bluuebunny/crossref_metadata_2025 huggingface dataset:
Examining the Efficacy of Calcium Hydroxylapatite Filler With Integral Lidocaine in Correcting Volume Loss of the Jawline—A Pilot Study
Authors: Juhász Margit L.W. , Marmur Ellen S.
Published: April 2018

BACKGROUND

Patients seek 3-dimensional volume restoration of the jawline to obtain a “defined” line. Injection of filler into the jawline is not approved by the Food and Drug Administration; however, dermatologists have injected this area with positive results, minimal adverse events, and high patient satisfaction.

OBJECTIVE

This study explores the efficacy of premixed calcium hydroxylapatite filler with integral lidocaine [CaHA(+)] to correct volume defects of the jawline. It examines the longevity, safety, and patient satisfaction (up to 12 months) of CaHA(+) for jawline volume loss correction.

MATERIALS AND METHODS

This is a single-investigator, nonblinded study. Twenty subjects received CaHA(+) filler injection in the jawline, with follow-up evaluations conducted at 14 days, 6 weeks, and 3, 6, 9, and 12 months.

RESULTS

CaHA(+) injection in the jawline results in statistically significant restoration in volume and improvement in appearance lasting up to 12 months. Overall, subjects report “moderate” improvement on the Global Aesthetic Improvement Scale.

CONCLUSION

It is important for cosmetic surgeons and dermatologists to have access to data on the efficacy and safety of injectables. The data obtained in this study show that CaHA(+) is an effective and safe option to correct jawline volume loss and is associated with high patient satisfaction.
What Drives Patient Choice: Preferences for Approaches to Surgical Treatments for Breast Cancer Beyond Traditional Clinical Benchmarks
Authors: Storm-Dickerson Toni , Das Lopamudra , Gabriel Allen , Gitlin Matthew , Farias Jorge , Macarios David
Published: April 2018

Importance:

Understanding what drives breast cancer (BC) patient’s surgical decision-making and why, as survival continues to improve, are women continuing to choose mastectomy in increasing numbers.

Objective:

We sought to understand better what drives patient choice in surgical decision-making regarding BC treatment options.

Design:

We used a dynamic model, adaptive choice-based conjoint survey experiment, to assess multiple factors concurrently impacting patient choice, conducted from December 2016 to January 2017 using the Army of Women.

Setting:

Army of Women is a U.S.–based nationwide registry of women, both healthy and previous BC patients.

Participants:

An e-mail invitation was sent to the AWOL’s 108,933 members, with 1,233 signing up to participate and 858 responding (548 healthy, 310 previous BC). Two hundred thirty-nine BC patients who underwent treatment > 5 years were excluded due to potential recall bias and changes in BC treatment paradigms. All subjects who did not complete the adaptive choice-based conjoint survey were also excluded due to inability to calculate preferences. The final sample consisted of 522 healthy women and 71 previous BC patients.

Interventions or Exposures:

Study of patient preference and decision drivers without interventions or exposures.

Main Outcome(s) and Measure(s):

Shares of preferences for various surgical treatment options were calculated using the highest-ranked factors by the importance that drove patient decision-making.

Results:

Survey response rate was 69.5%. Among healthy women, the most important of the 9 factors in making a surgical choice were doctor’s recommendation at 21.4% (SD, 13.6%) and 20-year survival at 20.5% (SD, 9.8%) while among previous BC patients, the most important factor was 20-year survival at 19.0% (SD, 9.0%) and doctor’s recommendation at 17.2% (SD, 10.3%).

Conclusion and Relevance:

While 20-year survival accounted for the largest single driver of patient choice at ~20 %, it is notable that 80% of patient decision-making was driven by factors unrelated to survival such as cost, intensity and recovery time, and breast image. By understanding what drives choice, we can provide better patient-centric education and treatments.
CHOROIDAL MORPHOLOGY IN EYES WITH PERIPAPILLARY POLYPOIDAL CHOROIDAL VASCULOPATHY
Authors: Baek Jiwon , Dansingani Kunal K. , Lee Jae Hyung , Lee Won Ki , Freund K. Bailey
Published: April 2018

Purpose:

This study analyzes a subset of patients with peripapillary polypoidal choroidal vasculopathy (PCV) to determine whether quantifiable pachychoroid features colocalize with disease foci.

Methods:

Patients with PCV diagnosed by indocyanine green angiography were identified for the analysis of medical records and multimodal imaging and classified as having peripapillary or macular PCV. The ratio of Haller layer thickness to total choroidal thickness was calculated at the fovea and at the site of dilated Haller vessels that showed spatial correlation with the origin of neovascularization. Choroidal thickness was measured horizontally across the fovea and circumferentially around the temporal side of the disk to study its relationship to neovascularization.

Results:

Three hundred and fourteen eyes of 299 patients with PCV were identified, of which 17 eyes (5%) had peripapillary disease. Although eyes with peripapillary PCV exhibited thinner subfoveal choroids than those with macular PCV, at the extrafoveal disease foci, choroidal thickness, Haller’s layer thickness, and its ratio to total choroidal thickness were relatively high.

Conclusion:

Quantitative indices of choroidal structure previously identified in macular PCV performed consistently when applied to a peripapillary PCV cohort, thus supporting the hypothesis that inner choroidal thinning and Haller vessel enlargement are mechanistically relevant to these related entities.
Clinical Outcomes of Hospital-Acquired and Healthcare-Associated Pneumonia With and Without Empiric Vancomycin in a Noncritically Ill Population
Authors: Liu Wenxi , Rose Dusten T. , Helmink Brady J. , Jaso Theresa C. , Mondy Kristin E.
Published: April 2018

Background

Recent evidence suggests that not all patients diagnosed with hospital-acquired pneumonia (HAP) and healthcare-associated pneumonia (HCAP) are at risk for methicillin-resistant Staphylococcus aureus. The objective of the study was to examine outcomes of noncritically ill HAP/HCAP patients who received empiric vancomycin compared with those who did not.

Methods

This was a multicenter retrospective cohort study. Chart review was used to identify HAP/HCAP patients for study inclusion. Treatment groups were patients who received empiric vancomycin versus those who did not. Primary outcome was clinical success at the time of antibiotic completion or discharge for pneumonia treatment. Secondary outcomes included c, time to clinical stability, all-cause mortality, time to antibiotic de-escalation, and 30-day readmission rates for pneumonia. Safety was examined by rates of nephrotoxicity.

Results

A total of 279 patients met study criteria (105 vancomycin vs. 174 nonvancomycin). There was no significant difference in clinical success (vancomycin 93.3% vs. nonvancomycin 96.6%; P = 0.124). The vancomycin group had longer length of stay (P < 0.001) and time to therapy deescalation (P < 0.001). No significant difference was observed in hospital all-cause mortality and 30-day readmission for pneumonia. Patients who did not receive vancomycin reached clinical stability faster. Rate of nephrotoxicity was similar between both groups (vancomycin 33.3% vs nonvancomycin 28.7%; P = 0.437).

Conclusions

No difference in clinical success was observed for empiric vancomycin therapy. This study supports the updated HAP guideline that empiric vancomycin therapy may not be necessary in this population.
Coupled OPG-Fc on Decellularized Aortic Valves by EDC/NHS Attenuates Rat MSCs Calcification In Vitro
Authors: Zhang Qiao , Chen Si , Shi Jiawei , Li Fei , Shi Xucong , Hu Xingjian , Deng Cheng , Shi Feng , Han Guichun , Dong Nianguo
Published: April 2018

Abstract: Valve calcification commonly damages natural human heart valves and tissue-engineered heart valves (TEHVs), and no ideal intervention is available in clinical practice. It is increasingly considered that osteoprotegerin (OPG) inhibits vascular calcification. Herein we aimed to explore whether free OPG-Fc fusion protein or coupled OPG-Fc on decellularized aortic valves attenuates calcification. Calcification of rat bone marrow–derived mesenchymal stromal cells (MSCs) was induced by osteogenic differentiation media, and the effects of free OPG-Fc or OPG-Fc coupled on the decellularized porcine aortic heart valve leaflet scaffolds by coupling agents 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC)/N-hydroxysuccinimide (NHS) on calcification were observed. Mineralization of the extracellular matrix, alkaline phosphatase (ALP) activity, and expression of osteoblastic markers were assessed to determine the calcification kinetics. Our results indicated that the matrix calcium content and the ALP activity, as well as the mRNA expression levels of a bone morphogenetic protein-2 (BMP-2), osteopontin (OPN), and osteocalcin (OC), of the MSCs seeded on plates with free OPG-Fc or on the OPG-Fc–coupled scaffolds decreased compared with their control MSCs without coupled OPG-Fc. The results suggest that both free and immobilized OPG-Fc on the decellularized aortic valve scaffolds by EDC/NHS can attenuate the calcification of MSCs induced by osteogenic differentiation media, implying that OPG-Fc might be a new treatment or prevention strategy for the calcification of natural human heart valves and TEHVs in the future.
A study of familial Char syndrome involving the TFAP2B gene with a focus on facial shape characteristics
Authors: Nyboe Daniel , Kreiborg Sven , Darvann Tron , Dunø Morten , Nissen Kamilla R. , Hove Hanne B.
Published: April 2018

In this case study, we investigate a child presenting with patent ductus arteriosus, short philtrum, duck-bill lips, strabismus, a flat nasal bridge, a broad forehead, low-set ears, hypertelorism, up-slanting palpebral fissures, almond-shaped eyes, and hypodontia, all leading to the clinical diagnosis of Char syndrome. Genetic analysis showed heterozygosity for the novel variant c.851T>C, p. Leu284Ser in the TFAP2B gene. Family analysis suggested that at least 20 members, extending six generations back, were affected. All 10 members available for genetic testing were heterozygous for the novel pathogenic variant. Qualitative analysis of the facial dysmorphology in the proband and three of the affected family members using three-dimensional surface scanning showed that the major deviations were observed in the forehead/eyebrow, nose, upper lip, and chin regions with, for example, a flattened nose and reduced height of the upper lip and the face. Furthermore, it is suggested that Char syndrome is associated with disturbances of tooth formation and eruption.
Pentoxifylline Added to Steroid Window Treatment Phase Modified Apoptotic Gene Expression in Pediatric Patients With Acute Lymphoblastic Leukemia
Authors: Meza-Arroyo Jesus , Bravo-Cuellar Alejandro , Jave-Suárez Luis Felipe , Hernández-Flores Georgina , Ortiz-Lazareno Pablo , Aguilar-Lemarroy Adriana , Padilla-Corona Marlin , Sanchez-Zubieta Fernando , Gonzalez-Ramella Oscar
Published: April 2018

Pentoxifylline is a xanthine that possesses antitumor properties and that can induce higher apoptosis in the leukemic cells of pediatric patients with acute lymphoblastic leukemia (ALL) during treatment with prednisone. We conducted a phase 1 pilot, controlled, randomized trial to evaluate the gene expression modified by pentoxifylline during the steroid window of induction to remission phase in patients newly diagnosed with ALL. Experimental and control treatments induced broad changes in the gene expression profile. Patients who received just prednisone upregulated 377 and downregulated 344 genes, in contrast with patients treated with the experimental treatment (combination of prednisone and pentoxifylline), who demonstrated upregulation of 1319 and downregulation of 1594 genes. The most important genes modified in this pathway are those with proapoptotic activity, the majority of these overexpressed. Thus, the addition of pentoxifylline to the treatment with prednisone during steroid window in patients with ALL modified the gene expression profile and changed different signal pathways of the leukemic cell. The combination of both drugs represents a therapeutic alternative for potentiating antileukemic therapy.
Biliary Rhabdomyosarcoma in an Infant Male With Neurofibromatosis Type 1
Authors: Alhashem Fatema , Yilmaz Ebru , Ozdemir Mehmet A. , Deniz Kemal , Yikilmaz Ali , Patiroglu Turkan , Karakukcu Musa , Unal Ekrem
Published: April 2018

Different types of malignancies can be seen in patients with neurofibromatosis type 1 (NF-1). Herein we present a rare combination of NF-1 and biliary rhabdomyosarcoma in a male infant. An 11-month-old boy, who was recently diagnosed with NF-1, presented to the outpatient clinic with a 3-month history of prolonged jaundice, and failure to thrive. Clinical examination showed >20 café au let spots distributed mainly over the abdominal trunk. Hepatomegaly (4 cm below the costal margin) was additionally observed. His father was diagnosed with NF-1. Radiologic imaging studies showed a 6×5×5 cm in diameter cystic mass with multiple septations in the segment 4A of the liver. Surgical excision of the left hepatic lobe followed by hepatojejunostomy was further performed. Histopathology examination showed embryonal type rhabdomyosarcoma originating from the biliary duct. Chemotherapy regimen consisting of cyclophosphamide, actinomycin D, and vincristine, and radiotherapy were then initiated. This treatment led to a significant improvement in the patient’s clinical status, and radiologic finding portrayed attainment of complete resolution. He is still in complete remission without any sequelae for 8 years.
Case Report: Linezolid Optic Neuropathy and Proposed Evidenced-based Screening Recommendation
Authors: Dempsey Sean P. , Sickman Amy , Slagle William Scott
Published: April 2018

SIGNIFICANCE

This case illustrates a novel screening protocol for linezolid-induced toxic optic neuropathy.

PURPOSE

To present a case report and analysis of linezolid-induced optic neuropathies in adult patients to develop screening recommendations.

CASE REPORT

A case report of optic neuropathy from extended use of linezolid illustrates its potential effects on vision. We conduct a retrospective analysis of 39 reported cases to derive a recommended screening protocol for linezolid-induced toxic optic neuropathy in adult patients. Of 39 reported adult cases, 32 presented with optic neuropathy within 90 to 365 days of treatment. Within this subset, the duration of linezolid dosage to first symptoms is 235 ± 71 days. Seven outliers either experienced optic neuropathy within the first 28 days or between 600 and 1125 days. Of the 33 cases that quantified visual recovery, 30 reported final binocular visual acuity equivalent to 20/40 or better when the medication was discontinued from 0 to 268 days after symptom onset. Recovery potential was reported over a period of 2 weeks to approximately 6 months after cessation. To evaluate the effect of cumulative dose, the data were separated into patients taking 600 mg twice daily and those at 600 mg once daily. At the higher dosage, a mean of 180 ± 96 days with a mean cumulative dosage of 216 ± 115 g was noted at first symptom, whereas at lower dosage, a mean of 201 ± 102 days was noted with a mean cumulative dose of 138 ± 69 g.

CONCLUSIONS

We recommend screening adult patients within 1 month after initiating linezolid, followed by a subsequent evaluation every 30 to 60 days beginning 3 months from initiation. Substantial visual recovery is reported when linezolid is discontinued. Toxicity appears to be correlated to duration of treatment, rather than cumulative dose.
Case Report: Ocular Myasthenia Gravis Associated with In Vitro Fertilization Procedures
Authors: Yoo Yung Ju , Han Sang Beom , Yang Hee Kyung , Hwang Jeong-Min
Published: April 2018

SIGNIFICANCE

Ocular myasthenia gravis is a localized form of myasthenia gravis, which is a postsynaptic disorder of the neuromuscular junction that causes fluctuating weakness of extraocular muscles resulting from autoimmune mechanisms. In women with myasthenia, changes in sex hormone levels and administration of corticosteroids can trigger or worsen symptoms of myasthenia gravis.

PURPOSE

To describe a case of seronegative ocular myasthenia gravis whose first symptom appeared a day after in vitro fertilization procedure.

CASE REPORT

A 37-year-old woman suddenly developed mild ptosis and fluctuating diplopia that worsened in the evening. Before the development of symptoms, she had undergone in vitro fertilization procedure and had taken oral steroids. Ocular motility examination revealed an intermittent exotropia in primary gaze at both distance and near. The neostigmine test confirmed her diagnosis as ocular myasthenia gravis.

CONCLUSIONS

When taking a history for young women with sudden onset of binocular diplopia, steroids and sex hormones should be taken into account, which may trigger or exacerbate symptoms of ocular myasthenia gravis.
Pan-Trk Immunohistochemistry Identifies NTRK Rearrangements in Pediatric Mesenchymal Tumors
Authors: Rudzinski Erin R. , Lockwood Christina M. , Stohr Bradley A. , Vargas Sara O. , Sheridan Rachel , Black Jennifer O. , Rajaram Veena , Laetsch Theodore W. , Davis Jessica L.
Published: April 2018

Activating neurotrophic receptor kinase (NTRK) fusions define certain pediatric mesenchymal tumors, including infantile fibrosarcoma and cellular mesoblastic nephroma. Traditionally, molecular confirmation of these fusions has included either fluorescent in situ hybridization for ETV6 rearrangements or reverse-transcriptase polymerase chain reaction for the classic ETV6-NTRK3 fusion. However, these methods overlook variant NTRK rearrangements, which are increasingly appreciated as recurrent events in a subset of pediatric mesenchymal tumors. New therapeutic agents successfully target these fusions and may prevent morbid surgeries in very young children, making recognition of tumors harboring NTRK rearrangements of increasing importance. We evaluated the performance of immunohistochemical (IHC) staining using pan-Trk and TrkA antibodies in 79 pediatric mesenchymal tumors. Negative controls included pediatric mesenchymal tumors not harboring (n=28) or not expected to harbor (n=22) NTRK fusions. NTRK rearrangements were detected predominantly by DNA-based next-generation sequencing assays, specifically UW OncoPlex and UCSF500 Cancer Gene Panel. Pan-Trk IHC (EPR17341) was 97% sensitive and 98% specific for the presence of an NTRK rearrangement, and TrkA IHC (EP1058Y) was 100% sensitive and 63% specific for the presence of an NTRK rearrangement. Tumors with NTRK1 or NTRK2 rearrangements showed cytoplasmic staining, whereas tumors with NTRK3 rearrangements showed nuclear +/− cytoplasmic staining. We conclude that pan-Trk IHC is a highly sensitive and specific marker for NTRK rearrangements in pediatric mesenchymal tumors.
Immunohistochemical Detection and Molecular Characterization of IDH-mutant Sinonasal Undifferentiated Carcinomas
Authors: Mito Jeffrey K. , Bishop Justin A. , Sadow Peter M. , Stelow Edward B. , Faquin William C. , Mills Stacey E. , Krane Jeffrey F. , French Christopher A. , Fletcher Christopher D.M. , Hornick Jason L. , Sholl Lynette M. , Jo Vickie Y.
Published: April 2018

Recent studies have identified recurrent isocitrate dehydrogenase 2 (IDH2) mutations in a subset of sinonasal undifferentiated carcinomas (SNUCs); however, the true frequency of IDH mutations in SNUC is unknown. We evaluated the utility of mutation-specific IDH1/2 immunohistochemistry (IHC) in a large multi-institutional cohort of SNUC and morphologic mimics. IHC using a multispecific antibody for IDH1/2 (R132/R172) mutant protein was performed on 193 sinonasal tumors including: 53 SNUCs, 8 poorly differentiated carcinomas (PDCARs) and 132 histologic mimics. Mutant IDH1/2 IHC was positive in 26/53 SNUCs (49%; 20 strongly positive and 6 weak) and 3/8 PDCARs (37.5%; 2 strong; 1 weak) but was absent in all other tumor types (0/132). Targeted next-generation sequencing (NGS) on a subset of SNUC/PDCAR (6 strong and 3 weak positive for IDH1/2 IHC; 7 negative) showed frequent IDH2 R172X mutations (10/16) and a single IDH1 R132C mutation. All 6 cases with strong positive mutant IDH1/2 staining and NGS had IDH2 R172S/G mutations. The 3 IHC-weak cases all had IDH2 R172T mutations. Among the 7 tested cases that were negative for mutant IDH1/2 IHC, NGS detected 1 case each with IDH2 R172T and IDH1 R132C mutation. IDH-mutant carcinomas also had frequent mutations in TP53 (55%) and activating mutations in KIT (45%) or the PI3K pathway (36%). Mutation-specific IDH1/2 IHC identifies IDH mutations in SNUC, however, it lacks sensitivity for the full range of IDH mutations. These findings suggest that IDH-mutant sinonasal carcinoma may represent a distinct pathobiological entity with therapeutic implications that can be identified by a combined approach of multispecific IDH1/2 IHC and sequencing.
Transfusion Rates and the Utility of Type and Screen for Pelvic Organ Prolapse Surgery
Authors: Brueseke Taylor J. , Wilkins Maggie F. , Willis-Gray Marcella G. , Husk Katherine E. , Peedin Alexis R. , Geller Elizabeth J. , Wu Jennifer M.
Published: April 2018

Objectives

Limited data exist directly comparing the likelihood of blood transfusion by route of apical pelvic organ prolapse (POP) surgery. In addition, limited evidence is available regarding the risk of not ordering preoperative type and screen (T&S) in apical POP surgery. The objectives of the study are to (1) provide baseline data regarding the current need for preoperative T&S by comparing perioperative blood transfusion rates between 3 routes of apical POP surgery and (2) determine the rate of a positive preoperative antibody screen in women who underwent apical POP surgery.

Methods

This was a retrospective cohort study of women who underwent apical POP surgery by 3 different routes: abdominal (abdominal sacrocolpopexy), robotic (robotic sacrocolpopexy), or vaginal (uterosacral or sacrospinous ligament fixation).

Results

Among 610 women who underwent apical POP surgeries between May 2005 and May 2016, 24 women (3.9%) received a perioperative blood transfusion. The rate of transfusion was higher in the abdominal group (11.1%) compared with robotic (0.5%, P < 0.001) and vaginal (0.5%, P < 0.001). In a logistic regression model, abdominal route of POP surgery remained significantly associated with transfusion (odds ratio, 20.7; 95% confidence interval, 2.7–156.6). Among the 572 women who had a preoperative T&S performed, 9 (1.5%) had a positive antibody screen.

Conclusions

Blood transfusion was significantly more common in abdominal compared with robotic and vaginal apical POP surgeries. The rate of a positive antibody screen was low, suggesting that type O blood is low risk if cross-matched blood is not available. Thus, it may be reasonable to not order a preoperative T&S prior to robotic or vaginal apical POP surgery.
Endothelial Dysfunction in Steatotic Human Donor Livers: A Pilot Study of the Underlying Mechanism During Subnormothermic Machine Perfusion
Authors: Beijert Irene , Mert Safak , Huang Viola , Karimian Negin , Geerts Sharon , Hafiz Ehab O.A. , Markmann James F. , Yeh Heidi , Porte Robert J. , Uygun Korkut
Published: April 2018

Background

Steatosis is a major risk factor for primary nonfunction in liver transplantations. Steatotic livers recover poorly from ischemia reperfusion injury, in part due to alterations in the microcirculation, although the exact mechanism is unclear. In this study, we tested if there were any alterations in the shear stress sensing Kruppel-like factor 2 (KLF2) and its likely downstream consequences in the ex vivo perfused human liver endothelium, which would imply perturbations in microcirculatory flow in macrosteatotic livers disrupts laminar flow to evaluate if this is a potential therapeutic target for steatotic livers.

Methods

Using a subnormothermic machine perfusion system, 5 macrosteatotic and 4 nonsteatotic human livers were perfused for 3 hours. Flow, resistance, and biochemical profile were monitored. Gene expression levels of nitric oxide synthase 3 (eNOS), KLF2, and thrombomodulin were determined. Nitric oxide (NO) was measured in the perfusion fluid and activation of eNOS was measured with Western blotting.

Results

Flow dynamics, injury markers, and bile production were similar in both groups. Kruppel-like factor 2 expression was significantly higher in nonsteatotic livers. Western blotting analyses showed significantly higher levels of activated eNOS in nonsteatotic livers, consistent with an increase in NO production over time. Macrosteatotic livers showed decreased KLF2 upregulation, eNOS activity, and NO production during machine perfusion.

Conclusions

These results indicate a perturbed KLF2 sensing in steatotic livers, which aligns with perturbed microcirculatory state. This may indicate endothelial dysfunction and contribute to poor posttransplantation outcomes in fatty livers, and further studies to confirm by evaluation of flow and testing treatments are warranted.
Accessory Gallbladder Complicating Liver Transplantation
Authors: Kesseli Samuel J. , Barbas Andrew S. , Vikraman Deepak
Published: April 2018

Accessory gallbladder in a donor liver allograft is an uncommon anatomical finding that can complicate liver transplantation if unrecognized. This case describes a patient who underwent liver transplantation with a donor graft containing an accessory gallbladder that was obscured during transplantation; as a result, the patient experienced a prolonged postoperative course complicated by multiple readmissions for suspected biloma and intra-abdominal infection. The diagnosis of accessory gallbladder was not made until operative exploration several months after the initial transplant. Removal of the accessory gallbladder has led to resolution of clinical problems.
Investigating the bioavailability of graphene quantum dots in lung tissues via Fourier transform infrared spectroscopy
Authors: Tabish Tanveer A. , Lin Liangxu , Ali Muhammad , Jabeen Farhat , Ali Muhammad , Iqbal Rehana , Horsell David W. , Winyard Paul G. , Zhang Shaowei
Published: April 2018

Biomolecular fractions affect the fate and behaviour of quantum dots (QDs) in living systems but how the interactions between biomolecules and QDs affect the bioavailability of QDs is a major knowledge gap in risk assessment analysis. The transport of QDs after release into a living organism is a complex process. The majority accumulate in the lungs where they can directly affect the inhalation process and lung architecture. Here, we investigate the bioavailability of graphene quantum dots (GQDs) to the lungs of rats by measuring the alterations in macromolecular fractions via Fourier transform infrared spectroscopy (FTIR). GQDs were intravenously injected into the rats in a dose-dependent manner (low (5 mg kg
−1
) and high (15 mg kg
−1
) doses of GQDs per body weight of rat) for 7 days. The lung tissues were isolated, processed and haematoxylin–eosin stained for histological analysis to identify cell death. Key biochemical differences were identified by spectral signatures: pronounced changes in cholesterol were found in two cases of low and high doses; a change in phosphorylation profile of substrate proteins in the tissues was observed in low dose at 24 h. This is the first time biomolecules have been measured in biological tissue using FTIR to investigate the biocompatibility of foreign material. We found that highly accurate toxicological changes can be investigated with FTIR measurements of tissue sections. As a result, FTIR could form the basis of a non-invasive pre-diagnostic tool for predicting the toxicity of GQDs.
Mechano-bactericidal mechanism of graphene nanomaterials
Authors: Linklater Denver P. , Baulin Vladimir A. , Juodkazis Saulius , Ivanova Elena P.
Published: April 2018

Growing interest in the bactericidal effect of graphene and graphene-derived nanomaterials has led to the investigation and effective publication of the bactericidal effects of the substratum, many of which present highly conflicting material. The nature of bacterial cell death on graphene bio-interfaces, therefore, remains poorly understood. Here, we review recent findings on the bactericidal effect of graphene and graphene-derived nanomaterials, and proposed mechanisms of cell inactivation, due to mechanical contact with graphene materials, including lipid extraction, physical damage to membranes and pore formation.
The biomedical applications of graphene
Authors: Edirisinghe Mohan
Published: April 2018

This issue of
Interface Focus
is a collection of papers on ‘The biomedical applications of graphene’. The idea to put together this theme issue evolved during discussions between Prof. Peter N.T. Wells CBE, FREng, FMedSci, FRS and myself in mid-2016. Very sadly, about a year ago, Prof. Wells passed away. However, before that and even in the various last stages of his life he was intensely involved in planning this theme issue with me. I am deeply indebted to him for his contributions towards this and I dedicate this theme issue to him as a memorial.
Genome-wide association analyses of chronotype in 697,828 individuals provides new insights into circadian rhythms in humans and links to disease
Authors: Jones Samuel E. , Lane Jacqueline M. , Wood Andrew R. , van Hees Vincent T. , Tyrrell Jessica , Beaumont Robin N. , Jefferies Aaron , Dashti Hassan S. , Hillsdon Melvyn , Ruth Katherine S. , Tuke Marcus A. , Yaghootkar Hanieh , Sharp Seth , Jie Yingjie , Thompson William D. , Harrison Jamie W. , Dawes Amy , Byrne Enda M. , Tiemeier Henning , Allebrandt Karla V. , Bowden Jack , Ray David W. , Freathy Rachel M. , Murray Anna , Mazzotti Diego R. , Gehrman Philip R. ,   the 23andMe Research Team, Lawlor Debbie A. , Frayling Timothy M. , Rutter Martin K. , Hinds David , Saxena Richa , Weedon Michael N.
Published: April 2018

Using genome-wide data from 697,828 research participants from 23andMe and UK Biobank, we increase the number of identified loci associated with being a morning person, a behavioural indicator of a person’s underlying circadian rhythm, from 24 to 351. Using data from 85,760 individuals with activity-monitor derived measures of sleep timing we show that the chronotype loci influence sleep timing: the mean sleep timing of the 5% of individuals carrying the most “morningness” alleles was 25 minutes earlier than the 5% carrying the fewest. The loci were enriched for genes involved in circadian regulation, cAMP, glutamate and insulin signalling pathways, and those expressed in the retina, hindbrain, hypothalamus, and pituitary. We provide evidence that being a morning person is causally associated with better mental health but does not appear to affect BMI or Type 2 diabetes. This study offers new insights into the biology of circadian rhythms and links to disease in humans.
Overlapping neural processes for stopping and economic choice in orbitofrontal cortex
Authors: Balasubramani Pragathi Priyadharsini , Hayden Benjamin Y.
Published: April 2018

Economic choice and stopping are not traditionally treated as related phenomena. However, we were motivated by foraging models of economic choice to hypothesize that they may reflect similar neural processes occurring in overlapping brain circuits. We recorded neuronal activity in orbitofrontal cortex (OFC), while macaques performed a stop signal task interleaved with a structurally matched economic choice task. Decoding analyses show that OFC ensembles predict successful versus failed stopping both before the trial and immediately after the stop signal, even after controlling for value predictions. These responses indicate that OFC contributes both proactively and reactively to stopping. Moreover, OFC neurons’ engagement in one task positively predicted their engagement in the other. Finally, firing patterns that distinguished low from high value offers in the economic task distinguished failed and successful trials in the stopping task. These results endorse the idea that economic choice and inhibition may be subject to theoretical unification.
Intact memory for local and distal cues in male and female rats that lack adult neurogenesis
Authors: Seib Desiree R , Chahley Erin , Princz-Lebel Oren , Snyder Jason S
Published: April 2018

The dentate gyrus is essential for remembering the fine details of experiences that comprise episodic memory. Dentate gyrus granule cells receive highly-processed sensory information and are hypothesized to perform a pattern separation function, whereby similar sensory inputs are transformed into orthogonal neural representations. Behaviorally, this is believed to enable distinct memory for highly interfering stimuli. Since the dentate gyrus is comprised of a large number of adult-born neurons, which have unique synaptic wiring and neurophysiological firing patterns, it has been proposed that neurogenesis may contribute to this process in unique ways. Some behavioral evidence exists to support this role, whereby neurogenesis-deficient rodents are impaired at discriminating the fine visuospatial details of experiences. However, the extent to which newborn neurons contribute to dentate gyrus-dependent learning tasks is unclear. Furthermore, since most studies of dentate gyrus function are conducted in male rats, little is known about how females perform in similar situations, and whether there might be sex differences in the function of adult neurogenesis. To address these issues, we examined spatial discrimination memory in transgenic male and female rats that lacked adult neurogenesis. The first task probed memory for the position of local objects in an open field, assessed by behavioral responses to novel object locations. The second task examined memory for distal environmental cues. All rats were able to successfully discriminate local and distal cue changes. Males and females also performed comparably, although females displayed higher levels of rearing and locomotion. Collectively, our results indicate that rats are capable of learning about local and distal cues in the absence of adult neurogenesis.
Generative Adversarial Networks Conditioned on Brain Activity Reconstruct Seen Images
Authors: St-Yves Ghislain , Naselaris Thomas
Published: April 2018

We consider the inference problem of reconstructing a visual stimulus from brain activity measurements (e.g. fMRI) that encode this stimulus. Recovering a complete image is complicated by the fact that neural representations are noisy, high-dimensional, and contain incomplete information about image details. Thus, reconstructions of complex images from brain activity require a strong prior. Here we propose to train generative adversarial networks (GANs) to learn a generative model of images that is conditioned on measurements of brain activity. We consider two challenges of this approach: First, given that GANs require far more data to train than is typically collected in an fMRI experiment, how do we obtain enough samples to train a GAN that is conditioned on brain activity? Secondly, how do we ensure that our generated samples are robust against noise present in fMRI data? Our strategy to surmount both of these problems centers around the creation of surrogate brain activity samples that are generated by an encoding model. We find that the generative model thus trained generalizes to real fRMI data measured during perception of images and is able to reconstruct the basic outline of the stimuli.
Cis- and Trans-Acting Expression Quantitative Trait Loci Differentially Regulate Gamma-Globin Gene Expression
Authors: Shaikho Elmutaz M. , Farrell John J. , Chui David H. K. , Sebastiani Paola , Steinberg Martin H.
Published: April 2018

Genetic association studies have detected two trans-acting quantitative trait loci (QTL) on chromosomes 2, 6 and one cis-acting QTL on chromosome 11 that were associated with fetal hemoglobin (HbF) levels. In these studies, HbF was expressed as a percentage of total hemoglobin or the number of erythrocytes that contain HbF (F-cells). As theγ-globin chains of HbF are encoded by two non-allelic genes(HBG2, HBG1)that are expressed at different levels we used normalized gene expression and genotype data from The Genotype-Tissue Expression (GTEx)-project to study the effects of cis- and trans-acting HbF expression or eQTL. This allowed us to examine mRNA expression ofHBG2and HBG1individually. In addition to studying eQTL for globin genes we examined genes co-expressed withHBG1, studied upstream regulators ofHBG1co-expressed genes and performed a correlation analysis betweenHBG2andHBG1and known HbF regulators. Our results suggest differential effect of cis and trans-acting QTL onHBGandHBG1expression. Trans-acting eQTLs have the same magnitude of effect on the expression of bothHBG2andHBG1while the sole cis-acting eQTL affected onlyHBG2. Furthermore, the analysis of upstream regulators and the correlation analysis suggested thatBCL2L1might be a new potential trans-acting HbF activator. HbF is the major modulator of the phenotype of sickle cell anemia and β thalassemia. Depending on the effect size, modification of trans-acting elements might have a greater impact on HbF levels than cis-acting elements alone.
Preliminary study on the application of PspA as carrier
Authors: Lichan-Wang  , Yajun-Tan  , Chen-Wei  , Huajie-Zhang  , Peng-Luo  , Shumin-Zhang  , Xiao-Ma
Published: April 2018

The aim of the study is to research the feasibility of pneumococcal surface protein A (PspA) using as carrier protein. Three recombinant pneumococcal surface proteins A (come from family1 and family 2) were expressed by prokaryotic expression system and were conjugated to group A meningococcal polysaccharide (GAMP) to make three polysaccharide-protein conjugates. The conjugates, un-conjugated proteins, GAMP and GAMP-TT vaccine bulk (used as positive control) were immunized to mice and their immune effects were evaluated by the method of ELISA, FCM and SBA. The results showed that the polysaccharide-protein conjugates can produce higher levels of anti-GAMP IgG titers (P < 0.05), higher ratios of Th1/Th2 (P < 0.05) and higher levels of serum bactericidal activity (P < 0.05) compared with the un-conjugated GAMP. The conjugation of PspAs to GAMP also enhanced the anti-PspA responses compared with un-conjugated PspAs except PspA3. In conclusion, all the results indicated that three PspAs were suitable carrier protein as demonstrated by the characteristics of a T-cell dependent response to the GAMP, and would protect against group A of epidemic cerebrospinal meningitis and also have the potential to provide broad protection from Streptococcus pneumonia.
Biphasic recruitment of TRF2 to DNA damage sites promotes non-sister chromatid homologous recombination repair
Authors: Kong Xiangduo , Saquilabon Cruz Gladys Mae , Trinh Sally Loyal , Zhu Xu-Dong , Berns Michael W. , Yokomori Kyoko
Published: April 2018

TRF2 binds to telomeric repeats and is critical for telomere integrity. Evidence suggests that it also localizes to non-telomeric DNA damage sites. However, this recruitment appears to be precarious and functionally controversial. We find that TRF2 recruitment to damage sites occurs by a two-step mechanism: the initial rapid recruitment (phase I) and stable and prolonged association with damage sites (phase II). Phase I is poly(ADP-ribose) polymerase (PARP)-dependent and requires the N-terminal basic domain. The phase II recruitment requires the C-terminal MYB/SANT domain and the iDDR region in the hinge domain, which is mediated by the MRE11 complex and is stimulated by hTERT. PARP-dependent recruitment of intrinsically disordered proteins contributes to transient displacement of TRF2 that separates two phases. TRF2 binds to the I-PpoI-induced DNA double-strand break sites, which is enhanced by the presence of complex damage and is dependent on PARP and the MRE11 complex. TRF2 depletion affects non-sister chromatid homologous recombination (HR) repair, but not HR between sister chromatids or non-homologous endjoining pathways. Our results demonstrate a unique recruitment mechanism and function of TRF2 at non-telomeric DNA damage sites.

Summary Statement

TRF2 is recruited to DNA double-strand break damage sites by a two-step mechanism and functions in non-sister chromatid homologous recombination repair
Dissecting bacterial resistance and resilience in antibiotic responses
Authors: Meredith Hannah R. , Andreani Virgile , Lopatkin Allison J. , Lee Anna J. , Anderson Deverick J. , Batt Gregory , You Lingchong
Published: April 2018

An essential property of microbial communities is the ability to survive a disturbance. Survival can be achieved throughresistance, the ability to absorb effects of a disturbance without a significant change, orresilience, the ability to recover after being perturbed by a disturbance. These concepts have long been applied to the analysis of ecological systems, though their interpretations are often subject to debate. Here we show that this framework readily lends itself to the dissection of the bacterial response to antibiotic treatment, where both terms can be unambiguously defined. The ability to tolerate the antibiotic treatment in the short term corresponds to resistance, which primarily depends on traits associated with individual cells. In contrast, the ability to recover after being perturbed by an antibiotic corresponds to resilience, which primarily depends on traits associated with the population. This framework effectively reveals the phenotypic signatures of bacterial pathogens expressing extended spectrum β-lactamases (ESBLs), when treated by a β-lactam antibiotic. Our analysis has implications for optimizing treatment of these pathogens using a combination of a β-lactam and a β-lactamase (Bla) inhibitor. In particular, our results underscore the need to dynamically optimize combination treatments based on the quantitative features of the bacterial response to the antibiotic or the Bla inhibitor.
Fusobacterium genomics using MinION and Illumina sequencing enables genome completion and correction
Authors: Todd S. Michelle , Settlage Robert E. , Lahmers Kevin K. , Slade Daniel J.
Published: April 2018

Understanding the virulence mechanisms of human pathogens from the genus Fusobacterium has been hindered by a lack of properly assembled and annotated genomes. Here we report the first complete genomes for seven Fusobacterium strains, as well as resequencing of the reference strain F. nucleatum subsp. nucleatum ATCC 25586 (seven total species, eight total genomes). A highly efficient and cost-effective sequencing pipeline was achieved using sample multiplexing for short-read Illumina (150 bp) and long-read Oxford Nanopore MinION (>80 kbp) platforms, coupled with genome assembly using the open-source software Unicycler. When compared to currently available draft assemblies (previously 24-67 contigs), these genomes are highly accurate and consist of only one complete chromosome. We present the complete genome sequence of F. nucleatum 23726, a genetically tractable and biomedically important strain, and in addition, reveal that the previous F. nucleatum 25586 genome assembly contains a 452 kb genomic inversion that has been corrected using our sequencing and assembly pipeline. To enable the scientific community, we concurrently use these genomes to launch FusoPortal, a repository of interactive and downloadable genomic data, genome maps, gene annotations, and protein functional analysis and classification. In summary, this study provides detailed methods for accurately sequencing, assembling, and annotating Fusobacterium genomes, which will enhance efforts to properly identify virulence proteins that may contribute to a repertoire of diseases including periodontitis, pre-term birth, and colorectal cancer.
Development Defects of Hydroxy-Fatty Acid-Accumulating Seeds Are Reduced by Castor Acyltransferases
Authors: Lunn Daniel , Smith Gracen A. , Wallis James G. , Browse John
Published: April 2018

Researchers have long endeavored to produce modified fatty acids in easily managed crop plants where they are not natively found. An important step toward this goal has been the biosynthesis of these valuable products in model oilseeds. The successful production of such fatty acids has revealed barriers to the broad application of this technology, including low seed oil and low proportion of the introduced fatty acid and reduced seed vigor. Here, we analyze the impact of producing hydroxy-fatty acids on seedling development. We show that germinating seeds of a hydroxy-fatty acid-accumulating Arabidopsis (Arabidopsis thaliana) line produce chlorotic cotyledons and suffer reduced photosynthetic capacity. These seedlings retain hydroxy-fatty acids in polar lipids, including chloroplast lipids, and exhibit decreased fatty acid synthesis. Triacylglycerol mobilization in seedling development also is reduced, especially for lipids that include hydroxy-fatty acid moieties. These developmental defects are ameliorated by increased flux of hydroxy-fatty acids into seed triacylglycerol created through the expression of either castor (Ricinus communis) acyltransferase enzyme ACYL-COA:DIACYLGLYCEROL ACYLTRANSFERASE2 or PHOSPHOLIPID:DIACYLGLYCEROL ACYLTRANSFERASE1A. Such expression increases both the level of total stored triacylglycerol and the rate at which it is mobilized, fueling fatty acid synthesis and restoring photosynthetic capacity. Our results suggest that further improvements in seedling development may require the specific mobilization of triacylglycerol-containing hydroxy-fatty acids. Understanding the defects in early development caused by the accumulation of modified fatty acids and providing mechanisms to circumvent these defects are vital steps in the development of tailored oil crops.
Managing operations in customer-intensive services with forward-looking customers
Authors: Li Chengzhang , Jiang Minghui , Yuan Xuchuan
Published: April 2018

Purpose

This paper aims to investigate the optimal price and service rate decisions in a customer-intensive service, where customers’ perceived service quality decreases in the service speed. Customers are assumed to be forward-looking in purchase decision-making and heterogeneous in their reservation utilities. The purpose of this paper is to study the impact of customers’ forward-looking behavior and the heterogeneity on the operational decisions in a customer-intensive context.

Design/methodology/approach

The service is delivered through an M/M/1 queue system with unobservable queues. Customers are forward-looking in queue joining decisions, where the purchase decisions are made when the expected utility is greater than the reservation utility. The optimal price and service rate decisions are analyzed with both homogeneous and heterogeneous customers, where homogenous customers have the same reservation utility in purchase decision-making, while heterogeneous customers have different reservation utilities, which are captured by a random variable.

Findings

The optimal price and service rate decisions with forward-looking customers depend on the customer intensity, potential market size and customers’ reservation utility distribution. The results suggest that customers’ heterogeneity in terms of their reservation utilities affects the optimal decisions, market coverage and the expected revenue. Service providers need to take customers’ heterogeneity and the forward-looking behavior into operational decision-making.

Originality/value

This paper extends previous studies in customer-intensive service and contribute to the service operations management area by explicitly incorporating customers’ forward-looking behavior and heterogeneity in purchase decision-making. Assuming customers are forward-looking and heterogeneous is more realistic and practical. The results highlight that knowing customers’ behavioral characteristics can better improve decision-making in service operations, which is critical for enhancing customers’ satisfaction and loyalty, thus critical to a firm’s success in the market with intensive competition.