bluuebunny/crossref_metadata_2025 huggingface dataset:
The relationship between machine-learning-derived sleep parameters and behavior problems in 3- and 5-year-old children: results from the CHILD Cohort study
Authors: Hammam Nevin , Sadeghi Dorna , Carson Valerie , Tamana Sukhpreet K , Ezeugwu Victor E , Chikuma Joyce , van Eeden Charmaine , Brook Jeffrey R , Lefebvre Diana L , Moraes Theo J , Subbarao Padmaja , Becker Allan B , Turvey Stuart E , Sears Malcolm R , Mandhane Piushkumar J
Published: June 2020

Study Objectives

Machine learning (ML) may provide insights into the underlying sleep stages of accelerometer-assessed sleep duration. We examined associations between ML-sleep patterns and behavior problems among preschool children.

Methods

Children from the CHILD Cohort Edmonton site with actigraphy and behavior data at 3-years (n = 330) and 5-years (n = 304) were included. Parent-reported behavior problems were assessed by the Child Behavior Checklist. The Hidden Markov Model (HMM) classification method was used for ML analysis of the accelerometer sleep period. The average time each participant spent in each HMM-derived sleep state was expressed in hours per day. We analyzed associations between sleep and behavior problems stratified by children with and without sleep-disordered breathing (SDB).

Results

Four hidden sleep states were identified at 3 years and six hidden sleep states at 5 years using HMM. The first sleep state identified for both ages (HMM-0) had zero counts (no movement). The remaining hidden states were merged together (HMM-mov). Children spent an average of 8.2 ± 1.2 h/day in HMM-0 and 2.6 ± 0.8 h/day in HMM-mov at 3 years. At age 5, children spent an average of 8.2 ± 0.9 h/day in HMM-0 and 1.9 ± 0.7 h/day in HMM-mov. Among SDB children, each hour in HMM-0 was associated with 0.79-point reduced externalizing behavior problems (95% CI −1.4, −0.12; p < 0.05), and a 1.27-point lower internalizing behavior problems (95% CI −2.02, −0.53; p < 0.01).

Conclusions

ML-sleep states were not associated with behavior problems in the general population of children. Children with SDB who had greater sleep duration without movement had lower behavioral problems. The ML-sleep states require validation with polysomnography.
Informalization of EU Bilateral Instruments: Categorization, Contestation, and Challenges
Authors: Ott Andrea
Published: June 2020

The EU and its Member States both contribute to the informalization of international relations’ tools by concluding bilateral soft law instruments which prepare, implement, and especially replace international agreements. This contribution analyses the EU practice of applying international soft law and focuses on the institutional challenges deriving from external relations’ soft law instruments. It has the three-fold aim of explaining why the informalization or ‘softification’ of EU bilateral instruments has proliferated, categorizing them according to their function and purpose in international law and EU external relations law and finally assessing the legal implications in EU law resulting from their application. The paper will argue that while, in practice, differences between international treaty law and bilateral soft law disappear, more legal challenges arise in the EU system through bilateral soft law measures than international agreements. This is caused by the rules on EU external representation, dispersed among supranational and intergovernmental EU actors and characterized by their general wording. International soft law tools operate in a politically contested area with several actors and a variety of informal instruments. The flexibility and hybrid character of soft law form an advantage for the institutions at the expense of the rule of law, legal certainty, and legal review.
Impact of Fiber-Based Enteral Nutrition on the Gut Microbiome of ICU Patients Receiving Broad-Spectrum Antibiotics: A Randomized Pilot Trial
Authors: Freedberg Daniel E. , Messina Megan , Lynch Elissa , Tess Monika , Miracle Elizabeth , Chong David H. , Wahab Romina , Abrams Julian A. , Wang Harris H. , Munck Christian
Published: June 2020

Objectives:

Dietary fiber increases the abundance of bacteria that metabolize fiber into short-chain fatty acids and confers resistance against gut colonization with multidrug-resistant bacteria. This pilot trial estimated the effect of fiber on gut short-chain fatty acid–producing bacteria in the ICU.

Design:

Randomized, controlled, open label trial.

Setting:

Medical ICU.

Patients:

Twenty ICU adults receiving broad-spectrum IV antibiotics for sepsis.

Intervention:

1:1 randomization to enteral nutrition with mixed soy- and oat-derived fiber (14.3 g fiber/L) versus calorie- and micronutrient-identical enteral nutrition with 0 g/L fiber.

Measurements:

Rectal swabs and whole stools were collected at baseline and on study Days 3, 7, 14, and 30. The primary outcome was within-individual change in the cumulative relative abundance of short-chain fatty acid–producing taxa from baseline to Day 3 based on 16S sequencing of rectal swabs. The secondary outcome was Day 3 cumulative short-chain fatty acid levels based on mass spectrometry of whole stools. Analyses were all intent to treat.

Main Results:

By Day 3, the fiber group received a median of 32.1 g fiber cumulatively (interquartile range, 17.6–54.6) versus 0 g fiber (interquartile range, 0–4.0) in the no fiber group. The median within-individual change in short-chain fatty acid producer relative abundance from baseline to Day 3 was +61% (interquartile range −51 to +1,688) in the fiber group versus −46% (interquartile range, −78 to +13) in the no fiber group (p = 0.28). Whole stool short-chain fatty acid levels on Day 3 were a median of 707 μg short-chain fatty acids/g stool (interquartile range, 190–7,265) in the fiber group versus 118 μg short-chain fatty acids/g stool (interquartile range, 22–1,195) in the no fiber group (p = 0.16).

Conclusions:

Enteral fiber was associated with nonsignificant trends toward increased relative abundance of short-chain fatty acid–producing bacteria and increased short-chain fatty acid levels among ICU patients receiving broad-spectrum IV antibiotics. Larger studies should be undertaken and our results can be used for effect size estimates.
Consideration of Severe Coronavirus Disease 2019 As Viral Sepsis and Potential Use of Immune Checkpoint Inhibitors
Authors: Odabasi Zekaver , Cinel Ismail
Published: June 2020

Taking into consideration the multisystemic clinical and autopsy findings in “severe” coronavirus disease 2019 patients, viral sepsis would be a more accurate term to describe the whole clinical picture. The most significant pathophysiological components of this picture are intense cytokine release, prolonged inflammation, immunosuppression with T cell exhaustion, and the development of organ dysfunctions. Currently, the optimal treatment for severe coronavirus disease 2019 is uncertain. Supportive treatment and immunomodulators have a critical place in the treatment of severe patients until effective antivirals are developed. Interleukin-6 antagonists, one of the immunomodulating agents, appears to be effective in the treatment of cytokine storm, but some patients continue to have severe lymphopenia and immunosuppression. We believe it can be useful as immunomodulator therapy in critical coronavirus disease 2019 patients because of the benefits of immune checkpoint inhibitors in cancer and sepsis patients.
Statewide Real-Time Tracking of Beds and Ventilators During Coronavirus Disease 2019 and Beyond
Authors: Merkel Matthias Johannes , Edwards Renee , Ness Joe , Eriksson Carl , Yoder Susan , Gilliam Stephanie , Ellero Katie , Barreto-Costa Coral , Graven Peter , Terry Jeffrey R. , Heilman James
Published: June 2020

This brief report describes the rapid deployment of a real-time electronic tracking board for all hospitals in the state of Oregon. In preparation for the coronavirus disease 2019 surge on hospital resources, and in collaboration across health systems, with health authorities and an industry partner, we combined existing infrastructures to create the first automated tracking board for our entire state, including bed types by health system and geographic area, and with granularity to the individual unit level for each participating hospital. At the time of submission, we have a live snapshot of 87% of beds in the state, including real-time ventilator data across eight health systems. The tracking board allows for rapid assessment of available bed and ventilator resources and pulls electronic health record data that is created through normal care processes rather than relying upon manual entry. It is updated every 5 minutes and is drillable from state to unit level. Together these factors make the data actionable, which is essential in a crisis. The new tracking system integrates seamlessly with our preexisting statewide, manually updated tracking board via bidirectional data sharing to ensure existing processes across the state can continue. This new tool allows any health system in our state to visualize occupancy by type and location in real time. Amid pandemic uncertainty, having a reliable tool for tracking critical hospital resources will enhance our statewide ability to maintain healthcare functionality in a world with coronavirus disease 2019.
Venoarterial Extracorporeal Membranous Oxygenation: Treatment Option for Sepsis-Induced Cardiogenic Shock? A Systematic Review
Authors: Sato Ryota , Kuriyama Akira
Published: June 2020

Objectives:

Clinicians often encounter adult patients with septic shock who fail to respond to fluid therapy and vasopressors. There is an increasing interest in venoarterial extracorporeal membranous oxygenation in the treatment of patients with septic shock, but its outcomes and safety remain unclear. The aim of this study is to describe in-hospital mortality and complication rate in adult patients with septic shock who underwent venoarterial extracorporeal membranous oxygenation, and to identify patients who may potentially benefit from venoarterial extracorporeal membranous oxygenation.

Data Sources:

The protocol for this systematic review was registered at International Prospective Register of Systematic Reviews (CRD42018098848). We searched MEDLINE, Embase, and Igaku Chuo Zasshi for studies of any design in which patients with septic shock were treated with venoarterial extracorporeal membranous oxygenation. Our search was updated on October 6, 2019.

Study Selection:

Two independent reviewers assessed whether titles and abstracts met the eligibility criteria. Studies were included when patients met the following criteria: 1) age 18 years old or older; 2) septic shock; and 3) treated with venoarterial extracorporeal membranous oxygenation as hemodynamic support. When there were disagreements between reviewers, the full text was reviewed, and discussion was continued until a consensus was reached.

Data Extraction:

Two authors independently extracted the selected patient and study characteristics and outcomes.

Data Synthesis:

A total of 6,457 studies were screened. Six retrospective studies were included. The in-hospital mortality rate of patients with septic shock who underwent venoarterial extracorporeal membranous oxygenation was 76.7% (188/245). Four studies provided cardiac function with left ventricular ejection fraction and/or cardiac index. In two of these four studies where median left ventricular ejection fraction and cardiac index were 16.0% and 1.3 L/min/m2 and median left ventricular ejection fraction and mean cardiac index were 30.0% and 2.4 L/min/m2, respectively, the in-hospital mortalities were markedly lower (14.8% and 28.6%, respectively) than the other two studies (78.1% and 91.5%, respectively) that included populations with median left ventricular ejection fraction of 25.0% and mean cardiac index of 2.1 L/min/m2. Complications were reported in five studies (39 events/174 cases), hemorrhage (22 events/174 cases) being the most common.

Conclusions:

Venoarterial extracorporeal membranous oxygenation remains a controversial treatment strategy in septic shock. The reported in-hospital mortality rates in patients with sepsis-induced cardiogenic shock who underwent venoarterial extracorporeal membranous oxygenation were quite inconsistent. There is a need for well-designed studies to assess the benefit and safety of venoarterial extracorporeal membranous oxygenation in patients with sepsis-induced cardiogenic shock.
ACUTE ZONAL OCCULT OUTER RETINOPATHY: A CASE REPORT OF REGRESSION AFTER AN INTRAVITREAL DEXAMETHASONE (OZURDEX) IMPLANT
Authors: Vadboncoeur Julie , Jampol Lee M. , Goldstein Debra A.
Published: June 2020

Purpose:

To report the use of the dexamethasone (Ozurdex, Allergan Inc) intravitreal implant in the management of acute zonal occult outer retinopathy.

Methods:

Observational case report.

Results:

A 63-year-old woman presented with a 10-year history of progressing bilateral, although asymmetric, visual impairment and scotomata with clinical and imaging findings compatible with acute zonal occult outer retinopathy. The right eye had recently progressed rapidly until macular involvement occurred with loss of visual acuity. Under our observation, progression toward the fovea in the left eye occurred, Ozurdex intravitreal implant treatment was offered and administered. Autofluorescence imaging documented resolution of the hyperautofluorescent borders and slight regression of the involved retina. An injection was repeated every 6 months for 3 injections, and after a follow-up period, 20 months after the first and 8 months after the last injection, no further signs of progression were observed in her left eye.

Conclusion:

The dexamethasone implant effectively achieved regression of active disease in a patient with longstanding, progressive acute zonal occult outer retinopathy.
TWO-YEAR RESULTS OF INTRAVITREAL INJECTIONS OF AFLIBERCEPT IN COATS DISEASE: A CASE REPORT
Authors: Georgakopoulos Constantinos D. , Tsapardoni Foteini N. , Makri Olga E. , Vavvas Demetrios
Published: June 2020

Purpose:

To report long-term results of treatment with intravitreal injections of aflibercept in a newly diagnosed case of Coats disease.

Methods:

An 18-year-old man presented to the retina clinic of our hospital complaining of blurred vision in the right eye for the past 3 months. His past medical and ocular history were unremarkable. The best-corrected visual acuity was 20/200 in the right eye and 20/20 in the left eye. Fundoscopy in the right eye revealed extensive macular edema with a circinate ring of hard exudates in the posterior pole temporally to the macula. Optical coherence tomography demonstrated macular edema with subretinal fluid. Peripheral telangiectasias and light bulb aneurysms in the inferior temporal arcade as well as in the nasal far periphery were found in the right eye in fluorescein angiography, confirming the diagnosis of stage 2B Coats disease. The left eye was normal.

Results:

The original therapeutic strategy proposed was antivascular endothelial growth factor injections in the right eye, followed by laser photocoagulation. However, the patient did not consent to laser treatment and was treated with aflibercept monotherapy with 8 monthly intravitreal injections of aflibercept, followed by 6 injections every 2 months for a total of 14 injections over a period of 2 years. The best-corrected visual acuity in the right eye improved to 20/25 while optical coherence tomography imaging revealed significant decrease in retinal thickness with resolution of macular edema, and fluorescein angiography demonstrated prominent regression of aneurysms and leakage.

Conclusion:

To the best of our knowledge, this is the first case treated with aflibercept monotherapy, suggesting the significant role of vascular endothelial growth factor in vascular permeability in Coats and supporting the rationale that antivascular endothelial growth factors are a valuable therapeutic option for Coats disease.
A NOVEL VITREOUS CULTURE TECHNIQUE
Authors: Khong Jennifer , Joondeph Brian C.
Published: June 2020

Background/Purpose:

This is the first case series of a novel method of collecting and transporting a vitreous specimen after a vitreous tap and injection for infectious endophthalmitis.

Methods:

Case series.

Results:

Four consecutive cases of presumed infectious endophthalmitis underwent an in-office vitreous tap and antibiotic injection. The vitreous specimen was injected into the ESwab liquid-based collection and transport system for microbiology samples. Three of the four cases had a positive culture.

Conclusion:

The ESwab is a simple and efficacious method of collecting a vitreous specimen, increasing the probability of a positive culture, particularly when there is a delay between specimen collection and delivery to the laboratory for processing.
MACULAR INFARCTION IN A PATIENT WITH SICKLE CELL TRAIT
Authors: Dow Eliot R. , Tsui Irena , Sarraf David
Published: June 2020

Purpose:

Sickle cell trait affects 8% of African Americans. Once believed to represent a benign carrier state, it has been linked to an increased risk of several of the pathological conditions that arise in sickle cell disease in at-risk individuals with hematologic and vascular comorbidities. Macular infarction is a known complication of sickle cell disease; this article illustrates this unique presentation in a patient with sickle cell trait.

Methods:

Case report.

Patient:

A 74-year-old African American man presented with the complaint of a central scotoma of the right eye.

Results:

Multimodal retinal imaging identified central macular infarction with severe inner retinal atrophy. Laboratory testing confirmed the presence of sickle cell trait. Other pertinent positives included low levels of protein C and protein S, untreated obstructive sleep apnea, and elevated levels of homocysteine in the setting of alcoholic liver cirrhosis and chronic kidney disease.

Conclusion:

Ocular manifestations of sickle cell trait have most frequently been reported in individuals with systemic medical comorbidities that predispose to erythrocyte sickling and vaso-occlusive disease. This case identifies a novel complication of sickle cell trait disorder, macular infarction, in a patient with comorbid associations.
YELLOW SUBRETINAL PIGMENT EPITHELIUM DEPOSITS: A NOVEL SIGN IN OCULAR TUBERCULOSIS
Authors: Agarwal Aniruddha , Aggarwal Kanika , Katoch Deeksha , Invernizzi Alessandro , Arora Atul , Handa Sabia , Sharma Aman , Sharma Kusum , Gupta Vishali
Published: June 2020

Purpose:

To describe a novel clinical and imaging finding in patients with tubercular posterior uveitis.

Methods:

A retrospective review of 3 cases presented at a tertiary referral eye centre in North India was performed between June 2016 and March 2019. All the patients had received an initial diagnosis of noninfective etiologies (sympathetic ophthalmia, necrotizing scleritis, and lymphoma). Fundus photography, fluorescein angiography, fundus autofluorescence, and enhanced-depth imaging optical coherence tomography were reviewed.

Results:

Three patients (all Asian Indian women: aged 18, 49, and 52 years) diagnosed with panuveitis were investigated for various etiologies based on the initial clinical suspicion. During the course of therapy, all the patients developed peripheral yellow subretinal pigment epithelium deposits (YSRPE) which appeared hypoautofluorescent on fundus autofluorescence and initially hypofluorescent with late hyperfluorescence on fluorescein angiography. The patients were subjected to detailed systemic evaluation and laboratory tests. All the patients showed acid-fast bacilli on invasive tissue biopsies. After initiation of antitubercular therapy, the lesions resolved in all eyes.

Conclusion:

Yellow subretinal pigment epithelium deposits represent a novel and important diagnostic sign of tubercular posterior uveitis.
JUXTAPAPILLARY CAPILLARY RETINAL ANGIOMA AND EPIRETINAL MEMBRANE MANAGEMENT IN A MONOCULAR PATIENT WITH VON HIPPEL–LINDAU SYNDROME
Authors: Schönbach Etienne M. , Trichonas Georgios
Published: June 2020

Purpose:

To report a case of von Hippel–Lindau syndrome in a monocular patient with progressive vision loss due to a juxtapapillary capillary retinal angioma and an epiretinal membrane (ERM) formation.

Patient:

We describe a 37-year-old white male patient with von Hippel–Lindau syndrome who presented for retinal evaluation. The right eye was blind with no light perception vision. The left eye had a best-corrected visual acuity of 20/30 and exhibited a peripheral capillary hemangioblastoma at 12 o'clock and a juxtapapillary capillary hemangioma with an ERM covering the fovea. The patient underwent two sessions of fluorescein-potentiated argon laser treatment to the peripheral capillary hemangioblastoma with initial stabilization of vision. After 18 months of follow-up, the ERM contracted causing decline in vision to 20/50. Intravitreal injection of bevacizumab was given without improvement in vision or distortion. Twenty-five–gauge pars plana vitrectomy with ERM peeling and internal limiting membrane removal was performed with immediate improvement in vision and distortion.

Conclusion:

This case suggests that pars plana vitrectomy is a reasonable treatment option for vision loss due to a juxtapapillary capillary retinal angioma and ERM formation.
COCCIDIOIDAL ENDOPHTHALMITIS: EXCELLENT RECOVERY OF VISION WITH AGGRESSIVE USE OF INTRAVITREAL ANTIFUNGALS AND VITRECTOMY
Authors: Ahmad Tessnim R. , Li Jonathan , Wu Frances , Rahman Salman , Bever Gregory J. , Afshar Armin R.
Published: June 2020

Purpose:

To report a case of Coccidioides immitis endophthalmitis with severe vision loss and a return to excellent vision after aggressive intervention.

Methods:

Case report.

Results:

A 41-year-old man with a history of solid organ transplantation who complained of floaters and decreased vision in the setting of disseminated Coccidioides infection was found to have presumed coccidioidal endophthalmitis with visual acuities of 20/20 in the right eye and 20/200 in the left eye. The patient was managed with intravenous amphotericin B, oral voriconazole, and intravitreal injections of amphotericin B and voriconazole in the left eye every three days. Five weeks after presentation, his visual acuity remained 20/20 in the right eye and improved to 20/40 in the left eye. The patient was transitioned to twice weekly intravitreal injections and oral voriconazole on hospital discharge. One week later, vision in the left eye decreased to 20/500 with worsening vitritis, prompting vitrectomy. Vision in the left eye subsequently improved to 20/30. Five weeks later, the patient developed a macula-on inferior rhegmatogenous retinal detachment in the left eye and underwent a second vitrectomy, with scleral buckle, laser, and gas injection. Vision in the left eye returned to 20/25. In total, the patient received 22 amphotericin B and 17 voriconazole intravitreal injections in the left eye with two vitrectomies. Vision in the right eye remained 20/20 throughout his treatment course. At four months after presentation, the patient remained on oral voriconazole with no evidence of active intraocular infection on examination.

Conclusion:

Aggressive medical and surgical management can be successful in ocular conservation and restoration of vision in coccidioidal endophthalmitis. Very mild disease may be conservatively monitored and managed with systemic antifungal therapy alone. In severe disease, early diagnosis and prompt and aggressive use of systemic and intravitreal antifungals may spare panophthalmitis and preserve vision.
DARK WITHOUT PRESSURE IN A CASE OF CHOROIDAL OSTEOMA
Authors: Sherman Tatyana , Palileo Bea M. , Adam Christopher R. , Abrams Gary W.
Published: June 2020

Purpose:

To report a novel case of dark without pressure in a patient with a choroidal osteoma. To our knowledge, this association has not been previously reported.

Methods:

Observational case report. Review of clinical examination and multi-modal imaging findings in a patient with a choroidal osteoma and dark without pressure.

Results:

A 21-year-old African American woman with no significant past medical history presented with a large, unilateral, juxtapapillary, subretinal, orange-colored, ovoid-shaped lesion with macular involvement. An overlying area of mottled pigmentary changes, fibrosis, and atrophy were present. Adjacent to and surrounding the osteoma was an annular band of hyperpigmented mid-peripheral retina with a sharply demarcated scalloped border that abruptly changed to normal-appearing peripheral retina. Multi-modal imaging including wide-field fluorescein angiography, optical coherence tomography, and ophthalmic B-scan were performed. The funduscopic and imaging findings were consistent with a diagnosis of choroidal osteoma and dark without pressure.

Conclusion:

The examination and imaging findings in this patient suggest a unique association between two relatively uncommon lesions, choroidal osteoma, and dark without pressure. Although these two lesions may simply be coinciding in the same eye, there may be an association with space-occupying lesions causing a change in photoreceptor structure.
SPONTANEOUS CLOSURE OF SECONDARY ECCENTRIC MACULAR HOLES FOLLOWING VITREORETINAL SURGERY
Authors: Venkatesh Ramesh , Pereira Arpitha , Yadav Naresh K.
Published: June 2020

Purpose:

To report two cases of secondary eccentric macular holes that developed following vitrectomy and present their outcomes.

Methods:

Retrospective, observational case report.

Case Description:

A 69-year-old woman and a 57-year-old man developed secondary paracentral retinal hole following vitrectomy surgery for stage 4 macular hole and proliferative diabetic retinopathy respectively. In Case 1, the hole was left untreated, whereas in Case 2, laser photocoagulation was done around the paracentral retinal hole. In both cases, spontaneous closure of the paracentral retinal holes was noted 12 weeks and 3 weeks after presentation respectively.

Conclusion:

Secondary eccentric retinal holes are extremely rare following vitrectomy. The pathogenesis of macular holes in our cases is most consistent with contraction of the residual internal limiting membrane or preretinal fibrous tissue. Spontaneous closure of small eccentric retinal holes can occur as well which to the best of our knowledge has not yet been reported in literature.
Duration and reliability of the silent period in individuals with spinal cord injury
Authors: Sfreddo Hannah , Wecht Jaclyn R. , Alsalman Ola , Wu Yu-Kuang , Harel Noam Y.
Published: June 2020

Objective

We aim to better understand the silent period (SP), an inhibitory counterpart to the well-known motor evoked potential (MEP) elicited by transcranial magnetic stimulation (TMS), in individuals with spinal cord injury (SCI).

Methods

Electromyographic responses were measured in the target abductor pollicis brevis at rest (TMS at 120% of resting motor threshold (RMT)) and during maximal effort (TMS at 110% of RMT). Participants with chronic cervical SCI (n=9) and able-bodied volunteers (n=12) underwent between 3-7 sessions of stimulation on separate days. The primary outcomes were the magnitude and reliability of SP duration, resting and active MEP amplitudes, and RMT.

Results

SCI participants showed significantly increased RMT, decreased MEP amplitudes, and non-significantly longer SP duration compared to AB participants. In contrast to high inter-participant variability, SP duration demonstrated reduced intra-participant variability within and across sessions compared with resting and active MEP amplitudes. SCI participants also demonstrated a higher prevalence of SP ‘interruptions’ compared to AB participants.

Conclusions

SP reflects a balance between corticospinal excitatory and inhibitory processes. SP duration is more reliable within and across multiple sessions than MEP amplitude.

Significance

The higher reliability of SP duration may make it a useful outcome measure for future trials of SCI interventions.

Highlights

We compared characteristics of the silent period between individuals with spinal cord injury and able-bodied volunteers.

Silent period duration was insignificantly longer in spinal cord injury individuals.

Silent period duration was found to be a more reliable within-subject metric than motor evoked potential amplitude.
Thiamine pyrophosphokinase deficiency induces Alzheimer’s pathology
Authors: Sang Shaoming , Qian Ting , Cai Fang , Qiu Hongyan , Xu Yangqi , Zhang Yun , Zhang Qing , Huang Shajin , Jiang Donglang , Wu Yun , Tong Haiyang , Pan Xiaoli , Wang Changpeng , Cheng Xiaoqin , Zhong Kai , Guan Yihui , Zhu Michael X. , Yu Xiang , Song Weihong , Zhong Chunjiu
Published: June 2020

Background

Thiamine diphosphate (TDP) reduction plays an important role in cerebral glucose hypometabolism, the neurodegenerative indicator, in Alzheimer’s disease (AD). The mechanism underlying TDP reduction remains elusive. Thus, it is critical to define the mechanism and its effect on neurodegeneration, the pathological basis of the disease occurrence and progression.

Methods

The mRNA levels of all known genes associated with thiamine metabolism, includingthiamine pyrophosphokinase(TPK),Solute Carrier Family 19 Member 2 (SLC19A2),SLC19A3, andSLC25A19, in brain samples of patients with AD and other neurodegenerative disorders in multiple independent datasets were analyzed. TPK protein levels were further examined in the brain tissues of AD patients and control subjects. A mouse model with conditional knockout (cKO) ofTPKgene in the excitatory neurons of adult brain was established.

Results

The brainTPKmRNA level was markedly lower in AD patients, but not in other neurodegenerative disorders. The brain TPK protein level was also significantly decreased in AD patients.TPKgene knockout in the mice caused cerebral glucose hypometabolism, β-amyloid deposition, Tau hyperphosphorylation, neuroinflammation, and neuronal loss and brain atrophy. Cross-species correlation analysis revealed the similar changes of gene profiling between the cKO mice and AD patients.

Conclusions

The deficiency of brain TPK, a key enzyme for TDP synthesis, is specific to AD. The cKO mice show AD-associated phenotypes and could serve as a new mouse model for AD studies. Our study provides a novel insight into the critical role of TPK in AD pathogenesis and its potential for the disease treatment.
Temperature-dependent fasciation mutants connect mitochondrial RNA processing to control of lateral root morphogenesis
Authors: Otsuka Kurataka , Mamiya Akihito , Konishi Mineko , Nozaki Mamoru , Kinoshita Atsuko , Tamaki Hiroaki , Arita Masaki , Saito Masato , Yamamoto Kayoko , Hachiya Takushi , Noguchi Ko , Ueda Takashi , Yagi Yusuke , Kobayashi Takehito , Nakamura Takahiro , Sato Yasushi , Hirayama Takashi , Sugiyama Munetaka
Published: June 2020

Although mechanisms that activate organogenesis in plants are well established, much less is known about the subsequent fine-tuning of cell proliferation, which is crucial for creating properly structured and sized organs. Here we show, through analysis of temperature-dependent fasciation (TDF) mutants of Arabidopsis,root redifferentiation defective 1(rrd1),rrd2, androot initiation defective 4(rid4), that mitochondrial RNA processing is required for limiting cell division during early lateral root (LR) organogenesis. These mutants formed abnormally broadened (i.e., fasciated) LRs under high-temperature conditions due to excessive cell division. All TDF proteins localized to mitochondria, where they were found to participate in RNA processing: RRD1 in mRNA deadenylation, and RRD2 and RID4 in mRNA editing. Further analysis suggested that LR fasciation in the TDF mutants is triggered by reactive oxygen species generation caused by defective mitochondrial respiration. Our findings provide novel clues for the physiological significance of mitochondrial activities in plant organogenesis.
Histone deacetylase inhibitor givinostat attenuates nonalcoholic steatohepatitis and liver fibrosis
Authors: Huang He-ming , Fan Shi-jie , Zhou Xiao-ru , Liu Yan-jun , Li Xiao , Liao Li-ping , Huang Jing , Shi Cui-cui , Yu Liang , Fu Rong , Fan Jian-gao , Zhang Yuan-yuan , Luo Cheng , Li Guang-ming
Published: June 2020

Non-alcoholic steatohepatitis (NASH) is a common chronic liver disease that causes worldwide morbidity and mortality, yet there is still a lack of pharmacological therapies. Liver inflammation is an important contributor for disease progression from non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH). We identified HDAC inhibitor givinostat as a potent inhibitor of macrophages inflammatory activation, and aimed to evaluate the therapeutic potential of givinostat for treatment of NASH. Daily administration of givoinostat (10mg/kg) alleviated inflammation and attenuated hepatic fibrosis in methionine- and choline-deficient diet (MCD)-induced NASH mice. RNA-seq analysis of liver tissues form MCD-fed mice revealed givinostat potently blocked expression of inflammation-related genes and regulated a broad set of lipid metabolism-related genes. In hepatocyte givinostat reduced palmitic acid induced intracellular lipid accumulation. The benefit of givinostat was further confirmed in fructose, palmitate, cholesterol diet (FPC) induced NASH mice. Givinostat attenuated hepatic steatosis, inflammation as well as liver injury in FPC-induced NASH. In conclusion, givinostat appears to be efficacious in reversing diet-induced NASH, and may serve as a therapeutic agent for treatment of human NASH.
Genomic Profiling Identifies Somatic Mutations Predicting Thromboembolic Risk in Patients with Solid Tumors
Authors: Dunbar Andrew , Bolton Kelly L. , Devlin Sean M. , Sanchez-Vega Francisco , Gao Jianjiong , Mones Jodi V. , Wills Jonathan , Kelly Daniel , Farina Mirko , Cordner Keith , Park Young , Kishore Sirish , Juluru Krishna , Iyengar Neil M. , Levine Ross L. , Zehir Ahmet , Park Wungki , Khorana Alok A. , Soff Gerald A. , Mantha Simon
Published: June 2020

Cancer-associated venous thromboembolism (CAT) is a well-described complication of cancer and a leading cause of death in cancer patients. The purpose of this study was to assess potential associations of molecular signatures with CAT, including tumor-specific mutations and the presence of clonal hematopoiesis. We analyzed deep-coverage targeted DNA-sequencing data of >14,000 solid tumor samples using the MSK-IMPACT™ platform to identify somatic alterations associated with VTE. Endpoint was defined as the first instance of cancer-associated pulmonary embolism and/or proximal/distal lower extremity deep vein thrombosis. Cause-specific Cox proportional hazards regression was used, adjusting for pertinent clinical covariates. Of 11,695 evaluable individuals, 72% had metastatic disease at time of IMPACT. Tumor-specific mutations in KRAS (HR=1.34 [1.09-1.64]; adjusted p=0.08), STK11 (HR=2.12 [1.55-2.89]; adjusted p<0.001), KEAP1 (HR=1.84 [1.21-2.79]; adjusted p=0.07), CTNNB1 (HR=1.73 [1.15-2.60]; adjusted p=0.09), CDKN2B (HR= 1.45 [1.13-1.85], adjusted p=0.07) and MET (HR=1.83 [1.15-2.92]; adjusted p=0.09) were associated with a significantly increased risk of CAT independent of tumor type. Mutations in SETD2 were associated with a decreased risk of CAT (HR=0.35 [0.16-0.79], adjusted p=0.09). The presence of clonal hematopoiesis was not associated with an increased VTE rate. This is the first large-scale analysis to elucidate tumor-specific genomic events associated with CAT. Somatic tumor mutations of STK11, KRAS, CTNNB1, KEAP1, CDKN2B and MET were associated with an increased risk of VTE in solid tumor patients. Further analysis is needed to validate these findings and identify additional molecular signatures unique to individual tumor types.

Key Points

Tumor mutations in STK11, KRAS, CTNNB1, KEAP1, CDKN2B, MET and SETD2 modulate the risk of cancer-associated thrombosis.

The presence of clonal hematopoiesis does not affect the risk of cancer-associated thrombosis.
Clinical validation and performance evaluation of the automated Vitros Total Anti-SARS-CoV-2 Antibodies assay for screening of serostatus in COVID-19
Authors: Garnett Emily , Jung Joanna , Tam Estella , Rajapakshe Deepthi , Cheney Stephen , Brown Cameron , Muldrew Kenneth L. , Cao Jing , Singh Ila , Versalovic James , Devaraj Sridevi
Published: June 2020

Objectives

Evaluation of serostatus against SARS-CoV-2 has emerged as an important tool in identification of exposure to COVID-19. We report on the validation of the Vitros Anti-SARS-CoV-2 Total (CoV2T) assay for qualitative serological testing of SARS-CoV-2 antibodies.

Methods

We performed validation studies according to COLA guidelines, using samples previously tested for SARS-CoV-2 by RT-PCR. We evaluated precision, analytical interferences, and cross-reactivity with other viral infections. We also evaluated concordance with molecular and other serological testing, and evaluated seroconversion.

Results

The Vitros CoV2T assay exhibited acceptable precision, was resistant to analytical interference, and did not exhibit cross-reactivity with samples positive for other respiratory viruses. The CoV2T assay exhibited 100% negative predictive agreement (56/56) and 71% positive predictive agreement (56/79) with RT-PCR across all patient samples, and was concordant with other serological assays. Concordance with RT-PCR was 97% > 7 days after symptom onset.

Conclusions

The Vitros CoV2T assay was successfully validated in our laboratory. We anticipate it will be a useful tool in screening for exposure to SARS-CoV-2, however, the use of the CoV2T and other serological assays in clinical management of COVID-19 patients is yet unknown, and must be evaluated in future studies.

Key points

What issue or core problem does the study address?

Multiple serological assays for detection of anti-SARS-CoV-2 antibodies have received FDA Emergency Use Authorizations, but few data have been published on the performance of these assays.

What would one take-home point for the working medical professional be?

The Vitros Anti-SARS-CoV-2 Total assay is a total antibody test to be used as a serological screen for exposure to COVID-19. This assay performs well, and is comparable to other serological tests.

What is the most significant or most interesting finding of the study?

We confirmed that the Vitros Anti-SARS-CoV-2 Total assay, like other serological tests, is not suitable for diagnosis of acute infection, as it is not sensitive to infection <7 days post-onset.
Use of face coverings in public during the COVID-19 pandemic: an observational study
Authors: Arp Nicholas L. , Nguyen Tung H. , Linck Emma J. Graham , Feeney Austin K. , Schrope Jonathan H. , Ruedinger Katrina L. , Gao Anqi , Miranda-Katz Margot , Kates Ashley E. , Safdar Nasia
Published: June 2020

Public health agencies have recommended that the public wear face coverings, including face masks, to mitigate COVID-19 transmission. However, the extent to which the public has adopted this recommendation is unknown. An observational study of 3,271 members of the public in May and June 2020 examined face covering use at grocery stores across Wisconsin. We found that only 41.2% used face coverings. Individuals who appeared to be female or older adults had higher odds of using face coverings. Additionally, location-specific variables such as expensiveness of store, county-level population and county-level COVID-19 case prevalence were associated with increased odds of using face coverings. To our knowledge, this is the first direct observational study examining face covering behavior by the public in the U.S., and our findings have implications for public health agencies during the COVID-19 pandemic.
Opto-E-Dura: a Soft, Stretchable ECoG Array for Multimodal, Multi-scale Neuroscience
Authors: Renz Aline F. , Lee Jihyun , Tybrandt Klas , Brzezinski Maciej , Lorenzo Dayra A. , Cheraka Mouna Cerra , Lee Jaehong , Helmchen Fritjof , Vörös Janos , Lewis Christopher M.
Published: June 2020

Soft, stretchable materials hold great promise for the fabrication of biomedical devices due to their capacity to integrate gracefully with and conform to biological tissues. Conformal devices are of particular interest in the development of brain interfaces where rigid structures can lead to tissue damage and loss of signal quality over the lifetime of the implant. Interfaces to study brain function and dysfunction increasingly require multimodal access in order to facilitate measurement of diverse physiological signals that span the disparate temporal and spatial scales of brain dynamics. Here we present the Opto-e-Dura, a soft, stretchable, 16-channel electrocorticography array that is optically transparent. We demonstrate its compatibility with diverse optical and electrical readouts enabling multimodal studies that bridge spatial and temporal scales. The device is chronically stable for weeks, compatible with wide-field and 2-photon calcium imaging and permits the repeated insertion of penetrating multi-electrode arrays. As the variety of sensors and effectors realizable on soft, stretchable substrates expands, similar devices that provide large-scale, multimodal access to the brain will continue to improve fundamental understanding of brain function.
PD-L1hiplasmablasts limit the T cell response during the acute phase of parasite infections
Authors: Serrán Melisa Gorosito , Vernengo Facundo Fiocca , Almada Laura , Beccaria Cristian G , Canete Pablo F , Alegre Jonathan Rocco , Boari Jimena Tosello , Ramello Maria Cecilia , Wehrens Ellen , Cai Yeping , Zuniga I Elina , Montes Carolina L , Rodriguez Eva V Acosta , Cockburn Ian A. , Vinuesa Carola G , Gruppi Adriana
Published: June 2020

During infections with protozoan parasites or virus, T cell immunosuppression is generated simultaneously with a high B cell activation. Here, we show that inT. cruziinfection, all plasmablasts detected had higher surface expression of PD-L1, than other mononuclear cells. PD-L1hiplasmablasts were inducedin vivoin an antigen-specific manner and required help from Bcl-6+CD4+T cells. PD-L1hiexpression was not a characteristic of all antibody-secreting cells since plasma cells found during the chronic phase of infection express PD-L1 but at lower levels. PD-L1hiplasmablasts were also present in mice infected withPlasmodiumor with lymphocytic choriomeningitis virus, but not in mice with autoimmune disorders or immunized with T cell-dependent antigens. PD-L1hiplasmablasts suppressed T cell response, via PD-L1,in vitroandin vivo. Thus, this study reveals that extrafollicular PD-L1hiplasmablasts, which precede the germinal center (CG) response, are a suppressive population in infections that may influence T cell response.

Brief summary

Pathogens develop different strategies to settle in the host. We identified a plasmablats population induced by pathogens in acute infections which suppress T cell response.
A distributed network of noise-resistant neurons in the central auditory system
Authors: Souffi S. , Lorenzi C. , Huetz C. , Edeline J.-M.
Published: June 2020

Background noise strongly penalizes auditory perception of speech in humans or vocalizations in animals. Despite this, auditory neurons successfully detect and discriminate behaviorally salient sounds even when the signal-to-noise ratio is quite poor. Here, we collected neuronal recordings in cochlear nucleus, inferior colliculus, auditory thalamus, primary and secondary auditory cortex in response to vocalizations presented either against a stationary or a chorus noise. Using a clustering approach, we provide evidence that five behaviors exist at each level of the auditory system from neurons with high fidelity representations of the target, named target-specific neurons, mostly found in inferior colliculus and thalamus, to neurons with high fidelity representations of the noise, named masker-specific neurons mostly found in cochlear nucleus in stationary noise but in similar proportions in each structure in chorus noise. This indicates that the neural bases of auditory perception in noise rely on a distributed network along the auditory system.
Emotional Metacognition: Stimulus Valence Modulates Cardiac Arousal and Metamemory
Authors: Legrand Nicolas , Engen Sebastian Scott , Correa Camile Maria Costa , Mathiasen Nanna Kildahl , Nikolova Niia , Fardo Francesca , Allen Micah
Published: June 2020

Emotion alters how we feel, see, and experience the world. In the domain of memory, the emotional valence and arousal of memorised stimuli can modulate both the acuity and content of episodic recall. However, no experiment has investigated whether arousal and valence also influence metacognition for memory (i.e., the process of self-monitoring memories). In a pre-registered study, we applied a novel psychophysiological design together with computational models of metacognition to assess the influence of stimulus valence and arousal on the sensitivity, bias, and efficiency of metamemory. To estimate the role of physiological arousal in mediating these effects, we recorded cardiac measures through pulse oximetry. We found that negative valence substantially decreased both memory performance and subjective confidence, in particular for low arousal words. Simultaneously, we found that emotional valence modulated both heart rate and heart-rate variability (HRV) during recognition memory. Exploratory trial-level analyses further revealed that subjective confidence was encoded in instantaneous heart-rate fluctuations and that this relationship was also modulated by emotional valence. Our results demonstrate that recognition memory and metacognition are influenced by the emotional valence of encoded items and that this correlation is in part related to cardiac activity.
Rich resource environment of fish farms facilitates phenotypic variation and virulence in an opportunistic fish pathogen
Authors: Pulkkinen Katja , Ketola Tarmo , Laakso Jouni , Mappes Johanna , Sundberg Lotta-Riina
Published: June 2020

Phenotypic variation allows adaptation of opportunistic pathogens to variable conditions in the outside-host environment with strong effects on their epidemiology and pathogenicity in hosts. Here we found that the isolates of an opportunistic fish pathogenFlavobacterium columnarefrom fish farming environment had higher phenotypic variation between two morphotypes in growth, as compared to the isolates from the natural water environment. The rough morphotypes had higher growth rate than the rhizoid morphotypes especially in the higher resource concentrations and in the higher temperature, but only if the isolate was originating from the fish farms. Rhizoid morphotype was more virulent than the rough type regardless of their origin. However, the virulence of the rough type increased sharply with the size of the fish, and the bacterial isolates from the gills of diseased fish were rhizoid type, indicating a reversal of the rough morphotype into rhizoid in contact with the fish. The high growth rate of the rough morphotype combined with the morphotype reversibility could increase the probability of columnaris epidemics at fish farms. Our findings suggest that intensive farming imposes different selection pressures on bacterial survival in the outside-host environment and its transmission compared to the natural water environment.