Does higher hospital cost imply higher quality of care?

This study investigates whether higher input use per stay in the hospital (treatment intensity) and longer length of stay improve outcomes of care. We allow for endogeneity of intensity and length of stay by estimating a quasi-maximum-likelihood discrete factor model, where the distribution of the unmeasured variable is modeled using a discrete distribution. Data on elderly persons come from several waves of the National Long-Term Care Survey merged with Medicare claims data for 1984-1995 and the National Death Index. We find that higher intensity improves patient survival and some dimensions of functional status among those who survive.

The impact of shame on health-related quality of life among HIV-positive adults with a history of childhood sexual abuse.

Childhood sexual abuse is prevalent among people living with HIV, and the experience of shame is a common consequence of childhood sexual abuse and HIV infection. This study examined the role of shame in health-related quality of life among HIV-positive adults who have experienced childhood sexual abuse. Data from 247 HIV-infected adults with a history of childhood sexual abuse were analyzed. Hierarchical linear regression was conducted to assess the impact of shame regarding both sexual abuse and HIV infection, while controlling for demographic, clinical, and psychosocial factors. In bivariate analyses, shame regarding sexual abuse and HIV infection were each negatively associated with health-related quality of life and its components (physical well-being, function and global well-being, emotional and social well-being, and cognitive functioning). After controlling for demographic, clinical, and psychosocial factors, HIV-related, but not sexual abuse-related, shame remained a significant predictor of reduced health-related quality of life, explaining up to 10% of the variance in multivariable models for overall health-related quality of life, emotional, function and global, and social well-being and cognitive functioning over and above that of other variables entered into the model. Additionally, HIV symptoms, perceived stress, and perceived availability of social support were associated with health-related quality of life in multivariable models. Shame is an important and modifiable predictor of health-related quality of life in HIV-positive populations, and medical and mental health providers serving HIV-infected populations should be aware of the importance of shame and its impact on the well-being of their patients.

Micro-Anatomical Quantitative Imaging Towards Enabling Automated Diagnosis of Thick Tissues at the Point of Care

Histopathology is the clinical standard for tissue diagnosis. However, histopathology has several limitations including that it requires tissue processing, which can take 30 minutes or more, and requires a highly trained pathologist to diagnose the tissue. Additionally, the diagnosis is qualitative, and the lack of quantitation leads to possible observer-specific diagnosis. Taken together, it is difficult to diagnose tissue at the point of care using histopathology.

Several clinical situations could benefit from more rapid and automated histological processing, which could reduce the time and the number of steps required between obtaining a fresh tissue specimen and rendering a diagnosis. For example, there is need for rapid detection of residual cancer on the surface of tumor resection specimens during excisional surgeries, which is known as intraoperative tumor margin assessment. Additionally, rapid assessment of biopsy specimens at the point-of-care could enable clinicians to confirm that a suspicious lesion is successfully sampled, thus preventing an unnecessary repeat biopsy procedure. Rapid and low cost histological processing could also be potentially useful in settings lacking the human resources and equipment necessary to perform standard histologic assessment. Lastly, automated interpretation of tissue samples could potentially reduce inter-observer error, particularly in the diagnosis of borderline lesions.

To address these needs, high quality microscopic images of the tissue must be obtained in rapid timeframes, in order for a pathologic assessment to be useful for guiding the intervention. Optical microscopy is a powerful technique to obtain high-resolution images of tissue morphology in real-time at the point of care, without the need for tissue processing. In particular, a number of groups have combined fluorescence microscopy with vital fluorescent stains to visualize micro-anatomical features of thick (i.e. unsectioned or unprocessed) tissue. However, robust methods for segmentation and quantitative analysis of heterogeneous images are essential to enable automated diagnosis. Thus, the goal of this work was to obtain high resolution imaging of tissue morphology through employing fluorescence microscopy and vital fluorescent stains and to develop a quantitative strategy to segment and quantify tissue features in heterogeneous images, such as nuclei and the surrounding stroma, which will enable automated diagnosis of thick tissues.

To achieve these goals, three specific aims were proposed. The first aim was to develop an image processing method that can differentiate nuclei from background tissue heterogeneity and enable automated diagnosis of thick tissue at the point of care. A computational technique called sparse component analysis (SCA) was adapted to isolate features of interest, such as nuclei, from the background. SCA has been used previously in the image processing community for image compression, enhancement, and restoration, but has never been applied to separate distinct tissue types in a heterogeneous image. In combination with a high resolution fluorescence microendoscope (HRME) and a contrast agent acriflavine, the utility of this technique was demonstrated through imaging preclinical sarcoma tumor margins. Acriflavine localizes to the nuclei of cells where it reversibly associates with RNA and DNA. Additionally, acriflavine shows some affinity for collagen and muscle. SCA was adapted to isolate acriflavine positive features or APFs (which correspond to RNA and DNA) from background tissue heterogeneity. The circle transform (CT) was applied to the SCA output to quantify the size and density of overlapping APFs. The sensitivity of the SCA+CT approach to variations in APF size, density and background heterogeneity was demonstrated through simulations. Specifically, SCA+CT achieved the lowest errors for higher contrast ratios and larger APF sizes. When applied to tissue images of excised sarcoma margins, SCA+CT correctly isolated APFs and showed consistently increased density in tumor and tumor + muscle images compared to images containing muscle. Next, variables were quantified from images of resected primary sarcomas and used to optimize a multivariate model. The sensitivity and specificity for differentiating positive from negative ex vivo resected tumor margins was 82% and 75%. The utility of this approach was further tested by imaging the in vivo tumor cavities from 34 mice after resection of a sarcoma with local recurrence as a bench mark. When applied prospectively to images from the tumor cavity, the sensitivity and specificity for differentiating local recurrence was 78% and 82%. The results indicate that SCA+CT can accurately delineate APFs in heterogeneous tissue, which is essential to enable automated and rapid surveillance of tissue pathology.

Two primary challenges were identified in the work in aim 1. First, while SCA can be used to isolate features, such as APFs, from heterogeneous images, its performance is limited by the contrast between APFs and the background. Second, while it is feasible to create mosaics by scanning a sarcoma tumor bed in a mouse, which is on the order of 3-7 mm in any one dimension, it is not feasible to evaluate an entire human surgical margin. Thus, improvements to the microscopic imaging system were made to (1) improve image contrast through rejecting out-of-focus background fluorescence and to (2) increase the field of view (FOV) while maintaining the sub-cellular resolution needed for delineation of nuclei. To address these challenges, a technique called structured illumination microscopy (SIM) was employed in which the entire FOV is illuminated with a defined spatial pattern rather than scanning a focal spot, such as in confocal microscopy.

Thus, the second aim was to improve image contrast and increase the FOV through employing wide-field, non-contact structured illumination microscopy and optimize the segmentation algorithm for new imaging modality. Both image contrast and FOV were increased through the development of a wide-field fluorescence SIM system. Clear improvement in image contrast was seen in structured illumination images compared to uniform illumination images. Additionally, the FOV is over 13X larger than the fluorescence microendoscope used in aim 1. Initial segmentation results of SIM images revealed that SCA is unable to segment large numbers of APFs in the tumor images. Because the FOV of the SIM system is over 13X larger than the FOV of the fluorescence microendoscope, dense collections of APFs commonly seen in tumor images could no longer be sparsely represented, and the fundamental sparsity assumption associated with SCA was no longer met. Thus, an algorithm called maximally stable extremal regions (MSER) was investigated as an alternative approach for APF segmentation in SIM images. MSER was able to accurately segment large numbers of APFs in SIM images of tumor tissue. In addition to optimizing MSER for SIM image segmentation, an optimal frequency of the illumination pattern used in SIM was carefully selected because the image signal to noise ratio (SNR) is dependent on the grid frequency. A grid frequency of 31.7 mm-1 led to the highest SNR and lowest percent error associated with MSER segmentation.

Once MSER was optimized for SIM image segmentation and the optimal grid frequency was selected, a quantitative model was developed to diagnose mouse sarcoma tumor margins that were imaged ex vivo with SIM. Tumor margins were stained with acridine orange (AO) in aim 2 because AO was found to stain the sarcoma tissue more brightly than acriflavine. Both acriflavine and AO are intravital dyes, which have been shown to stain nuclei, skeletal muscle, and collagenous stroma. A tissue-type classification model was developed to differentiate localized regions (75x75 µm) of tumor from skeletal muscle and adipose tissue based on the MSER segmentation output. Specifically, a logistic regression model was used to classify each localized region. The logistic regression model yielded an output in terms of probability (0-100%) that tumor was located within each 75x75 µm region. The model performance was tested using a receiver operator characteristic (ROC) curve analysis that revealed 77% sensitivity and 81% specificity. For margin classification, the whole margin image was divided into localized regions and this tissue-type classification model was applied. In a subset of 6 margins (3 negative, 3 positive), it was shown that with a tumor probability threshold of 50%, 8% of all regions from negative margins exceeded this threshold, while over 17% of all regions exceeded the threshold in the positive margins. Thus, 8% of regions in negative margins were considered false positives. These false positive regions are likely due to the high density of APFs present in normal tissues, which clearly demonstrates a challenge in implementing this automatic algorithm based on AO staining alone.

Thus, the third aim was to improve the specificity of the diagnostic model through leveraging other sources of contrast. Modifications were made to the SIM system to enable fluorescence imaging at a variety of wavelengths. Specifically, the SIM system was modified to enabling imaging of red fluorescent protein (RFP) expressing sarcomas, which were used to delineate the location of tumor cells within each image. Initial analysis of AO stained panels confirmed that there was room for improvement in tumor detection, particularly in regards to false positive regions that were negative for RFP. One approach for improving the specificity of the diagnostic model was to investigate using a fluorophore that was more specific to staining tumor. Specifically, tetracycline was selected because it appeared to specifically stain freshly excised tumor tissue in a matter of minutes, and was non-toxic and stable in solution. Results indicated that tetracycline staining has promise for increasing the specificity of tumor detection in SIM images of a preclinical sarcoma model and further investigation is warranted.

In conclusion, this work presents the development of a combination of tools that is capable of automated segmentation and quantification of micro-anatomical images of thick tissue. When compared to the fluorescence microendoscope, wide-field multispectral fluorescence SIM imaging provided improved image contrast, a larger FOV with comparable resolution, and the ability to image a variety of fluorophores. MSER was an appropriate and rapid approach to segment dense collections of APFs from wide-field SIM images. Variables that reflect the morphology of the tissue, such as the density, size, and shape of nuclei and nucleoli, can be used to automatically diagnose SIM images. The clinical utility of SIM imaging and MSER segmentation to detect microscopic residual disease has been demonstrated by imaging excised preclinical sarcoma margins. Ultimately, this work demonstrates that fluorescence imaging of tissue micro-anatomy combined with a specialized algorithm for delineation and quantification of features is a means for rapid, non-destructive and automated detection of microscopic disease, which could improve cancer management in a variety of clinical scenarios.

A new instrument for measuring anticoagulation-related quality of life: development and preliminary validation.

BACKGROUND: Anticoagulation can reduce quality of life, and different models of anticoagulation management might have different impacts on satisfaction with this component of medical care. Yet, to our knowledge, there are no scales measuring quality of life and satisfaction with anticoagulation that can be generalized across different models of anticoagulation management. We describe the development and preliminary validation of such an instrument - the Duke Anticoagulation Satisfaction Scale (DASS). METHODS: The DASS is a 25-item scale addressing the (a) negative impacts of anticoagulation (limitations, hassles and burdens); and (b) positive impacts of anticoagulation (confidence, reassurance, satisfaction). Each item has 7 possible responses. The DASS was administered to 262 patients currently receiving oral anticoagulation. Scales measuring generic quality of life, satisfaction with medical care, and tendency to provide socially desirable responses were also administered. Statistical analysis included assessment of item variability, internal consistency (Cronbach's alpha), scale structure (factor analysis), and correlations between the DASS and demographic variables, clinical characteristics, and scores on the above scales. A follow-up study of 105 additional patients assessed test-retest reliability. RESULTS: 220 subjects answered all items. Ceiling and floor effects were modest, and 25 of the 27 proposed items grouped into 2 factors (positive impacts, negative impacts, this latter factor being potentially subdivided into limitations versus hassles and burdens). Each factor had a high degree of internal consistency (Cronbach's alpha 0.78-0.91). The limitations and hassles factors consistently correlated with the SF-36 scales measuring generic quality of life, while the positive psychological impact scale correlated with age and time on anticoagulation. The intra-class correlation coefficient for test-retest reliability was 0.80. CONCLUSIONS: The DASS has demonstrated reasonable psychometric properties to date. Further validation is ongoing. To the degree that dissatisfaction with anticoagulation leads to decreased adherence, poorer INR control, and poor clinical outcomes, the DASS has the potential to help identify reasons for dissatisfaction (and positive satisfaction), and thus help to develop interventions to break this cycle. As an instrument designed to be applicable across multiple models of anticoagulation management, the DASS could be crucial in the scientific comparison between those models of care.

The quantity and quality of worldwide new drug introductions, 1982-2003.

We examined trends in the introduction of new chemical entities (NCEs) worldwide from 1982 through 2003. Although annual introductions of NCEs decreased over time, introductions of high-quality NCEs (that is, global and first-in-class NCEs) increased moderately. Both biotech and orphan products enjoyed tremendous growth, especially for cancer treatment. Country-level analyses for 1993-2003 indicate that U.S. firms overtook their European counterparts in innovative performance or the introduction of first-in-class, biotech, and orphan products. The United States also became the leading market for first launch.

Quality of Life and Neurocognitive Functioning in Children with Sickle Cell Disease: Investigating the Feasibility of a Computerized Cognitive Training Program

Children with sickle cell disease (SCD) have a high risk of neurocognitive impairment. No known research, however, has examined the impact of neurocognitive functioning on quality of life in this pediatric population. In addition, limited research has examined neurocognitive interventions for these children. In light of these gaps, two studies were undertaken to (a) examine the relationship between cognitive functioning and quality of life in a sample of children with SCD and (b) investigate the feasibility and preliminary efficacy of a computerized working memory training program in this population. Forty-five youth (ages 8-16) with SCD and a caregiver were recruited for the first study. Participants completed measures of cognitive ability, quality of life, and psychosocial functioning. Results indicated that cognitive ability significantly predicted child- and parent-reported quality of life among youth with SCD. In turn, a randomized-controlled trial of a computerized working memory program was undertaken. Eighteen youth with SCD and a caregiver enrolled in this study, and were randomized to a waitlist control or the working memory training condition. Data pertaining to cognitive functioning, psychosocial functioning, and disease characteristics were obtained from participants. The results of this study indicated a high degree of acceptance for this intervention but poor feasibility in practice. Factors related to feasibility were identified. Implications and future directions are discussed.

Impact of a Point-of-Care Rapid Influenza Test on Antibiotic Prescribing Patterns in Southern Sri Lanka

Background: Acute febrile respiratory illnesses, including influenza, account for a large proportion of ambulatory care visits worldwide. In the developed world, these encounters commonly result in unwarranted antibiotic prescriptions; data from more resource-limited settings are lacking. The purpose of this study was to describe the epidemiology of influenza among outpatients in southern Sri Lanka and to determine if access to rapid influenza test results was associated with decreased antibiotic prescriptions.

Methods: In this pretest- posttest study, consecutive patients presenting from March 2013- April 2014 to the Outpatient Department of the largest tertiary care hospital in southern Sri Lanka were surveyed for influenza-like illness (ILI). Patients meeting World Health Organization criteria for ILI-- acute onset of fever ≥38.0°C and cough in the prior 7 days--were enrolled. Consenting patients were administered a structured questionnaire, physical examination, and nasal/nasopharyngeal sampling. Rapid influenza A/B testing (Veritor System, Becton Dickinson) was performed on all patients, but test results were only released to patients and clinicians during the second phase of the study (December 2013- April 2014).

Results: We enrolled 397 patients with ILI, with 217 (54.7%) adults ≥12 years and 188 (47.4%) females. A total of 179 (45.8%) tested positive for influenza by rapid testing, with April- July 2013 and September- November 2013 being the periods with the highest proportion of ILI due to influenza. A total of 310 (78.1%) patients with ILI received a prescription for an antibiotic from their outpatient provider. The proportion of patients prescribed antibiotics decreased from 81.4% in the first phase to 66.3% in the second phase (p=.005); among rapid influenza-positive patients, antibiotic prescriptions decreased from 83.7% in the first phase to 56.3% in the second phase (p=.001). On multivariable analysis, having a positive rapid influenza test available to clinicians was associated with decreased antibiotic use (OR 0.20, 95% CI 0.05- 0.82).

Conclusions: Influenza virus accounted for almost 50% of acute febrile respiratory illness in this study, but most patients were prescribed antibiotics. Providing rapid influenza test results to clinicians was associated with fewer antibiotic prescriptions, but overall prescription of antibiotics remained high. In this developing country setting, a multi-faceted approach that includes improved access to rapid diagnostic tests may help decrease antibiotic use and combat antimicrobial resistance.

Gender and racial/ethnic differences in addiction severity, HIV risk, and quality of life among adults in opioid detoxification: results from the National Drug Abuse Treatment Clinical Trials Network.

PURPOSE: Detoxification often serves as an initial contact for treatment and represents an opportunity for engaging patients in aftercare to prevent relapse. However, there is limited information concerning clinical profiles of individuals seeking detoxification, and the opportunity to engage patients in detoxification for aftercare often is missed. This study examined clinical profiles of a geographically diverse sample of opioid-dependent adults in detoxification to discern the treatment needs of a growing number of women and whites with opioid addiction and to inform interventions aimed at improving use of aftercare or rehabilitation. METHODS: The sample included 343 opioid-dependent patients enrolled in two national multi-site studies of the National Drug Abuse Treatment Clinical Trials Network (CTN001-002). Patients were recruited from 12 addiction treatment programs across the nation. Gender and racial/ethnic differences in addiction severity, human immunodeficiency virus (HIV) risk, and quality of life were examined. RESULTS: Women and whites were more likely than men and African Americans to have greater psychiatric and family/social relationship problems and report poorer health-related quality of life and functioning. Whites and Hispanics exhibited higher levels of total HIV risk scores and risky injection drug use scores than African Americans, and Hispanics showed a higher level of unprotected sexual behaviors than whites. African Americans were more likely than whites to use heroin and cocaine and to have more severe alcohol and employment problems. CONCLUSIONS: Women and whites show more psychopathology than men and African Americans. These results highlight the need to monitor an increased trend of opioid addiction among women and whites and to develop effective combined psychosocial and pharmacologic treatments to meet the diverse needs of the expanding opioid-abusing population. Elevated levels of HIV risk behaviors among Hispanics and whites also warrant more research to delineate mechanisms and to reduce their risky behaviors.

Clinical utility of a Web-enabled risk-assessment and clinical decision support program.

PURPOSE: Risk-stratified guidelines can improve quality of care and cost-effectiveness, but their uptake in primary care has been limited. MeTree, a Web-based, patient-facing risk-assessment and clinical decision support tool, is designed to facilitate uptake of risk-stratified guidelines. METHODS: A hybrid implementation-effectiveness trial of three clinics (two intervention, one control). PARTICIPANTS: consentable nonadopted adults with upcoming appointments. PRIMARY OUTCOME: agreement between patient risk level and risk management for those meeting evidence-based criteria for increased-risk risk-management strategies (increased risk) and those who do not (average risk) before MeTree and after. MEASURES: chart abstraction was used to identify risk management related to colon, breast, and ovarian cancer, hereditary cancer, and thrombosis. RESULTS: Participants = 488, female = 284 (58.2%), white = 411 (85.7%), mean age = 58.7 (SD = 12.3). Agreement between risk management and risk level for all conditions for each participant, except for colon cancer, which was limited to those <50 years of age, was (i) 1.1% (N = 2/174) for the increased-risk group before MeTree and 16.1% (N = 28/174) after and (ii) 99.2% (N = 2,125/2,142) for the average-risk group before MeTree and 99.5% (N = 2,131/2,142) after. Of those receiving increased-risk risk-management strategies at baseline, 10.5% (N = 2/19) met criteria for increased risk. After MeTree, 80.7% (N = 46/57) met criteria. CONCLUSION: MeTree integration into primary care can improve uptake of risk-stratified guidelines and potentially reduce "overuse" and "underuse" of increased-risk services.Genet Med 18 10, 1020-1028.