bluuebunny/crossref_metadata_2025 huggingface dataset:
CEP3 levels affect starvation-related growth responses of the primary root
Authors: Delay Christina , Chapman Kelly , Taleski Michael , Wang Yaowei , Tyagi Sonika , Xiong Yan , Imin Nijat , Djordjevic Michael A
Published: June 2019

CEPs (C-TERMINALLY ENCODED PEPTIDEs) inhibit Arabidopsis primary root growth by unknown mechanisms. We investigated how CEP3 levels control primary root growth. CEP3 peptide application decreased cell division, S-phase cell number, root meristematic cell number, and meristem zone (MZ) size in a dose- and CEP RECEPTOR1-dependent manner. Grafting showed that CEP3-dependent growth inhibition requires root and shoot CEPR1. CEP3 induced mitotic quiescence in MZ cells significantly faster than that induced by nutrient limitation alone. CEP3 also inhibited the restoration of S-phase to mitotically quiescence cells by nutrient resupply without quantitatively reducing TARGET OF RAPAMYCIN (TOR) kinase activity. In contrast, cep3-1 had an increased meristem size and S-phase cell number under nitrogen (N)-limited conditions, but not under N-sufficient conditions. Furthermore, cep3-1 meristematic cells remained in S-phase longer than wild-type cells during a sustained carbon (C) and N limitation. RNA sequencing showed that CEP3 peptide down-regulated genes involved in S-phase entry, cell wall and ribosome biogenesis, DNA replication, and meristem expansion, and up-regulated genes involved in catabolic processes and proteins and peptides that negatively control meristem expansion and root growth. Many of these genes were reciprocally regulated in cep3-1. The results suggest that raising CEP3 induces starvation-related responses that curtail primary root growth under severe nutrient limitation.
The HD-Zip transcription factor LcHB2 regulates litchi fruit abscission through the activation of two cellulase genes
Authors: Li Caiqin , Zhao Minglei , Ma Xingshuai , Wen Zhenxi , Ying Peiyuan , Peng Manjun , Ning Xiping , Xia Rui , Wu Hong , Li Jianguo
Published: June 2019

The expression of two cellulases, LcCEL2 and LcCEL8, is strongly associated with fruitlet abscission in litchi and is regulated by direct binding of an HD-Zip transcription factor to the gene promotors.
Taking the path computably traveled
Authors: Franklin Johanna N Y , Turetsky Dan
Published: June 2019

We define a real $A$ to be low for paths in Baire space (or Cantor space) if every $\varPi ^0_1$ class with an $A$-computable element has a computable element. We prove that lowness for paths in Baire space and lowness for paths in Cantor space are equivalent and, furthermore, that these notions are also equivalent to lowness for isomorphism.
The study of unclassified B[e] stars and candidates in the Galaxy and Magellanic Clouds†
Authors: Condori C A H , Borges Fernandes M , Kraus M , Panoglou D , Guerrero C A
Published: June 2019

We investigated 12 unclassified B[e] stars or candidates, 8 from the Galaxy, 2 from the Large Magellanic Cloud (LMC), and 2 from the Small Magellanic Cloud (SMC). Based on the analysis of high-resolution spectroscopic (FEROS) and photometric data, we confirmed the presence of the B[e] phenomenon for all objects of our sample, except for one (IRAS 07455-3143). We derived their effective temperature, spectral type, luminosity class, interstellar extinction and, using the distances from Gaia DR2, we obtained their bolometric magnitude, luminosity, and radius. Modelling of the forbidden lines present in the FEROS spectra revealed information about the kinematics and geometry of the circumstellar medium of these objects. In addition, we analysed the light curves of four stars, finding their most probable periods. The evolutionary stage of 11 stars of our sample is suggested from their position on the HR diagram, taking into account evolutionary tracks of stars with solar, LMC, and SMC metallicities. As results, we identified B and B[e] supergiants, B[e] stars probably at the main sequence or close to its end, post-AGB and HAeB[e] candidates, and A[e] stars in the main sequence or in the pre-main sequence. However, our most remarkable results are the identification of the third A[e] supergiant (ARDB 54, the first one in the LMC), and of an ‘LBV impostor’ in the SMC (LHA 115-N82).
A joint ALMA–Bolocam–Planck SZ study of the pressure distribution in RX J1347.5−1145
Authors: Di Mascolo Luca , Churazov Eugene , Mroczkowski Tony
Published: June 2019

We report the joint analysis of single-dish and interferometric observations of the Sunyaev–Zeldovich (SZ) effect from the galaxy cluster RX J1347.5−1145. We have developed a parametric fitting procedure that uses native imaging and visibility data, and tested it using the rich data sets from ALMA, Bolocam, and Planck available for this object. RX J1347.5−1145 is a very hot and luminous cluster showing signatures of a merger. Previous X-ray-motivated SZ studies have highlighted the presence of an excess SZ signal south-east of the X-ray peak, which was generally interpreted as a strong shock-induced pressure perturbation. Our model, when centred at the X-ray peak, confirms this. However, the presence of two almost equally bright giant elliptical galaxies separated by ∼100 kpc makes the choice of the cluster centre ambiguous, and allows for considerable freedom in modelling the structure of the galaxy cluster. For instance, we have shown that the SZ signal can be well described by a single smooth ellipsoidal generalized Navarro–Frenk–White profile, where the best-fitting centroid is located between the two brightest cluster galaxies. This leads to a considerably weaker excess SZ signal from the south-eastern substructure. Further, the most prominent features seen in the X-ray can be explained as predominantly isobaric structures, alleviating the need for highly supersonic velocities, although overpressurized regions associated with the moving subhaloes are still present in our model.
Enhanced X-ray emission from candidate Lyman continuum emitting galaxies
Authors: Bluem J , Kaaret P , Prestwich A , Brorby M
Published: June 2019

X-ray binaries may have helped reionize the early Universe by enabling Lyman continuum escape. We analysed a set of eight local galaxies that are potential Lyman leaking galaxies, identified by a blue colour and weak emission lines, using Chandra X-ray observations. Five of the galaxies feature X-ray sources, while three galaxies are not significantly detected in X-rays. X-ray luminosities were found for the galaxies and X-ray sources. Four of the galaxies have elevated X-ray luminosity versus what would be expected based on star formation rate and metallicity. The presence of detected X-ray sources within the galaxies is found to correlate with the ratio of the star formation rate estimated from the near-ultraviolet flux to that estimated from the infrared. This implies reduced obscuration due to dust in the galaxies with X-ray sources. These results support the idea that X-ray binaries may be an important part of the process of reionziation.
X-ray dips and a complex UV/X-ray cross-correlation function in the black hole candidate MAXI J1820+070
Authors: Kajava J J E , Motta S E , Sanna A , Veledina A , Del Santo M , Segreto A
Published: June 2019

MAXI J1820+070, a black hole candidate first detected in early 2018 March, was observed by XMM–Newton during the outburst rise. In this letter we report on the spectral and timing analysis of the XMM–Newton X-ray and UV data, as well as contemporaneous X-ray data from the Swift satellite. The X-ray spectrum is well described by a hard thermal Comptonization continuum. The XMM–Newton X-ray light curve shows a pronounced dipping interval, and spectral analysis indicates that it is caused by a moderately ionized partial covering absorber. The XMM–Newton/OM U-filter data do not reveal any signs of the 17 h orbital modulation that was seen later on during the outburst decay. The UV/X-ray cross-correlation function shows a complex shape, with a peak at positive lags of about 4 s and a precognition dip at negative lags, which is absent during the X-ray dipping episode. Such shape could arise if the UV emission comes partially from synchrotron self-Compton emission near the black hole, as well as from reprocessing of the X-rays in the colder accretion disc further out.
Rapid Evolution of Gained Essential Developmental Functions of a Young Gene via Interactions with Other Essential Genes
Authors: Lee Yuh Chwen G , Ventura Iuri M , Rice Gavin R , Chen Dong-Yuan , Colmenares Serafin U , Long Manyuan
Published: June 2019

New genes are of recent origin and only present in a subset of species in a phylogeny. Accumulated evidence suggests that new genes, like old genes that are conserved across species, can also take on important functions and be essential for the survival and reproductive success of organisms. Although there are detailed analyses of the mechanisms underlying new genes’ gaining fertility functions, how new genes rapidly become essential for viability remains unclear. We focused on a young retro-duplicated gene (CG7804, which we named Cocoon) in Drosophila that originated between 4 and 10 Ma. We found that, unlike its evolutionarily conserved parental gene, Cocoon has evolved under positive selection and accumulated many amino acid differences at functional sites from the parental gene. Despite its young age, Cocoon is essential for the survival of Drosophila melanogaster at multiple developmental stages, including the critical embryonic stage, and its expression is essential in different tissues from those of its parental gene. Functional genomic analyses found that Cocoon acquired unique DNA-binding sites and has a contrasting effect on gene expression to that of its parental gene. Importantly, Cocoon binding predominantly locates at genes that have other essential functions and/or have multiple gene–gene interactions, suggesting that Cocoon acquired novel essential function to survival through forming interactions that have large impacts on the gene interaction network. Our study is an important step toward deciphering the evolutionary trajectory by which new genes functionally diverge from parental genes and become essential.
Targeting the PI3K/Akt/mTOR pathway with the pan-Akt inhibitor GDC-0068 in PIK3CA-mutant breast cancer brain metastases
Authors: Ippen Franziska Maria , Grosch Julia Katharina , Subramanian Megha , Kuter Benjamin Macfarlane , Liederer Bianca M , Plise Emile G , Mora Joana Liliana , Nayyar Naema , Schmidt Stephen Paul , Giobbie-Hurder Anita , Martinez-Lage Maria , Carter Scott L , Cahill Daniel P , Wakimoto Hiroaki , Brastianos Priscilla Kaliopi
Published: June 2019

Background

Activating mutations in the pathway of phosphatidylinositol-3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) occur in 43–70% of breast cancer brain metastasis patients. To date, the treatment of these patients presents an ongoing challenge, mainly because of the lack of targeted agents that are able to sufficiently penetrate the blood–brain barrier. GDC-0068 is a pan-Akt inhibitor that has shown to be effective in various preclinical tumor models as well as in clinical trials. The purpose of this study was to analyze the efficacy of GDC-0068 in a breast cancer brain metastases model.

Methods

In in vitro studies, antitumor activity of GDC-0068 was assessed in breast cancer cells of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)–mutant and PIK3CA-wildtype breast cancer cell lines using cell viability and apoptosis assays, cell cycle analysis, and western blots. In vivo, the efficacy of GDC-0068 was analyzed in a PIK3CA-mutant breast cancer brain metastasis orthotopic xenograft mouse model and evaluated by repeated bioluminescent imaging and immunohistochemistry.

Results

GDC-0068 decreased cell viability, induced apoptosis, and inhibited phosphorylation of proline rich Akt substrate 40 kDa and p70 S6 kinase in a dose-dependent manner in PIK3CA-mutant breast cancer brain metastatic cell lines compared with PIK3CA-wildtype cell lines. In vivo, treatment with GDC-0068 notably inhibited the growth of PIK3CA-mutant tumors and resulted in a significant survival benefit compared with sham, whereas no effect was detected in a PIK3CA-wildtype model.

Conclusions

This study suggests that the Akt inhibitor GDC-0068 may be an encouraging targeted treatment strategy for breast cancer brain metastasis patients with activating mutations in the PI3K pathway. These data provide a rationale to further evaluate the efficacy of GDC-0068 in patients with brain metastases.
Validation of a Prediction Rule forLegionellaPneumonia in Emergency Department Patients
Authors: Bolliger Rebekka , Neeser Olivia , Merker Meret , Vukajlovic Tanja , Felder Laetitia , Fiumefreddo Rico , Haubitz Sebastian , Koch Daniel , Hammerer-Lercher Angelika , Ottiger Cornelia , Fux Christoph A , Mueller Beat , Schuetz Philipp
Published: June 2019

We validated a clinical prediction rule for Legionella based on clinical parameters (dry cough, fever) and laboratory findings (C-reactive protein, lactate dehydrogenase, sodium, platelet counts) in 713 consecutive patients with community-acquired pneumonia. The Legionella Score performed well in estimating the likelihood for Legionella infection and thus may help to direct diagnostic and therapeutic decisions.
Democratisation without Coercion: Parliamentary Bodies as Democracy Promoters in the Mediterranean
Authors: Harwood Mark A
Published: June 2019

In an attempt to decentre the debate of democracy promotion in the Mediterranean, this article applies social constructivism to an analysis of the work undertaken by two International Parliamentary Bodies in the Mediterranean. With a focus on the European Parliament and the Parliamentary Assembly of the Mediterranean, we analyse how effective their role can be without coercion and move on to discuss whether newly formed democratic parliaments, as in Tunisia, may represent a more legitimate and viable source of parliamentary-driven democracy promotion.
CXCL13 as biomarker for histological involvement in Sjögren’s syndrome
Authors: Colafrancesco Serena , Priori Roberta , Smith Charlotte G , Minniti Antonina , Iannizzotto Valentina , Pipi Elena , Lucchesi Davide , Pontarini Elena , Nayar Saba , Campos Joana , Arienzo Francesca , Fusconi Massimo , Cerbelli Bruna , Giordano Carla , Valesini Guido , Bombardieri Michele , Fisher Benjamin A , Barone Francesca
Published: June 2019

Objectives

SS is an autoimmune condition characterized by systemic B-cell activation, autoantibody production and ectopic germinal centres’ formation within the salivary gland (SG). The extent of SG infiltrate has been proposed as a biomarker of disease severity. Plasma levels of CXCL13 correlate with germinal centres’ activity in animal models and disease severity in SS, suggesting its potential use as a surrogate serum marker to monitor local B-cell activation. The aim of this study was to evaluate the potential role of CXCL13 as a biomarker of SG pathology in two independent SS cohorts.

Methods

109 patients with SS were recruited at Sapienza University of Rome (Italy) (n = 60), or at Queen Elizabeth Hospital in Birmingham and Barts Health NHS Trust in London (n = 49). Both sera and matched minor SG biopsy were available. Sicca (n = 57) and healthy subjects’ (n = 19) sera were used as control.

Results

CXCL13 serum level was higher in SS patients compared with controls. Correlations between its serum levels and a series of histomorphological parameters, including size of the aggregates and the presence germinal centres', were observed.

Conclusion

Our data foster the use of CXCL13 to monitor the extent of local pathology in SS and its validation in longitudinal clinical studies.
High angiopoietin-2 levels associate with arterial inflammation and long-term glucocorticoid requirement in polymyalgia rheumatica
Authors: van Sleen Yannick , Boots Annemieke M H , Abdulahad Wayel H , Bijzet Johan , Sandovici Maria , van der Geest Kornelis S M , Brouwer Elisabeth
Published: June 2019

Objectives

PMR frequently co-occurs with GCA. So far, a simple biomarker for detecting concomitant arterial inflammation in PMR patients is lacking. Furthermore, biomarkers predicting disease course in PMR are awaited. We here investigated the diagnostic and prognostic value of acute-phase markers (ESR, CRP, IL-6, serum amyloid A) and angiogenesis markers (VEGF, soluble Tie2, angiopoietin-1, angiopoietin-2) in isolated PMR and PMR/GCA overlap patients.

Methods

We prospectively included 39 treatment-naïve PMR patients, of whom 10 patients also showed evidence of large vessel GCA by PET-CT. Age-matched healthy controls (n = 32) and infection controls (n = 13) were included for comparison. Serum marker levels were measured by an ELISA or Luminex assay. Receiver operating characteristic and Kaplan–Meier analyses were used to asses diagnostic and prognostic accuracy, respectively.

Results

All acute-phase and angiogenesis markers, except angiopoietin-1, were higher in isolated PMR patients than in healthy controls. Angiopoietin-2, ESR and soluble Tie-2 were significantly higher in patients with PMR/GCA overlap than in isolated PMR patients. Angiopoeietin-2, but not soluble Tie2, outperformed ESR and CRP in discriminating patients with and without overlapping GCA (area under the curve: 0.90; sensitivity: 100%; specificity: 76%). Moreover, high angiopoietin-2 levels were associated with long-term glucocorticoid requirement.

Conclusion

Assessment of angiopoietin-2 at baseline may assist diagnosis of concomitant vasculitis in PMR. Moreover, high levels of angiopoietin-2 were associated with an unfavourable disease course in isolated PMR patients. These findings imply that angiopoietin-2 is an interesting diagnostic and prognostic biomarker in PMR.
Innate Immune Cells and C-Reactive Protein in Acute First-Episode Psychosis and Schizophrenia: Relationship to Psychopathology and Treatment
Authors: Steiner Johann , Frodl Thomas , Schiltz Kolja , Dobrowolny Henrik , Jacobs Roland , Fernandes Brisa S , Guest Paul C , Meyer-Lotz Gabriela , Borucki Katrin , Bahn Sabine , Bogerts Bernhard , Falkai Peter , Bernstein Hans-Gert
Published: June 2019

Innate immunity has been linked to initiation of Alzheimer’s disease and multiple sclerosis. Moreover, risk of first-episode psychosis (FEP) and schizophrenia (Sz) is increased after various infections in predisposed individuals. Thus, we hypothesized an analogous role of innate immunity with increased C-reactive protein (CRP) in non-affective psychosis. Differential blood count, CRP, neutrophil and monocyte–macrophage activation markers, cortisol and psychotic symptoms (Positive and Negative Syndrome Scale [PANSS]) were assessed in controls (n = 294) and acutely ill unmedicated FEP (n = 129) and Sz (n = 124) patients at baseline and after 6 weeks treatment. Neutrophils, monocytes, and CRP were increased in patients vs controls at baseline (P < .001), and neutrophil and monocyte counts correlated positively with activation markers. Eosinophils were lower at baseline in FEP (P < .001) and Sz (P = .021) vs controls. Differences in neutrophils (P = .023), eosinophils (P < .001), and CRP (P < .001) were also present when controlling for smoking and cortisol, and partially remitted after antipsychotic treatment. FEP patients with high neutrophils (P = .048) or monocytes (P = .021) had higher PANSS-P scores at baseline but similar disease course. CRP correlated with PANSS-P at baseline (ρ = 0.204, P = .012). Improvement of positive symptoms after treatment correlated with declining neutrophils (ρ = 0.186, P = .015) or CRP (ρ = 0.237, P = .002) and rising eosinophils (ρ = −0.161, P = .036). In FEP, normalization of neutrophils (ρ = −0.231, P = .029) and eosinophils (ρ = 0.209, P = .048) correlated with drug dosage. In conclusion, innate immune system activation correlated with PANSS-P, supporting the immune hypothesis of psychosis. Neutrophil and monocyte counts and CRP levels may be useful markers of disease acuity, severity, and treatment response.
Open (in)justice: privacy, open justice and human rights
Authors: Cooper Gilead
Published: June 2019

The principle that court hearings must be open to the public is regarded as sacrosanct. It has recently been invoked by the Court of Appeal in MN v OP as the reason for refusing an application to anonymise the approval of an arrangement under the Variation of Trusts Act 1958 Act. Yet the reasons generally given for insisting on open justice as a matter of principle are unconvincing when applied to civil cases as opposed to criminal cases or those, such as judicial review, in which the power of the state is pitted against the individual citizen. If private citizens are free to resolve their disputes privately through arbitration or mediation, why should they not be allowed to have their cases heard by the court in chambers unless there is some special feature of the case requiring publicity? Why are anonymised judgments not sufficient to ensure that justice is administered fairly and in accordance with the law? Could not more use be made of reporting restrictions? In this article, it is argued that the courts should do more to protect the privacy of litigants, and should not bow to populist demands to pry into the affairs of others (particularly the very wealthy). If they do not, those who can afford to do so will choose arbitration, or litigate in off-shore jurisdictions that are more sympathetic to their reasonable desire for privacy.
Effects of microbial phytase on standardized total tract digestibility of phosphorus in hybrid rye, barley, wheat, corn, and sorghum fed to growing pigs1
Authors: McGhee Molly L , Stein Hans H
Published: June 2019

An experiment was conducted to determine the apparent total tract digestibility (ATTD) and the standardized total tract digestibility (STTD) of P in three varieties of hybrid rye and in one source of barley, wheat, corn, and sorghum. The STTD of P in each cereal grain was determined both without and with addition of microbial phytase. In total, 112 growing barrows (13.7 ± 1.3 kg initial BW) were allotted to a randomized complete block design with four blocks of 28 pigs. Pigs were randomly allotted to 14 diets with two replicate pigs per diet in each block, resulting in a total of eight replicate pigs per diet for the four blocks. Each diet contained one of the cereal grains as the sole source of P. There were two diets with each cereal grain with one diet containing no microbial phytase and the other diet containing 1,000 units of microbial phytase per kilogram of diet. In each period, fecal output was collected for 5 d following a 5-d adaptation period according to the marker-to-marker procedure. Among the diets that did not include microbial phytase, one hybrid of rye had greater (P < 0.05) STTD of P than wheat, corn, and sorghum, which is likely a result of the greater intrinsic phytase activity in rye than in the other cereal grains. Without microbial phytase, there was no difference in the STTD of P in the three hybrids of rye and barley. Among the diets containing microbial phytase, there was no difference in STTD of P among the three hybrids of rye, barley, and corn. The STTD of P in the three hybrids of rye with microbial phytase was 61.9%, 70.8%, and 63.0%, respectively. Overall, microbial phytase improved (P < 0.05) the STTD of P in all cereal grains, although the magnitude of the increase in STTD of P differed among the grains.
Both GSK-3β/CRMP2 and CDK5/CRMP2 Pathways Participate in the Protection of Dexmedetomidine Against Propofol-Induced Learning and Memory Impairment in Neonatal Rats
Authors: Li Junhua , Guo Mingyan , Liu Yafang , Wu Guiyun , Miao Liping , Zhang Jing , Zuo Zhiyi , Li Yujuan
Published: June 2019

Dexmedetomidine has been reported to ameliorate propofol-induced neurotoxicity in neonatal animals. However, the underlying mechanism is still undetermined. Glycogen synthase kinase-3β (GSK-3β), cycline-dependent kinase-5 (CDK5), and Rho-kinase (RhoA) pathways play critical roles in neuronal development. The present study is to investigate whether GSK-3β, CDK5, and RhoA pathways are involved in the neuroprotection of dexmedetomidine. Seven-day-old (P7) Sprague Dawley rats were anesthetized with propofol for 6 h. Dexmedetomidine at various concentrations were administered before propofol exposure. Neuroapoptosis, the neuronal proliferation, and the level of neurotransmitter in the hippocampus were evaluated. The effects of GSK-3β inhibitor SB415286, CDK5 inhibitor roscovitine, or RhoA inhibitor Y276321 on propofol-induced neurotoxicity were assessed. Propofol-induced apoptosis in the hippocampal neurons and astrocytes, inhibited neuronal proliferation in the dentate gyrus region, down-regulated the level of γ-aminobutyric acid and glutamate in the hippocampus, and impaired long-term cognitive function. These harmful effects were reduced by pretreatment with 50 μg·kg−1 dexmedetomidine. Moreover, propofol-activated GSK-3β and CDK5 pathways, but not RhoA pathway, by reducing the phosphorylation of GSK-3β (ser 9), increasing the expression of CDK5 activator P25 and increasing the phosphorylation of their target sites on collapsin response mediator protein 2 (CRMP2) shortly after exposure. These effects were reversed by pretreatment with 50 μg·kg−1 dexmedetomidine. Furthermore, SB415286 and roscovitine, not Y276321, attenuated the propofol-induced neuroapoptosis, brain cell proliferation inhibition, γ-aminobutyric acid and glutamate downregulation, and learning and memory dysfunction. Our results indicate that dexmedetomidine reduces propofol-induced neurotoxicity and neurocognitive impairment via inhibiting activation of GSK-3β/CRMP2 and CDK5/CRMP2 pathways in the hippocampus of neonatal rats.
Hepatitis C Contamination of Medication Vials Accessed with Sterile Needles and Syringes
Authors: van Vlymen Janet M. , Magnus Julie , Jaeger Melanie , Breton Sophie , Taylor Nathan G. , Phelan Rachel , Sagan Selena M.
Published: June 2019

Editor’s Perspective

What We Already Know about This Topic

What This Article Tells Us That Is New

Background

Health care–associated hepatitis C virus outbreaks from contaminated medication vials continue to be reported even though most practitioners deny reusing needles or syringes. The hypothesis was that when caring for hepatitis C virus–infected patients, healthcare providers may inadvertently contaminate the medication vial diaphragm and that subsequent access with sterile needles and syringes can transfer hepatitis C virus into the medication, where it remains stable in sufficient quantities to infect subsequent patients.

Methods

A parallel-arm lab study (n = 9) was performed in which contamination of medication vials in healthcare settings was simulated using cell culture–derived hepatitis C virus. First, surface-contaminated vials were accessed with sterile needles and syringes, and then hepatitis C virus contamination was assessed in cell culture. Second, after contaminating several medications with hepatitis C virus, viral infectivity over time was assessed. Last, surface-contaminated vial diaphragms were disinfected with 70% isopropyl alcohol to determine whether disinfection of the vial surface was sufficient to eliminate hepatitis C virus infectivity.

Results

Contamination of medication vials with hepatitis C virus and subsequent access with sterile needles and syringes resulted in contamination of the vial contents in sufficient quantities to initiate an infection in cell culture. Hepatitis C virus remained viable for several days in several commonly used medications. Finally, a single or 2- to 3-s wipe of the vial diaphragm with 70% isopropyl alcohol was not sufficient to eliminate hepatitis C virus infectivity.

Conclusions

Hepatitis C virus can be transferred into commonly used medications when using sterile single-use needles and syringes where it remains viable for several days. Furthermore, cleaning the vial diaphragm with 70% isopropyl alcohol is not sufficient to eliminate the risk of hepatitis C virus infectivity. This highlights the potential risks associated with sharing medications between patients.
Common Elements in Surgical Site Infection Care Bundles for Adolescent Idiopathic Scoliosis at North American Pediatric Institutions: A Survey of POSNA QSVI Challenge Participants
Authors: Oetgen Matthew E. , Shirley Eric D. , Choi Paul D. , Sanders James O.
Published: June 2019

Background:

Surgical site infection (SSI) following posterior spinal fusion for idiopathic scoliosis is a difficult complication, with little information published regarding the best preventative comprehensive care plan. The Spine Subgroup of the Quality, Safety, Value Initiative (QSVI) committee of the Pediatric Orthopaedic Society of North America undertook a survey to generate an overview of bundle elements in comprehensive SSI care bundles across institutions in North America. The purpose of this study was to develop a toolkit of SSI care bundle elements that could be used in developing future SSI care bundles.

Methods:

A survey email was sent to pediatric orthopaedic surgeons requesting a copy of the SSI prevention care bundle used in their practice. Surgeons were included if they had participated in the 2016 POSNA QSVI challenge, indicated they performed pediatric spine surgery, and had a spine SSI bundle. These bundles were evaluated by the QSVI committee and divided into preoperative, intraoperative, and postoperative elements with the frequency of use of each element recorded. A follow-up qualitative questionnaire was sent assessing the implementation and development of these SSI bundles.

Results:

In total, 16 care bundles from 15 different institutions were included for review. The response rate for this survey was 44% of individuals (50/113 QSVI challenge participants) and 43% (15/35) of unique institutions. The most common elements included: use of preoperative antibiotics, use of preoperative chlorhexidine wipes, use of wound irrigation intraoperatively, and a standardized prescription for the length of postoperative antibiotic. Each of these elements was included in ≥75% of the SSI bundles evaluated.

Conclusions:

SSI care bundles are increasingly being used by pediatric institutions to lower the risk of SSI following pediatric spinal surgery. This study provides an overview of various care elements used in established SSI care bundles across multiple institutions in North America. It is hoped this data will provide institutions interested in developing their own SSI care bundle with useful information for beginning this process.

Level of Evidence:

Level V—Decision Analysis.
Anatomic Dissection and CT Imaging of the Anterior Cruciate and Medial Collateral Ligament Footprint Anatomy in Skeletally Immature Cadaver Knees
Authors: Shea Kevin G. , Cannamela Peter C. , Dingel Aleksei B. , Fabricant Peter D. , Polousky John D. , Anderson Allen F. , Ganley Ted J.
Published: June 2019

Background:

Anterior cruciate ligament (ACL) and medial collateral ligament (MCL) injuries in skeletally immature patients are increasingly recognized and surgically treated. However, the relationship between the footprint anatomy and the physes are not clearly defined. The purpose of this study was to identify the origin and insertion of the ACL and MCL, and define the footprint anatomy in relation to the physes in skeletally immature knees.

Methods:

Twenty-nine skeletally immature knees from 16 human cadaver specimens were dissected and divided into 2 groups: group A (aged 2 to 5 y), and group B (aged 7 to 11 y). Metallic markers were placed to mark the femoral and tibial attachments of the ACL and MCL. Computed tomography scans were obtained for each specimen used to measure the distance from the center of the ligament footprints to the respective distal femoral and proximal tibial physes.

Results:

The median distance from the ACL femoral epiphyseal origin to the distal femoral physis was 0.30 cm (interquartile range, 0.20 to 0.50 cm) and 0.70 cm (interquartile range, 0.45 to 0.90 cm) for groups A and B, respectively. The median distance from the ACL epiphyseal tibial insertion to the proximal tibial physis for groups A and B were 1.50 cm (interquartile range, 1.40 to 1.60 cm) and 1.80 cm (interquartile range, 1.60 to 1.85 cm), respectively. The median distance from the MCL femoral origin on the epiphysis to the distal femoral physis was 1.20 cm (interquartile range, 1.00 to 1.20 cm) and 0.85 cm (interquartile range, 0.63 to 1.00 cm) for groups A and B, respectively. The median distance from the MCL insertion on the tibial metaphysis to the tibial physis was 3.05 cm (interquartile range, 2.63 to 3.30 cm) and 4.80 cm (interquartile range, 3.90 to 5.10 cm) for groups A and B, respectively.

Conclusion:

Surgical reconstruction is a common treatment for ACL injury. Computed tomography scanning of pediatric tissue clearly defines the location of the ACL and MCL with respect to the femoral and tibial physes, and may guide surgeons for physeal respecting procedures.

Clinical Relevance:

In addition to ACL reconstruction, recent basic science and clinical research suggest that ACL repair may be more commonly performed in the future. MCL repair and reconstruction is also occasionally required in skeletally immature patients. This information may be useful to help surgeons avoid or minimize physeal injury during ACL/MCL reconstructions and/or repair in skeletally immature patients.
Prognostic Significance of Tumor Subtypes in Women With Breast Cancer According to Stage
Authors: Leone José P. , Leone Julieta , Zwenger Ariel O. , Vallejo Carlos T. , Leone Bernardo A.
Published: June 2019

Objectives:

The contribution of tumor subtypes (TS) in each stage of breast cancer with the use of contemporary therapies is unclear. The aim of this study was to analyze differences in overall survival (OS) by TS according to stage compared with other factors.

Materials and Methods:

We evaluated women with breast cancer diagnosed between 2010 and 2013 with known estrogen receptor and progesterone receptor (together hormone receptor [HR]) status and human epidermal growth factor receptor 2 (HER2) status reported to the SEER program. Patient characteristics were compared between TS. Univariate and multivariate analyses were performed to determine the effect of each variable on OS. Breast cancer–specific survival was a secondary endpoint.

Results:

We included 166,054 patients. TS distribution was: 72.5% HR-positive/HER2-negative, 10.8% HR-positive/HER2-positive, 4.8% HR-negative/HER2-positive, and 12% triple-negative (TN). Patients with HR-positive/HER2-negative tumors were older, had a lower grade and presented with the earlier stage (all P<0.0001). OS was significantly different according to TS in each stage (P
interaction<0.0001). HR-positive/HER2-negative had the best OS in stage I (3-year OS, 97.2%). In contrast, HR-positive/HER2-positive had the best 3-year OS in stage II (94.5%), stage III (87.8%), and stage IV (54.8%). There was a 40.1% difference in OS at 3 years in stage IV between TN and HR-positive/HER2-positive. Multivariate analysis adjusted for age, race, grade, histology, and marital status confirmed these results.

Conclusions:

Although HR-positive/HER2-negative tumors had better clinicopathologic features, the HR-positive/HER2-positive group had the best OS in most stages. OS was significantly different by TS in each of the 4 stages and these results remained significant in the multivariate model.
Quantitative Evaluation of Content and Age Concordance Across Developmental Milestone Checklists
Authors: Wilkinson Carol L. , Wilkinson M. Jackson , Lucarelli Jennifer , Fogler Jason M. , Becker Ronald E. , Huntington Noelle
Published: June 2019

Objective:

Clinicians and caregivers rely on milestone checklists as tools for tracking a child's development. In addition, medical students and residents use milestone checklists to learn about normal child development. However, there are multiple published milestone checklists that vary qualitatively in structure and content, hindering their effective use in developmental surveillance and medical education. This project systematically evaluated the consistency and variability between commonly used milestone checklists.

Methods:

A team of child psychologists and developmental pediatricians reviewed a total of 1094 milestones derived from 4 published checklists (2 developed for providers, 2 developed for caregivers) to create a comprehensive set of 728 discrete developmental observations, with each observation mapped to corresponding milestones. This observation-milestone relational database was then used to determine the degree of content overlap and milestone age range concordance across milestone checklists.

Results:

Of the 728 discrete developmental observations, 40 (5.5%) were mapped to milestones in all 4 milestone checklists, and an additional 90 (12.4%) were mapped to 3 checklists. Among these 40 “universal” observations, most (42.5%) were in the motor domain. Of those 130 observations mapped to milestones in at least 3 of the 4 checklists, 26.9% (35/130) were mapped to milestones that were discordant in their associated age range.

Conclusion:

Four commonly used developmental milestone checklists were found to have limited overlap in content, and those that overlapped were inconsistent in their associated age ranges. The resulting observation-milestone relational database could be used to further validate age estimates of milestones and facilitate milestone surveillance through the electronic health record.
High risk for cardiovascular disease in postmenopausal breast cancer survivors
Authors: Buttros Daniel de Araujo Brito , Branco Mauro Terra , Orsatti Claudio Lera , Almeida-Filho Benedito de Sousa , Nahas-Neto Jorge , Nahas Eliana A.P.
Published: June 2019

Objective:

Breast cancer patients have a higher mortality risk of cardiovascular disease (CVD) than women from the general population. CVD risk may increase significantly in postmenopausal women with early-stage breast cancer. The aim of this study was to evaluate risk factors for CVD in postmenopausal breast cancer survivors.

Methods:

In this cross-sectional study, 96 postmenopausal breast cancer survivors were compared with 192 postmenopausal women. The main group included women with amenorrhea >12 months, aged ≥45 years, with breast cancer, and without established CVD. The control group fulfilled the same criteria, but did not have breast cancer. Groups were matched by age, time since menopause, and body mass index, in a ratio of 1 case to 2 controls (1:2). Women with three or more of the following criteria were diagnosed with metabolic syndrome: waist circumference >88 cm; triglycerides ≥150 mg/dL; high-density lipoprotein cholesterol <50 mg/dL; blood pressure ≥130/85 mm Hg; and glucose ≥100 mg/dL. Immunoassays were used (enzyme-linked immunosorbent assay test) for measurement of plasma heat shock proteins (HSP) 60 and 70 concentrations. Atherosclerotic disease was determined by intima-media thickness (>1 mm) of the carotid arteries and/or the presence of atheromatous plaque assessed by carotid artery ultrasound (scanner duplex).

Results:

Breast cancer patients had higher HSP60 levels and lower HSP70 levels than controls (P < 0.05). Analysis showed that the odds of developing metabolic syndrome (odds ratio [OR] = 4.21, 95% CI, 2.28-7.76), atheromatous plaque (OR = 2.61, 95% CI, 1.19-5.72), diabetes (OR = 4.42; 95% CI, 1.86-10.49), hypertriglyceridemia (OR = 2.32, 95% CI, 1.33-4.0), and increased waist circumference (OR = 11.22, 95% CI, 4.0-31.65) was significantly higher in women treated for cancer than in women without breast cancer.

Conclusions:

Postmenopausal breast cancer survivors had a stronger association with risk factors for cardiovascular disease than postmenopausal women without breast cancer.
FUNDUS AUTOFLUORESCENCE PATTERNS IN CENTRAL SEROUS CHORIORETINOPATHY
Authors: Han Jisang , Cho Nam Suk , Kim Kiyoung , Kim Eung Suk , Kim Do Gyun , Kim Joon Mo , Yu Seung-Young
Published: June 2019

Purpose:

To investigate the patterns of fundus autofluorescence (FAF) abnormalities in patients with central serous chorioretinopathy (CSC).

Methods:

This cross-sectional observational study included 126 eyes of 118 patients who were diagnosed with central serous chorioretinopathy from December 2006 to April 2012 at Kyung Hee University Hospital, Seoul, Korea. Fundus autofluorescence patterns were analyzed with spectral domain optical coherence tomography and visual acuity.

Results:

Fundus autofluorescence patterns were grouped as blocked (38.9%), mottled (8.7%), hyper (31.0%), hyper/hypo (13.5%), or descending tract (8.0%). The duration of symptoms was 7.8 (±20.4), 28.3 (±31.8), 42.5 (±69.1), 163.8 (±183.5), and 174.5 (±162.3) days in the blocked, mottled, hyper, descending tract, and hyper/hypo groups, respectively (P < 0.001). The blocked FAF group had the best visual acuity (P = 0.011). The intact ellipsoid zone on the spectral domain optical coherence tomography was mostly found in the blocked FAF group (P < 0.001), and the disrupted ellipsoid zone was commonly exhibited in the hyper/hypo and descending tract groups. Disrupted external limiting membrane line on the spectral domain optical coherence tomography was seen in two patients of the descending tract group only.

Conclusion:

The FAF abnormalities in central serous chorioretinopathy show multiple patterns and are related with the chronicity and visual acuity. Fundus autofluorescence patterns in central serous chorioretinopathy are helpful when considering the timing of treatment and predicting the disease status.
Three-Dimensional Optical Coherence Tomography Imaging For Glaucoma Associated With Boston Keratoprosthesis Type I and II
Authors: Khoueir Ziad , Jassim Firas , Braaf Boy , Poon Linda Yi-Chieh , Tsikata Edem , Chodosh James , Dohlman Claes H. , Vakoc Benjamin J. , Bouma Brett E. , de Boer Johannes F. , Chen Teresa C.
Published: June 2019

Precis:

Three-dimensional (3D) spectral domain optical coherence tomography (OCT) volume scans of the optic nerve head (ONH) and the peripapillary area are useful in the management of glaucoma in patients with a type I or II Boston Keratoprosthesis (KPro).

Purpose:

The purpose of this study was to report the use of spectral domain OCT in the management of glaucoma in patients with a type I or II Boston KPro.

Materials and Methods:

This study is an observational case series. Four consecutive patients with KPro implants were referred for glaucoma evaluation. A comprehensive eye examination was performed which included disc photography, visual field testing, and high-density spectral domain OCT volume scans of the ONH and the peripapillary area. 2D and 3D parameters were calculated using custom-designed segmentation algorithms developed for glaucoma management.

Results:

Spectral domain OCT parameters provided useful information in the diagnosis and management of 4 KPro patients. OCT parameters which can be used in KPro patients included 2D retinal nerve fiber layer (RNFL) thickness, 3D peripapillary RNFL volume, 3D peripapillary retinal thickness and volume, 3D cup volume, and 3D neuroretinal rim thickness and volume. In 3 of 4 cases where the traditional 2D RNFL thickness scan was limited by artifacts, 3D spectral domain OCT volume scans provided useful quantitative objective measurements of the ONH and peripapillary region. Therefore, 3D parameters derived from high-density volume scans as well as radial scans of the ONH can be used to overcome the limitations and artifacts associated with 2D RNFL thickness scans.

Conclusions:

Spectral domain OCT volume scans offer the possibility to enhance the evaluation of KPro patients with glaucoma by using both 2D and 3D diagnostic parameters that are easily obtained in a clinic setting.
Transcriptional profile of spinal dynorphin-lineage interneurons in the developing mouse
Authors: Serafin Elizabeth K. , Chamessian Alexander , Li Jie , Zhang Xiang , McGann Amanda , Brewer Chelsie L. , Berta Temugin , Baccei Mark
Published: June 2019

Mounting evidence suggests that the spinal dorsal horn (SDH) contains multiple subpopulations of inhibitory interneurons that play distinct roles in somatosensory processing, as exemplified by the importance of spinal dynorphin-expressing neurons for the suppression of mechanical pain and chemical itch. Although it is clear that GABAergic transmission in the SDH undergoes significant alterations during early postnatal development, little is known about the maturation of discrete inhibitory “microcircuits” within the region. As a result, the goal of this study was to elucidate the gene expression profile of spinal dynorphin (pDyn)-lineage neurons throughout life. We isolated nuclear RNA specifically from pDyn-lineage SDH interneurons at postnatal days 7, 21, and 80 using the Isolation of Nuclei Tagged in Specific Cell Types (INTACT) technique, followed by RNA-seq analysis. Over 650 genes were ≥2-fold enriched in adult pDyn nuclei compared with non-pDyn spinal cord nuclei, including targets with known relevance to pain such as galanin (Gal), prepronociceptin (Pnoc), and nitric oxide synthase 1 (Nos1). In addition, the gene encoding a membrane-bound guanylate cyclase, Gucy2d, was identified as a novel and highly selective marker of the pDyn population within the SDH. Differential gene expression analysis comparing pDyn nuclei across the 3 ages revealed sets of genes that were significantly upregulated (such as Cartpt, encoding cocaine- and amphetamine-regulated transcript peptide) or downregulated (including Npbwr1, encoding the receptor for neuropeptides B/W) during postnatal development. Collectively, these results provide new insight into the potential molecular mechanisms underlying the known age-dependent changes in spinal nociceptive processing and pain sensitivity.
Enforcing the checkpoints: harnessing T-cell exhaustion for therapy of T1D
Authors: Linsley Peter S. , Long S. Alice
Published: June 2019

Purpose of review

Although checkpoint inhibitor blockade is now widely used clinically for cancer immunotherapy, the reverse process, (i.e. induction of checkpoints to slow autoimmunity) has not been extensively explored. CD8 T-cell exhaustion is a state of immune hyporesponsiveness that may be harnessed to treat autoimmunity.

Recent findings

We focus on the potential role of CD8 T-cell exhaustion as a mechanism of peripheral tolerance in T1D and its therapeutic implications.

CD8 T-cell exhaustion is a continuum in which cells change from precursor to terminally exhausted cells. Current thinking based on studies in cancer and chronic viral infection invokes a three-signal model for development of T-cell exhaustion, with persistent antigen, negative costimulatory signals and chronic inflammation comprising signals 1–3, respectively. Transcriptional signatures of CD8 T-cell exhaustion were associated with better prognosis across several autoimmune diseases, most profoundly in systemic diseases. In T1D, CD8 exhaustion was promoted by treatment with anti-CD3 therapy (teplizumab) and was more evident in islet-specific CD8 T cells of slow progressors, suggesting a beneficial role in T1D also. Thus, we apply this three-step process of exhaustion to discuss potential treatments to augment CD8 T-cell exhaustion in T1D.