Glasdegib plus intensive or non-intensive chemotherapy for untreated acute myeloid leukemia: results from the randomized, phase 3 BRIGHT AML 1019 trial.

This is the primary report of the randomized, placebo-controlled phase 3 BRIGHT AML 1019 clinical trial of glasdegib in combination with intensive chemotherapy (cytarabine and daunorubicin) or non-intensive chemotherapy (azacitidine) in patients with untreated acute myeloid leukemia. Overall survival (primary endpoint) was similar between the glasdegib and placebo arms in the intensive (n = 404; hazard ratio [HR] 1.05; 95% confidence interval [CI]: 0.782-1.408; two-sided p = 0.749) and non-intensive (n = 325; HR 0.99; 95% CI: 0.768-1.289; two-sided p = 0.969) studies. The proportion of patients who experienced treatment-emergent adverse events was similar for glasdegib versus placebo (intensive: 99.0% vs. 98.5%; non-intensive: 99.4% vs. 98.8%). The most common treatment-emergent adverse events were nausea, febrile neutropenia, and anemia in the intensive study and anemia, constipation, and nausea in the non-intensive study. The addition of glasdegib to either cytarabine and daunorubicin or azacitidine did not significantly improve overall survival and the primary efficacy endpoint for the BRIGHT AML 1019 phase 3 trial was not met. Clinical trial registration: ClinicalTrials.gov: NCT03416179.

Metastatic Melanoma Presenting as a Gastric Mass.

Melanoma is the most deadly form of skin cancer. While the jejunum, ileum, colon, and rectum are common gastrointestinal sites of metastasis, metastatic melanoma to the stomach is rare and usually not discovered until late in the disease. We report a patient who presented with weight loss and hematemesis; on esophagogastroduodenoscopy, a gastric mass was found, and pathology was consistent with melanoma.

Preoperative Ultrasound-Guided Botulinum Toxin A Injection Facilitates Closure of a Complex Abdominal Wall Hernia: A Case Report.

Complex abdominal wall hernia repairs can have high failure rates. Many surgical techniques have been proposed with variable success. We report our experience with a new collaborative protocol between general surgery and regional anesthesiology and acute pain medicine services to provide preoperative botulinum toxin A injections to a patient with a large complex ventral hernia to facilitate primary closure. Toxin was administered into the 3 abdominal wall muscle layers under ultrasound guidance at multiple sites 2 weeks before surgery. The resulting flaccid paralysis of the abdominal musculature facilitated a successful primary surgical closure with no postoperative complications.

Targeting iron metabolism in high-grade glioma with 68Ga-citrate PET/MR.

Noninvasive tools that target tumor cells could improve the management of glioma. Cancer generally has a high demand for Fe(III), an essential nutrient for a variety of biochemical processes. We tested whether 68Ga-citrate, an Fe(III) biomimetic that binds to apo-transferrin in blood, detects glioma in preclinical models and patients using hybrid PET/MRI. Mouse PET/CT studies showed that 68Ga-citrate accumulates in subcutaneous U87MG xenografts in a transferrin receptor-dependent fashion within 4 hours after injection. Seventeen patients with WHO grade III or IV glioma received 3.7-10.2 mCi 68Ga-citrate and were imaged with PET/MR 123-307 minutes after injection to establish that the radiotracer can localize to human tumors. Multiple contrast-enhancing lesions were PET avid, and tumor to adjacent normal white matter ratios were consistently greater than 10:1. Several contrast-enhancing lesions were not PET avid. One minimally enhancing lesion and another tumor with significantly reduced enhancement following bevacizumab therapy were PET avid. Advanced MR imaging analysis of one patient with contrast-enhancing glioblastoma showed that metabolic hallmarks of viable tumor spatially overlaid with 68Ga-citrate accumulation. These early data underscore that high-grade glioma may be detectable with a radiotracer that targets Fe(III) transport.

Urinary Iodine, Perchlorate, and Thiocyanate Concentrations in U.S. Lactating Women.

BACKGROUND: Iodine is an essential micronutrient for thyroid hormone production. Adequate iodine intake and normal thyroid function are important during early development, and breastfed infants rely on maternal iodine excreted in breast milk for their iodine nutrition. The proportion of women in the United States of childbearing age with urinary iodine concentration (UIC) <50 µg/L has been increasing, and a subset of lactating women may have inadequate iodine intake. UIC may also be influenced by environmental exposure to perchlorate and thiocyanate, competitive inhibitors of iodine transport into thyroid, and lactating mammary glands. Data regarding UIC in U.S. lactating women are limited. To adequately assess the iodine sufficiency of lactating women and potential associations with environmental perchlorate and thiocyanate exposure, we conducted a multicenter, cross-sectional study of urinary iodine, perchlorate, and thiocyanate concentrations in healthy U.S. lactating women. METHODS: Lactating women ≥18 years of age were recruited from three U.S. geographic regions: California, Massachusetts, and Ohio/Illinois from November 2008 to June 2016. Demographic information and multivitamin supplements use were obtained. Iodine, perchlorate, and thiocyanate levels were measured from spot urine samples. Correlations between urinary iodine, perchlorate, and thiocyanate levels were determined using Spearman's rank correlation. Multivariable regression models were used to assess predictors of urinary iodine, perchlorate, and thiocyanate levels, and UIC <100 µg/L. RESULTS: A total of 376 subjects (≥125 from each geographic region) were included in the final analyses [mean (SD) age 31.1 (5.6) years, 37% white, 31% black, and 11% Hispanic]. Seventy-seven percent used multivitamin supplements, 5% reported active cigarette smoking, and 45% were exclusively breastfeeding. Median urinary iodine, perchlorate, and thiocyanate concentrations were 143 µg/L, 3.1 µg/L, and 514 µg/L, respectively. One-third of women had UIC <100 µg/L. Spot urinary iodine, perchlorate, and thiocyanate levels all significantly positively correlated to each other. No significant predictors of UIC, UIC <100 µg/L, or urinary perchlorate levels were identified. Smoking, race/ethnicity, and marital status were significant predictors of urinary thiocyanate levels. CONCLUSION: Lactating women in three U.S. geographic regions are iodine sufficient with an overall median UIC of 143 µg/L. Given ubiquitous exposure to perchlorate and thiocyanate, adequate iodine nutrition should be emphasized, along with consideration to decrease these exposures in lactating women to protect developing infants.

Iodine Content in Milk Alternatives.

BACKGROUND: Iodine is necessary for the production of thyroid hormones and is acquired through the diet. Cow's milk is a primary source of iodine in the U.S. diet. The objective of this study was to measure the iodine content in a variety of milk alternatives to determine whether milk alternatives contain iodine levels comparable to that of cow's milk. METHODS: Iodine levels from 30 different brands of milk alternatives from 16 different companies were measured by the spectrophotometric method of the Sandell-Kolthoff reaction. RESULTS: The 30 brands of milk alternatives contained an average of 3.1 ± 2.5 µg/250 mL (∼8 oz. or one cup, serving size) of iodine or 12.3 ± 10.1 µg/L (∼24 oz. or four cups, daily recommended serving for adequate calcium intake) of iodine. CONCLUSIONS: These results indicate that milk alternatives contain far less iodine than cow's milk. Individuals with restricted dairy product consumption are at risk for inadequate dietary iodine intake.

Safety and pharmacology of ponezumab (PF-04360365) after a single 10-minute intravenous infusion in subjects with mild to moderate Alzheimer disease.

OBJECTIVE: Ponezumab (PF-04360365) is a humanized anti-amyloid beta (Aß) monoclonal antibody designed for treatment of Alzheimer disease (AD). A single 2-hour intravenous infusion of 0.1 to 10 mg/kg was previously shown to be safe and well tolerated in subjects with mild to moderate AD, with measurable effects on plasma and cerebrospinal fluid Aß. This phase I, dose-escalation, open-label study evaluated the safety, pharmacokinetics, and pharmacodynamics of a single 10-minute intravenous infusion. METHODS: Subjects with mild to moderate AD received ponezumab 1 mg/kg (n = 3), 3 mg/kg (n = 3), 5 mg/kg (n = 4), or 10 mg/kg (n = 5). They were followed up as outpatients for 6 months. RESULTS: All subjects completed the trial. Ponezumab was safe and well tolerated with no deaths, withdrawals, or drug-related moderate, severe, or serious adverse events. Mild drug-related adverse events included headache (3 patients) and lethargy and hypoesthesia (both in 1 patient). No infusion reactions, clinically meaningful laboratory abnormalities, vital sign changes, electrocardiographic changes, or antidrug antibodies were detected. There was no evidence of brain microhemorrhage, vasogenic edema, encephalitis, or other imaging abnormality. Cognitive function showed no treatment-related trends. Ponezumab displayed approximately dose-proportional increases in plasma exposure. Steady-state volume of distribution was 113 to 172 mL/kg, clearance was 2.7 to 3.0 mL/d/kg, and terminal half-life was 35 to 52 days. Plasma maximum observed concentration and the area under the plasma concentration-time profile from time 0 extrapolated to infinite time of Aß(1-x) and Aß(1-40) increased dose-dependently. CONCLUSIONS: Administration of ponezumab as a 10-minute infusion was safe and well tolerated and produced effects on plasma Aß species comparable with a 2-hour infusion. Shorter infusions may provide more flexibility, comfort, and convenience for patients and caregivers.

Unconscious structural knowledge of tonal symmetry: Tang poetry redefines limits of implicit learning.

The study aims to help characterize the sort of structures about which people can acquire unconscious knowledge. It is already well established that people can implicitly learn n-grams (chunks) and also repetition patterns. We explore the acquisition of unconscious structural knowledge of symmetry. Chinese Tang poetry uses a specific sort of mirror symmetry, an inversion rule with respect to the tones of characters in successive lines of verse. We show, using artificial poetry to control both n-gram structure and repetition patterns, that people can implicitly learn to discriminate inversions from non-inversions, presenting a challenge to existing models of implicit learning.

Acquisition of conscious and unconscious knowledge of semantic prosody.

An experiment explored the acquisition of conscious and unconscious knowledge of semantic prosody in a second language under incidental and intentional learning conditions. Semantic prosody is the conotational coloring of the semantics of a word, largely uncaptured by dictionary definitions. Contrary to some claims in the literature, we revealed that both conscious and unconscious knowledge were involved in the acquisition of semantic prosody. Intentional learning resulted in similar unconscious but more conscious knowledge than incidental learning. The results are discussed in terms of second language learning and the nature of unconscious knowledge.

Effects of varenicline on smoking cessation in patients with mild to moderate COPD: a randomized controlled trial.

BACKGROUND: Smoking is the most important risk factor for COPD and accelerates its progression. Despite the health implications, a large proportion of patients with COPD continue to smoke, so finding effective smoking cessation interventions for this population is paramount. To our knowledge, this is the first randomized clinical trial to compare the efficacy and safety of varenicline tartrate vs placebo in smokers with mild to moderate COPD. METHODS: In a 27-center, double-blind, multinational study, 504 patients with mild to moderate COPD (postbronchodilator FEV1/FVC, <70%; FEV1 percent predicted normal value, ≥50%) and without known psychiatric disturbances were randomized to receive varenicline (n=250) or placebo (n=254) for 12 weeks, with a 40-week nontreatment follow-up. The primary end point was carbon monoxide-confirmed continuous abstinence rate (CAR) for weeks 9 to 12. A secondary end point was CAR for weeks 9 to 52. RESULTS: CAR for weeks 9 to 12 was significantly higher for patients in the varenicline group (42.3%) than for those in the placebo group (8.8%) (OR, 8.40; 95% CI, 4.99-14.14; P<.0001). CAR in the patients treated with varenicline remained significantly higher than in those treated with placebo through weeks 9 to 52 (18.6% vs 5.6%) (OR, 4.04; 95% CI, 2.13-7.67; P<.0001). Nausea, abnormal dreams, upper-respiratory tract infection, and insomnia were the most commonly reported adverse events (AEs) for patients in the varenicline group. Serious AEs were infrequent in both treatment groups. Two patients in the varenicline group and one patient in the placebo group died during the study. Reports of psychiatric AEs were similar for both treatment groups. CONCLUSIONS: Varenicline was more efficacious than placebo for smoking cessation in patients with mild to moderate COPD and demonstrated a safety profile consistent with that observed in previous trials. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00285012; URL: www.clinicaltrials.gov.

Varenicline treatment for smoking cessation in Asian populations: a pooled analysis of placebo-controlled trials conducted in six Asian countries.

OBJECTIVE: A pooled analysis to evaluate the efficacy and safety of varenicline versus placebo for smoking cessation in Asian populations. A secondary objective was to compare the data to pooled trials among predominantly Western populations. RESEARCH DESIGN AND METHODS: Smokers (n = 893) in three randomized, double-blind, placebo-controlled, multicenter, phase IIb or III trials conducted in six Asian countries (Japan, Taiwan, Korea, China, Singapore, and Thailand), received varenicline (1 mg twice daily; n = 447) or placebo (n = 446) for 12 weeks. Non-treatment follow-up lasted 12 weeks (40 weeks in Japan). Primary endpoint was the carbon monoxide-confirmed continuous abstinence rate (CAR) for weeks 9-12 (last 4 weeks of treatment). Secondary endpoint was CAR for weeks 9-24. RESULTS: CAR was higher for varenicline than placebo during weeks 9-12 (58.6 vs. 34.3%; odds ratio [OR]: 2.74; 95% confidence interval [CI]: 2.08-3.60; p < 0.0001), and through 12 weeks of follow-up (CAR weeks 9-24; 41.4 vs. 25.3%; OR: 2.08; 95% CI: 1.56-2.77; p < 0.0001). The most frequent adverse events (AEs) in the varenicline group (greater incidence than the placebo group) were: nausea (31.5%), headache (8.5%), dizziness (7.8%), insomnia (7.4%), and upper abdominal pain (5.4%). Serious AEs occurred in four varenicline and five placebo participants. Discontinuations due to AEs occurred in 3.6% of varenicline and 1.6% of placebo participants. Compared with the Western studies, abstinence rates for both varenicline and placebo were numerically higher in the Asian studies, although treatment effects were similar between the two populations. AEs reported in the Asian trials were largely similar to those in the Western populations. CONCLUSIONS: Varenicline significantly improved smoking abstinence in Asian populations from six countries. AEs were predominantly of mild or moderate intensity. These data were largely the same as those seen in Western populations, but the studies were not designed to explore racial or cultural differences.

Interrater reliability of drug-induced sleep endoscopy.

OBJECTIVE: To determine the interrater reliability of drug-induced sleep endoscopy (DISE). DESIGN: Prospective cohort; blinded comparison. SETTING: Academic referral center. PARTICIPANTS: Subjects with obstructive sleep apnea unable to tolerate positive airway pressure therapy. INTERVENTIONS: Drug-induced sleep endoscopy was performed with intravenous propofol infusion to achieve sedation, and the videoendoscopy recording was evaluated by 2 independent reviewers. MAIN OUTCOME MEASURES: The following outcomes were measured: a global assessment of obstruction at the palate and/or hypopharynx; the degree of obstruction at the palate and hypopharynx; and the contribution of individual structures (palate, tonsils, tongue, epiglottis, and lateral pharyngeal walls) to obstruction. RESULTS: A total of 108 subjects underwent DISE examination. Diagnostic sleep studies demonstrated a mean (SD) apnea-hypopnea index of 39.6 (24.0). Three-quarters of the subjects demonstrated multilevel airway obstruction at the palate and hypopharynx, with a diversity of individual structures contributing to obstruction. The interrater reliability for the presence of obstruction at the palate and hypopharynx (kappa values, 0.76 and 0.79, respectively) was higher than for the degree of obstruction (weighted kappa values, 0.60 and 0.44). The interrater reliability for the assessment of primary structures contributing to obstruction at the palate and hypopharynx (0.70 and 0.86) was higher than for the contributions of individual structures (kappa values, 0.42-0.71). The interrater reliability for evaluation of the hypopharyngeal structures was higher than for those of the palate region. CONCLUSION: The interrater reliability of DISE is moderate to substantial. Trial Registration clinicaltrials.gov Identifier: NCT00695214.

Autofluorescent proteins with excitation in the optical window for intravital imaging in mammals.

Fluorescent proteins have become valuable tools for biomedical research as protein tags, reporters of gene expression, biosensor components, and cell lineage tracers. However, applications of fluorescent proteins for deep tissue imaging in whole mammals have been constrained by the opacity of tissues to excitation light below 600 nm, because of absorbance by hemoglobin. Fluorescent proteins that excite efficiently in the "optical window" above 600 nm are therefore highly desirable. We report here the evolution of far-red fluorescent proteins with peak excitation at 600 nm or above. The brightest one of these, Neptune, performs well in imaging deep tissues in living mice. The crystal structure of Neptune reveals a novel mechanism for red-shifting involving the acquisition of a new hydrogen bond with the acylimine region of the chromophore.

Structural basis for DNase activity of a conserved protein implicated in CRISPR-mediated genome defense.

Acquired immunity in prokaryotes is achieved by integrating short fragments of foreign nucleic acids into clustered regularly interspaced short palindromic repeats (CRISPRs). This nucleic acid-based immune system is mediated by a variable cassette of up to 45 protein families that represent distinct immune system subtypes. CRISPR-associated gene 1 (cas1) encodes the only universally conserved protein component of CRISPR immune systems, yet its function is unknown. Here we show that the Cas1 protein is a metal-dependent DNA-specific endonuclease that produces double-stranded DNA fragments of approximately 80 base pairs in length. The 2.2 A crystal structure of the Cas1 protein reveals a distinct fold and a conserved divalent metal ion-binding site. Mutation of metal ion-binding residues, chelation of metal ions, or metal-ion substitution inhibits Cas1-catalyzed DNA degradation. These results provide a foundation for understanding how Cas1 contributes to CRISPR function, perhaps as part of the machinery for processing foreign nucleic acids.