bluuebunny/crossref_metadata_2025 huggingface dataset:
Selenium isotopes record extensive marine suboxia during the Great Oxidation Event
Authors: Kipp Michael A. , Stüeken Eva E. , Bekker Andrey , Buick Roger
Published: January 2017

Significance

Oxygen is essential for eukaryotic life. The geologic record of early Earth contains abundant evidence of low oxygen levels, and accordingly, a lack of eukaryote fossils. The rise of oxygen to near-modern levels at the end of the Proterozoic Era is thus often cited as the trigger for the evolutionary radiation of complex life forms at this same time. Here we present selenium geochemical data that indicate an expansion of suboxic (>0.4 μM O
2
) habitats in the shallow oceans between 2.32 and 2.1 Ga––more than one billion years before eukaryotes become abundant in the fossil record. These environments could have harbored the earliest stages of eukaryotic evolution, but may have been too transient for substantial diversification to occur.
Tuning the ion selectivity of two-pore channels
Authors: Guo Jiangtao , Zeng Weizhong , Jiang Youxing
Published: January 2017

Significance

Ion channels selectively transfer ions across cell membranes, and their selectivity is controlled by a special region of the channel protein called the selectivity filter. Two-pore channels (TPCs) belong to the superfamily of voltage-gated tetrameric cation channels and possess a unique set of filter residues that define their ion selectivity. Despite extensive studies, debate still lingers about the selectivity properties of mammalian TPCs. Here, we provide structural and functional insights into the selectivity properties of TPC channels. We confirm the Na
+
selectivity of human TPC2, identify the key residues in the TPC filters that differentiate the selectivity between mammalian TPC2 and plant TPC1, and reveal the structural basis of Na
+
selectivity in mammalian TPCs.
Multi-institute analysis of carbapenem resistance reveals remarkable diversity, unexplained mechanisms, and limited clonal outbreaks
Authors: Cerqueira Gustavo C. , Earl Ashlee M. , Ernst Christoph M. , Grad Yonatan H. , Dekker John P. , Feldgarden Michael , Chapman Sinéad B. , Reis-Cunha João L. , Shea Terrance P. , Young Sarah , Zeng Qiandong , Delaney Mary L. , Kim Diane , Peterson Ellena M. , O’Brien Thomas F. , Ferraro Mary Jane , Hooper David C. , Huang Susan S. , Kirby James E. , Onderdonk Andrew B. , Birren Bruce W. , Hung Deborah T. , Cosimi Lisa A. , Wortman Jennifer R. , Murphy Cheryl I. , Hanage William P.
Published: January 2017

Significance

Carbapenem-resistant Enterobacteriaceae (CRE) are an urgent threat: as an increasing cause of disease and as the staging ground for resistance to “last line” drugs. Thus, we must understand how CRE evolve, diversify, and spread and especially the potential for asymptomatic transmission without outbreaks. Our broad sample of species and genetic determinants that defined four hospital CRE communities over 16 mo revealed a significant degree of CRE diversity, with little evidence for clonal spread but extensive movement of resistance determinants. We provide evidence for considerable asymptomatic carriage and unrecognizable mechanisms of carbapenem resistance that, together, indicate continued innovation by these organisms to thwart the action of this important class of antibiotics and underscore the need for continued surveillance of CRE.
Phylogenetic analysis of the human antibody repertoire reveals quantitative signatures of immune senescence and aging
Authors: de Bourcy Charles F. A. , Angel Cesar J. Lopez , Vollmers Christopher , Dekker Cornelia L. , Davis Mark M. , Quake Stephen R.
Published: January 2017

Significance

The world’s population is growing older, and senescence of the immune system is a fundamental factor underlying morbidity and mortality. We report a direct molecular characterization of the effects of aging on the adaptive immune system by high-throughput sequencing of antibody transcripts in the peripheral blood of humans. Using a phylogenetic approach to quantify dissimilarity, we compared the immunoglobulin repertoires of young and elderly individuals at baseline and during a well-defined immunogenic perturbation in the form of influenza vaccination; we also studied the long-term effects of chronic infection. Our work reveals previously unappreciated signatures of immune senescence that may find diagnostic use and guide approaches for improving elderly patients’ antibody responses.
Stromal cues regulate the pancreatic cancer epigenome and metabolome
Authors: Sherman Mara H. , Yu Ruth T. , Tseng Tiffany W. , Sousa Cristovao M. , Liu Sihao , Truitt Morgan L. , He Nanhai , Ding Ning , Liddle Christopher , Atkins Annette R. , Leblanc Mathias , Collisson Eric A. , Asara John M. , Kimmelman Alec C. , Downes Michael , Evans Ronald M.
Published: January 2017

Significance

Stromal fibroblasts of the pancreatic tumor microenvironment (TME) have been shown to play both tumor-supportive and tumor-suppressive roles in enacting a dysregulated wound-healing response. This apparent complexity suggests that an improved understanding of the molecular basis of cell–cell interactions in the TME is required to identify and target stroma-derived, growth-permissive mechanisms. Here we show that stromal cues induce transcriptional and metabolic changes in pancreatic cancer cells implicated in anabolic metabolism, which overlap with those previously demonstrated downstream of oncogenic Kras. Stromal signals broadly induce histone acetylation in the pancreatic cancer epigenome, and we highlight inhibition of acetyl-lysine sensing by the bromodomain and extraterminal (BET) bromodomain family, Bromodomain-containing protein 2 (BRD2) in particular, as a potential therapeutic strategy.
Phosphorylation by PKC and PKA regulate the kinase activity and downstream signaling of WNK4
Authors: Castañeda-Bueno Maria , Arroyo Juan Pablo , Zhang Junhui , Puthumana Jeremy , Yarborough Orlando , Shibata Shigeru , Rojas-Vega Lorena , Gamba Gerardo , Rinehart Jesse , Lifton Richard P.
Published: January 2017

Significance

The kinase WNK4 (with-no-lysine kinase 4) is an important regulator of the Na-Cl cotransporter (NCC) in the renal distal convoluted tubule (DCT). Volume depletion induces angiotensin II, activating PKC, which prevents WNK4 degradation by phosphorylating the KLHL3/CUL3 ubiquitin ligase. We now show that PKC also directly phosphorylates WNK4 at multiple sites in cell culture. Phosphorylation of two of these sites, S64 and S1196, promotes increased WNK4 kinase activity by increasing autophosphorylation of the WNK4 T-loop at S332. Volume depletion also induces phosphorylation of WNK4-S64 in the DCT in vivo, promoting NCC activity. These findings provide insights into the mechanisms regulating activity of NCC and the promotion of renal Na-Cl reabsorption without concomitant K
+
secretion in volume depletion.
Role of CCT chaperonin in the disassembly of mitotic checkpoint complexes
Authors: Kaisari Sharon , Sitry-Shevah Danielle , Miniowitz-Shemtov Shirly , Teichner Adar , Hershko Avram
Published: January 2017

Significance

The mitotic checkpoint system has an important role in ensuring correct segregation of chromosomes in mitosis. As long as not all chromosomes are attached correctly to the mitotic spindle, a mitotic checkpoint complex (MCC) is assembled and prevents chromosome separation by inhibiting the action of the ubiquitin ligase anaphase-promoting complex/cyclosome (APC/C). When the mitotic checkpoint system is turned off, MCC is disassembled to allow chromosome separation, but the mechanisms of MCC disassembly are poorly understood. Here we show that an important pathway in MCC disassembly is mediated by chaperonin containing TCP1, a complex previously known to play a role only in protein folding. The present study provides insight into molecular events responsible for mitotic checkpoint inactivation.
Induction, purification, and characterization of a thermo and pH stable laccase from Abortiporus biennis J2 and its application on the clarification of litchi juice
Authors: Yin Liang , Ye Jiayin , Kuang Sibi , Guan Yanqing , You Rong
Published: January 2017

A fungus J2 producing laccase with high yield was screened in soils and identified as Abortiporus biennis. The production of laccase was induced by 0.1 mM Cu2+, 0.1 mM tannic acid, and 0.5 M ethanol. The laccase from Abortiporus biennis J2 was purified to electrophoretic homogeneity by a couple of steps. The N-terminal amino acid sequence of the enzyme was AIGPTADLNISNADI. The properties of the purified laccase were investigated. The result showed the laccase from Abortiporus biennis J2 is a thermo and pH stable enzyme. The laccase activity was inhibited by Hg2+, Cd2+, Fe2+, Ag+, Cu2+, and Zn2+, while promoted by Mg2+, Mn2+ at 10 mM level. Purified laccase was used to the clarification of litchi juice. After treatment with this laccase, the phenolic content of litchi juice had been found to be greatly reduced along with an increase in the clarity of the juice. The result indicated the potential of this laccase for application in juice procession.
Anaerobic biodegradation of spiramycin I and characterization of its new metabolites
Authors: Yao Jian , Shao Lei , Chen Daijie , Liu Pengyu , Zhang Yubin
Published: January 2017

Activated sludge was used to treat the wastewater containing spiramycin I. Three new metabolites were isolated and identified, which produced by oxidation of C6-aldehyde, hydrolysis of C5-mycaminose-mycarose and macrolactone ring-open reaction of spiramycin I in anaerobic digestion. And their antimicrobial activities were inactivated. Our results indicated that anaerobic biodegradation metabolites of spiramycin I could not induce bacterial resistance in environment.
Heat stress induces ferroptosis-like cell death in plants
Authors: Distéfano Ayelén Mariana , Martin María Victoria , Córdoba Juan Pablo , Bellido Andrés Martín , D’Ippólito Sebastián , Colman Silvana Lorena , Soto Débora , Roldán Juan Alfredo , Bartoli Carlos Guillermo , Zabaleta Eduardo Julián , Fiol Diego Fernando , Stockwell Brent R. , Dixon Scott J. , Pagnussat Gabriela Carolina
Published: January 2017

In plants, regulated cell death (RCD) plays critical roles during development and is essential for plant-specific responses to abiotic and biotic stresses. Ferroptosis is an iron-dependent, oxidative, nonapoptotic form of cell death recently described in animal cells. In animal cells, this process can be triggered by depletion of glutathione (GSH) and accumulation of lipid reactive oxygen species (ROS). We investigated whether a similar process could be relevant to cell death in plants. Remarkably, heat shock (HS)–induced RCD, but not reproductive or vascular development, was found to involve a ferroptosis-like cell death process. In root cells, HS triggered an iron-dependent cell death pathway that was characterized by depletion of GSH and ascorbic acid and accumulation of cytosolic and lipid ROS. These results suggest a physiological role for this lethal pathway in response to heat stress in Arabidopsis thaliana. The similarity of ferroptosis in animal cells and ferroptosis-like death in plants suggests that oxidative, iron-dependent cell death programs may be evolutionarily ancient.
Enhanced Recovery Implementation in Major Gynecologic Surgeries: Effect of Care Standardization
Authors: Modesitt Susan C. , Sarosiek Bethany M. , Trowbridge Elisa R. , Redick Dana L. , Shah Puja M. , Thiele Robert H. , Tiouririne Mohamed , Hedrick Traci L.
Published: January 2017

(Abstracted from Obstet Gynecol 2016;128:457–466)

The concept of enhanced recovery after surgery (ERAS) emerged as a multimodal approach focused on optimizing patient experience, standardizing perioperative care, and improving surgical outcomes. This concept has been refined in several different surgical fields including both colorectal and gynecologic.
Effect of Wearable Technology Combined With a Lifestyle Intervention on Long-term Weight Loss: The IDEA Randomized Clinical Trial
Authors: Jakicic John M. , Davis Kelliann K. , Rogers Renee J. , King Wendy C. , Marcus Marsha D. , Helsel Diane , Rickman Amy D. , Wahed Abdus S. , Belle Steven H.
Published: January 2017

(Abstracted from JAMA 2016;316:1161–1171)

There is a critical need for effective long-term interventions to address the obesity epidemic. Treatments emphasizing both diet and physical activity are effective for achieving short-term weight loss (6-month weight loss of 8%–10% of initial weight).
Conundrums in the Management of Malignant Ovarian Germ-Cell Tumors: Toward Lessening Acute Morbidity and Late Effects of Treatment
Authors: Gershenson David M. , Frazier A. Lindsay
Published: January 2017

(Abstracted from Gynecol Oncol 2016;143:428–432)

Prior to the mid-1960s, most girls and young women with malignant ovarian germ cell tumors died of the disease. The only treatments available during this era were included surgery alone or combined with postoperative treatment (consisting of radiotherapy or radioisotopes, or single alkylating agents).
Antenatal Betamethasone: A Prolonged Time Interval from Administration to Delivery Is Associated With an Increased Incidence of Severe Intraventricular Hemorrhage in Infants Born Before 28 Weeks’ Gestation
Authors: Liebowitz Melissa , Clyman Ronald I.
Published: January 2017

(Abstracted from J Pediatr 2016;177:114–120)

Studies, including several randomized controlled trials, have reported that neonates exposed to antenatal corticosteroids have reduced incidence of death, respiratory distress syndrome (RDS), and severe grades of intraventricular hemorrhage (IVH). The present study aimed to investigate the effects of antenatal corticosteroids on severe IVH in infants born at less than 28 weeks’ gestation based on the hypothesis that the beneficial effects of antenatal steroids on severe IVH diminish with time in these infants and that retreatment with a second course of antenatal betamethasone (BMZ) can restore its beneficial effects.
Will Precision Medicine Improve Population Health?
Authors: Khoury Muin J. , Galea Sandro
Published: January 2017

(Abstracted from JAMA 2016;316(13):1357–1358)

This article discusses the pros and cons of the precision medicine initiative in the improvement of population health. It has been stated that precision medicine may not improve population health primarily due to 3 reasons.
Evidence for Feasibility of Fetal Trophoblastic Cell-Based Noninvasive Prenatal Testing
Authors: Breman Amy M. , Chow Jennifer C. , U’Ren Lance , Normand Elizabeth A. , Qdaisat Sadeem , Zhao Li , Henke David M. , Chen Rui , Shaw Chad A. , Jackson Laird , Yang Yaping , Vossaert Liesbeth , Needham Rachel H. V. , Chang Elizabeth J. , Campton Daniel , Werbin Jeffrey L. , Seubert Ron C. , Van den Veyver Ignatia B. , Stilwell Jackie L. , Kaldjian Eric P. , Beaudet Arthur L.
Published: January 2017

(Abstracted from Prenat Diagn 2016;36:1–11)

The potential use of fetal cells in maternal blood for prenatal diagnosis has been a promising technology for decades. Several strategies have been tried and tested for recovering fetal cells, although they are inconsistent and not reproducible.
Association of Labor Induction With Offspring Risk of Autism Spectrum Disorders
Authors: Oberg Anna Sara , D’Onofrio Brian M. , Rickert Martin E. , Hernandez-Diaz Sonia , Ecker Jeffrey L. , Almqvist Catarina , Larsson Henrik , Lichtenstein Paul , Bateman Brian T.
Published: January 2017

(Abstracted from JAMA Pediatr 2016;170(9):e160965)

Autism spectrum disorders (ASDs) are a collection of permanent developmental disabilities exemplified by impairments in social interaction and language development and stereotyped and repetitive behaviors. This study aimed to examine the association of labor induction with ASD by comparison of differentially exposed relatives and to follow up on their diagnosis of ASD.
Whole Women’s Victory—or Not?
Authors: Charo R. Alta
Published: January 2017

(Abstracted from N Engl J Med 2016;375:809–811)

The Whole Woman’s Health v. Hellerstedt was a US Supreme Court case whose verdict decreed that Texas could not place restrictions on the delivery of abortion services that created an undue burden for women seeking an abortion.
Medical Students’ Perspectives on Implementing Curriculum Change at One Institution
Authors: Yengo-Kahn Aaron M. , Baker Courtney E. , Lomis and Kimberly D.
Published: January 2017

Training physicians to be effective practitioners throughout their careers begins in undergraduate medical education with particular focus on self-directed inquiry, professional and interprofessional development, and competency-based assessment. A select number of medical schools are restructuring their curricula by placing the student at the center of content delivery to enhance the learning experience. While this restructuring may benefit the adult learner, administrators often make assumptions about how students will perceive and respond to such innovative and unfamiliar educational concepts. This can create a disconnect between students and their curriculum. Administrative mindfulness of student experiences is needed to ensure successful implementation of curricular change, facilitate the transition from old to new modalities, and train competent physician graduates.

Vanderbilt University School of Medicine (VUSM) recently completed a curriculum update, and student representatives have been essential participants in the transition, from the earliest stages in preplanning to rapid-cycle feedback as the curriculum runs. Two of the authors are members of VUSM’s Student Curriculum Committee, which facilitates gathering and relaying student feedback to the administration. Drawing from their experiences, five specific considerations to address and manage when implementing student-centered curricular change are presented: (1) Communicate the rationale, (2) acknowledge anxiety, (3) adjust extracurricular leadership roles, (4) manage “The Bulge” of learners in the clinical environment, and (5) foster ongoing collaboration of students and administrators. For each consideration, examples and proposed solutions are provided.
Paradoxical Emergence
Authors: Hambrecht-Wiedbusch Viviane S. , Li Duan , Mashour George A.
Published: January 2017

Background

Promoting arousal by manipulating certain brain regions and/or neurotransmitters has been a recent research focus, with the goal of trying to improve recovery from general anesthesia. The current study tested the hypothesis that a single subanesthetic dose of ketamine during isoflurane anesthesia would increase cholinergic tone in the prefrontal cortex and accelerate recovery.

Methods

Adult male rats were implanted with electroencephalography electrodes (frontal, parietal, and occipital cortex) and a microdialysis guide cannula targeted for the prefrontal cortex. After establishing general anesthesia with isoflurane, animals were randomly assigned to receive a saline control or ketamine injection. When isoflurane was discontinued nearly 90 min after drug or saline administration, recovery from anesthesia was measured by experimenters and blinded observers. During the entire experiment, electrophysiologic signals were recorded and acetylcholine was quantified by high-performance liquid chromatography with electrochemical detection.

Results

A single dose of subanesthetic ketamine caused an initial 125% increase in burst suppression ratio (last isoflurane sample: 37.48 ± 24.11% vs. isoflurane after ketamine injection: 84.36 ± 8.95%; P < 0.0001), but also a significant 44% reduction in emergence time (saline: 877 ± 335 s vs. ketamine: 494 ± 108 s; P = 0.0005; n = 10 per treatment). Furthermore, ketamine caused a significant 317% increase in cortical acetylcholine release (mean after ketamine injection: 0.18 ± 0.16 pmol vs. ketamine recovery: 0.75 ± 0.41 pmol; P = 0.0002) after isoflurane anesthesia was discontinued.

Conclusions

Administration of subanesthetic doses of ketamine during isoflurane anesthesia increases anesthetic depth but—paradoxically—accelerates the recovery of consciousness, possibly through cholinergic mechanisms.
Presepsin (sCD14-ST) Is a Novel Marker for Risk Stratification in Cardiac Surgery Patients
Authors: Bomberg Hagen , Klingele Matthias , Wagenpfeil Stefan , Spanuth Eberhard , Volk Thomas , Sessler Daniel I. , Schäfers Hans-Joachim , Groesdonk Heinrich Volker
Published: January 2017

Background

Presepsin (soluble cluster-of-differentiation 14 subtype [sCD14-ST]) is a humoral risk stratification marker for systemic inflammatory response syndrome and sepsis. It remains unknown whether presepsin can be used to stratify risk in elective cardiac surgery. The authors therefore determined the usefulness of presepsin for risk stratification in patients having elective cardiac surgery.

Methods

Eight hundred fifty-six cardiac surgical patients were prospectively studied. Preoperative plasma concentrations of presepsin, procalcitonin, N-terminal pro–hormone natriuretic peptide, cystatin C, and the additive European System of Cardiac Operative Risk Evaluation 2 were compared to mortality at 30 days (primary outcome), 6 months, and 2 yr. Discrimination was assessed with C statistic. Logistic regression analysis was used to calculate univariable and multivariable odds ratios.

Results

Thirty-day mortality was 3.2%, 6-month mortality was 6.1%, and 2-yr mortality was 10.4% across the population. Median preoperative presepsin concentrations were significantly greater in 30-day nonsurvivors than in survivors: 842 pg/ml (interquartile range, 306 to 1,246) versus 160 pg/ml (interquartile range, 122 to 234); difference, 167 pg/ml (interquartile range, 92 to 301; P < 0.001). The results were similar for 6-month and 2-yr mortality. Compared to the European System of Cardiac Operative Risk Evaluation 2, presepsin concentration provided better discrimination for postoperative mortality at all follow-up periods, including 30 days (C statistic 0.88 vs. 0.74), 6 months (0.87 vs. 0.76), and 2 yr (0.81 vs. 0.74). Presepsin also provided better discrimination than cystatin C, N-terminal pro–hormone natriuretic peptide, or procalcitonin. Elevated presepsin remained an independent risk predictor after adjustment for potential confounding factors.

Conclusions

Elevated preoperative plasma presepsin concentration is an independent predictor of postoperative mortality in elective cardiac surgery patients and is a stronger predictor than several other commonly used assessments.
After the Fall: The Tapestry of Disturbance and Recovery
Authors: Nadkarni Nalini M.
Published: January 2017

On July 3, 2015, Nalini Nadkarni, a world-renowned ecologist who had been studying the biologic processes of ecosystem disturbance and recovery, sustained a catastrophic 50-foot free-fall from the top of the rainforest canopy to the forest floor at her remote field research site. She lost consciousness in shock and sustained life-threatening injuries. Her accompanying students hiked out, radio-called 911, and the Harborview Medical Center (Seattle) Medivac team arrived 4 hours later to rescue her. Her prognosis was extremely grim; her family gathered in anticipation of her death as she underwent four operations during her 10 days in the ICU. As she emerged from coma, she spent weeks of hospital recovery and months of progressive mobility and physical therapy during medical leave from work. She experienced ICU psychosis and postintensive care syndrome, but slowly recovered nearly totally, to the point where she can solo hike up to 18 miles in a day, and has fully resumed her professional responsibilities as professor of biology, including climbing tall trees for her canopy research. She attributes her survival and remarkable recovery to both exquisite medical critical care and support she received, and also to incorporating lessons learned from her interdisciplinary study of how diverse natural systems commonly experience and recover from catastrophic disturbances (e.g., forest fires, traffic jams, orphaned children, and refugee survivors of war). Insights from her own encounter with critical illness and study of disturbance and recovery led her to reflect on the tapestry of disturbance and recovery that permeate all ecosystems, and with relevance to the evolving Society of Critical Care Medicine, postintensive care syndrome, and THRIVE initiatives.
Melanoma during pregnancy: a report of 60 pregnancies complicated by melanoma
Authors: de Haan Jorine , Lok Christianne A. , de Groot Christianne J. , Crijns Marianne B. , Van Calsteren Kristel , Dahl Steffensen Karina , Halaska Michael J. , Altintas Sevilay , Boere Ingrid A. , Fruscio Robert , Kolawa Wojciech , Witteveen Petronella O. , Amant Frédéric
Published: January 2017

The management of melanoma during pregnancy is challenging as maternal benefits and fetal risks need to be balanced. Here, we present an overview of the incidence, the demographic and clinical characteristics and the treatment modalities used. After analysis of obstetric, fetal and maternal outcome, recommendations for clinical practice are provided. From the ‘International Network on Cancer, Infertility and Pregnancy’ database, pregnant patients with melanoma were identified and analysed. Sixty pregnancies were eligible for analysis. Fifty percent of the patients presented with advanced melanoma during pregnancy (14 stage III and 16 stage IV), and 27% were diagnosed with recurrent melanoma. Surgery was the main therapeutic strategy during pregnancy. Only four patients with advanced melanoma were treated during pregnancy with systemic therapy (n=1) or radiotherapy (n=3). Premature delivery was observed in 18% of the ongoing pregnancies, all which were induced and 78% of which involved patients with advanced melanoma. Thirty-nine percent of the patients died within 5 years; all had been diagnosed with stage III or IV disease during pregnancy. Melanoma can present in a more advanced stage during pregnancy. New systemic therapies may be beneficial for patients with metastatic melanoma but may not be pregnancy compatible. In these patients, preterm induction of labour need to be discussed, despite the short-term and long-term negative effects on the child.
Recurrence behavior in early-stage cutaneous melanoma: pattern, timing, survival, and influencing factors
Authors: Tas Faruk , Erturk Kayhan
Published: January 2017

Nearly one-third of all melanoma patients will experience disease recurrence and the majority of the relapses eventually develop metastatic disease as a consequence of disease progression in the early-stage melanoma patients. As very few number of studies have investigated the natural recurrence history of early-stage cutaneous melanoma at the first relapse, we analyzed the time until recurrence along with the patterns and outcomes of the relapses in this retrospective study. A total of 332 patients who were initially diagnosed with nonmetastatic melanoma and developed recurrence during the disease course and/or follow-up were included in the analysis. Locoregional relapse alone defined regional lymph node metastases, distant skin, subcutaneous, and satellite/in-transit metastases. Nearly half of the primary recurrences were locoregional metastasis alone (50.6%), followed by mixed locoregional and distant metastases (25.9%), and distant metastases alone (23.5%). In terms of distant metastasis, the lung was the most frequently affected site (30.7%), followed by bone (15.7%), liver (13.9%), and brain (10.8%). The time intervals for each of the recurrence patterns and distant metastasis sites were identical and nearly 16 months. Nearly two-thirds of the relapses occurred within the first 2 years of diagnosis. A significant survival advantage was observed in locoregional relapse alone compared with other relapse patterns (P<0.0001). In conclusion, about half of the melanoma patients developed locoregional relapse alone and it was found to be associated with a favorable prognosis for outcome. Because nearly two-thirds of the relapses occurred within the first 2 years of diagnosis, we suggest that all early-stage melanoma patients should be kept under a strict, thorough, and close follow-up program for at least 2 years following the diagnosis.
The cessation of anti-PD-1 antibodies of complete responders in metastatic melanoma
Authors: Ladwa Rahul , Atkinson Victoria
Published: January 2017

The optimal duration of PD-1 antibodies for metastatic melanoma is unknown. In previous trials, there has been the potential to cease therapy if the patient achieves a complete response (CR). We aimed to assess the outcomes of patients who had ceased anti-PD-1 antibodies in this setting. A retrospective review was carried out of CR to PD-1-based therapy across two institutions. Patients were from the Pembrolizumab Named Patient Program (PEM NPP), Nivolumab monotherapy (NIVO), and reimbursed Pembrolizumab (r PEM). Patients had to have experienced a CR to PD-1-based therapy and ceased therapy because of this. Disease recurrence was the primary outcome measured. Twenty-nine patients (PEM NPP, N=20; Nivo, N=3; r PEM, N=6) ceased anti-PD-1 therapy after CR for observation. The median age was 64 (27–83) years. All patients had treatment discontinued for observation. The median time to CR was 10.5 months in the PEM NPP, 7.5 months on r PEM groups, and 17 months in the NIVO group. The median time off therapy in PEM NPP was 10 months, NIVO was 9 months, and r PEM was 4.5 months. To date, three patients have shown a relapse at a median follow-up off treatment of 8 months. This is the first report of patients who have intentionally ceased PD-1-based therapy because of CR. With a follow-up of 8 months off treatment, the risk of relapse was low. Data such as these are clinically relevant as we need to be able to discuss cessation of therapy and relevant from a pharmacoeconomic perspective, given the cost of PD-1 antibodies to society.
STARGARDT DISEASE
Authors: Light Jacob G. , Fard Masoud A. , Yaseri Mehdi , Aiyetan Paul , Handa James T. , Ebrahimi Katayoon B.
Published: January 2017

Purpose:

To identify changes in the outer retina in areas without atrophy or flecks of Stargardt disease (STGD) using spectral-domain optical coherence tomography.

Methods:

Twenty-three STGD patients and 26 control subjects were assessed for outer retina (from the outer border of Bruch membrane [BrM] to the inner border of the inner segment ellipsoid zone [EZ]), BrM–retinal pigment epithelium apex, the EZ thickness, and apical process interdigitation zone.

Results:

Patients with STGD had increased BrM–EZ thickness in areas without apparent disease versus control subjects at 1,000, 1,500, 2,000, and 2,500 μm superior and 1,500 μm, 2,000 μm, and 2,500 μm inferior to the fovea (P < 0.05 to P < 0.001), greatest difference (3.4 μm) at 2,500 μm superiorly. The BrM–retinal pigment epithelium segment showed larger fractional contribution of 0.48 to 0.51 to the overall BrM-EZ thickness compared with 0.35 to 0.42 in control subjects. The thickness of EZ and the interspace between the retinal pigment epithelium apex and EZ were smaller in the STGD patients (P < 0.05 to P < 0.001). Patients with STGD displayed an interrupted interdigitation zone in 16 (84.2%) of 19 eyes versus 6 (23.1%) of 26 eyes of the control subjects (P < 0.001). The BrM-EZ segment of the outer retina of STGD patients lacked the typical normal trilaminar pattern.

Conclusion:

Subtle changes are present within the BrM-EZ segment of the outer retina of STGD patients in areas that are devoid of atrophy and flecks. These findings suggest that pathologic changes in STGD are more widespread than that seen by clinical examination.
FACTORS ASSOCIATED WITH VISUAL OUTCOME AFTER MACULA-OFF RHEGMATOGENOUS RETINAL DETACHMENT SURGERY
Authors: Park Dae Hyun , Choi Kyung Seek , Sun Hae Jung , Lee Sung Jin
Published: January 2017

Purpose:

To evaluate preoperative factors influencing the visual outcome and postoperative factors associated with the changes in visual acuity, after reattachment surgery to treat macula-off rhegmatogenous retinal detachment.

Methods:

A total of 180 eyes of 180 patients who underwent reattachment surgery to treat macula-off rhegmatogenous retinal detachment, and who were followed up for more than 12 months, were reviewed retrospectively. Preoperative and postoperative characteristics, including optical coherence tomography findings, were comprehensively analyzed using univariate and multivariate models to evaluate preoperative factors influencing best-corrected visual acuity 12 months after macula-off rhegmatogenous retinal detachment surgery and postoperative factors associated with changes in best-corrected visual acuity after surgery.

Results:

Preoperatively, the extent of detachment (P = 0.037), macula-off duration (P < 0.001), and integrity of the external limiting membrane (β = 0.163; P = 0.002) were significantly associated with postoperative visual prognosis. Six factors were associated with changes in visual acuity after surgery: disruption of ellipsoid zone integrity (β = 0.167; P < 0.001), the Henle's fiber layer and the outer nuclear layer (HFL + ONL)/photoreceptor layer ratio (β = 0.199; P < 0.001), the photoreceptor outer segment length (β = −0.020; P < 0.001), the photoreceptor inner segment length/photoreceptor outer segment length ratio (β = 0.047; P = 0.005), the ratio of photoreceptor layer thickness between the RD eye and fellow eye (β = −0.126; P = 0.018), and the photoreceptor outer segment length ratio between the RD eye and fellow eye (β = −0.425; P < 0.001).

Conclusion:

Preoperative factors associated with the visual outcome after macula-off rhegmatogenous retinal detachment surgery were the extent of detachment, macula-off duration, and external limiting membrane integrity. Postoperatively, predictive factors were the outer retinal microstructures, particularly the photoreceptor outer segment layer.
The Presence of Conjunctivochalasis in Obstructive Sleep Apnea Patients
Authors: Acar Mutlu , Firat Hikmet , Yüceege Melike , Şanal Doğan Aysun , Çalişkan Sinan , Gürdal Canan
Published: January 2017

Objectives:

The aim of our study was to detect the presence of conjunctivochalasis (CCh) in obstructive sleep apnea (OSA) patients.

Methods:

We included 54 subjects (41 OSA patients and 14 control subjects) in the study. All the patients were assessed regarding the presence and stage of CCh.

Results:

The patients were grouped according to their apnea-hypopnea index as determined during nocturnal polysomnography in our laboratory as mild (12 patients), moderate (16 patients), and severe (13 patients) OSA. The CCh rate was 87.8% in the OSA group and 57.1% in the control group (P=0.022). Mean CCh stage was 1.58±1.24, 2.38±0.88, and 2.15±0.98 in the mild, moderate, and severe OSA groups, respectively, and 0.71±0.72 in the control group (P=0.0001).

Conclusions:

The moderate and severe OSA groups were associated with higher rates and more advanced stages of CCh. We believe that detailed conjunctival assessment is necessary for patients with complaints such as burning, stinging, and foreign body sensation, which we frequently confront in daily practice. In particular, young patients diagnosed with CCh must be carefully assessed regarding sleep apnea. In light of the above findings, we suggest that patients with ocular surface symptoms that are not relieved by topical medical treatment should be assessed for CCh and OSA. Longitudinal studies monitoring the response of CCh to OSA treatment are needed to clarify the relationship between CCh and OSA.
Effect of Combination Vaccines on Hepatitis B Vaccine Compliance in Children in the United States
Authors: Kurosky Samantha K. , Davis Keith L. , Galindo Claudia M.
Published: January 2017

Background:

An increasingly crowded immunization schedule threatens the completion and compliance of hepatitis B vaccinations (HepB), the primary method of hepatitis B prevention. Combination vaccines have been proposed to alleviate this problem.

Methods:

Data from the 2011 National Immunization Survey Public-Use Data File were utilized (GSK study identifier: HO-11–770) to compare HepB completion and compliance rates between 3 groups of children: those who received HepB combination vaccine, those who received non-HepB combination vaccine and those who received HepB single-antigen vaccine only. Completion was defined as the accumulation of 3 HepB doses by 18 months. Compliance was defined as the receipt of vaccine doses within the Advisory Committee on Immunization Practices’ recommended age ranges.

Results:

Of a sample of 4,040,116 children, 39.4% received a HepB combination vaccine, 43.0% received a non-HepB combination vaccine and 17.5% received a HepB single-antigen vaccine. Overall, 91.2% of children completed all 3 recommended doses, but only 61.8% completed them at age-appropriate times. Those receiving single-antigen only (odds ratio = 0.25, 95% confidence interval: 0.17–0.35) or non-HepB combination vaccines (odds ratio = 0.50, 95% confidence interval: 0.37–0.69) were substantially less likely to complete 3 doses of HepB than those who received the HepB combination vaccine.

Conclusions:

Although completion rates were high, a large proportion of children did not receive HepB doses at age-appropriate times. Combination vaccine was associated with both higher completion and compliance outcomes compared with HepB single-antigen vaccine.
A tailored-guided internet-based cognitive-behavioral intervention for patients with rheumatoid arthritis as an adjunct to standard rheumatological care: results of a randomized controlled trial
Authors: Ferwerda Maaike , van Beugen Sylvia , van Middendorp Henriët , Spillekom-van Koulil Saskia , Donders A. Rogier T. , Visser Henk , Taal Erik , Creemers Marjonne C.W. , van Riel Piet C.L.M. , Evers Andrea W.M.
Published: January 2017

For patients with chronic pain conditions such as rheumatoid arthritis (RA), who experience elevated levels of distress, tailored-guided internet-based cognitive-behavioral treatment may be effective in improving psychological and physical functioning, and reducing the impact of RA on daily life. A multicenter, randomized controlled trial was conducted for RA patients with elevated levels of distress as assessed by a disease-specific measure. The control group (n = 71) received standard care and the intervention group (n = 62) additionally received an internet-based tailored cognitive-behavioral intervention. Main analyses were performed using a linear mixed model estimating differences between the intervention and control groups in scores of psychological functioning, physical functioning, and impact of RA on daily life at preassesment and postassessment, and at 3, 6, 9, and 12 months. Patients who received the internet-based intervention reported a larger improvement in psychological functioning compared with the control group, indicating less depressed mood (P< 0.001,d= 0.54), negative mood (P= 0.01,d= 0.38), and anxiety (P< 0.001,d= 0.48) during the course of the 1-year follow-up period. Regarding physical functioning, a trend was found for the intervention group reporting less fatigue than the control group (P= 0.06,d= 0.24), whereas no effect was found on pain. No effects were found for the impact of RA on daily life, except for the intervention group experiencing fewer role limitations due to emotional problems (P< 0.001,d= 0.53). Offering guided internet-based cognitive-behavioral therapy is a promising development to aid patients with psychological distress particularly in improving psychological functioning. Further research on adherence and specific intervention ingredients is warranted.
Memantine as an Adjuvant Treatment for Obsessive Compulsive Symptoms in Manic Phase of Bipolar Disorder
Authors: Sahraian Ali , Jahromi Leila Razeghian , Ghanizadeh Ahmad , Mowla Arash
Published: January 2017

Purpose/Background

The aim of this study is to examine the effects of memantine as an adjuvant treatment for obsessive compulsive (OC) symptoms in patients with bipolar disorder (BD) type I, manic phase.

Methods/Procedures

In this 16-week double-blind placebo-controlled randomized clinical trial, 58 patients in the manic phase of BD who had OC symptoms were randomly allocated to receive memantine or placebo plus their routine medications (lithium + olanzapine + clonazepam). The Yale Brown Obsessive Compulsive Behavior Scale was used to assess the outcomes. Adverse effects were also recorded.

Findings/Results

Thirty-eight patients (19 in the memantine group and 19 in the placebo group) completed the trial. Throughout the trial, the mean score decreased from 20.26 ± 5.91 to 9.73 ± 5.44 in the memantine group (P < 0.000) and from 22.89 ± 5.70 to 16.63 ± 4.00 in the placebo group (P < 0.000). At the end of the study, 15 (78.94%) patients in the memantine group and 7 (36.84%) patients in the placebo group demonstrated more than 34% decline in the Yale Brown Obsessive Compulsive Behavior Scale score (P < 0.01). No serious adverse effects were reported.

Implications/Conclusions

Our double-blind controlled clinical trial showed that memantine is an effective adjuvant agent for reducing OC symptoms in patients with BD. However, it needs to be noted that our study is preliminary, and larger double-blind controlled studies are needed to confirm the results.
Helicobacter pylori and Risk of Nonalcoholic Fatty Liver Disease
Authors: Wijarnpreecha Karn , Thongprayoon Charat , Panjawatanan Panadeekarn , Manatsathit Wuttiporn , Jaruvongvanich Veeravich , Ungprasert Patompong
Published: January 2017

Background/Objectives:

Helicobacter pylori (H. pylori) is the most common chronic bacterial infection. Patients with H. pylori infection may be at an increased risk of nonalcoholic fatty liver disease (NAFLD) because of chronic inflammation and insulin resistance. Several epidemiologic studies attempting to determine this risk have yielded inconsistent results. This meta-analysis was conducted with the aims to summarize all available evidence and estimate the risk of NAFLD in patients with H. pylori infection.

Methods:

A literature search was performed using MEDLINE and EMBASE database from inception to June 2016. Studies that reported relative risks, odd ratios, or hazard ratios comparing the risk of NAFLD among patients with H. pylori infection versus without H. pylori infection were included. Pooled odds ratios and 95% confidence intervals were calculated using a random-effect, generic inverse variance method.

Results:

Six studies met our eligibility criteria and were included in this analysis. We found a statistically significant increased risk of NAFLD among patients with H. pylori infection with the pooled odds ratios of 1.21 (95% confidence interval, 1.07-1.37). The statistical heterogeneity was low with an I
2 of 49%.

Conclusions:

A significantly increased risk of NAFLD among patients with H. pylori infection was demonstrated in this meta-analysis. Further studies are required to clarify how this risk should be addressed in clinical practice.
Narrowing in on the anti-β cell-specific T cells: looking ‘where the action is’
Authors: Kent Sally C. , Babon Jenny Aurielle B.
Published: January 2017

Purpose of review

By necessity, the vast majority of information we have on autoreactive T cells in human type 1 diabetes (T1D) has come from the study of peripheral blood of donors with T1D. It is not clear how representative the peripheral autoreactive T-cell repertoire is of the autoreactive T cells infiltrating the islets in T1D. We will summarize and discuss what is known of the immunohistopathology of insulitis, the T-cell receptor repertoire expressed by islet-infiltrating T cells, and the autoreactivity and function of islet-infiltrating T cells in T1D.

Recent findings

Recovery and analysis of live, islet-infiltrating T cells from the islets of cadaveric donors with T1D revealed a broad repertoire and proinflammatory phenotype of CD4+ T-cell autoreactivity to peptide targets from islet proteins, including proinsulin, as well as CD4+ T-cell reactivity to a number of post-translationally modified peptides, including peptides with citrullinations and hybrid insulin peptide fusions. Islet-infiltrating CD8+ T cells were also derived and required further isolation and characterization.

The recovery of live, islet-infiltrating T cells from donors with T1D, reactive with a broad range of known targets and post-translationally modified peptides, allows for the specific functional analysis of islet-infiltrating T cells for the development of antigen-specific immunotherapies.
Adverse events and risk factors during emergency intubation in a tertiary paediatric emergency department
Authors: Löllgen Ruth M.C. , Pontin Jennifer , Gow Matthew , McCaskill Mary E.
Published: January 2017

Background

Rapid sequence intubation and emergency intubation in the emergency department (ED) can be life-saving procedures, but require the appropriate skills, experience and preparation to avoid complications ranging from simple trauma to life-threatening desaturation. Only scarce data exist in the published literature on complications following emergency intubation in children and most guidelines are extrapolated from the adult population.

Patients and methods

We reviewed all emergency intubations of patients in our tertiary paediatric ED within a 2-year period to estimate the incidence of complications and to analyse the risk factors associated with this procedure.

Results

Seventy-two children were intubated; complications occurred in one in four and repeated attempts at intubation in 17/23 children. The median age of the children was 2 years (range: 0 days–6 years). The most common reason for intubation was altered level of consciousness and the most frequent diagnosis at the time of intubation was seizure/status epilepticus. Complications were related to desaturation (n=7), equipment failure (n=3), intravenous access (n=2) and hypotension (n=2), erroneous or insufficient drug preparation (n=1) and other reasons (n=3). There was no significant association of complications with the child’s age or weight, time of arrival to ED, preintubation hypotension or combination of drugs used.

Conclusion

Complications of rapid sequence intubation, a relatively low-frequency procedure in the paediatric ED, occurred in one of four children and repeat attempts at intubation were made in another 24%. We suggest that the use of an intubation checklist including the preparation of equipment and recommendations for drug use would minimize the occurrence of adverse events of intubation in children.
Innovative strategies for adverse karyotype acute myeloid leukemia
Authors: Blum Sabine , Greve Gabriele , Lübbert Michael
Published: January 2017

Purpose of review

Adverse karyotype acute myeloid leukemia is a disease particularly of older patients, but also observed in younger patients. Despite all efforts, standard chemotherapy is still generally applied in fit patients, as already for decades, and for nearly all different subtypes of acute myeloid leukemia. Lack of more specifically targeted therapy and the often older age of the patients are complicating treatment, and in the subgroup of patients achieving a complete remission, the strikingly high frequency of relapse is a characteristic of this disease. This review aims to give an overview of current treatment approaches as well as emerging therapies.

Recent findings

Currently, the approach of a targeted therapy specific to the genetic and/or epigenetic aberrations detected in the individual patient is still not possible, and a ‘one treatment fits all’ course of action is still used, with allografting as curative consolidation. However, first immunotherapeutic approaches are emerging as treatment options and first phase 1 and 2 studies are described.

Treatment of acute myeloid leukemia with adverse karyotype is still not individualized, most treatment options currently not being curative. This can change in the near future, but recent findings will have to be implemented into larger phase 3 studies before being standard of care.