Carfilzomib and the cardiorenal system in myeloma: an endothelial effect?

Carfilzomib (Cfz) has been associated with an ~5% incidence of unexplained and unpredictable cardiovascular toxicity in clinical trials. We therefore implemented a detailed, prospective, clinical cardiac and renal evaluation of 62 Cfz-treated myeloma patients, including serial blood pressure (BP), creatinine, troponin, NT-proBNP and pre- and post-treatment echocardiograms, including ejection fraction (EF), average global longitudinal strain and compliance. Pre-treatment elevations in NT-proBNP and BP, as well as abnormal cardiac strain were common. A rise in NT-proBNP occurred frequently post-treatment often without corresponding cardiopulmonary symptoms. A rise in creatinine was common, lessened with hydration and often reversible. All patients had a normal EF pre-treatment. Five patients experienced a significant cardiac event (four decline in EF and one myocardial infarction), of which 2 (3.2%) were considered probably attributable to Cfz. None were rechallenged with Cfz. The ideal strategy for identifying patients at risk for cardiac events, and parameters by which to monitor for early toxicity have not been established; however, it appears baseline echocardiographic testing is not consistently predictive of toxicity. The toxicities observed suggest an endothelial mechanism and further clinical trials are needed to determine whether or not this represents a class effect or is Cfz specific.

Bone mineral density in breast cancer patients treated with adjuvant letrozole, tamoxifen, or sequences of letrozole and tamoxifen in the BIG 1-98 study (SAKK 21/07).

BACKGROUND: The risk of osteoporosis and fracture influences the selection of adjuvant endocrine therapy. We analyzed bone mineral density (BMD) in Swiss patients of the Breast International Group (BIG) 1-98 trial [treatment arms: A, tamoxifen (T) for 5 years; B, letrozole (L) for 5 years; C, 2 years of T followed by 3 years of L; D, 2 years of L followed by 3 years of T]. PATIENTS AND METHODS: Dual-energy X-ray absorptiometry (DXA) results were retrospectively collected. Patients without DXA served as control group. Repeated measures models using covariance structures allowing for different times between DXA were used to estimate changes in BMD. Prospectively defined covariates were considered as fixed effects in the multivariable models. RESULTS: Two hundred and sixty-one of 546 patients had one or more DXA with 577 lumbar and 550 hip measurements. Weight, height, prior hormone replacement therapy, and hysterectomy were positively correlated with BMD; the correlation was negative for letrozole arms (B/C/D versus A), known osteoporosis, time on trial, age, chemotherapy, and smoking. Treatment did not influence the occurrence of osteoporosis (T score < -2.5 standard deviation). CONCLUSIONS: All aromatase inhibitor regimens reduced BMD. The sequential schedules were as detrimental for bone density as L monotherapy.

[ICD-10 adaptation of 15 Agency for Healthcare Research and Quality patient safety indicators]. / Adaptation au codage CIM-10 de 15 indicateurs de la sécurité des patients proposés par l'Agence étasunienne pour la recherche et la qualité des soins de santé (AHRQ).

BACKGROUND: In the United States, the Agency for Healthcare Research and Quality (AHRQ) has developed 20 Patient Safety Indicators (PSIs) to measure the occurrence of hospital adverse events from medico-administrative data coded according to the ninth revision of the international classification of disease (ICD-9-CM). The adaptation of these PSIs to the WHO version of ICD-10 was carried out by an international consortium. METHODS: Two independent teams transcoded ICD-9-CM diagnosis codes proposed by the AHRQ into ICD-10-WHO. Using a Delphi process, experts from six countries evaluated each code independently, stating whether it was "included", "excluded" or "uncertain". During a two-day meeting, the experts then discussed the codes that had not obtained a consensus, and the additional codes proposed. RESULTS: Fifteen PSIs were adapted. Among the 2569 proposed diagnosis codes, 1775 were unanimously adopted straightaway. The 794 remaining codes and 2541 additional codes were discussed. Three documents were prepared: (1) a list of ICD-10-WHO codes for the 15 adapted PSIs; (2) recommendations to the AHRQ for the improvement of the nosological frame and the coding of PSI with ICD-9-CM; (3) recommendations to the WHO to improve ICD-10. CONCLUSIONS: This work allows international comparisons of PSIs among the countries using ICD-10. Nevertheless, these PSIs must still be evaluated further before being broadly used.

Antibiotic use: is appropriateness expensive?

Antibiotics are prone to misuse. In this study, 37% of 600 antibiotic prescriptions in three hospitals were considered unnecessary. When antibiotic therapy was indicated, 45% were considered to be inadequate. In multivariate analyses, the indicated treatments were found to be more expensive than the unjustified ones, probably because the latter were more often oral regimens. However, for indicated treatments, the cost of adequate and inadequate treatments did not differ significantly.

Redimune NF Liquid, a ready-to-use, high-concentration intravenous immunoglobulin therapy preparation, is safe and typically well tolerated in the routine clinical management of a broad range of conditions.

In clinical practice, intravenous immunoglobulin therapy (IVIG) is used in the management of a wide variety of medical conditions. Observational studies examining IVIG use in routine clinical practice are therefore an important means of validating findings from more strictly randomized controlled trials of patients with specific conditions. In this observational study, we examined the tolerability of a high-concentration (12%) ready-to-use liquid IVIG (Redimune NF Liquid) when used in the standard management of a diverse range of conditions (including primary immunodeficiency diseases, neurology conditions, oncology conditions and immune thrombocytopaenic purpura). IVIG regimen and dose were selected by the physician based on the summary of product characteristics. During the study, 193 infusions were administered to 51 patients in 153 infusion cycles (per infusion cycle: one to five infusions; mean dose, 347.6 mg/kg; mean duration, 202.4 min). The mean maximum infusion rate per cycle was 2.9 mg/kg/min, demonstrating that the infusion rate was often higher than that recommended in the summary of product characteristics. Redimune NF Liquid was well tolerated: there were 36 adverse reactions (at least probably associated with IVIG) in 10 patients (19.6% of sample, 0.24 per infusion cycle, 0.19 per infusion). The most common adverse reaction was headache (50% of reactions), followed by chills (13.8%). Most reactions (69%) were mild and there were no serious or unexpected reactions. In conclusion, in routine clinical practice involving patients with many different conditions, Redimune NF Liquid was well tolerated by the majority of patients.

Impact of an interdisciplinary strategy on antibiotic use: a prospective controlled study in three hospitals.

OBJECTIVES: Evaluation of the impact of the implementation of practice guidelines, with or without their reinforcement by a pharmacist, on the intra-hospital use of antibiotics. MATERIALS AND METHODS: The duration of antibiotic treatment, their cost, and the length of patient stay were compared in three secondary-care hospitals, before and after interventions that were designed to promote rational antibiotic use. After randomization, hospital A received no intervention (control), local practice guidelines were implemented in hospital B (low grade intervention), and these guidelines were reinforced by a clinical pharmacist in hospital C (high grade intervention). Adherence to the guidelines was measured in hospitals B and C. Multivariable statistical analyses were carried out to adjust for confounding factors. RESULTS: None of the outcomes measured in the 1200 included patients decreased between the two study periods in any hospital. Hospital A was significantly and independently associated with an increase in the duration of antibiotic treatments, the cost of antibiotics (acquisition and global costs), and the length of stay. Although these differences were not statistically significant, increases in hospital B were higher than in hospital C. Adherence to guidelines was significantly higher in hospital C. CONCLUSIONS: Even though interdisciplinary interventions aiming at rationalizing antibiotic use could not diminish the duration of treatments, their costs or the length of stay, they proved useful to control the progression of these parameters.

Is readmission to hospital an indicator of poor process of care for patients with heart failure?

BACKGROUND: Controversy exists about the appropriateness of using readmission as an indicator of the quality of care. A study was undertaken to measure the validity and predictive ability of readmission in this context. METHODS: An evaluation study was performed in patients discharged alive with heart failure from three Swiss academic medical centres. Process quality indicators were derived from evidence based guidelines for the management and treatment of heart failure. Readmissions were calculated from hospital administrative data. The predictive ability of readmissions was evaluated using bivariate and multivariate analyses, and validity by calculating sensitivity, specificity, positive and negative predictive value, using process indicators as the "gold standard". RESULTS: Of 1055 eligible patients discharged alive, 139 (13.2%) were readmitted within 30 days. The adjusted odds ratio (OR) for absence of measurement of left ventricular function was 0.70 (95% CI 0.45 to 1.08) for readmissions. In patients with left ventricular systolic dysfunction, three dose categories of angiotensin converting enzyme inhibitor were examined using ordinal logistic regression. The adjusted OR for these categories was 1.07 (95% CI 0.56 to 2.06) for readmissions. When using process indicators as the gold standard to assess the validity of readmissions, sensitivity ranged from 0.08 to 0.17 and specificity from 0.86 to 0.93. CONCLUSIONS: Readmission did not predict and was not a valid indicator of the quality of care for patients with heart failure admitted to three Swiss university hospitals.

Membrane localization is not required for Mpl function in normal hematopoietic cells.

Cellular trafficking of growth factor receptors, including cross-talk among receptors at the cell surface, may be important for signal transduction in normal hematopoietic cells. To test this idea, the signaling domain of Mpl (the thrombopoietin receptor) was targeted to the plasma membrane, or to the cytoplasm of murine marrow cells, and the ability of the cells to proliferate and differentiate in response to Mpl dimerized at the plasma membrane or free in the cytoplasm was assessed. Constructs encoding the signaling domain of Mpl linked to an FK506 binding protein domain (to permit dimerization by the membrane-permeable ligand AP20187) with or without a myristylation sequence (to target the receptor to the plasma membrane) and a hemagglutinin epitope tag were generated and introduced into murine marrow cells using a murine stem cell virus (MSCV)-based retroviral vector. Both populations of transduced marrow cells proliferated in Iscoves modified Dulbecco medium-10% FCS-100 nM AP20187 without exogenous growth factors for more than 100 days and achieved greater than a 10(7)-fold expansion of cells by day 50 (n = 4 transductions). Growth was dimerizer dependent, and myeloid, erythroid, and megakaryocytic progenitors were generated. Activation of Mpl either at the plasma membrane or in the cytoplasm allowed for the terminal maturation of transduced progenitor cells. Introduction of membrane-targeted or cytoplasmic Mpl into fetal liver cells from homozygous JAK2 knock-out mice or wild-type littermates demonstrated that both forms of Mpl require JAK2 for signaling. These data show that the activation of Mpl independent of its normal plasma membrane location can support production of the full range of normal hematopoietic progenitor cells in vitro.

Variations among hospitals in the quality of care for heart failure.

CONTEXT: Determining variations in quality of care among hospitals can help direct attention to poorly performing institutions. PRACTICE PATTERN EXAMINED: The proportion of patients with congestive heart failure meeting various quality criteria in 69 hospitals. HOSPITAL SELECTION: The hospitals were voluntary participants in a quality improvement program in five states (Colorado, Connecticut, Georgia, Oklahoma, and Virginia). PATIENT SELECTION: All patients with congestive heart failure discharged from the participating hospitals during a 15-month period in 1995 to 1996 (or, for hospitals with more than 50 eligible patients, a random sample of 50 patients). The total sample consisted of 2077 patients. DATA SOURCE: Documentation in the hospital medical record of left ventricular function, discharge medications, and discharge instructions. RESULTS: Left ventricular function was determined in 72% of patients (range across hospitals, 18% to 97%). Among patients with left ventricular systolic dysfunction, 79% were prescribed an angiotensin-converting enzyme inhibitor (range, 54% to 94%). Only 23% of the patients prescribed angiotensin-converting enzyme inhibitors received the target dose (range, 0% to 60%). Sixty-four percent of patients were counseled about the importance of a low-sodium diet at discharge (range, 25% to 97%), but only 8% were counseled about daily weight monitoring (range, 0% to 30%). CONCLUSION: Our results show substantial hospital-to-hospital variation in the quality of care for patients with heart failure.

The occurrence of percutaneous injuries to health care workers: a cross sectional survey in seven Swiss hospitals.

OBJECTIVES: In 1995, a cross sectional survey was conducted in 7 Swiss hospitals to estimate the incidence of percutaneous injuries among nurses, surgeons, anesthetists and domestic personnel, and to describe the circumstances of these injuries and the reporting process within the hospital. METHODS: An anonymous questionnaire was distributed and filled out on-site in the case of nursing staff and domestic personnel, and was sent by post to physicians (anesthetists and surgeons). Participants were asked to report in detail on percutaneous injuries of the last workday and the last working month (nurses and physicians), and of the last month and the last year for domestic personnel. The overall response rate was 72%, representing a total of 3116 health care workers. RESULTS: The annual incidence rates of percutaneous injury with material contaminated with blood or other biological fluids were calculated by type of worker for the two available units of time. For nurses, the incidence was 0.49 and 2.23, for surgeons 4.28 and 11.05, for anesthetists 2.11 and 3.14, and for domestic personnel 0.11 and 0.17 respectively. Most of the injuries occurred in a "normal" situation (no emergency, no stress, no fatigue) and were described as avoidable. Compliance with universal precautions was not optimal and declaration rates within the hospital rather low (nurses 39.7%, physicians 3.4%, domestic personnel 87.9%). CONCLUSION: Percutaneous injuries with blood-contaminated material are frequent in health care workers, and are not always adequately assessed because of under-reporting of accidents within the hospital. This may result in underestimation of current occupational exposure of health care workers to HIV and other blood-borne viruses.

[Bias due to non-responders in an epidemiological study (SAPALDIA)]. / Etude du biais dû aux non-répondants dans une étude épidemiologique (SAPALDIA).

Within the Swiss Study on Air Pollution and Lung Diseases in Adults (SAPALDIA) 16267 adults aged 18 to 60 years from 8 different locations in Switzerland were randomly selected for answering a questionnaire about respiratory health and have a lung function examination with allergy test. 9561 subjects agreed with the examination (59%) (= responders, R). In order to study the possible influence of the bias introduced by non-responders (NR), 221 subjects who refused to participate among the 966 first subjects selected in Payerne were contacted by phone. 142 accepted a home visit and answered a shortened questionnaire about the main respiratory symptoms and diseases and indicated furthermore the reasons for their refusal. Non-responders have a lower mean educational level and belong to lower social classes than responders. The frequency of respiratory symptoms and diseases, allergies and smoking is similar in R and NR except a higher frequency of wheezing during the last 12 month (R: 12.5%, NR: 5.6%, p = 0.03). The level of carbon monoxide in expired air is higher in NR (17.6 ppm) that in R (11.9 ppm) (p = 0.01). A similar difference exists between NR (30.7 pp) and R (24.8 ppm) among current smokers (p < 0.01). The main reasons for refusal are lack of time (27.5%), lack of interest for medical study (22.6%), fear of health professionals (18.3%) or the existence of a another disease (9.9%). Furthermore, 2.8% of the subjects consider a medical study as useless and refuse principally any participation. The role of local press and media in the decision to participate seems to be important. Globally, the differences between R and NR are minimal and should not influence the validity of the results of the SAPALDIA study.

[A survey on vaccine efficacy in the city of Bongor (Chad) and its operational consequences for the vaccination program]. / Une enquête d'efficacité vaccinale dans la ville de Bongor (Tchad) et ses conséquences opérationnelles pour le programme de vaccination.

A measles epidemic occurred in the city of Bongor, Chad, from 22 September 1993 to 26 June 1994. A total of 792 patients were hospitalized, with a case fatality rate of 5.2%. After the epidemic, the district management team evaluated the expanded programme on immunization (EPI). Through a cluster survey the attack rate was estimated to be 29.1% (95% confidence interval (CI) = 20.4-37.8%) for the age group 12-59 months (n = 206). For this same age group, the measles immunization coverage was estimated to be 44.2% (95% CI = 34.6-53.8%) and the vaccine efficacy 9.5% (95% CI = 0-41.5%). Several flaws in the logistic handling of the vaccines and especially in the cold chain were identified. These results indicated a serious management problem in the EPI, which the district team then immediately started to rectify. The method used to estimate the immunization coverage and efficacy in the study is rapid and low cost. Also, it is feasible at the district level and permits identification of management problems in the EPI.

[Hyper-HDL-cholesterolemia: prevalence and clinical aspects]. / Hyper-HDL-cholestérolémie: prévalence et aspects cliniques.

The prevalence and clinical aspects of high-HDL-cholesterolemia were investigated in 2000 patients (1215 males and 785 females) aged 14-88 years in our medical outpatient department. The incidence of high-HDL-cholesterolemia was 7% (greater than 1.68 mmol/l) in males and 9.9% (greater than 1.94 mmol/l) in females and was associated in 80% of cases with a normal lipid profile according to the Fredrickson classification. Compared with patients with low-HDL-cholesterolemia, high-HDL-cholesterolemia distinguished by a lower incidence of obesity, of hyperlipidemia, of diabetes and of cigarette smoking. In contrast, daily alcohol intake was significantly higher. Fewer patients had a history of ischemic cardiovascular events. High-HDL-cholesterolemia appears to arise from both environmental and genetic factors.

[The injured and the immobilized muscle cell: ultrastructural observations]. / Die verletzte und die immobilisierte Muskelzelle: ultrastrukturelle Betrachtungen.

Muscle soreness is a common feature among athletes and untrained individuals who engage in unusual, especially intense eccentric exercise. Various biochemical markers as for example elevated CK demonstrate a damage of muscle cells. The most prominent structural finding is a varying degree of disruption of the contractile material up to cell degeneration. These morphological findings reach their maximum 2 or 3 days after exercise. Signs of regeneration, however, are seen even weeks after exercise. In a prospective study we investigated the structures of the quadriceps muscle in 41 patients with chronic symptomatic instability of the anterior cruciate ligament before, 9 and 26 weeks after operation using the needle biopsy technique. The immobilized muscle showed a rapid and large atrophy which markedly reduced aerobic capacity as well as maximal strength. Preoperative values weren't attained 26 weeks postoperative despite intense physiotherapeutic exercise. The control leg showed an atrophy as well, but only aerobic capacity was reduced, maximal strength remained about the same.

Muscle filament spacing and short-term heavy-resistance exercise in humans.

1. Six weeks of a dynamic heavy-resistance training of the quadriceps muscle in healthy young men resulted in a continuous increase in muscle strength, in an increase in muscle cross-sectional area (significant only in the second half of the training period) and in an increase in radiological density of the muscle tissue of 3.1% (2P less than 0.001) in the first three weeks and 1.6% (2P less than 0.01) in the second three weeks. 2. The linear distance between myosin filaments (38.7 +/- 0.3 nm before, 38.7 +/- 0.4 nm after training; mean +/- S.E.M.) as well as the ratio of actin to myosin filaments (3.94 +/- 0.03 before, 3.86 +/- 0.06 after training) did not change with training. 3. These results refute the concept that the increases in muscle strength or radiological density during short-term heavy-resistance training are caused by changes in myofilament spacing.

Structural changes in skeletal muscle tissue with heavy-resistance exercise.

Muscle strength, muscle cross-sectional area, fiber size, fiber type distribution, capillarity, and mitochondrial volume were estimated before and after 6 weeks of heavy-resistance exercise. Isokinetic torque production of the knee extensor muscles increased by a total of 17.6%, mainly during the first half of the training period. The cross-sectional area of the vastus lateralis muscle increased by 8.4%, mainly during the second half of the training period. Morphometrically determined fiber size, fiber type distribution, and capillarity from biopsies of vastus lateralis did not change significantly with training. Likewise, the surface densities of inner and outer mitochondrial membranes as well as the volume density of myofibrils remained unchanged. In contrast, the volume density of mitochondria decreased by 9.6%. However, due to the increase in total muscle volume, the calculated absolute volume of mitochondria remained constant, whereas the absolute volume of myofibrils increased by 10%. It is concluded that strength training of short duration in previously untrained young male subjects does not change the ultrastructural composition of mitochondria and that the apparent dilution of mitochondria can quantitatively be accounted for by the increase in myofibrillar volume.