A large scale prospective clinical and psychometric validation of the EORTC colorectal (QLQ-CR29) module in Polish patients with colorectal cancer.

The purpose of our study was to assess if the Polish translation of the European Organisation for Research and Treatment of Cancer (EORTC) Colorectal Cancer (CRC)-Specific Quality of Life Questionnaire (QLQ-CR29) is an acceptable and psychometrically valid measure to collect quality of life (QoL) data in Polish patients with CRC for use in clinical trials and clinical practice. A total of 150 patients undergoing treatment for CRC were prospectively enrolled in the study. Psychometric assessment of the translated QLQ-CR29 structure, reliability, convergent and divergent validity, and clinical validity was subsequently performed. The Cronbach's alpha coefficient ranged from 0.70-0.89, indicating acceptable internal consistency. For test-retest reliability, the ICCs for each item ranged from 0.59-0.91, with exceptions for urinary incontinence and dysuria, indicating good to excellent reproducibility. In multi-trait scaling analyses, the criterion for item convergent and divergent validity was satisfied. The correlations between the EORTC QLQ-CR29 and QLQ-C30 scales were mostly low (r < .40), with a few items demonstrating higher correlations. The known group comparisons analyses demonstrated the ability of the questionnaire to distinguish between patients' differing age, stoma status, and treatment intent. The Polish translation of the QLQ-CR29 is a psychometrically reliable and valid tool. The results of this study are congruent with that of EORTC validation.

Preoverwintering Copulation and Female Ratio Bias: Life History Characteristics Contributing to the Invasiveness and Rapid Spread of Megacopta cribraria (Heteroptera: Plataspidae).

Prewinter copulation, sperm storage, and oocyte development in overwintering adult Megacopta cribraria (F.) was examined in Alabama (Lee Co.). Microscopic examinations of the spermathecae and ovaries were made in females and of the testes in males that were collected approximately weekly from September 2013 through March 2014. The results indicated that approximately 15% of females mated before entering winter dormancy and sperm was stored in their spermatheca for up to seven months, oocytes in mated overwintering females proceeded to postblastoderm stage before the onset of spring feeding and mating in March, all of the overwintering males had sperm in their testes, and the ratio of females gradually increased in populations during overwintering. This study indicates that both males and females are capable of reproductive dormancy. The biological significance of these life cycle aspects is discussed from the viewpoints of invasiveness and adaptation.

A non-catalytic role of choline kinase alpha is important in promoting cancer cell survival.

Choline kinase alpha (ChoKα) is regarded as an attractive cancer target. The enzyme catalyses the formation of phosphocholine(PCho), an important precursor in the generation of phospholipids essential for cell growth. ChoKα has oncogenic properties and is critical for the survival of cancer cells. Overexpression of the ChoKα protein can transform noncancer cells into cells with a cancerous phenotype, and depletion of the ChoKα protein can result in cancer cell death. However, the mechanisms underlying the tumourigenic properties of ChoKα are not fully understood. ChoKα was recently demonstrated to associate with other oncogenic proteins, raising the possibility that a non-catalytic protein scaffolding function drives the tumourigenic properties of ChoKα rather than a catalytic function. In order to differentiate these two roles, we compared the impact on cancer cell survival using two tools specific for ChoKα: (1) small interfering RNA (siRNA) to knockdown the ChoKα protein levels; and (2) compound V-11-0711, a novel potent and selective ChoKα inhibitor (ChoKα IC50 20 nM), to impede the catalytic activity. Both treatments targeted the endogenous ChoKα protein in HeLa cells, as demonstrated by a substantial reduction in the PCho levels. siRNA knockdown of the ChoKα protein in HeLa cells resulted in significant cell death through apoptosis. In contrast, compound V-11-0711 caused a reversible growth arrest. This suggests that inhibition of ChoKα catalytic activity alone is not sufficient to kill cancer cells, and leads us to conclude that there is a role for the ChoKα protein in promoting cancer cell survival that is independent of its catalytic activity.

Structural basis for potent inhibition of the Aurora kinases and a T315I multi-drug resistant mutant form of Abl kinase by VX-680.

The small molecule inhibitor of the Aurora-family of protein kinases VX-680 or MK-0457, demonstrates potent anti-cancer activity in multiple in vivo models and has recently entered phase II clinical trials. Although VX-680 shows a high degree of enzyme selectivity against multiple kinases, it unexpectedly inhibits both Flt-3 and Abl kinases at low nanomolar concentrations. Furthermore VX-680 potently inhibits Abl and the Imatinib resistant mutant (T315I) that is commonly expressed in refractory CML and ALL. We describe here the crystal structure of VX-680 bound to Aurora-A and show that this inhibitor exploits a centrally located hydrophobic pocket in the active site that is only present in an inactive or "closed" kinase conformation. A tight association of VX-680 with this hydrophobic pocket explains its high affinity for the Aurora kinases and also provides an explanation for its selectivity profile, including its ability to inhibit Abl and the Imatinib-resistant mutant (T315I).

Synthesis and in vitro evaluation of a series of diketopiperazine inhibitors of plasminogen activator inhibitor-1.

We have synthesized and evaluated a series of diketopiperazine-based inhibitors of PAI-1. These studies resulted in the identification of 34 which inhibited PAI-1 in vitro with an IC(50)=0.2 microM. The synthesis and SAR of these compounds are described.

Comparing uninsured and privately insured hospital patients: admission severity, health outcomes and resource use.

This paper compares uninsured hospital patients with privately insured patients in terms of severity of illness on admission, emergency department use, leaving the hospital against medical advice, length of stay, and in-hospital mortality and morbidity rates. This cross-sectional study includes 29,237 admissions to 100 US hospitals in 1993 and 1994. We found that uninsured patients are sicker, indicating that hospitals should expect uninsured patients to have increased service needs. Our results indicate that the uninsured exhibit higher likelihood of leaving against medical advice, shorter lengths of stay and poorer health outcomes suggest that the uninsured may not be receiving necessary care. Further studies are needed.

The structures of caspases-1, -3, -7 and -8 reveal the basis for substrate and inhibitor selectivity.

BACKGROUND: Peptide inhibitors of caspases have helped define the role of these cysteine proteases in biology. Structural and biochemical characterization of the caspase enzymes may contribute to the development of new drugs for the treatment of caspase-mediated inflammation and apoptosis. RESULTS: The crystal structure of the previously unpublished caspase-7 (Csp7; 2.35 A) bound to the reversible tetrapeptide aldehyde inhibitor acetyl-Asp-Glu-Val-Asp-CHO is compared with crystal structures of caspases-1 (2.3 A), -3 (2.2 A), and -8 (2.65 A) bound to the same inhibitor. Csp7 is a close homolog of caspase-3 (Csp3), and these two caspases possess some quarternary structural characteristics that support their unique role among the caspase family. However, although Csp3 and Csp7 are quite similar overall, they were found to have a significantly different substitution pattern of amino acids in and around the S4-binding site. CONCLUSIONS: These structures span all three caspase subgroups, and provide a basis for inferring substrate and inhibitor binding, as well as selectivity for the entire caspase family. This information will influence the design of selective caspase inhibitors to further elucidate the role of caspases in biology and hopefully lead to the design of therapeutic agents to treat caspase-mediated diseases, such as rheumatoid arthritis, certain neurogenerative diseases and stroke.

Linking health outcomes and resource efficiency for hospitalized patients: do physicians with low mortality and morbidity rates also have low resource expenditures?

This study addresses the question of whether physicians with better health outcomes for their patients spend more or less to accomplish these results. Several studies have examined this outcome-cost relationship at the hospital level, but the results are conflicting. The study sample (using an administrative database [1995 MQPro Comparative Database, MediQual Systems, Inc., Westborough, MA, USA]) comprised 175,249 adult medical service admissions to 100 hospitals in 25 states spanning 26 diagnosis-related groups (DRGs) during 1993 and 1994. Logistic regression models were used to estimate the expected probability of in-hospital mortality or morbidity; age, sex, severity of illness on admission, year of admission, insurance status and hospital were controlled for. The regression residuals were employed as quality indicators. Residual charges and length of stay (LOS) were estimated for each patient using an ordinary least squares regression model and were employed as resource efficiency indicators. A positive, statistically significant association at the physician level was found between mean morbidity residuals and each of the three mean resource efficiency residuals (LOS, 1.42 beta coefficient; ancillary charges, 1.78; and total charges, 1.27, all significant at the P < 0.001 level). The same positive and significant association was found between mortality residuals and each resource efficiency residual (LOS, 0.77 beta coefficient; ancillary charges, 0.80; and total charges, 0.68, all significant at the P < 0.01 level) when patients staying only one or two days were excluded. The results support our hypothesis that, on average, physicians with lower adjusted mortality or morbidity rates also have lower adjusted resource expenditures.

Toward a systems quality paradigm: relating health outcomes, resource expenditures, and appropriateness of cholecystectomy patients.

This study addresses the question for cholecystectomy patients of whether there is an association among manifesting better health outcomes and the quantity of hospital resources consumed when the appropriateness of this surgery is also considered. 10,043 cholecystectomies performed by 218 surgeons in 43 Pennsylvanian hospitals are analysed using data from an administrative data set. Performance measures are adjusted for admission severity of illness and other patient variables. The results demonstrate a statistically significant positive association between adjusted hospital total charges and adjusted morbidity controlling for whether specified clinical criteria are met that validate the need for a cholecystectomy. This study illustrates a systems quality paradigm wherein performance is examined in terms of health outcomes, appropriateness and resource expenditures, as well as the relationships among these three dimensions.

Evidence for an interleukin-1beta converting enzyme (ICE)-like activity distinct from ICE and responsible for ICE and CPP32 cleavage during apoptosis.

IL-1beta converting enzyme (ICE) and ICE-related proteases (IRPs) have been suggested to play a central role in apoptosis. We report the use of peptidic ICE inhibitors to reassess the role of this enzyme in the apoptosis induced by Fas or TNFalpha receptor ligation in Jurkat cells, U937 cells or monocytes. Our results show that inhibition of IL-1beta processing can be dissociated from inhibition of apoptosis. Indeed, two out of three com-pounds active on ICE are not inhibitory for apoptosis. This shows that ICE is not required for progression in the apoptotic pathway, but that one or several IRPs are necessary. In addition, Western blot analysis of cell lysates shows that both ICE and CPP32 precursors disappear rapidly after apoptosis induction, while ICH-1L precursor remains intact. Concomitant appearance of cleavage products can be visualized for CPP32, but not for ICE, suggesting that the former is proteolytically activated. In addition, this precursor cleavage can be blocked by an ICE inhibitor active on apoptosis. Altogether, our data support the hypothesis that one or several IRPs are necessary for apoptosis and are responsible for ICE and CPP32 cleavage during this process.

Prediction of relative potency of ketone protease inhibitors using molecular orbital theory.

Molecular orbital calculations were carried out on a series of model ketonic protease inhibitors. A comparison of the LUMO energy of the ketones in a variety of model heterocyclic ketone protease inhibitors shows a correlation with the electrophilicity of the carbonyl, and the sigma 1 experimental data. It is also observed that the more negative charge on the nitrogen atom in the heterocyclic ring the greater its potential as a hydrogen bond acceptor. The results of this study provide a simple means of predicting relative inhibitor potency and is therefore of use both to medicinal chemists designing protease inhibitors and in QSAR studies.

Occurrence of validating clinical findings in the hospital record for appendectomy, cholecystectomy and intervertebral disc excision patients: comparisons among hospitals and among surgeons.

This study examines the variation among 36 Pennsylvania hospitals, and the individual surgeons practicing in them, in the proportion of appendectomy, cholecystectomy and intervertebral disc excision patients with clinical findings in the hospital record that validate the need for surgery. Using admissions from January 1990 through June 1991, we performed logistic regressions on the probability of validating clinical findings controlling for patient age, sex, admission severity of illness, and Medicaid and Health Maintenance Organization membership. Our results show that hospitals, and surgeons, vary significantly in their validation rates for cholecystectomy and disc surgery and, to a lesser extent, appendectomy. We also found that increased procedure-specific volume at both the hospital and surgeon levels is not related to the odds of validating clinical findings. We define a future research agenda to investigate the reasons for the observed differences among hospitals and among surgeons.

Indications for hysterectomy: variation within and across hospitals.

This study investigates the factors associated with the probability of finding specific clinical indicators (benign or malignant tumor, cancer in situ, fibroid, abscess/empyema, or positive culture of salpinx, fallopian tube, fetus, or uterus) that validate necessity for hysterectomy. Data for the 4,660 cases in the study come from 42 Pennsylvania hospitals. The probability that validating indicators were present varied significantly at the hospital level but not at the level of individual surgeons within hospital, suggesting that physicians in different hospitals adopted different practice styles. The results at the hospital level indicate that higher hysterectomy volume increased the probability of validating findings, whereas presence of an OB/GYN program was associated with lower probability of validating findings. The policy and management implications of these results are discussed.

Surgeon volume and hospital resource utilization.

This study examines whether surgeons who perform a particular procedure more often incur lower hospital charges and shorter lengths of stay than surgeons with less volume. The 43 Pennsylvania hospitals included in the 1991 MedisGroups Comparative Hospital Database form the study hospitals. The analysis looks at four frequently occurring surgical procedures: cholecystectomy, prostatectomy, hysterectomy, and intervertebral disc excision. Regression models are estimated separately for total charges, ancillary charges, and length of stay for each surgical procedure. The explanatory variable of interest is surgeon volume for the specific procedure. Control variables include patient age, sex, admission severity of illness, insurance plan, and hospital. For cholecystectomy, prostatectomy, and intervertebral disc surgery, we find a significant negative association between surgeon volume and both hospital charges and length of stay. We find no such volume effect for hysterectomy. The paper discusses management and policy implications of these findings.

Relating hospital health outcomes and resource expenditures.

This study addresses the question of whether hospitals with better health outcomes for their patients spend more or less to accomplish these results. Adult medical service admissions to 43 Pennsylvania hospitals are analyzed. Health outcomes and resource expenditures are adjusted for admission severity of illness and other patient variables. The results demonstrate a positive correlation between adjusted mortality (logit regression) and adjusted total charges, ancillary charges, and length of stay (ordinary least squares regression), but only the mortality/length-of-stay relationship is statistically significant (p < .05). For patients staying at least four days, however, there is a statistically significant, positive relationship between adjusted mortality and all three adjusted measures of resource expenditures. The relationship between the adjusted morbidity and each of these three adjusted resource measures is positive and statistically significant. The positive relationship is largely unrelated to such readily observable hospital characteristics as size, staffing, teaching status, and location in urban areas.

Comparing surgical efficiency in independent practice association HMOS and traditional insurance programs.

This study examines the effect of Independent Practice Association (IPA) HMO membership on hospital total charges, ancillary charges and length of stay (LOS) for surgical patients. Intrahospital comparisons of IPA and traditional insurance patients are made after adjusting for surgical procedure, admission severity of illness, age, sex and year of admission. Our multiple regression model indicates that IPA patients undergoing 12 frequently occurring surgical procedures have lower resource use. Eight (80%) of the 10 study hospitals exhibit a negative IPA beta coefficient for total charges, ancillary charges and LOS. Five (50%) hospitals have statistically significant (p < 0.05) negative coefficients for total charges, while one (10%) hospital has a significant positive coefficient. IPA patients exhibit adjusted total charges that are 6% lower than traditional insurance, ancillary charges that are 4.3% lower, and LOS that is 10% shorter.

Comparing low-severity hospital admissions in IPA HMOs and indemnity-type programs.

This study compares the proportion of low-severity hospital patients in independent practice association (IPA) HMOs and indemnity-type programs. The length of stay of such low-severity patients is also studied. Admissions of IPA patients under age 65 to ten hospitals are compared with admissions to the same hospital of patients covered by Blue Cross and Blue Shield plans or commercial insurance programs. Admissions to the adult medical service for the eight most frequently occurring DRGs with 5 percent or more patients in the low-severity category are included. A Logit model of the probability of low-severity admission controlling for age, sex, DRG, and hospital shows no significant IPA effect. However, a multiple regression model shows that the IPAs have significantly lower average length of stay for these low-severity patients.

Inter-hospital mortality and morbidity variation in Pennsylvania.

A 1986 Pennsylvania law requires the public disclosure of hospital mortality and morbidity rates. This study of hospital admissions in 1989 and 1990 examines the variation in these health-outcome indicators for the 10 most frequently occurring DRGs in the adult medical service in a sample of 20 Pennsylvania hospitals. These mortality and morbidity rates are adjusted for admission severity, DRG, age, and sex, using a logistic regression model. The null hypothesis of no significant variation among hospitals is rejected by the statistically significant (p < 0.01) results of a likelihood ratio test on the hospital variables in logit models for both mortality and morbidity. Test results also show that 4 (20 percent) of 20 hospitals have statistically significant (p < 0.05) adjusted mortality rates, and 4 (20 percent) of 20 hospitals have significant morbidity rates. Such information may impact hospital management practices in a variety of ways.

Comparing hospital length of stay in independent practice association HMOs and traditional insurance programs.

This study compares length of hospital stay in Independent Practice Association (IPA) HMOs and traditional insurance programs. Hospital admissions from 10 IPAs are compared with admissions to the same hospital of persons covered by Blue Cross and Blue Shield Plans or commercial insurance programs. Admissions of patients under age 65 to the adult medical service for the 10 most frequently occurring DRGs are included. Regression equations are estimated using length of stay as the dependent variable and IPA membership and hospital and patient characteristics as control variables. All 10 IPAs exhibit shorter lengths of stay as indicated by negative beta coefficients, and in 6 of the 10 IPAs this coefficient is statistically significant (p less than .05). This IPA effect occurs for 7 of the 10 study DRGs, and for MedisGroups Admission Severity Groups 0, 1, and 2.