Browsing by Subject "Acute Disease"
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Item Open Access A clinical prediction model for long-term functional outcome after traumatic spinal cord injury based on acute clinical and imaging factors.(Journal of neurotrauma, 2012-09) Wilson, Jefferson R; Grossman, Robert G; Frankowski, Ralph F; Kiss, Alexander; Davis, Aileen M; Kulkarni, Abhaya V; Harrop, James S; Aarabi, Bizhan; Vaccaro, Alexander; Tator, Charles H; Dvorak, Marcel; Shaffrey, Christopher I; Harkema, Susan; Guest, James D; Fehlings, Michael GTo improve clinicians' ability to predict outcome after spinal cord injury (SCI) and to help classify patients within clinical trials, we have created a novel prediction model relating acute clinical and imaging information to functional outcome at 1 year. Data were obtained from two large prospective SCI datasets. Functional independence measure (FIM) motor score at 1 year follow-up was the primary outcome, and functional independence (score ≥ 6 for each FIM motor item) was the secondary outcome. A linear regression model was created with the primary outcome modeled relative to clinical and imaging predictors obtained within 3 days of injury. A logistic model was then created using the dichotomized secondary outcome and the same predictor variables. Model validation was performed using a bootstrap resampling procedure. Of 729 patients, 376 met the inclusion criteria. The mean FIM motor score at 1 year was 62.9 (±28.6). Better functional status was predicted by less severe initial American Spinal Injury Association (ASIA) Impairment Scale grade, and by an ASIA motor score >50 at admission. In contrast, older age and magnetic resonance imaging (MRI) signal characteristics consistent with spinal cord edema or hemorrhage predicted worse functional outcome. The linear model predicting FIM motor score demonstrated an R-square of 0.52 in the original dataset, and 0.52 (95% CI 0.52,0.53) across the 200 bootstraps. Functional independence was achieved by 148 patients (39.4%). For the logistic model, the area under the curve was 0.93 in the original dataset, and 0.92 (95% CI 0.92,0.93) across the bootstraps, indicating excellent predictive discrimination. These models will have important clinical impact to guide decision making and to counsel patients and families.Item Open Access A Phase 3, Single-Arm, Prospective Study of Remestemcel-L, Ex Vivo Culture-Expanded Adult Human Mesenchymal Stromal Cells for the Treatment of Pediatric Patients Who Failed to Respond to Steroid Treatment for Acute Graft-versus-Host Disease.(Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2020-05) Kurtzberg, Joanne; Abdel-Azim, Hisham; Carpenter, Paul; Chaudhury, Sonali; Horn, Biljana; Mahadeo, Kris; Nemecek, Eneida; Neudorf, Steven; Prasad, Vinod; Prockop, Susan; Quigg, Troy; Satwani, Prakash; Cheng, Annie; Burke, Elizabeth; Hayes, Jack; Skerrett, Donna; MSB-GVHD001/002 Study GroupSteroid-refractory acute graft-versus-host disease (SR-aGVHD) following hematopoietic cell transplantation (HSCT) is associated with poor clinical outcomes. Currently, there are no safe and effective therapies approved for use in the pediatric population under the age of 12 years. Accordingly, there is an urgent need for new treatments that are safe, well tolerated, and effective in managing this debilitating and potentially fatal complication of HSCT. In early phase clinical trials, mesenchymal stromal cells (MSCs) have demonstrated efficacy in the treatment of acute GVHD (aGVHD) in pediatric patients. We now report the results of a phase 3, prospective, single-arm, multicenter study (NCT02336230) in 54 children with primary SR-aGVHD who were naive to other immunosuppressant therapies for aGVHD treated with MSC product (remestemcel-L) dosed at 2 × 106 cells/kg twice weekly for 4 weeks. Remestemcel-L therapy significantly improved day 28 overall response rate (OR) compared with the prespecified control OR value of 45% (70.4% versus 45%, P = .0003). The statistically significant OR (70.4%) was sustained through day 100, including an increase in complete response from 29.6% at day 28 to 44.4% at day 100. Overall survival was 74.1% at day 100 and 68.5% at day 180. Overall response in all participants at day 28 was highly predictive of improved survival through 180 days, and survival was significantly greater in day 28 responders compared with nonresponders through day 100 (86.8% versus 47.1% for responders and nonresponders, respectively, P = .0001) and through day 180 (78.9% versus 43.8%, P = .003). Remestemcel-L was well tolerated with no identified infusion-related toxicities or other safety concerns. This study provides robust, prospective evidence of the safety, tolerability, and efficacy of remestemcel-L as first-line therapy after initial steroid failure in pediatric SR-aGVHD.Item Open Access Acute myocardial infarction in sub-Saharan Africa: the need for data.(PloS one, 2014-01) Hertz, Julian T; Reardon, Joseph M; Rodrigues, Clarissa G; de Andrade, Luciano; Limkakeng, Alexander T; Bloomfield, Gerald S; Lynch, Catherine ABACKGROUND: Trends in the prevalence of acute myocardial infarction in sub-Saharan Africa have not been well described, despite growing recognition of the increasing burden of cardiovascular disease in low- and middle-income countries. The aim of this systematic review was to describe the prevalence of acute myocardial infarction in sub-Saharan Africa. METHODS: We searched PubMed, EMBASE, Global Health Archive, CINAHL, and Web of Science, and conducted reference and citation analyses. Inclusion criteria were: observational studies, studies that reported incidence or prevalence of acute myocardial infarction, studies conducted in sub-Saharan Africa, and studies that defined acute myocardial infarction by EKG changes or elevation of cardiac biomarkers. Studies conducted prior to 1992 were excluded. Two independent reviewers analyzed titles and abstracts, full-texts, and references and citations. These reviewers also performed quality assessment and data extraction. Quality assessment was conducted with a validated scale for observational studies. FINDINGS: Of 2292 records retrieved, seven studies met all inclusion criteria. These studies included a total of 92,378 participants from highly heterogeneous study populations in five different countries. Methodological quality assessment demonstrated scores ranging from 3 to 7 points (on an 8-point scale). Prevalence of acute myocardial infarction ranged from 0.1 to 10.4% among the included studies. INTERPRETATION: There is insufficient population-based data describing the prevalence of acute myocardial infarction in sub-Saharan Africa. Well-designed registries and surveillance studies that capture the broad and diverse population with acute myocardial infarction in sub-Saharan Africa using common diagnostic criteria are critical in order to guide prevention and treatment strategies. REGISTRATION: Registered in International Prospective Register of Systematic Reviews (PROSPERO) Database #CRD42012003161.Item Open Access Antibiotic overuse for acute respiratory tract infections in Sri Lanka: a qualitative study of outpatients and their physicians.(BMC Fam Pract, 2018-03-01) Tillekeratne, L Gayani; Bodinayake, Champica K; Dabrera, Thushani; Nagahawatte, Ajith; Arachchi, Wasantha Kodikara; Sooriyaarachchi, Anoji; Stewart, Kearsley; Watt, Melissa; Østbye, Truls; Woods, Christopher WBACKGROUND: Acute respiratory tract infections (ARTIs) are a common reason for antibiotic overuse worldwide. We previously showed that over 80% of outpatients presenting to a tertiary care hospital in Sri Lanka with influenza-like illness received antibiotic prescriptions, although almost half were later confirmed to have influenza. The purpose of this qualitative study was to assess Sri Lankan patients' and physicians' attitudes towards ARTI diagnosis and treatment. METHODS: Semi-structured interviews were conducted with 50 outpatients with ARTIs and five physicians in the Outpatient Department (OPD) at a large, public tertiary care hospital in southern Sri Lanka. Interviews were audio-recorded, transcribed, and analyzed for themes related to ARTI diagnosis and treatment. RESULTS: Patients frequently sought ARTI care in the public sector due to the receipt of free care and the perception that government hospitals carried a sense of responsibility for patients' health. Patients reported multiple medical visits for their illnesses of short duration and many indicated that they were seeking care in the OPD while at the hospital for another reason. While patients generally expected to receive medication prescriptions at their visit, most patients were not specifically seeking an antibiotic prescription. However, more than 70% of patients received antibiotic prescriptions at their OPD visit. Physicians incorrectly perceived that patients desired antibiotics or "capsules," a common formulation of antibiotics dispensed in this outpatient setting, and cited patient demand as an important cause of antibiotic overuse. Physicians also indicated that high patient volume and fear of bacterial superinfection drove antibiotic overuse. CONCLUSIONS: Patients in this study were seeking medication prescriptions for their ARTIs, but physicians incorrectly perceived that antibiotic prescriptions were desired. High patient volume and fear of bacterial superinfection were also important factors in antibiotic overuse. Training of physicians regarding guideline-concordant management and dealing with diagnostic uncertainty, education of patients regarding ARTI etiology and management, and systematic changes in the public outpatient care structure may help decrease unnecessary antibiotic prescriptions for ARTIs in this setting.Item Open Access Association between stroke center hospitalization for acute ischemic stroke and mortality.(JAMA, 2011-01) Xian, Ying; Holloway, Robert G; Chan, Paul S; Noyes, Katia; Shah, Manish N; Ting, Henry H; Chappel, Andre R; Peterson, Eric D; Friedman, BruceAlthough stroke centers are widely accepted and supported, little is known about their effect on patient outcomes.To examine the association between admission to stroke centers for acute ischemic stroke and mortality.Observational study using data from the New York Statewide Planning and Research Cooperative System. We compared mortality for patients admitted with acute ischemic stroke (n = 30,947) between 2005 and 2006 at designated stroke centers and nondesignated hospitals using differential distance to hospitals as an instrumental variable to adjust for potential prehospital selection bias. Patients were followed up for mortality for 1 year after the index hospitalization through 2007. To assess whether our findings were specific to stroke, we also compared mortality for patients admitted with gastrointestinal hemorrhage (n = 39,409) or acute myocardial infarction (n = 40,024) at designated stroke centers and nondesignated hospitals.Thirty-day all-cause mortality.Among 30,947 patients with acute ischemic stroke, 15,297 (49.4%) were admitted to designated stroke centers. Using the instrumental variable analysis, admission to designated stroke centers was associated with lower 30-day all-cause mortality (10.1% vs 12.5%; adjusted mortality difference, -2.5%; 95% confidence interval [CI], -3.6% to -1.4%; P < .001) and greater use of thrombolytic therapy (4.8% vs 1.7%; adjusted difference, 2.2%; 95% CI, 1.6% to 2.8%; P < .001). Differences in mortality also were observed at 1-day, 7-day, and 1-year follow-up. The outcome differences were specific for stroke, as stroke centers and nondesignated hospitals had similar 30-day all-cause mortality rates among those with gastrointestinal hemorrhage (5.0% vs 5.8%; adjusted mortality difference, +0.3%; 95% CI, -0.5% to 1.0%; P = .50) or acute myocardial infarction (10.5% vs 12.7%; adjusted mortality difference, +0.1%; 95% CI, -0.9% to 1.1%; P = .83).Among patients with acute ischemic stroke, admission to a designated stroke center was associated with modestly lower mortality and more frequent use of thrombolytic therapy.Item Open Access Association of Preceding Antithrombotic Treatment With Acute Ischemic Stroke Severity and In-Hospital Outcomes Among Patients With Atrial Fibrillation.(JAMA, 2017-03) Xian, Ying; O'Brien, Emily C; Liang, Li; Xu, Haolin; Schwamm, Lee H; Fonarow, Gregg C; Bhatt, Deepak L; Smith, Eric E; Olson, DaiWai M; Maisch, Lesley; Hannah, Deidre; Lindholm, Brianna; Lytle, Barbara L; Pencina, Michael J; Hernandez, Adrian F; Peterson, Eric DImportance:Antithrombotic therapies are known to prevent stroke for patients with atrial fibrillation (AF) but are often underused in community practice. Objectives:To examine the prevalence of patients with acute ischemic stroke with known history of AF who were not receiving guideline-recommended antithrombotic treatment before stroke and to determine the association of preceding antithrombotic therapy with stroke severity and in-hospital outcomes. Design, Setting, and Participants:Retrospective observational study of 94 474 patients with acute ischemic stroke and known history of AF admitted from October 2012 through March 2015 to 1622 hospitals participating in the Get With the Guidelines-Stroke program. Exposures:Antithrombotic therapy before stroke. Main Outcomes and Measures:Stroke severity as measured by the National Institutes of Health Stroke Scale (NIHSS; range of 0-42, with a higher score indicating greater stroke severity and a score ≥16 indicating moderate or severe stroke), and in-hospital mortality. Results:Of 94 474 patients (mean [SD] age, 79.9 [11.0] years; 57.0% women), 7176 (7.6%) were receiving therapeutic warfarin (international normalized ratio [INR] ≥2) and 8290 (8.8%) were receiving non-vitamin K antagonist oral anticoagulants (NOACs) preceding the stroke. A total of 79 008 patients (83.6%) were not receiving therapeutic anticoagulation; 12 751 (13.5%) had subtherapeutic warfarin anticoagulation (INR <2) at the time of stroke, 37 674 (39.9%) were receiving antiplatelet therapy only, and 28 583 (30.3%) were not receiving any antithrombotic treatment. Among 91 155 high-risk patients (prestroke CHA2DS2-VASc score ≥2), 76 071 (83.5%) were not receiving therapeutic warfarin or NOACs before stroke. The unadjusted rates of moderate or severe stroke were lower among patients receiving therapeutic warfarin (15.8% [95% CI, 14.8%-16.7%]) and NOACs (17.5% [95% CI, 16.6%-18.4%]) than among those receiving no antithrombotic therapy (27.1% [95% CI, 26.6%-27.7%]), antiplatelet therapy only (24.8% [95% CI, 24.3%-25.3%]), or subtherapeutic warfarin (25.8% [95% CI, 25.0%-26.6%]); unadjusted rates of in-hospital mortality also were lower for those receiving therapeutic warfarin (6.4% [95% CI, 5.8%-7.0%]) and NOACs (6.3% [95% CI, 5.7%-6.8%]) compared with those receiving no antithrombotic therapy (9.3% [95% CI, 8.9%-9.6%]), antiplatelet therapy only (8.1% [95% CI, 7.8%-8.3%]), or subtherapeutic warfarin (8.8% [95% CI, 8.3%-9.3%]). After adjusting for potential confounders, compared with no antithrombotic treatment, preceding use of therapeutic warfarin, NOACs, or antiplatelet therapy was associated with lower odds of moderate or severe stroke (adjusted odds ratio [95% CI], 0.56 [0.51-0.60], 0.65 [0.61-0.71], and 0.88 [0.84-0.92], respectively) and in-hospital mortality (adjusted odds ratio [95% CI], 0.75 [0.67-0.85], 0.79 [0.72-0.88], and 0.83 [0.78-0.88], respectively). Conclusions and Relevance:Among patients with atrial fibrillation who had experienced an acute ischemic stroke, inadequate therapeutic anticoagulation preceding the stroke was prevalent. Therapeutic anticoagulation was associated with lower odds of moderate or severe stroke and lower odds of in-hospital mortality.Item Open Access Clinical and echocardiographic predictors of mortality in acute pulmonary embolism.(Cardiovasc Ultrasound, 2016-10-28) Dahhan, Talal; Siddiqui, Irfan; Tapson, Victor F; Velazquez, Eric J; Sun, Stephanie; Davenport, Clemontina A; Samad, Zainab; Rajagopal, SudarshanPURPOSE: The aim of this study was to evaluate the utility of adding quantitative assessments of cardiac function from echocardiography to clinical factors in predicting the outcome of patients with acute pulmonary embolism (PE). METHODS: Patients with a diagnosis of acute PE, based on a positive ventilation perfusion scan or computed tomography (CT) chest angiogram, were identified using the Duke University Hospital Database. Of these, 69 had echocardiograms within 24-48 h of the diagnosis that were suitable for offline analysis. Clinical features that were analyzed included age, gender, body mass index, vital signs and comorbidities. Echocardiographic parameters that were analyzed included left ventricular (LV) ejection fraction (EF), regional, free wall and global RV speckle-tracking strain, RV fraction area change (RVFAC), Tricuspid Annular Plane Systolic Excursion (TAPSE), pulmonary artery acceleration time (PAAT) and RV myocardial performance (Tei) index. Univariable and multivariable regression statistical analysis models were used. RESULTS: Out of 69 patients with acute PE, the median age was 55 and 48 % were female. The median body mass index (BMI) was 27 kg/m(2). Twenty-nine percent of the cohort had a history of cancer, with a significant increase in cancer prevalence in non-survivors (57 % vs 29 %, p = 0.02). Clinical parameters including heart rate, respiratory rate, troponin T level, active malignancy, hypertension and COPD were higher among non-survivors when compared to survivors (p ≤ 0.05). Using univariable analysis, NYHA class III symptoms, hypoxemia on presentation, tachycardia, tachypnea, elevation in Troponin T, absence of hypertension, active malignancy and chronic obstructive pulmonary disease (COPD) were increased in non-survivors compared to survivors (p ≤ 0.05). In multivariable models, RV Tei Index, global and free (lateral) wall RVLS were found to be negatively associated with survival probability after adjusting for age, gender and systolic blood pressure (p ≤ 0.05). CONCLUSION: The addition of echocardiographic assessment of RV function to clinical parameters improved the prediction of outcomes for patients with acute PE. Larger studies are needed to validate these findings.Item Open Access Comparison of performance achievement award recognition with primary stroke center certification for acute ischemic stroke care.(J Am Heart Assoc, 2013-10-14) Fonarow, Gregg C; Liang, Li; Smith, Eric E; Reeves, Mathew J; Saver, Jeffrey L; Xian, Ying; Hernandez, Adrian F; Peterson, Eric D; Schwamm, Lee H; GWTG-Stroke Steering Committee & InvestigatorsBACKGROUND: Hospital certification and recognition programs represent 2 independent but commonly used systems to distinguish hospitals, yet they have not been directly compared. This study assessed acute ischemic stroke quality of care measure conformity by hospitals receiving Primary Stroke Center (PSC) certification and those receiving the American Heart Association's Get With The Guidelines-Stroke (GWTG-Stroke) Performance Achievement Award (PAA) recognition. METHODS AND RESULTS: The patient and hospital characteristics as well as performance/quality measures for acute ischemic stroke from 1356 hospitals participating in the GWTG-Stroke Program 2010-2012 were compared. Hospitals were classified as PAA+/PSC+ (hospitals n = 410, patients n = 169,302), PAA+/PSC- (n = 415, n = 129,454), PAA-/PSC+ (n = 88, n = 26,386), and PAA-/PSC- (n = 443, n = 75,565). A comprehensive set of stroke measures were compared with adjustment for patient and hospital characteristics. Patient characteristics were similar by PAA and PSC status but PAA-/PSC- hospitals were more likely to be smaller and nonteaching. Measure conformity was highest for PAA+/PSC+ and PAA+/PSC- hospitals, intermediate for PAA-/PSC+ hospitals, and lowest for PAA-/PSC- hospitals (all-or-none care measure 91.2%, 91.2%, 84.3%, and 76.9%, respectively). After adjustment for patient and hospital characteristics, PAA+/PSC+, PAA+/PSC-, and PAA-/PSC+ hospitals had 3.15 (95% CIs 2.86 to 3.47); 3.23 (2.93 to 3.56) and 1.72 (1.47 to 2.00), higher odds for providing all indicated stroke performance measures to patients compared with PAA-/PSC- hospitals. CONCLUSIONS: While both PSC certification and GWTG-Stroke PAA recognition identified hospitals providing higher conformity with care measures for patients hospitalized with acute ischemic stroke, PAA recognition was a more robust identifier of hospitals with better performance.Item Open Access Differential prevalence and geographic distribution of hepatitis C virus genotypes in acute and chronic hepatitis C patients in Vietnam.(PloS one, 2019-01) Le Ngoc, Chau; Tran Thi Thanh, Thanh; Tran Thi Lan, Phuong; Nguyen Mai, Trinh; Nguyen Hoa, Trang; Nghiem My, Ngoc; Le Van, Tan; Le Manh, Hung; Le Thanh, Phuong; Nguyen Van Vinh, Chau; Thwaites, Guy; Cooke, Graham; Heilek, Gabrielle M; Shikuma, Cecilia; Le, Thuy; Baker, Stephen; Rahman, Motiur; VIZIONS consortiumBACKGROUND:The highest burden of disease from hepatitis C virus (HCV) is found in Southeast Asia, but our understanding of the epidemiology of infection in many heavily burdened countries is still limited. In particular, there is relatively little data on acute HCV infection, the outcome of which can be influenced by both viral and host genetics which differ within the region. We studied HCV genotype and IL28B gene polymorphism in a cohort of acute HCV-infected patients in Southern Vietnam alongside two other cohorts of chronic HCV-infected patients to better understand the epidemiology of HCV infection locally and inform the development of programs for therapy with the increasing availability of directly acting antiviral therapy (DAAs). METHODS:We analysed plasma samples from patients with acute and chronic HCV infection, including chronic HCV mono-infection and chronic Human Immunodeficiency Virus (HIV)-HCV coinfection, who enrolled in four epidemiological or clinical research studies. HCV infection was confirmed with RNA testing. The 5' UTR, core and NSB5 regions of HCV RNA positive samples were sequenced, and the genotype and subtype of the viral strains were determined. Host DNA from all HCV positive patients and age- and sex-matched non-HCV-infected control individuals were analysed for IL28B single nucleotide polymorphism (SNP) (rs12979860 and rs8099917). Geolocation of the patients were mapped using QGIS. RESULTS:355 HCV antibody positive patients were analysed; 54.6% (194/355) and 46.4% (161/355) were acute and chronic infections, respectively. 50.4% (81/161) and 49.6.4% (80/161) of chronic infections had HCV mono-infection and HIV-HCV coinfection, respectively. 88.7% (315/355) and 10.1% (36/355) of the patients were from southern and central regions of Vietnam, respectively. 92.4% (328/355) of patients were HCV RNA positive, including 86.1% (167/194) acute and 100% (161/161) chronic infections. Genotype could be determined in 98.4% (322/328) patients. Genotypes 1 (56.5%; 182/322) and 6 (33.9%; 109/322) predominated. Genotype 1 including genotype 1a was significantly higher in HIV-HCV coinfected patients compared to acute HCV patients [43.8% (35/80) versus 20.5% (33/167)], (p = <0.001), while genotype 6 was significantly higher in chronic HCV mono-infected patients [(44.4% (36/81) versus 20.0% (16/80)] (p = < 0.004) compared to HIV-HCV coinfected patients. The prevalence of IL28B SNP (rs12979860) homozygous CC was 86.46% (83/96) in control individuals and was significantly higher in acutely-infected compared to chronically-infected patients [93.2 (82/88) versus 76.1% (35/46)] (p = < 0.005). CONCLUSION:HCV genotype 6 is highly prevalent in Vietnam and the high prevalence in treatment naïve chronic HCV patients may results from poor spontaneous clearance of acute HCV infection with genotype 6.Item Open Access Efficacy and safety of ex vivo cultured adult human mesenchymal stem cells (Prochymal™) in pediatric patients with severe refractory acute graft-versus-host disease in a compassionate use study.(Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2011-04) Prasad, Vinod K; Lucas, Kenneth G; Kleiner, Gary I; Talano, Julie An M; Jacobsohn, David; Broadwater, Gloria; Monroy, Rod; Kurtzberg, JoannePreliminary studies using directed-donor ex vivo expanded human mesenchymal stem cells (hMSCs) have shown promise in the treatment of acute graft-versus-host disease (aGVHD). However, their production is cumbersome and standardization is difficult. We describe the first experience of using a premanufactured, universal donor, formulation of hMSCs (Prochymal) in children (n = 12; 10 boys; 9 Caucasian; age range: 0.4-15 years) with treatment-resistant grade III and IV aGVHD who received therapy on compassionate use basis between July 2005 and June 2007 at 5 transplant centers. All patients had stage III or IV gut (GI) symptoms and half had additional liver and/or skin involvement. Disease was refractory to steroids in all cases and additionally to a median of 3 other immunosuppressive therapies. The hMSCs (8 × 10(6)cells/kg/dose in 2 patients and 2 × 10(6)cells/kg/dose in the rest) were infused intravenously over 1 hour twice a week for 4 weeks. Partial and mixed responders received subsequent weekly therapy for 4 weeks. HLA or other matching was not needed. The hMSCs were started at a median of 98 days (range: 45-237) posttransplant. A total of 124 doses were administered, with a median of 8 doses (range: 2-21) per patient. Overall, 7 (58%) patients had complete response, 2 (17%) partial response, and 3 (25%) mixed response. Complete resolution of GI symptoms occurred in 9 (75%) patients. Two patients relapsed after initial response and showed partial response to retreatment. The cumulative incidence of survival at 100 days from the initiation of Prochymal therapy was 58%. Five of 12 patients (42%) were still alive after a median follow-up of 611 days (range: 427-1111) in surviving patients. No infusional or other identifiable acute toxicity was seen in any patient. Multiple infusions of hMSCs were well tolerated and appeared to be safe in children. Clinical responses, particularly in the GI system, were seen in the majority of children with severe refractory aGVHD. Given the favorable results observed in a patient population with an otherwise grave prognosis, we conclude that hMSCs hold potential for the treatment of aGVHD, and should be further studied in phase III trials in pediatric and adult patients.Item Restricted Elucidation of hepatitis C virus transmission and early diversification by single genome sequencing.(PLoS Pathog, 2012) Li, Hui; Stoddard, Mark B; Wang, Shuyi; Blair, Lily M; Giorgi, Elena E; Parrish, Erica H; Learn, Gerald H; Hraber, Peter; Goepfert, Paul A; Saag, Michael S; Denny, Thomas N; Haynes, Barton F; Hahn, Beatrice H; Ribeiro, Ruy M; Perelson, Alan S; Korber, Bette T; Bhattacharya, Tanmoy; Shaw, George MA precise molecular identification of transmitted hepatitis C virus (HCV) genomes could illuminate key aspects of transmission biology, immunopathogenesis and natural history. We used single genome sequencing of 2,922 half or quarter genomes from plasma viral RNA to identify transmitted/founder (T/F) viruses in 17 subjects with acute community-acquired HCV infection. Sequences from 13 of 17 acute subjects, but none of 14 chronic controls, exhibited one or more discrete low diversity viral lineages. Sequences within each lineage generally revealed a star-like phylogeny of mutations that coalesced to unambiguous T/F viral genomes. Numbers of transmitted viruses leading to productive clinical infection were estimated to range from 1 to 37 or more (median = 4). Four acutely infected subjects showed a distinctly different pattern of virus diversity that deviated from a star-like phylogeny. In these cases, empirical analysis and mathematical modeling suggested high multiplicity virus transmission from individuals who themselves were acutely infected or had experienced a virus population bottleneck due to antiviral drug therapy. These results provide new quantitative and qualitative insights into HCV transmission, revealing for the first time virus-host interactions that successful vaccines or treatment interventions will need to overcome. Our findings further suggest a novel experimental strategy for identifying full-length T/F genomes for proteome-wide analyses of HCV biology and adaptation to antiviral drug or immune pressures.Item Open Access Etiologies of illness among patients meeting integrated management of adolescent and adult illness district clinician manual criteria for severe infections in northern Tanzania: implications for empiric antimicrobial therapy.(Am J Trop Med Hyg, 2015-02) Rubach, Matthew P; Maro, Venance P; Bartlett, John A; Crump, John AWe describe the laboratory-confirmed etiologies of illness among participants in a hospital-based febrile illness cohort study in northern Tanzania who retrospectively met Integrated Management of Adolescent and Adult Illness District Clinician Manual (IMAI) criteria for septic shock, severe respiratory distress without shock, and severe pneumonia, and compare these etiologies against commonly used antimicrobials, including IMAI recommendations for emergency antibacterials (ceftriaxone or ampicillin plus gentamicin) and IMAI first-line recommendations for severe pneumonia (ceftriaxone and a macrolide). Among 423 participants hospitalized with febrile illness, there were 25 septic shock, 37 severe respiratory distress without shock, and 109 severe pneumonia cases. Ceftriaxone had the highest potential utility of all antimicrobials assessed, with responsive etiologies in 12 (48%) septic shock, 5 (14%) severe respiratory distress without shock, and 19 (17%) severe pneumonia illnesses. For each syndrome 17-27% of participants had etiologic diagnoses that would be non-responsive to ceftriaxone, but responsive to other available antimicrobial regimens including amphotericin for cryptococcosis and histoplasmosis; anti-tuberculosis therapy for bacteremic disseminated tuberculosis; or tetracycline therapy for rickettsioses and Q fever. We conclude that although empiric ceftriaxone is appropriate in our setting, etiologies not explicitly addressed in IMAI guidance for these syndromes, such as cryptococcosis, histoplasmosis, and tetracycline-responsive bacterial infections, were common.Item Open Access Faced joint locking.(Journal of neurosurgery. Spine, 2011-01) Shaffrey, Christopher IItem Open Access Hepatic histological findings in suspected drug-induced liver injury: systematic evaluation and clinical associations.(Hepatology (Baltimore, Md.), 2014-02) Kleiner, David E; Chalasani, Naga P; Lee, William M; Fontana, Robert J; Bonkovsky, Herbert L; Watkins, Paul B; Hayashi, Paul H; Davern, Timothy J; Navarro, Victor; Reddy, Rajender; Talwalkar, Jayant A; Stolz, Andrew; Gu, Jiezhun; Barnhart, Huiman; Hoofnagle, Jay H; Drug-Induced Liver Injury Network (DILIN)Drug-induced liver injury (DILI) is considered to be a diagnosis of exclusion. Liver biopsy may contribute to diagnostic accuracy, but the histological features of DILI and their relationship to biochemical parameters and outcomes are not well defined. We have classified the pathological pattern of liver injury and systematically evaluated histological changes in liver biopsies obtained from 249 patients with suspected DILI enrolled in the prospective, observational study conducted by the Drug Induced Liver Injury Network. Histological features were analyzed for their frequency within different clinical phenotypes of liver injury and to identify associations between clinical and laboratory findings and histological features. The most common histological patterns were acute (21%) and chronic hepatitis (14%), acute (9%) and chronic cholestasis (10%), and cholestatic hepatitis (29%). Liver histology from 128 patients presenting with hepatocellular injury had more severe inflammation, necrosis, and apoptosis and more frequently demonstrated lobular disarray, rosette formation, and hemorrhage than those with cholestasis. Conversely, histology of the 73 patients with cholestatic injury more often demonstrated bile plugs and duct paucity. Severe or fatal hepatic injury in 46 patients was associated with higher degrees of necrosis, fibrosis stage, microvesicular steatosis, and ductular reaction among other findings, whereas eosinophils and granulomas were found more often in those with milder injury.We describe an approach for evaluating liver histology in DILI and demonstrate numerous associations between pathological findings and clinical presentations that may serve as a foundation for future studies correlating DILI pathology with its causality and outcome.Item Open Access Identifying Barriers and Practical Solutions to Conducting Site-Based Research in North America: Exploring Acute Heart Failure Trials As a Case Study.(Heart Fail Clin, 2015-10) Ambrosy, Andrew P; Mentz, Robert J; Krishnamoorthy, Arun; Greene, Stephen J; Severance, Harry WAlthough the prognosis of ambulatory heart failure (HF) has improved dramatically there have been few advances in the management of acute HF (AHF). Despite regional differences in patient characteristics, background therapy, and event rates, AHF clinical trial enrollment has transitioned from North America and Western Europe to Eastern Europe, South America, and Asia-Pacific where regulatory burden and cost of conducting research may be less prohibitive. It is unclear if the results of clinical trials conducted outside of North America are generalizable to US patient populations. This article uses AHF as a paradigm and identifies barriers and practical solutions to successfully conducting site-based research in North America.Item Open Access Phenytoin, levetiracetam, and pregabalin in the acute management of refractory status epilepticus in patients with brain tumors.(Neurocrit Care, 2012-02) Swisher, Christa B; Doreswamy, Meghana; Gingrich, Krista J; Vredenburgh, James J; Kolls, Brad JBACKGROUND: There were nearly 700,000 patients in the United States in 2010 living with brain tumor diagnoses. The incidence of seizures in this population is as high as 70% and is historically difficult to control. Approximately 30-40% of brain tumors patients who present with status epilepticus (SE) will not respond to typical therapy consisting of benzodiazepines and phenytoin (PHT), resulting in patients with refractory status epilepticus (RSE). RSE is usually treated with anesthetic doses of propofol or midazolam infusions. This therapy can have significant risk, particularly in patients with cancer. METHODS: A retrospective chart review was performed on 23 patients with primary or metastatic brain tumors whose SE was treated with intravenous PHT, levetiracetam (LEV), and oral pregabalin (PGB). RESULTS: In all the patients under study, PHT or LEV was used as first-line therapy. PGB was typically used as third-line treatment. The median daily dose of PGB was 375 mg (usually divided BID or TID), and the median daily dose of LEV 3000 mg (usually divided BID). Cessation of SE was seen in 16/23 (70%) after administration of PHT, LEV, and PGB. SE was aborted, on average, 24 h after addition of the third antiepileptic drug. Only one patient in the responder group required intubation. Mortality rate was zero in the responder group. No adverse reactions to this medication regimen were observed. CONCLUSION: Our study suggests that the administration of PHT, LEV, and PGB in brain tumor patients with RSE is safe and highly effective.Item Open Access Profiles of serum cytokines in acute drug-induced liver injury and their prognostic significance.(PloS one, 2013-01) Steuerwald, Nury M; Foureau, David M; Norton, H James; Zhou, Jie; Parsons, Judith C; Chalasani, Naga; Fontana, Robert J; Watkins, Paul B; Lee, William M; Reddy, K Rajender; Stolz, Andrew; Talwalkar, Jayant; Davern, Timothy; Saha, Dhanonjoy; Bell, Lauren N; Barnhart, Huiman; Gu, Jiezhun; Serrano, Jose; Bonkovsky, Herbert LDrug-induced liver injury (DILI) is the most common cause of acute liver failure in the United-States. The aim of the study was to describe serum immune profiles associated with acute DILI, to investigate whether there are profiles associated with clinical features or types of DILI and/or with prognosis, and to assess temporal changes in levels. Twenty-seven immune analytes were measured in the sera of 78 DILI subjects in the Drug-Induced Liver Injury Network (DILIN) and compared with 40 healthy controls. Immune analytes (14 cytokines, 7 chemokines and 6 growth factors) were measured by BioPlex multiplex ELISA at DILI onset and after 6 months. A modeling process utilizing immune principles was used to select a final set of variables among 27 immune analytes and several additional clinical lab values for prediction of early death (within 6 months of DILI onset). Nineteen of the 27 immune analytes were differentially expressed among healthy control, DILI onset and 6-month cohorts. Disparate patterns of immune responses, especially innate and adaptive cellular (mostly TH17) immunity were evident. Low values of four immune analytes (IL-9, IL-17, PDGF-bb and RANTES) and serum albumin are predictive of early death [PPV = 88% (95% CI, 65%-100%), NPV = 97% (95% CI, 93%-100%), accuracy = 96% (95% CI, 92%-100%)].Acute DILI is associated with robust and varying immune responses. High levels of expression of cytokines associated with innate immunity are associated with a poor prognosis, whereas high levels of expression of adaptive cytokines are associated with good long-term prognosis and eventual recovery. Serum immune analyte profiles at DILI onset appear to be of prognostic, and perhaps, diagnostic significance.Item Open Access Quality of Care and Outcomes for Patients With Stroke in the United States Admitted During the International Stroke Conference.(Journal of the American Heart Association, 2018-11) Messé, Steven R; Mullen, Michael T; Cox, Margueritte; Fonarow, Gregg C; Smith, Eric E; Saver, Jeffrey L; Reeves, Mathew J; Bhatt, Deepak L; Matsouaka, Roland; Schwamm, Lee HBackground Patients presenting to hospitals during non-weekday hours experience worse outcomes, often attributed to reduced staffing. The American Heart Association International Stroke Conference ( ISC ) is well attended by stroke clinicians. We sought to determine whether patients with acute ischemic stroke ( AIS ) admitted during the ISC receive less guideline-adherent care and experience worse outcomes. Methods and Results We performed a retrospective cohort study of US hospitals participating in Get With The Guidelines-Stroke and assessed use of intravenous tissue plasminogen activator, other quality measures, and outcomes for patients with AIS admitted during the ISC compared with those admitted the weeks before and after the conference. A total of 69 738 patients with AIS were included: mean age, 72 years; 52% women; 29% nonwhite. There was no difference between the average weekly number of AIS cases admitted during ISC weeks versus non- ISC weeks (1984 versus 1997; P=0.95). Patient and hospital characteristics were similar between ISC and non- ISC time periods. There were no significant differences in 14 quality metrics and 5 clinical outcomes between patients with AIS treated during the ISC versus non- ISC weeks. Patients with AIS who presented within 2 hours of onset had no difference in the likelihood of receiving intravenous tissue plasminogen activator within 3 hours (adjusted odds ratio, 0.89; 95% confidence interval, 0.77-1.03; P=0.13) or the likelihood of receiving intravenous tissue plasminogen activator within 60 minutes of arrival (adjusted odds ratio, 0.92; 95% confidence interval, 0.83-1.02; P=0.13). Conclusions Patients with acute stroke admitted to Get With The Guidelines-Stroke hospitals during ISC received the same quality care and had similar outcomes as patients admitted at other times.Item Open Access Relationship of physical function with quality of life in older patients with acute heart failure.(Journal of the American Geriatrics Society, 2021-07) Aladin, Amer I; Whellan, David; Mentz, Robert J; Pastva, Amy M; Nelson, M Benjamin; Brubaker, Peter; Duncan, Pamela; Reeves, Gordon; Rosenberg, Paul; Kitzman, Dalane WBackground
Older patients with acute decompensated heart failure (ADHF) have severely impaired physical function (PF) and quality of life (QOL). However, relationships between impairments in PF and QOL are unknown but are relevant to clinical practice and trial design.Methods
We assessed 202 consecutive patients hospitalized with ADHF in the multicenter Rehabilitation Therapy in Older Acute HF Patients (REHAB-HF) Trial. PF measures included Short Physical Performance Battery (SPPB) and 6-min walk distance (6MWD). Disease-specific QOL was assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ). General QOL was assessed by the Short Form-12 (SF-12) and EuroQol-5D-5L. PF was evaluated as a predictor of QOL using stepwise regression adjusted for age, sex, race, and New York Heart Association class.Results
Participants were 72 ± 8 years, 54% women, 55% minority race, 52% with reduced ejection fraction, and body mass index 33 ± 9 kg/m2 . Participants had severe impairments in PF (6MWD 185 ± 99 m, SPPB 6.0 ± 2.5 units) and disease-specific QOL (KCCQ Overall Score 41 ± 21 and Physical Score 47 ± 24) and general QOL (SF-12 Physical Score 28 ± 9 and EuroQol Visual Analog Scale 57 ± 23). There were modest, statistically significant correlations between 6MWD and KCCQ Overall, KCCQ Physical Limitation, and SF-12 Physical Scores (r = 0.23, p < 0.001; r = 0.30, p < 0.001; and r = 0.24, p = 0.001, respectively); and between SPPB and KCCQ Physical and SF-12 Physical Scores (r = 0.20, p = 0.004, and r = 0.19, p = 0.007, respectively). Both 6MWD and SPPB were correlated with multiple components of the EuroQol-5D-5L. 6MWD was a significant, weak predictor of KCCQ Overall Score and SF-12 Physical Score (estimate = 0.05 ± 0.01, p < 0.001 and estimate = 0.05 ± 0.02, p = 0.012, respectively). SPPB was a significant, weak predictor of KCCQ Physical Score and SF-12 Physical Score (estimate = 1.37 ± 0.66, p = 0.040 and estimate = 0.54 ± 0.25, p = 0.030, respectively).Conclusion
In older, hospitalized ADHF patients, PF and QOL are both severely impaired but are only modestly related, suggesting that PF and QOL provide complementary information and assessment of both should be considered to fully assess clinically meaningful patient-oriented outcomes.Item Open Access Relief and Recurrence of Congestion During and After Hospitalization for Acute Heart Failure: Insights From Diuretic Optimization Strategy Evaluation in Acute Decompensated Heart Failure (DOSE-AHF) and Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARESS-HF).(Circ Heart Fail, 2015-07) Lala, Anuradha; McNulty, Steven E; Mentz, Robert J; Dunlay, Shannon M; Vader, Justin M; AbouEzzeddine, Omar F; DeVore, Adam D; Khazanie, Prateeti; Redfield, Margaret M; Goldsmith, Steven R; Bart, Bradley A; Anstrom, Kevin J; Felker, G Michael; Hernandez, Adrian F; Stevenson, Lynne WBACKGROUND: Congestion is the most frequent cause for hospitalization in acute decompensated heart failure. Although decongestion is a major goal of acute therapy, it is unclear how the clinical components of congestion (eg, peripheral edema, orthopnea) contribute to outcomes after discharge or how well decongestion is maintained. METHODS AND RESULTS: A post hoc analysis was performed of 496 patients enrolled in the Diuretic Optimization Strategy Evaluation in Acute Decompensated Heart Failure (DOSE-AHF) and Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF) trials during hospitalization with acute decompensated heart failure and clinical congestion. A simple orthodema congestion score was generated based on symptoms of orthopnea (≥2 pillows=2 points, <2 pillows=0 points) and peripheral edema (trace=0 points, moderate=1 point, severe=2 points) at baseline, discharge, and 60-day follow-up. Orthodema scores were classified as absent (score of 0), low-grade (score of 1-2), and high-grade (score of 3-4), and the association with death, rehospitalization, or unscheduled medical visits through 60 days was assessed. At baseline, 65% of patients had high-grade orthodema and 35% had low-grade orthodema. At discharge, 52% patients were free from orthodema at discharge (score=0) and these patients had lower 60-day rates of death, rehospitalization, or unscheduled visits (50%) compared with those with low-grade or high-grade orthodema (52% and 68%, respectively; P=0.038). Of the patients without orthodema at discharge, 27% relapsed to low-grade orthodema and 38% to high-grade orthodema at 60-day follow-up. CONCLUSIONS: Increased severity of congestion by a simple orthodema assessment is associated with increased morbidity and mortality. Despite intent to relieve congestion, current therapy often fails to relieve orthodema during hospitalization or to prevent recurrence after discharge. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00608491, NCT00577135.