Enhancement of the selectivity and antitumor efficacy of a CC-1065 analogue through immunoconjugate formation
Bis-indolyl-(seco)-1,2,9a-tetrahydrocyclopropa[c]benz[e]indol-4-on e compounds are synthetic analogues of CC-1065 that are highly cytotoxic toward a broad spectrum of tumor cell lines. One of these compounds, called DC1, was conjugated to antibodies via novel cleavable disulfide linkers. Conjugates of DC1 with murine mAbs anti-B4 and N901 directed against tumor-associated antigens CD19 and CD56, respectively, proved to be extremely potent and antigen selective in killing target cells in culture. DC1 conjugates with humanized versions of anti-B4 and N901 antibodies were also constructed and demonstrated to be as cytotoxic and selective as the respective murine antibody conjugates. The anti-B4-DC1 conjugate showed antitumor efficacy in an aggressive metastatic human B-cell lymphoma survival model in SCID mice and completely cured animals hearing large tumors. Anti-B4-DC1 was considerably more effective in this tumor model than doxorubicin, cyclophosphamide, etoposide, or vincristine at their maximum tolerated doses.
The maytansinoid drug DM1 is 100- to 1000-fold more cytotoxic than anticancer drugs that are currently in clinical use. The immunoconjugate C242-DM1 was prepared by conjugating DM1 to the monoclonal antibody C242, which recognizes a mucin-type glycoprotein expressed to various extents by human colorectal cancers. C242-DM1 was found to be highly cytotoxic toward cultured colon cancer cells in an antigen-specific manner and showed remarkable antitumor efficacy in vivo. C242-DM1 cured mice bearing subcutaneous COLO 205 human colon tumor xenografts (tumor size at time of treatment 65-130 mm3), at doses that showed very little toxicity and were well below the maximum tolerated dose. C242-DM1 could even effect complete regressions or cures in animals with large (260- to 500-mm3) COLO 205 tumor xenografts. Further, C242-DM1 induced complete regressions of subcutaneous LoVo and HT-29 colon tumor xenografts that express the target antigen in a heterogeneous manner. C242-DM1 represents a new generation of immunoconjugates that may yet fulfill the promise of effective cancer therapy through antibody targeting of cytotoxic agents.
Uninsured children in Connecticut represent a diverse group, and insuring them is a monumental task. In August 1997, President Clinton signed into law the Children's Health Insurance Program, which provides $47 billion in funds to states over the next 10 years to insure the nation's low-income children. Connecticut has been a leader in modeling the federal Children's Health Insurance Program into action. Connecticut's version of the program, Healthcare for UninSured Kids and Youth, (HUSKY), was enacted over the summer, and, to date, has enrolled over 4,000 children in the program. Connecticut's HUSKY program provides a timely opportunity for the state, as well as community health centers and other primary-care facilities, to reach those uninsured children in Connecticut's communities and move the children into the HUSKY program. In order to achieve this goal, innovative outreach strategies need to be designed that utilize cultural and community resources to locate and insure these children.
Several studies have demonstrated that workforce roles and salaries differ substantially between men and women in administrative positions within the health care industry. Recent studies of graduates with masters of business administration (MBA) and masters of health administration (MHA) degrees have indicated that women tend to experience lower salaries, given like responsibilities. However, the impact of gender on salary has been less studied among masters of public health (MPH) graduates in the health care field. Our objective was to assess the impact of gender on salary among MPH degree graduates. Using a cross-sectional survey of all graduates from the MPH program at Yale University between 1991-1997 (n = 201, response rate = 51%), we ascertained graduates' reported salary in the first job post-graduation and reported salary in their current position. Bivariate and multivariate analyses were used to assess the unadjusted and adjusted associations between gender and salary. Salaries in both the first job post-graduation and in the current job differed significantly by gender, with women earning less than men (p-values < .05). Moreover, these differences persisted after controlling for a set of human capital measures including pre-MPH work experience, age at graduation, years since graduation, area of specialization within the MPH degree, and type of work site (governmental or nonprofit versus for-profit). Unlike studies of MBA and MHA graduates, however, this study did not find evidence that the gender-related salary gap widened as the years since graduation increased, although the sample size did not allow comprehensive testing of this trend.
Randomized controlled trials often rely on placebo control groups to estimate treatment differences. Recently, the high frequency of negative trials and ethical concerns surrounding the use of placebos have brought the use of placebo control groups under increased scrutiny. Although many psychiatric researchers argue that placebo control groups should be replaced with active control groups, we argue that preferential use of active control groups will not reduce the number of negative trials. Rather, we suggest that some of the variation and contradiction in randomized controlled trial results arises from the clinical heterogeneity of patient characteristics, disease severity, comorbidity, and cotherapies. Further characterization of patient heterogeneity, through improved disease taxonomies, severity indices, and classification of comorbid diseases, will serve to reduce clinical heterogeneity among patients and reduce the number of negative trials produced by wide variation in treatment and control response rates.
African Americans in the United States are disproportionately affected by HIV/AIDS. We focus in this paper on the structural and contextual sources of HIV/AIDS risk, and suggest that among the most important of these sources are drug policy and the corrections system. In particular, high rates of exposure to the corrections system (including incarceration, probation, and parole) spurred in large part by federal and state governments' self-styled war on drugs in the United States, have disproportionately affected African Americans. We review a wide range of research literature to suggest how exposure to the corrections system may affect the HIV/AIDS related risks of drug users in general, and the disproportionate HIV risk faced by African Americans in particular. We then discuss the implications of the information reviewed for structural interventions to address African American HIV-related risk. Future research must further our understanding of the relations among drug policy, corrections, and race-based disparities in HIV/AIDS.
The state of physician office-based health information technology in Connecticut: current use, barriers and future plans
Qualidigm and the Connecticut State Medical Society-Independent Practice Association (CSMS-IPA), Inc. have conducted a survey of the physicians participating in the CSMS-IPA to assess current use of health information technology in their offices and their plans for future use. The survey was conducted to assist eHealth Connecticut, a Connecticut-based nonprofit organization, in its charge to promote electronic health information exchange in Connecticut. The survey was distributed to 2,366 medical offices representing 6,956 physicians in Connecticut. Survey results revealed that the most commonly utilized types of technology were practice management systems (70%) and e-mail (64%). The most common barriers to the adoption of new technologies were cost (71%) and time requirements (39%). Primary-care providers and small practices were more likely to cite cost as a barrier to technology implementation. Despite these challenges, many physicians reported plans to implement electronic medical records (25%) or electronic prescribing (20%) in the next year.
Drug toxicity, HIV progression, or comorbidity of aging: does tipranavir use increase the risk of intracranial hemorrhage
The US Food and Drug Administration has issued a warning that tipranavir may be associated with increased risk of intracranial hemorrhage. We studied 2 large cohorts to estimate the background rate of intracranial hemorrhage and compared it with rates reported among persons who had been exposed to tipranavir.
Development of an electronic medical record-based clinical decision support tool to improve HIV symptom management
Common symptoms associated with HIV disease and its management are often underrecognized and undertreated. A clinical decision support tool for symptom management was developed within the Veterans Health Administration electronic medical record (EMR), aiming at increasing provider awareness of and response to common HIV symptoms. Its feasibility was studied in March to May 2007 by implementing it within a weekly HIV clinic, comparing a 4-week intervention period with a 4-week control period. Fifty-six patients and their providers participated in the study. Patients' perceptions of providers' awareness of their symptoms, proportion of progress notes mentioning any symptom(s) and proportion of care plans mentioning any symptom(s) were measured. The clinical decision support tool used portable electronic "tablets" to elicit symptom information at the time of check-in, filtered, and organized that information into a concise and clinically relevant EMR note available at the point of care, and facilitated clinical responses to that information. It appeared to be well accepted by patients and providers and did not substantially impact workflow. Although this pilot study was not powered to detect effectiveness, 25 (93%) patients in the intervention group reported that their providers were very aware of their symptoms versus 27 (75%) control patients (p = 0.07). The proportion of providers' notes listing symptoms was similar in both periods; however, there was a trend toward including a greater number of symptoms in intervention period progress notes. The symptom support tool seemed to be useful in clinical HIV care. The Veterans Health Administration EMR may be an effective "laboratory" for developing and testing decision supports.
Gender differences in rates of depression, PTSD, pain, obesity, and military sexual trauma among Connecticut War Veterans of Iraq and Afghanistan
PURPOSE: The current wars in Iraq and Afghanistan have led to an increasing number of female veterans seeking medical and mental healthcare in the Department of Veterans Affairs (VA) healthcare system. To better understand gender differences in healthcare needs among recently returned veterans, we examined the prevalence of positive screenings for depression, posttraumatic stress disorder (PTSD), military sexual trauma (MST), obesity, and chronic pain among female and male veterans of Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) receiving care at the VA Connecticut Healthcare System. METHODS: We performed a retrospective, cross-sectional data analysis of OEF/OIF veterans at VA Connecticut who received services in either Primary Care or the Women's Health Clinic between 2001 and 2006. RESULTS: In this study, 1129 electronic medical records (1032 men, 197 women) were examined. Female veterans were more likely to screen positive for MST (14% vs. 1%, p < 0.001) and depression (48% vs. 39%, p = 0.01) and less likely to screen positive for PTSD (21% vs. 33%, p = 0.002). There was no significant gender difference in clinically significant pain scores. Men were more likely than women to have body mass index (BMI) >30 kg/m(2) (21% vs. 13%, p = 0.008). CONCLUSIONS: These results suggest that important gender differences exist in the prevalence of positive screenings for MST, depression, obesity, and PTSD. As the VA continues to review and improve its services for women veterans, clinicians, researchers, and senior leaders should consider innovative ways to ensure that female veterans receive the health services they need within the VA system.
Erectile dysfunction drug receipt, risky sexual behavior and sexually transmitted diseases in HIV-infected and HIV-uninfected men
BACKGROUND: Health care providers may be concerned that prescribing erectile dysfunction drugs (EDD) will contribute to risky sexual behavior. OBJECTIVES: To identify characteristics of men who received EDD prescriptions, determine whether EDD receipt is associated with risky sexual behavior and sexually transmitted diseases (STDs), and determine whether these relationships vary for certain sub-groups. DESIGN: Cross-sectional study. PARTICIPANTS: Two thousand seven hundred and eighty-seven sexually-active, HIV-infected and HIV-uninfected men recruited from eight Veterans Health Affairs outpatient clinics. Data were obtained from participant surveys, electronic medical records, and administrative pharmacy data. MEASURES: EDD receipt was defined as two or more prescriptions for an EDD, risky sex as having unprotected sex with a partner of serodiscordant or unknown HIV status, and STDs, according to self-report. RESULTS: Overall, 28% of men received EDD in the previous year. Eleven percent of men reported unprotected sex with a serodiscordant/unknown partner in the past year (HIV-infected 15%, HIV-uninfected 6%, P < 0.001). Compared to men who did not receive EDD, men who received EDD were equally likely to report risky sexual behavior (11% vs. 10%, p = 0.9) and STDs (7% vs 7%, p = 0.7). In multivariate analyses, EDD receipt was not significantly associated with risky sexual behavior or STDs in the entire sample or in subgroups of substance users or men who had sex with men. CONCLUSION: EDD receipt was common but not associated with risky sexual behavior or STDs in this sample of HIV-infected and uninfected men. However, risky sexual behaviors persist in a minority of HIV-infected men, indicating ongoing need for prevention interventions.
Zoonotic diseases are infectious diseases transmittable between animals and humans and outbreaks of these diseases in animals can signify that humans are also infected (or vice versa). Thus, communication between animal and human health agencies is critical for surveillance. Understanding how these agencies conduct surveillance and share information is important for the development of successful automated zoonotic monitoring systems. Individual interviews were conducted with 13 professionals who perform animal or human zoonotic disease surveillance in one of the New England states. Questions centred on existing surveillance methods, collaborations between animal and human health agencies, and technological and data needs. The results showed that agencies routinely communicate over suspected zoonotic disease cases, yet there are barriers preventing automated electronic linking of health data of animals and humans. These include technological barriers and barriers due to sensitivity and confidentiality of information. Addressing these will facilitate the development of electronic systems for integrating animal and human zoonotic disease surveillance data.
BACKGROUND: Multiple factors, including patient characteristics, competing demands, and clinic type, impact delivery of depression treatment in primary care. OBJECTIVE: Assess whether depression severity and HIV serostatus have a differential effect on time to depression treatment among depressed patients receiving primary care at Infectious Disease or General Medicine clinics. DESIGN: Multicenter prospective cohort, (Veterans Aging Cohort Study), comparing HIV-infected to uninfected patients. PARTICIPANTS AND MEASURES: The total cohort consisted of 3,239 HIV-infected and 3,227 uninfected patients. Study inclusion criteria were untreated depressive symptoms, based on a Patient Health Questionnaire (PHQ-9) score of greater than 9, and no antidepressants or mental health visits in the 90 days prior to PHQ-9 assessment. Treatment was defined as antidepressant receipt or mental health visit within 90 days following PHQ-9 assessment. Depression severity based on PHQ-9 scores was defined as mild-moderate (greater than 9 to 19) and severe (20 or greater). Kaplan-Meier curves were used to estimate time to treatment by depression severity and HIV serostatus. Cox proportional hazards methods adjusted for covariates were used. KEY RESULTS: Overall, 718 (11%) of the cohort met inclusion criteria, 258 (36%) of whom received treatment. Median time to treatment was 7 days [95% confidence interval (CI) = 4, 13] and was shortest for severely depressed HIV-infected patients (0.5 days; 95% CI = 0.5, 6, p = 0.04). Compared to mildly-moderately depressed uninfected patients, severely depressed HIV-infected patients were significantly more likely to receive treatment [adjusted hazard ratio (HR) 1.67, 95% CI = 1.07, 2.60), whereas mildly-moderately depressed HIV-infected patients (adjusted HR 1.10, 95% CI = 0.79, 1.52) and severely depressed uninfected patients (adjusted HR 0.93, 95% CI = 0.60, 1.44) were not. CONCLUSIONS: In this large cohort, time to primary care treatment of depression was shortest among severely depressed HIV-infected patients. Regardless of HIV serostatus, if depression was not treated on the assessment day, then it was unlikely to be treated within a 90-day period, leading to the majority of depression being untreated.
A budget impact analysis of rapid human immunodeficiency virus screening in Veterans Administration emergency departments
BACKGROUND: Human immunodeficiency virus (HIV) screening is cost-effective and recommended in populations with low disease prevalence. However, because screening is not cost-saving, its financial feasibility must be understood. STUDY OBJECTIVES: We forecast the costs of two Emergency Department-based HIV testing programs in the Veterans Administration: 1) implementing a non-targeted screening program and providing treatment for all patients thusly identified (Rapid Testing); and 2) treating patients identified due to late-stage symptoms (Usual Care); to determine which program was the most financially feasible. METHODS: Using a dynamic decision-analysis model, we estimated the financial impact of each program over a 7-year period. Costs were driven by patient disease-severity at diagnosis, measured by CD4+ category, and the proportion of patients in each disease-severity category. Cost per CD4+ category was modeled from chart review and database analysis of treatment-naive HIV-positive patients. Distributions of CD4+ counts differed in patients across the Rapid Testing and Usual Care arms. RESULTS: A non-targeted Rapid Testing program was not significantly more costly than Usual Care. Although Rapid Testing had substantial screening costs, they were offset by lower inpatient expenses associated with earlier identification of disease. Assuming an HIV prevalence of 1% and 80% test acceptance, the cost of Rapid Testing was $1,418,088, vs. $1,320,338 for Usual Care (p=0.5854). Results support implementation of non-targeted rapid HIV screening in integrated systems. CONCLUSIONS: This analysis adds a new component of support for HIV screening by demonstrating that rapid, non-targeted testing does not cost significantly more than a diagnostic testing approach.
Comparison of outpatient health care utilization among returning women and men veterans from Afghanistan and Iraq
BACKGROUND: The number of women serving in the United States military increased during Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF), leading to a subsequent surge in new women Veterans seeking health care services from the Veterans Administration (VA). The objective of this study was to examine gender differences among OEF/OIF Veterans in utilization of VA outpatient health care services. METHODS: Our retrospective cohort consisted of 1,620 OEF/OIF Veterans (240 women and 1380 men) who enrolled for outpatient healthcare at a single VA facility. We collected demographic data and information on military service and VA utilization from VA electronic medical records. To assess gender differences we used two models: use versus nonuse of services (logistic regression) and intensity of use among users (negative binomial regression). RESULTS: In our sample, women were more likely to be younger, single, and non-white than men. Women were more likely to utilize outpatient care services (odds ratio [OR] = 1.47, 95% confidence interval [CI]:1.09, 1.98), but once care was initiated, frequency of visits over time (intensity) did not differ by gender (incident rate ratio [IRR] = 1.07; 95% CI: 0.90, 1.27). CONCLUSION: Recently discharged OEF/OIF women Veterans were more likely to seek VA health care than men Veterans. But the intensity of use was similar between women and men VA care users. As more women use VA health care, prospective studies exploring gender differences in types of services utilized, health outcomes, and factors associated with satisfaction will be required.
The burden of illness in the first year home: do male and female VA users differ in health conditions and healthcare utilization
BACKGROUND: we sought to describe gender differences in medical and mental health conditions and health care utilization among veterans who used Veterans Health Administration (VA) services in the first year after combat in Iraq and Afghanistan. METHODS: this is an observational study, using VA administrative and clinical data bases, of 163,812 Operation Enduring Freedom/Operation Iraqi Freedom veterans who had enrolled in VA and who had at least one visit within 1 year of last deployment. RESULTS: female veterans were slightly younger (mean age, 30 years vs. 32 for men; p <.0001), twice as likely to be African American (30% vs. 15%; p <.0001), and less likely to be married (32% vs. 49%; p < .0001). Women had more visits to primary care (2.6 vs. 2.0; p < .001) and mental health (4.0 vs. 3.6; p < .001) clinics and higher use of community care outside the VA (14% vs. 10%; p < .001). After adjustment for significant demographic differences, women were more likely to have musculoskeletal and skin disorders, mild depression, major depression, and adjustment disorders, whereas men were more likely to have ear disorders and posttraumatic stress disorder. Thirteen percent of women sought care for gynecologic examination, 10% for contraceptive counseling, and 7% for menstrual disorders. CONCLUSION: female veterans had similar rates of physical conditions, but higher rates of some mental health disorders and additionally, used the VA for reproductive health needs. They also had slightly greater rates of health care service use. These findings highlight the complexity of female Veteran health care and support the development of enhanced comprehensive women's health services within the VA.