bluuebunny/crossref_metadata_2025 huggingface dataset:
Patient Satisfaction and Press Ganey Scores for Spine Versus Nonspine Neurosurgery Clinics
Authors: Chen Yi-Ren , Johnson Eli , Montalvo Carlos , Stratford Shelley , Veeravagu Anand , Tharin Suzanne , Desai Atman , Ratliff John , Shuer Lawrence , Park Jon
Published: April 2019

Study Design:

Retrospective survey review.

Objective:

We seek to evaluate satisfaction scores in patients seen in neurosurgical spine versus neurosurgical nonspine clinics.

Summary of Background Data:

The Press Ganey survey is a well-established metric for measuring hospital performance and patient satisfaction. These measures have important implications in setting hospital policy and guiding interventions to improve patient perceptions of care.

Methods:

Retrospective Press Ganey survey review was performed to identify patient demographics and patient visit characteristics from January 1st, 2012 to October 10th, 2017 at Stanford Medical Center. A total of 40 questions from the Press Ganey survey were investigated and grouped in categories addressing physician and nursing care, personal concerns, admission, room, meal, operating room, treatment and discharge conditions, visitor accommodations and overall clinic assessment. Raw ordinal scores were converted to continuous scores of 100 for unpaired student t test analysis. We identified 578 neurosurgical spine clinic patients and 1048 neurosurgical nonspine clinic patients.

Results:

Spine clinic patients reported lower satisfaction scores in aggregate (88.2 vs. 90.1; P=0.0014), physician (89.5 vs. 92.6; P=0.0002) and nurse care (91.3 vs. 93.4; P=0.0038), personal concerns (88.2 vs. 90.9; P=0.0009), room (81.0 vs. 83.1; P=0.0164), admission (90.8 vs. 92.6; P=0.0154) and visitor conditions (87.0 vs. 89.2; P=0.0148), and overall clinic assessment (92.9 vs. 95.5; P=0.005).

Conclusions:

This study is the first to evaluate the relationship between neurosurgical spine versus nonspine clinic with regards to patient satisfaction. The spine clinic cohort reported less satisfaction than the nonspine cohort in all significant questions on the Press Ganey survey. Our findings suggest that efforts should be made to further study and improve patient satisfaction in spine clinics.

Level of Evidence:

Level III.
Adoption and Use of Mobile Learning in Continuing Professional Development by Health and Human Services Professionals
Authors: Curran Vernon , Fleet Lisa , Simmons Karla , Lannon Heather , Gustafson Diana L. , Wang Chenfang , Garmsiri Mahyar , Wetsch Lyle
Published: April 2019

Introduction:

Health and human services professionals are increasingly using mobile devices to support clinical decision-making and evidence-based practice. However, research on self-directed learning in an era of growing digital technology utilization is underdeveloped. This study explored the adoption and use of mobile learning as a continuing professional development (CPD) activity.

Methods:

A mixed-methods case study using semistructured interviews and a web-based questionnaire was conducted with health and human services professionals in Newfoundland and Labrador, Canada.

Results:

Respondents reported using a smartphone (53.8%), tablets (50.4%), YouTube (43.0%), and mobile apps (35.8%) for CPD. The highest-rated benefits of mobile learning included improved access to information (M = 3.51); potential for enhanced knowledge acquisition (M = 3.45); staying up to date (M = 3.44); and verifying information (M = 3.40). The greatest barriers included cost of some apps and resources (M = 3.07); websites/programs not functional on mobile devices (M = 2.84); workplace barriers preventing access to digital resources (M = 2.82); and social media use linked to negative perceptions of professionalism (M = 2.65). Interview respondents described the flexibility and convenience of mobile learning, the level of autonomy it offered, and the advantages of learning on their own time. Technical issues, particularly for rural and remote practitioners, and digital professionalism also emerged as potential barriers.

Discussion:

A systems model organizes the factors influencing the adoption and use of mobile devices and resources to support “just-in-time” learning. Addressing policies, practices, and regulations that enable or inhibit adoption of mobile learning for CPD may foster enhanced use to support better clinical decision-making, improved accuracy, and greater patient safety.
Ultraviolet radiation and cutaneous melanoma: a historical perspective
Authors: Autier Philippe , Doré Jean-François
Published: April 2019

In this article, we summarize the research that eventually led to the classification of the full ultraviolet (UV) radiation spectrum as carcinogenic to humans. We recall the pioneering works that led to the formulation of novel hypotheses on the reasons underlying the increasing burden of melanoma in light-skinned populations. It took long before having compelling evidence on the association between UV and melanoma, in particular, the importance of UV exposure during childhood for both the occurrence of melanoma and death. The role of UVA was established only after 2005. If molecular lesions caused by UV radiation are better known, the precise mechanism by which UV exposure drives melanoma occurrence and progression still needs to be elucidated. More research on the UV–melanoma relationships has led to more evidence-based sun-protection recommendations, especially for children, and to effective control of the artificial UV tanning fashion. Since around 1985–1995, the mortality because of melanoma has started to decrease in younger age groups in most light-skinned populations. If sun protection among children remain on top of public health agendas, there is a fairly great chance that melanoma mortality will stabilize and steadily decrease in all light-skinned populations. The introduction of effective therapies against metastatic disease will improve this reversal in mortality trends.
Multimodal Imaging Report of Crystalline Keratopathy in Relapsing Polychondritis
Authors: Wang Kaidi , Gonzales John , Pawar Varun , Cheewaruangroj Nontawat , Seitzman Gerami D.
Published: April 2019

Purpose:

To describe a case of bilateral multifocal stromal crystalline keratopathy in the setting of relapsing polychondritis (RP).

Methods:

Case report.

Results:

We describe a 31-year-old woman who presented with ocular inflammation, bilateral auricular chondritis, and nasal chondritis, meeting the clinical criteria of RP. We illustrate her auricular cartilaginous abnormalities, saddle nose deformity, scleritis, and discrete mid-stromal opacities in both corneas that extend through the central cornea. Uniquely, her opacities feature a marked crystalline component as demonstrated on photography, anterior segment optical coherence tomography, and confocal microscopy.

Conclusion:

A central keratopathy is not typically reported in patients with RP. In this case report, we describe a unique diffuse bilateral nummular mid-stromal crystalline keratitis that extends into the central cornea and further define it using multimodal imaging.
Evidence for a GPR18 Role in Chemotaxis, Proliferation, and the Course of Wound Closure in the Cornea
Authors: Murataeva Natalia , Daily Laura , Taylor Xavier , Dhopeshwarkar Amey , Hu Sherry Shu-Jung , Miller Sally , McHugh Douglas , Oehler Olivia , Li Shimin , Bonanno Joseph A. , Mackie Ken , Straiker Alex
Published: April 2019

Purpose:

We previously showed that cannabinoid-related GPR18 receptors are present in the murine corneal epithelium, but their function remains unknown. The related CB1 receptors regulate corneal healing, possibly via chemotaxis. We therefore examined a potential role for GPR18 in corneal epithelial chemotaxis and wound healing.

Methods:

We examined GPR18 messenger RNA (mRNA) and protein expression in the cornea. We additionally examined GPR18 action in cultured bovine corneal epithelial cells (bCECs) using Boyden and tracking assays, as well as proliferation and signaling. Finally, we examined wound closure in murine corneal explants.

Results:

GPR18 mRNA was upregulated with injury in the mouse cornea. GPR18 protein was present in basal epithelial cells of the mouse and cow and redistributed to the wound site upon injury. GPR18 ligand N-arachidonoylglycine induced bCEC chemotaxis. The endocannabinoid arachidonoylethanolamine also induced chemotaxis via fatty acid amide hydrolase–mediated metabolism to N-arachidonoylglycine. GPR18 receptor activation additionally induced bCEC proliferation. In an explant model, the GPR18 antagonist O-1918 slowed corneal epithelial cell migration and the rate of corneal wound closure.

Conclusions:

Corneal GPR18 activation induced both chemotaxis and proliferation in corneal epithelial cells in vitro and impacted wound healing. GPR18 may contribute to the maintenance of corneal integrity.
Corneal Evaluation in Patients With Parkinsonism on Long-Term Amantadine Therapy
Authors: Daggumilli Satyasudha , Vanathi Murugesan , Ganger Anita , Goyal Vinay , Tandon Radhika
Published: April 2019

Purpose:

To evaluate the progression of corneal endothelial changes in patients with Parkinson disease (PD) on long-term oral amantadine therapy.

Methods:

A prospective comparative longitudinal observational study of 90 patients (180 eyes) with PD on more than 6 months of oral amantadine therapy, 30 amantadine naive patients with PD, and 30 healthy controls (age and gender matched). Corneal endothelial cell parameters (endothelial cell density, percentage hexagonality of the cells, and coefficient of variation) and corneal subbasal nerve fiber layer changes were studied over a follow-up period of 1 year.

Results:

The amantadine patients with PD group had a statistically significant decrease in endothelial cell density (1.51% vs. 0.94% vs. 0.55%) (P = 0.04), decrease of percentage hexagonality of the cells (4.98% vs. 3.56% vs. 2.31%) (P = 0.01), and increase of coefficient of variation (6.12% vs. 4.80% vs. 3.30%) (P = 0.03) compared with amantadine naive patients with PD and controls, respectively. Analysis of changes in the patients with PD based on the daily dosage of amantadine showed greater change in endothelial parameters in patients who were on 400 mg amantadine.

Conclusions:

Long-term amantadine therapy seems to effect changes on corneal endothelium.
Autonomic Dysregulation in Adolescent Concussion Is Sex- and Posture-Dependent
Authors: Balestrini Christopher S. , Moir Marcy Erin , Abbott Kolten C. , Klassen Stephen A. , Fischer Lisa K. , Fraser Douglas D. , Shoemaker Joel Kevin
Published: April 2019

Objective:

To study autonomic responses to postural changes in concussed adolescents. The influence of sex was also studied.

Design:

Longitudinal cohort observational study.

Participants:

Concussed adolescents (CONC; n = 65; 26 male adolescents; age 15 ± 1 years, range = 12-18 years) and a control (CTRL) group of nonconcussed adolescents of similar age and sport (CTRL; n = 54; 29 male adolescents; age 14 ± 1 years, range = 12-18 years).

Interventions:

Concussed participants were monitored through 6 weekly visits throughout usual physician care. Control participants underwent 2 visits separated by at least 1 week to account for intrapersonal variation in testing measures.

Main Outcome Measures:

Heart rate variability as the root mean square of successive differences in R–R intervals (RMSSD), heart rate (HR), and blood pressure [mean arterial pressure (MAP) and diastolic blood pressure (DBP)] were measured in supine, sitting, and standing postures.

Results:

A mixed analysis of variance revealed a group × sex × posture interaction (P = 0.04) where seated values of RMSSD were less in concussed female participants versus control female participants (42 ± 4 vs 61 ± 7 ms; P = 0.01; Mann–Whitney rank test). Compared with CTRL, CONC exhibited increased pretesting seated DBP (69 ± 1 vs 74 ± 1 mm Hg; P < 0.01), MAP (83 ± 1 vs 86 ± 1 mm Hg; P = 0.02), and baseline seated HR (72 ± 1 vs 77 ± 2 bpm; P = 0.03). Values of DBP (P = 0.03) and MAP (P < 0.01) improved at clinical discharge, whereas the RMSSD in female participants did not (P > 0.5). Data are mean ± SEM.

Conclusions:

A modest reduction in female cardiac autonomic regulation was observed during seated postures. Alterations in seated concussed DBP and MAP, but not RMSSD, resolved at clinical discharge (median = 37 days). The results indicate that, in adolescents, concussion may impair cardiovagal function in a sex- and posture-dependent manner. The findings also suggest that BP metrics, but not RMSSD, are associated with clinical concussion recovery.
Non–transfusion-dependent β-Thalassemia Because of a Single β-Thalassemia Mutation and Coinherited α-Globin Gene Triplication: Need for Increased Awareness to Prevent Incorrect and Delayed Diagnosis
Authors: Gurunathan Arun , Tarango Cristina , McGann Patrick T. , Niss Omar , Quinn Charles T.
Published: April 2019

The thalassemias are genetically complex and usually autosomal recessive. We describe 5 unrelated individuals with non–transfusion-dependent β-thalassemia (NTDT), some with apparently dominant transmission, because of a single β-thalassemia mutation coinherited with a triplicated α-globin locus. Each had an initial, incorrect diagnosis of β-thalassemia trait. The correct diagnosis of NTDT was made at a mean of 7 years of age. Despite reports of this compound genotype causing NTDT, it remains unfamiliar to many clinicians. To increase awareness, we highlight its varied and sometimes subtle clinical and laboratory features and the need for comprehensive genetic testing for timely and correct diagnosis.
Primary Mediastinal Large B-Cell Lymphoma in a Child Presenting With Superior Mediastinal Syndrome and Chylous Pleural and Pericardial Effusion
Authors: Trivedi Maharshi , Chandar Rumesh , Nair Manjusha , Jacob Priya Mary , Thankamony Priyakumari
Published: April 2019

Primary mediastinal (thymic) large B-cell lymphoma is an aggressive B-cell lymphoma. It comprises <3% of all pediatric non-Hodgkin lymphomas (NHLs). Primary mediastinal (thymic) large B-cell lymphoma usually presents with serous pleural effusion, but presentation with chylous pleural and pericardial effusions is rare. We present a child who presented with features of a superior mediastinal syndrome. Biopsy of the mediastinal mass confirmed the diagnosis of large B-cell lymphoma. In view of nonimprovement of respiratory distress with chemotherapy and persistence of features of superior mediastinal syndrome, the child was evaluated and found to have massive pleural and pericardial effusion on imaging. Therapeutic thoracentesis and pericardiocentesis revealed chylous nature of the fluid.
What is the Role of Hematopoietic Cell Transplantation (HCT) for Pediatric Acute Lymphoblastic Leukemia (ALL) in the Age of Chimeric Antigen Receptor T-Cell (CART) Therapy?
Authors: Taraseviciute Agne , Broglie Larisa , Phelan Rachel , Bhatt Neel S. , Becktell Kerri , Burke Michael J.
Published: April 2019

CD19 chimeric antigen receptor T-cell (CART) therapy has revolutionized the treatment of patients with relapsed/refractory hematologic malignancies, especially B-cell acute lymphoblastic leukemia. As CART immunotherapy expands from clinical trials to FDA-approved treatments, a consensus among oncologists and hematopoietic cell transplant (HCT) physicians is needed to identify which patients may benefit from consolidative HCT post-CART therapy. Here, we review CD19 CART therapy and the outcomes of published clinical trials, highlighting the use of post-CART HCT and the pattern of relapse after CD19 CART. At this time, the limited available long-term data from clinical trials precludes us from making definitive HCT recommendations. However, based on currently available data, we propose that consolidative HCT post-CART therapy be considered for all HCT-eligible patients and especially for pediatric patients with KMT2A-rearranged B-cell acute lymphoblastic leukemia.
Brincidofovir as a Salvage Therapy in Controlling Adenoviremia in Pediatric Recipients of Hematopoietic Stem Cell Transplant
Authors: Meena Jagdish P. , Phillips Robert S. , Kinsey Sally
Published: April 2019

Adenovirus infection is a well-known complication in patients receiving hematopoietic stem cell transplantation (HSCT). Brincidofovir (BCV) is an orally bioavailable lipid conjugate of cidofovir, which has activity against adenoviruses. We present a review of adenovirus infections treated with BCV which were unresponsive to cidofovir initially in 4 patients and it was used upfront in one patient. Children with adenovirus infection following HSCT treated with BCV, between July 2014 and February 2018 were recognized. Five patients including 3 male and 2 female with a median age of 10 years (range, 2.2 to 10 y) were identified. The median days of adenoviremia detection was 18 days (range, 7 to 303 d) posttransplant. The median peak viral load by quantitative polymerase chain reaction was 21,38,000 copies/mL (range, 1,77,200 to 31,97,000 copies/mL). The median time from first detection of adenoviremia to become negative was 30 days (range, 15 to 113 d). The sites involved were gastrointestinal tract in all patients and 2 patients had additional respiratory tract involvement. Two patients survived and 3 patients died of sepsis. All patients responded well to BCV and no adverse effect was noticed. We saw the good safety profile and excellent antiadenoviral activity of BCV in pediatric patients receiving HSCT without the nephrotoxicity and it may have a role in preemptive therapy.
Pediatric Patients With SHH Medulloblastoma Fail Differently as Compared With Adults: Possible Implications for Treatment Modifications
Authors: Dasgupta Archya , Gupta Tejpal , Sridhar Epari , Shirsat Neelam , Krishnatry Rahul , Goda Jayant Sastri , Chinnaswamy Girish , Jalali Rakesh
Published: April 2019

Purpose:

The purpose of this work was to study the diversity of sonic hedgehog (SHH) medulloblastoma across different age groups with an emphasis on patterns of relapse.

Methods:

All data for the study were obtained through review of medical records, imaging, radiation charts, treatment planning, and chemotherapy details.

Results:

Sixty-three patients with SHH medulloblastoma were identified from a prospectively maintained database and classified into 3 groups—infantile: ≤3 years (i-SHH, n=11); pediatric: >3 to <18 years (p-SHH, n=21); and adult: ≥18 years (a-SHH; n=31). Lateralized tumors were common with increasing age (81% a-SHH, 67% p-SHH, 27% i-SHH; P=0.01). Large cell anaplastic histology was relatively common for p-SHH (33%), while the nodular/desmoplastic variant was more frequent in i-SHH (64%) and adults (51%). Median follow-up was 38 months (range, 5 to 91 mo). Five-year event-free survival was 80%, 31%, and 52% for i-SHH, p-SHH, and a-SHH, respectively (P=0.001). Median time to failure for p-SHH and a-SHH were 12 and 36 months, respectively. For p-SHH, 83% were metastatic relapses compared with localized failure in 75% for a-SHH. Five-year overall survival for i-SHH, p-SHH, and a-SHH were 91%, 31%, and 70%, respectively (P=0.001). On univariate analysis, event-free survival was significantly worse for superiorly located tumors (P=0.01), nondesmoplastic histology (P=0.02), and histology alone for overall survival (P=0.04) (none on multivariate analysis).

Conclusions:

SHH medulloblastoma demonstrates varied outcomes depending on age, with p-SHH associated with early and metastatic relapses, while for a-SHH it tends to be delayed and localized.
Validation of a Congestive Hepatic Fibrosis Scoring System
Authors: Bosch Dustin E. , Koro Konstantin , Richards Elizabeth , Hoch Benjamin L. , Jalikis Florencia , Koch Lisa K. , Swanson Paul E. , Truong Camtu D. , Liou Iris , Yu Lei , Bhattacharya Renuka , Yeh Matthew M.
Published: April 2019

Congestive hepatopathy is a complication of right heart failure and chronically elevated right heart pressure. Histologic findings include sinusoidal dilatation, centrilobular hepatocellular plate atrophy, and fibrosis. We performed a validation study of a recently proposed scoring system (0 to 4 scale) for congestive hepatic fibrosis on 38 liver biopsies. Glutamine synthetase immunohistochemistry was also performed, and loss of centrizonal immunoreactivity correlated with increasing fibrosis score (P<0.01). Interobserver concordance for congestive hepatic fibrosis score based on Masson trichrome stain was initially fair (Fleiss κ=0.28, weighted concordance coefficient=0.60) and significantly improved (κ=0.40, weighted concordance coefficient=0.66) following a multiheaded microscope training session and inclusion of glutamine synthetase immunohistochemistry. Average congestive hepatic fibrosis score correlated with significantly higher right atrial pressure, severity of right atrial dilation, presence of right ventricular dilation, elevated serum alanine aminotransferase, platelet counts, prothrombin time, and model for end-stage liver disease score. In conclusion, the congestive hepatic fibrosis scoring system is reproducible among pathologists and correlates with clinical and laboratory markers of congestive hepatopathy.
Short-term and Long-term Outcomes Following Laparoscopic Gastrectomy for Advanced Gastric Cancer Compared With Open Gastrectomy
Authors: Shibuya Kazuaki , Kawamura Hideki , Takahashi Shusaku , Ohno Yosuke , Ichikawa Nobuki , Yoshida Tadashi , Homma Shigenori , Ishizu Hiroyuki , Takahashi Masahiro , Taketomi Akinobu
Published: April 2019

Introduction:

To investigate the oncological feasibility and technical safety of laparoscopic gastrectomy with D2 lymphadenectomy for advanced gastric cancer.

Methods:

A total of 186 advanced gastric cancer patients treated by gastrectomy with D2 lymphadenectomy were eligible for inclusion including those with invasion into the muscularis propria, subserosa, and serosa without involvement of other organs, and stages N0-2 and M0. We retrospectively compared the short-term and long-term outcomes between laparoscopic gastrectomy and open gastrectomy.

Results:

We analyzed short-term outcomes by comparing distal with total gastrectomy results. We found no significant difference for distal gastrectomy for postoperative morbidity [laparoscopic vs. open: n=4 (4.6%) vs. n=1 (3.6%); P=1.00]. We also found no significant difference in postoperative morbidity for total gastrectomy [laparoscopic vs. open: n=2 (4.0%) vs. n=1 (4.0%); P=1.00]. No deaths occurred in any group.

The entire cohort analysis revealed no statistically significant differences in overall-free or recurrence-free survival between the laparoscopic and open groups. For overall survival, there were no significant differences between open and laparoscopic groups for clinical stage II or III (P=0.29 and 0.27, respectively), and for pathologic stage II or III (P=0.88 and 0.86, respectively). For recurrence-free survival, there were no significant differences between open and laparoscopic groups for clinical stage II or III (P=0.63 and 0.60, respectively), and for pathologic stage II or III (P=0.98 and 0.72, respectively).

Conclusion:

Laparscopic gastrectomy for advanced gastric cancer compared favorably with open gastrectomy regarding short-term and long-term outcomes.
Active head motion reduction in Magnetic Resonance Imaging using tactile feedback
Authors: Krause Florian , Benjamins Caroline , Eck Judith , Luehrs Michael , van Hoof Rick , Goebel Rainer
Published: April 2019

Head motion is a common problem in clinical as well as empirical (functional) Magnetic Resonance Imaging applications, as it can lead to severe artefacts that reduce image quality. The scanned individuals themselves, however, are often not aware of their head motion. The current study explored whether providing subjects with this information using tactile feedback would reduce their head motion and consequently improve image quality. In a single session that included six runs, 24 participants performed three different cognitive tasks: (1) passive viewing, (2) mental imagery, and (3) speeded responses. These tasks occurred in two different conditions: (a) with a strip of medical tape applied from one side of the MR head-coil, via the participant’s forehead, to the other side, and (b) without the medical tape being applied. Results revealed that application of medical tape to the forehead of subjects to provide tactile feedback significantly reduced both translational as well as rotational head motion. While this effect did not differ between the three cognitive tasks, there was a negative quadratic relationship between head motion with and without feedback. That is, the more head motion a subject produced without feedback, the stronger the motion reduction given the feedback. In conclusion, the here tested method provides a simple and cost-efficient way to reduce subjects’ head motion, and might be especially beneficial when extensive head motion is expected a priori.
Gene modules associated with human diseases revealed by network analysis
Authors: Ma Shisong , Gong Jiazhen , Zuo Wanzhu , Geng Haiying , Zhang Yu , Wang Meng , Han Ershang , Peng Jing , Wang Yuzhou , Wang Yifan , Chen Yanyan
Published: April 2019

Despite many genes associated with human diseases have been identified, disease mechanisms often remain elusive due to the lack of understanding how disease genes are connected functionally at pathways level. Within biological networks, disease genes likely map to modules whose identification facilitates etiology studies but remains challenging. We describe a systematic approach to identify disease-associated gene modules. A gene co-expression network based on the graphical Gaussian model (GGM) was constructed using the GTEx dataset and assembled into 652 gene modules. Screening these modules identified those with disease genes enrichment for obesity, cardiomyopathy, hypertension, and autism, which illuminated the molecular pathways underlying their pathogenesis. Using mammalian phenotypes derived from mouse models, potential disease candidate genes were identified from these modules. Also analyzed were epilepsy, schizophrenia, bipolar disorder, and depressive disorder, revealing shared and distinct disease modules among brain disorders. Thus, disease genes converge on modules within our GGM gene co-expression network, which provides a general framework to dissect genetic architecture of human diseases.
DNA Methylation Associated with Postpartum Depressive Symptoms Overlaps Findings from a Genome-wide Association Meta-Analysis of Depression
Authors: Lapato Dana M. , Roberson-Nay Roxann , Kirkpatrick Robert M. , Webb Bradley T. , York Timothy P. , Kinser Patricia
Published: April 2019

Background

Perinatal depressive symptoms have been linked to adverse maternal and infant health outcomes. The etiology associated with perinatal depressive psychopathology is poorly understood, but accumulating evidence suggests that understanding inter-individual differences in DNA methylation (DNAm) patterning may provide insight regarding the genomic regions salient to the risk liability of perinatal depressive psychopathology.

Results

Genome-wide DNAm was measured in maternal peripheral blood using the Infinium MethylationEPIC microarray. Ninety-two participants (46% African-American) had DNAm samples that passed all quality control metrics, and all participants were within seven months of delivery. Linear models were constructed to identify differentially methylated sites and regions, and permutation testing was utilized to assess significance. Differentially methylated regions (DMRs) were defined as genomic regions of consistent DNAm change with at least two probes within 1kb of each other. Maternal age, current smoking status, estimated cell-type proportions, ancestry-relevant principal components, days since delivery, and chip position served as covariates to adjust for technical and biological factors. Current postpartum depressive symptoms were measured using the Edinburgh Postnatal Depression Scale. Ninety-eight DMRs were significant (False Discovery Rate < 5%) and overlapped 92 genes. Synaptic signaling, neural development, and platelet formation were the most represented biological processes in gene set analysis, and comparison to the 44 loci discovered in the latest Psychiatric Genomics Consortium meta-analysis of depression revealed 3 overlapping regions and significant enrichment (p<0.03).

Conclusions

Many of the genes identified in this analysis corroborate previous allelic, transcriptomic, and DNAm association results related to depressive phenotypes. Future work should integrate data from multi-omic platforms to understand the functional relevance of these DMRs and refine DNAm association results by limiting phenotypic heterogeneity and clarifying if DNAm differences relate to the timing of onset, severity, duration of perinatal mental health outcomes of the current pregnancy or to previous history of depressive psychopathology.
ecTMB: a robust method to estimate and classify tumor mutational burden
Authors: Yao Lijing , Fu Yao , Mohiyuddin Marghoob , Lam Hugo YK
Published: April 2019

Tumor Mutational Burden (TMB) is a measure of the abundance of somatic mutations in a tumor, which has been shown to be an emerging biomarker for both anti-PD-(L)1 treatment and prognosis. Nevertheless, multiple challenges still hinder the adoption of TMB for clinical decision-making. The key challenges are the inconsistency of TMB measurement among assays and a lack of meaningful threshold for TMB classification. We describe a powerful and flexible statistical framework for estimation and classification of TMB (ecTMB). ecTMB uses an explicit background mutation model to predict TMB robustly and consistently. In addition to the two known TMB subtypes, TMB-high and TMB-low, we discovered a novel TMB subtype, named TMB-extreme, which was significantly associated with patient survival outcome. This discovery enabled ecTMB to classify samples to biologically and clinically relevant subtypes defined by TMB.
Prospects for transcranial temporal interference stimulation in humans: a computational study
Authors: Rampersad Sumientra , Roig-Solvas Biel , Yarossi Mathew , Kulkarni Praveen P. , Santarnecchi Emiliano , Dorval Alan D. , Brooks Dana H.
Published: April 2019

Transcranial alternating current stimulation (tACS) is a noninvasive method used to modulate activity of superficial brain regions. Deeper and more steerable stimulation could potentially be achieved using transcranial temporal interference stimulation (tTIS): two high-frequency alternating fields interact to produce a wave with an envelope frequency in the range thought to modulate neural activity. Promising initial results have been reported for experiments with mice. In this study we aim to better understand the electric fields produced with tTIS and examine its prospects in humans through simulations with murine and human head models. A murine head finite element model was used to simulate previously published experiments of tTIS in mice. With a total current of 0.776 mA, tTIS electric field strengths up to 383 V/m were reached in the modeled mouse brain, affirming experimental results indicating that suprathreshold stimulation is possible in mice. Using a detailed anisotropic human head model, tTIS was simulated with systematically varied electrode configurations and input currents to investigate how these parameters influence the electric fields. An exhaustive search with 88 electrode locations covering the entire head (146M current patterns) was employed to optimize tTIS for target field strength and focality. In all analyses, we investigated maximal effects and effects along the predominant orientation of local neurons. Our results showed that it was possible to steer the peak tTIS field by manipulating the relative strength of the two input fields. Deep brain areas received field strengths similar to conventional tACS, but with less stimulation in superficial areas. Maximum field strengths in the human model were much lower than in the murine model, too low to expect direct stimulation effects. While field strengths from tACS were slightly higher, our results suggest that tTIS is capable of producing more focal fields and allows for better steerability. Finally, we present optimal four-electrode current patterns to maximize tTIS in regions of the pallidum (0.37 V/m), hippocampus (0.24 V/m) and motor cortex (0.57 V/m).
Basal Contamination of Sequencing: Lessons from the GTEx dataset
Authors: Nieuwenhuis Tim O. , Yang Stephanie , Verma Rohan X. , Pillalamarri Vamsee , Arking Dan E. , Rosenberg Avi Z. , McCall Matthew N. , Halushka Marc K.
Published: April 2019

One of the challenges of next generation sequencing (NGS) is read contamination. We used the Genotype-Tissue Expression (GTEx) project, a large, diverse, and robustly generated dataset, to understand the factors that contribute to contamination. We obtained GTEx datasets and technical metadata and validating RNA-Seq from other studies. Of 48 analyzed tissues in GTEx, 26 had variant co-expression clusters of four known highly expressed and pancreas-enriched genes (PRSS1, PNLIP, CLPS, and/or CELA3A). Fourteen additional highly expressed genes from other tissues also indicated contamination. Sample contamination by non-native genes was associated with a sample being sequenced on the same day as a tissue that natively expressed those genes. This was highly significant for pancreas and esophagus genes (linear model, p=9.5e-237 and p=5e-260 respectively). Nine SNPs in four genes shown to contaminate non-native tissues demonstrated allelic differences between DNA-based genotypes and contaminated sample RNA-based genotypes, validating the contamination. Low-level contamination affected 4,497 (39.6%) samples (defined as 10 PRSS1 TPM). It also led ≥ to eQTL assignments in inappropriate tissues among these 18 genes. We note this type of contamination occurs widely, impacting bulk and single cell data set analysis. In conclusion, highly expressed, tissue-enriched genes basally contaminate GTEx and other datasets impacting analyses. Awareness of this process is necessary to avoid assigning inaccurate importance to low-level gene expression in inappropriate tissues and cells.
ViraMiner: Deep Learning on Raw DNA Sequences for Identifying Viral Genomes in Human Samples
Authors: Tampuu Ardi , Bzhalava Zurab , Dillner Joakim , Vicente Raul
Published: April 2019

Despite its clinical importance, detection of highly divergent or yet unknown viruses is a major challenge. When human samples are sequenced, conventional alignments classify many assembled contigs as “unknown” since many of the sequences are not similar to known genomes. In this work, we developed ViraMiner, a deep learning-based method to identify viruses in various human biospecimens. ViraMiner contains two branches of Convolutional Neural Networks designed to detect both patterns and pattern-frequencies on raw metagenomics contigs. The training dataset included sequences obtained from 19 metagenomic experiments which were analyzed and labeled by BLAST. The model achieves significantly improved accuracy compared to other machine learning methods for viral genome classification. Using 300 bp contigs ViraMiner achieves 0.923 area under the ROC curve. To our knowledge, this is the first machine learning methodology that can detect the presence of viral sequences among raw metagenomic contigs from diverse human samples. We suggest that the proposed model captures different types of information of genome composition, and can be used as a recommendation system to further investigate sequences labeled as “unknown” by conventional alignment methods. Exploring these highly-divergent viruses, in turn, can enhance our knowledge of infectious causes of diseases.
FIN-Seq: Transcriptional profiling of specific cell types in frozen archived tissue from the human central nervous system
Authors: Amamoto Ryoji , Zuccaro Emanuela , Curry Nathan C. , Khurana Sonia , Chen Hsu-Hsin , Cepko Constance L. , Arlotta Paola
Published: April 2019

Thousands of frozen, archived tissues from postmortem human central nervous system (CNS) are currently available in brain banks. As single cell and single nucleus technologies are beginning to elucidate the cellular diversity present within the human CNS, it is becoming clear that transcriptional analysis of the human CNS requires cell type specificity. Single cell and single nucleus RNA profiling provide one avenue to decipher this heterogeneity. An alternative, complementary approach is to profile isolated, pre-defined cell types and use methods that can be applied to many archived human tissue samples. Here, we developed FIN-Seq (FrozenImmunolabeledNucleiSequencing), a method that accomplishes these goals. FIN-Seq uses immunohisto-chemical isolation of nuclei of specific cell types from frozen human tissue, followed by RNA-Sequencing. We applied this method to frozen postmortem samples of human cerebral cortex and retina and were able to identify transcripts, including low abundance transcripts, in specific cell types.
Automated design of highly diverse riboswitches
Authors: Wu Michelle J , Andreasson Johan O L , Kladwang Wipapat , Greenleaf William , Das Rhiju
Published: April 2019

Riboswitches that couple binding of ligands to recruitment of molecular machines offer sensors and control elements for RNA synthetic biology and medical biotechnology. Current approaches to riboswitch design enable significant changes in output activity in the presence vs. absence of input ligands. However, design of these riboswitches has so far required expert intuition and explicit specification of complete target secondary structures, both of which limit the structure-toggling mechanisms that have been explored. We present a fully automated method called RiboLogic for these design tasks and high-throughput experimental tests of 2,875 molecules using RNA-MaP (RNA on a massively parallel array) technology. RiboLogic designs explore an unprecedented diversity of structure-toggling mechanisms validated through experimental tests. These synthetic molecules consistently modulate their affinity to the MS2 bacteriophage coat protein upon binding of flavin mononucleotide, tryptophan, theophylline, and microRNA miR-208a, achieving activation ratios of up to 20 and significantly better performance than control designs. The data enable dissection of features of structure-toggling mechanisms that correlate with higher performance. The diversity of RiboLogic designs and their quantitative experimental characterization provides a rich resource for further improvement of riboswitch models and design methods.
Immunomodulatory effects of extract ofGanoderma lucidumbasidiocarps cultivated on alternative substrate
Authors: Nedeljković Biljana Božić , Ćilerdžić Jasmina , Zmijanjac Dragana , Marković Milan , Džopalić Tanja , Vasilijić Saša , Stajić Mirjana , Vučević Dragana
Published: April 2019

The aim of the study was to investigate if there are any differences in effects of extracts of commercially (GC) and alternatively (wheat straw) (GA) cultivatedGanoderma lucidumbasidiocarps on properties of peritoneal macrophages (PM) and monocyte-derived dendritic cells (MoDCs). GA extract stronger stimulated the metabolic and phagocytic activity of PMs, their adhesion capability and ability to produce ROS and NO compared to GC. Both tested extracts significantly increased allostimulatory and Th1 polarization capacity of simultaneous TLR3 and TLR7-activated MoDCs, but GA extract was more effective. The GA extract increased the production of ROS and NO by TLR4 stimulated PMs and up-regulated the production of certain cytokines as well as allostimulatory and Th1 polarization capacity of MoDCs. The GA extract could be a potent immunostimulatory agent for activation of MoDCs with the simultaneous engagement of TLRs that seems to be a promising strategy for preparation of DC-based anti-tumor vaccines.
Integrative functional genomics decodes herpes simplex virus 1
Authors: Whisnant Adam W. , Jürges Christopher S. , Hennig Thomas , Wyler Emanuel , Prusty Bhupesh , Rutkowski Andrzej J , L’hernault Anne , Göbel Margarete , Döring Kristina , Menegatti Jennifer , Antrobus Robin , Matheson Nicholas J. , Künzig Florian W.H. , Mastrobuoni Guido , Bielow Chris , Kempa Stefan , Chunguang Liang , Dandekar Thomas , Zimmer Ralf , Landthaler Markus , Grässer Friedrich , Lehner Paul J. , Friedel Caroline C. , Erhard Florian , Dölken Lars
Published: April 2019

Since the genome of herpes simplex virus 1 (HSV-1) was first sequenced more than 30 years ago, its predicted 80 genes have been intensively studied. Here, we unravel the complete viral transcriptome and translatome during lytic infection with base-pair resolution by computational integration of multi-omics data. We identified a total of 201 viral transcripts and 284 open reading frames (ORFs) including all known and 46 novel large ORFs. Multiple transcript isoforms expressed from individual gene loci explain translation of the vast majority of novel viral ORFs as well as N-terminal extensions (NTEs) and truncations thereof. We show that key viral regulators and structural proteins possess NTEs, which initiate from non-canonical start codons and govern subcellular protein localization and packaging. We validated a novel non-canonical large spliced ORF in the ICP0 locus and identified a 93 aa ORF overlapping ICP34.5 that is thus also deleted in the FDA-approved oncolytic virus Imlygic. Finally, we extend the current nomenclature to include all novel viral gene products. Taken together, this work provides a valuable resource for future functional studies, vaccine design and oncolytic therapies.
Preparation and characterization of phospholipid stabilized nanoemulsions in small-scale
Authors: Gurung Shila , Holzer Martin , Barnert Sabine , Schubert Rolf
Published: April 2019

Phospholipids have been used to prepare liposomes. The use of phospholipids to stabilize nanoemulsions may cause spontaneous formation of liposomes. The main objective of this study is to develop a method to prepare phospholipid stabilized nanoemulsions in small scale (< 1 mL) and to minimize the formation of liposomes.

A combination of hand extrusion and detergent removal methods was used in this study. Extrusion through polycarbonate membranes was performed in two steps, firstly using membranes of 400 nm followed by 200 nm membranes as the second step. Sodium cholate was used as a detergent to solubilize the formed liposomes which was later removed via dialysis. Nanoemulsions were characterized by measuring their particle size, polydispersity index and zeta-potential using Photon Correlation Spectroscopy and Cryo-TEM pictures. The stability of nanoemulsion stored under refrigeration was also studied.

Fifty-one extrusion cycles through polycarbonate membrane of 400 nm pore size followed by one-hundred fifty-three cycles through polycarbonate membrane of 200 nm produced nanoemulsions having particle size below 200 nm (diameter). The nanoemulsions were found to be homogenous as depicted by polydispersity index (PDI) value below 0.1. Similarly, the zeta-potential was measured to be above −30 mV which is sufficient to keep nanoemulsions stable for as long as 7 months when stored under refrigeration. The Cryo-TEM pictures revealed 30 mM to be an optimum concentration of sodium cholate to prepare homogenous nanoemulsions with negligible proportion of liposomes.

It was concluded that this method could be established as a small scale method of preparing nanoemulsions which will not only reduce the cost of preparation but also the disposal cost of toxic chemicals used for functionalizing nanoemulsions for scientific research.
Modulated Zika virus NS1 conjugate offers advantages for accurate detection of Zika virus specific antibody in double antigen binding and Ig capture enzyme immunoassays
Authors: Tedder Richard S , Dicks Steve , Ijaz Samreen , de Souza Nathalia Caroline Santiago , de Paula Anderson Vincente , Levy Flavia , Medialdea-Carrera Raquel , Levi José Eduardo , Pannuti Claudio S , de Sequeira Patrícia Carvalho , Brown David W G , Lumb Ines Ushiro
Published: April 2019

The accurate diagnosis and seroprevalence investigations of Zika virus (ZKV) infections remain complex due to cross reactivity with other flaviviruses. Two assay formats, both using labelled Zika virus NS1 antigen as a revealing agent (a double antigen binding assay, DABA, and an immunoglobulin Ig capture assay, IgG capture) were initially developed and compared with the indirect EuroimmunZ assay for the detection of anti-Zika antibody. Of 147 pre-Zika period serum samples, 39 (27%) were reactive in the EuroimmunZ or the DABA assays, 28 sera concordantly so. Such false reactivity was influenced by the serotype of Dengue virus (DV) to which individuals had been exposed to. Thus, of sera from patients undergoing secondary Dengue virus infection of known serotype, 91%, 45% and 28% of Dengue virus serotype 2, 3 and 4 respectively were reactive in one or more of the three assays. A novel method of quenching false sero-reactivity was therefore developed for the DABA and IgG capture assays. Initial addition of a single homologous Dengue virus serotype 3 NS1Ag quench significantly ablated false reactivities in the pre-Zika period sera. An equipotent quadrivalent quench comprising homologous Dengue virus serotypes 1 to 4 NS1Ag was shown to be optimum yet retained sensitivity for the detection of specific anti-Zika antibody. Comparing DABA and IgG capture assays using quenched and unquenched conjugates in comparison with EuroimmunZ early in the course of PCR-confirmed infection indicated that a significant component of the apparent early anti-ZIKA antibody response is likely to be due to a Zika virus-driven anamnestic anti-Dengue virus response. The increased specificity provided by homologous antigen quenching is likely to provide a significant improvement in sero-diagnostics and to be of clinical value.
The physiological response in the mammary gland to Escherichia coli infection reflects a conflict between glucose need for milk production and immune response
Authors: Blum Shlomo E. , Heller Dan E. , Jacoby Shamay , Krifucks Oleg , Merin Uzi , Silanikove Nissim , Leitner Gabriel
Published: April 2019

Upon entry into the mammary gland, mammary pathogenic strains of Escherichia coli rapidly grow using milk as a nutrient source, in a manner highly dependent on the expression of the ferric-dicitrate system by these bacteria. Intra-mammary challenge with distinct mammary pathogenic E. coli (MPEC) strains result in development of clinical acute mastitis, with peak bacterial counts in milk at 16-24 h post-challenged and profound immune changes found in the milk. The main biochemical changes measured in milk were partially in accord with lipopolysaccharide-induced mastitis, with increased glucose-6-phosphate and lactate dehydrogenase activity or prolonged lactate dehydrogenase, and Glu6P/Glu alterations. Changes also reflect physiological responses to inflammation in the mammary gland, as in the balance between aerobic and anaerobic metabolism (citrate to lactate ratios). Some alterations measured in milk resolved with days after challenge but other remained for above one month, regardless of bacterial clearance. The results suggest that E. coli mastitits can be divided into two stages: an acute, clinical phase, as an immediate response to bacterial infection in the mammary gland and a chronic phase, independent of bacteria clearance, and in response to the tissue damage caused in the first phase.