Gradient-based optimization with B-splines on sparse grids for solving forward-dynamics simulations of three-dimensional, continuum-mechanical musculoskeletal system models.

Investigating the interplay between muscular activity and motion is the basis to improve our understanding of healthy or diseased musculoskeletal systems. To be able to analyze the musculoskeletal systems, computational models are used. Albeit some severe modeling assumptions, almost all existing musculoskeletal system simulations appeal to multibody simulation frameworks. Although continuum-mechanical musculoskeletal system models can compensate for some of these limitations, they are essentially not considered because of their computational complexity and cost. The proposed framework is the first activation-driven musculoskeletal system model, in which the exerted skeletal muscle forces are computed using 3-dimensional, continuum-mechanical skeletal muscle models and in which muscle activations are determined based on a constraint optimization problem. Numerical feasibility is achieved by computing sparse grid surrogates with hierarchical B-splines, and adaptive sparse grid refinement further reduces the computational effort. The choice of B-splines allows the use of all existing gradient-based optimization techniques without further numerical approximation. This paper demonstrates that the resulting surrogates have low relative errors (less than 0.76%) and can be used within forward simulations that are subject to constraint optimization. To demonstrate this, we set up several different test scenarios in which an upper limb model consisting of the elbow joint, the biceps and triceps brachii, and an external load is subjected to different optimization criteria. Even though this novel method has only been demonstrated for a 2-muscle system, it can easily be extended to musculoskeletal systems with 3 or more muscles.

Anteroposterior stability after posterior cruciate-retaining total knee arthroplasty.

PURPOSE: A functional posterior cruciate ligament (PCL) is important for the knee stability after PCL-retaining total knee arthroplasty (TKA). The objectives of this study were to determine the anteroposterior (AP) displacement of the knee after a mobile- or fixed-bearing PCL-retaining TKA operated with a ligament-balancing technique and the correlation of AP stability with the clinical outcome. METHODS: The AP displacement of 160 TKAs in 143 patients was measured pre- and intra-operatively, and the results were compared to the AP displacement measured 4 years post-surgery. RESULTS: The change in AP displacement from intra-operative measurement to follow-up at the 25° measuring point was -1.2 mm; at 90°, it was -0.2 mm. Mobile bearings showed significantly greater AP displacement than fixed bearings. Older patients, male patients and patients receiving a fixed prosthesis had lower post-operative laxity compared with the overall population. CONCLUSIONS: The small change in AP displacement indicates that the PCL remains functional over time. In our study, we could not find any correlation between knee AP stability and clinical outcome, including passive flexion, Knee Society Score or Visual Analogue Scale of pain and satisfaction.

Unicondylar knee replacement with a new tensioner device: clinical results of a multicentre study on 168 cases.

INTRODUCTION: Ligament balancing is an established surgical technique in total knee arthroplasty with good clinical results. A similar technique for unicondylar knee arthroplasty was developed. The aim of this study was to asses the outcomes of a unicondylar knee replacement implanted with a ligament tensor. MATERIALS AND METHODS: A prospective multicentre study of 168 medial compartment unicondylar knee prosthesis with a minimum follow-up of 2 years. Clinically, the knee society score was recorded. For subjective assessment, the visual analogue scale (VAS) for pain and satisfaction was used. Radiographic analysis was performed to determine radiolucent lines. The surgical technique was based on a ligament-orientated procedure. With this technique, the femoral orientation, flexion/extension gaps and limb alignment is determined with a unique ligament tensor. RESULTS: The total KSS increased from 110.9 +/- 27.5 points preoperative to 176.5 +/- 21.1 points after 24 months. VAS for pain decreased from 6.0 +/- 1.9 preoperative to 2.8 +/- 1.7 after 24 months. VAS for satisfaction increased in the same period from 4.3 +/- 1.9 to 8.9 +/- 1.7. Four tibia implants had thin continuous radiolucent lines. Nine adverse events are reported. One patient died of unrelated causes. Five polyethylene inlays dislocated, one of five dislocated due to a fall. Three unicondylar knee prostheses were revised to a total knee arthroplasty, one because of undiagnosed pain, one for infection and one for femoral component malalignment. CONCLUSION: We have demonstrated the efficacy of a tension-controlled ligament-balanced surgical technique for unicompartmental knee prosthesis that gives satisfying and reproducible short-term results.

The results of the titanium-coated RM acetabular component at 20 years: a long-term follow-up of an uncemented primary total hip replacement.

In a prospective study, 93 unselected consecutive uncemented hip arthroplasties were performed in 80 patients using the titanium-coated RM acetabular component and the CLS femoral component. The mean age of the patients at operation was 52 years (28 to 81). None were lost to follow-up. In the 23 patients who had died (26 hips) only one acetabular component had been revised. In the 57 living patients (67 hips), 13 such revisions had been performed. Of the 14 revisions, seven were for osteolysis, five for loosening and two for infection. Survival analysis of this implant showed a total probability of survival of 83% (95% confidence interval 73 to 90), with all revisions as the endpoint, and a probability of 94% (95% confidence interval 87 to 98) with revision for aseptic loosening as the endpoint, indicating reliable long-term fixation of the titanium-coated RM acetabular component.

Does total knee joint replacement with the soft tissue balancing surgical technique maintain the natural joint line?

INTRODUCTION: The outcomes of 106 total knee arthroplasties implanted using a soft tissue balancing surgical technique at one surgical centre were used to assess the accuracy maintaining the knee's original joint line (JL). The aim of the study was to determine whether there is a shift of the presumed joint line after surgery. MATERIALS AND METHODS: Preoperative and post-operative radiographs were compared to determine any changes in the articulation height. The preoperative distance of the fibular head to the natural joint line was measured and compared with the post-operative measurement of the fibular head to the femoral articulation line (measured on the radiograph and defined as Rxmm). Based on the actual medio-lateral dimension of the tibial metal back, the measured difference (RXmm) could be converted into true distances (in mm). The Blackburn-Peel index was assessed as an additional outcome prior to and following surgery. RESULTS: Preoperatively, the average distance from the fibular head to the joint line was 15.1 Rxmm (SD 4.3) while the post-surgical distance was 15.5 Rxmm (SD 5.6). The average deviation of the post-surgical JL in relation to the original JL amounted to 0.4 Rxmm (SD 3.7). The average deviation of the joint line converted into the true distance was -0.3 mm (with a range of -5.9 mm in distal direction to + 8.3 mm in the proximal direction). Valgus position appeared to generate rather a shift in proximal direction whereas varus deformity favours a shift in distal direction. Seven patients exhibited a deviation of more than 5 mm in either the distal or proximal direction. All of the patients of this subgroup had a preoperative anatomical abnormality including a severe malalignment, serious bone destruction or had previously undergone a high tibial osteotomy. CONCLUSION: An exact reconstruction of the natural Joint Line is achievable when using the described soft tissue balancing surgical technique with the posterior cruciate ligament (PCL) retaining prosthesis design used in this series.

[High-resolution T1-weighted MR-lymphography of inguinal lymph nodes after interstitial application of Gadomer-17 in animal experiments]. / Hochauflösende T1-gewichtete MR-Lymphographie inguinaler Lymphknoten nach interstitieller Applikation von Gadomer-17 im Tierexperiment.

PURPOSE: To evaluate the microstructural anatomy of inguinal lymph nodes in pigs after interstitial MR-lymphography with the dendritic contrast agent Gadomer-17. MATERIAL AND METHODS: High-resolution T1-weighted MR-lymphography was performed in inguinal lymph nodes of 10 domestic pigs (39 - 46 kg) after subcutaneous injection of 10 mumol/kg body weight Gadomer-17 in the hind legs of the animals. A 1.5T MR scanner and a ring-shaped surface coil were used. Two different high-resolution gradient-echo sequences with additionally reconstructed maximum-intensity projections were evaluated in a total of 20 lymph nodes. The high-resolution MR-findings were correlated with the histologic sections of the excised inguinal lymph nodes. RESULTS: Coronal T1-weighted 3D gradient-echo images (TR = 20 msec, TE = 6.1 - 8.3 msec, FA = 20 degrees ) with a slice thickness of 1 mm, a field-of-view of 120 mm and a matrix size of 256 x 256 (reconstructed to 1024 x 1024 voxels) yielding a reconstructed in-plane resolution of 117 x 117 microm (2) were best suited for the high-resolution MR lymphography of inguinal lymph nodes and enabled the differentiation of the hyperintense lymph node sinuses and hypointense lymphoid parenchyma of each lymph node (100 %). Even dilated lymphatic vessels evident in the histologic specimen were best demonstrated on the MIP images. CONCLUSION: High-resolution interstitial MR lymphography with Gadomer-17 allows the visualization of different tissue compartments of inguinal lymph nodes. This new technique is feasible on a routine 1.5T scanner and may offer potential for the detection of micrometastases in lymph nodes of cancer patients.

Waveform magnetic field survey in Russian DC and Swiss AC powered trains: a basis for biologically relevant exposure assessment.

Recent epidemiological studies suggest a link between transport magnetic fields (MF) and certain adverse health effects. We performed measurements in workplaces of engineers on Russian DC and Swiss AC powered (16.67 Hz) electric trains using a computer based waveform capture system with a 200 Hz sampling rate. MF in DC and AC trains show complex combinations of static and varying components. The most probable levels of quasistatic MF (0.001-0.03 Hz) were in the range 40 microT. Maximum levels of 120 microT were found in DC powered locomotives. These levels are much higher than the geomagnetic field at the site of measurements. MF encountered both in DC and AC powered rail systems showed irregular temporal variability in frequency composition and amplitude characteristics across the whole frequency range studied (0-50 Hz); however, more than 90% of the magnetic field power was concentrated in frequencies

[Interstitial T1-weighted MR lymph fistulography with Gadomer-17 in an experimental animal model]. / Interstitielle T1-gewichtete MR-Lymphfistulographie mittels Gadomer-17 im Tierexperiment.

PURPOSE: To visualize and localize fistulas of the thoracic duct with interstitial T 1 -weighted MR lymphography using Gadomer-17. MATERIALS AND METHODS: In 10 domestic pigs, leaks of the thoracic duct were created surgically or interventional-radiologically. The lymphatic leakage was located within the abdominal portion of the thoracic duct in 5 pigs, within the thoracic portion of the thoracic duct in 3 pigs, and in both, abdominal and thoracic portions of the thoracic duct, in 2 pigs. Subsequently, 10 micro mol/kg KG Gadomer-17 (1.5-1.8 ml) was administered interstitially in both hind legs of the animals. MR lymphography was performed with a 1.5 T MR unit using two different 3D gradient echo sequences before and 10 - 90 minutes after administration of contrast material. RESULTS: Leaks within the abdominal portion of the thoracic duct were directly visible as opacified fistulas. Indirect signs of active lymphatic fistulas were increasing extravasations of contrast material and free abdominal fluid. The 3D gradient echo sequence with the highest planar resolution (TR = 8,7 - 8,8 ms, TE = 4,2 - 4,3 ms, FA = 40 degrees, matrix size = 327 x 512) was best suited for distinct delineation of the lymphatic system and detailed demonstration of the thoracic duct fistulas. Intrathoracic leaks could not be demonstrated by MR lymphography due to reduced lymphatic flow or extravasated contrast medium at the abdominal puncture site. CONCLUSION: Interstitial MR lymphography with Gadomer-17 allows sensitive detection and localization of abdominally located leaks of the thoracic duct.

[Interstitial T1-weighted MR lymphography with use of the dendritic contrast agent Gadomer-17 in pigs]. / Interstitielle T1-gewichtete MR-Lymphographie mit dem polymeren Kontrastmittel Gadomer-17 im Tierexperiment.

PURPOSE: To investigate the enhancement of regional lymph nodes, lymph vessels and the thoracic duct after subcutaneous administration of the dendritic contrast agent Gadomer-17. MATERIALS AND METHODS: Interstitial T(1)-weighted MR lymphography was performed in 15 domestic pigs in a 1.5 T MR scanner using the body coil. The contrast agent was injected subcutaneously at a dose of 2.5, 10 and 20 micromol gadolinium/kg/bw (1.4 - 2.3 ml) in the hind legs of 5 pigs, respectively. T(1)-weighted coronal 3D-gradient-echo images were obtained 1 to 150 minutes and 24 hours after contrast material injection. RESULTS: Inguinal lymph nodes, iliac lymph nodes and lymph vessels showed peak enhancement within 10 minutes after subcutaneous administration of the contrast agent. The enhancement of the lymphatic system decreased slowly until 150 minutes post injection. The time-response study, which was performed for inguinal and iliac lymph nodes, revealed the best lymphographic effect for Gadomer-17 at a dose of 10 micromol gadolinium/kg/bw. At this dose the paraaortic lymph nodes and the thoracic duct were also best visualized. CONCLUSION: Interstitial administration of the evaluated dendritic contrast agent Gadomer-17 is highly efficient for the performance of T(1)-weighted MR lymphography in regional lymph nodes, lymph vessels and the thoracic duct.

Radiological signs of osteitis around extramedullary metal implants. A radiographic-microbiological correlative analysis in rabbit tibiae after local inoculation of Staphylococcus aureus.

Radiographic changes in the early stages of osteomyelitis may be subtle and, especially after plate osteosynthesis, frequently missed. A previously described experimental model of local bacterial infection was used in an attempt to determine the reliability of specific changes on conventional radiographs for the diagnosis of osteitis after metal-plate implantation and subsequent inoculation of Staphylococcus aureus in rabbit tibiae. Roentgenograms of the treated limbs were evaluated, and seven radiographic parameters, to which numerical scores were assigned, were determined for each bone. Our results substantiate the conclusion that a radiographically verified periosteal reaction is a constant and early skeletal feature of acute osteomyelitis and has the strongest association to the microbiological results (P < 0.05), emphasising its high predictive value. Plate implantation does not notably impede the diagnosis of osteomyelitis. An association between the amount of inoculated bacteria and the extent of radiographic changes could be found. The results of this present study closely resemble those described in man and suggest that this model may be useful for future experimental investigations in determining a score judging the severity of osseous involvement in local bacterial infection after plate osteosynthesis.

Leukemia, brain tumors, and exposure to extremely low frequency electromagnetic fields in Swiss railway employees.

Railway engineers provide excellent opportunities for studying the relation between exposure to extremely low frequency magnetic fields and leukemia or brain tumors. In a cohort study of Swiss railway personnel with 2.7 x 10(5) person-years of follow-up (1972--1993), the authors compared occupations with high average exposures (line engineers: 25.9 microT) to those with medium and low exposures (station masters: 1 microT). The mortality rate ratio for leukemia was 2.4 (95% confidence interval (CI): 1.0, 6.1) among line engineers (reference category: station masters). The mortality rate ratio for brain tumors was 1.0 (95% CI: 0.2, 4.6) among line engineers and 5.1 (95% CI: 1.2, 21.2) among shunting yard engineers (compared with station masters). Two exposure characteristics were evaluated: cumulative exposure in microT-years and years spent under exposure to magnetic fields of > or =10 microT. There was a significant increase in leukemia mortality of 0.9% (95% CI: 0.2, 1.7) per microT-year of cumulative exposure to extremely low frequency magnetic fields. The increase by years spent under exposure of > or =10 microT was even stronger: 62% per year (95% CI: 15, 129). Brain cancer risk did not show a dose-response relation. This study contributes to the evidence for a link between heavy exposure to extremely low frequency magnetic fields and leukemia. Its strengths include reliable measurements and reliable historical reconstruction of exposures.

[Preissler endoscopic carpal ligament release. Experiences from 1,000 operations]. / Die endoskopische Karpalbandspaltung nach Preissler. Erfahrungen aus 1,000 Operationen.

To reduce the postoperative morbidity different methods of endoscopic carpal tunnel release have been developed since 1989. We report our results and experiences with the method described by Preissler. Since its introduction in our clinic 1995, 1,000 patients have been operated until now. Out of 477 with an electrophysiological examination, 396 patients (83%) showed no symptoms. In three cases it was necessary to change to an open approach during operation, there were no other intraoperative complications. To evaluate our results we sent a questionnaire to 32 of our patients that were operated on one hand with an open technique and on the other hand with the endoscopic technique of Preissler. The results demonstrated that the endoscopic method was significantly better. From our experience endoscopic technique for carpal tunnel release Preissler's is a safe, well accepted, easy for learning and cheap alternative to the open procedure.

Cost-effectiveness of azithromycin for preventing Mycobacterium avium complex infection in HIV-positive patients in the era of highly active antiretroviral therapy. The Swiss HIV Cohort Study.

We conducted a cost-effectiveness analysis to determine the clinical and economic consequences of Mycobacterium avium complex (MAC) prophylaxis in HIV-infected patients in the era of highly active antiretroviral therapy (HAART) in a health care system with access unrestricted by financial barriers. The analysis was performed from a health care perspective and compared azithromycin (1200 mg/week) with no prophylaxis over a period of 10 years based on data from the Swiss HIV Cohort Study (SHCS) and randomized controlled trials. The main outcome measures were: expected survival; average health care costs; and cost-effectiveness in 1997 Swiss francs ( pound1 corresponds to about 2.3 CHF) per life-year saved. In patients with an initial CD4 count <50 cells/mm(3) and no AIDS, azithromycin increased expected survival by 4 months. In patients with AIDS, HAART durability had a major impact on expected survival and costs. Incremental survival increased from 2 to 4 months if we assumed a 10 year, instead of a 3 year, HAART effect. The cost-effectiveness of azithromycin relative to no prophylaxis in patients without AIDS was between 47,000 CHF (3-year HAART effect) and 60,000 CHF (10-year HAART effect) per life-year saved. The cost-effectiveness ratio increased to 118,000 CHF per life-year saved in patients with symptomatic AIDS. In conclusion, in the era of HAART, MAC prophylaxis with azithromycin increases expected survival and reduces health care costs substantially. Starting MAC prophylaxis in patients without AIDS is more effective and cost-effective than in patients with AIDS.

Systematic validation of disease models for pharmacoeconomic evaluations. Swiss HIV Cohort Study.

Pharmacoeconomic evaluations are often based on computer models which simulate the course of disease with and without medical interventions. The purpose of this study is to propose and illustrate a rigorous approach for validating such disease models. For illustrative purposes, we applied this approach to a computer-based model we developed to mimic the history of HIV-infected subjects at the greatest risk for Mycobacterium avium complex (MAC) infection in Switzerland. The drugs included as a prophylactic intervention against MAC infection were azithromycin and clarithromycin. We used a homogenous Markov chain to describe the progression of an HIV-infected patient through six MAC-free states, one MAC state, and death. Probability estimates were extracted from the Swiss HIV Cohort Study database (1993-95) and randomized controlled trials. The model was validated testing for (1) technical validity (2) predictive validity (3) face validity and (4) modelling process validity. Sensitivity analysis and independent model implementation in DATA (PPS) and self-written Fortran 90 code (BAC) assured technical validity. Agreement between modelled and observed MAC incidence confirmed predictive validity. Modelled MAC prophylaxis at different starting conditions affirmed face validity. Published articles by other authors supported modelling process validity. The proposed validation procedure is a useful approach to improve the validity of the model.

Rare AIDS-defining diseases in the Swiss HIV Cohort Study.

The objective of this study was to investigate the spectrum and frequency of rare AIDS-defining diseases in the Swiss HIV Cohort Study. AIDS-defining diseases contributing less than 1% to the absolute number of all recorded AIDS-defining diseases in at least one of five periods (1988-1990, 1991-1992, 1993-1994, 1995-1996, 1997) were defined as being rare. A total of 9110 HIV-infected subjects were included in this study. Over the entire 9-year period, the following rare diseases were diagnosed: progressive multifocal leukoencephalopathy (n = 138), disseminated cryptococcosis (n = 67), visceral herpes simplex disease (n = 66), primary cerebral lymphoma (n = 65), indeterminate cerebral lesion (n = 50), cryptococcal meningitis (n = 34), Mycobacterium kansasii disease (n = 32), recurrent Salmonella septicemia (n = 22), intestinal isosporiasis (n = 21), candidiasis of the trachea, bronchi and lungs (n = 19), toxoplasma retinitis (n = 16), disseminated toxoplasmosis (n = 8), invasive cervical carcinoma (n = 8), extrapulmonary Pneumocystis disease (n = 5), disseminated histoplasmosis (n = 1) and disseminated coccidioidomycosis (n = 1). Rare diseases accounted for 7.3% of all AIDS-defining diseases over the entire 9-year period. Physicians should be aware of the likelihood of a broad spectrum of AIDS-defining diseases in HIV-infected patients.

Cost effectiveness of highly active antiretroviral therapy in HIV-infected patients. Swiss HIV Cohort Study.

BACKGROUND: Highly active antiretroviral therapy (HAART) has become the most important strategy for treating HIV infection in developed countries; however, access to HAART might vary under different funding policies. The Swiss health care system provides unrestricted access to HAART for all patients who need these newer combination therapies. This study investigated the impact of this funding policy on the society and health care system. METHODS: A cost-effectiveness analysis with natural history data and productivity estimates was based on the Swiss HIV Cohort Study. A random sample of patient charts was used to estimate health care costs. In addition to a base-case scenario, a pessimistic and an optimistic scenario of natural disease history was developed. Costs were expressed in 1997 Swiss francs (100 CHF correspond to about US$67) and effects as projected years of life gained. RESULTS: In the analysis limited to health care costs, on the basis of projected survival in each scenario, the cost-effectiveness ratio was 33,000 CHF (base case), 14,000 CHF (optimistic), and 45,000 CHF (pessimistic) per year of life gained. When changes in productivity were included, cost savings occurred in the base-case and optimistic scenarios. The cost-effectiveness ratio was 11,000 CHF per year of life gained in the pessimistic scenario. CONCLUSIONS: HAART increases expected survival and health care costs. However, when productivity gains are included, society will probably save costs or pay a low price for substantial health benefits. The study provides strong arguments, from a societal perspective, to continue the current policy of providing unrestricted access to HAART in Switzerland. The presented results also suggest that this policy could be of interest for other developed countries. Decision makers in developed countries where access to HAART is limited should re-evaluate their policy for the benefit of the society at large.

Triglyceride as a risk factor for ischaemic heart disease in British men: effect of adjusting for measurement error.

OBJECTIVE: To assess the influence of differential precision in the measurement of the correlated variables total cholesterol and high density lipoprotein (HDL) cholesterol on the estimates of the risk of ischaemic heart disease (IHD) associated with plasma triglyceride levels. DESIGN, SETTING AND PARTICIPANTS: The Caerphilly Heart Disease Study (CHDS), a prospective cohort study of 2512 middle-aged men living in the town of Caerphilly, south Wales, UK. The results from two sub-studies were used to estimate the degree of measurement imprecision (laboratory error and within-person variation) in triglycerides, total cholesterol and HDL cholesterol. MAIN OUTCOME MEASURES: Multivariable risk estimates for major IHD calculated from logistic regression analysis, adjusted and not adjusted for measurement imprecision. Major IHD events were defined as death from IHD, clinical non-fatal myocardial infarction or electrocardiographic myocardial infarction. RESULTS: There were 261 men with major IHD events during follow-up. In age-adjusted analyses, taking measurement imprecision into account strengthened associations with IHD for all lipid factors. The odds ratio (OR) for one S.D. increase in triglycerides, ignoring measurement imprecision, was 1.36 (95% confidence interval [95% CI] 1.20-1.55) but 1.57 (95% CI 1.30-1.89) when taking imprecision into account. The standardised odds ratio for triglycerides adjusted for measurement imprecision and the two other lipid factors was 1.35 (95% CI 1.09-1.69). In this model, the triglyceride level showed a stronger association than total cholesterol (OR 1.28; 95% CI 1.05-1.56) and HDL cholesterol (OR for one S.D. decrease 1.20; 95% CI 0.97-1.49). When adding fasting blood glucose and diastolic blood pressure, however, the effect of triglycerides was reduced and ceased to be statistically significant (OR 1.19; 95% CI 0.95-1.49). This was further attenuated upon inclusion of body mass index, smoking status and history of pre-existing IHD. Total cholesterol remained a statistically significant (P < 0.05) risk factor in all models. CONCLUSIONS: In contrast to other cohort studies, triglyceride concentration in the CHDS shows an association with the risk of IHD which is independent of total and HDL cholesterol. This effect was pronounced after adjustment for measurement imprecision. It was reduced, however, when adjusted for other factors. While hypertriglyceridaemia may exert an influence independent of other lipid factors, insulin resistance is probably the underlying metabolic disturbance.

Estimating AIDS-free survival in a severely immunosuppressed asymptomatic HIV-infected population in the era of antiretroviral triple combination therapy. Swiss HIV Cohort Study.

BACKGROUND: Antiretroviral triple combination therapies have been evaluated in randomized controlled trials and cohort studies. Little is known about their impact on asymptomatic, severely immunosuppressed, HIV-infected individuals in a real world population. OBJECTIVES: To describe disease progression in a broad asymptomatic population of HIV-infected individuals with a CD4 count <100 cells/mm3 before and after the introduction of combination triple therapy. DESIGN: Six-month homogenous Markov chain consisting of four recurrent AIDS-free states and one absorbing AIDS state: (1) CD4 count > or =100 cells/mm3, (2) CD4 count 75 to 99 cells/mm3, (3) CD4 count 50 to 74 cells/mm3, (4) CD4 count 0 to 49 cells/mm3, and AIDS. SETTING: Swiss HIV Cohort Study database. PATIENTS: A total of 1027 patients contributed to 2634 pairs of 6-month observations from 1993 to 1995, and 681 patients contributed to 2077 pairs of 6-month observations from 1996 to 1997. MEASUREMENT: AIDS-free survival probabilities and the expected AIDS-free survival time. RESULTS: The expected number of AIDS-free months in a 3-year period was 17 (95% confidence interval [CI], 16-19) for patients starting in state 4 prior to 1996 versus 26 months (95% CI, 24-28) for patients starting in state 4 after 1996. For these two time periods, the corresponding expected numbers of AIDS-free months were 21 (95% CI, 20-22) versus 30 (95% CI, 28-32) for state 3 and 23 (95% CI, 21-24) versus 33 (95% CI, 32-34) for state 2. CONCLUSION: Expected 3-year AIDS-free survival in severely immunosuppressed individuals with CD4 counts <100 cells/mm3 improved significantly between 1993 to 1995 and 1996 to 1997.

Does pregnancy influence the course of HIV infection? Evidence from two large Swiss cohort studies.

The question whether the natural history of HIV infection in women is affected by pregnancy has not so far been convincingly answered. We used prospective cohort data to compare pregnant and nonpregnant HIV-infected women during follow-up within the Swiss HIV Cohort Study (SHCS) and the Swiss Collaborative HIV and Pregnancy Study (SCHPS). Pregnant women were eligible if a CD4 cell count had been made before conception had taken place. Additional inclusion criteria were a pregnancy completed to delivery during follow-up and an observation period of at least 6 months after delivery. Thirty-two women who fulfilled these criteria were compared with 416 controls, matched for age and CD4 cell count at entry, who had not been pregnant during follow-up. Mean follow-up time was 4.8 years for pregnant women and 3.6 years for controls. The rate of any AIDS-defining event was higher in pregnant women (rate ratio [RR] from Cox regression, 1.92; 95% confidence interval [CI], 0.80-4.64) but this did not reach statistical significance (p = .15). A statistically significant difference (p = .008) emerged only for one AIDS-defining event, recurrent bacterial pneumonia (RR, 7.98; 95% CI, 1.73-36.8). The rate of death was similar in the two groups (RR, 1.14; 95% CI, 0.48-2.72; p = .8). Our results thus indicate that, after taking CD4 cell counts before conception into account, acceleration of disease progression is inconsistent among HIV-infected women who become pregnant during follow-up.

Disseminated Mycobacterium avium complex disease in the Swiss HIV Cohort Study: increasing incidence, unchanged prognosis.

OBJECTIVES: Disseminated disease due to Mycobacterium avium complex (MAC) bacteria is thought to occur less frequently in Europe than in the USA. This study investigated time trends in the occurrence of, and survival with, disseminated MAC disease in the Swiss HIV Cohort Study (SHCS). DESIGN, SETTING AND PARTICIPANTS: The SHCS participants who were free of disseminated MAC disease at registration were stratified by calendar period (1987-1989, 1990-1992, 1993-1995) in which the first recorded CD4 count was 0-49, 50-99, or 100-199 x 10(6)/l. Kaplan-Meier estimates of the probability of developing and surviving disseminated MAC disease were calculated for these nine independent groups. Multivariate analyses were performed using Cox proportional hazards regression. RESULTS: The analysis was based on 6052 participants enrolled between January 1987 and December 1995 and 202 incident episodes of disseminated MAC disease recorded during a mean follow-up time of 3.5 years. The cumulative probability of MAC disease at 2 years in individuals with CD4 counts of 0-49 x 10(6)/l in 1987-1989 was 9.8% [95% confidence interval (CI) 4.4-15.2%], increasing to 29.8% (95% CI, 20.8-38.8%) in 1993-1995. Amongst those with CD4 counts from 50-99 x 10(6)/l these probabilities were 11.9% (95% CI, 5.9-17.8%), and 21.6% (95% CI, 13.9-29.2%), respectively. After adjusting for CD4 count the relative hazard of developing disseminated MAC disease in 1993-1995, compared with 1987-1989, was 1.37 (95% CI, 0.92-2.04). Median survival following diagnosis was 7.9 months with no improvement over time. CONCLUSIONS: The incidence of disseminated MAC disease among SHCS participants has increased over time. More profound levels of immunosuppression amongst recent study entrants were found to explain this. When compared with US cohorts studied over the same calendar period the incidence of disseminated MAC disease in the SHCS appears to be lower. These findings are consistent with a secular effect of a more mature HIV epidemic in the US but direct comparison between the SHCS and a similar prospective cohort in the US should be undertaken to clarify this issue.