bluuebunny/crossref_metadata_2025 huggingface dataset:
Integrin β3 Modulates TLR4-Mediated Inflammation by Regulation of CD14 Expression in Macrophages in Septic Condition
Authors: Chen Zhixia , Wang Shuang , Chen Yihui , Shao Zhenzhen , Yu Zhuang , Mei Shuya , Li Quan
Published: May 2019

Sepsis is a major challenge in clinical practice and responsible for high mortality. Recent studies indicated that integrins participated in toll-like-receptor (TLR)-mediated innate immunity. In the present study, we investigated the mechanism of integrin β3 and TLR4 signaling using a cecal ligation and puncture (CLP)-induced sepsis and lipopolysaccharide (LPS)-treated macrophage cell model. In a lethal CLP model, the survival rate of integrin β3-/- mice was higher than that of wild-type mice. The levels of alanine aminotransferase, aspartate transaminase, creatinine, blood urea nitrogen , and lactate dehydrogenase in the serum and cluster of differentiation 14 (CD14) protein expression in the tissues were significantly decreased in integrin β3-/- mice. A similar effect with regard to CD14 down-regulation was observed in septic TLR4-/- mice. In wild-type macrophages, the inhibition of integrin β3 by P11 or with a specific antibody, inhibited TNF-α, and IL-6 release at the early time period of LPS stimulation. However, during the late periods of LPS stimulation this effect was not noted. CD14 expression levels had no change in such treatment. In contract, LPS-induced TNF-α and IL-6 release and LPS-induced CD14 expression were significantly decreased in integrin β3-/-macrophages. The inhibition of the TLR4 pathway by TAK-242, or in TLR4 mutant macrophages abolished LPS-induced CD14 expression. Integrin β3 pathway activation by vitronectin exhibited no effect in CD14 expression. Furthermore, recombinant CD14 protein stimulation reversed integrin β3 deficiency and caused lower TNF-α and IL-6 release. Moreover, the molecular interaction of TLR4 and integrin β3 was significantly increased following LPS stimulation. In conclusion, integrin β3 positively regulated TLR4-mediated inflammatory responses via CD14 expression in macrophages in septic condition. Specifically targeting integrin β3/TLR4-CD14 signaling pathway may be a potential treatment strategy for polymicrobial sepsis.
Nicotine Improves Survivability, Hypotension, and Impaired Adenosinergic Renal Vasodilations in Endotoxic Rats: Role of α7-nAChRs/HO-1 Pathway
Authors: Wedn Abdalla M. , El-Gowilly Sahar M. , El-Mas Mahmoud M.
Published: May 2019

The nicotinic/cholinergic antiinflammatory pathway protects against acute kidney injury and other end-organ damages induced by endotoxemia. In this study, we tested the hypothesis that functional α7-nAChRs/heme oxygenase-1 (HO-1) pathway is imperative for the nicotine counteraction of hemodynamic and renovascular dysfunction caused by acute endotoxemia in rats. Renal vasodilations were induced by cumulative bolus injections of acetylcholine (ACh, 0.01 nmol–7.29 nmol) or ethylcarboxamidoadenosine (NECA, adenosine receptor agonist, 1.6 nmol–100 nmol) in isolated phenylephrine-preconstricted perfused kidneys. The data showed that 6-h treatment with lipopolysaccharide (LPS, 5 mg/kg i.p.) decreased systolic blood pressure and renal vasodilations caused by NECA but not Ach. The endotoxic insult also increased the mortality rate and elevated serum urea and creatinine. These LPS effects were sex-unrelated, except hypotension, and enhanced mortality which were more evident in male rodents, and abrogated after co-administration of nicotine (0.5, 1 mg/kg and 2 mg/kg) in a dose-dependent fashion. The advantageous effects of nicotine on NECA vasodilations, survivability, and kidney biomarkers in endotoxic male rats disappeared upon concurrent exposure to methyllycaconitine citrate (α7-nAChR blocker) or zinc protoporphyrin (HO-1 inhibitor) and were reproduced after treatment with bilirubin, but not hemin (HO-1 inducer) or tricarbonyldichlororuthenium (II) dimer (carbon monoxide-releasing molecule). Together, current biochemical and pharmacological evidence suggests key roles for α7-nAChRs and the bilirubin byproduct of the HO-1 signaling in the nicotine counteraction of renal dysfunction and reduced adenosinergic renal vasodilator capacity in endotoxic rats.
Postconditioning with Calreticulin Attenuates Myocardial Ischemia/Reperfusion Injury and Improves Autophagic Flux
Authors: Wang Jian-Li , Li Yu-Zhen , Tao Tian-Qi , Wang Xiao-Reng , Wang You , Song Dan-Dan , Liu Xiu-Hua
Published: May 2019

Background:

Impaired autophagic flux contributes to cardiomyocyte death in ischemia/reperfusion (I/R) injury. Restoring the impaired autophagic flux by using agents may be a promising strategy that alleviates myocardial I/R injury. The present study aimed to evaluate the effect of exogenous calreticulin (CRT) postconditioning on impaired autophagic flux induced by hypoxia/reoxygenation (H/R) injury in H9c2 cells.

Methods:

Rat myocardial I/R injury model was prepared. CRT postconditionging was fulfilled by an intraperitoneal injection of CRT (0.5 mg/kg body weight) 5 min before reperfusion. Hemodynamics, serum lactate dehydrogenase (LDH) activity and Cardiac troponin T (TnT) content, and infarct size were measured. The H/R injury model of H9c2 cells was prepared. CRT postconditioning was performed by adding 25 pg/mL CRT to the medium at the onset of reoxygenation. Cell death rate, lactate dehydrogenase (LDH) leakage, intracellular reactive oxygen species (ROS), and malondialdehyde (MDA) were assessed. Autophagic flux was monitored by mRFP-GFP-LC3 adenovirus infection. The number of autophagosomes and autolysosomes in cells were determined by counting the fluorescence dots. Western blot assay was used to determine the expression of autophagy-related proteins.

Results:

CRT postconditionging improved cardiac function, reduced serum LDH activity and TnT content, and limited myocardial infarct size after myocardial I/R injury in rat. H/R induced H9c2 cells injury and autophagosomes accumulation in cells. CRT postconditioning attenuated H/R-induced cell death, LDH leakage, and the increase of intracellular ROS and MDA. Meanwhile, CRT postconditioning suppressed H/R-induced excessive formation of autophagosomes, as shown by a decrease of autophagosomes and the ratio of LC3-II/LC3-I, LC3-II, and Beclin1. It also improved H/R-induced impaired autophagosomes clearance, as shown by an increase of autolysosomes and the level of LAMP-2, and a decrease of the level of p62.

Conclusion:

These findings suggested that CRT postconditioning reduced myocardial I/R injury. CRT postconditioning also inhibited the excessive formation of autophagosomes, promoted the clearance of autophagosomes, and resorted the autophagic flux, consequently reduced the H/R injury in H9c2 cells.
Improving Reproducibility and Transparency in Shock: the Arrive Guidelines Need Better Implementation and Enforcement
Authors: Reynolds Penny S.
Published: May 2019

Reporting standards for animal research in Shock have not improved since Shock Society endorsed the ARRIVE guidelines in 2012. Particularly troubling is the omission of key information describing methodological quality and animal welfare. Both investigators and journal reviewers are strongly encouraged to actively consult the checklist to improve manuscript quality, and ensure that Shock upholds the highest standards of research quality and the humane treatment of animals.
Simulation-Based Event Analysis Improves Error Discovery and Generates Improved Strategies for Error Prevention
Authors: Lobos Anna-Theresa , Ward Natalie , Farion Ken J. , Creery David , Fitzgibbons Colleen , Ramsay Christa , Hogue Melanie , Langevin Mélissa
Published: May 2019

Introduction

An adverse event (AE) is a negative consequence of health care that results in unintended injury or illness. The study investigates whether simulation-based event analysis is different from traditional event analysis in uncovering root causes and generating recommendations when analyzing AEs in hospitalized children.

Methods

Two simulation scenarios were created based on real-life AEs identified through the hospital's Safety Reporting System. Scenario A involved an error of commission (inpatient drug error) and scenario B involved detecting an error that already occurred (drug infusion error). Each scenario was repeated 5 times with different, voluntary clinicians. Content analysis, using deductive and inductive approaches to coding, was used to analyze debriefing data. Causes and recommendations were compiled and compared with the traditional event analysis.

Results

Errors were reproduced in 60% (3/5) of scenario A. In scenario B, participants identified the error in 100% (5/5) of simulations (average time to error detection = 15 minutes). Debriefings identified reasons for errors including product labeling, memory aid interpretation, and lack of standard work for patient handover. To prevent error, participants suggested improved drug labeling, specialized drug kits, alert signs, and handoff checklists. Compared with traditional event analysis, simulation-based event analysis revealed unique causes for error and new recommendations.

Conclusions

Using simulation to analyze AEs increased unique error discovery and generated new recommendations. This method is different from traditional event analysis because of the immediate clinician debriefings in the clinical environment. Hospitals should consider simulation-based event analysis as an important addition to the traditional process.
Comparing the Learning Effectiveness of Healthcare Simulation in the Observer Versus Active Role: Systematic Review and Meta-Analysis
Authors: Delisle Megan , Ward Mellissa A. R. , Pradarelli Jason C. , Panda Nikhil , Howard Jeffery D. , Hannenberg Alexander A.
Published: May 2019

Summary Statement

The benefits of observation in simulation-based education in healthcare are increasingly recognized. However, how it compares with active participation remains unclear. We aimed to compare effectiveness of observation versus active participation through a systematic review and meta-analysis. Effectiveness was defined using Kirkpatrick's 4-level model, namely, participants' reactions, learning outcomes, behavior changes, and patient outcomes. The peer-reviewed search strategy included 8 major databases and gray literature. Only randomized controlled trials were included. A total of 13 trials were included (426 active participants and 374 observers). There was no significant difference in reactions (Kirkpatrick level 1) to training between groups, but active participants learned (Kirkpatrick level 2) significantly better than observers (standardized mean difference = −0.2, 95% confidence interval = −0.37 to −0.02, P = 0.03). Only one study reported behavior change (Kirkpatrick level 3) and found no significant difference. No studies reported effects on patient outcomes (Kirkpatrick level 4). Further research is needed to understand how to effectively integrate and leverage the benefits of observation in simulation-based education in healthcare.
Reducing Perineal Lacerations Through Team-Based Simulation
Authors: Marko Emily K. , Fausett Merlin B. , Deering Shad , Staat Barton C. , Stormes Stephanie , Freund Elizabeth , Maxwell G. Larry
Published: May 2019

Introduction

Vaginal deliveries that result in perineal trauma involve significant morbidity to women. Multiple strategies have been identified to reduce the risk of severe perineal lacerations. The objective of this study was to evaluate the effectiveness of an interprofessional simulation-based teams-training program aimed at reducing severe perineal lacerations during childbirth.

Methods

A quasi-experimental pre-post single-group design was used to examine the performance of labor and delivery personnel at a large multihospital system after participating in a mixed-modality simulation program for reducing perineal lacerations. Multiple educational strategies aimed at management of second stage of labor (including laboring down, warm compresses, coaching, positioning, perineal support, controlled delivery of fetal head, and mediolateral episiotomy techniques) were taught using patients, task trainers, and a standardized curriculum during interprofessional educational sessions. Primary study outcomes were as follows: (a) pre-post differences in knowledge; (b) pre-post differences in team performance assessments; and (c) pre-post differences in safety culture. Secondary outcomes were severe perineal laceration rates.

Results

During an 18-month period, 675 personnel in 4 hospitals participated in the program. Significant improvement was noted in pre-post scores of knowledge (59.86%, 93.87%, P < 0.0001), performance (36.54%, 93.45%, P < 0.0001), and safety culture (3.24, 1.45, 1 = high, 5 = low, P < 0.0001). Severe perineal laceration rates decreased by 33.38% since initiation. Rates fluctuated with the addition of new personnel and renewed educational programs.

Conclusions

A multimodal interprofessional simulation program of strategies to prevent severe perineal lacerations significantly improved knowledge, skills, and attitudes in labor and delivery personnel within a healthcare system. Severe perineal laceration rates were reduced.
Comparison of the Effects of Midazolam/Fentanyl, Midazolam/Propofol, and Midazolam/Fentanyl/Propofol on Cognitive Function After Gastrointestinal Endoscopy
Authors: Thompson Russell , Seck Victor , Riordan Stephen , Wong Shing
Published: May 2019

Background:

Drugs used for sedation/analgesia during gastrointestinal (GI) endoscopy, including midazolam, fentanyl, and propofol, result in short-term, reversible decline in cognitive function. This prospective cohort trial aimed to identify the sedative/analgesic regimen associated with the least impairment of cognition at the time of discharge.

Methods:

Patients undergoing elective GI endoscopy were included. Patients investigated at the Prince of Wales Hospital, Sydney, received midazolam/fentanyl (M/F), whereas patients investigated at the Prince of Wales Private Hospital, Sydney, received midazolam/fentanyl/propofol (M/F/P) or midazolam/propofol (M/P). Patients underwent a computerized neurocognitive test, the CogState Brief Battery, before sedation and at discharge.

Results:

Patients in the M/F group who received gastroscopy (n=22) were administered midazolam 3.36 mg (±0.79 mg) and fentanyl 61.36 μg (±16.77 μg), those who received colonoscopy (n=50) were administered midazolam 3.98 mg (±1.06 mg) and fentanyl 74.50 μg (±24.48 μg), and those who received gastroscopy/colonoscopy (n=28) were administered midazolam 4.82 mg (±1.41 mg) and fentanyl 94.64 μg (±24.35 μg). Patients in the M/F/P group who received colonoscopy (n=45) were administered midazolam 2.77 mg (±0.55 mg), fentanyl 45.11 μg (±25.78 μg), and propofol 148.64 mg (±57.65 mg), and those who received gastroscopy/colonoscopy (n=36) were administered midazolam 2.64 mg (±0.472 mg), fentanyl 35.28 μg (±19.16 μg), and propofol 168.06 mg (±60.75 mg). Nineteen patients in the M/P group who received gastroscopy (n=19) were administered midazolam 2.37 mg (±0.04 mg) and propofol 13.68 mg (±37.74 mg). Neurocognitive scores were significantly lower in the postprocedure test compared with baseline scores for detection, identification, and one card learning (P<0.001). Postprocedure detection test scores were significantly impaired in the M/F group compared with the M/F/P and M/P groups. Predictors of poorer neurocognitive function were midazolam dosage >3 mg (P<0.006) and fentanyl dosage >50 μg (P<0.009).

Conclusion:

The use of propofol in GI endoscopy allows for less exposure to midazolam and fentanyl and is associated with improved cognition at the time of discharge.
Totally Extraperitoneal Repair in Inguinal Hernia: More Than a Decade’s Experience at a Tertiary Care Hospital
Authors: Krishna Asuri , Bansal Virinder K. , Misra Mahesh C. , Prajapati Omprakash , Kumar Subodh
Published: May 2019

Introduction:

There are 2 standard techniques of laparoscopic groin hernia repair, totally extraperitoneal repair (TEP) and transabdominal preperitoneal repair (TAPP). TEP has the advantage that the peritoneal cavity is not breached but is, however, considered to be more difficult to master when compared with TAPP. We describe herein our experience of TEP repair of inguinal hernia over the last 14 years.

Materials and Methods:

This study is a retrospective analysis of a prospectively maintained database of all patients with groin hernia who underwent TEP repair in a single surgical unit between January 2004 and January 2018. Patients’ demographic profile and hernia characteristics (duration, side, extent, content, and reducibility) were noted in the prestructured proforma. Clinical outcomes included the operation time, intraoperative and postoperative complications, length of postoperative hospital stay, hernia recurrence, chronic pain, recurrence, seroma, and wound infections. Long-term follow-up was carried out in the outpatient department.

Results:

Over the last 14 years, TEP repair was performed in 841 patients and a total of 1249 hernias were repaired. The mean age of patients was 50.7 years. There were 748 primary and 345 unilateral hernias. The majority were direct (61%) inguinal hernias. Telescopic dissection was the commonest method of space creation. The average operating time was 54.8 and 77.9 minutes for unilateral and bilateral hernias, respectively. With 81 conversions, the success rate for TEP was 93.5%. Seroma was the most common postoperative complication seen in 81 patients. The incidence of chronic groin pain was 1.4%. The follow-up ranged from 3 months to 10 years, and there were only 3 recurrences (<1%).

Conclusion:

In conclusion, TEP repair is an excellent technique of laparoscopic inguinal hernia repair with acceptable complications after long-term follow-up.
Titrate to equilibrate and not exsanguinate! Characterization and validation of a novel partial resuscitative endovascular balloon occlusion of the aorta catheter in normal and hemorrhagic shock conditions
Authors: Forte Dominic M. , Do Woo S. , Weiss Jessica B. , Sheldon Rowan R. , Kuckelman John P. , Eckert Matthew J. , Martin Matthew J.
Published: May 2019

BACKGROUND

Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a significant advancement in the control of noncompressible truncal hemorrhage. However, its ischemic burden and reperfusion injury following balloon deflation limits its utilization. Partial restoration of aortic flow during REBOA has the potential to balance hemorrhage control and ischemia. This study validates the mechanics, physiology, and optimal partial flow rates using a prototype partial REBOA (pREBOA) device.

METHODS

Twenty-five swine underwent placement of aortic flow probes and zone 1 pREBOA. Experiment 1 (N = 5) animals were not injured and assessed the tested the catheters ability to titrate and control flow. Experiment 2 (N = 10) added 20% hemorrhage and either solid organ, or abdominal vascular injury to compare flow rate and rebleeding from injuries. Experiment 3 (N = 10) swine were similarly prepared, hemorrhaged, and underwent pREBOA at set partial flow rates for 2 hours followed by complete deflation for 30 minutes.

RESULTS

Balloon volume at minimum flow (mean, 0.09 L/min) was 3.5 mL to 6.0 mL. Half maximal flow was achieved with 56.5% of maximum balloon inflation. Partial REBOA allowed very fine titration of flow rates. Rebleeding occurred at 0.45 L/min to 0.83 L/min. Distal flow of 0.7 L/min had 50% survival, 0.5 had 100% survival, and 0.3 L had 50% survival with mean end lactates of 9.6, 12.6, and 13.3, respectively. There was a trend toward hyperkalemia and hypocalcemia in nonsurvivors.

CONCLUSION

The pREBOA device demonstrated a high level of titratability for restoration of aortic flow. An optimal partial flow of 0.5 L/min was effective at hemorrhage control while limiting the burden of ischemic injury, and extending the tolerable duration of zone 1 occlusion. Aggressive calcium supplementation prior to and during partial occlusion and reperfusion may be warranted to prevent hyperkalemic arrest.
A preliminary analysis of Level IV trauma centers within an organized trauma system
Authors: Vernon Tawnya M. , Cook Alan D. , Horst Michael A. , Gross Brian W. , Bradburn Eric H. , Jammula Shreya , Altenburg Juliet , Bradley David , Rogers Frederick B.
Published: May 2019

BACKGROUND

The effect of Level IV trauma center (TC) accreditation within an existing trauma network remains understudied. This study compared preaccreditation to postaccreditation data from Level IV TCs within a mature trauma system in Pennsylvania to determine whether TC designation affected time to and/or rate of transfer to definitive care. Level IV TCs were hypothesized to have a decreased time to transfer following accreditation and improved mortality.

METHODS

The Pennsylvania Trauma Systems Foundation collects predesignation and postdesignation data from hospitals pursuing accreditation. Data from Pennsylvania Trauma Systems Foundation between 2012 and 2017 were analyzed. Variables of interest included patient demographics, injury severity, mortality, and incidence of surgical interventions precredentialingto postcredentialing. A multilevel mixed-effects logistic regression model assessed the adjusted impact of Level IV TC accreditation on transfer rate. ArcGIS Desktop was used for geospatial mapping of lives and geographic area covered by the addition of Level IV TCs in Pennsylvania.

RESULTS

Five hospitals underwent Level IV credentialing from 2012 to 2017, providing data on 5,076 cases (pre, 2,395 [47.2%]; post, 2,681 [52.8%]). No significant difference in age, admission Glasgow Coma Scale score, or shock index was observed preaccreditation to postaccreditation. A difference in transfer rate was observed after credentialing in unadjusted (62.7% vs. 63.3%; p < 0.014) and adjusted analyses (adjusted odds ratios, 1.13, p = 0.389). There was a trend toward reduced odds of mortality postcredentialing (adjusted odds ratios, 0.59, p = 0.261). Major surgical intervention decreased (Pre, 0.42%; Post, 0.04%; p = 0.004).

CONCLUSION

Level IV TC accreditation has beneficial effects on increased transfer rates and may improve mortality. It is important to continue to observe the impact of Level IV TCs on patient outcomes within a mature trauma system.

LEVEL OF EVIDENCE

Prognostic and epidemiological, level III.
Variability in international normalized ratio and activated partial thromboplastin time after injury are not explained by coagulation factor deficits
Authors: Stettler Gregory R. , Moore Ernest E. , Moore Hunter B. , Nunns Geoffrey R. , Coleman Julia R. , Colvis Arthur , Ghasabyan Arsen , Cohen Mitchell J. , Silliman Christopher C. , Banerjee Anirban , Sauaia Angela
Published: May 2019

BACKGROUND

Conventional coagulation assays (CCAs), prothrombin time (PT)/international normalized ratio (INR) and activated partial thromboplastin time (aPTT), detect clotting factor (CF) deficiencies in hematologic disorders. However, there is controversy about how these CCAs should be used to diagnose, treat, and monitor trauma-induced coagulopathy. Study objectives were to determine whether CCA abnormalities are reflective of deficiencies of coagulation factor activity in the setting of severe injury.

METHODS

Patients without previous CF deficiency within a prospective database at an ACS-verified Level I trauma center had CF activity levels, PT/INR, aPTT, and fibrinogen levels measured upon emergency department arrival from 2014 to 2017. Linear regression assessed how CF activity explained the aPTT and PT/INR variation. Prolonged CCA values were set as INR greater than 1.3 and aPTT greater than 34 seconds. CF deficiency was defined as less than 30% activity, except for fibrinogen, defined as less than 150 mg/dL.

RESULTS

Sixty patients with a mean age of 35.8 (SD, 13.6) years and median New Injury Severity Score of 32 (interquartile range, 12–43) were included; 53.3% sustained blunt injuries, 23.3% required massive transfusion, and mortality was 11.67%. Overall, 44.6% of the PT/INR variance and 49.5% of the aPTT variance remained unexplained by CF activity. Deficiencies of CFs were: common pathway, 25%; extrinsic pathway, 1.7%; and intrinsic pathway, 6.7%. The positive predictive value for CF deficiencies were: (1) PT/INR greater than 1.3:4.4% for extrinsic pathway, 56.5% for the common pathway; (2) aPTT greater than 34 seconds:16.7% for the intrinsic pathway, 73.7% for the common pathway.

CONCLUSION

Almost half of the variances of PT/INR and aPTT were unexplained by CF activity. Prolonged PT/INR and aPTT were poor predictors of deficiencies in the intrinsic or extrinsic pathways; however, they were indicators of common pathway deficiencies.

LEVEL OF EVIDENCE

Prognostic, level III.
Relationship Turmoil and Emotional Empathy in Frontotemporal Dementia
Authors: Takeda Akitoshi , Sturm Virginia E. , Rankin Katherine P. , Ketelle Robin , Miller Bruce L. , Perry David C.
Published: May 2019

Background:

Behavioral variant frontotemporal dementia (bvFTD) is characterized by marked deficits in empathy and social behavior; however, the effect of these symptoms on partner relationships has not been quantitatively measured.

Objective:

We aimed to determine the effect of empathy loss and behavioral symptoms on partner and familial relationship status in bvFTD. We ascertained whether patients were currently in marriage/partner relationships or were separated/divorced, the timing and duration of these relationships, and whether the patients had relationship infidelity. We investigated the relationship status of 483 patients (156 with bvFTD, 38 with nonfluent variant primary progressive aphasia, 72 with semantic variant primary progressive aphasia, 49 with corticobasal syndrome, 45 with progressive supranuclear palsy syndrome, and 123 with Alzheimer disease) over the course of follow-up, and correlated relationship status with patients’ first visit Interpersonal Reactivity Index and Neuropsychiatric Inventory.

Results:

Relationship dissolution and infidelity were significantly more frequent among patients with bvFTD than in the other groups. Across all patients, empathy loss was associated with relationship dissolution. In the bvFTD group, patients who experienced relationship dissolution or infidelity had significantly lower empathy than those who did not.

Conclusions:

Changes in relationship status differed across dementia groups and were associated with empathy decline.
The atypical social brain network in autism: advances in structural and functional MRI studies
Authors: Sato Wataru , Uono Shota
Published: May 2019

Purpose of review

To review advances in structural and functional MRI studies regarding the neural underpinnings of social atypicalities in autism spectrum disorder (ASD).

Recent findings

According to the hypothesis that the social brain network, which includes brain regions, such as the amygdala and superior temporal sulcus, may be atypical in ASD, recent structural MRI studies have identified regional gray matter volume abnormalities in the social brain regions in ASD groups compared with the typically developing groups. Studies evaluating gray matter volume covariance and white matter volume/integrity suggested network-level abnormalities associated with the social brain regions. Recent functional MRI studies assessing resting-state neural activity showed reduced functional connectivity among the social brain regions in individuals with ASD compared with typically developing groups. Similarly, task-based functional MRI studies recently revealed a reduction in regional activity and intraregional functional coupling in the social brain regions during the processing of social stimuli in individuals with ASD.

These structural and functional MRI studies provide supportive evidence for the hypothesis that an atypical social brain network underlies behavioral social problems in ASD.
Sex differences in neurodevelopmental disorders
Authors: May Tamara , Adesina Ife , McGillivray Jane , Rinehart Nicole J.
Published: May 2019

Purpose of review

There continues to be more males than females diagnosed with neurodevelopmental disorders, which may provide clues about their cause. This review will focus on the two most common neurodevelopmental disorders – autism spectrum disorder (autism) and attention deficit hyperactivity disorder (ADHD), and explore recent research to understand recent developments in the field.

Recent findings

Biological mechanisms including genetics, hormones and their interaction with other risk factors, such as stress and lead exposure, point to complex causal pathways for neurodevelopmental disorders. Over recent years, the research focus on sex differences in symptom profiles in autism has continued; however, a meta-analysis of existing studies indicated minimal sex differences in core autism symptoms. In ADHD, changes in the sex ratio from disparity in childhood to parity in adulthood may relate to the onset and trajectory of hyperactivity symptoms in females. Research into medical and psychiatric comorbidities, such as polycystic ovary syndrome and gender dysphoria, is also providing insights into the role of early androgen exposure as a potential causal factor for neurodevelopmental disorders.

The factors, which contribute to an increased number of males with neurodevelopmental disorders in most cases are complex involving interactions between genetics, hormones and environmental factors.
Memantine Rescues Neurosyphilis-Related Schizophrenic-like Features and Cognitive Deficit
Authors: Chen Wen-Chien , Wang Hui-Yi , Chen Po-An , Chen I-Chia , Chen Yi-Chyan
Published: May 2019

Objectives

Neurosyphilis, an infectious neuroinflammatory disorder, could cause diverse neuropsychiatric symptoms mimicking disorders of schizophrenia and dementia; hence, it is known as the “chameleon of psychiatry.” Here, we present a subject with neurosyphilis with schizophrenic features and share the treatment outcome.

Methods

A 42-year-old single man had schizophrenic-like features and cognitive dysfunction for 1 year. Neurosyphilis was confirmed by a cerebral spinal fluid study. The brain image revealed multiple punctuated white matter gliosis in the bilateral frontal lobes and old lacunar infarctions in the bilateral basal hippocampus. The neuropsychiatric functions were declined until adjunctive memantine therapy.

Results

With the add-on therapy of memantine 10 mg daily, the psychotic and dementic symptoms markedly improved, and the patient recovered to the premorbid state in the 2-year follow-up course.

Conclusions

Memantine has an adjunctive effect on neurosyphilis-related neuropsychiatric disorder via modulation of the glutamatergic neurotransmission and microglia-induced neuroinflammation.
Grades, motivation, and resilience: the role cognitive and non-cognitive traits play in the undergraduate research student selection process
Authors: Suart Celeste , Heirwegh Meagan , Vulcu Felicia
Published: May 2019

The academic research experience is extremely rewarding but is also froth with many challenges, setbacks, and frustrations. The publish-or-perish mentality of a research-intensive academic environment demands a certain skill set in its trainees. This selection criterion begins with the undergraduate research selection process, but what is the ideal skill set of an incoming student entering the research experience? The current landscape on this topic is bleak, with little examination of how students are chosen for these positions. We therefore conducted an analysis examining student selection methods, non-cognitive traits, emphasis on grades and medical school future ambitions. Our findings suggest that the top five student traits valued by principal investigators are: motivation, resilience, hard work, inquisitiveness and honesty. Surprisingly, emphasis on grades as a screening tool decreased as age of laboratory and frequency of publication increased. Additionally, we identified an inverse correlation between student interest in medical school and research supervisor interest in selecting the student for an undergraduate research experience. Taken together, our study culminates in a defined set of skills beneficial for an incoming student at the beginning of their research experience. We feel our findings will greatly facilitate the overall undergraduate student selection process in any academic environment.
Galaxy External Display Applications: Closing a dataflow interoperability loop
Authors: Blankenberg Daniel , Chilton John , Coraor Nate
Published: May 2019

Interoperability of datasets, tools, and resources is essential to modern scientific investigation and analysis. The necessity to gather disparate datasets together, perform analysis with a collection of discrete tools, and visualize the results remains a standard approach for exploring and making sense across scientific research domains. Here, we describe the Galaxy External Display Application (GEDA) framework which provides researchers with the ability to facilitate the interoperability of Galaxy user data and external resources, while promoting findability, accessibility, and reuse. The only requirement on the external resource for GEDA accessibility is that it is able to accept a parameter value that contains a URL pointing to user data.
Relationship between footshock intensity, post-training corticosterone release and contextual fear memory specificity over time
Authors: dos Santos Corrêa Moisés , dos Santos Vaz Barbara , Grisanti Gabriel David Vieira , de Paiva Joselisa Péres Queiroz , Tiba Paula Ayako , Fornari Raquel Vecchio
Published: May 2019

Overgeneralized fear has long been implicated in generalized anxiety and post-traumatic stress disorder, however, time-dependent mechanisms underlying memory retrieval are still not completely understood. Previous studies have revealed that stronger fear conditioning training protocols are associated with both increased post-training corticosterone (CORT) levels and fear responses at later retrieval tests. Here we used discriminative contextual fear conditioning (CFC) to investigate the relationship between post-training CORT levels and memory specificity in different retrieval timepoints. Wistar rats were exposed to CFC training with increasing footshock intensities (0.3, 0.6 or 1.0mA) and had their blood collected 30 min afterwards to measure post-training plasma CORT. After 2, 14 or 28 days, rats were tested for memory specificity either in the training or in the novel context. Regression analysis was used to verify linear and non-linear interactions between CORT levels and freezing. Higher footshock intensities increased post-training CORT levels and freezing times during tests in all timepoints. Moreover, stronger trainings elicited faster memory generalization, which was associated with higher CORT levels during memory consolidation. The 0.3mA training maintained memory specificity up to 28 days. Additionally, linear regressions suggest that the shift from specific to generalized memories is underway at 14 days after training. These results are consistent with the hypotheses that stronger training protocols elicit a faster generalization rate, and that this process is associated with increased post-training CORT release.

HIGHLIGHTS

Stronger contextual fear conditioning (CFC) elicits higher plasma corticosterone (CORT).

Strong CFC and high CORT levels increase the rate of memory generalization.

Weak CFC and low CORT levels retain memory specificity up to 28 days.

Post-training plasma CORT is linearly associated with remote generalized fear.
Retinal stabilization reveals limited influence of extraretinal signals on heading tuning in the medial superior temporal area
Authors: Manning Tyler S , Britten Kenneth H
Published: May 2019

Heading perception in primates depends heavily on visual optic-flow cues. Yet during self-motion, heading percepts remain stable even though smooth-pursuit eye movements often distort optic flow. Electrophysiological studies have identified visual areas in monkey cortex, including the dorsal medial superior temporal area (MSTd), that signal the true heading direction during pursuit. According to theoretical work, self-motion can be represented accurately by compensating for these distortions in two ways: via retinal mechanisms or via extraretinal efference-copy signals, which predict the sensory consequences of movement. Psychophysical evidence strongly supports the efference-copy hypothesis, but physiological evidence remains inconclusive. Neurons that signal the true heading direction during pursuit are found in visual areas of monkey cortex, including the dorsal medial superior temporal area (MSTd). Here we measured heading tuning in MSTd using a novel stimulus paradigm, in which we stabilize the optic-flow stimulus on the retina during pursuit. This approach isolates the effects on neuronal heading preferences of extraretinal signals, which remain active while the retinal stimulus is prevented from changing. Our results demonstrate a significant but small influence of extraretinal signals on the preferred heading directions of MSTd neurons. Under our stimulus conditions, which are rich in retinal cues, we find that retinal mechanisms dominate physiological corrections for pursuit eye movements, suggesting that extraretinal cues, such as predictive efference-copy mechanisms, have a limited role under naturalistic conditions.

Significance Statement

Sensory systems discount stimulation caused by the animal’s own behavior. For example, eye movements cause irrelevant retinal signals that could interfere with motion perception. The visual system compensates for such self-generated motion, but how this happens is unclear. Two theoretical possibilities are a purely visual calculation or one using an internal signal of eye movements to compensate for their effects. Such a signal can be isolated by experimentally stabilizing the image on a moving retina, but this approach has never been adopted to study motion physiology. Using this method, we find that eye-movement signals have little influence on neural activity in visual cortex, while feed-forward visual calculation has a strong effect and is likely important under real-world conditions.
Dissociating proprioceptive deficits in Autism Spectrum Disorders: Intact acuity but impaired sensory integration in postural control
Authors: Doumas Michail , Knox Rebekah , O’Brien Cara , Craig Chesney E.
Published: May 2019

We investigated the presence of proprioceptive deficits in adults with Autism Spectrum Disorder (ASD), by assessing peripheral proprioceptive information (or proprioceptive acuity) as well as integration of proprioceptive information in the context of postural control. We hypothesized that proprioceptive acuity would be intact but that integration during a postural control task would be impaired. Sixteen adults with ASD and sixteen Neurotypical (NT) adults were screened using an IQ test and the adolescent-adult sensory profile. Proprioceptive acuity was assessed using an ankle Joint Position Sense (JPS) task and integration of proprioceptive information was assessed using a postural adaptation task. This task comprised standing upright, without vision in three phases: standing on a fixed surface for 2 minutes (baseline), followed by standing on a surface tilting in proportion to participants’ body sway, or support-surface sway reference for 3 minutes (adaptation) and finally standing on the restored fixed surface for 3 minutes (reintegration). Results showed no group differences in proprioceptive acuity and in the baseline phase, but greater postural sway during adaptation in individuals with ASD compared with NT controls. Specifically, group differences were not present in the first 30s of adaptation, but emerged after the second window suggesting a deficit in sensory integration of proprioception in adults with ASD. Our results suggest that peripheral proprioceptive information is intact in ASD but neural sensory integration of proprioception is impaired in this group.
Genetic comorbidity between major depression and cardio-metabolic disease, stratified by age at onset of major depression
Authors: Hagenaars SP , Coleman JRI , Choi S , Gaspar H , Adams MJ , Howard D , Hodgson K , Traylor M , Air TM , Andlauer TFM , Arolt V , Baune BT , Binder EB , Blackwood DHR , Boomsma DI , Campbell A , Cearns M , Czamara D , Dannlowski U , Domschke K , de Geus EJC , Hamilton SP , Hayward C , Hickie I , Hottenga JJ , Ising M , Jones I , Jones LA , Kutalik Z , Lucae S , Martin NG , Milaneschi Y , Mueller-Myhsok B , Owen MJ , Padmanabhan S , Penninx BWJH , Pistis G , Porteous DJ , Preisig M , Ripke S , Shyn SI , Sullivan PF , Whitfield J , Wray NR ,   Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium,   MEGASTROKE consortium, McIntosh AM , Deary IJ , Breen G , Lewis CM
Published: May 2019

Introduction

It’s imperative to understand the specific and shared aetiologies of major depression and cardio-metabolic disease, as both traits are frequently comorbid and each represents a major burden to society. This study examined whether there is a genetic association between major depression and cardio-metabolic traits and if this association is stratified by age at onset for major depression.

Methods

Polygenic risk scores analysis and linkage disequilibrium score regression was performed to examine whether differences in shared genetic aetiology exist between depression case control status (N cases = 40,940, N controls = 67,532), earlier (N = 15,844), and later onset depression (N = 15,800) with body mass index, coronary artery disease, stroke, and type 2 diabetes in eleven data sets from the Psychiatric Genomics Consortium, Generation Scotland, and UK Biobank.

Results

All cardio-metabolic polygenic risk scores were associated with depression status. Significant genetic correlations were found between depression and body mass index, coronary artery disease, and type 2 diabetes. Higher polygenic risk for body mass index, coronary artery disease and type 2 diabetes was associated with both early and later onset depression, while higher polygenic risk for stroke was associated with later onset depression only. Significant genetic correlations were found between body mass index and later onset depression, and between coronary artery disease and both early and late onset depression.

Conclusions

The phenotypic associations between major depression and cardio-metabolic traits may partly reflect their overlapping genetic aetiology irrespective of the age depression first presents.
Bayesian model discrimination for partially-observed epidemic models
Authors: Walker James N. , Black Andrew J. , Ross Joshua V.
Published: May 2019

An efficient method for Bayesian model selection is presented for a broad class of continuous-time Markov chain models and is subsequently applied to two important problems in epidemiology. The first problem is to identify the shape of the infectious period distribution; the second problem is to determine whether individuals display symptoms before, at the same time, or after they become infectious. In both cases we show that the correct model can be identified, in the majority of cases, from symptom onset data generated from multiple outbreaks in small populations. The method works by evaluating the likelihood using a particle filter that incorporates a novel importance sampling algorithm designed for partially-observed continuous-time Markov chains. This is combined with another importance sampling method to unbiasedly estimate the model evidence. These come with estimates of precision, which allow for stopping criterion to be employed. Our method is general and can be applied to a wide range of model selection problems in biological and epidemiological systems with intractable likelihood functions.
Species-specific InDel markers for authentication of the Korean herbsZanthoxylum schinifoliumandZanthoxylum piperitum
Authors: Kim Yonguk , Shin Jawon , Cho Seung-Sik , Hwang Yong-Pil , Choi Chulyung
Published: May 2019

Objective

Zanthoxylum schinifoliumandZanthoxylum piperitumare the sources of the well-known traditional Korean herbal medicines “sancho” (prickly ash) and “chopi” (Korean pepper), respectively. Sancho and chopi are often indiscriminately mixed due to the similar appearance of the herbal materials when used as spices and herbal medicines. Moreover, commercial sancho and chopi products often contain adulterants, which could compromise drug efficacy and safety.

Methods

In this study, we developed hypervariable InDel markers to distinguish between sancho and chopi products by comparing the complete chloroplast genome sequences of fourZanthoxylumspecies deposited in NCBI GenBank.

Results

Comparative analyses of the nucleotide diversity (Pi) of theseZanthoxylumgenomes revealed four hypervariable divergent sites (trnH-psbA, psbZ-trnG, trnfM-rps14, andtrnF-ndhK) withPi> 0.025 among 520 windows. Of these four regions, including two genic and two intergenic regions, onlypsbZ-trnGyielded accurate PCR amplification results between commercial sancho and chopi products from the Korean herbal medicine market. We therefore selectedpsbZ-trnG, an InDel-variable locus with high discriminatory powers, as a candidate DNA barcode locus.

Conclusion

This InDel marker could be used as a valuable, simple, and efficient tool for identifying these medicinal herbs, thereby increasing the safety of these spices and herbal materials in the commercial market.
PfCERLI1, a conserved rhoptry associated protein essential for invasion byPlasmodium falciparummerozoites
Authors: Liffner Benjamin , Frölich Sonja , Heinemann Gary K. , Liu Boyin , Dixon Matthew W. A. , Gilberger Tim-Wolf , Wilson Danny W.
Published: May 2019

The disease-causing blood stage of thePlasmodium falciparumlifecycle begins with invasion of human erythrocytes by merozoites. Many vaccine candidates with key roles in binding to the erythrocyte surface and entry are secreted from the large bulb-like rhoptry organelles at the apical tip of the merozoite. Here we identify an essential role for the conserved proteinP. falciparumCytosolicallyExposedRhoptryLeafletInteracting protein 1 (PfCERLI1) in rhoptry function. We show that PfCERLI1 localises to the cytosolic face of the rhoptry bulb membrane and knockdown of PfCERLI1 inhibits merozoite invasion. While schizogony and merozoite organelle biogenesis appear normal, biochemical techniques and semi-quantitative super-resolution microscopy show that PfCERLI1 knockdown prevents secretion of key rhoptry antigens that coordinate merozoite invasion. PfCERLI1 is the first rhoptry associated protein identified to have a direct role in function of this essential malaria invasion organelle which has broader implications for understanding apicomplexan invasion biology.