmeta.info).

Cost-utility analysis for advanced breast cancer therapy in Germany: results of the fulvestrant sequencing model.

Therapy decisions in advanced breast cancer (ABC) increasingly require assessment not only of treatment efficacy but also of cost-effectiveness. To this end, we performed a cost-utility analysis by comparing treatment sequences including/omitting fulvestrant in a hypothetical population of hormone receptor-positive (HR+) postmenopausal women with ABC. The analysis was performed from the German health care perspective. Using a first-order sequential Markov model, expected costs and utilities were calculated over a time horizon of 10 years for cohorts of patients with HR+ ABC, previously treated for at least 5 years using adjuvant endocrine therapies. Utilities were primarily quantified in terms of quality adjusted life years (QALY). "Base-case" estimates of state transition rates, resource utilization, and other model parameters were derived from published evidence and expert assessment. The impacts of uncertainties in all key model parameters were evaluated by sensitivity analysis. Costs and benefits were discounted at 3% annually. Including second-line fulvestrant in the treatment sequence led to greater estimated health gains (0.021 QALY) and cost savings of 564 euros ($745, 380 pounds) per patient, i.e. the fulvestrant-containing sequence was "dominant". The prediction of a cost savings was robust with respect to variations in all key parameters. The probability of acceptable cost-effectiveness for the fulvestrant sequence was 72% at a willingness to pay (WTP) of 30,000 euros/QALY ($39,621/QALY, 20,198 pounds/QALY); the probability was even higher at lower WTP and substantially exceeded 50% for any realistic WTP. In a representative population of women with HR+ advanced breast cancer, inclusion of fulvestrant in the treatment sequence provides a cost-effective alternative from the German health care perspective. A high probability of cost-effectiveness is maintained under variations in all key parameters. The results reflect a tendency for patients receiving fulvestrant at an early stage to maintain high quality of life for a longer interval.

Impact of a theoretically based sex education programme (SHARE) delivered by teachers on NHS registered conceptions and terminations: final results of cluster randomised trial.

OBJECTIVE: To assess the impact of a theoretically based sex education programme (SHARE) delivered by teachers compared with conventional education in terms of conceptions and terminations registered by the NHS. DESIGN: Follow-up of cluster randomised trial 4.5 years after intervention. SETTING: NHS records of women who had attended 25 secondary schools in east Scotland. PARTICIPANTS: 4196 women (99.5% of those eligible). INTERVENTION: SHARE programme (intervention group) v existing sex education (control group). MAIN OUTCOME MEASURE: NHS recorded conceptions and terminations for the achieved sample linked at age 20. RESULTS: In an "intention to treat" analysis there were no significant differences between the groups in registered conceptions per 1000 pupils (300 SHARE v 274 control; difference 26, 95% confidence interval -33 to 86) and terminations per 1000 pupils (127 v 112; difference 15, -13 to 42) between ages 16 and 20. CONCLUSIONS: This specially designed sex education programme did not reduce conceptions or terminations by age 20 compared with conventional provision. The lack of effect was not due to quality of delivery. Enhancing teacher led school sex education beyond conventional provision in eastern Scotland is unlikely to reduce terminations in teenagers. TRIAL REGISTRATION: ISRCTN48719575 [controlled-trials.com].

Analysing sequential events in clinical trials.

BACKGROUND: Data from clinical trials where the endpoint is a single survival time are readily analysed by standard methods, most commonly using a semi-parametric proportional hazards approach. However, when the outcome involves two sequential survival times, standard methods may not be applicable. METHODS: We consider methods appropriate for the analysis of survival data in clinical trials where there are two distinct, sequential and opposing survival endpoints and where inferences about the second event are of particular interest. Two motivating examples of randomized clinical trials with different designs provide important illustrations of the methodology in practice. RESULTS: Bivariate log-normal survival models are proposed as useful way of modeling such data. These models can be simply implemented in two stages, each of which is a univariate log-normal survival analysis. Different approaches to the analyses are described according to whether a second randomized treatment assignment is made at the time when the first event occurs and the second phase of the study commences. In the absence of a second randomization, the bivariate log-normal model adjusts for selection into the second phase of the study. CONCLUSIONS: The investigation of 'treatment sequences' should, wherever possible, be handled by repeat randomization, which can then be followed by valid, unbiased analyses. However, in many clinical trial scenarios, this is simply not possible. In this case, the best approach is to consider the data as arising from an observational study, whilst controlling for all appropriate covariates. LIMITATIONS: The approach we describe is appropriate for log-normally distributed data but could be generalised to handle other distributions, although the process of model fitting would be less straight-forward.

From medical invention to clinical practice: the reimbursement challenge facing new device procedures and technology--part 1: issues in medical device assessment.

Although reimbursement shapes medical practice, it is hard to get a handle on this issue because reimbursement requirements seem to change and evolve over time, and different insurers approach it in different ways for different technologies. This paper and the 2 that follow attempt to explain the reimbursement challenges facing new medical device technology. This first paper addresses the particular characteristics of medical device innovation and explains how they complicate the technology assessment process. It also notes the importance of codes as a means to identify new technologies and procedures, citing some issues that affect technology adoption. The subsequent papers delve into specific coverage and payment matters affecting medical devices. The perspective presented in these papers is that of a medical device manufacturer, and the focus tends to be on Medicare, given the size of this insurance program and its impact on the US health care system, but the issues that are raised affecting medical innovation can be extended to all payers.

From medical invention to clinical practice: the reimbursement challenge facing new device procedures and technology--part 2: coverage.

This paper, the second of 3 that discuss the reimbursement challenges facing new medical device technology in various issues of this journal, explains the key aspects of coverage that affect the adoption of medical devices. The process Medicare uses to make coverage determinations has become more timely and open over the past several years, but it still lacks the predictability that product innovators prefer. The continued uncertainty surrounding evidence requirements undermines the predictability needed for optimal product planning and innovation. Recent steps taken by the Centers for Medicare and Medicaid Services to provide coverage in return for evidence development should provide patients with access to promising new technologies and procedures while generating important evidence concerning their effectiveness.

From medical invention to clinical practice: the reimbursement challenge facing new device procedures and technology--part 3: payment.

This paper, the last of 3 that discuss the reimbursement challenges facing new medical device technology in various issues of this journal, addresses the structural diversity of Medicare's various payment systems. These systems vary widely in how they establish prices, how they incorporate new technologies and procedures, and the means by which they are updated and maintained. Their importance extends beyond Medicare because other payers use these payment rates as a basis for setting rates of their own. Device manufacturers and medical practitioners must often navigate several of these payment systems concurrently to ensure that technologies and procedures (that are already coded properly and covered) receive a fair payment rate. It is important to recognize that coverage can be undermined without adequate payment and that this situation will dampen further product innovation. The 3 papers, taken together, document the challenges posed by insurer reimbursement policies and show that a close working relationship between the manufacturers that develop new medical technologies and physician practitioners is needed if reimbursement hurdles are to be managed and medical innovation is to continue.

Bypass versus angioplasty in severe ischaemia of the leg (BASIL): multicentre, randomised controlled trial.

BACKGROUND: The treatment of rest pain, ulceration, and gangrene of the leg (severe limb ischaemia) remains controversial. We instigated the BASIL trial to compare the outcome of bypass surgery and balloon angioplasty in such patients. METHODS: We randomly assigned 452 patients, who presented to 27 UK hospitals with severe limb ischaemia due to infra-inguinal disease, to receive a surgery-first (n=228) or an angioplasty-first (n=224) strategy. The primary endpoint was amputation (of trial leg) free survival. Analysis was by intention to treat. The BASIL trial is registered with the National Research Register (NRR) and as an International Standard Randomised Controlled Trial, number ISRCTN45398889. FINDINGS: The trial ran for 5.5 years, and follow-up finished when patients reached an endpoint (amputation of trial leg above the ankle or death). Seven individuals were lost to follow-up after randomisation (three assigned angioplasty, two surgery); of these, three were lost (one angioplasty, two surgery) during the first year of follow-up. 195 (86%) of 228 patients assigned to bypass surgery and 216 (96%) of 224 to balloon angioplasty underwent an attempt at their allocated intervention at a median (IQR) of 6 (3-16) and 6 (2-20) days after randomisation, respectively. At the end of follow-up, 248 (55%) patients were alive without amputation (of trial leg), 38 (8%) alive with amputation, 36 (8%) dead after amputation, and 130 (29%) dead without amputation. After 6 months, the two strategies did not differ significantly in amputation-free survival (48 vs 60 patients; unadjusted hazard ratio 1.07, 95% CI 0.72-1.6; adjusted hazard ratio 0.73, 0.49-1.07). We saw no difference in health-related quality of life between the two strategies, but for the first year the hospital costs associated with a surgery-first strategy were about one third higher than those with an angioplasty-first strategy. INTERPRETATION: In patients presenting with severe limb ischaemia due to infra-inguinal disease and who are suitable for surgery and angioplasty, a bypass-surgery-first and a balloon-angioplasty-first strategy are associated with broadly similar outcomes in terms of amputation-free survival, and in the short-term, surgery is more expensive than angioplasty.

In vivo chemosensitivity-adapted preoperative chemotherapy in patients with early-stage breast cancer: the GEPARTRIO pilot study.

BACKGROUND: Response to the first two cycles of preoperative chemotherapy might differentiate subgroups of breast cancer patients with high or minimal chances for a pathologic complete response (pCR) and may be used as an in vivo chemosensitivity test. METHODS: Breast cancer patients were treated with two cycles of TAC (docetaxel 75 mg/m(2), doxorubicin 50 mg/m(2), cyclophosphamide 500 mg/m(2) every 21 days). Patients whose tumors showed a response received four more cycles. Patients whose tumors did not respond were randomized to four additional cycles TAC or NX (vinorelbine 25 mg/m(2) days 1 and 8, capecitabine 2000 mg/m(2) days 1-14, every 21 days). The primary end point was pCR at surgery. RESULTS: Two hundred and eighty-five patients showed a clinical response, in 73.0% after two cycles, in 88.4% at surgery, and a pCR was seen in 17.9%. Breast conservation was possible in 72.2%. Responding patients obtained a pCR in 22.6% whereas non-responding patients reached a pCR in 7.3% and 3.1% with TAC or NX, respectively. Grade III/IV neutropenia and febrile neutropenia were observed during TAC in 70.2% and 13.5%, respectively. Significantly less toxicity were observed with NX. CONCLUSION: Early response to TAC can reliably identify patients with a high chance of achieving a pCR. New effective treatments need to be explored for patients without an early response.

Designing follow-up intervals.

When an examination is needed to determine if an event has occurred there will be a loss of efficiency in using the resulting interval-censored data instead of the exact event times. In designing follow-up intervals this loss for longer intervals needs to be weighed against extra visits required by shorter intervals. We obtain results to quantify this for the estimation of the median and mean survival and for covariates in parametric regression models with equally spaced examination times. Asymptotic information loss for the log-normal and Weibull distributions are similar when comparisons are made between corresponding members of the two families. For distributions with coefficients of variation of 50 per cent or more, a choice of interval from 0.25 to 0.7 times the median is recommended.

[Preoperative chemotherapy in primary operable breast cancer with a dose-dense combination of doxorubicin and docetaxel (ADoc) - Experience of the GEPARDO-GABG study group]. / Präoperative Chemotherapie operabler primärer Mammakarzinome mit einer dosisdichten Kombination von Adriamycin und Docetaxel (ADoc) - Die Erfahrungen der GEPARDO-GABG-Studiengruppe -

OBJECTIVE: The German Adjuvant Breast Cancer Study Group (GABG) conducts trials of preoperative chemotherapy in patients with primary breast cancer using a combination of doxorubicin and docetaxel (ADoc). - PATIENTS AND METHODS: We conducted a parallel-grouped phase IIa-study with 42 patients with a conventionally dosed and a dose-dense ADoc-schedule (4 cycles of Doxorubicin 50 mg/m(2), Docetaxel 75 mg/m(2) i. v. day 1, q day 15 or 22; G-CSF day 3-15 only for the dose-dense schedule) and a randomized phase IIb-study (GEPARDO-Study) with 250 patients with ADoc +/- Tamoxifen. Biological factors were determined immunohistochemically on 197 core biopsies before treatment. A comparison to a sequential AC-Doc regimen including 913 patients has been completed recently. - RESULTS: ADoc can be applicated on schedule in 93 % of all patients. The dose-dense regimen shows a tendency to more toxicity but also to more efficacy. The rate of complete pathological remissions (pCR) was 9.7 %. No difference was found between chemo- and chemoendocrine treatment. Clinically negative lymphnodes and a negative estrogen receptor status is predictive for a higher pCR-rate. To date no differences in toxicity could be found between ADoc and AC-Doc. - CONCLUSIONS: The dose-dense ADoc regimen is well tolerated and highly effective as preoperative therapy of breast cancer.

[Development and integration of the Oncological Documentation System ODS]. / Entwicklung und Integration des Onkologischen Dokumentationssystems ODS.

PURPOSE: To simplify clinical routine and to improve medical quality without exceeding the existing resources. Intensifying communication and cooperation between all institutions of patients' health care. The huge amount of documentation work of physicians can no longer be done without modern tools of paperless data processing. METHODS: The development of ODS was a tight cooperation between physician and technician which resulted in a mutual understanding and led to a high level of user convenience. - At present all cases of gynecology, especially gynecologic oncology can be documented and processed by ODS. Users easily will adopt the system as data entry within different program areas follows the same rules. In addition users can choose between an individual input of data and assistants guiding them through highly specific areas of documentation. RESULTS: ODS is a modern, modular structured and very fast multiuser database environment for in- and outpatient documentation. It automatically generates a lot of reports for clinical day to day business. Statistical routines will help the user reflecting his work and its quality. Documentation of clinical trials according to the GCP guidelines can be done by ODS using the internet or offline datasharing. CONCLUSIONS: As ODS is the synthesis of a computer based patient administration system and an oncological documentation database, it represents the basis for the construction of the electronical patient chart as well as the digital documentation of clinical trials. The introduction of this new technology to physicians and nurses has to be done slowly and carefully, in order to increase motivation and to improve the results.

Dose-dense doxorubicin, docetaxel, and granulocyte colony-stimulating factor support with or without tamoxifen as preoperative therapy in patients with operable carcinoma of the breast: a randomized, controlled, open phase IIb study.

PURPOSE: To investigate the effect of adding tamoxifen to a preoperative dose-dense doxorubicin and docetaxel regimen on the pathologic response of primary operable breast cancer. PATIENTS AND METHODS: Patients (tumor size > or = 3 cm, N0 to 2, M0) were prospectively randomized to receive every 14 days a total of four cycles of doxorubicin 50 mg/m2 and docetaxel 75 mg/m(2), either with (ADocT) or without (ADoc) simultaneous tamoxifen. Granulocyte colony-stimulating factor (G-CSF) was routinely given on days 5 to 10. Surgery followed 8 to 10 weeks after the start of treatment. RESULTS: Within 14 months, 250 patients were included in the study at 56 centers. Of 992 planned cycles, 97.9% were administered. Pathologically complete remission (pCR) with no detectable viable tumor cells was achieved in 9.7%. There was a nonsignificant difference of -1.2% in favor of ADoc, with a 95% confidence interval of -8.6% to 6.2%. A further 2.4% had only noninvasive tumor residues, and 13.8% had focal invasive residues. Complete and partial responses detected by palpation were observed in 28.9% and 52.4%, respectively. The response rates (complete and partial) by best appropriate imaging methods were 77.5% and 67.5% for ADocT and ADoc, respectively. Breast conservation was possible in 68.8% of the patients. A tendency toward more frequent toxic events was observed with ADocT treatment. Significant predictors of pCR to chemotherapy were negative lymph node and negative estrogen receptor status. CONCLUSION: A dose-dense regimen of ADoc with G-CSF offers high compliance, moderate toxicity, and rapid efficacy as a form of preoperative chemotherapy in operable breast cancer. Concurrent treatment with tamoxifen for 8 weeks could not improve the pathologic response rate.

BAG-1 is a novel cytoplasmic binding partner of the membrane form of heparin-binding EGF-like growth factor: a unique role for proHB-EGF in cell survival regulation.

Several cell functions related to growth and survival regulation have been attributed specifically to the membrane form of heparin-binding EGF-like growth factor (proHB-EGF), rather than to the diffusible, processed HB-EGF isoform. These findings suggest the existence of a functional binding partner specifically for the membrane form of the growth factor. In this study we have identified the prosurvival cochaperone, BAG-1, as a protein that interacts with the cytoplasmic tail domain of proHB-EGF. Interaction between BAG-1 and the 24-amino acid proHB-EGF cytoplasmic tail was initially identified in a yeast two-hybrid screen and was confirmed in mammalian cells. The proHB-EGF tail bound BAG-1 in an hsp70-independent manner and within a 97-amino acid segment that includes the ubiquitin homology domain in BAG-1 but does not include the hsp70 binding site. Effects of BAG-1 and proHB-EGF co-expression were demonstrated in cell adhesion and cell survival assays and in quantitative assays of regulated secretion of soluble HB-EGF. Because the BAG-1 binding site is not present on the mature, diffusible form of the growth factor, these findings suggest a new mechanism by which proHB-EGF, in isolation from the diffusible form, can mediate cell signaling events. In addition, because effects of BAG-1 on regulated secretion of soluble HB-EGF were also identified, this interaction has the potential to alter the signaling capabilities of both the membrane-anchored and the diffusible forms of the growth factor.

Random effects models for HIV marker data: practical approaches with currently available software.

The analysis of marker data from HIV positive patients has been the motivation for many new developments in applied statistics. As well as reviewing these methods, this paper considers the extent to which programs to implement them are available in current software. Particular areas of development have been the joint modelling of markers and survival outcomes, non-linear random effects models that are of particular relevance for studying the efficacy of treatments and the use of Bayesian computational methods for inference from marker data. The package WinBUGS is recommended as being particularly well suited to the analysis of marker data.

Effect of combination therapy on immunologic progression of human immunodeficiency virus at a population level.

There is accumulating evidence from clinical trials and cohort studies that highly active antiretroviral combination therapy is effective at halting immunologic and clinical progression of human immunodeficiency virus (HIV). Its impact at a population level is less well known because the regimes may be difficult to tolerate and compliance poorer. The authors make use of population data for almost all of the HIV-infected people in Scotland in 1997 who were under clinical care and monitor their response to therapy during the first year when these effective treatments became widely available. More than two thirds of the HIV-positive patients were on some form of antiretroviral therapy during the year. The authors show that all treated groups, even those who were on changing regimes, showed net improvement in immunologic status during the year. For the group of patients on triple or quadruple therapy, there was an average increase of more than 100 CD4 cells/mm(3) over the year, with other treatment groups showing more modest, but significant, increases.