bluuebunny/crossref_metadata_2025 huggingface dataset:
Orbital Emphysema: A Case Report and Comprehensive Review of the Literature
Authors: Roelofs Kelsey A. , Starks Victoria , Yoon Michael K.
Published: August 2018

Purpose:

The objective of this study was to report a case of persistent and likely self-induced orbital emphysema (OE) following functional endoscopic sinus surgery with dislodgement of a previously placed orbital floor implant and to review the literature surrounding etiologies, pathophysiology, and management of OE.

Methods:

Case report and review of the literature.

Results and Discussion:

While blunt trauma resulting in disruption of the medial orbital wall is the most common cause of OE, there are an additional 25 underlying etiologies reported in the current literature. Pathophysiology of OE is somewhat dependent on underlying etiology but often involves a 1-way ball valve mechanism such that air may enter the orbit but not exit. When sufficient air enters the orbit, complications secondary to increased intraorbital pressure, including central retinal artery occlusion and compressive optic neuropathy, can occur. Mild cases of OE are typically observed, with most resolving within 7 to 10 days. Moderate cases are often managed by lateral canthotomy and cantholysis with possible needle decompression. Severe cases may require urgent surgical decompression. While the majority of cases of OE are benign and self-limited, there have been 4 reports in the literature documenting significant vision loss.

Conclusions:

Although there is often a history of trauma in patients presenting with OE, many other underlying etiologies have been reported with several cases occurring spontaneously. As such, OE should be included on the differential for a patient presenting with a sudden onset of orbital signs.
The onset of treatment with the antidepressant desipramine is critical for the emotional consequences of neuropathic pain
Authors: Alba-Delgado Cristina , Llorca-Torralba Meritxell , Mico Juan Antonio , Berrocoso Esther
Published: August 2018

Neuropathic pain is a chronic condition that is challenging to treat. It often produces considerable physical disability and emotional distress. Patients with neuropathic pain often experience depression and anxiety both of which are known to be temporally correlated with noradrenergic dysfunction in the locus coeruleus (LC) as pain becomes chronic. Antidepressants are the first-line drug therapy for neuropathic pain, and the LC represents a potential target for such therapy. In this study, we evaluated the efficacy of the tricyclic antidepressant desipramine (DMI, a noradrenaline reuptake inhibitor) in preventing or relieving the noradrenergic impairment induced by neuropathic pain. The treatment started before or after the onset of the anxiodepressive phenotype (“early or late treatment”) in adult rats subjected to chronic sciatic constriction. Electrophysiological and western blotting assays showed LC dysfunction (increased bursting activity, alpha2-adrenoceptor sensitivity, tyrosine hydroxylase, and noradrenaline transporter expression) in chronic constriction injury at long term. These noradrenergic changes were concomitant to the progression of anxiety and despair-like features. Desipramine induced efficient analgesia, and it counteracted the despair-like behavior in chronic constriction injury-DMI animals, reducing the burst rate and tyrosine hydroxylase expression. Surprisingly, “early” DMI treatment did not modify pain-induced anxiety, and it dampened pain aversion, although these phenomena were abolished when the treatment commenced after noradrenaline impairment had been established. Hence, DMI seems to produce different outcomes depending when the treatment commences, indicating that the balance between the benefits and adverse effects of DMI therapy may shift as neuropathy progresses.
Inhibition of spinal 15-LOX-1 attenuates TLR4-dependent, nonsteroidal anti-inflammatory drug–unresponsive hyperalgesia in male rats
Authors: Gregus Ann M. , Buczynski Matthew W. , Dumlao Darren S. , Norris Paul C. , Rai Ganesha , Simeonov Anton , Maloney David J. , Jadhav Ajit , Xu Qinghao , Wei Spencer C. , Fitzsimmons Bethany L. , Dennis Edward A. , Yaksh Tony L.
Published: August 2018

Although nonsteroidal anti-inflammatory drugs are the first line of therapeutics for the treatment of mild to moderate somatic pain, they are not generally considered to be effective for neuropathic pain. In the current study, direct activation of spinal Toll-like 4 receptors (TLR4) by the intrathecal (IT) administration of KDO2 lipid A (KLA), the active component of lipopolysaccharide, elicits a robust tactile allodynia that is unresponsive to cyclooxygenase inhibition, despite elevated expression of cyclooxygenase metabolites in the spinal cord. Intrathecal KLA increases 12-lipoxygenase-mediated hepoxilin production in the lumbar spinal cord, concurrent with expression of the tactile allodynia. The TLR4-induced hepoxilin production was also observed in primary spinal microglia, but not in astrocytes, and was accompanied by increased microglial expression of the 12/15-lipoxygenase enzyme 15-LOX-1. Intrathecal KLA-induced tactile allodynia was completely prevented by spinal pretreatment with the 12/15-lipoxygenase inhibitor CDC or a selective antibody targeting rat 15-LOX-1. Similarly, pretreatment with the selective inhibitors ML127 or ML351 both reduced activity of the rat homolog of 15-LOX-1 heterologously expressed in HEK-293T cells and completely abrogated nonsteroidal anti-inflammatory drug–unresponsive allodynia in vivo after IT KLA. Finally, spinal 12/15-lipoxygenase inhibition by nordihydroguaiaretic acid (NDGA) both prevents phase II formalin flinching and reverses formalin-induced persistent tactile allodynia. Taken together, these findings suggest that spinal TLR4-mediated hyperpathic states are mediated at least in part through activation of microglial 15-LOX-1.
Caring as Coercion: Exploring the Nurse's Role in Mandated Treatment
Authors: Jager Fiona , Perron Amélie
Published: August 2018

When nurses work in environments that have overlapping medical, legal, institutional, social, and therapeutic priorities, nursing care can become an effective tool in advancing the competing goals of these multiple systems. During the provision of patient care, nurses manage the tensions inherent in the competing priorities of these different systems, and skillful nursing can have the effect of rendering these tensions invisible. This puts nurses in an ethically complex position, where on one hand, their humanizing empathy has the potential to improve the delivery and effect of mandated care yet, on the other hand, their skillfulness can render invisible the weaknesses in medicolegal structures. In this article, we present a composite case study as a vehicle to illustrate the way this dilemma manifests in day-to-day nursing interactions and explore the potential of microethics to inform the everyday decisions of nurses delivering care-as-coercion.
Vitamin D deficiency in a European inflammatory bowel disease inception cohort: an Epi-IBD study
Authors: Chetcuti Zammit Stefania , Ellul Pierre , Girardin Giulia , Valpiani Daniela , Nielsen Kári R. , Olsen Jóngerð , Goldis Adrian , Lazar Daniela , Shonová Olga , Nováková Marie , Sebastian Shaji , Whitehead Emma , Carmona Amalia , Martinez-Cadilla Jesus , Dahlerup Jens F. , Kievit Adriana L.H. , Thorsgaard Niels , Katsanos Konstantinos H. , Christodoulou Dimitrios K. , Magro Fernando , Salupere Riina , Pedersen Natalia , Kjeldsen Jens , Carlsen Katrine , Ioannis Kaimaklioti , Bergemalm Daniel , Halfvarson Jonas , Duricova Dana , Bortlik Martin , Collin Pekka , Oksanen Pia , Kiudelis Gediminas , Kupcinskas Limas , Kudsk Karen , Andersen Vibeke , O’Morain Colm , Bailey Yvonne , Doron Schwartz , Shmuel Odes , Almer Sven , Arebi Naila , Misra Ravi , Čuković-Čavka Silvija , Brinar Marko , Munkholm Pia , Vegh Zsuzsanna , Burisch Johan
Published: August 2018

Background

Serum vitamin D level is commonly low in patients with inflammatory bowel disease (IBD). Although there is a growing body of evidence that links low vitamin D level to certain aspects of IBD such as disease activity and quality of life, data on its prevalence and how it varies across disease phenotype, smoking status and treatment groups are still missing.

Materials and methods

Patients diagnosed with IBD between 2010 and 2011 were recruited. Demographic data and serum vitamin D levels were collected. Variance of vitamin D level was then assessed across different treatment groups, disease phenotype, disease activity and quality of life scores.

Results

A total of 238 (55.9% male) patients were included. Overall, 79% of the patients had either insufficient or deficient levels of vitamin D at diagnosis. Patients needing corticosteroid treatment at 1 year had significantly lower vitamin D levels at diagnosis (median 36.0 nmol/l) (P=0.035). Harvey–Bradshaw Index (P=0.0001) and Simple Clinical Colitis Activity Index scores (P=0.0001) were significantly lower in patients with higher vitamin D level. Serum vitamin D level correlated significantly with SIBQ score (P=0.0001) and with multiple components of SF12. Smokers at diagnosis had the lowest vitamin D levels (vitamin D: 34 nmol/l;P=0.053).

Conclusion

This study demonstrates the high prevalence of low vitamin D levels in treatment-naive European IBD populations. Furthermore, it demonstrates the presence of low vitamin D levels in patients with IBD who smoke.
Effect of an Evidence-based Inpatient Tobacco Dependence Treatment Service on 1-Year Postdischarge Health Care Costs
Authors: Cartmell Kathleen B. , Dismuke Clara E. , Dooley Mary , Mueller Martina , Nahhas Georges J. , Warren Graham W. , Fallis Peter , Cummings K. Michael
Published: August 2018

Background:

In 2014, the Medical University of South Carolina (MUSC) implemented a Tobacco Dependence Treatment Service (TDTS) consistent with the Joint Commission (JC) standards recommending that hospitals screen patients for smoking, provide cessation support, and follow-up contact for relapse prevention within 1 month of discharge. We previously demonstrated that patients exposed to the MUSC TDTS were approximately half as likely to be smoking one month after discharge and 23% less likely to have a 30-day hospital readmission. This paper examines whether exposure to the TDTS influenced downstream health care charges 12 months after patients were discharged from the hospital.

Methods:

Data from MUSC’s electronic health records, the TDTS, and statewide health care utilization datasets (eg, hospitalization, emergency department, and ambulatory surgery visits) were linked to assess how exposure to the MUSC TDTS impacted health care charges. Total health care charges were compared for patients with and without TDTS exposure. To reduce potential TDTS exposure selection bias, propensity score weighting was used to balance baseline characteristics between groups. The cost of delivering the MUSC TDTS intervention was calculated, along with cost per smoker.

Results:

The overall adjusted mean health care charges for smokers exposed to the TDTS were $7299 lower than for those who did not receive TDTS services (P=0.047). The TDTS cost per smoker was modest by comparison at $34.21 per smoker eligible for the service.

Discussion:

Results suggest that implementation of a TDTS consistent with JC standards for smoking cessation can be affordably implemented and yield substantial health care savings that would benefit patients, hospitals, and insurers.
Current CPT Coding and Payment Policy Implications for Immunohistology Services
Authors: Myles Jonathan L. , Synovec Mark , Klemp Todd , Black-Schaffer William S.
Published: August 2018

Immunohistology is essential to the practice of modern surgical and cytopathology. There are 3 major types of immunohistologic services provided in clinical practice: traditional immunohistochemistry, morphometric analysis of tumor immunohistochemistry, and immunofluorescence. Proper Current Procedural Terminology coding for these services has been updated to reflect current medical practice. Subsequent to changes in the Current Procedural Terminology coding structure for these services, the valuation of these services have been reviewed by the American Medical Association/Specialty Society Relative Value Update Committee and new valuations instituted by the Centers for Medicare and Medicaid Services. Although valuations for services may be established, the circumstances of payment may be affected by Medicare Contractor’s Local Coverage Determinations or service limits imposed by the National Correct Coding Initiative.
Top Citations of Pediatric Emergency Medicine Publications in the Emergency Medicine Literature
Authors: Waseem Muhammad , Rodriguez Javier , Josephson Elaine
Published: August 2018

Objectives

The goal of this study was to identify and analyze the 100 most frequently cited journal articles pertaining to the field of pediatric emergency medicine (PEM) and published in emergency medicine (EM) peer-reviewed literature.

Methods

The 3 databases, Scopus Library, Google Scholar, and Web of Science, were subjected to a search by topic, keyword, and publication journal to identify the 100 most frequently cited articles addressing PEM issues in the EM literature. Our search included articles published beginning in 1983 and ending in 2016. Median citation frequency, study topics within the specialty of PEM, years of publication, and countries of origin were each compiled and analyzed. Mean citation frequencies were used to rank the articles, which accounted for differences in the results among the 3 databases. Once organized into a list of the 100 most often cited articles in PEM, those with an outcome of the same mean citation frequency were ranked in alphabetical order, according to the initial letter of last name of the first author of the publication.

Results

A ranking was created of the 100 most frequently cited articles in pediatric emergency medicine by the mean number of citations. Citation counts ranged from a high of 249 to a low of 71, with a median frequency of 101. The United States had 92 articles on the list, whereas the remainder was comprised of the following countries: Australia (3), Canada (3), Germany (1), and Spain (1). The most common topic areas (and their numbers) noted were related to resuscitation (23) and anesthesia (22). The most frequently cited 100 articles were all published between the years 1983 and 2010. Top publication years (and number of articles) included 2000 (11), 2002 (8), and 2003 (8). The years ranging from 1993 to 2005 covered 69% of published articles. Journals of publications (and article counts) wereAnnals of Emergency Medicine(69),Pediatric Emergency Care(15),Academic Emergency Medicine(12), andResuscitation(4).

Conclusions

This analysis provides a review of citation frequency of top-cited PEM articles published in EM journals. This determines the influence of these PEM publications on the EM specialty. The importance of education on resuscitation and anesthesia topics in PEM was evident. Most of the articles were published more than 10 to 15 years ago, indicating that they could be considered landmarks in the subspecialty of PEM. This signifies their importance to other authors in this field, who chose to cite them as having created a significant impact on their own publications.
Invasive Bacterial Infections in Infants Younger Than 60 Days With Skin and Soft Tissue Infections
Authors: Foradori Dana M. , Lopez Michelle A. , Hall Matt , Cruz Andrea T. , Markham Jessica L. , Colvin Jeffrey D. , Nead Jennifer A. , Queen Mary Ann , Raphael Jean L. , Wallace Sowdhamini S.
Published: August 2018

Objective

The objective of this study was to describe the frequency of invasive bacterial infections (IBIs) in young infants with skin and soft tissue infections (SSTIs) and the impact of IBI evaluation on disposition, length of stay (LOS), and cost.

Methods

This retrospective (2009–2014) cohort study used data from 35 children's hospitals in the Pediatric Health Information System. We included infants younger than 60 days who presented to an emergency department (ED) with SSTI. Invasive bacterial infection was defined as bacteremia/sepsis, bone/joint infection, or bacterial meningitis. Readmission and return ED visits within 30 days were evaluated to identify missed IBIs for infants.

Results

A total of 2734 infants were included (median age, 33 days; interquartile range [IQR], 21–44); 62% were hospitalized. Invasive bacterial infection was identified in 2%: bacteremia (1.8%), osteomyelitis (0.1%), and bacterial meningitis (0.1%). Hospitalization occurred in 78% of infants with blood cultures, 95% with cerebrospinal fluid cultures, and 23% without cultures. Median hospitalization LOS was 2 days (IQR, 1–3). Median cost was US $4943 for infants with cerebrospinal fluid cultures (IQR, US $3475–6780) compared with US $419 (IQR, US $215–1149) for infants without IBI evaluations (P < 0.001). Five infants (0.2%) returned to the ED within 30 days with new IBI diagnoses (4 bacteremia, 1 meningitis).

Conclusions

Invasive bacterial infection occurs infrequently in infants younger than 60 days who present to children's hospital EDs with SSTI. Bacteremia is the most common IBI. More extensive evaluation for IBI is associated with increased rate of admission, LOS, and cost. Further studies are needed to evaluate the safety of a limited IBI evaluation in young infants with SSTI.
Epidemiology of and Risk Factors for BK Polyomavirus Replication and Nephropathy in Pediatric Renal Transplant Recipients: An International CERTAIN Registry Study
Authors: Höcker Britta , Schneble Lukas , Murer Luisa , Carraro Andrea , Pape Lars , Kranz Birgitta , Oh Jun , Zirngibl Matthias , Dello Strologo Luca , Büscher Anja , Weber Lutz T. , Awan Atif , Pohl Martin , Bald Martin , Printza Nikoleta , Rusai Krisztina , Peruzzi Licia , Topaloglu Rezan , Fichtner Alexander , Krupka Kai , Köster Lennart , Bruckner Thomas , Schnitzler Paul , Hirsch Hans H. , Tönshoff Burkhard
Published: August 2018

Background.

BK polyomavirus-associated nephropathy (BKPyVAN) constitutes a serious cause of kidney allograft failure, but large-scale data in pediatric renal transplant recipients and a comprehensive analysis of specific risk factors are lacking.

Methods.

We analyzed the data of 313 patients in the Cooperative European Pediatric Renal Transplant Initiative Registry, with an observation period of 3.3 years (range, 1–5). The net state of immunosuppressive therapy was assessed by the modified Vasudev score.

Results.

Presumptive BKPyVAN (defined as sustained [>3 wk] high-level BK viremia >104 copies/mL) within 5 years posttransplant occurred in 49 (15.8%) of 311 patients, and biopsy-proven BKPyVAN in 14 (4.5%) of 313. BKPyV viremia was observed in 115 (36.7%) of 311 patients, of whom 11 (9.6%) of 115 developed viremia late, that is, after the second year posttransplant. In 6 (12.5%) of 48 patients with high-level viremia and in 3 (21.4%) of 14 with BKPyVAN, this respective event occurred late. According to multivariable analysis, BKPyV viremia and/or BKPyVAN were associated not only with a higher net state of immunosuppression (odds ratio [OR], 1.3; P < 0.01) and with tacrolimus-based versus ciclosporin-based immunosuppression (OR, 3.6; P < 0.01) but also with younger recipient age (OR, 1.1 per y younger; P < 0.001) and obstructive uropathy (OR, 12.4; P < 0.01) as primary renal disease.

Conclusions.

Uncontrolled BKPyV replication affects a significant proportion of pediatric renal transplant recipients and is associated with unique features of epidemiology and risk factors, such as young recipient age, obstructive uropathy, and overall intensity of immunosuppressive therapy. BKPyV surveillance should be considered beyond 2 years posttransplant in pediatric patients at higher risk.
A Gene Regulatory Model of Cortical Neurogenesis
Authors: Pfister Sabina S. , Hauri Andreas , Zubler Frederic , Michel Gabriela , Kennedy Henry , Dehay Colette , Douglas Rodney J.
Published: August 2018

Sparse data describing mouse cortical neurogenesis were used to derive a model gene regulatory network (GRN) that is then able to control the quantitative cellular dynamics of the observed neurogenesis. Derivation of the network begins by estimating from the biological data a set of cell states and transition probabilities necessary to explain neurogenesis. We show that the stochastic transition between states can be implemented by the dynamics of a GRN comprising only 36 abstract genes. Finally, we demonstrate using detailed physical simulations of cell mitosis, and differentiation that this GRN is able to steer a population of neuroepithelial precursors through mitotic expansion and differentiation to form the quantitatively correct complex multicellular architectures of mouse cortical areas 3 and 6. We find that the same GRN is able to generate both areas though modulation of only one gene, suggesting that arealization of the cortical sheet may require only simple improvisations on a fundamental gene network. We conclude that even sparse phenotypic and cell lineage data can be used to infer fundamental properties of neurogenesis and its organization.

1.

Highlights

Estimation of the cell states and transition probabilities of neurogenesis from experimental data.

Design of an abstract gene regulatory network (GRN) whose dynamics implement cell states and their stochastic transitions.

Detailed simulation of GRN-guided neurogenesis for mouse cortical areas 3 and 6.

Different dynamics of neurogenesis of distinct cortical areas arise through modulation of only a single gene.

2.

In brief

Pfister et al. show how sparse phenotypic and cell lineage data can be used to infer a small abstract gene regulatory network (GRN), which, when inserted into model precursor cells, is able to control in a distributed manner the quantitative cellular dynamics of neocortical neurogenesis.
Response Inhibition in Adolescents is Moderated by Brain Connectivity and Social Network Structure
Authors: Tompson Steven H. , Falk Emily B. , O’Donnell Matthew Brook , Cascio Christopher N. , Bayer Joseph B. , Vettel Jean M. , Bassett Danielle S.
Published: August 2018

Self-control is vital for a wide range of outcomes across our lifespan, yet the developmental trajectory of its core components during adolescence remains elusive. Many adolescents can successfully regulate their behavior even when they do not show strong activation in brain regions typically recruited during self-control in adults. Thus, adolescents may rely on other neural and cognitive resources to compensate, including daily experiences navigating and managing complex social relationships that likely bolster self-control processes. Here, we tested whether activity and connectivity in brain systems associated with social cognition (i.e., self-processing and mentalizing) facilitated successful self-control. We measured brain activity using fMRI as 62 adolescents completed a Go/No-Go response inhibition task. Recruitment of social brain systems, especially the self-processing system, was associated with better response inhibition in adolescents. Interestingly, the reliance on the self-processing system was stronger in adolescents with weaker activation in the canonical response inhibition system, suggesting a compensatory role for social brain systems during adolescent development. Furthermore, we examined the importance of social context by computing the size, number of communities, and modularity of our participants’ real-life social network. We found that adolescents with more friends and more communities in their social networks demonstrated a stronger relationship between response inhibition and recruitment of social brain systems. Collectively, our results identify the importance of social context and its moderating role on the relationship between brain activity and behavior. Furthermore, our results indicate a critical role for social brain systems during the developmental trajectory of self-control throughout adolescence.

Significance Statement

We employed a network neuroscience approach to investigate the role of social context and social brain systems in facilitating self-control in adolescents. We found that recruitment of social brain systems was associated with better response inhibition in adolescents, especially for adolescents with weaker activation in the response inhibition system. Moreover, adolescents with more friends and communities in their social networks showed stronger relationships between response inhibition and recruitment of social brain systems. Our results advance understanding of how brain systems facilitate self-control in adolescents, and how these brain responses are associated with features of an adolescent’s real-life social network. Bringing together findings related to brain networks and social networks provides key insights into how biology and environment mutually influence development.
Genome-wide patterns of gene expression in a wild primate indicate species-specific mechanisms associated with tolerance to natural simian immunodeficiency virus infection
Authors: Simons Noah D. , Eick Geeta N. , Ruiz-Lopez Maria J. , Hyeroba David , Omeja Patrick A. , Weny Geoffrey , Chapman Colin A. , Goldberg Tony L. , Zheng HaoQiang , Shankar Anupama , Switzer William M. , Frost Simon D.W. , Jones James H. , Sterner Kirstin N. , Ting Nelson
Published: August 2018

Over 40 species of nonhuman primates host simian immunodeficiency viruses (SIVs). In natural hosts, infection is generally assumed to be nonpathogenic due to a long coevolutionary history between host and virus, although pathogenicity is difficult to study in wild nonhuman primates. We used whole-blood RNA-seq and SIV prevalence from 29 wild Ugandan red colobus (Piliocolobus tephrosceles) to assess the effects of SIV infection on host gene expression in wild, naturally SIV-infected primates. We found no evidence for chronic immune activation in infected individuals, suggesting that SIV is not immunocompromising in this species, in contrast to HIV in humans. Notably, an immunosuppressive gene, CD101, was upregulated in infected individuals. This gene has not been previously described in the context of nonpathogenic SIV infection. This expands the known variation associated with SIV infection in natural hosts, and may suggest a novel mechanism for tolerance of SIV infection in the Ugandan red colobus.
Glenohumeral Injection Using Anatomic Landmark Versus Sonographic Needle Guidance
Authors: Moore Timothy S. , Paffett Cole L. , Sibbitt Wilmer L. , Hayward William A. , Gibb James I. , Kettwich Selma D. , Fields Roderick A. , Emil N. Suzanne , Fangtham Monthida , Bankhurst Arthur D
Published: August 2018

Objective

We hypothesized ultrasound (US) guidance improves outcomes of corticosteroid injection of the painful shoulder.

Methods

30 patients with symptomatic shoulders due to osteoarthritis were randomized to glenohumeral injection with 3 milliliters of 1% lidocaine and 60 mg of triamcinolone acetonide using the anterior approach with 1) conventional anatomic landmark palpation-guidance or 2) US-guidance. Injection pain (visual analogue pain scale (VAS)), pain at outcome (2 weeks and 6 months), therapeutic duration, time-to-next-injection, and costs were determined.

Results

Injection pain was less with US (VAS: 0.3±0.6 cm) vs. landmark-guidance (VAS: 1.4±2.4 cm, 95% CI of difference: 0.5<1.1<1.7, p=0.05). Pain scores were similar at 2 weeks: US: 2.2±2.4 cm; Landmark: 1.8±2.7 cm, 95% CI of difference: −2.2<−0.4<1.4, p=0.66 and 6 months: US: 5.8±2.8 cm; Landmark: 6.4±2.9 cm, 95% CI of difference: −0.4<0.6< 1.1, p =0.71. Therapeutic duration (US: 3.9±1.5 months; Landmark: 3.0±1.2 months, 95% CI of difference: − 1.4 <−0.9<−0.4, p=0.045) and time-to-next-injection (US: 8.1±3.5 months; Landmark: 5.7±2.9 months, 95% CI of difference: −3.6<−2.4<−1.3, p=0.025) were longer, and fewer injections per year (29% less) were required: US: 1.5±0.2 injections/year; Landmark: 2.1±0.2 injections/year (p<0.037; 95% CI of difference −0.9<−0.6<−0.3). However, cost/patient/year was modestly greater with US (US: $318±89, Landmark: $301±67; p=0.28).

Conclusion

Anatomic landmark guidance in the short-term is equally effective as US for injection of the osteoarthritic shoulder and modestly less costly, however, US may reduce the need for repetitive injections by prolonging the therapeutic effect and thus time to next injection.

IRB Statement

This project was in compliance with the Helsinki Declaration, was approved by the Institutional Review Board (IRB) as ultrasound subset of a syringe safety trial (Human Research Review Committee approval 04-347), and was registered at ClinicalTrials.gov (Clinical Trial Identifier NCT00651625). The subjects gave informed consent to participate prior to all studies and interventions. Patient confidentiality was protected according to the U.S. Health Insurance Portability and Accountability Act (HIPAA) and all data was de-identified.
Probabilistic modeling of personalized drug combinations from integrated chemical screen and molecular data in sarcoma
Authors: Berlow Noah E. , Rikhi Rikhi , Geltzeiler Mathew N. , Abraham Jinu , Svalina Matthew N. , Davis Lara E. , Wise Erin , Mancini Maria , Noujaim Jonathan , Mansoor Atiya , Quist Michael J. , Matlock Kevin L. , Goros Martin W. , Hernandez Brian S. , Doung Yee C. , Thway Khin , Tsukahara Tomohide , Nishio Jun , Huang Elaine C. Huang , Airhart Susan , Bult Carol J. , Gandour-Edwards Regina , Maki Robert G. , Jones Robin L. , Michalek Joel E. , Milovancev Milan , Ghosh Souparno , Pal Ranadip , Keller Charles
Published: August 2018

Cancer patients with advanced disease exhaust available clinical regimens and lack actionable genomic medicine results, leaving a large patient population without effective treatments options when their disease inevitably progresses. To address the unmet clinical need for evidence-based therapy assignment when standard clinical approaches have failed, we have developed a probabilistic computational modeling approach which integrates sequencing data with functional assay data to develop patient-specific combination cancer treatments. This computational modeling approach addresses three major challenges in personalized cancer therapy, which we validate across multiple species via computationally-designed personalized synergistic drug combination predictions, identification of unifying therapeutic targets to overcome intra-tumor heterogeneity, and mitigation of cancer cell resistance and rewiring mechanisms. These proof-of-concept studies support the use of an integrative functional approach to personalized combination therapy prediction for the population of high-risk cancer patients lacking viable clinical options and without actionable DNA sequencing-based therapy.
Defining the core essential genome ofPseudomonas aeruginosa
Authors: Poulsen Bradley E. , Yang Rui , Clatworthy Anne E. , White Tiantian , Osmulski Sarah J. , Li Li , Penaranda Cristina , Lander Eric S. , Shoresh Noam , Hung Deborah T.
Published: August 2018

Genomics offered the promise of transforming antibiotic discovery by revealing many new essential genes as good targets, but the results fell short of the promise. It is becoming clear that a major limitation was that essential genes for a bacterial species were often defined based on a single or limited number of strains grown under a single or limited number ofin vitrolaboratory conditions. In fact, the essentiality of a gene can depend on both genetic background and growth condition. We thus developed a strategy for more rigorously defining the core essential genome of a bacterial species by studying many pathogen strains and growth conditions. We assessed how many strains must be examined to converge on a set of core essential genes for a species. We used transposon insertion sequencing (Tn-Seq) to define essential genes in nine strains ofPseudomonas aeruginosaon five different media and developed a novel statistical model,FiTnEss, to classify genes as essential versus non-essential across all strain-media combinations. We defined a set of 321 core essential genes, representing 6.6% of the genome. We determined that analysis of 4 strains was typically sufficient inP. aeruginosato converge on a set of core essential genes likely to be essential across the species across a wide range of conditions relevant toin vivoinfection, and thus to represent attractive targets for novel drug discovery.
Systems therapeutics analyses identify genomic signatures defining responsiveness to allopurinol and combination therapy for lung cancer
Authors: Tavassoly Iman , Hu Yuan , Zhao Shan , Mariottini Chiara , Boran Aislyn , Chen Yibang , Li Lisa , Tolentino Rosa E. , Jayaraman Gomathi , Goldfarb Joseph , Gallo James , Iyengar Ravi
Published: August 2018

The ability to predict responsiveness to drugs in individual patients is limited. We hypothesized that integrating molecular information from databases would yield predictions that could be experimentally tested to develop genomic signatures for sensitivity or resistance to specific drugs. We analyzed TCGA data for lung adenocarcinoma (LUAD) patients and identified a subset where xanthine dehydrogenase expression correlated with decreased survival. We tested allopurinol, a FDA approved drug that inhibits xanthine dehydrogenase on a library of human Non Small Cell Lung Cancer (NSCLC) cell lines from CCLE and identified sensitive and resistant cell lines. We utilized the gene expression profiles of these cell lines to identify six-gene signatures for allopurinol sensitive and resistant cell lines. Network building and analyses identified JAK2 as an additional target in allopurinol-resistant lines. Treatment of resistant cell lines with allopurinol and CEP-33779 (a JAK2 inhibitor) resulted in cell death. The effectiveness of allopurinol alone or allopurinol and CEP-33779 were verified in vivo using tumor formation in NCR-nude mice. We utilized the six-gene signatures to predict five additional allopurinolsensitive NSCLC lines, and four allopurinol-resistant lines susceptible to combination therapy. We found that drug treatment of all cell lines yielded responses as predicted by the genomic signatures. We searched the library of patient derived NSCLC tumors from Jackson Laboratory to identify tumors that would be predicted to be sensitive or resistant to allopurinol treatment. Both patient derived tumors predicted to be allopurinol sensitive showed the predicted sensitivity, and the predicted resistant tumors were sensitive to combination therapy. These data indicate that we can use integrated molecular information from cancer databases to predict drug responsiveness in individual patients and thus enable precision medicine.
Orientation processing by synaptic integration across first-order tactile neurons
Authors: Hay Etay , Pruszynski J Andrew
Published: August 2018

Our ability to manipulate objects relies on tactile inputs from first-order tactile neurons that innervate the glabrous skin of the hand. The distal axon of these neurons branches in the skin and innervates many mechanoreceptors, yielding spatially-complex receptive fields. Here we show that synaptic integration across the complex signals from the first-order neuronal population could underlie human ability to accurately (< 3°) and rapidly process the orientation of edges moving across the fingertip. We first derive spiking models of human first-order tactile neurons that fit and predict responses to moving edges with high accuracy. We then use the model neurons in simulating the peripheral neuronal population that innervates a fingertip. We use machine learning to train classifiers performing synaptic integration across the neuronal population activity, and show that synaptic integration across first-order neurons can process edge orientations with high acuity and speed. In particular, our models suggest that integration of fast-decaying (AMPA-like) synaptic inputs within short timescales is critical for discriminating fine orientations, whereas integration of slow-decaying (NMDA-like) synaptic inputs refine discrimination and maintain robustness over longer timescales. Taken together, our results provide new insight into the computations occurring in the earliest stages of the human tactile processing pathway and how they may be critical for supporting hand function.

Author Summary

Our ability to manipulate objects relies on tactile inputs signaled by first-order neurons that innervate mechanoreceptors in the skin of the hand and have spatially-complex receptive fields. Here we show how synaptic integration across the rich inputs from first-order neurons can rapidly and accurately process the orientation of edges moving across the fingertip. We derive spiking models of human first-order tactile neurons, then use the models to simulate the peripheral neuronal population that innervates a fingertip. We use machine learning to train classifiers performing synaptic integration across the neuronal population activity, and show that synaptic integration across first-order neurons could underlie human ability to process edge orientations with high acuity and speed.
Confidence in predicted position error explains saccadic decisions during pursuit
Authors: Coutinho Jonathan D , Lefèvre Philippe , Blohm Gunnar
Published: August 2018

A fundamental problem in motor control is the coordination of complementary movement types to achieve a common goal. As a common example, humans view moving objects through coordinated pursuit and saccadic eye movements. Pursuit is initiated and continuously controlled by retinal image velocity. During pursuit, eye position may lag behind the target. This can be compensated by the discrete execution of a catch-up saccade. The decision to trigger a saccade is influenced by both position and velocity errors and the timing of saccades can be highly variable. The observed distributions of saccade occurrence and trigger time remain poorly understood and this decision process remains imprecisely quantified. Here we propose a predictive, probabilistic model explaining the decision to trigger saccades during pursuit to foveate moving targets. In this model, expected position error and its associated uncertainty are predicted through Bayesian inference across noisy, delayed sensory observations (Kalman filtering). This probabilistic prediction is used to estimate the confidence that a saccade is needed (quantified through log-probability ratio), triggering a saccade upon accumulating to a fixed threshold. The model qualitatively explains behavioural observations on the probability of occurrence and trigger time distributions of saccades during pursuit over a range of target motion trajectories. Furthermore, this model makes novel predictions about the influence of sensory uncertainty and target motion parameters on saccade decisions. We suggest that this predictive, confidence-based decision making strategy represents a fundamental principle for the probabilistic neural control of coordinated movements.

New & Noteworthy

This is the first stochastic dynamical systems model of pursuit-saccade coordination accounting for noise and delays in the sensorimotor system. The model uses Bayesian inference to predictively estimate visual motion, triggering saccades when confidence in predicted position error accumulates to a threshold. This model explains saccade probability and trigger time distributions across target trajectories and makes novel predictions about the influence of sensory uncertainty in saccade decisions during pursuit.
Antibacterial activity ofActinomycetesisolated from the soil sample of South India and polyketide synthase gene identification
Authors: Srivastava Ashu , Shanmugaiah Vellasamy
Published: August 2018

TheStreptomycesgenus is well studied owing to its capacity in producing more than 70% of antibiotics. This study was undertaken to characterizeStreptomycesstrains, occurring in soils of different districts of Tamilnadu, India as well as to evaluate their potential to produce antimicrobial compounds. Samples were collected from rice rhizosphere from different district of Tamilnadu agricultural zone. In primary screening by cross streak method,Streptomyces strainswere assessed for antibiotic production and activity against different human bacterial. Then active isolates were selected for secondary screening by agar well diffusion method. Solvent extraction method was used to identify the best crude samples which are exhibiting better antibacterial activity. Then, 16S rRNA PCR was carried out for confirmation of isolates. In primary screening among all of the isolates, 50% isolates were active against at least one of the test organisms and 21.31% strains exhibited a broad-spectrum activity against almost all of the test bacteria. The minimum inhibitory concentrations (MICs) of the ethyl acetate extracts measured. Out of 26 positive strains two of the most active isolates SVG-07-15 and TK-01-05 were taken for further studies. These results highlight the importance ofStreptomycesisolates in antibiotic production. Together with antibacterial activity, the PKS gene based approach can be applied for efficient screening of isolated strains of pharmaceutical value and related compounds.

Highlights

Isolation of actinomycetes from soil samples collected from South India.

Screening of isolated actinomycetes for antibacterial activity

Details study of potent strains against human pathogens

Identification of PKS gene from the active strains
Dynamic regulation of HYL1 provides new insights into its multifaceted role in Arabidopsis
Authors: Bhagat Prakash Kumar , Verma Deepanjali , Badmi Raghuram , Sinha Alok Krishna
Published: August 2018

MicroRNAs (miRNAs) are 21 to 24 nucleotide non-coding RNAs that regulate gene expression. Biogenesis of miRNAs is fine-tuned by specialized microprocessor complex, the regulation of which is being continuously understood. Recruitment of HYL1 to the microprocessor complex is crucial for accurate primary-miRNA (pri-miRNA) processing and accumulation of mature miRNA inArabidopsis thaliana. HYL1 is a double-stranded RNA binding protein also termed as DRB1, has two double-stranded RNA binding domain at N-terminal and a highly disordered C-terminal region. Also, the biological activity of HYL1 is dynamically regulated through transition from hyperphosphorylation to hypophosphorylation state. HYL1 is known to be phosphorylated by a MAP kinase MPK3 and SnRK2. However, the precise role of its phosphorylation are still unknown. Recently, the stability of HYL1 protein has been shown to be regulated by an unknown protease X. However, the identity of the protease and its molecular mechanisms are poorly understood. Here, we describe, three functionally important facets of HYL1, which provide a better picture of its association with molecular processes. First, we identified a conserved MPK3 phosphorylation site on HYL1 and its possible role in the miRNA biogenesis. Secondly, the C-terminal region of HYL1 displays tendencies to bind dsDNA. Lastly, the role of C-terminal region of HYL1 in the regulation of its protein stability and the regulation of miRNA biogenesis is documented. We show the unexplored role of C-terminal and hypothesize the novel functions of HYL1 in addition to miRNA biogenesis. We anticipate that the data presented in this study, will open a new dimension of understanding the role of double stranded RNA binding proteins in diverse biological processes of plants and animal.
A Latent Allocation Model for the Analysis of Microbial Composition and Disease
Authors: Abe Ko , Hirayama Masaaki , Ohno Kinji , Shimamura Teppei
Published: August 2018

Background

Establishing the relationship between microbiota and specific disease is important but requires appropriate statistical methodology. A specialized feature of microbiome count data is the presence of a large number of zeros, which makes it difficult to analyze in case-control studies. Most existing approaches either add a small number called a pseudo-count or use probability models such as the multinomial and Dirichlet-multinomial distributions to explain the excess zero counts, which may produce unnecessary biases and impose a correlation structure taht is unsuitable for microbiome data.

Results

The purpose of this article is to develop a new probabilistic model, called BERMUDA (BERnoulli and MUltinomial Distribution-based latent Allocation), to address these problems. BERMUDA enables us to describe the differences in bacteria composition and a certain disease among samples. We also provide a simple and efficient learning procedure for the proposed model using an annealing EM algorithm.

Conclusion

We illustrate the performance of the proposed method both through both the simulation and real data analysis. BERMUDA is implemented with R and is available from GitHub (https://github.com/abikoushi/Bermuda).
Pyrite formation from FeS and H2S is mediated by a novel type of microbial energy metabolism
Authors: Thiel Joana , Byrne James , Kappler Andreas , Schink Bernhard , Pester Michael
Published: August 2018

The exergonic reaction of FeS with H2S to form FeS2(pyrite) and H2was postulated to have operated as an early form of energy metabolism on primordial Earth. Since the Archean, sedimentary pyrite formation played a major role in the global iron and sulfur cycles, with direct impact on the redox chemistry of the atmosphere. To date, pyrite formation was considered a purely geochemical reaction. Here, we present microbial enrichment cultures, which grew with FeS, H2S, and CO2as their sole substrates to produce FeS2and CH4. Cultures grew over periods of three to eight months to cell densities of up to 2–9×106cells mL−1. Transformation of FeS with H2S to FeS2was followed by57Fe Mössbauer spectroscopy and showed a clear biological temperature profile with maximum activity at 28°C and decreasing activities towards 4°C and 60°C. CH4was formed concomitantly with FeS2and exhibited the same temperature dependence. Addition of either penicillin or 2-bromoethanesulfonate inhibited both FeS2and CH4production, indicating a syntrophic coupling of pyrite formation to methanogenesis. This hypothesis was supported by a 16S rRNA gene-based phylogenetic analysis, which identified at least one archaeal and five bacterial species. The archaeon was closely related to the hydrogenotrophic methanogenMethanospirillum stamsiiwhile the bacteria were most closely related to sulfate-reducingDeltaproteobacteria, as well as unculturedFirmicutesandActinobacteria. We identified a novel type of microbial metabolism able to conserve energy from FeS transformation to FeS2, which may serve as a model for a postulated primordial iron-sulfur world.

Significance statement

Pyrite is the most abundant iron-sulfur mineral in sediments. Over geological times, its burial controlled oxygen levels in the atmosphere and sulfate concentrations in seawater. Its formation in sediments is so far considered a purely geochemical process that is at most indirectly supported by microbial activity. We show that lithotrophic microorganisms can directly transform FeS and H2S to FeS2and use this exergonic reaction as a novel form of energy metabolism that is syntrophically coupled to methanogenesis. Our results provide insights into a syntrophic relationship that could sustain part of the deep biosphere and lend support to the iron-sulfur-world theory that postulated FeS transformation to FeS2as a key energy-delivering reaction for life to emerge.