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What is known and Objective A pandemic can strain all aspects of the healthcare system, including the ability to monitor the safety of medication use. Reviewing the adequacy of medication safety practices during the COVID‐19 pandemic is critical to informing responses to future pandemics. The purpose of this study was to evaluate medication safety practices at a height of both COVID‐19 cases and hydroxychloroquine use. Methods This was a multicentre observational point prevalence study. Adult inpatients receiving hydroxychloroquine for COVID‐19 between March 22 and 28, 2020 were included. The primary outcome was the percentage of patients receiving appropriate QTc monitoring. Secondary outcomes included QTc prolongation, early discontinuation of hydroxychloroquine and ventricular arrhythmias. Results and discussion A total of 59% (167/284) of patients treated with hydroxychloroquine received appropriate QTc monitoring. QTc prolongation occurred in 25%. Hydroxychloroquine was prematurely discontinued in 1.4% of patients, all due to QTc prolongation. Ventricular arrhythmia occurred in 1.1%. What is new and Conclusion Medication safety practices were suboptimal with regard to hydroxychloroquine monitoring at the height of the COVID‐19 pandemic. Preparation for future pandemics should devote considerable attention to medication safety., This point prevalence study found that at the height of the COVID‐19 pandemic use of hydroxychloroquine was widespread despite being unproven. At the same time, medication safety practices in the form of QTc monitoring were suboptimal. Preparation for future pandemics should devote considerable attention to medication safety.

The Fourth Annual Symposium on Hidradenitis Suppurativa (SHSA) took place on November 1-3, 2019, at the Westin Book Cadillac Hotel in Detroit, Michigan. This symposium was a joint meeting of the US Hidradenitis Suppurativa Foundation and the Canadian Hidradenitis Suppurativa Foundation. This cross-disciplinary meeting with experts from around the world was an opportunity to discuss the most recent advances in the study of hidradenitis suppurativa (HS) pathogenesis, clinical trials, classification, scoring systems, complementary/alternative medical treatments, diet, pain management, surgical and laser treatment, and ultrasonographic assessment. A special preconference workshop was held on the use of neodymium-doped yttrium-aluminum-garnet laser hair reduction, sinus tract deroofing, and carbon dioxide laser excision with ultrasonographic mapping and tumescent anesthesia for the treatment of HS. The focused workshops on establishing an HS clinic, setting up an HS support group, the Hidradenitis Suppurativa Prospective Observational Registry and Biospecimen Repository, and wound care were held during the meeting. A special program called HS Ambassadors was established for patients who may have questions about the conference presentations, and in addition, a meet and greet for patients and HS Ambassadors was arranged. To facilitate networking between those early in their careers and clinical and research experts, a mentoring reception was held.

Socioeconomic status (SES) has led to treatment and survival disparities; however, limited data exist for non‐small cell lung cancer (NSCLC). This study investigates the impact of SES on NSCLC diagnostic imaging, treatment, and overall survival (OS), and describes temporal disparity trends. The Ontario Cancer Registry was used to identify NSCLC patients diagnosed between 2007 and 2016. Through linkage to administrative datasets, patients’ demographics, imaging, treatment, and survival were obtained. Based on median household neighborhood income, the Ontario population was divided into five income quintiles (Q1‐Q5; Q1 = lowest income). Multivariable regressions assessed SES association with OS, imaging, treatment receipt, and treatment delay, and their interaction with year of diagnosis to understand temporal trends. Endpoints were adjusted for demographics, stage and comorbidities, along with treatments and imaging for OS. A total of 50 542 patients were identified. Higher SES patients (Q5 vs. Q1) showed improved 5‐year OS (hazard ratio, 0.89; 95% confidence interval [CI], 0.87‐0.92; P .05) despite widening income inequality., Longstanding socioeconomic disparities in non‐small cell lung cancer imaging, treatments, and survival persist without improvement despite a universal health care system. Although these socioeconomic disparities remain largely unchanged over time, further exploratory research is necessary to better understand their causal pathways in efforts to reduce these inequalities.

Hair removal practices have evolved from adhering to social, cultural, and religious traditions to meeting aesthetic standards. Hair removal methods can be divided into two categories: 1) depilation, which involves removing the hair shaft and includes shaving and chemical depilatories, and 2) epilation, which involves removing the hair shaft, follicle, and bulb, and includes plucking, threading, waxing, sugaring, lasers, intense pulsed light system, electrolysis, and photodynamic therapy. Furthermore, an eflornithine hydrochloride 13.9% cream (Vaniqa®, neither an epilatory or depilatory technique), has been US FDA- and Health Canada-approved to slow the rate of facial hair growth and to be used in combination with other hair removal methods. All methods are temporary except for electrolysis, and each technique has advantages and disadvantages in terms of efficacy and adverse events. Importantly, most studies examining the efficacy of hair removal techniques are limited to darker hair and fairer skin, and further research is required especially for those with light-colored hair.

Background:. Patients born with a cleft lip and palate undergo multiple surgical procedures, increasing the infants’ exposure to anesthesia and potential risk of neurocognitive delays. In addition, these numerous procedures lead to greater use of hospital resources. This study analyzes the differences in anesthetic exposure and perioperative characteristics between performing combined versus separate primary palatoplasty (PP) and placement of bilateral myringotomy tubes (BMT). Methods:. We reviewed patients younger than 2 years who underwent PP and BMT at our institution from June 2014 to January 2019. Patients who underwent PP and BMT during the same admission (combined group = 74) and during separate admissions (separate group = 26) were studied. Due to the small sample size in the separate group, additional data for this group were gathered by propensity score matching by gender, race, and American Society of Anesthesiology class. Statistical analyses were carried out to identify significant differences between the 2 groups. Linear regression was performed to compare perioperative variables. Results:. One hundred patients met the inclusion criteria. There were no significant differences in demographic characteristics or American Society of Anesthesiology class, surgery and anesthesia duration, dosage of intraoperative dexmedetomidine, hospital length of stay, and perioperative complications (P > 0.05). Per contra, combined group had significantly lower intraoperative dosages of fentanyl (P = 0.01) and shorter postoperative care unit stay (P = 0.047). Conclusions:. This study documents decreased postoperative care unit time and anesthesia drug exposure without increased length of stay or perioperative complications in patients undergoing combined PP and BMT. These results support combining PP and BMT to reduce exposure to potentially neurotoxic medications and to increase efficient utilization of hospital resources.

Background Various cutaneous manifestations have been observed in patients with COVID-19 infection. However, overall similarities in the clinical presentation of these dermatological manifestations have not yet been summarized. Objective This review aims to provide an overview of various cutaneous manifestations in patients with COVID-19 through three case reports and a literature review. Methods A literature search was conducted using PubMed, OVID, and Google search engines for original and review articles. Studies written in the English language that mentioned cutaneous symptoms and COVID-19 were included. Results Eighteen articles and three additional cases reported in this paper were included in this review. Of these studies, 6 are case series and 12 are case report studies. The most common cutaneous manifestation of COVID-19 was found to be maculopapular exanthem (morbilliform), presenting in 36.1% (26/72) patients. The other cutaneous manifestations included: a papulovesicular rash (34.7%, 25/72), urticaria (9.7%, 7/72), painful acral red purple papules (15.3%, 11/72) of patients, livedo reticularis lesions (2.8%, 2/72) and petechiae (1.4%, 1/72). Majority of lesions were localized on the trunk (66.7%, 50/72), however, 19.4% (14/72) of patients experienced cutaneous manifestations in the hands and feet. Skin lesion development occurred before the onset of respiratory symptoms or COVID-19 diagnosis in 12.5% (9/72) of the patients, and lesions spontaneously healed in all patients within 10 days. Majority of the studies reported no correlation between COVID-19 severity and skin lesions. Conclusion Infection with COVID-19 may result in dermatological manifestations with various clinical presentations, which may aid in the timely diagnosis of this infection.

Streptococci bacteremia is an unusual source of sepsis from spontaneous cerebrospinal fluid (CSF) rhinorrhea due to sphenoid meningoencephalocele. A spontaneous cause of CSF rhinorrhea should be on the differential along with trauma and congenital and neoplastic lesions. Moxifloxacin 400 mg daily for 2 weeks has a satisfactory CSF penetration to treat Streptococcus viridans bacteremia due to CSF rhinorrhea.

PurposeTo summarize the current literature on the use and clinical efficacy of extended-infusion (EI) beta-lactam antibiotics, including piperacillin–tazobactam, meropenem, and cefepime.SummaryGram-negative infections are a serious concern among hospitalized patients and require innovative pharmacokinetic dosing strategies to achieve clinical success, especially as the emergence of resistant gram-negative pathogens has outpaced the development of new antibiotics. Beta-lactam antibiotics exhibit time-dependent activity, which means that optimal efficacy is achieved when free drug concentrations stay above the minimum inhibitory concentration for an extended duration of the recommended dosage interval. EI piperacillin–tazobactam therapy has demonstrated improved clinical outcomes and decrease mortality in critically ill patients with gram-negative infections, particularly Pseudomonas aeruginosa infections. EI meropenem has shown higher therapeutic success rates for patients with febrile neutropenia and shorter intensive care unit (ICU) length of stay (LOS) with a reduction in ventilator days in patients with multidrug-resistant ventilator-associated pneumonia. However, a larger study showed no difference in clinical outcomes between standard-infusion and EI meropenem. EI cefepime has been associated with decreased mortality and shorter ICU LOS in patients with Pseudomonas aeruginosa infections. Common challenges associated with EI beta-lactam antibiotics include Y-site incompatibilities, lack of intravenous access, and tubing residuals. It is important to note that factors such as diverse patient populations and study methodology, along with various antibiotic dose regimens, may have contributed to conflicting data on EI beta-lactam therapy.ConclusionBased on most published literature, there appears to be a favorable trend toward use of EI beta-lactam therapy in clinical practice, particularly in critically ill patients with gram-negative infections.

Background An antibiotic time out is when a clinician is prompted to reevaluate antibiotic therapy for appropriateness after 48–72 hrs. The purpose of this study is to evaluate the impact of a prescriber-led electronic antibiotic timeout alert. Methods This was a retrospective cohort study conducted at seven hospitals of a health system. The alert prompts prescribers to reevaluate antibiotic therapy after > 72 hours upon opening the electronic chart. Prescribers can then choose to “Continue”, “Renew”, “Discontinue” or “Defer” for each antibiotic. The alert fires for every time the chart is opened, for every prescriber, every time any antibiotic has been active for > 72 hours and no action response (i.e., “Continue”, “Renew”, “Discontinue”) has been selected. This was a 6 month study from November 1, 2018 – April 30, 2019. The primary outcome measure was the percentage of patients having > 1 antibiotic discontinued via the electronic antibiotic timeout alert. Secondary outcomes included frequency of timeout alerts per patient, and percentage of discontinuations per response, by drug, by indication and by patient age. Results A total of 213950 alerts fired for 13263 patients during the study period. 94.2% and 0.4% of responses were “Defer” and “Discontinue”, respectively. The average number of alerts per patient was 16.1. The percentage of patients who had at least one discontinuation was 5.3%. 38.2% of patients had no response other than “Defer”. There were a total of 10306 action responses, 4.8% of which were “Discontinue”. Among action responses, discontinue rates for the indications of “COPD exacerbation”, “Prophylaxis, Surgical/Procedural”, “Prophylaxis, Immunosuppression”, “Osteomyelitis” were 9.6%, 12%, 1.3% and 1%, respectively. Azithromycin and trimethoprim/sulfamethoxazole had discontinuation rates of 9.3% and 0.9%, respectively. Patient age had a significant impact on discontinuation rates with rates of 4.7%, 3.5%, and 10.9% for patients > 18, 2–17 and < 2 years of age (p< 0.001). Conclusion An electronic antibiotic timeout alert implemented at seven hospitals was largely ignored. This alert may be refined by limiting it to antibiotic orders with specific features associated with higher rates of discontinuation. Disclosures All Authors: No reported disclosures

Highlights • COVID-19 pandemic-induced psychosocial stressors and stay-at-home orders may exacerbate eating disorder-related triggers. • Appropriate management of eating disorders is crucial to help mitigate long-term impacts such as increased risk of suicide.

Objective For those with type 2 diabetes mellitus (T2DM), impact of short-term high-dose glucocorticoid exposure on beta-cell function is unknown. This study aims to compare the impact on beta-cell function and insulin resistance of prednisone 40 mg between adults with newly diagnosed T2DM and healthy adults. Methods Five adults with T2DM and five healthy adults, all between 18–50 years, were enrolled. T2DM diagnosis was less than one year prior, HbA1c

Study Objectives Although sleep disturbance is common in acutely ill patients during and after a hospitalization, how hospitalization affects sleep in general medicine patients has not been well characterized. We describe how sleep and activity patterns vary during and after hospitalization in a small population of older, predominately African American general medicine patients. Methods Patients wore a wrist accelerometer during hospitalization and post-discharge to provide objective measurements of sleep duration, efficiency, and physical activity. Random effects linear regression models clustered by subject were used to test associations between sleep and activity parameters across study days from hospitalization through post-discharge. Results We recorded 404 nights and 384 days from 54 patients. Neither nighttime sleep duration nor sleep efficiency increased from hospitalization through post-discharge (320.2 vs. 320.2 min, p = 0.99; 74.0% vs. 71.7%, p = 0.24). Daytime sleep duration also showed no significant change (26.3 vs. 25.8 min/day, p = 0.5). Daytime physical activity was significantly less in-hospital compared to post-discharge (128.6 vs. 173.2 counts/min, p < 0.01) and increased 23.3 counts/min (95% CI = 16.5 to 30.6, p < 0.01) per hospital day. A study day and post-discharge period interaction was observed demonstrating slowed recovery of activity post-discharge (β 3 = −20.8, 95% CI = −28.8 to −12.8, p < 0.01). Conclusions Nighttime sleep duration and efficiency and daytime sleep duration were similar in-hospital and post-discharge. Daytime physical activity, however, was greater post-discharge and increased more rapidly during hospitalization than post-discharge. Interventions, both in hospital and at home, to restore patient sleep and sustain activity improvements may improve patient recovery from illness.

Because cord blood (CB) lacks memory T and B cells and recent decreases in herd immunity to vaccine-preventable diseases in many developed countries have been documented, vaccine responses in CB transplantation (CBT) survivors are of great interest. We analyzed vaccine responses in double-unit CBT recipients transplanted for hematologic malignancies. In 103 vaccine-eligible patients, graft-versus-host disease (GVHD) most commonly precluded vaccination. Sixty-five patients (63%; engrafting units median HLA-allele match 5/8; range, 2 to 7/8) received protein conjugated vaccines, and 63 patients (median age, 34 years; range, .9 to 64) were evaluated for responses. Median vaccination time was 17 months (range, 7 to 45) post-CBT. GVHD (n = 42) and prior rituximab (n = 13) delayed vaccination. Responses to Prevnar 7 and/or 13 vaccines (serotypes 14, 19F, 23F) were seen in children and adults (60% versus 49%, P = .555). Responses to tetanus, diphtheria, pertussis, Haemophilus influenzae, and polio were observed in children (86% to 100%) and adults (53% to 89%) even if patients had prior GVHD or rituximab. CD4+CD45RA+ and CD19+ cell recovery significantly influenced tetanus and polio responses. In a smaller cohort responses were seen to measles (65%), mumps (50%), and rubella (100%) vaccines. No vaccine side effects were identified, and all vaccinated patients survived (median follow-up, 57 months). Although GVHD and rituximab can delay vaccination, CBT recipients (including adults and those with prior GVHD) have similar vaccine response rates to adult donor allograft recipients supporting vaccination in CBT recipients.

Key Points Question How frequently do immune checkpoint inhibitor (ICI) agents vs non-ICI agents qualify for American Society of Clinical Oncology Value Framework version 2 (ASCO-VF v2) tail-of-the-curve bonuses or European Society of Medical Oncology Magnitude of Clinical Benefit Scale version 1.1 (ESMO-MCBS v1.1) immunotherapy-triggered long-term plateau adjustments? Findings In this cohort study of 100 randomized clinical trials comparing ICI with non-ICI agents, ASCO-VF v2 tail-of-the-curve bonuses and ESMO-MCBS v1.1 immunotherapy-triggered long-term plateau adjustments were not awarded to ICI agents more often than non-ICI agents. Meaning The ASCO-VF v2 and ESMO-MCBS v1.1 may be flawed in accurately capturing long-term survival., This study of 100 randomized clinical trials determines how frequently immune checkpoint inhibitor (ICI) and non-ICI anticancer agents displayed trends of long-term durable survival as defined by the American Society of Clinical Oncology (ASCO) Value Framework and the European Society of Medical Oncology (ESMO) Magnitude of Clinical Benefit Scale., Importance Recently, anticancer agents have generated excitement owing to their capacity to preserve long-term durable survival in some patients who are represented by a tail of the survival curve. However, because traditional measures of clinical benefit may not accurately capture durable survival, amendments to various valuation frameworks have been proposed to capture this benefit. Objectives To determine how frequently immune checkpoint inhibitor (ICI) anticancer agents vs non-ICI anticancer agents displayed trends of long-term durable survival, as defined by the American Society of Clinical Oncology Value Framework version 2 (ASCO-VF v2) and European Society of Medical Oncology Magnitude of Clinical Benefit Scale version 1.1 (ESMO-MCBS v1.1), as well as to further analyze the degree of agreement between ASCO and ESMO frameworks. Design, Setting, and Participants In this cohort study, anticancer agents from phase 2 or 3 randomized clinical trials (RCTs) cited for clinical efficacy evidence in drug approval by the US Food and Drug Administration between January 2011 and March 2018 were identified. Data required for the ASCO-VF v2 tail-of-the-curve bonus and the ESMO-MCBS v1.1 immunotherapy-triggered long-term plateau adjustments were extracted from relevant RCTs. Frequency and difference in proportions were calculated to determine how often survival benefits were awarded to anticancer agents overall and to ICI and non-ICI anticancer agents individually. Main Outcomes and Measures American Society of Clinical Oncology Value Framework v2 tail-of-the-curve bonuses and ESMO-MCBS v1.1 immunotherapy-triggered long-term plateau adjustments. Results In total, 247 RCTs were identified, and 100 RCTs involving 57 164 patients were included, with 14 examining ICI agents (1 ipilimumab, 5 pembrolizumab, 5 nivolumab, 2 atezolizumab, and 1 durvalumab) and 86 examining non-ICI agents (74 targeted therapy, 8 chemotherapy, 3 hormone therapy, and 1 radiopharmaceutical). Randomized clinical trials were awarded ASCO-VF v2 tail-of-the-curve bonuses more often than ESMO-MCBS v1.1 immunotherapy-triggered long-term plateau adjustments (ASCO-VF v2, 45.0% [8 of 14 ICI RCTs and 37 of 86 non-ICI RCTs] vs ESMO-MCBS v1.1, 2.6% [1 of 12 ICI RCTs and 1 of 66 non-ICI RCTs). Randomized clinical trials for ICIs were not more likely to receive an ASCO-VF v2 bonus or ESMO-MCBS v1.1 adjustment than non-ICI RCTs (ASCO-VF: risk difference, 0.14; 95% CI, −0.14 to 0.42; P = .32; ESMO-MCBS: risk difference, 0.07; 95% CI, −0.09 to 0.23; P = .40). Poor agreement was found between the framework algorithms in identifying long-term survival benefits from RCTs (κ = 0.01; 95% CI, −0.23 to 0.22; P = .50). Conclusions and Relevance The ASCO-VF v2 and ESMO-MCBS v1.1 may require additional refinement to accurately capture the benefit of durable long-term survival, or ICI agents may not preserve long-term survival as conventionally thought.

The goal of this study was to examine the expression and regulation of aquaporin2 (AQP2), a tonicity-sensitive water channel in nucleus pulposus cells of the intervertebral disc. We found that AQP2 protein was expressed in vivo in both rat and human discs. We determined whether AQP2 promoter expression was regulated by osmolarity in a tonicity enhancer binding protein (TonEBP)-dependent manner.When TonEBP was suppressed under hypertonic conditions or overexpressed under isotonic conditions,AQP2 promoter activity was correspondingly inhibited or induced. The role of TonEBP in controlling AQP2 expression was confirmed using mouse embryonic fibroblasts (MEFs) derived from TonEBP-null mice. We studied whether calcium in addition to osmolarity played a role in regulation of AQP2 in nucleus pulposus cells. We also determined whether both TonEBP and calcineurin-nuclear factor of activated T cells (NFAT)signaling contributed to ionomycin, a calcium ionophore, mediated induction of AQP2. Co-transfection of AQP2 reporter with calcineurin (CnA/B) and/or NFAT1-4 vectors suggested that this pathway did not control AQP2 promoter activity in nucleus pulposus cells. These findings were also validated using MEFs from TonEBP, fibroblasts from CnAalpha- and CnAbeta-null mice, and mutant TonE reporter constructs. Results of these studies suggest that, in nucleus pulposus cells, osmotic pressure and calcium modulate AQP2 expression through TonEBP and are independent of the calcineurin-NFAT pathway. Because calcium flux reflects a change in applied stress, the possibility exists that NFAT5/TonEBP modulate not just water balance in the disc but also accommodate applied biomechanical forces.

Hepatitis C virus (HCV) infection is a major health burden and associated with substantial morbidity and mortality. However, the disease often remains underdiagnosed and untreated. The treatment of HCV infection has evolved dramatically with the introduction of novel, interferon-free therapies that are now able to achieve high cure rates. However, improved and more effective strategies for controlling the high costs of managing patients with HCV, especially in light of the shifting treatment paradigm, need to be developed. This article, the second in a series of 3 focused on hepatitis C, will discuss the diagnosis and management of HCV infection, including treatment recommendations from practice guidelines and emerging agents to treat HCV, and provide suggestions for incorporating these options into treatment algorithms.

Chronic hepatitis C virus (HCV) infection is highly prevalent and associated with a wide range of hepatic and extrahepatic complications. The treatment landscape for HCV infection has evolved to include regimens without interferon formulations and/or ribavirin. This change simplifies therapy, improves tolerability, and decreases therapy duration, while improving virologic response rates. This article, the first in a series of 3, will provide an overview of the hepatitis C disease state, identify populations at risk for HCV, describe testing recommendations for the diagnosis of HCV infection, and distinguish new and emerging HCV therapies.

Introduction: Current therapies for relapsed/refractory (rel/ref) T-cell lymphomas (TCLs) induce responses in only 25-30% of patients (pts). Phosphoinositide-3-kinases (PI3K) play a pivotal role in cell signaling and PI3K isoforms have distinct roles in the development, function and survival of T cells. A phase I study of the oral PI3K-δ/γ inhibitor duvelisib (DUV) in pts with TCLs showed promising activity in rel/ref TCL (Horwitz, Blood 2014). We assessed mechanisms of response and resistance to DUV in T-cell lymphomas in vitro and in vivo. Based on in vitro evidence of synergy, we initiated a phase I study to evaluate the safety and efficacy of DUV combined with romidepsin or bortezomib in pts with rel/ref TCL. Methods: Preclinical: We characterized the PI3K-signaling pathway across 11 cell lines of TCL by immunoblotting and assessed the in vitro activity of isotype specific PI3K inhibitors, including DUV. A targeted phosphoproteomic approach (P100) was utilized to identify mechanisms of resistance and response of DUV across 6 cell lines in vitro. We assessed the effects of DUV on immune response within the TCL microenvironment in vivo using a patient-derived xenograft (PDX). Clinical: We conducted multicenter, parallel phase I trials of DUV in combination with romidepsin (arm A) or bortezomib (arm B) in rel/ref TCL. For each arm, a standard 3+3 phase I design was used to determine maximum tolerated dose (MTD). DUV was dosed at 25mg, 50mg, or 75mg BID on days 1-28. Romidepsin 10mg/m2 was dosed on days 1, 8, and 15 (arm A) or bortezomib 1mg/m2 on days 1, 4, 8, and 11 (arm B), both on 28-day cycles. All pts received prophylaxis against Varicella and Pneumocystis. Results: Preclinical: DUV potently killed 3 of 4 TCL cell lines that showed constitutive phosphorylation of AKT (pAKT) versus 0 of 7 lines lacking pAKT (p=0.024). Killing by DUV exceeded killing by the PI3K-δ-specific inhibitor idelalisib and was similar to pan-PI3K inhibition. The phosphoproteomic analysis identified resistance through either PI3Kα activation, which was overcome by pan-PI3K inhibition, or by epigenetic reprogramming, which was overcome by co-treatment with romidepsin. Administration of DUV to mice engrafted with a TCL PDX resulted in reprogramming of tumor-infiltrating macrophages from the immunosuppressive M2-like phenotype to the pro-phagocytic M1-like phenotype. Clinical: 12 pts (4 in each dose level [DL]) were treated on arm A (romidepsin+DUV); 8 are evaluable for efficacy. There were no dose limiting toxicities (DLTs), therefore DL 3 was accepted as MTD. 2 serious adverse events (SAEs) possibly related to study drug included grade (Gr) 3 fatigue and Gr 2 aspartate aminotransferase (AST) elevation. 1 fatal event (diffuse alveolar hemorrhage following allogeneic transplant) occurred 31 days after last dose of study drug and was assessed as unrelated to study treatment. Gr 3 or 4 adverse events (AEs) occurring in ≥10% of pts included only neutropenia (Gr 3, n=4, Gr 4, n=2). Overall response rate (ORR) and median time to response (TTR) were 4/8 (50%) and 51 (range 49-54) days. Two of 4 responders proceeded to transplant after 90 and 108 days and 1 remains on treatment for 107+ days. 17 pts were treated on arm B (bortezomib+DUV), including 8 in DL 1, 3 in DL 2, and 6 in DL 3; 15 pts are evaluable for efficacy. 1 out of 6 pts evaluable for DLT on DL 1 experienced DLT (pneumonia). There were no other DLTs, however Gr 3 elevations of alanine aminotransferase (ALT) or AST following cycle 2 were observed for 3 pts treated at DL 2 and 2 treated at DL 3 leading to DL 1 being accepted as MTD. There were 5 SAEs possibly related to study drug including Gr 3 pneumonia (n=2), Gr 3 infectious colitis (n=1), Gr 3 colitis (n=1), and Gr 4 AST/ALT elevation (1). Gr 3 or 4 AEs occurring in ≥10% of pts included only neutropenia (Gr 3, n=3). ORR, complete response (CR), and median time to response (TTR), were 8/15 (53%), 3/15 (20%), and 52 (range 47-57) days. Among the 8 responders, 5 remain on treatment for 103-377+ days. Conclusion: DUV shows activity in T-cell lymphomas with pre-clinical evidence of both tumor cell-autonomous and non-autonomous effects. The combinations of DUV plus romidepsin and DUV plus bortezomib are safe and well tolerated, with limited incidence of AST/ALT elevation from romidepsin+DUV. Promising response rates of at least 50% were observed across TCL histologies with both regimens. Expansion cohorts of pts with peripheral and cutaneous TCL are currently enrolling. Disclosures Moskowitz: ADC Therapeutics: Research Funding; Seattle Genetics: Honoraria, Research Funding; Takeda: Honoraria; Incyte: Research Funding; Bristol Myers-Squibb: Consultancy, Research Funding. Mehta-Shah: Celgene: Research Funding; Verastem: Research Funding; Bristol Myers Squibb: Research Funding. Dogan: Roche Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Peer Review Institute: Consultancy; Celgene: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kim: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Research Funding; Soligenix: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Portola: Consultancy, Research Funding; Horizon Pharma: Consultancy, Research Funding; Forty Seven Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa-Kirin-Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Consultancy, Research Funding; Medivir: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; miRagen: Research Funding; Neumedicine: Research Funding; Tetralogic: Research Funding; Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Jacobsen: GSK: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees. Horwitz: Forty-Seven: Consultancy, Research Funding; Aileron Therapeutics: Research Funding; Kyowa-Hakka-Kirin: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; BMS: Consultancy; Mundipharma: Consultancy; ADCT Therapeutics: Research Funding; Infinity/Verastem: Consultancy, Research Funding; HUYA: Consultancy.

This review aims to evaluate the literature on the safety and efficacy of novel toxoid vaccines for the prophylaxis of Clostridium difficile infections (CDI) in healthy adults. Literature searches for clinical trials were performed through MEDLINE, ClinicalTrials.gov, and Web of Science using the keywords bacterial vaccines, Clostridium difficile, and vaccine. English-language clinical trials evaluating the efficacy and/or safety of Clostridium difficile toxoid vaccines that were completed and had results posted on ClinicalTrials.gov or in a published journal article were included. Six clinical trials were included. The vaccines were associated with mild self-reported adverse reactions, most commonly injection site reactions and flu-like symptoms, and minimal serious adverse events. Five clinical trials found marked increases in antibody production in vaccinated participants following each dose of the vaccine. Clinical trials evaluating C. difficile toxoid vaccines have shown them to be well tolerated and relatively safe. Surrogate markers of efficacy (seroconversion and geometric mean antibody levels) have shown significant immune responses to a vaccination series in healthy adults, indicating that they have the potential to be used as prophylaxis for CDI. However, more research is needed to determine the clinical benefits of the vaccines.

Most acute heart failure (AHF) patients have dyspnea but their most bothersome (worst) symptom (WS) may vary. We hypothesized that improvement in a patient's WS over time would be associated with decongestion efficacy and outcomes in AHF. Patients with AHF enrolled (< 24 hr from admission) in ROSE

Clostridial bacteremia (CB) is a rare clinical entity, accounting for less than 2-3% of all blood cultures. CB is frequently associated with intra-abdominal infections and underlying malignancy, particularly colon cancer or leukemia.Clostridiumspecies are commonly isolated from blood cultures as a part of polymicrobial bacteremia. The mortality rate among patients with CB has been reported to be as high as 50%. The presentation and outcome of CB depends on underlying host defenses and the type ofClostridiumspecies causing infection. A favorable outcome for CB appears to depend on the prompt initiation of appropriate antibiotics and surgical intervention. All patients with positive blood cultures forClostridiumspecies, from January 1995 to December 2003, were included in this study. Medical records of these patients were reviewed for age, sex, underlying diseases (such as malignancy and diabetes), antibiotic use, and outcome. Antimicrobial therapy was defined as either “appropriate” or “insufficient” based on its activity againstClostridiumspecies. In-hospital, postdiagnosis survival was examined by Kaplan-Meier methodology and comparisons made by the Mantel-Cox Log-Rank test. Ninety-two percent of the patients had monomicrobial CB. C. perfringens was the most frequently isolated pathogen, seen in 60% of cases. The most common underlying conditions were genitourinary and gastrointestinal malignancies, and diabetes. The overall mortality was 48%. Patients with malignancy had a significantly higher 2-day mortality rate (54%) compared to patients without malignancy (8%, p = 0.023). The mortality rates varied according to type ofClostridiumspecies. Patients with C. innocuum bacteremia had a significantly higher 2-day mortality rate (100%) compared to patients with C. septicum (67%), and to patients with C. perfringens (27%) (p = 0.004). “appropriate” antibiotics were given to 64% of the patients, 16% were on antibiotics with “insufficient” coverage, and 20% were not given any antibiotics. Patients receiving “insufficient” antibiotic therapy had a significantly higher 2-day mortality rate (75%) compared to patients on “appropriate” antibiotics forClostridium(12.5%) (p = 0.011). CB is associated with high and rapid mortality, especially in patients with malignancy. Early mortality was significantly lower in patients receiving antibiotics with adequate coverage forClostridiumspecies.

We assessed the rates of influenza vaccine acceptance and the reasons for acceptance or refusal among medical residents in different disciplines during the 2004-2005 influenza season. Rates varied among disciplines; emergency department residents had the lowest acceptance rate (24%). The perception of a low risk of contracting influenza was the most common reason reported for vaccine refusal.

We examined the ESCAPE (Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness) database to understand the impact and pathophysiology of renal dysfunction in patients hospitalized with advanced decompensated heart failure (HF).Baseline renal insufficiency (RI) (estimated glomerular filtration rate [eGFR]60 ml/min) and worsening renal function (WRF) (upward arrow serum creatinine [SCr]or=0.3 mg/dl) during treatment of decompensated HF are associated with adverse outcomes.We used a Cox proportional hazards model to evaluate the impact of renal function on 6-month outcomes. Renal parameters were correlated with hemodynamic measurements. The impact of a strategy using pulmonary artery catheter (PAC) guidance on WRF and outcomes in patients with baseline RI was compared with treatment based on clinical assessment alone.Baseline and discharge RI, but not WRF, were associated with an increased risk of death and death or rehospitalization. Among the hemodynamic parameters measured in patients randomized to the PAC arm (n = 194), only right atrial pressure correlated weakly with baseline SCr (r = 0.165, p = 0.03). There was no correlation between baseline hemodynamics or change in hemodynamics and WRF. A PAC-guided strategy was associated with less average increase in creatinine but did not decrease the incidence of defined WRF during hospitalization or affect renal function after discharge relative to clinical assessment alone.Among patients with advanced decompensated HF, baseline RI impacts outcomes more than WRF. Poor forward flow alone does not appear to account for the development of RI or WRF in these patients. The addition of hemodynamic monitoring to clinical assessment does not prevent WRF or improve renal function after discharge.

Objective Inefficiencies in clinical trial data collection cause delays, increase costs, and may reduce clinician participation in medical research. In this proof-of-concept study, we examine the feasibility of using point-of-care data capture for both the medical record and clinical research in the setting of a working clinical trial. We hypothesized that by doing so, we could increase reuse of patient data, eliminate redundant data entry, and minimize disruption to clinic workflow. Design We developed and used a point-of-care electronic data capture system to record data during patient visits. The standards-based system was used for clinical research and to generate the clinic note for the medical record. The system worked in parallel with data collection procedures already in place for an ongoing multicenter clinical trial. Our system was iteratively designed after analyzing case report forms and clinic notes, and observing clinic workflow patterns and business procedures. Existing data standards from CDISC and HL7 were used for database insertion and clinical document exchange. Results Our system was successfully integrated into the clinic environment and used in two live test cases without disrupting existing workflow. Analyses performed during system design yielded detailed information on practical issues affecting implementation of systems that automatically extract, store, and reuse healthcare data. Conclusion Although subject to the limitations of a small feasibility study, our study demonstrates that electronic patient data can be reused for prospective multicenter clinical research and patient care, and demonstrates a need for further development of therapeutic area standards that can facilitate researcher use of healthcare data.

A recent study reported a higher than expected prevalence of hypothyroidism among patients with cutaneous melanoma. To further characterize and validate those findings, we conducted a retrospective review of the prevalence of hypothyroidism among all consecutive patients diagnosed with cutaneous melanoma in the dermatology clinic at the Michael E. DeBakey VA Medical Center (VAMC) in Houston, Texas. To accomplish this task, the electronic medical records of all patients diagnosed with cutaneous melanoma at the VAMC from January 2001 through October 2004 were examined for signs of hypothyroidism. Data regarding the site of melanoma and age at diagnosis were obtained for these hypothyroid cases and for age- and gender-matched euthyroid controls from the same melanoma cohort. Among 156 cutaneous melanoma patients (151 male and 5 female), 8 (5.1 %) showed a history of hypothyroidism [7 of 151 male (4.6 %) and 1 of 5 female (20 %)]. The prevalence of hypothyroidism among the male melanoma patients was significantly higher than that reported for the general population. The prevalence data concerning hypothyroidism among our female patients was not considered evaluable due to the primarily male distribution of our study population. We conclude that hypothyroidism (excluding iatrogenic etiologies) is frequent among male patients with cutaneous melanoma. Our results further suggest that a subset of melanoma tumors may respond to hormones of the hypothalamus-pituitary-thyroid axis, raising many questions that could influence the diagnosis, care, and treatment of a subset of melanoma patients.

Dyspnea relief is a regulatory benchmark in acute heart failure (AHF) and typically assessed by a dyspnea visual analog scale (DVAS). We hypothesized that a provocative dyspnea score (PDS) assessing dyspnea under incrementally more difficult conditions is a more sensitive metric of change (Δ) in