Development of an improved blood-stage malaria vaccine targeting the essential RH5-CyRPA-RIPR invasion complex.

Reticulocyte-binding protein homologue 5 (RH5), a leading blood-stage Plasmodium falciparum malaria vaccine target, interacts with cysteine-rich protective antigen (CyRPA) and RH5-interacting protein (RIPR) to form an essential heterotrimeric "RCR-complex". We investigate whether RCR-complex vaccination can improve upon RH5 alone. Using monoclonal antibodies (mAbs) we show that parasite growth-inhibitory epitopes on each antigen are surface-exposed on the RCR-complex and that mAb pairs targeting different antigens can function additively or synergistically. However, immunisation of female rats with the RCR-complex fails to outperform RH5 alone due to immuno-dominance of RIPR coupled with inferior potency of anti-RIPR polyclonal IgG. We identify that all growth-inhibitory antibody epitopes of RIPR cluster within the C-terminal EGF-like domains and that a fusion of these domains to CyRPA, called "R78C", combined with RH5, improves the level of in vitro parasite growth inhibition compared to RH5 alone. These preclinical data justify the advancement of the RH5.1 + R78C/Matrix-M™ vaccine candidate to Phase 1 clinical trial.

Human Basigin (CD147) Does Not Directly Interact with SARS-CoV-2 Spike Glycoprotein.

Basigin, or CD147, has been reported as a coreceptor used by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to invade host cells. Basigin also has a well-established role in Plasmodium falciparum malaria infection of human erythrocytes, where it is bound by one of the parasite's invasion ligands, reticulocyte binding protein homolog 5 (RH5). Here, we sought to validate the claim that the receptor binding domain (RBD) of SARS-CoV-2 spike glycoprotein can form a complex with basigin, using RH5-basigin as a positive control. Using recombinantly expressed proteins, size exclusion chromatography and surface plasmon resonance, we show that neither RBD nor full-length spike glycoprotein bind to recombinant human basigin (expressed in either Escherichia coli or mammalian cells). Further, polyclonal anti-basigin IgG did not block SARS-CoV-2 infection of Vero E6 cells. Given the immense interest in SARS-CoV-2 therapeutic targets to improve treatment options for those who become seriously ill with coronavirus disease 2019 (COVID-19), we would caution the inclusion of basigin in this list on the basis of its reported direct interaction with SARS-CoV-2 spike glycoprotein. IMPORTANCE Reducing the mortality and morbidity associated with COVID-19 remains a global health priority. Vaccines have proven highly effective at preventing infection and hospitalization, but efforts must continue to improve treatment options for those who still become seriously ill. Critical to these efforts is the identification of host factors that are essential to viral entry and replication. Basigin, or CD147, was previously identified as a possible therapeutic target based on the observation that it may act as a coreceptor for SARS-CoV-2, binding to the receptor binding domain of the spike protein. Here, we show that there is no direct interaction between the RBD and basigin, casting doubt on its role as a coreceptor and plausibility as a therapeutic target.

At the birth of pediatric anesthesia in Mexico: An interview with Dr. Estela Melman, a pioneering woman in medicine.

Dr. Estela Melman (1939-present), Professor in the Department of Anesthesiology, the American British Cowdray Medical Center, Mexico, is an influential pioneer who has shaped the scope and practice of pediatric anesthesia in Mexico and throughout the world. Her early work to reintroduce neural blockade into routine pediatric anesthetic care, particularly the caudal approach to the epidural space, helped to transform current anesthesia practice. Based on a series of interviews held with Dr. Melman between 2016 and 2017, this article reviews the remarkable career of a pioneering pediatric anesthesiologist.

Extension of overall survival beyond objective responses in patients with metastatic renal cell carcinoma treated with high-dose interleukin-2.

PURPOSE: In metastatic renal cell carcinoma (mRCC), survival benefit associated with objective response rates of 16-20 % with high-dose interleukin-2 (HDIL-2) is well established and discussed. Based on recently emerged data on efficacy of cancer immunotherapy, we hypothesized that the survival benefit with HDIL-2 extends beyond those achieving objective responses, i.e., to those who achieve stable disease as the best response to treatment. MATERIALS AND METHODS: All sequential treatment naïve mRCC patients treated with HDIL-2 at the University of Utah (1988-2013) and University of Michigan (1997-2013) were included. Best responses on treatment were associated with survival outcomes using log-rank and COX regression with a landmark analysis at 2 months. RESULTS: 391 patients (75 % male; median age 55 years) were included and belonged to the following prognostic risk categories: 20 % good, 64 % intermediate, and 15 % poor. Best responses on treatment were complete response (9 %), partial response (10 %), stable disease (32 %), progressive disease (42 %), and not evaluable for response (7 %). No significant differences in progression-free survival (HR 0.74, 95 % CI 0.48-1.1, p = 0.14) or overall survival (HR 0.66, 95 % CI 0.39-1.09, p = 0.11) were observed between patients achieving partial response versus stable disease. Significant differences in progression-free survival (HR 0.13, 95 % CI 0.09-0.22, p < 0.0001) and overall survival (HR 0.33, 95 % CI 0.23-0.48, p < 0.0001) were observed between patients achieving stable disease compared to those with progressive disease and who were not evaluable. CONCLUSIONS: Survival benefit with HDIL-2 is achieved in ~50 % patients and extends beyond those achieving objective responses.

Assessing the role of alternative response rates and reinforcer rates in resistance to extinction of target responding when combining stimuli.

Studies of behavioral momentum reveal that reinforcing an alternative response in the presence of a target response reduces the rate of target responding but increases its persistence, relative to training the target response on its own. Because of the parallels between these studies and differential-reinforcement techniques to reduce problem behavior in clinical settings, alternative techniques to reduce problem behavior without enhancing its persistence are being explored. One potential solution is to train an alternative response in a separate stimulus context from problem behavior before combining the alternative stimulus with the target stimulus. The present study assessed how differences in reinforcement contingencies and rate for alternative responding influenced resistance to extinction of target responding when combining alternative and target stimuli in pigeons. Across three experiments, alternative stimuli signaling a response-reinforcer dependency and greater reinforcer rates more effectively decreased the persistence of target responding when combining alternative and target stimuli within the same extinction tests, but not when compared across separate extinction tests. Overall, these findings reveal that differences in competition between alternative and target responding produced by contingencies of alternative reinforcement could influence the effectiveness of treating problem behavior through combining stimulus contexts.

Prophage induction is enhanced and required for renal disease and lethality in an EHEC mouse model.

Enterohemorrhagic Escherichia coli (EHEC), particularly serotype O157:H7, causes hemorrhagic colitis, hemolytic uremic syndrome, and even death. In vitro studies showed that Shiga toxin 2 (Stx2), the primary virulence factor expressed by EDL933 (an O157:H7 strain), is encoded by the 933W prophage. And the bacterial subpopulation in which the 933W prophage is induced is the producer of Stx2. Using the germ-free mouse, we show the essential role 933W induction plays in the virulence of EDL933 infection. An EDL933 derivative with a single mutation in its 933W prophage, resulting specifically in that phage being uninducible, colonizes the intestines, but fails to cause any of the pathological changes seen with the parent strain. Hence, induction of the 933W prophage is the primary event leading to disease from EDL933 infection. We constructed a derivative of EDL933, SIVET, with a biosensor that specifically measures induction of the 933W prophage. Using this biosensor to measure 933W induction in germ-free mice, we found an increase three logs greater than was expected from in vitro results. Since the induced population produces and releases Stx2, this result indicates that an activity in the intestine increases Stx2 production.

Archaeal intrinsic transcription termination in vivo.

Thermococcus kodakarensis (formerly Thermococcus kodakaraensis) strains have been constructed with synthetic and natural DNA sequences, predicted to function as archaeal transcription terminators, identically positioned between a constitutive promoter and a beta-glycosidase-encoding reporter gene (TK1761). Expression of the reporter gene was almost fully inhibited by the upstream presence of 5'-TTTTTTTT (T(8)) and was reduced >70% by archaeal intergenic sequences that contained oligo(T) sequences. An archaeal intergenic sequence (t(mcrA)) that conforms to the bacterial intrinsic terminator motif reduced TK1761 expression approximately 90%, but this required only the oligo(T) trail sequence and not the inverted-repeat and loop region. Template DNAs were amplified from each T. kodakarensis strain, and transcription in vitro by T. kodakarensis RNA polymerase was terminated by sequences that reduced TK1761 expression in vivo. Termination occurred at additional sites on these linear templates, including at a 5'-AAAAAAAA (A(8)) sequence that did not reduce TK1761 expression in vivo. When these sequences were transcribed on supercoiled plasmid templates, termination occurred almost exclusively at oligo(T) sequences. The results provide the first in vivo experimental evidence for intrinsic termination of archaeal transcription and confirm that archaeal transcription termination is stimulated by oligo(T) sequences and is different from the RNA hairpin-dependent mechanism established for intrinsic bacterial termination.

Health status among 28,000 women veterans. The VA Women's Health Program Evaluation Project.

BACKGROUND: Male veterans receiving Veterans Health Administration (VA) care have worse health than men in the general population. Less is known about health status in women veteran VA patients, a rapidly growing population. OBJECTIVE: To characterize health status of women (vs men) veteran VA patients across age cohorts, and assess gender differences in the effect of social support upon health status. DESIGN AND PATIENTS: Data came from the national 1999 Large Health Survey of Veteran Enrollees (response rate 63%) and included 28,048 women and 651,811 men who used VA in the prior 3 years. MEASUREMENTS: Dimensions of health status from validated Veterans Short Form-36 instrument; social support (married, living arrangement, have someone to take patient to the doctor). RESULTS: In each age stratum (18 to 44, 45 to 64, and > or =65 years), Physical Component Summary (PCS) and Mental Component Summary (MCS) scores were clinically comparable by gender, except that for those aged > or =65, mean MCS was better for women than men (49.3 vs 45.9, P<.001). Patient gender had a clinically insignificant effect upon PCS and MCS after adjusting for age, race/ethnicity, and education. Women had lower levels of social support than men; in patients aged <65, being married or living with someone benefited MCS more in men than in women. CONCLUSIONS: Women veteran VA patients have as heavy a burden of physical and mental illness as do men in VA, and are expected to require comparable intensity of health care services. Their ill health occurs in the context of poor social support, and varies by age.

Applications of methodologies of the Veterans Health Study in the VA healthcare system: conclusions and summary.

The Veterans Health Study (VHS) had as its overarching goal the development, testing, and application of patient-centered assessments for monitoring patient outcomes in ambulatory care in large integrated care systems such as the Department of Veterans Affairs (VA). Unlike other previous studies, the VHS has capitalized on rich administrative databases restricted to the VA and linked to patient-centered outcomes. The VHS has developed a comprehensive set of general and disease-specific measures for use by systems of care for ambulatory patients. Chief among these assessments is the Veterans SF-36 Health Survey for measuring health-related quality of life in veteran ambulatory populations. The Veterans SF-36 Health Survey provides the cornerstone for this study and historically has been extensively disseminated and used in the VA with close to 2 million administrations nationally as part of its quality management system. National surveys administered by the VA since 1996 using the Veterans SF-36 Health Survey indicate important regional differences with implications for varying resource needs. Based upon the rich foundation provided by the VHS methodology, the VA has implemented some of these approaches as part of its quality monitoring system and can serve as a model for other large integrated systems of care.

The illness burden of alcohol-related disorders among VA patients: the veterans health study.

Little is known about the illness burden associated with alcohol-related disorders (ie, problem drinking, alcohol abuse, and alcohol dependence) among patients in outpatient medical care. The objective of this study was to examine several aspects of illness burden-medical comorbidities, patterns of health services use, and functional status-among Veterans Health Administration (VA) ambulatory care patients with alcohol-related disorders. Male participants (N = 2425) were recruited at 1 of 4 Boston-area VA outpatient clinics. They completed self-report screening measures of current alcohol-related disorders (CAGE score > or =2 with past year alcohol consumption), health behaviors, medical comorbidities, and functional status (SF-36). A medical history interview, which assessed comorbid conditions and use of recent health services, was also administered. Screening criteria for current alcohol-related disorders were satisfied by 12%; however, only 40% of these reported ever receiving treatment specifically for alcohol-related disorders. Patients who screened positive for alcohol-related disorders reported significantly greater limitations in mental health function, longer hospitalizations for medical care in the prior year, and fewer outpatient medical visits in the previous 3 months. Findings suggest considerable illness burden associated with alcohol-related disorders among VA ambulatory care patients. Efforts to increase detection and treatment of alcohol-related disorders may lessen the illness burden and cost of alcohol-related disorders.

Disparities in diabetes care: impact of mental illness.

BACKGROUND: Emerging evidence indicates that patients with mental health conditions (MHCs) may receive less intensive medical care. Diabetes serves as a useful condition in which to test for MHC-related disparities in care. We examined whether quality measures for diabetes care are worse for patients with or without MHCs. METHODS: This national, cross-sectional study included 313 586 noninstitutionalized Veterans Health Administration patients with diabetes (identified from diagnostic codes and prescriptions) whose Veterans Health Administration facility transmitted laboratory data to a central database; 76 799 (25%) had MHCs (based on diagnostic codes for depressed mood, anxiety, psychosis, manic symptoms, substance use disorders, personality disorders, and other categories). National data from Veterans Health Administration records, Medicare claims, and a national survey were linked to characterize 1999 diabetes care. RESULTS: Failure to meet diabetes performance measures was more common in patients with MHCs: unadjusted odds ratio (95% confidence interval) was 1.24 (1.22-1.27) for no hemoglobin A(1c) testing, 1.25 (1.23-1.28) for no low-density lipoprotein cholesterol testing, 1.05 (1.03-1.07) for no eye examination, 1.32 (1.30-1.35) for poor glycemic control, and 1.17 (1.15-1.20) for poor lipemic control. Disparities persisted after case mix adjustment and were more pronounced with specific MHCs (psychotic, manic, substance use, and personality disorders). The percentage not meeting diabetes care standards increased with increasing number of MHCs. CONCLUSION: Patients with mental illness merit special attention in national diabetes quality improvement efforts.

Concordance between respondent self-reports and medical records for chronic conditions: experience from the Veterans Health Study.

Researchers have frequently relied on case identification using clinician-based screening as the standard. This study evaluates a self-administered screening questionnaire developed for use in the Veterans Health Study. We compared concordance between elderly patients' reports of selected chronic illnesses and the medical record. The purpose of this study was to determine the feasibility of using a self-report screening questionnaire for case identification in an outcomes study of elderly respondents. Reports of the presence of selected chronic illnesses were compared in a sample of patients (N=402) receiving outpatient care between 2 data sources, patient self-report and medical record, to determine overall concordance in 5 common chronic conditions (hypertension, adult-onset diabetes mellitus, chronic low-back pain, osteoarthritis of the knee, and chronic lung disease). Discordance between the 2 data sources varied by condition. Differences in reporting were small for diabetes and hypertension, intermediate for chronic lung disease, and larger for osteoarthritis of the knee and chronic low-back pain, where the chart did not identify substantial proportions of cases reported in the questionnaire. Use of patient-reported screening questionnaires, which are self-administered, is a valid, cost-efficient method to identify some chronic illnesses. Using medical records alone may result in underestimation of some symptom-based conditions.

The influence of place of administration on health-related quality-of-life assessments: findings from the Veterans Health Study.

Patient-based assessments of functional status and well-being, such as the short form survey (SF-36) developed in the Medical Outcomes Study, are increasingly used to monitor patient health status and the effects of medical care. Although they have been used in many populations under a variety of circumstances, little is known about how environmental factors, such as place of administration, influence patients' responses. We administered the SF-36 as part of comprehensive quality-of-life assessments to 304 participants in the pilot phase of the Veterans Health Study, a large observational study of health outcomes in VA ambulatory care. SF-36 questionnaires were self-administered twice by patients, once at home and again as part of an interview in a clinic setting. For most participants, less than a week passed between the 2 administrations. Scores from these questionnaires were compared as a measure of reliability and of the possible influence of place of administration. Questionnaires self-administered at the time of the interview yielded mean scores that were significantly (P<.05) higher across all 8 SF-36 scales (physical function, role function with physical and emotional limitations, vitality, bodily pain, social function, mental health, general health perceptions) and both the physical and mental component summary scales. With scores scaled from 0 to 100, differences ranged from 2.1 (bodily pain) to 5.7 (role limitations due to emotional problems). Mean physical function was 56.8 at the time of the interview, and 52.4 at home. Higher scores from questionnaires administered at interview outnumbered lower scores by 3 to 2 for most scales. These differences remained even after restricting the sample to those with the highest cognitive function scores and the shortest interval between administrations. Because selection factors and order of administration could not be completely dismissed, a large number of other administrative, clinical, and sociodemographic factors were examined, which, however, failed to provide adequate explanation for these differences. Careful consideration should be given concerning the physical and social environment in the administration of health-related quality-of-life assessments. Findings from this study suggest that more favorable measures of self-reported functional status and well-being may be expected from clinic administrations of instruments.

Utilization of medical services by Veterans Health Study (VHS) respondents.

The first objective of this study was to profile Veterans Health Study (VHS) respondents' use of medical services-the types of services used, use of a regular source of care, and the propensity to use services for selected symptoms. We focused on differential use of VA and non-VA services and highlighted differences in use by age group. The second objective was to use multivariate analysis to identify factors associated with respondents' use of any medical services and with VA services specifically. We incorporated 2 self-reported variables not used in previous studies of VA utilization-health status and disease burden. Patients receiving ambulatory care services in 4 VA ambulatory outpatient clinics in the greater Boston area were eligible for inclusion in the VHS. A sample of 2425 community-dwelling male veterans was randomly selected from among veterans receiving ambulatory services at Boston-area VA facilities. This analysis focuses on 1909 respondents for whom we had complete data. Interviews and questionnaires were used to collect cross-sectional, observational data on sociodemographic, economic, and clinical characteristics; health status; disease burden; and service-connected disability (SCD) rating. To measure health status, we used 2 summary measures, the Physical Component Summary (PCS) and the Mental Component Summary (MCS), derived from the 8 scales of the Medical Outcomes Study Short Form 36-item Health Survey (MOS SF-36). To measure disease burden, we used the Physical Comorbidity Index (PHYCI) and Mental Comorbidity Index (MENCI), composed of 30 physical and 6 mental health conditions and symptoms, respectively. Information on the availability of non-VA insurance was obtained from administrative VA files. Information on utilization prior to the interview was self-reported. Recall periods of 3 and 12 months were used for ambulatory and inpatient services, respectively. We used descriptive statistics to profile respondents and their utilization patterns. We used multivariate probit models to identify respondent characteristics associated with use of any medical services, medical visits, mental health visits, and hospital stays. Independent variables used in the models were socioeconomic and demographic characteristics, and measures of disease burden, health status, and VA eligibility. The respondents relied heavily on the VA for medical care: 74% of the respondents said the VA was their regular source of care; 72% of all the respondents and 87% of those who had used any medical service in the recall period had used a VA service; 68% of those who were hospitalized used a VA hospital; and 76% of the medical care the respondents received and 60% of their hospital stays were in VA facilities. Younger veterans (aged 22-44) used substantially more mental health services than older respondents, but they were less likely than older veterans to have seen a doctor recently for most of the medical symptoms studied. PHYCI and PCS were significantly related to use of any medical services and to use of inpatient services; MENCI and MCS were significantly related to use of mental health services (P<.05 for each, respectively). Lower income and lack of alternatives to VA care were directly related to use of any VA services and VA inpatient services. Information on the reasons for differential use of VA and non-VA services can be useful to the VA as it serves an aging veteran population, seeks to provide comprehensive care to a wider spectrum of veterans, and moves into a more competitive healthcare marketplace.

Preliminary validation of a patient-based self-assessment measure of severity of illness in type 2 diabetes: results from the pilot phase of the Veterans Health Study.

Measures of case mix are needed to control for patients' clinical status in studies assessing the process and outcomes of care. The Veterans Health Study (VHS) is a longitudinal study of determinants of health outcomes in ambulatory veterans. This study assessed the validity of a case-mix measure developed to quantify severity of illness in ambulatory type 2 diabetic patients. As part of the pilot phase of the VHS, 245 veterans using 4 primary care clinics in Boston were screened for diabetes and 5 other chronic illnesses when they presented for care. Subjects screening positive for diabetes returned to complete severity of illness and outcome measures. The variables for the diabetes case-mix module were chosen based upon the principles of parsimony, duration of follow-up, and clinical validity and credibility. Variables were selected to predict function, as measured by the Medical Outcomes Study Short-Form 36 (SF-36). The diabetic patients in this study had a heavy burden of chronic illness, with an average of 3.9 comorbid conditions and a mean general health perceptions score of 48 on the SF-36 (scored from 0 to 100, with 100 indicating best health). A summary variable called DMSEV was created for "diabetes severity". This included atherosclerotic complications(stroke, transient ischemic attack or myocardial infarction; chest pain frequency; and claudication), plus any history of eye, foot, or neuropathic symptoms. DMSEV correlated with all 8 outcome scales of the SF-36, and in particular was highly associated with physical function (r=0.49, P=.0001). Least squares linear regression analysis controlling for age and comorbidity confirmed the association of DMSEV with all 8 SF-36 scales. The correlation with physical function remained highly significant (P<.0001), with an R of 0.31. This patient-based self-assessment questionnaire and the summary variable DMSEV appear to be valid measures of severity of illness in ambulatory diabetic veterans with multiple comorbidities. After further testing, this case-mix measure may be suitable for controlling for severity of illness in ambulatory-based studies of diabetic patients with multiple chronic illnesses.

Patient-based measures of illness severity in the Veterans Health Study.

The Veterans Health Study (VHS) was designed to produce patient-based measures of health status suitable for monitoring the health of men served by the Veterans Health Administration. This article summarizes the objectives, conceptual framework, and results of 6 substudies of the VHS that were designed to develop disease-focused measures of illness severity, that is, patient-perceived, clinically significant manifestations of disease processes that are associated with decrements in health-related quality of life. Developmental psychometric studies used cross-sectional survey data from the baseline comprehensive evaluations conducted in the VHS. Patients who screened positive for the 6 study medical conditions in the VHS (osteoarthritis of the knee, n = 511; type 2 diabetes, n = 425; chronic lung disease, n = 352; hypertension, n = 996; chronic low-back pain, n = 574; and alcohol-related disorder, n = 175) were administered structured interview modules that assessed symptoms and complications of these chronic diseases. Psychometric analyses were conducted to identify internally coherent and reliable indices, which were validated with respect to their correlations with measures of health-related quality of life (eg, Short Form-36) and the utilization of health services. We constructed 6 indices of illness severity. The severities of osteoarthritis of the knee and chronic lung disease were defined by brief (12 and 6 items, respectively) assessments of symptoms (eg, knee pain and dyspnea). Since diabetes and hypertension are largely asymptomatic, illness severity for these conditions was assessed by ascertaining complications such as angina and vascular disorders. Alcohol-related disorder, which involves both behavioral symptoms and physical complications, was assessed by separate scales for these 2 dimensions of its severity. Chronic low-back pain required a unique solution. Rather than assessing the intensity of back pain, it is more productive to construct a measure that focuses on manifestations of radiculopathy, that is, whether back pain radiated down the leg to below the knee. The 5 symptoms or complication indices and the assessment of radiculopathy in chronic low-back pain were significantly correlated with Short Form-36 scores and intensity of recent use of health services. The 6 measures may complement measures of health-related quality of life in providing more comprehensive assessments of health status in Veterans Affairs patients.

Comparing the health status of VA and non-VA ambulatory patients: the veterans' health and medical outcomes studies.

The purpose of this study was to compare health status and disease profiles of ambulatory patients in specific Veterans Administration (VA) and civilian healthcare settings. A random sample of 2425 male veterans seeking care at 4 Boston-area VA outpatient clinics, who took part in the Veterans Health Study (VHS) in 1993-1995, were compared to 1318 male patients seeking civilian outpatient care in 3 major metropolitan areas covered in the Medical Outcomes Study (MOS) in 1986. The MOS sampled patients who had 1 of 5 conditions--hypertension, noninsulin-dependent diabetes, recent myocardial infarction, congestive heart failure, or depression. These 2 samples were age adjusted and compared in terms of the SF-36 Health Status/Quality of Life measures, and a list of 100 clinical variables (diagnostic, symptom, and medical event reports) collected with comparable instruments by a trained clinical observer. Individual odds ratios (VHS to MOS) were calculated for each measure and clinical variables. SF-36 measures of patient health in the VHS were lower than those in the MOS by more than one half of a standard deviation (SD) on 4 of 8 scales, by more than one quarter of a SD on the other 4, by 58% of a SD on the physical health summary scale, and by 37% of a SD on the mental health summary scale (P < .0001 in all cases). The median odds ratio was 2.2 among the SF-36 scales and 1.9 among clinical variables. Outpatients in the 4 VA clinics had more than twice the illness burden than did patients in the MOS. Current economic condition and service-connected disability explain most, if not all, of the differences. The differences were clinically and socially meaningful and would be consistent with substantially higher expected healthcare use.

Comorbidity assessments based on patient report: results from the Veterans Health Study.

The objective of the study was to develop a self-reported measure of patients' comorbid illnesses that could be readily administered in ambulatory care settings and that would improve assessment of their health-related quality of life and utilization of health services. Data were analyzed from the Veterans Health Study, an observational study of health outcomes in patients receiving Veterans Administration (VA) ambulatory care. Patients who received ambulatory care services in 4 VA outpatient clinics in the greater Boston area between August 1993 and March 1996 were eligible for inclusion. Among the 4137 patients recruited, 2425 participated in the Veterans Health Study, representing a response rate of 59%. Participants were mailed a health-related quality of life questionnaire, the Medical Outcomes Study Short Form Health Survey (SF-36). They were also scheduled for an in-person interview at which time they completed a medical history questionnaire. We developed a comorbidity index (CI) that included 30 self-reported medical conditions (physical CI) and 6 self-reported mental conditions (mental CI). The physical CI and the mental CI were significantly associated with all SF-36 scales and explained 24% and 36%, respectively, of the variance in the physical component summary and the mental component summary of the SF-36. Both indexes were also significant predictors of future outpatient visits and mortality. The CI is an independent predictor of health status, outpatient visits, and mortality. Its use appears to be a practical approach to case-mix adjustment to account for differences in comorbid illnesses in observational studies of the quality of healthcare. It can be administered to large patient populations at relatively low cost. This method may be particularly valuable for clinicians and researchers interested in population-based studies, case-mix adjustment, and clinical trials.

Improving the response choices on the veterans SF-36 health survey role functioning scales: results from the Veterans Health Study.

Role functioning and its limitations due to one's health is an important aspect of health-related quality of life (HRQoL). The Medical Outcomes Study (MOS) SF-36 includes 2 role functioning scales: role limitations due to physical health problems (RP) or emotional problems (RE). Although they capture important concepts of HRQoL, these 2 scales have some limitations in their measurement properties. Using dichotomized sets of response choices, the scales are limited in their distributional properties (eg, higher standard deviation than other SF-36 scales) and ability to discriminate between clinically relevant groups. In this study, we ascertain the improvements to these 2 scales using 5-point ordinal response choices for each of the scale items. Two thousand one hundred sixty-two patients from the Veterans Health Study (VHS), an observational study of health outcomes in patients receiving ambulatory care, completed a health status questionnaire and a medical history. The health questionnaire included (1) the MOS SF-36, in which the RP and RE items used dichotomized yes/no responses; and (2) a set of modified RP and RE items that used 5-response choices for each of the items, ranging from "no, none of the time" to "yes, all of the time." We compared the original and modified RP and RE scales using internal consistency reliability and factor analysis. We tested item convergent and discriminant validity using multitrait scaling, and scale discriminant validity using ordinary least squares regression. Results indicate that the modifications to the original RP and RE scales accomplish important gains in the distributional properties of the scales. The floor and ceiling effects of the 2 scales have been reduced and the reliability of the RP scale has increased (0.87-0.95). Factor analysis and multitrait scaling tests indicate that the modified items have the same interpretation as the original items. Tests of discriminant validity indicate that the modified RP and RE scales have greater explanatory power for measures of disease burden, depression, and disease severity. The modified SF-36 role scales are clearly superior to the original versions. The modifications have increased the explained variability, suggesting greater explanatory power and more information obtained by the role functioning measures. The modified RP and RE are capturing a wider spectrum of disease severity, in part due to the lowering of the floor and raising of the ceiling of the scales. Additional work needs to test these improvements in other populations and to expand the analysis to track the responsiveness of the modified scales to clinically and socially important changes over time.

Burden of medical illness in women with depression and posttraumatic stress disorder.

BACKGROUND: Depression and posttraumatic stress disorder (PTSD) are important women's health issues. Depression is known to be associated with poor physical health; however, associations between physical health and PTSD, a common comorbidity of depression, have received less attention. OBJECTIVES: To examine number of medical symptoms and physical health status in women with PTSD across age strata and benchmark them against those of women with depression alone or with neither depression nor PTSD. METHODS: A random sample of Veterans Health Administration enrollees received a mailed survey in 1999-2000 (response rate, 63%). The 30 865 women respondents were categorized according to whether a health care provider had ever told them that they had PTSD, depression (without PTSD), or neither. Outcomes were self-reported medical conditions and physical health status measured with the Veterans SF-36 instrument, a version of the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) modified for use in veteran populations. RESULTS: Across age strata, women with PTSD (n = 4348) had more medical conditions and worse physical health status (physical functioning, role limitations due to physical problems, bodily pain, and energy/vitality scales from the Veterans SF-36) than women with depression alone (n = 7580) or neither (n = 18 937). In age-adjusted analyses, the Physical Component Summary score was on average 3.4 points lower in women with depression alone and 6.3 points lower in women with PTSD than in women with neither (P<.001). CONCLUSIONS: Posttraumatic stress disorder is associated with a greater burden of medical illness than is seen with depression alone. The presence of PTSD may account for an important component of the excess medical morbidity and functional status limitations seen in women with depression.