Topography dependence of the metamagnetic phase transition in FeRh thin films.

The equiatomic alloy FeRh is of great scientific and technological interest due its highly unusual first-order antiferromagnetic (AF) to ferromagnetic (FM) phase transition. Here we report an exploration of the interplay between topography and phase evolution with a comprehensive magnetic force microscopy study of nominal 50 nm thick FeRh thin films and subtractively patterned wires of width 0.2 µm-2 µm. In continuous films where the surface morphology had not been optimised for smoothness, the topographical variation was observed to dominate the distribution of the magnetic transition temperatures and dictates the nucleation and growth of the magnetic phases. This observation was repeated for patterned elements, where the effects of surface morphology were more significant than those of spatial confinement. These results have clear implications for future studies of low-dimensional FeRh films, as surface topography must be considered when analysing and comparing the transition behaviour of FeRh thin films.

Circulating vitamin D levels are associated with the presence and severity of coronary artery disease but not peripheral arterial disease in patients undergoing coronary angiography.

BACKGROUND AND AIMS: To investigate the association between vitamin D levels, angiographic severity of coronary artery disease, arterial stiffness and degree of peripheral arterial disease (PAD) as assessed by ankle brachial index (ABI). METHODS AND RESULTS: 375 patients undergoing coronary angiography from November 2012 to September 2013 were recruited. Serum 25-hydroxyvitamin D (25OHD) levels were measured as were ABI and pulse wave velocity (PWV). Based on the findings of the coronary angiogram, patients were divided into subgroups: Absent, Single, Double and Triple Vessel Disease (as defined by >50% stenosis in each major coronary artery) 0.275 patients not taking vitamin D supplements were included in the analysis. Mean age was 66.0 ± 11.2 (mean ± SD) years. Levels of 25(OH)D were significantly lower in patients with CAD when compared to patients without CAD (57.0 ± 1.73 versus 70.1 ± 2.46 nmol/L; p < 0.01). One way ANOVA revealed triple vessel disease patients had significantly lower 25(OH)D levels when compared to single vessel disease patients (50.6 ± 2.84 nmol/L versus 61.3 ± 3.16 p < 0.01) and trended to be lower when compared to double vessel disease patients (50.6 ± 2.84 versus 59.0 ± 2.99 nmol/L; p = 0.07). Stepwise regression revealed that age, gender (male), hypertension, hyperlipidemia and 25(OH)D were significant predictors of CAD (p < 0.05). Vitamin D was the most significant predictor for CAD (p < 0.001) There was no correlation between 25(OH)D levels, ABI and PWV. CONCLUSION: Among patients presenting for coronary angiography, low serum 25-hydroxyvitamin D levels are associated with the presence and extent of angiographic CAD but not arterial stiffness or PAD.

Risk of cardiovascular adverse events from trastuzumab (Herceptin(®)) in elderly persons with breast cancer: a population-based study.

Randomized controlled trials have reported a 4-5 times increased risk of heart failure (HF) in breast cancer patients receiving trastuzumab (Herceptin (®) ) compared to patients who do not receive trastuzumab. However, data regarding the cardiac effects of trastuzumab on elderly patients treated in general practice remain very limited. Using the US surveillance, epidemiology, and end results (SEER)-Medicare database, we conducted a retrospective cohort study on the cardiac effects of trastuzumab use in all incident breast cancer patients diagnosed from 1998 to 2007 who were 66 years and older, had no prior recent claims for cardiomyopathy (CM) or HF, and were followed through 2009. We defined our outcome as the first CM/HF event after diagnosis. We performed Cox-proportional hazard models with propensity score adjustment to estimate CM/HF risk associated with trastuzumab use. A total of 6,829 out of 68,536 breast cancer patients (median age: 75) had an incident CM/HF event. Patients who received trastuzumab tended to be younger, non-white, diagnosed more recently, and had a stage IV diagnosis. Trastuzumab use was associated with an increased risk of CM/HF (HR = 2.08, 95 % CI 1.77-2.44, p < 0.001). The trastuzumab-associated CM/HF risk was stronger in patients who were younger (HR = 2.52 for 66-75 years and HR = 1.44 for 76 years and older, p < 0.001) and diagnosed in recent years (HR = 2.58 for 2006-2007 vs. 1.86 for 1998-2005, p = 0.01). The twofold risk of CM/HF associated with trastuzumab remained regardless of patients' diagnosis stage, presence of hypertension, cardiovascular comorbidities, or receipt of anthracyclines, taxanes, or radiation. Trastuzumab may double CM/HF risk among elderly breast cancer patients. Our findings reinforce the need to prevent and manage cardiac risk among elderly breast cancer patients receiving trastuzumab.

Bevacizumab use and risk of cardiovascular adverse events among elderly patients with colorectal cancer receiving chemotherapy: a population-based study.

BACKGROUND: Cardiovascular risk attributable to bevacizumab (Avastin(®), BEV) for treatment of metastatic colorectal cancer (CRC) remains unclear. We conducted a population-based cohort study to assess the safety of BEV use among patients aged ≥ 65. PATIENTS AND METHODS: We identified CRC patients diagnosed from 2005 to 2007 who received chemotherapy and were followed until 31 December 2009. Outcomes were 3-year risk of arterial thromboembolic events (ATEs), cardiomyopathy or congestive heart failure (CM/CHF), and cardiac death (CD) after chemotherapy initiation. We fitted Cox-proportional hazards (PHs) models with inverse-probability-of-treatment-weights and calculated hazard ratios (HRs) for the risk of adverse events. RESULTS: We identified 6803 CRC patients (median age: 73 years). Those with cardiac comorbidity were less likely to receive BEV (P < 0.0001). BEV is associated with an elevated risk of ATEs (HR = 1.82, 95% CI = 1.20-2.76, P < 0.001; rate difference: 3.5 additional cases/1000 person-years). We observed no association between BEV and CD or CM/CHF. CONCLUSIONS: In general practice, the cardiovascular risk of BEV in elderly CRC is modest. The observed ATEs risk is lower than reported in clinical trials, which may be due to careful patient selection. Our findings may facilitate clinical decision-making of BEV use in elderly patients.

Iodothyronamines are oxidatively deaminated to iodothyroacetic acids in vivo.

3-Iodothyronamine (T(1)AM) and 3,3',5-triiodothyroacetic acid (Triac) are bioactive metabolites of the hormone thyroxine (T(4)). In the present study, the ability of T(1)AM and 3,3',5-triiodothyronamine (T(3)AM) to be metabolized to 3-iodothyroacetic acid (TA(1)) and Triac, respectively, was investigated. Both T(1)AM and T(3)AM were converted to their respective iodinated thyroacetic acid analogues in both cell and tissue extracts. This conversion could be significantly inhibited with the monamine oxidase (MAO) and semicarbazide-sensitive amine oxidase (SSAO) inhibitor iproniazid. TA(1) was found to be present in trace quantities in human serum and in substantial levels in serum from T(1)AM-treated rats. These results demonstrate that iodothyronamines are substrates for amine oxidases and that this metabolism may be the source of the corresponding endogenous arylacetic acid products Triac and TA(1).

Substrate activity screening (SAS): a general procedure for the preparation and screening of a fragment-based non-peptidic protease substrate library for inhibitor discovery.

Substrate activity screening (SAS) is a fragment-based method for the rapid development of novel substrates and their conversion into non-peptidic inhibitors of Cys and Ser proteases. The method consists of three steps: (i) a library of N-acyl aminocoumarins with diverse, low-molecular-weight N-acyl groups is screened to identify protease substrates using a simple fluorescence-based assay; (ii) the identified N-acyl aminocoumarin substrates are optimized by rapid analog synthesis and evaluation; and (iii) the optimized substrates are converted into inhibitors by direct replacement of the aminocoumarin with known mechanism-based pharmacophores. This protocol describes a general procedure for the solid-phase synthesis of a library of N-acyl aminocoumarin substrates and the screening procedure to identify weak binding substrates.

Identification of selective, nonpeptidic nitrile inhibitors of cathepsin s using the substrate activity screening method.

The substrate activity screening method, a substrate-based fragment identification and optimization method for the development of enzyme inhibitors, was previously applied to cathepsin S to obtain low nanomolar 1,4-disubstituted-1,2,3-triazole-based aldehyde inhibitors (Wood, W. J. L.; Patterson, A. W.; Tsuruoka, H.; Jain, R. K.; Ellman, J. A. J. Am. Chem. Soc. 2005, 127, 15521-15527). Replacement of the metabolically labile aldehyde pharmacophore with the nitrile pharmacophore provided inhibitors with moderate potency for cathepsin S. The inhibitors showed good selectivity over cathepsins B and L but no selectivity over cathepsin K. X-ray structures of two crystal forms (1.5 and 1.9 A) of a complex between cathepsin S and a triazole inhibitor incorporating a chloromethyl ketone pharmacophore guided the design of triazole substrates with increased cleavage efficiency and selectivity for cathepsin S over cathepsins B, L, and K. Conversion of select substrates to nitrile inhibitors yielded a low molecular weight (414 Da) and potent (15 nM) cathepsin S inhibitor that showed >1000-fold selectivity over cathepsins B, L, and K.

Substrate activity screening: a fragment-based method for the rapid identification of nonpeptidic protease inhibitors.

A new fragment-based method for the rapid development of novel and distinct classes of nonpeptidic protease inhibitors, Substrate Activity Screening (SAS), is described. This method consists of three steps: (1) a library of N-acyl aminocoumarins with diverse, low molecular weight N-acyl groups is screened to identify protease substrates using a simple fluorescence-based assay, (2) the identified N-acyl aminocoumarin substrates are optimized by rapid analogue synthesis and evaluation, and (3) the optimized substrates are converted to inhibitors by direct replacement of the aminocoumarin with known mechanism-based pharmacophores. The SAS method was successfully applied to the cysteine protease cathepsin S, which is implicated in autoimmune diseases. Multiple distinct classes of nonpeptidic substrates were identified upon screening an N-acyl aminocoumarin library. Two of the nonpeptidic substrate classes were optimized to substrates with >8000-fold improvements in cleavage efficiency for each class. Select nonpeptidic substrates were then directly converted to low molecular weight, novel aldehyde inhibitors with nanomolar affinity to cathepsin S. This study demonstrates the unique characteristics and merits of this first substrate-based method for the rapid identification and optimization of weak fragments and provides the framework for the development of completely nonpeptidic inhibitors to many different proteases.

Synthesis of a diverse library of mechanism-based cysteine protease inhibitors.

We report improvements of our method for the solid-phase synthesis of mechanism-based mercaptomethyl ketone inhibitors of cysteine proteases (Lee, A.; Huang, L.; Ellman, J. A. J. Am. Chem. Soc. 1999, 121, 9907-9914). Specifically, Fmoc-protected chloromethyl ketones were used, rather than the Alloc-protected counterparts. In addition, we further demonstrated that diverse polar functionality can be incorporated at the R1', R1, and R2 sites, in contrast to our previous efforts, where primarily hydrophobic groups were incorporated at these positions. On the basis of these results, a 2016-membered library of potential mercaptomethyl ketone inhibitors was prepared that incorporated diverse functionality. The library was screened against cathepsin B, which is implicated in cancer, resulting in the identification of single-digit nanomolar inhibitors. Because of the diverse functionality incorporated in this library, it should be a rich source of potent inhibitors against many other cysteine proteases.

Bowel surveillance patterns after a diagnosis of colorectal cancer in Medicare beneficiaries.

BACKGROUND: Postoperative colon surveillance has been recommended for patients with a diagnosis of local/regional colorectal cancer. The extent to which these recommendations are followed in practice is poorly characterized. Patterns of surveillance after surgery for colorectal cancer were determined by using a large population-based database. METHODS: This is a retrospective cohort study with cancer registry data linked to Medicare claims. Identified were 52,283 patients treated for local/regional colorectal cancer between 1986 and 1996, and surveillance patterns through 1998 were determined. Surveillance patterns were analyzed by using survival analysis and by computing the proportion of surviving patients who underwent procedures during 4 time periods after treatment: 2 to 14 months, 15 to 50 months, 51 to 86 months and more than 87 months. RESULTS: Median times to first through fifth surveillance events were 20, 14, 15, 15, and 15 months, respectively. For 17% of the cohort there was no surveillance event. Younger patients were more likely to undergo surveillance. Surveillance patterns were not affected by stage. The proportions of the cohort that underwent no surveillance during the 4 respective time periods were 54%, 52%, 60%, and 69%. The percentages of patients who underwent surveillance annually or more frequently in the latter 3 time periods, respectively, were 19%, 10%, and 5%, or 11% overall, treating the data for the 3 events as a whole. Over the period from 1986 to 1998, the proportion of patients who had no surveillance procedures gradually decreased, whereas the proportion of those who underwent procedures annually or more frequently remained relatively constant. CONCLUSIONS: During the period from 1986 to 1998 there was low utilization of postdiagnosis colon surveillance in a substantial proportion of elderly patients with a diagnosis of local/regional colorectal cancer. Over time there was a trend toward increasing receipt of any surveillance procedures. The percentages of patients undergoing surveillance annually or more frequently did not change between earlier and later periods.

Influence of hospital procedure volume on outcomes following surgery for colon cancer.

CONTEXT: Survival following high-risk cancer surgery, such as pancreatectomy and esophagectomy, is superior at hospitals where high volumes of these procedures are performed. Conflicting evidence exists as to whether the association between hospital experience and favorable health outcomes also applies to more frequently performed operations, such as those for colon cancer. OBJECTIVE: To determine whether hospital procedure volume predicts survival following colon cancer surgery. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study of data from the Surveillance, Epidemiology and End Results-Medicare linked database on 27 986 colon cancer patients aged 65 years and older who had surgical resection for primary adenocarcinoma diagnosed between 1991 and 1996. MAIN OUTCOME MEASURES: Thirty-day postoperative mortality and overall and cancer-specific long-term survival, by hospital procedure volume. RESULTS: We found small differences in 30-day postoperative mortality for patients treated at low- vs high-volume hospitals (3. 5% at hospitals in the top-volume quartile vs 5.5% at hospitals in the bottom-volume quartile). However, the correlation was statistically significant and persisted after adjusting for age at diagnosis, sex, race, cancer stage, comorbid illness, socioeconomic status, and acuity of hospitalization (P<.001). The association was evident for subgroups with stage I, II, and III disease. Hospital volume directly correlated with survival beyond 30 days and also was not attributable to differences in case mix (P<.001). The association between hospital volume and long-term survival was concentrated among patients with stage II and III disease (P<.001 for both). Among stage III patients, variation in use of adjuvant chemotherapy did not explain this finding. CONCLUSION: Our data suggest that hospital procedure volume predicts clinical outcomes following surgery for colon cancer, although the absolute magnitudes of these differences are modest in comparison with the variation observed for higher-risk cancer surgeries.

Accuracy and completeness of Medicare claims data for surgical treatment of breast cancer.

BACKGROUND: Although a number of studies have used Medicare claims data to study trends and variations in breast cancer treatment, the accuracy and completeness of information on surgical treatment for breast cancer in the Medicare data have not been validated. OBJECTIVES: This study assessed the accuracy and completeness of Medicare claims data for breast cancer surgery to determine whether Medicare claims can serve as a source of data to augment information collected by cancer registries. METHODS: We used the Surveillance, Epidemiology and End Results (SEER) Cancer Registry-Medicare data and compared Medicare claims on surgery with the surgery recorded by the SEER registries for 23,709 women diagnosed with breast cancer at > or =65 years of age from 1991 through 1993. RESULTS: More than 95% of women having mastectomies according to the Medicare data were confirmed by SEER. For breast-conserving surgery, 91% of cases were confirmed by SEER. The Medicare physician services claims and inpatient claims were approximately equal in accuracy on type of surgery. The Medicare outpatient claims were less accurate for breast-conserving surgery. In terms of completeness, when the 3 claims sources were combined, 94% of patients receiving breast cancer surgery according to SEER were identified by Medicare. CONCLUSIONS: The combined Medicare claims database, which includes the inpatient, outpatient, and physician service claims, provides valid information on surgical treatment among women known to have breast cancer. The claims are a rich source of data to augment the information collected by tumor registries and provide information that can be used to follow long-term outcomes of Medicare beneficiaries.

Is there cross-format transfer in implicit invariance learning?

Three experiments investigated cross-form transfer in the invariance learning paradigm introduced by McGeorge and Burton (1990). The results suggest that the transfer observed by McGeorge and Burton depended on subjects' ability to use a response strategy discovered by Wright and Burton (1995). When that strategy was denied to subjects (Experiments 1 and 2), no cross-form transfer was observed; when the strategy was made available (Experiment 3), cross-form transfer re-emerged. These results suggest that this form of learning, like many other forms of implicit learning and memory, is hyperspecific.

Development of a comorbidity index using physician claims data.

Important comorbidities recorded on outpatient claims in administrative datasets may be missed in analyses when only inpatient care is considered. Using the comorbid conditions identified by Charlson and colleagues, we developed a comorbidity index that incorporates the diagnostic and procedure data contained in Medicare physician (Part B) claims. In the national cohorts of elderly prostate (n = 28,868) and breast cancer (n = 14,943) patients assessed in this study, less than 10% of patients had comorbid conditions identified when only Medicare hospital (Part A) claims were examined. By incorporating physician claims, the proportion of patients with comorbid conditions increased to 25%. The new physician claims comorbidity index significantly contributes to models of 2-year noncancer mortality and treatment received in both patient cohorts. We demonstrate the utility of a disease-specific index using an alternative method of construction employing study-specific weights. The physician claims index can be used in conjunction with a comorbidity index derived from inpatient hospital claims, or employed as a stand-alone measure.

Racial differences in the treatment of early-stage lung cancer.

BACKGROUND: If discovered at an early stage, non-small-cell lung cancer is potentially curable by surgical resection. However, two disparities have been noted between black patients and white patients with this disease. Blacks are less likely to receive surgical treatment than whites, and they are likely to die sooner than whites. We undertook a population-based study to estimate the disparity in the rates of surgical treatment and to evaluate the extent to which this disparity is associated with differences in overall survival. METHODS: We studied all black patients and white patients 65 years of age or older who were given a diagnosis of resectable non-small-cell lung cancer (stage I or II) between 1985 and 1993 and who resided in 1 of the 10 study areas of the Surveillance, Epidemiology, and End Results (SEER) program (10,984 patients). Data on the diagnosis, stage of disease, treatment, and demographic characteristics of the patients were obtained from the SEER data base. Information on coexisting illnesses, type of Medicare coverage, and survival was obtained from linked Medicare inpatient-discharge records. RESULTS: The rate of surgery was 12.7 percentage points lower for black patients than for white patients (64.0 percent vs. 76.7 percent, P<0.001), and the five-year survival rate was also lower for blacks (26.4 percent vs. 34.1 percent, P<0.001). However, among the patients undergoing surgery, survival was similar for the two racial groups, as it was among those who did not undergo surgery. Furthermore, analyses in which adjustments were made for factors that are predictive of either candidacy for surgery or survival did not alter the influence of race on these outcomes. CONCLUSIONS: Our analyses suggest that the lower survival rate among black patients with early-stage, non-small-cell lung cancer, as compared with white patients, is largely explained by the lower rate of surgical treatment among blacks. Efforts to increase the rate of surgical treatment for black patients appear to be a promising way of improving survival in this group.

Role of transurethral resection of the prostate in population-based prostate cancer incidence rates.

The extensive pool of asymptomatic prostate disease in the population, which increases substantially with age, suggests that the frequent use of transurethral resection of the prostate (TURP) in recent decades has had a large effect on prostate cancer incidence. The authors identified the effect of TURP-detected prostate cancer on the observed incidence rates between 1973 and 1993 for men aged 65 years and older. They linked population-based cancer registry data from the Surveillance, Epidemiology, and End Results Program to Medicare records between 1986 and 1993 to determine whether a TURP occurred sufficiently close to the time of a prostate cancer diagnosis for them to assume that it led to the diagnosis. TURP-detected cases prior to 1986 were calculated using an indirect method that involved multiplying the TURP procedure rate in the general population (from the National Hospital Discharge Survey) by estimates of the proportion of TURPs resulting in a prostate cancer diagnosis (from Medicare data and the literature). TURP explained much of the observed increase in overall prostate cancer incidence between 1973 and 1986 and possibly all of it in men aged 70 years and older. However, its influence on the trend and overall magnitude of the rates diminished between 1987 and 1993. The changing role of TURP in detecting prostate cancer is attributed to changes in medical technology and screening practices. The declining influence of TURP on prostate cancer incidence is likely to have continued beyond the study period due to the recent introduction and increasing use of medications for treating obstructive uropathy.

Cancer surveillance series [corrected]: brain and other central nervous system cancers: recent trends in incidence and mortality.

BACKGROUND: During the 1980s, the incidence of primary malignant brain and other central nervous system tumors (hereafter called brain cancer) was reported to be increasing among all age groups in the United States, while mortality was declining for persons younger than 65 years. We analyzed these data to provide updates on incidence and mortality trends for brain cancer in the United States and to examine these patterns in search of their causes. METHODS: Data on incidence, overall and according to histology and anatomic site, and on relative survival were obtained from the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute for 1975 through 1995. Mortality data were obtained from the National Center for Health Statistics. Medicare procedure claims from the National Cancer Institute's SEER-Medicare database were used for imaging trends. Statistically significant changes in incidence trends were identified, and annual percent changes were computed for log linear models. RESULTS/CONCLUSIONS: Rates stabilized for all age groups during the most recent period for which SEER data were available, except for the group containing individuals 85 years of age or older. Mortality trends continued to decline for the younger age groups, and the steep increases in mortality seen in the past for the elderly slowed substantially. Patterns differed by age group according to the site and grade of tumors between younger and older patients. During the last decade, use of computed tomography scans was relatively stable for those 65-74 years old but increased among those 85 years old or older. IMPLICATIONS: Improvements in diagnosis and changes in the diagnosis and treatment of elderly patients provide likely explanations for the observed patterns in brain cancer trends.

Rising incidence of renal cell cancer in the United States.

CONTEXT: Clinical surveys have revealed that incidental detection of renal cell carcinoma is rising because of increased use of imaging procedures. OBJECTIVE: To examine incidence, mortality, and survival trends of renal cell and renal pelvis cancers by age, sex, race, and tumor stage at diagnosis. DESIGN: Calculation of age-adjusted incidence and mortality rates, along with 5-year relative survival rates, using data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program. SETTING AND PARTICIPANTS: Patients diagnosed as having kidney cancer from 1975 through 1995 in the 9 geographic areas covered by tumor registries in the SEER program, which represent about 10% of the US population. MAIN OUTCOME MEASURES: Incidence, mortality, and 5-year relative survival rates by time periods. RESULTS: The age-adjusted incidence rates for renal cell carcinoma between 1975 and 1995 for white men, white women, black men, and black women were 9.6, 4.4, 11.1, and 4.9 per 100000 person-years, respectively. The corresponding rates for renal pelvis cancer were 1.5, 0.7, 0.8, and 0.5 per 100000 person-years. Renal cell cancer incidence rates increased steadily between 1975 and 1995, by 2.3% annually among white men, 3.1 % among white women, 3.9% among black men, and 4.3% among black women. Increases were greatest for localized tumors but were also seen for more advanced and unstaged tumors. In contrast, the incidence rates for renal pelvis cancer declined among white men and remained stable among white women and blacks. Although 5-year relative survival rates for patients with renal cell cancer improved among whites but not among blacks, kidney cancer mortality rates increased in all race and sex groups. CONCLUSIONS: Increasing detection of presymptomatic tumors by imaging procedures, such as ultrasonography, computed tomography, and magnetic resonance imaging, does not fully explain the upward incidence trends of renal cell carcinoma. Other factors may be contributing to the rapidly increasing incidence of renal cell cancer in the United States, particularly among blacks.