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The presence of residual undifferentiated pluripotent stem cells (PSCs) in PSC-derived cell therapy products (CTPs) is a major safety issue for their clinical application, due to the potential risk of PSC-derived tumor formation. An international multidisciplinary multisite study to evaluate a droplet digital PCR (ddPCR) approach to detect residual undifferentiated PSCs in PSC-derived CTPs was conducted as part of the Health and Environmental Sciences Institute Cell Therapy-TRAcking, Circulation & Safety Technical Committee. To evaluate the use of ddPCR in quantifying residual iPSCs in a cell sample, different quantities of induced pluripotent stem cells (iPSCs) were spiked into a background of iPSC-derived cardiomyocytes (CMs) to mimic different concentrations of residual iPSCs. A one step reverse transcription ddPCR (RT-ddPCR) was performed to measure mRNA levels of several iPSC-specific markers and to evaluate the assay performance (precision, sensitivity, and specificity) between and within laboratories. The RT-ddPCR assay variability was initially assessed by measuring the same RNA samples across all participating facilities. Subsequently, each facility independently conducted the entire process, incorporating the spiking step, to discern the parameters influencing potential variability. Our results show that a RT-ddPCR assay targeting ESRG, LINC00678, and LIN28Agenes offers a highly sensitive and robust detection of impurities of iPSC-derived CMs and that the main contribution to variability between laboratories is the iPSC-spiking procedure, and not the RT-ddPCR. The RT-ddPCR assay would be generally applicable for tumorigenicity evaluation of PSC-derived CTPs with appropriate marker genes suitable for each CTP.Graphical Abstract

Background: Studies have reported positive outcomes of blended care therapy (BCT), which combines face-to-face care with internet modules. However, there is insufficient evidence of its effectiveness across racial and ethnic groups. This study evaluated outcomes of a BCT program, which combined video psychotherapy with internet cognitive-behavioral modules, across race and ethnicity. Methods: Participants were 6492 adults, with elevated anxiety (Generalized Anxiety Disorder-7 [GAD-7] ≥ 8) and/or depression (Patient Health Questionnaire-9 [PHQ-9] ≥ 10) symptoms, enrolled in employer-offered BCT. Changes in anxiety (GAD-7) and depression (PHQ-9) symptoms during treatment were evaluated using individual growth curve models. Interaction terms of time with race and ethnicity tested for between-group differences. Treatment satisfaction was assessed using a Net Promoter measure (range = 1 (lowest satisfaction) to 5 (greatest satisfaction)). Results: Participants’ self-reported race and ethnicity included Asian or Pacific Islander (27.5%), Black or African American (5.4%), Hispanic or Latino (9.3%), and White (47.2%). Anxiety symptoms decreased during treatment (p< 0.01), with greater reductions among Hispanic or Latino participants compared to White participants (p< 0.05). Depressive symptoms decreased across treatment (p< 0.01), with significantly greater decreases among some racial and ethnic groups compared to White participants. Declines in anxiety and depressive symptoms slowed across treatment (p’s < 0.01), with statistically significant differences in slowing rates of depressive symptoms across some racial and ethnic groups. Among participants with responses (28.45%), average treatment satisfaction ranged from 4.46 (SD = 0.73) to 4.67 (SD = 0.68) across race and ethnicity (p= 0.001). Racial and ethnic differences in outcomes were small in magnitude. Conclusions: BCT for anxiety and depression can be effective across diverse racial and ethnic groups.

Resident cardiac macrophages are critical mediators of cardiac function. Despite their known importance to cardiac electrophysiology and tissue maintenance, there are currently no stem-cell-derived models of human engineered cardiac tissues (hECTs) that include resident macrophages. In this study, we made an induced pluripotent stem cell (iPSC)-derived hECT model with a resident population of macrophages (iM0) to better recapitulate the native myocardium and characterized their impact on tissue function. Macrophage retention within the hECTs was confirmed via immunofluorescence after 28 days of cultivation. The inclusion of iM0s significantly impacted hECT function, increasing contractile force production. A potential mechanism underlying these changes was revealed by the interrogation of calcium signaling, which demonstrated the modulation of β-adrenergic signaling in +iM0 hECTs. Collectively, these findings demonstrate that macrophages significantly enhance cardiac function in iPSC-derived hECT models, emphasizing the need to further explore their contributions not only in healthy hECT models but also in the contexts of disease and injury.

Skin injury is repaired through a multi-phase wound healing process of tissue granulation and re-epithelialization. Any failure in the healing process may lead to chronic non-healing wounds or abnormal scar formation. Although significant progress has been made in developing novel scaffolds and/or cell-based therapeutic strategies to promote wound healing, effective management of large chronic skin wounds remains a clinical challenge. Keratinocytes are critical to re-epithelialization and wound healing. Here, we investigated whether exogenous keratinocytes, in combination with a citrate-based scaffold, enhanced skin wound healing. We first established reversibly immortalized mouse keratinocytes (iKera), and confirmed that the iKera cells expressed keratinocyte markers, and were responsive to UVB treatment, and were non-tumorigenic. In a proof-of-principle experiment, we demonstrated that iKera cells embedded in citrate-based scaffold PPCN provided more effective re-epithelialization and cutaneous wound healing than that of either PPCN or iKera cells alone, in a mouse skin wound model. Thus, these results demonstrate that iKera cells may serve as a valuable skin epithelial source when, combining with appropriate biocompatible scaffolds, to investigate cutaneous wound healing and skin regeneration.

Monitoring of measurable residual disease (MRD) is essential to the management of acute lymphoblastic leukemia (ALL) and is typically performed through repeated bone marrow (BM) assessments. Using a next-generation sequencing (NGS) MRD platform, we performed a prospective observational study evaluating the correlation between peripheral blood (PB) and BM MRD in adults with ALL receiving cellular therapies (hematopoietic cell transplantation [HCT] and chimeric antigen receptor T-cell [CAR-T] therapies). Among the study cohort (N = 69 patients; 126 paired PB/BM samples), we found strong correlation between PB and BM MRD (r = 0.87; P < .001), with a sensitivity and specificity of MRD detection in the PB of 87% and 90%, respectively, relative to MRD in the BM. MRD became detectable in the PB in 100% of patients who subsequently relapsed following HCT, with median time from MRD+ to clinical relapse of 90 days, and in 85% of patients who relapsed following CAR T, with median time from MRD+ to clinical relapse of 60 days. In adult patients with ALL undergoing cellular therapies, we demonstrate strong concordance between NGS-based MRD detected in the PB and BM. Monitoring of ALL MRD in the PB appears to be an adequate alternative to frequent invasive BM evaluations in this clinical setting.

Measurable residual disease (MRD) is associated with poor prognosis in acute myeloid leukemia (AML), even after allogeneic hematopoietic cell transplantation (HCT). New next-generation sequencing (NGS) methods have emerged as a highly sensitive and specific method to detect MRD. In addition to defining the role of post-HCT MRD monitoring in FLT3-ITD mutated AML, there is great interest in the optimal use of oral FLT3 tyrosine kinase inhibitors (FLT3 inhibitors) to maintain remission following HCT. In this study, we evaluated the clinical impact of sensitive FLT3 MRD testing early after HCT and maintenance FLT3 inhibitor use at our transplant center. We found that there was a trend towards inferior progression-free survival (PFS) for patients with early post-HCT MRD, but that overall survival (OS) was not significantly impacted by MRD. The use of maintenance FLT3 inhibitors led to a significantly superior PFS and OS in our cohort, and improved PFS and OS in both MRD-negative and MRD-positive patients. Altogether, our results demonstrate the prognostic significance of NGS-based MRD monitoring for FLT3-ITD and the ability of post-HCT maintenance therapy to prevent relapse and death in FLT3-ITD mutated AML.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ajo.2008.02.001 Byline: Connie J. Chen (b), Christopher E. Starr (a) Abstract: To describe the epidemiologic features, risk factors, and antibiotic susceptibilities for gram-negative conjunctivitis among neonatal intensive care unit (NICU) patients. Author Affiliation: (a) Department of Ophthalmology, Weill Cornell Medical Center, New York-Presbyterian Hospital, New York, New York (b) Weill Cornell Medical College, New York, New York. Article History: Accepted 5 February 2008

Error-corrected next-generation sequencing (ecNGS) is an emerging technology with the potential to revolutionize the field of genetic toxicology. Here, we present recommendations from an expert working group convened to discuss potential applications, advantages and challenges associated with implementing ecNGS in nonclinical safety studies.

Leukapheresis is a resource-intensive and high-risk treatment with unclear benefits when used for leukostasis syndrome in hematologic malignancies. In this case report and literature review we discuss the pathophysiology of leukostasis syndrome associated with chronic lymphocytic leukemia (CLL) and the rapidly evolving paradigm of CLL treatment through the lens of a 51-year-old man who was diagnosed with CLL. He presented with clinical manifestations of leukostasis syndrome with an absolute lymphocyte count of 522.6×109/L. We identified 15 additional cases of CLL-associated leukostasis syndrome in our literature review. Pulmonary and neurologic manifestations of leukostasis were most common. In combination with pharmacologic cytoreduction, leukapheresis was used successfully in most cases with few reports of complications. In the context of greater adoption of first line therapies for CLL that are known to induce transient leukocytosis, we explore leukapheresis as an adjunctive therapy that can rapidly reduce the lymphocyte count and in select instances possibly mitigate the effects of Bruton's tyrosine kinase inhibitor-induced hyperleukocytosis.

Tofacitinib is an oral JAKinhibitor indicated for the treatment of rheumatoid arthritis (RA). We characterized lymphoma events in the tofacitinib RAclinical development program. Lymphoma events (up to March 2015) were identified from 19 tofacitinib studies (2 phase I, 9 phase II, 6 phase III, and 2 long‐term extension) of patients with moderate to severe RA. Patients in these studies received tofacitinib dosed at 1–30 mg twice daily or 20 mg once daily, as monotherapy or with conventional synthetic disease‐modifying antirheumatic drugs. Lymphoma incidence rates (IRs; number of patients with events/100 patient‐years) and standardized incidence ratios (SIRs) were calculated. A descriptive case–matched control analysis (1:4) was performed to identify potential risk factors for lymphoma. A total of 6,194 patients received tofacitinib (19,406 patient‐years of exposure, 3.4 years median treatment duration). Nineteen lymphomas occurred (IR0.10 [95% confidence interval (95% CI) 0.06–0.15]), with no increase observed with time of exposure. The age‐ and sex‐adjusted SIRof lymphoma was 2.62 (95% CI1.58–4.09) (Surveillance, Epidemiology, and End Results [SEER] program database). The clinical characteristics of the 19 lymphomas were typical for the RApopulation. Three lymphomas were positive for Epstein‐Barr virus, 8 were negative, 2 were equivocal, and 6 were untested. Numerically, more lymphoma cases had a history of Sjögren's syndrome and were positive for anti–cyclic citrullinated protein and rheumatoid factor at baseline versus matched controls. The mean corticosteroid dose was higher for lymphoma cases versus controls. In the tofacitinib RAclinical development program, lymphoma rates were stable over time and there were minimal differences in the baseline characteristics of patients with and without lymphoma.

IMPORTANCE: Incontinentia pigmenti (IP) is a rare, X-linked dominant disease with potentially severe ocular complications that predominantly affect the peripheral retina. However, little is known about its effects on the macula. OBJECTIVE: To describe the structural and vascular abnormalities observed in the maculas of patients with IP and to correlate these findings with peripheral pathologies. DESIGN, SETTING, AND PARTICIPANTS: Prospective, cross-sectional study at Wilmer Eye Institute, Johns Hopkins University. Five participants with a clinical diagnosis of IP were included and underwent multimodal imaging with ultra–wide-field fluorescein angiography (FA), spectral-domain optical coherence tomography (OCT), and OCT angiography. MAIN OUTCOMES AND MEASURES: The structural and vascular abnormalities observed on spectral-domain OCT and OCT angiography and their correlation with peripheral pathologies seen on ultra–wide-field FA. RESULTS: A total of 9 eyes from 5 patients (median age, 20.5 years; range, 8.4-54.2 years) were included. Median Snellen visual acuity was 20/32 (range, 20/16 to 20/63). ultra–wide-field FA-identified retinal vascular abnormalities in all 7 eyes in which FA was obtained. These abnormalities included microaneurysms, areas of nonperfusion, and vascular anastomoses, most of which were peripheral to the standard view of 30° FA with peripheral sweeps. Structural abnormalities were observed in 6 eyes on spectral-domain OCT, including inner retinal thinning and irregularities in the outer plexiform layer. Optical coherence tomography angiography abnormalities were noted in all 9 eyes, including decreased vascular density, abnormal vascular loops, and flow loss in the superficial and deep plexuses, which corresponded to areas of retinal thinning on spectral-domain OCT. CONCLUSIONS AND RELEVANCE: Although our study is limited by the small sample size, the findings suggest that multimodal imaging is useful for detecting structural and vascular abnormalities that may not be apparent on ophthalmoscopy in patients with IP. Macular pathologies, especially a decrease in vascular density on OCT angiography, are common. Further studies are needed to characterize further the association between macular and peripheral abnormalities in patients with IP.

Asymmetric retinal disease in the same individual and variable retinal manifestations among family members with incontinentia pigmenti can be explained by random X-chromosome inactivation or other epigenetic modifications.

Objectives:To conduct a systematic review and network meta-analysis (NMA) to assess effectiveness of first-line treatments for advanced renal cell carcinoma (RCC).Methods:Database searches were conducted to identify randomized controlled trials (RCTs) reporting results for eligible treatments. A fixed-effect Bayesian NMA was conducted to assess the relative effectiveness of treatments, with progression-free survival (PFS) reported as hazard ratios (HRs) and 95% credible intervals (CrIs).Results:Eleven unique RCTs were suitable for inclusion in the NMA. In the base case, in terms of PFS, sunitinib was superior compared with bevacizumab IFN-α (HR 0.79, 95% CrI: 0.64 – 0.96), everolimus (HR 0.70, 95% CrI: 0.56 – 0.87), sorafenib (HR 0.56, 95% CrI: 0.40 – 0.77) and temsirolimus bevacizumab (HR 0.74, 95% CrI: 0.56 – 0.96). Although, the point values for the mean and median HRs were < 1.0, there was no significant difference in PFS between sunitinib and axitinib, pazopanib or tivozanib. Although sensitivity analyses impacted the results of the NMA, no treatment was significantly more efficacious than sunitinib.Conclusion:Results from this analysis suggest that there is no treatment superior to the current benchmark treatment, sunitinib, in the management of advanced RCC in the first-line setting.

Aim:To identify the most common first, second, and third lines of therapy and associated costs among patients treated for lung cancer. Methods:This retrospective analysis of healthcare claims identified patients treated for lung cancer from January 2007 through April 2012. Patients were enrolled in first-, second-, or third-line therapy cohorts and stratified by the number of discrete treatments received or by the specific chemotherapy or biologically targeted agent or combination of agents. Results:Of patients receiving first-line treatment (either chemotherapy or biologically targeted therapies), 18.3 and 4.4 received second-line and third-line treatment, respectively. Pemetrexed, topotecan, docetaxel, and erlotinib were the most commonly second-line regimens; pemetrexed and erlotinib were the most common third-line regimens. While total costs increased with increasing lines of treatment, costs per patient per month remained stable or decreased overall. Conclusion:Platinum/taxane combined treatment is still the mainstay of first-line therapy for lung cancer treatment for those with advanced disease. Second- and third-line therapy is still prescribed infrequently, although newer agents are more commonly used in this setting.

IMPORTANCE: Extended follow-up of treated and untreated retinopathy in incontinentia pigmenti (IP) has not previously been documented, to our knowledge. OBJECTIVE: To determine which eyes with IP are at risk for retinal detachment. DESIGN, SETTING, AND PARTICIPANTS: Observational cohort study of patients with IP who were retrospectively identified at a tertiary care academic center between 1976 and 2013. Fifty eyes of 25 female participants meeting clinical criteria for IP were followed up for at least 6 months. The last year of follow-up was between 1987 and 2014. MAIN OUTCOMES AND MEASURES: Progression of retinopathy or the development of retinal detachment was assessed with fluorescein angiography, clinical examination, or both. RESULTS: The median duration of follow-up was 9.3 years (range, 0.5-22.8 years). Over this period, 11 eyes (22%; 95% CI, 11%-33%) developed retinal detachment. The odds of retinal detachment were increased if there was retinal neovascularization (odds ratio, 11.61; 95% CI, 1.34-100.56; P = .03) or ischemic optic neuropathy (odds ratio, 5.27; 95% CI, 1.61-17.23; P = .006) on initial examination. A bimodal distribution of retinal detachments was observed, with most tractional detachments (7 eyes) occurring by age 2.5 years (median, 1.5 years; range, 14 days-7.0 years) and most rhegmatogenous detachments (4 eyes) occurring in adults (median age, 31.5 years; range, 14.0-47.0 years). Three eyes of young patients (≤2.5 years) developed tractional detachment, despite prophylactic ablation in 4 eyes; only one eye of older patients (≥14.0 years) developed retinal detachment following prophylactic ablation in 6 eyes. Persistent fetal vasculature appears to occur more commonly in IP (14%; 95% CI, 4%-25%) than in the general population. CONCLUSIONS AND RELEVANCE: All eyes with retinopathy due to IP should be monitored throughout adulthood for the development of retinal complications. During infancy and early childhood, ophthalmoscopic examination should be performed frequently so that prompt treatment can be initiated if there is progressive disease. Because of the nonrandomized nature of this study, the indications for prophylactic ablation and its success rate remain uncertain. Patients with less than 6 months of follow-up were excluded from the analysis, which could have biased this study cohort toward patients with more severe or less severe disease.

The purpose of this project was to provide educational materials to healthcare professionals to enhance their ability to deliver patient-centered education and, ultimately, improve patients’ comprehension of personal risk factors for developing various skin cancers. Participants were 30 future nurse practitioners selected from nursing master programs at a university in New York City. Each participant was given a knowledge-based skin cancer pretest, followed by a focused educational session regarding various types of skin cancer, methods of prevention, and methods of detection, which was heavily focused on skin cancer presentation and detection among minority populations. After the educational session, participants were given a posttest to evaluate the session and to assess their level of comfort in treating and educating patients on skin cancer awareness and protection. Ratings of the overall educational tools and their level of comfort were recorded. Overall, participants found the educational material beneficial in increasing their confidence to properly educate patients on skin cancer awareness and protection.

Emerging digital technologies offer enormous potential to improve quality, reduce cost, and increase patient-centeredness in healthcare. Academic Medical Centers (AMCs) play a key role in advancing medical care through cutting-edge medical research, yet traditional models for invention, validation and commercialization at AMCs have been designed around biomedical initiatives, and are less well suited for new digital health technologies. Recently, two large bi-coastal Academic Medical Centers, the University of California, San Francisco (UCSF) through the Center for Digital Health Innovation (CDHI) and Partners Healthcare through the Center for Connected Health (CCH) have launched centers focused on digital health innovation. These centers show great promise but are also subject to significant financial, organizational, and visionary challenges. We explore these AMC initiatives, which share the following characteristics: a focus on academic research methodology; integration of digital technology in educational programming; evolving models to support “clinician innovators”; strategic academic–industry collaboration and emergence of novel revenue models.

Progression-free survival (PFS) is commonly used to demonstrate therapeutic benefit. We created a joint community-academic registry of patients with metastatic renal cell carcinoma (mRCC) who had undergone at least 1 line of systemic therapy (N = 325). Patients treated with sunitinib had the longest PFS in the first and second lines of therapy. Despite some practice variation, practice-based PFS seems consistent with trial-based expectations.

Increased research to improve preclinical models to inform the development of therapeutics for neonatal diseases is an area of great need. This article reviews five common neonatal diseases – bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, perinatal hypoxic–ischemic encephalopathy and neonatal sepsis – and the available in vivo, in vitro and in silico preclinical models for studying these diseases. Better understanding of the strengths and weaknesses of specialized neonatal disease models will help to improve their utility, may add to the understanding of the mode of action and efficacy of a therapeutic, and/or may improve the understanding of the disease pathology to aid in identification of new therapeutic targets. Although the diseases covered in this article are diverse and require specific approaches, several high-level, overarching key lessons can be learned by evaluating the strengths, weaknesses and gaps in the available models. This Review is intended to help guide current and future researchers toward successful development of therapeutics in these areas of high unmet medical need.

Objectives:A systematic review/meta-analysis was conducted to assess the effectiveness and safety of second-line treatments for advanced renal cell carcinoma (RCC), which includes the vascular endothelial growth factor inhibitor axitinib.Methods:Database searches were conducted to identify randomised controlled trials (RCTs). Indirect comparisons using a fixed-effect Bayesian model were used to assess the relative effectiveness of treatments and reported as hazard ratio (HR) and 95% credible intervals (CrI).Results:Although 24 RCTs met eligibility criteria, only three studies were included in the fixed-effect Bayesian meta-analysis, due to differences in patient inclusion criteria/reported outcomes in the wider dataset. Robust meta-analysis was restricted to the subgroup pretreated with cytokines. In terms of progression-free survival (PFS), axitinib was superior compared with placebo (HR 0.25, 95% CrI: 0.17 – 0.38), sorafenib (HR 0.46, 95% CrI: 0.32 – 0.68) and pazopanib (HR 0.47, 95% CrI: 0.26 – 0.85). An analysis including all patients, regardless of previous first-line treatment, reported similar results. There was no significant difference in PFS between sorafenib and pazopanib.Conclusion:Results from the present study suggest that axitinib will be an important treatment option to extend PFS in the management of advanced RCC in the second-line setting. Ongoing research will define the optimal treatment algorithm leading to a patient-focused treatment strategy.

OBJECTIVE To characterize the phenotype of a white patient with occult macular dystrophy (OMD) and her clinically unaffected family members and to determine whether similar mutations were present in the RP1L1 gene in this family. Occult macular dystrophy is a rare macular dystrophy with central cone dysfunction hidden behind a normal fundus appearance that has been attributed to a mutation in the retinitis pigmentosa 1–like 1 (RP1L1) gene in 4 Japanese families. METHODS In this observational cross-sectional study of 1 white family with OMD, patients meeting the clinical criteria for OMD and their family members were evaluated by use of multifocal electroretinography, the Farnsworth D-15 color vision test, automated perimetry, spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence, and fundus photography. Fluorescein angiography was performed only on the proband. Members of this family were screened for genetic mutations in the RP1L1 gene. RESULTS In the family studied, the clinically affected proband was noted to have loss of the foveal outer segments and absence of bowing of the inner segment/outer segment junction on SD-OCT scans. In addition, 1 clinically unaffected family member also demonstrated loss of the foveal photoreceptor outer segments and, therefore, decreased bowing of the inner segment/outer segment junction on SD-OCT scans. The fundus autofluorescence images of the eyes of the proband and her family members were normal. Although mutations in the RP1L1 gene have been identified in sporadic and autosomal dominant OMD pedigrees, no mutations in the RP1L1 gene were found in any of the participants. CONCLUSIONS Loss of the outer segments of foveal photoreceptors can be detected and quantified by use of SD-OCT in patients with OMD. Similar findings are present in some clinically unaffected family members and may represent subclinical manifestations of the disease. Although mutations in the RP1L1 gene have been described in several Japanese families with OMD, there were no such mutations in this white family of European descent, which suggests that inherited OMD is a genetically heterogeneous disorder.

The treatment of advanced renal cell carcinoma has been revolutionised by targeted therapy with drugs that block angiogenesis. So far, no phase 3 randomised trials comparing the effectiveness of one targeted agent against another have been reported. We did a randomised phase 3 study comparing axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor (VEGF) receptors, with sorafenib, an approved VEGF receptor inhibitor, as second-line therapy in patients with metastatic renal cell cancer.

We retrospectively analyzed electronic medical records and performed supplemental chart reviews to assess compliance with National Comprehensive Cancer Network and St. Gallen guidelines with respect to adjuvant hormonal therapy (AHT) for early breast cancer. Women aged = 45 years with stages IB-IIIC breast cancer positive for estrogen receptors, progesterone receptors, or both and diagnosed between January 2005 and January 2007 were eligible. Patterns of receipt of tamoxifen, aromatase inhibitors, or both among women treated at a large community practice were evaluated regarding reasons for treatment selection, switch, or discontinuation. Of 206 patients meeting the inclusion criteria, 15 (7%) were lost to follow-up. Among the remaining 191 patients, most initiated AHT during the study period (n = 177; 89% postmenopausal) or had plans to initiate it after completing chemotherapy (n = 4); the rest did not receive AHT because they declined it (n = 5) or had medical contraindications (n = 5). Thus, guideline-adherent therapy was given in 181 (95%) of the patients, and the remaining 10 (5%) patients had warranted variations.

This longitudinal, prospective study sought to establish whether pediatric Crohn’s disease (CD) and ulcerative colitis (UC) are associated with increased levels of cytogenetic damage and whether folate supplementation in combination with other treatments mitigates cytogenetic damage in children with inflammatory bowel disease (IBD). After a 1-mo treatment and folate supplementation, all clinical tests in CD (n24) and UC (n17) patients improved. Patients with CD were comparable in the cytogenetic response with controls (n28) assessed by micronucleus (MN) assay, but both groups differed from the UC group. While the MN frequency in epithelial cells slightly decreased from first to second observations in CD patients (p0.05) and controls (p0.11), an increase was observed in UC patients (p0.001). Similar changes were observed in blood lymphocytes resulting in significantly higher levels of the MNs and chromosome bridges in UC patients. These preliminary findings of a difference in chromosome damage between pediatric UC patients compared with CD patients and healthy controls warrant confirmation and expansion to determine (1) the role of cytogenetic damage in the pathogenesis of these diseases, (2) relative contribution of treatment and folate supplementation, and (3) potential links to the eventual development of cancer in some patients.

Muffly: Adaptive: Research Funding; Amgen: Consultancy; Servier: Research Funding. Meyer:Orca Bio: Research Funding. Negrin:Amgen: Consultancy; Magenta Therapeutics: Consultancy, Current equity holder in publicly-traded company; BioEclipse Therapeutics: Current equity holder in private company; Biosource: Current equity holder in private company; UpToDate: Honoraria; KUUR Therapeutics: Consultancy. Rezvani:Pharmacyclics: Research Funding. Sidana:Janssen: Consultancy. Shiraz:ORCA BioSystems: Research Funding; Kite, a Gilead Company: Research Funding. Shizuru:Jasper Therapeutics, Inc: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees. Liedtke:Adaptive: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria. Miklos:Kite-Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Adaptive Biotech: Consultancy, Other: Travel support, Research Funding; Allogene Therapeutics Inc.: Research Funding; Novartis: Consultancy, Other: Travel support, Research Funding; Pharmacyclics: Consultancy, Other: Travel support, Patents & Royalties, Research Funding; Juno-Celgene-Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding; Janssen: Consultancy, Other: Travel support; Miltenyi Biotec: Research Funding.

The limited antioxidative capacity of the embryo and fetus may increase their risk for cancer initiation and/or promotion by reactive oxygen species (ROS)-mediated oxidative DNA damage and/or signaling. To determine if cancer can originate in utero, a high dietary dose of the antioxidant vitamin E (VE) (10% dl-α-tocopherol-acetate) was given to cancer-prone p53 knockout mice throughout pregnancy. Although reducing fetal death (P < 0.05), in utero exposure to VE enhanced postnatal tumorigenesis in both +/− (P < 0.04) and −/− (P < 0.0008) p53-deficient offspring. VE did not alter maternal weights, offspring p53 genotypic distribution or tumor spectrum. Constitutive embryonic DNA oxidation in untreated −/− p53 embryos [gestational day (GD) 13] was higher than in +/− and +/+ p53 littermates (P < 0.05). VE reduced DNA oxidation in −/− p53 embryos (P < 0.05) without affecting +/− and +/+ p53 littermates. VE had contrasting, tissue-dependent effects on fetal (GD 19) DNA oxidation, with reductions in −/− and +/− p53-deficient fetal brains (P < 0.01), increases in skin (P < 0.05) and no effect in liver and thymus. The 250-fold increase in dietary VE levels produced only 1.6–6.3-fold, tissue-dependent increases in tissue concentrations. The greatest increase, in fetal skin, correlated with increased DNA oxidation in that tissue in −/− and +/− p53-deficient fetuses and enhanced tumorigenesis in these genotypes. These results show that some cancers may originate in utero and the risk can be enhanced by embryonic and fetal exposure to high dietary levels of VE. The elevated DNA oxidation in some tissues of untreated −/− p53 offspring suggests that ROS may contribute to their higher baseline tumor incidence. The limited and tissue-dependent disposition of VE indicates substantial conceptal regulation. The similarly selective and contrasting effects of VE on DNA oxidation may contribute to its controversial protective efficacy and suggest that its effects on tumorigenesis are cell-specific, possibly in high doses involving a pro-oxidative mechanism.

This study examined the association between genetic polymorphisms and enzyme activity for antioxidant enzymes that share a common detoxification pathway manganese superoxide dismutase (MnSOD), glutathione peroxidase-1 (GPX1) and catalase.

ABSTRACT:Objective:The underuse of analgesics, or “oligoanalgesia,” is common in emergency departments (EDs). To improve care we must understand our patients’ pain experiences as well as our clinical practice patterns. To this end, we examined pain etiology, pain management practices and patient satisfaction in 2 urban EDs.Methods:We conducted a cross-sectional study using structured interviews and chart reviews for patients with pain who presented to either of 2 university-affiliated EDs. We assessed pain etiologies, patient pain experiences, pain management practices, and patient satisfaction with pain management.Results:The 525 study subjects reported high pain intensity levels on presentation, with a median rating of 8 on a 10-point numerical rating scale (NRS). At discharge, pain severity had decreased to a median rating of 4; however, 48% of patients were discharged from the ED in moderate to severe pain (NRS 5–10). Subjects reported spending 57% of their ED stay in moderate to severe pain. Analgesics were administered to only 50% of patients. The mean time to analgesic administration was almost 2 hours. Despite high levels of reported pain at discharge and low rates of analgesic administration, subjects reported high satisfaction with pain management.Conclusions:In the 2 EDs studied, we found high levels of pain severity for our patients, as well as low levels of analgesic use. When used, analgesic administration was often delayed. Despite these findings, patient satisfaction remained high. Despite recent efforts to improve pain management practice; oligoanalgesia remains a problem for our specialty.

BACKGROUND: The role of intravenous immunoglobulin (IVIG) in treating a variety of diseases is controversial and under active investigation for at least two reasons: first, a severe shortage of IVIG products exists in the US; second, numerous off-label (not specified in the Food and Drug Administration [FDA]–approved label) uses for IVIG have been, and continue to be, described in the literature. However, most off-label uses are not supported by evidence from properly designed clinical trials.OBJECTIVE: To assess inpatient use of IVIG in a sample of US academic health centers and to compare it with published evidence-based model guidelines for IVIG use.METHODS: Data on the use of IVIG and subsequent clinical outcomes in 251 patients were collected prospectively from 12 institutions. Recommendations from consensus guidelines were used to categorize patients who received IVIG into one of four groups: labeled uses; off-label, recommended; off-label, recommended as alternative; and off-label, not recommended. Outcomes were scored according to guideline criteria.RESULTS: One hundred seven patients (43%) received IVIG for indications contained in the FDA-approved product label, 130 patients (52%) received IVIG for off-label indications, and 14 (5%) received undefined treatment. Among all patients administered IVIG, 31 (12%) were treated for off-label recommended reasons; 64 (26%) received off-label recommended as alternative therapy; and 35 (14%) received off-label not recommended therapy, as defined by model guidelines. Outcomes were not significantly different between the groups.CONCLUSIONS: Our findings suggest that IVIG continues to be used to treat a wide variety of conditions not specified in the product label. Furthermore, a substantial proportion of the reported off-label uses are not recommended according to evidence-based guidelines.

This study audited the efficiency and accuracy of patient billing and reimbursement systems for epoetin alfa (Epo). The outpatient records of 604 chronic dialysis patients at eight academic health centers, from selected quarters during 1989 to 1993, were reviewed. The number of units administered or dispensed for home use was compared with Health Care Finance Administration (HCFA) reimbursement records. Overall, 18% (range 2% to 45% per institution) of the Epo administered or dispensed at the study sites was not represented in the HCFA reimbursement records. Institutions may be losing some entitled reimbursement for Epo and should evaluate their reporting/billing practices. The extent to which reimbursement for Epo, our test drug, reflects billing/reimbursement inefficiencies for other drugs deserves further evaluation.

We compared the rates of exposure to blood in the operating room among third-year medical students during 2005-2006 with the rates reported in a study completed at the same institution during 1990-1991. The number of medical students exposed to blood decreased from 66 (68%) of 97 students during 1990-1991 to 8 (11%) of 75 students during 2005-2006 (P< .001)

The β thalassemia trait is associated with over 300 mutations in the β-globin gene that lead to reduced (β+ allele) or absent (β0 allele) synthesis of the β globin chain. A subset of these mutations affect the canonic splicing of the β globin mRNA. Such mutations activate aberrant splice sites, which lead to an altered splicing pathway and consequently affects protein synthesis.

Dong: Aruvant Sciences INC: Employment. Motta:Sanofi-Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees. Guo:Ionis Pharmaceutical, INC: Employment, Other: shareholders. Peralta:Ionis Pharmaceutical, Inc: Employment. Freier:Ionis Pharmaceuticals: Employment. Watt:Ionis Pharmaceuticals: Employment. Manwani:Novartis: Consultancy; Pfizer: Consultancy; GBT: Consultancy, Research Funding. Cappellini:Genzyme/Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Honoraria; Vifor Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; CRISPR Therapeutics: Membership on an entity's Board of Directors or advisory committees. Abdulmalik:The Children's Hospital of Philadelphia: Patents & Royalties: Provisional Patent. Rivella:Meira GTx, Ionis Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Disc medicine, Protagonist, LIPC, Meira GTx: Consultancy.

Chen: Vida Health: Employment, Equity Ownership. Mao:Vida Health: Employment.

Guo: Ionis Pharmaceuticals: Employment, Equity Ownership. Peralta:Ionis Pharmacueticals: Employment. Cappellini:Celgene: Membership on an entity's Board of Directors or advisory committees; Genzyme-Sanofi: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.