We have shown that Alox5 is a critical regulator of leukemia stem cells (LSCs) in a BCR-ABL-induced chronic myeloid leukemia (CML) mouse model, and we hypothesize that the Alox5 pathway represents a major molecular network that regulates LSC function. Therefore, we sought to dissect this pathway by comparing the gene expression profiles of wild type and Alox5(-/-) LSCs. DNA microarray analysis revealed a small group of candidate genes that exhibited changes in the levels of transcription in the absence of Alox5 expression. In particular, we noted that the expression of the Msr1 gene was upregulated in Alox5(-/-) LSCs, suggesting that Msr1 suppresses the proliferation of LSCs. Using CML mouse model, we show that Msr1 is downregulated by BCR-ABL and this down-regulation is partially restored by Alox5 deletion, and that Msr1 deletion causes acceleration of CML development. Moreover, Msr1 deletion markedly increases LSC function through its effects on cell cycle progression and apoptosis. We also show that Msr1 affects CML development by regulating the PI3K-AKT pathway and beta-Catenin. Together, these results demonstrate that Msr1 suppresses LSCs and CML development. The enhancement of the tumor suppressor function of Msr1 may be of significance in the development of novel therapeutic strategies for CML.
Cancer stem cells (CSCs) are responsible for the initiation and maintenance of some types of cancer, suggesting that inhibition of these cells may limit disease progression and relapse. Unfortunately, few CSC-specific genes have been identified. Here, we determined that the gene encoding arachidonate 15-lipoxygenase (Alox15/15-LO) is essential for the survival of leukemia stem cells (LSCs) in a murine model of BCR-ABL-induced chronic myeloid leukemia (CML). In the absence of Alox15, BCR-ABL was unable to induce CML in mice. Furthermore, Alox15 deletion impaired LSC function by affecting cell division and apoptosis, leading to an eventual depletion of LSCs. Moreover, chemical inhibition of 15-LO function impaired LSC function and attenuated CML in mice. The defective CML phenotype in Alox15-deficient animals was rescued by depleting the gene encoding P-selectin, which is upregulated in Alox15-deficient animals. Both deletion and overexpression of P-selectin affected the survival of LSCs. In human CML cell lines and CD34+ cells, knockdown of Alox15 or inhibition of 15-LO dramatically reduced survival. Loss of Alox15 altered expression of PTEN, PI3K/AKT, and the transcription factor ICSBP, which are known mediators of cancer pathogenesis. These results suggest that ALOX15 has potential as a therapeutic target for eradicating LSCs in CML.
Durable Results with In Situ Graft Repair of Ruptured Salmonella Aneurysm in a Patient with Autoimmune Deficiency Syndrome
We describe a case of a 42-year-old male patient with advanced autoimmune deficiency syndrome (AIDS) (CD4 count of 16 cells/mm) found to have a ruptured infected infrarenal aortic aneurysm. Emergent in situ repair was performed with a Hemashield Dacron graft (Boston Scientific, Natick, MA). Aortic tissue cultures grew group DSalmonella. Patient was placed initially on intravenous ciprofloxacin followed by lifelong oral levofloxacin and trimethoprim. Over 2 years following repair, he remains asymptomatic, with repair intact and no recurrent infection. This case is the first reported successful long-term repair of a ruptured salmonella infected abdominal aortic aneurysm in the setting of advanced AIDS.
Association between First Trimester Pregnancy Associated Plasma Protein–A (PAPP-A) and Gestational Diabetes Mellitus Development
Background: Gestational diabetes (GDM) is a common pregnancy complication with significant cardiometabolic consequences for mothers and offspring. Previous research from our group suggests that adipose tissue IGFBP-5 and its unique metalloprotease PAPP-A (Pregnancy Associated Plasma Protein-A) may play mechanistic roles in GDM development by regulating functional IGF-1 levels and lipid storage and metabolism.
Aim: To examine the relationship between circulating PAPP-A levels and GDM development. We hypothesized that high first trimester PAPP-A levels would be associated with decreased GDM risk.
Methods: A retrospective cohort of women delivering singleton gestations at UMass Memorial Healthcare (2009, 2010, 2014, 2015) was assembled by abstracting electronic medical records. PAPP-A was measured in first trimester (11-14 weeks), and reported as quartiles of multiples of the mean (MoM) based on gestational age and adjusted for maternal weight and race/ethnicity. GDM diagnosis based on standard 2-step protocol (~24-28 weeks; failed 50g 1hr glucola screen then ≥2 abnormal values per Carpenter-Coustan criteria on 100g 3hr glucose tolerance test). Crude and multivariable-adjusted logistic regression models estimated the association between PAPP-A MoM quartiles and GDM.
Results: Women (N=1,251) were 29.7 (SD:5.7) years old and 12.5 (SD:0.6) weeks gestation at PAPP-A measurement. 7.6% (n=95) developed GDM. Median PAPP-A MoM were 0.7 (inter-quartile range [IQR]=0.5-1.0) among women with GDM and 0.9 (IQR=0.6-1.3) among controls; 39% versus 23% were in the 1st quartile, respectively. After adjusting for pre-pregnancy body mass index, nuchal translucency, crown rump length, smoking status, and parity, women with PAPP-A MoM in 2nd, 3rd, and 4th quartiles had 52% (OR=0.48, 95%CI=0.26-0.88), 45% (OR=0.55, 95%CI=0.30-0.99) and 73% (OR=0.27, 95%CI=0.13-0.53) lower odds of GDM compared to women in the 1st quartile.
Conclusion: Higher PAPP-A MoM levels were associated with lower GDM risk. Future studies will assess whether higher PAPP-A levels are associated with enhanced IGF-1 signaling and improved pregnancy metabolic homeostasis.
Treatment of bacterial skin infections in ED observation units: factors influencing prescribing practice
OBJECTIVE: The Infectious Disease Society of America (IDSA) publishes evidence-based guidelines for the treatment of skin and soft tissue infections. How closely physicians follow these guidelines is unknown, particularly in the emergency department observation unit (EDOU) where increasing numbers of patients are treatment for these infections. Our objectives were to describe (1) the antibiotic treatment patterns EDOU patients, (2) physicians' adherence to the IDSA guidelines, and (3) factors that influence physician's prescribing practices.
METHODS: This prospective cohort enrolled adult patients discharged from an EDOU at an academic medical center after treatment for a skin or soft tissue infection. Information was collected from chart review and patient interview pertaining to the patient's sociodemographic characteristics, presenting illness, and antibiotic treatment regimens. Treatment regimens were compared with national guidelines.
RESULTS: The study included 193 patients of which only 43% were treated according to IDSA guidelines, 42% were overtreated, and 15% were undertreated. Women were more likely to be undertreated (relative risk, 1.58; 95% confidence interval, 1.21-2.06), whereas patients 50 years and older were at risk for overtreatment (relative risk, 1.44; 95% confidence interval, 1.03-2.02). Women also received shorter courses of antibiotic therapy with an average of 9.6 days of treatment compared with 10.6 days for men.
CONCLUSIONS: Physician antibiotic prescribing practices demonstrated poor adherence to IDSA guidelines and were influenced by the patient's age and sex. Standardized antibiotic protocols for treatment of skin and soft tissue infections to IDSA guidelines in the EDOU would minimize physician bias.
Positive surgical margins in radical prostatectomy patients do not predict long-term oncological outcomes: results from the Shared Equal Access Regional Cancer Hospital (SEARCH) cohort
OBJECTIVE: To assess the impact of positive surgical margins (PSMs) on long-term outcomes after radical prostatectomy (RP), including metastasis, castrate-resistant prostate cancer (CRPC), and prostate cancer-specific mortality (PCSM).
PATIENTS AND METHODS: Retrospective study of 4 051 men in the Shared Equal Access Regional Cancer Hospital (SEARCH) cohort treated by RP from 1988 to 2013. Proportional hazard models were used to estimate hazard ratios (HRs) of PSMs in predicting biochemical recurrence (BCR), CRPC, metastases, and PCSM. To determine if PSMs were more predictive in certain patients, analyses were stratified by pathological Gleason score, stage, and preoperative prostate-specific antigen (PSA) level.
RESULTS: The median (interquartile range) follow-up was 6.6 (3.2-10.6) years and 1 127 patients had > 10 years of follow-up. During this time, 302 (32%) men had BCR, 112 (3%) developed CRPC, 144 (4%) developed metastases, and 83 (2%) died from prostate cancer. There were 1 600 (40%) men with PSMs. In unadjusted models, PSMs were significantly associated with all adverse outcomes: BCR, CRPC, metastases and PCSM (all P < /= 0.001). After adjusting for demographic and pathological characteristics, PSMs were associated with increased risk of only BCR (HR 1.98, P < 0.001), and not CRPC, metastases, or PCSM (HR < /=1.29, P > 0.18). Similar results were seen when stratified by pathological Gleason score, stage, or PSA level, and when patients who underwent adjuvant radiotherapy were excluded.
CONCLUSIONS: PSMs after RP are not an independent risk factor for CRPC, metastasis, or PCSM overall or within any subset. In the absence of other high-risk features, PSMs alone may not be an indication for adjuvant radiotherapy.
The diagnosis and management of obscure gastrointestinal bleeding (OGIB) have changed dramatically since the introduction of video capsule endoscopy (VCE) followed by deep enteroscopy and other imaging technologies in the last decade. Significant advances have been made, yet there remains room for improvement in our diagnostic yield and treatment capabilities for recurrent OGIB. In this review, we will summarize the latest technologies for the diagnosis of OGIB, limitations of VCE, technological enhancement in VCE, and different management options for OGIB.
Purpose: To determine how physicians' diagnoses, diagnostic uncertainty, and management decisions are affected by the results of computed tomography (CT) in emergency department settings.
Materials and Methods: This study was approved by the institutional review board and compliant with HIPAA. Data were collected between July 12, 2012, and January 13, 2014. The requirement to obtain patient consent was waived. In this prospective, four-center study, patients presenting to the emergency department who were referred for CT with abdominal pain, chest pain and/or dyspnea, or headache were identified. Physicians were surveyed before and after CT to determine the leading diagnosis, diagnostic confidence (on a scale of 0% to 100%), alternative "rule out" diagnosis, and management decisions. Primary measures were the proportion of patients for whom the leading diagnosis or admission decision changed and median changes in diagnostic confidence. Secondary measures addressed alternative diagnoses and return-to-care visits (eg, to emergency department) at 1-month follow-up. Regression analysis was used to identify associations between primary measures and site and participant characteristics.
Results: Both surveys were completed for 1280 patients by 245 physicians. The leading diagnosis changed in 235 of 460 patients with abdominal pain (51%), 163 of 387 with chest pain and/or dyspnea (42%), and 103 of 433 with headache (24%). Pre-CT diagnostic confidence was inversely associated with the likelihood of a diagnostic change (P < .0001). Median changes in confidence were substantial (increases of 25%, 20%, and 13%, respectively, for patients with abdominal pain, chest pain and/or dyspnea, and headache; P < .0001); median post-CT confidence was high (95% for all three groups). CT helped confirm or exclude at least 95% of alternative diagnoses. Admission decisions changed in 116 of 457 patients with abdominal pain (25%), 72 of 387 with chest pain and/or dyspnea (19%), and 81 of 426 with headache (19%). During follow-up, 70 of 450 patients with abdominal pain (15%), 53 of 387 with chest pain and/or dyspnea (14%), and 49 of 433 with headache (11%) returned for the same indication. In general, changes in leading diagnosis, diagnostic confidence, and admission decisions were not well explained with site or participant characteristics.
Conclusion: Physicians' diagnoses and admission decisions changed frequently after CT, and diagnostic uncertainty was alleviated.
Projected Effects of Radiation-Induced Cancers on Life Expectancy in Patients Undergoing CT Surveillance for Limited-Stage Hodgkin Lymphoma: A Markov Model
OBJECTIVE: Patients with limited-stage Hodgkin lymphoma (HL) undergo frequent posttreatment surveillance CT examinations, raising concerns about the cumulative magnitude of radiation exposure. The purpose of this study was to project radiation-induced cancer risks relative to competing risks of HL and account for the differential timing of each.
MATERIALS AND METHODS: We adapted a previously developed Markov model to project lifetime mortality risks and life expectancy losses due to HL versus radiation-induced cancers in HL patients undergoing surveillance CT. In the base case, we modeled 35-year-old men and women undergoing seven CT examinations of the chest, abdomen, and pelvis over 5 years. Radiation-induced cancer risks and deaths for 17 organ systems were modeled using an organ-specific approach, accounting for specific anatomy exposed at CT. Cohorts of 20-, 50-, and 65-year-old men and women were evaluated in secondary analyses. Markov chain Monte Carlo methods were used to estimate the uncertainty of radiation risk projections.
RESULTS: For 35-year-old adults, we projected 3324/100,000 (men) and 3345/100,000 (women) deaths from recurrent lymphoma and 245/100,000 (men, 95% uncertainty interval [UI]: 121-369) and 317/100,000 (women, 95% UI: 202-432) radiation-induced cancer deaths. Discrepancies in life expectancy losses between HL (428 days in men, 482 days in women) and radiation-induced cancers (11.6 days in men, [95% UI: 5.7-17.5], 15.6 days in women [95% UI: 9.8-21.4]) were proportionately greater because of the delayed timing of radiation-induced cancers relative to recurrent HL. Deaths and life expectancy losses from radiation-induced cancers were highest in the youngest cohorts.
CONCLUSION: Given the low rate of radiation-induced cancer deaths associated with CT surveillance, modest CT benefits would justify its use in patients with limited-stage HL.
OBJECTIVE. The purpose of this article is to project the effects of radiation exposure on life expectancy (LE) in patients who opt for CT-guided radiofrequency ablation (RFA) instead of surgery for renal cell carcinoma (RCC).
MATERIALS AND METHODS. We developed a decision-analytic Markov model to compare LE losses attributable to radiation exposure in hypothetical 65-year-old patients who undergo CT-guided RFA versus surgery for small ( < /= 4 cm) RCC. We incorporated mortality risks from RCC, radiation-induced cancers (for procedural and follow-up CT scans), and all other causes; institutional data informed the RFA procedural effective dose. Radiation-induced cancer risks were generated using an organ-specific approach. Effects of varying model parameters and of dose-reduction strategies were evaluated in sensitivity analysis.
RESULTS. Cumulative RFA exposures (up to 305.2 mSv for one session plus surveillance) exceeded those from surgery (up to 87.2 mSv). In 65-year-old men, excess LE loss from radiation-induced cancers, comparing RFA to surgery, was 11.7 days (14.6 days for RFA vs 2.9 days for surgery). Results varied with sex and age; this difference increased to 14.6 days in 65-year-old women and to 21.5 days in 55-year-old men. Dose-reduction strategies that addressed follow-up rather than procedural exposure had a greater impact. In 65-year-old men, this difference decreased to 3.8 days if post-RFA follow-up scans were restricted to a single phase; even elimination of RFA procedural exposure could not achieve equivalent benefits.
CONCLUSION. CT-guided RFA remains a safe alternative to surgery, but with decreasing age, the higher burden of radiation exposure merits explicit consideration. Dose-reduction strategies that target follow-up rather than procedural exposure will have a greater impact.
The relationship between coping styles in response to unfair treatment and understanding of diabetes self-care
PURPOSE: This study examined the relationship between coping style and understanding of diabetes self-care among African American and white elders in a southern Medicare-managed care plan.
METHODS: Participants were identified through a diabetes-related pharmacy claim or ICD-9 code and completed a computer-assisted telephone survey in 2006-2007. Understanding of diabetes self-care was assessed using the Diabetes Care Profile Understanding (DCP-U) scale. Coping styles were classified as active (talk about it/take action) or passive (keep it to yourself). Linear regression was used to estimate the associations between coping style with the DCP-U, adjusting for age, sex, education, and comorbidities. Based on the conceptual model, 4 separate categories were established for African American and white participants who displayed active and passive coping styles.
RESULTS: Of 1420 participants, the mean age was 73 years, 46% were African American, and 63% were female. Most respondents (77%) exhibited active coping in response to unfair treatment. For African American participants in the study, active coping was associated with higher adjusted mean DCP-U scores when compared to participants with a passive coping style. No difference in DCP-U score was noted among white participants on the basis of coping style.
CONCLUSIONS: Active coping was more strongly associated with understanding of diabetes self-care among older African Americans than whites. Future research on coping styles may give new insights into reducing diabetes disparities among racial/ethnic minorities.
BACKGROUND: The incidence and virulence of Clostridium difficile infection (CDI) are on the rise. The characteristics of patients who develop CDI following colorectal resection have been infrequently studied.
MATERIALS AND METHODS: We utilized the University HealthSystem Consortium database to identify adult patients undergoing colorectal surgery between 2008 and 2012. We examined the patient-related risk factors for CDI and 30-day outcomes related to its occurrence.
RESULTS: A total of 84,648 patients met our inclusion criteria, of which the average age was 60 years and 50% were female. CDI occurred in 1,266 (1.5%) patients during the years under study. The strongest predictors of CDI were emergent procedure, inflammatory bowel disease (IBD), and major/extreme APR-DRG severity of illness score. CDI was associated with a higher rate of complications, intensive care unit (ICU) admission, longer preoperative inpatient stay, 30-day readmission rate, and death within 30 days compared to non-CDI patients. Cost of the index stay was, on average, $14,130 higher for CDI patients compared with non-CDI patients.
CONCLUSION: Emergent procedures, higher severity of illness, and inflammatory bowel disease are significant risk factors for postoperative CDI in patients undergoing colorectal surgery. Once established, CDI is associated with worse outcomes and higher costs. The poor outcomes of these patients and increased costs highlight the importance of prevention strategies targeting high-risk patients.
Clinical and financial impact of hospital readmissions after colorectal resection: predictors, outcomes, and costs
BACKGROUND: After passage of the Affordable Care Act, 30 -day hospital readmissions have come under greater scrutiny. Excess readmissions for certain medical conditions and procedures now result in penalizations on all Medicare reimbursements.
OBJECTIVE: The purpose of this work was to define the risk factors, outcomes, and costs of 30-day readmissions after colorectal surgery.
DESIGN: Adults undergoing colorectal surgery were studied using data from the University HealthSystem Consortium. Univariate and multivariable analyses were used to identify patient-related risk factors for, and 30-day outcomes of, readmission after colorectal surgery.
SETTINGS: This study was conducted at an academic hospital and its affiliates.
PATIENTS: Adults > /=18 years of age who underwent colorectal surgery for cancer, diverticular disease, IBD, or benign tumors between 2008 and 2011 were included in this study.
MAIN OUTCOME MEASURES: Readmission within 30 days of index discharge was the main outcome measured.
RESULTS: A total of 70,484 patients survived the index hospitalization after colorectal surgery; 9632 (13.7%) were readmitted within 30 days of discharge. The strongest independent predictors of readmission were length of stay > /=4 days (OR 1.44; 95% CI 1.32-1.57), stoma (OR 1.54; 95% CI 1.46-1.51), and discharge to skilled nursing (OR 1.62; 95% CI 1.49-1.76) or rehabilitation facility (OR 2.93; 95% CI 2.53-3.40). Of those readmitted, half of the readmissions occurred within 7 days, 13% required the intensive care unit, 6% had a reoperation, and 2% died during the readmission stay. The median combined total direct hospital cost was more than 2 times higher ($26,917 vs $13,817; p < 0.001) for readmitted than for nonreadmitted patients.
LIMITATIONS: Follow-up was limited to 30 days after initial discharge.
CONCLUSIONS: Readmissions after colorectal resection occur frequently and incur a significant financial burden on the health-care system. Future studies aimed at targeted interventions for high-risk patients may reduce readmissions and curb escalating health-care costs.
Alternatively Activated M2 Macrophages Improve Autologous Fat Graft Survival in a Mouse Model through Induction of Angiogenesis
Comment on: Alternatively activated M2 macrophages improve autologous Fat Graft survival in a mouse model through induction of angiogenesis. [Plast Reconstr Surg. 2015]
Differentiating between superficial and deep-dermal (DD) burns remains challenging. Superficial-dermal burns heal with conservative treatment; DD burns often require excision and skin grafting. Decision of surgical treatment is often delayed until burn depth is definitively identified. This study's aim is to assess the ability of hyperspectral imaging (HSI) to differentiate burn depth.
METHODS: Thermal injury of graded severity was generated on the dorsum of hairless mice with a heated brass rod. Perfusion and oxygenation parameters of injured skin were measured with HSI, a noninvasive method of diffuse reflectance spectroscopy, at 2 minutes, 1, 24, 48 and 72 hours after wounding. Burn depth was measured histologically in 12 mice from each burn group (n = 72) at 72 hours.
RESULTS: Three levels of burn depth were verified histologically: intermediate-dermal (ID), DD, and full-thickness. At 24 hours post injury, total hemoglobin (tHb) increased by 67% and 16% in ID and DD burns, respectively. In contrast, tHb decreased to 36% of its original levels in full-thickness burns. Differences in deoxygenated and tHb among all groups were significant (P < 0.001) at 24 hours post injury.
CONCLUSIONS: HSI was able to differentiate among 3 discrete levels of burn injury. This is likely because of its correlation with skin perfusion: superficial burn injury causes an inflammatory response and increased perfusion to the burn site, whereas deeper burns destroy the dermal microvasculature and a decrease in perfusion follows. This study supports further investigation of HSI in early burn depth assessment.
BACKGROUND: The lifetime cost of a child with an orofacial cleft is estimated at $101,000, which amounts to $697 million total for those born each year with orofacial clefts. There has been a trend toward outpatient procedures for cleft lip repair (CLR) and alveolar bone grafting (ABG), and studies have shown no disparities in safety or outcome between inpatient and ambulatory treatment. The financial implications of outpatient versus inpatient procedures have not been compared.
METHODS: Financial data were collected for outpatient (n = 33) and inpatient (n = 2) CLR, as well as outpatient (n = 7) and inpatient (n = 5) ABG during a 5-year period at our institution. We examined hospital charges and reimbursement for these procedures by private insurance plans and Medicaid Managed Care (MMC) plans.
RESULTS: The average total reimbursements for inpatient and outpatient CLR were similar at $6848 and $5557, respectively. Average facility reimbursement for CLR was greater for inpatient ($5344) than outpatient ($4291) procedures. Average professional reimbursement was similar between inpatient ($1504) and outpatient ($1266) CLR.For ABG, the average total inpatient reimbursement was $14,573, whereas outpatient was $8877. Average facility reimbursements were greater for inpatient ($12,398) than outpatient ($7183) ABG. Average professional reimbursement was similar between inpatient ($2175) and outpatient ($1693) ABG, with 35% and 31% of charges reimbursed, respectively.A substantial difference existed between reimbursements based on insurance types for both outpatient CLR and outpatient ABG. On average for CLR, commercial payers reimbursed 52% ($7344) of overall charges, whereas Medicaid and MMC reimbursed 9% ($1447). For ABG, commercial payers reimbursed an average of 78% ($11,950) of overall charges, whereas Medicaid and MMC reimbursed 10% ($1192).
CONCLUSIONS: Fewer patients' insurance companies are reimbursing for inpatient stays; in many cases, even patients who remain hospitalized up to 48 hours are treated as "day surgery" from a reimbursement perspective. For outpatient surgery, a greater percentage of CLR and ABG charges were successfully recouped compared to inpatient surgery. Awareness of higher payment for inpatient surgery and potential savings through use of the outpatient setting is crucial for hospitals and the US health care system as a whole.
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Drug resistance is a major problem in health care, undermining therapy outcomes and necessitating novel approaches to drug design. Extensive studies on resistance to viral protease inhibitors, particularly those of HIV-1 and hepatitis C virus (HCV) protease, revealed a plethora of information on the structural and molecular mechanisms underlying resistance. These insights led to several strategies to improve viral protease inhibitors to counter resistance, such as exploiting the essential biological function and leveraging evolutionary constraints. Incorporation of these strategies into structure-based drug design can minimize vulnerability to resistance, not only for viral proteases but for other quickly evolving drug targets as well, toward designing inhibitors one step ahead of evolution to counter resistance with more intelligent and rational design.
Many academic institutions and their libraries have developed research data services, but sometimes institutional objectives, professional organizations, and librarians’ current and future roles aren’t always in sync. In this issue of the Journal of eScience Librarianship, librarians report on moving forward with various services, but frequently face institutional and professional obstacles.