Using Real-world Data to Define a Validated Nomogram for Advanced Bladder Cancer Patients Who Respond to Immunotherapy.

AIMS: Immune checkpoint inhibitors (ICIs) are used in incurable urothelial cancers, both in chemo-naïve and platinum-refractory patients. Efficacy and toxicity data published outside controlled clinical trials are limited. We report overall survival, progression-free survival and toxicities of ICIs in locally advanced (LABC) or metastatic bladder cancer (MBC). We aimed to develop and validate a prognostic model for these patients. MATERIALS AND METHODS: A multicentre real-world individual patient-level data study (n = 272) evaluating ICIs in the first-line platinum-ineligible or platinum-refractory setting for LABC/MBC between March 2017 and February 2020 was undertaken. Cox regression analyses evaluated the association of prognostic factors with overall survival. Data were split to create a training (n = 208) and validation (n = 64) cohort. The backward elimination method with a P-value cut-off of 0.05 was used to develop a reduced prognostic model using the training data set. The concordance index and assessment of observed versus predicted survival probabilities were used to evaluate the final model. RESULTS: The median follow-up was 18.9 (15.8-21.5) months. The median overall survival and progression-free survival in the training cohort were 9.2 (95% confidence interval 7.4-10.5) and 4.5 months (3.5-5.7), respectively. The most common grade 1/2 adverse events recorded were fatigue (47.8%) and infection (19.9%). Five key prognostic factors found in the training set were low haemoglobin, high neutrophil count, choice of immunotherapy favouring pembrolizumab, presence of liver metastasis and steroid use within 30 days of treatment. The concordance index for the training and validation cohorts was 0.66 (standard error = 0.05) and 0.64 (standard error = 0.04), respectively, for the final model. A nomogram was developed to calculate the expected survival probabilities based on risk factors. CONCLUSIONS: Real-world data were used to produce a validated prognostic model for overall survival in LABC/MBC treated with ICIs. This model could assist in patient stratification, interpreting and framing future trials incorporating PD-1/PD-L1 inhibitors in LABC/MBC.

A Multicentre Retrospective Study of Fulvestrant Use and Efficacy in Advanced/Metastatic Breast Cancer.

AIMS: Fulvestrant is a selective oestrogen receptor (ER) degrader used in postmenopausal women with hormone receptor-positive advanced breast cancer. The study aim was to analyse demographics and outcomes of UK patients treated with fulvestrant monotherapy at nine representative centres. MATERIALS AND METHODS: Medical records of 459 patients with locally advanced or metastatic ER-positive, HER2-negative breast cancer treated with fulvestrant between August 2011 and November 2018 at nine UK centres were reviewed. Data were collated on demographics, progression-free survival, overall survival and disease response at first radiological assessment following fulvestrant initiation. Patients still alive by December 2018 were censored. RESULTS: Data from 429 of the 459 patients identified were eligible for inclusion in the analysis. The median age was 69 (range 21-95) and 64% (n = 275) had Eastern Cooperative Oncology Group performance status 0-1. Bone was the most commonly involved metastatic site (72%, n = 306). However, 295 (69%) patients had visceral involvement. Patients had received a median 2 (range 0-5) prior lines of endocrine therapy and median 0 (range 0-6) prior chemotherapies. Fulvestrant was first-line therapy in 43 patients (10%). The median duration of treatment was 5 months (range 1-88). The median progression-free survival was 5.5 months. In 51% of 350 patients radiologically assessed, there was evidence of disease response to fulvestrant. Fifteen per cent of these had a complete/partial response. Fulvestrant was discontinued predominantly due to disease progression, with 3% discontinued solely due to adverse events. The median overall survival for the whole cohort was 22.5 months (range 0-88). CONCLUSIONS: This is one of the largest studied cohorts of breast cancer patients treated with fulvestrant. This heavily endocrine-pretreated population reflects real-life use in the UK. Within this context, our retrospective data show that patients can experience maintained disease response when treated with fulvestrant, supporting the importance of equitable availability for all UK patients.

Avoided climate impacts of urban and rural heat and cold waves over the U.S. using large climate model ensembles for RCP8.5 and RCP4.5.

Previous studies examining future changes in heat/cold waves using climate model ensembles have been limited to grid cell-average quantities. Here, we make use of an urban parameterization in the Community Earth System Model (CESM) that represents the urban heat island effect, which can exacerbate extreme heat but may ameliorate extreme cold in urban relative to rural areas. Heat/cold wave characteristics are derived for U.S. regions from a bias-corrected CESM 30-member ensemble for climate outcomes driven by the RCP8.5 forcing scenario and a 15-member ensemble driven by RCP4.5. Significant differences are found between urban and grid cell-average heat/cold wave characteristics. Most notably, urban heat waves for 1981-2005 are more intense than grid cell-average by 2.1°C (southeast) to 4.6°C (southwest), while cold waves are less intense. We assess the avoided climate impacts of urban heat/cold waves in 2061-2080 when following the lower forcing scenario. Urban heat wave days per year increase from 6 in 1981-2005 to up to 92 (southeast) in RCP8.5. Following RCP4.5 reduces heat wave days by about 50%. Large avoided impacts are demonstrated for individual communities; e.g., the longest heat wave for Houston in RCP4.5 is 38 days while in RCP8.5 there is one heat wave per year that is longer than a month with some lasting the entire summer. Heat waves also start later in the season in RCP4.5 (earliest are in early May) than RCP8.5 (mid-April), compared to 1981-2005 (late May). In some communities, cold wave events decrease from 2 per year for 1981-2005 to one-in-five year events in RCP4.5 and one-in-ten year events in RCP8.5.

Reframing Future Risks of Extreme Heat in the United States.

The goal of this study is to reframe the analysis and discussion of extreme heat projections to improve communication of future extreme heat risks in the United States. We combine existing data from 31 of the Coupled Model Intercomparison Project Phase 5 models to examine future exposure to extreme heat for global average temperatures of 1.5, 2, 3, and 4 °C above a preindustrial baseline. We find that throughout the United States, historically rare extreme heat events become increasingly common in the future as global temperatures rise and that the depiction of exposure depends in large part on whether extreme heat is defined by absolute or relative metrics. For example, for a 4 °C global temperature rise, parts of the country may never see summertime temperatures in excess of 100 °F, but virtually all of the country is projected to experience more than 4 weeks per summer with temperatures exceeding their historical summertime maximum. All of the extreme temperature metrics we explored become more severe with increasing global average temperatures. However, a moderate climate scenario delays the impacts projected for a 3 °C world by almost a generation relative to the higher scenario and prevents the most extreme impacts projected for a 4 °C world.

Evaluation of diagnostic and prognostic significance of Ki-67 index in pulmonary carcinoid tumours

Background. Pulmonary carcinoid (PC) tumours are classified as either typical (TC) or atypical (AC) according to mitotic index (MI) and presence of necrosis. The aim of this study was to analyse the diagnostic and prognostic values of the Ki-67 index in PC. Methods/patients. Between January 2001 and March 2015, we evaluated 94 consecutive patients with a confirmed diagnosis of TC (n = 75) or AC (n = 19) at our institution. Diagnostic histology was centrally reviewed by a local expert neuroendocrine pathologist, with assessment of Ki-67, MI, and necrosis. Results. Median patient follow-up was 35 months. Eighty-four patients who underwent curative surgical resection were included in the survival analysis for identification of prognostic factors. Ki-67 index showed high diagnostic accuracy to predict histological subtype when assessed by receiver operator characteristic curves with an area under the curve of 0.923 (95% CI 0.852-0.995, p < 0.001). Multivariate analysis showed that MI, Ki-67 index, and the presence or absence of necrosis were independent prognostic factors for relapse-free survival. Combination of MI, Ki-67, and necrosis led to the classification of patients into four different prognostic groups (very low, low, intermediate, and high risks of relapse). Conclusions. The current study proposes the incorporation of Ki-67 index in the prognostic classification of PC tumours. Due to the limited number of patients and length of follow-up, the current model needs validation by larger cohort studies. Nevertheless, our results suggest that Ki-67 index and MI have continuous effect on prognosis. Prognostic models incorporating multiple cutoffs of Ki-67 and MI might better predict outcome and inform clinical decisions (AU)

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Evaluation of diagnostic and prognostic significance of Ki-67 index in pulmonary carcinoid tumours.

BACKGROUND: Pulmonary carcinoid (PC) tumours are classified as either typical (TC) or atypical (AC) according to mitotic index (MI) and presence of necrosis. The aim of this study was to analyse the diagnostic and prognostic values of the Ki-67 index in PC. METHODS/PATIENTS: Between January 2001 and March 2015, we evaluated 94 consecutive patients with a confirmed diagnosis of TC (n = 75) or AC (n = 19) at our institution. Diagnostic histology was centrally reviewed by a local expert neuroendocrine pathologist, with assessment of Ki-67, MI, and necrosis. RESULTS: Median patient follow-up was 35 months. Eighty-four patients who underwent curative surgical resection were included in the survival analysis for identification of prognostic factors. Ki-67 index showed high diagnostic accuracy to predict histological subtype when assessed by receiver operator characteristic curves with an area under the curve of 0.923 (95% CI 0.852-0.995, p < 0.001). Multivariate analysis showed that MI, Ki-67 index, and the presence or absence of necrosis were independent prognostic factors for relapse-free survival. Combination of MI, Ki-67, and necrosis led to the classification of patients into four different prognostic groups (very low, low, intermediate, and high risks of relapse). CONCLUSIONS: The current study proposes the incorporation of Ki-67 index in the prognostic classification of PC tumours. Due to the limited number of patients and length of follow-up, the current model needs validation by larger cohort studies. Nevertheless, our results suggest that Ki-67 index and MI have continuous effect on prognosis. Prognostic models incorporating multiple cutoffs of Ki-67 and MI might better predict outcome and inform clinical decisions.

The MTT and Crystal Violet Assays: Potential Confounders in Nanoparticle Toxicity Testing.

The toxicological effects of nanoparticles (NPs) on humans, animals, and environment are largely unknown. Assessment of NPs cytotoxicity depends on the choice of the test system. Due to NPs optical activity and absorption values, they can influence the classical cytotoxicity assay. Eight NPs were spiked in the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and crystal violet assays and tested with HaCaT human skin cells. The MTT assay standard curve optical density (OD) measurements were altered by the presence of trisilanol phenyl and trisilanol isooctyl polyhedral oligomeric silsesquioxane particles. The crystal violet standard curve OD measurements were significantly shifted by gold NPs, but they did not affect the MTT assay. Carbon black decreased ODs in the MTT and crystal violet assays and was localized in the cell cytoplasm. These findings strongly indicate that a careful choice of in vitro viability systems is required to avoid flawed measurement of NPs toxicity.

Differential susceptibilities of human lung, breast and skin cancer cell lines to killing by five sea anemone venoms

Although sea anemones are well known for being rich sources of toxins, including cytolysins and neurotoxins, their venoms and toxins have been poorly studied. In the present study, the venoms from five sea anemones (Heteractis crispa, Heteractis magnifica, Heteractis malu, Cryptodendrum adhaesivum and Entacmaea quadricolor) were obtained by the milking technique, and the potential of these venoms to kill cancer cells was tested on three cell lines (A549 lung cancer, T47D breast cancer and A431 skin cancer). The total protein level in the crude extract was determined by the bicinchoninic acid (BCA) protein assay. The cytotoxicity on different cell lines was assayed using the 3-(4, 5-dimethylthiazol-2yl)-2, 5-diphenyltetrazolium bromide (MTT) assay which measures survival based on the detection of mitochondrial activity and by the crystal violet assay, which measures survival based on the ability of cells to remain adherent to microplates. The results indicate that the sea anemone venom is cytotoxic to human cancer cells. The A549 cell line was the most sensitive of the cell lines tested with a significant reduction in viability observed at 40 µg/mL. H. malu, C. adhaesivum and E. quadricolor had a significant inhibitory effect on A431 cells. Furthermore, H. malu and C. adhaesivum had a significant inhibitory effect on T47D cell line at 40 µg/mL. In conclusion, the sea anemone venoms tested have the potential to be developed as anticancer agents.(AU)

Adaptations of the in vitro MN assay for the genotoxicity assessment of nanomaterials.

The issue of appropriate testing strategies has been raised for the genotoxicity assessment of nanomaterials. Recently, efforts have been made to evaluate the adequacy of Organisation for Economic Co-operation and Development-standardised tests to assess the genotoxicity of nanomaterials. The aim of this review was to examine whether the current guideline for the in vitro micronucleus (MN) assay is applicable for testing nanomaterials. From a Pubmed literature search, 21 available studies were identified for analysis. We reviewed all protocols used for testing nanomaterials with the in vitro MN assay. All studies were categorised based on the particle type and size. Different aspects of the protocols were evaluated such as the exposure (duration and doses), the cytochalasin-B treatment, serum levels and cytotoxicity assessment. Sixteen of the 21 studies demonstrated increased frequencies of MN. Some recommendations regarding the protocol were formulated to maximise sensitivity and avoid false negatives. Determination of the cellular dose was advised for a better interpretation of MN frequency results. The level of serum can modulate the cellular response, therefore the serum percentage used should enable cell growth and proliferation and a maximal sensitivity of the assay. Furthermore, different types of cytochalasin-B treatment were used, co-treatment, post-treatment and delayed co-treatment. In order to avoid decreased cellular uptake as a consequence of actin inhibition, post-treatment or delayed co-treatment is suggested. Exposure during mitosis should be recommended to allow contact with the chromatin or mitotic apparatus for nanomaterials that are unable to cross the nuclear membrane. With these adaptations, the in vitro MN assay can be recommended for genotoxicity testing of nanomaterials.

Reaching agreement for an Aboriginal e-health research agenda: the Aboriginal Telehealth Knowledge Circle consensus method.

INTRODUCTION: In Canada, telehealth has been successfully implemented in a number of Aboriginal communities with subsequent improvements to access to health care and quality of life. However, there are many knowledge gaps that limit our understanding of the broad range of Aboriginal e-health issues; a research agenda is urgently required. The objective of this research was to develop an Aboriginal e-health research agenda designed to address the substantial knowledge gaps that impede e-health deployment and adoption particularly in rural and remote Aboriginal communities in Canada. A consensus method based on Aboriginal culture, values and approaches to consensus was developed to achieve this. METHODS: In this consensus methodology, a core group of Aboriginal telehealth leaders, led by a research facilitator, engaged in an iterative process of individual and group review of research data. The reviewed data included stakeholder interview data, questionnaires, literature and other resources and was prioritized in order to develop recommendations for an Aboriginal e-health research agenda. RESULTS: A total of 40 stakeholders including Aboriginal Telehealth Knowledge Circle (ATKC) members, communities of practice and regional, provincial and federal leaders and policy-makers participated in the consensus process. The research recommendations showed a high degree of consistency among stakeholders. Participants reached consensus on 6 areas: research ethics, internet-based e-health services data, educational resources, sustainability models, best practices and exploration of innovative applications. CONCLUSIONS: An ATKC consensus process was successfully applied to reach consensus on an Aboriginal e-health research agenda, demonstrating the potential of Indigenous research approaches for defining levels of agreement on complex topics. The resulting conceptual map for e-health research can be used as a springboard for partnership-based research initiatives involving Aboriginal communities, governments and researchers, and may be of interest to Indigenous e-health researchers at an international level.

Delayed ultraviolet erythema not suppressed by oral prednisolone: a randomized crossover study.

BACKGROUND: The anti-inflammatory potency of topical dermatological corticosteroids in suppressing ultraviolet (UV) erythema is routinely measured. No such model exists to assess the potency of systemically administered steroids. OBJECTIVE: To determine whether or not suppression of delayed UV erythema by a systemic corticosteroid could provide a useful model for assessing the anti-inflammatory potency of systemic corticosteroids. METHODS: We conducted a randomized, placebo-controlled, patient and assessor blinded, crossover study of oral prednisolone effects on the delayed UV-induced erythemal response in normal subjects. Six healthy volunteers were phototested with a xenon arc monochromator and then dosed with 30 mg of oral prednisolone or matching placebo daily for 4 days. Repeat phototesting was performed on the 4th day of dosing. The minimal erythema dose (MED) was assessed immediately after test UV doses were administered and 24 h later. After a 2-week washout period, the dosing and testing were repeated in a crossover fashion. RESULTS: A suppression index (SI) [1/(baseline MED value divided by on prednisolone/placebo value)] allowed comparison of the degree of suppression on and off prednisolone. Oral prednisolone did not significantly suppress the threshold UV erythema response (MED). We may have missed small effects in this study and possibly a larger dose or a longer duration of corticosteroid would have had an effect. Possibly, assessment of corticosteroid potency in suppressing established UV erythema rather than on the development of threshold erythema would have yielded different results. CONCLUSION: The threshold UV erythema suppression model assessed in this study could not distinguish between oral prednisolone and placebo. This UV-erythema suppression test system is not promising as a model to test the anti-inflammatory potency of systemic steroids.

A Community Health Advisor Program to reduce cardiovascular risk among rural African-American women.

The Uniontown, Alabama Community Health Project trained and facilitated Community Health Advisors (CHAs) in conducting a theory-based intervention designed to reduce the risk for cardiovascular disease (CVD) among rural African-American women. The multiphased project included formative evaluation and community organization, CHA recruitment and training, community intervention and maintenance. Formative data collected to develop the training, intervention and evaluation methods and materials indicated the need for programs to increase knowledge, skills and resources for changing behaviors that increase the risk of CVD. CHAs worked in partnership with staff to develop, implement, evaluate and maintain strategies to reduce risk for CVD in women and to influence city officials, business owners and community coalitions to facilitate project activities. Process data documented sustained increases in social capital and community capacity to address health-related issues, as well as improvements in the community's physical infrastructure. This project is unique in that it documents that a comprehensive CHA-based intervention for CVD can facilitate wide-reaching changes in capacity to address health issues in a rural community that include improvements in community infrastructure and are sustained beyond the scope of the originally funded intervention.

Standardized Mini-Mental State Examination. Use and interpretation.

OBJECTIVE: To review administration of the Standardized Mini-Mental State Examination (SMMSE) for dementia and depression and to evaluate how well it interprets older people's cognitive function. QUALITY OF EVIDENCE: Literature from January 1990 to December 1999 was searched via MEDLINE using the MeSH headings Alzheimer Disease, Vascular Dementia, Lewy Bodies, and Depression. Several studies have described the reliability and validity of the SMMSE. MAIN MESSAGE: The SMMSE, a standardized approach to scoring and interpreting older people's cognitive function, provides a global score of cognitive ability that correlates with daily function. Careful interpretation of results of the SMMSE, together with history and physical assessment, can assist in differential diagnosis of cognitive impairment resulting from Alzheimer's disease, vascular dementia, dementia with Lewy bodies, or depression. Repeated measurements can be used to assess change over time and response to treatment. CONCLUSION: The SMMSE is a valuable tool for family doctors who are often the first medical professionals to identify changes in patients' cognitive function. The SMMSE requires little time to complete and is a key component of a comprehensive dementia workup. Determining whether a patient has dementia is important because there are now effective medications that are most beneficial if started early.

Chronic obstructive pulmonary disease stage and 6-minute walk outcome.

PURPOSE: Although physicians generally reserve pulmonary rehabilitation (PR) referral for patients in later stages of chronic obstructive pulmonary disease (COPD), there is no evidence to suggest that PR programs are more effective for these persons than for those in earlier stages of the disease. This study examined the relationship between 6-minute walk change and COPD stage in patients completing PR. METHODS: The sample consisted of 76 patients who enrolled in the University of Alabama at Birmingham's Cardiopulmonary Rehabilitation Program with a primary diagnosis of COPD between January 1996 and June 2000. Data was collected on 6-minute walk upon entry into the program and upon program completion. Patients were stratified according to COPD stage using the American Thoracic Society staging system. RESULTS: There were significant differences among the three stages with regard to initial and ending 6-minute walk distances such that persons in later stages of the disease have shorter initial and ending 6-minute walk distances. However, all three stages show significant improvements in the 6-minute walk after PR. There were no significant differences in the median change among groups indicating that the median change was not better (or worse) for patients in any particular COPD stage. CONCLUSIONS: This study suggests that PR is equally effective in increasing physical performance for all patients regardless of COPD stage. This type of information can be used to support the recommendation of PR for patients early in the disease process.

Role of glutathione S-transferase mu (GSTM1) in styrene-7,8-oxide toxicity and mutagenicity.

In the human glutathione S-transferase (GST) mu gene family, homozygous deletion of GSTM1 is the null phenotype (frequency of approximately 50% in Caucasians). In the current study, GSTM1 status was determined in human cell lines using reverse transcriptase, polymerase chain reaction, and immunochemistry. Cell lines were challenged with a range of doses of styrene-7,8-oxide (SO) and then toxicity and genotoxicity were monitored. Toxicity was determined by growth in flasks and genotoxicity by cloning in microplates in the presence/absence of 6-thioguanine, to detect mutations at the hypoxanthine phosphoribosyltransferase (hprt) locus. A SO concentration-dependent decrease in survival was observed for all cell lines, with GSTM1-deficient lines being more sensitive. The IC(50)s of deficient and proficient cell lines were 0.45 and 0.55 mM SO, respectively. The difference between survival of GSTM1-deficient and -proficient cell lines approached statistical significance. The background mutation frequency of GSTM1-deficient cell lines was 2 x 10(-5), and that of GSTM1-proficient cell lines was 3 x 10(-6). GSTM1-deficient cell lines were significantly more sensitive than GSTM1-proficient cell lines to mutation induction for concentrations up to 2.5 mM SO (P < 0.001, regression analysis). These results suggest that cell lines containing metabolically competent GSTM1 are able to efficiently use GSTM1 to conjugate SO and reduce its hazard. This supports the epidemiological evidence that GSTM1 influences sensitivity to chemical carcinogenesis and subsequent risk of cancer induction.

Induction of mutant lymphocytes in cyclophosphamide- and chlorambucil-treated patients.

Monitoring patients treated with single antineoplastic agents is aiding our understanding of what hazard these drugs pose in vivo. In this study, the frequency of mutant 6-thioguanine-resistant (TG(R)) peripheral blood lymphocytes was monitored before treatment and for < or =35 weeks after treatment of patients with cyclophosphamide (CP) or chlorambucil (CAB). The mean mutant frequency before treatment for six multiple sclerosis patients treated with high-dose CP was 2.53 x 10(-5) and increased after treatment to 4.61 x 10(-5) (P = 0.08, paired t-test). Using each patient as their own control, there were significant increases (each at P < 0.04) detectable within 2-4 weeks in four of the multiple sclerosis patients treated with CP. There was no increase in an untreated control monitored over the same period. In a patient receiving five sequential CP treatments at 1 month intervals, there were cumulative increases in the frequency of mutant cells. The mutant frequency increased from 0.31 x 10(-5) before treatment to 3.64 x 10(-5) after the final treatment and had decreased to 0.53 x 10(-5) at 35 weeks after treatment. In one of two CAB-treated patients with indolent non-Hodgkin's lymphoma, there was a significant increase in mutant frequency (P < 0.03) after treatment. Freshly isolated peripheral blood lymphocytes treated with 4-hydroperoxy-CP in vitro demonstrate a dose-dependent increase in mutant frequency. The increment in mutant frequency observed in vivo is of the order expected from the in vitro experiments. Although this study demonstrates that single or multiple doses of a single antineoplastic agent are mutagenic in vivo for some patients, further studies are needed to determine the extent and mechanism of the inter-individual variations in mutagenic response.

Advance directives in cardiac and pulmonary rehabilitation patients.

PURPOSE: Advance directives have been available in parts of the United States for more than 20 years, but research shows that only a small percentage of adults (5-25%) have some form of written advance directive. The purose of this study was to examine the presence of advance directives among persons entering cardiac and pulmonary rehabilitation, and identify characteristics of persons most likely to have advance directives. METHODS: The sample consisted of 336 cardiac patients and 181 pulmonary patients who enrolled in the University of Alabama at Birmingham's Cardiopulmonary Rehabilitation Program between January 1996 and December 1999. As part of the initial program assessment, patients were asked two questions: (1) Do you have a living will? (2) Do you have any advance directives? For the purposes of this study, the two questions were combined to examine the presence of either a living will or other type of advance directive. RESULTS: Results indicate that 25% of both subgroups (cardiac and pulmonary patients) report having written advance directives. Logistic regression analysis indicates that among cardiac patients whites and older persons were more likely to have advance directives. Among pulmonary patients, females and whites were more likely to have advance directives. CONCLUSIONS: These results indicate that only a minority of cardiopulmonary rehabilitation patients have advance directives upon entry into the program, and that the prevalence differs among gender, racial, and age groups. Cardiac and pulmonary rehabilitation programs may be valuable sites for educating patients about advance directives and efforts by rehabilitation personnel may increase the prevalence of advance directives among patients.

The place of bigamy in the pantheon of crime?

Bigamy is officially classified as a 'sex offence'. The offence is rare and attracts little criminological attention, and the reaction of the courts has become more lenient in recent years, yet the media coverage of bigamy remains quite pervasive. An analysis of the criminal career profile over 32 years (1963-94) of the 42 bigamists convicted in 1973 indicates that they had no other convictions for bigamy and only two had convictions for a sex offence. Among the 25 persons with other convictions, the crimes of theft/handling stolen goods and fraud and forgery predominate. In fact, the criminal careers of these bigamists are more similar to the criminal careers of white collar offenders than of other sex offenders. It is suggested that by looking at convicted bigamists' criminal careers one can more appropriately categorize the crime as deception, and in this context we need to consider how to respond to its perpetrators and victims.

Referral patterns to a University-based cardiac rehabilitation program.

Referral rates to our cardiac rehabilitation program among patients hospitalized for coronary heart disease were computed over an 18-month period. Only 8.7% of eligible patients were referred, suggesting that more education targeting physicians, patients, and insurers is needed and barriers to participation must be systematically addressed.