bluuebunny/crossref_metadata_2025 huggingface dataset:
Novel NOX2 inhibitor Mito‐Apocynin Protects Against LPS‐induced Endotoxemia Pre‐Clinical Animal Model
Authors: Padhi Piyush , Lou Jie , Jin Huajun , Anantharam Vellareddy , Kanthasamy Arthi , Kanthasamy Anumantha
Published: June 2021

Sepsis is a serious medical condition caused by the body's response to an infectious or noninfectious insult. Various experimental data suggests that systemic inflammation resulting from the release of pro‐inflammatory cytokines and the chronic activation of the innate immune system is a key pathophysiological contributor to sepsis. The existing therapy for sepsis has largely been ineffective due to the heterogeneity in clinical severity and presentation among individuals. Commonly, Lipopolysaccharide (LPS) is used as an endotoxin to generate a pre‐clinical mouse model of sepsis model. Intraperitoneal injection of purified LPS has been shown to trigger systemic activation of the innate immune response followed by organ injury and mortality in mice. Recently, we demonstrated a newly‐synthesized and orally available derivative of apocynin that targets mitochondria, mito‐apocynin (Mito‐Apo), to be efficacious as an anti‐neuroinflammatory agent to inhibit NOX2 activity, oxidative damage and improve mitochondrial function in both cellular and pre‐clinical animal models of Parkinson's disease. Herein, we further evaluated the pre‐clinical efficacy of Mito‐Apo in the LPS‐induced endotoxemic mouse model of sepsis. C57BL6 mice were administered LPS (5 mg/kg, i.p. once) and Mito‐Apo (30 mg/kg, oral gavage, four times every 6 h at 0, 6, 12 and 18 h), and blood was collected at 1, 3 and 24 h post‐LPS treatment. Mice were sacrificed at 24 h post‐LPS injection. Initial results showed that oral interval administration of Mito‐Apo significantly attenuates LPS‐induced systemic inflammation evidenced by reduced circulating pro‐inflammatory cytokines interleukin‐β (IL‐1β) and tumor necrosis factor‐α (TNF‐α) in plasma and decreased proIL‐1β/TNF‐α mRNA expression levels in mouse liver. Importantly, Mito‐Apo was also shown to significantly reduce LPS‐induced mortality and protect against LPS‐induced motor deficits. Collectively, these findings demonstrate that Mito‐Apo could be used as a novel plausible therapeutic agent for treating sepsis.

Support or Funding Information

NS088206, ES026892 and NS100090, Lloyd Endowed Chair

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Formononetin attenuates isoproterenol‐induced cardiac toxicity in rats owing to its antioxidant, anti‐inflammatory and anti‐apoptotic activity
Authors: Suchal Kapil , Arya D S , Singh Sunita
Published: June 2021

Introduction

A high rate of mortality and morbidity is associated with myocardial infarction (MI), indicating a need to hunt for newer treatment modalities. Formononetin (FMN) is a dietary flavonoid with remarkable antioxidant and anti‐apoptotic properties. Therefore, the aim of this study was to evaluate the ability of FMN in attenuating isoproterenol (ISO) induced oxidative stress and myocardial infarction.

Methods

A total of 48 Male Wistar rats were administered either FMN (5, 10 or 20 mg/kg/day, i.p.) or vehicle for 15 days along with subcutaneous ISO, 85 mg/kg for 2 consecutive days i.e. 13th and 14th days. On the 15th day, rats were anaesthetized followed by cannulation of right coronary artery to record hemodynamic parameters. Blood sample was collected and heart was excised to evaluate for biochemical, histopathological, ultrastructural and immuohistochemical studies.

Results

ISO‐treated rats demonstrated disturbed hemodynamic. There was also a significant decrease in antioxidant enzyme levels and increase in the level, of malondialdehyde, serum TNF‐α and IL‐6. The cardiac injury markers like creatine kinase‐MB and lactate dehydrogenase were increased in the serum. Additionally, immunohistochemistry displayed an increased Bax/Bcl‐2 ratio in the myocardium. Histopathological and ultrastructural studies support the protective effect of FMN in ISO‐induced myocardial infarcted rats.

Conclusion

FMN alleviates myocardial damage in ISO induced cardiac injury by preserving hemodynamic and biochemical function and reducing inflammation due to its anti‐apoptotic, anti‐inflammatory and antioxidant activities.

Support or Funding Information

The Project has been funded by the AIIMS, Delhi

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Phoca vitulina swallowing physiology using videofluoroscopy: Creating a comparative rehabilitation model
Authors: Skoretz Stacey A , Haulena Martin , Akhurst Lindsaye , Johnson Emily , Dawson Camilla
Published: June 2021

Background

Up to 150 wild harbor seal pups (Phoca vitulina) are admitted annually to our rescue centre. All require medical management including gavage feeding until weaned to whole fish prior to release back to the wild. The rehabilitation model is personnel intensive requiring animal restraint and force feeding. To the best of our knowledge, no systematic imaging has been conducted on the upper aerodigestive tract of wild seal pups. As a result, the information regarding their swallowing physiology is limited as are ways in which to optimize their feeding and swallowing rehabilitation. Our objectives were to develop a videofluoroscopic swallowing study (VFSS) protocol and to determine the feasibility of conducting a VFSS with a wild seal.

Methods

Feasibility parameters included the determination of: contrast delivery methods, image capture and analyses, and the operational and infrastructure requirements. A Siemens mobile c‐arm fluoroscopy unit and retrofitted tub were utilized for imaging. After thawing, we injected whole flash‐frozen herring with liquid barium suspension (105% w/v). Recently weaned seals (N = 2) were imaged at 30 frames per second with loss less capture. Two blinded raters evaluated swallow physiology across 6 metrics with disagreements resolved by consensus. Results were summarized descriptively.

Results

We conducted a freely‐behaving videofluoroscopic swallowing study on two infant seals (1 male: 8 wks, 3 d; 1 female: 5 wks, 3 d). Personnel included veterinarian, veterinary technicians (2), imaging technician and VFSS raters (2). Five boluses were administered to each seal (67–90 g each) with a total exposure of 2 min, 54 sec. We identified three distinct swallow phases: preparatory (preswallow), oropharyngeal and esophageal. The preparatory phase was characterized by airway closure and base of tongue (BOT) positioning. The oropharyngeal phase included bolus transport via BOT retraction, repeated anterior‐superior hyolaryngeal excursion, and posterior pharyngeal wall contraction. Bolus propulsion to the stomach occurred during the esophageal phase.

Conclusions

We have successfully conducted the first‐ever VFSS on wild seal pups. With this protocol, we will gather the first normative swallowing data, enhance diagnostic capabilities and potentially improve feeding and swallowing rehabilitation for this population. Ultimately, this will inform our development of the first cross‐species conceptual swallowing framework between seals and humans facilitating a synergistic knowledge translation model.

Support or Funding Information

Dr. Skoretz’ startup funding from the Faculty of Medicine and the School of Audiology and Speech Sciences at UBC provided support for this project.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Inverse relationship between very low‐density lipoprotein (VLDL) ceramides, diacylglycerols, and triacylglycerols in human hepatic lipid accumulation
Authors: Mucinski Justine M , Syed‐Abdul Majid Mufaqam , Garrett Timothy J , Parks Elizabeth J
Published: June 2021

Ceramides (CER), along with other lipotoxic lipids (diacylglycerols, DAG and triacylglycerols, TG), have been implicated in the development and progression of nonalcoholic fatty liver disease (NAFLD). No study to date has measured CER, DAG, and TG concentrations in VLDL with relation to liver fat content. Twelve male subjects with characteristics that put them at risk for NAFLD (mean±SD, age 42.1±5.4y, BMI 37.8±3.5 kg/m2, ALT 45±21 U/L) were studied. VLDL particles were isolated in the fasted state and lipid species measured via UHPLC‐MS/MS analysis. VLDL‐apoB100 was measured by ELISA and intrahepatic triglycerides (IHTG) by MRS. Total VLDL‐CER concentrations were positively correlated with both VLDL‐TG (r = 0.572, P = 0.004) and VLDL‐apoB100 (r = 0.557, P = 0.005). Total VLDL‐DAG concentrations were significantly positively correlated with VLDL‐apoB100 (r = 0.724, P < 0.001), tended to correlate with VLDL‐TG (r = 0.263, P = 0.088) but were most strongly correlated with VLDL‐CER (figure, r = 0.860, P < 0.001). With regard to IHTG, both plasma VLDL‐CER and VLDL‐TG were negatively correlated with liver fat (r = −0.447, P = 0.018 and r = −0.551, P = 0.006, respectively), while the relationship between IHTG and VLDL‐DAG was more modest (r = −0.290, P = 0.071). These data suggest that CER, DAG, and TG are packaged together in the liver and secreted simultaneously on VLDL particles. A less likely scenario is that CER or DAG are added to VLDL after the particles have been secreted into the plasma. These data support the concept that hepatic secretion rates of CER and TG, and to some extent, DAG, are potentially beneficial physiological processes that lower excess hepatic lipid accumulation in metabolic syndrome to support overall liver health.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Co‐delivery of curcumin and fish oil in phospholipid nanoemulsions attenuates motor impairments and neuro‐inflammation in MPTP induced Parkinson's disease rat model
Authors: Dhavamani Sugasini , Lokesh B.R.
Published: June 2021

Parkinson disease (PD) is a major neurodegenerative disorder that affects mostly the elderly persons. More than 10 million people worldwide are living with PD. This disease causes neurofibrillary tangles, loss of neurons, synaptic dysfunction, mitochondrial dysfunction, postular instability, muscular rigidity and neurotransmitter imbalance and also triggers oxidative stress and enhanced inflammatory responses. However, there is no effective treatment for PD at present in spite of growing understanding of the disorder. Recent studies suggest that DHA may be a potential neuroprotective compound for PD. We have earlier demonstrated that nanocurcumin exhibit anti‐inflammatory activity and also reduce oxidative stress. Co‐ingestion of curcumin with omega 3 rich oils also enhanced DHA as well as neurotransmitter levels in rat brain. However their influence on PD has received very little attention. The present study was undertaken to investigate the effects of nanocurcumin along with fish oil containing DHA on behavioral deficits, oxidative damage and related mechanisms in MPTP administered rats. The results demonstrated that rats given nanocurcumin with DHA significantly alleviated motor dysfunction in MPTP administered rats. Biochemical measurements indicated that rats administered with nanocurcumin exhibited increased glutathione levels, reduced ROS, iNOS and malondialdehyde content. Mechanistic studies demonstrated that BDNF and NGF levels were marginally increased in striatum of rats given nanocurcumin with DHA as compared to MPTP administered rats. Rats given nanocurcumin with DHA enhanced the monoamines neurotransmitter levels and protected from dopaminergic neuronal loss. Moreover, DHA along with phospholipid emulsions played a major role as a neuroprotective agent. The DHA level of was significantly improved in all brain regions of rat given nanocurcumin in MPTP administered rats. The phospholipids of PC‐ DHA and PE‐ DHA also significantly enhanced in brain regions of rats given nanocurcumin in MPTP administered rats and restored it to the normal levels in all regions of brain. The novelty of these findings is the demonstration of improved motor functions, striatal neurotransmitters and dopaminergic neuronal loss protection by nano‐curcumin and fish oil enriched in DHA in MPTP intoxicated rats. These results suggest that the co‐delivery of nanocurcumin and DHA containing oil administered in phospholipid emulsions may benefit for the prevention and treatment for PD patients.

Support or Funding Information

ICMR, CSIR

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Astrocyte Activation is Increased in a Rat Endometriosis Model
Authors: Flores‐Bonilla Annabelle , Cruz Myrella L , Appleyard Caroline , Chompre Gladys
Published: June 2021

Peripheral inflammation produces an immune response in the brain by the activation of microglia and astrocytes. Astrocytes are also involved in the pain symptoms of chronic diseases such as endometriosis, which is characterized by the growth of uterine tissue outside the reproductive organs. Studies using a mouse model of endometriosis found an increase in astrocytes in the spinal cord but effects in the various brain regions such as the hippocampus are still unknown. However, decreased grey matter value in women with endometriosis experiencing chronic pelvic pain suggests the involvement of the central nervous system. Previous studies in our lab found an increase in hyperalgesia symptoms in a rat model of endometriosis, however, the activation of glia cells such astrocytes and microglia in the central nervous system is still unknown.

Aim

Study the effects of endometriosis on astrocyte and microglia activation in the hippocampus.

Methods

Endometriosis was induced by implanting uterine tissue in the intestinal mesentery in female Sprague Dawley rats that weighed more than 200g (ENDO group). Control animals received only sutures in the same region (SHAM). Sixty days after the induction of endometriosis, both groups underwent behavioral testing using open field followed by sacrifice to collect brain and endometrial tissue. Brain sections were stained against the astrocyte marker, Glial Fibric Acid Protein (GFAP), and the microglia marker, ionized calcium‐binding adapter molecule 1 (IBA‐1), and both the percent area and number and length of projections was measured using ImageJ.

Results

The ENDO group developed vesicles with a mean total area of 49.67 mm2, indicating development of endometriosis. The ENDO group showed no significant differences in entries to the center of the open field arena (p>0.05; n=4–6), however they had significantly less velocity and travelled less distance compared with the SHAM group (p<0.05; n=4–6). Brain immunofluorescence shows an increase in the percent of area of GFAP positive staining, and an increase in the number and length of astrocyte projections in the hippocampus in the ENDO group compared with the SHAM (p<0.05; n=4–6). No significant differences were found with microglia.

Conclusions

Our results demonstrate the possible involvement of astrocytes in the brain of the rat endometriosis model. Astrocyte activation in the hippocampus may be associated with peripheral inflammation and contribute to the hyperalgesia and depressive behavior often associated with endometriosis.

Support or Funding Information

Supported in part by P20 GM103475‐16 & R15AT009915.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Effects of Intracerebroventricular Administration of Colony Stimulating Factor 1 Receptor Inhibitor on Microglia
Authors: Kasihara Soichiro , Shinohara Keisuke , Tsutsui Hiroyuki
Published: June 2021

Background

Microglia play an important role in innate immunity in the brain and are suggested to be involved in the pathogenesis of cardiovascular diseases, as well as neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. Colony stimulating factor 1 (CSF1) regulates the proliferation, differentiation, and survival of microglia and macrophages. Although previous studies have demonstrated that repeated oral administration of a CSF1R inhibitor PLX3397 leads to microglia elimination, systemic administration of PLX3397 affects also peripheral macrophages. Therefore, to establish a method for selective elimination of microglia is needed in order to investigate the roles of microglia independently from peripheral macrophages particularly in systemic diseases, such as cardiovascular diseases. In this study, we evaluated the effects of intracerebroventricular administration of PLX3397 on microglia.

Methods and Results

We intracerebroventricularly injected PLX3397 (0.45mg/kg) in male 9‐week‐old Wistar‐Hannover rats and collected their brains on 1, 2 and 4 days after administration. Rats without PLX3397 treatment were used as control. We evaluated microglia in hypothalamic paraventricular nucleus, an important nucleus for cardiovascular control, by immunohistochemistry using anti‐Iba1 antibody. The number of microglia was decreased on 1 day after administration (Day 1) and was almost restored to control on Day 4 (control, 32.5±0.8/HPF, n=6; Day 1, 25.8±1.1/HPF, n=2; Day 2, 27.0±1.0/HPF, n=2; Day 4, 31.5±1.5/HPF, n=1). Morphological analyses of surviving microglia revealed a smaller cell size and an increased circularity (cell perimeter: control, 1282±70 μm; Day 1, 758±6 μm; Day 2, 850±30 μm; Day 4, 940±50 μm, cell area: control, 1049±35 μm2; Day 1, 700±35 μm2; Day 2, 798±50 μm2; Day 4, 838±51 μm2, circularity: control, 0.0087±0.00089; Day 1, 0.0174±0.00029; Day 2, 0.0159±0.00041; Day 4, 0.0134±0.0011), which are typically observed in activated microglia, in the PLX3397‐treated rats. These morphological changes tended to be restored as the time elapsed after the PLX3397 administration.

Conclusion and Perspectives

Single intracerebroventricular injection of CSF1R inhibitor PLX3397 reduced the number of microglia. However, the degree of microglial reduction was small and the effect was transient. Multiple injections or continuous infusion of PLX3397 intracerebroventricularly will be needed to robustly eliminate microglia. Further, it should be clarified whether the PLX3397‐induced morphological changes of microglia are resulted from microglial activation or process of microglial apoptosis.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Sex differences in vascular expression and activation of STIM‐1/Orai‐1 during hypertension: focus on calcium regulation
Authors: Giachini Fernanda , Carneiro Fernando S , Lima Victor V , Carneiro Zidonia N , Dorrance Anne , Tostes Rita C , Webb R. Clinton
Published: June 2021

Sex‐related differences in Ca2+‐dependent signaling contributes to greater contractile‐responses in male hypertensive rats. We hypothesized that vascular protection in females reflects differences in Ca2+ mobilization due to differential activation of CRAC (Ca2+ release‐activated Ca2+) channels through Orai1, via its interaction with the intracellular Ca2+ sensor STIM‐1 (stromal interaction molecules). Endothelium‐denuded aortic rings from male and female stroke prone spontaneously hypertensive rats (SHRSP) and Wistar‐Kyoto (WKY) rats were used to functionally evaluate Ca2+ influx‐induced contraction. Sarcoplasmic reticulum Ca+2 ATPase was inhibited with thapsigargin (10uM). During the Ca2+ loading period: (1) force development was augmented in aortas from male SHRSP (10.0±0.9mN, n=6) vs. female (7.5±1.1mN, n=6); (2) CRAC channel blockade with 2‐APB and Gd3+ as well as (3) neutralizing antibodies against STIM‐1 and Orai‐1 normalized differences in contraction between aortas from male and female SHRSP. Expression of Orai‐1 and STIM‐1 proteins was increased in aorta from male SHRSP, vs. female SHRSP or WKY. Augmented activation of STIM‐1/Orai‐1 in aorta from male SHRSP may represent a mechanism that contributes to sex‐related impaired control of intracellular Ca2+ levels.

Financial support: NIH ‐ HL71138 and HL74167
Children's Oral Health in Nursing Education and Practice: A Call for Action
Authors: Wilson Kristi Jo , Linton Mary , Koonmen Jamie
Published: June 2021

Dental caries are preventable but remain all too common.
Team-Based Care is Better for Chronic Disease Management
Authors: Rosenberg Karen
Published: June 2021

According to this study:

Provider teams of all compositions outperformed solo providers in managing three common new-onset chronic diseases.
Discontinuation of Thyroid Hormone Replacement is Possible in Some Cases
Authors: Rosenberg Karen
Published: June 2021

According to this study:

As many as one-third of patients remained euthyroid after the discontinuation of thyroid hormone replacement.
Intermittent Auscultation Reduces Risk of Emergency Cesarean Delivery
Authors: Rosenberg Karen
Published: June 2021

According to this study:

Compared with other fetal surveillance methods, intermittent auscultation seems to reduce the risk of emergency cesarean delivery without increasing that of adverse neonatal and maternal outcomes.

Newer methods of fetal surveillance didn't improve neonatal outcomes or reduce the risk of unnecessary maternal interventions.
Of Swamps and Pandemics
Authors: Sturtevant Pamela
Published: June 2021

Finding perspective on current events in an ancient and fabled landscape.
Smoking and Smoking Relapse in Postpartum: A Systematic Review and Meta-analysis
Authors: Amiri Sohrab , Saadat Seyed H.
Published: June 2021

Objectives:

Smoking is a well-known factor in the negative health outcomes worldwide. This study aims to determine the smoking prevalence and relapse in women in the postpartum period based on the meta-analysis method.

Methods:

The steps provided by Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) were followed. According to keywords extracted by authors, 3 sources were searched until April 2020. To analyze the prevalence of smoking and relapse, the size of the sample and the event were calculated for eligible studies, and then the prevalence was calculated. Heterogeneity for all analyses and subgroups was investigated.

Result:

Forty articles were eligible for evaluation of the prevalence of smoking and smoking relapse in the postpartum period. The pooled prevalence of smoking/smoking relapse was 30%, with a confidence interval (CI) of 26%-34% and I
2=99.5%. The prevalence of smoking was 19% (CI=15%-22%, I
2=98.86%) and the prevalence of smoking relapse was 46% (CI=39%-54%, I
2=98.86%). The prevalence of 6-month postpartum smoking/smoking relapse was 29% (CI=23%-34%, I
2=99.42%). The prevalence of smoking/smoking relapse between 6 and 18 months was 31% (CI=24%-39%, I
2=99.51%).

Discussion:

Due to the role of smoking in disease and predisposing individuals to various diseases, and the prevalence of smoking and relapse in the postpartum period, it is necessary to develop prevention and awareness programs in this respect.
Efficacy of intratracheal budesonide-surfactant combined therapy in surfactant-insufficient rat lungs with lipopolysaccharide insult
Authors: Tsao Pei-Chen , Lin Chih-Hsueh , Lee Yu-Sheng , Chen Wei-Yu , Jeng Mei-Jy , Kou Yu Ru
Published: June 2021

Background:

Intratracheal steroid therapy for lipopolysaccharide (LPS)-induced acute lung injury (ALI) remains challenging particularly in surfactant-insufficient lungs, a common problem of neonatal or pediatric ALI. Surfactant has been used as a vehicle for intratracheal steroid in the treatment of other types of ALI. This study investigated the efficacy of intratracheal budesonide (BUD) delivered by two concentrations of surfactant in the treatment of LPS-induced ALI in surfactant-insufficient rat lungs.

Methods:

Male adult rats were anesthetized and ventilated. Our ALI model was established by repeated saline lavage to produce surfactant insufficiency, followed by intratracheal LPS instillation. Five study groups (n = 5 for each) with different intratracheal treatments following ALI were used: control (no treatment), BUD (NS-BUD; BUD in saline), DS-BUD (BUD in diluted surfactant), FS-BUD (BUD in full-strength surfactant), FS (full-strength surfactant). Cardiopulmonary variables were monitored 4 hours post injury. Histological and immunohistochemical assessments of the lungs were performed.

Results:

The FS-BUD and FS groups presented better gas exchange, less metabolic acidosis, less oxygen index, and more stable hemodynamic changes than the DS-BUD, NS-BUD, and control groups. The total lung injury scores assessed by histological examination were ordered as follows: FS-BUD < DS-BUD or FS < NS-BUD < control. The immunostaining intensities of lung myeloperoxidase showed the following order: NS-BUD, DS-BUD, or FS-BUD < control or FS. Only the FS-BUD group displayed a smaller immunostaining intensity of lung tumor necrosis factor (TNF)-α than the control group.

Conclusion:

Among our therapeutic strategies, intratracheal BUD delivered by full-strength surfactant confers an optimal protection against LPS-induced ALI in surfactant-insufficient rat lungs.
Percutaneous Endoscopic Gastrostomy in Children: An Update to the ESPGHAN Position Paper
Authors: Homan Matjaž , Hauser Bruno , Romano Claudio , Tzivinikos Christos , Torroni Filippo , Gottrand Frédéric , Hojsak Iva , Dall’Oglio Luigi , Thomson Mike , Bontems Patrick , Narula Priya , Furlano Raoul , Oliva Salvatore , Amil-Dias Jorge
Published: June 2021

Background:

The European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) position paper from 2015 on percutaneous endoscopic gastrostomy (PEG) required updating in the light of recent clinical knowledge and data published in medical journals since 2014.

Methods:

A systematic review of medical literature from 2014 to 2020 was carried out. Consensus on the content of the manuscript, including recommendations, was achieved by the authors through electronic and virtual means. The expert opinion of the authors is also expressed in the manuscript when there was a lack of good scientific evidence regarding PEGs in children in the literature.

Results:

The authors recommend that the indication for a PEG be individualized, and that the decision for PEG insertion is arrived at by a multidisciplinary team (MDT) having considered all appropriate circumstances. Well timed enteral nutrition is optimal to treat faltering growth to avoid complications of malnutrition and body composition. Timing, device choice and method of insertion is dependent on the local expertise and after due consideration with the MDT and family. Major complications such as inadvertent bowel perforation should be avoided by attention to good technique and by ensuring the appropriate experience of the operating team. Feeding can be initiated as early as 3 hours after tube placement in a stable child with iso-osmolar feeds of standard polymeric formula. Low-profile devices can be inserted initially using the single-stage procedure or after 2–3 months by replacing a standard PEG tube, in those requiring longer-term feeding. Having had a period of non-use and reliance upon oral intake for growth and weight gain—typically 8–12 weeks—a PEG may then safely be removed after due consultation. In the event of non-closure of the fistula the most successful method for closing it, to date, has been a surgical procedure, but the Over-The-Scope-Clip (OTSC) has recently been used with considerable success in this scenario.

Conclusions:

A multidisciplinary approach is mandatory for the best possible treatment of children with PEGs. Morbidity and mortality are minimized through team decisions on indications for insertion, adequate planning and preparation before the procedure, subsequent monitoring of patients, timing of the change to low-profile devices, management of any complications, and optimal timing of removal of the PEG.
Neuromuscular complications of coronavirus disease-19
Authors: Suh Joome , Amato Anthony A.
Published: June 2021

Purpose of review

Since its outbreak in Wuhan, China in late 2019, coronavirus disease-19 (COVID-19) has become a global pandemic. The number of affected cases and deaths continues to rise. Primarily a respiratory illness, COVID-19 is now known to affect various organ systems including peripheral nerve and skeletal muscle. The purpose of this review is to discuss the scope of neuromuscular manifestations and complications of COVID-19.

Recent findings

Several neuromuscular conditions, including Guillain-Barré syndrome, rhabdomyolysis, and myositis, have been reported in patients infected with COVID-19, but even with a temporal association, a causal relationship remains unproven. Direct invasion of neurons or myocytes by the virus, and immune-mediated injury have been speculated but not consistently demonstrated. In addition to potentially causing the above conditions, COVID-19 can trigger exacerbations of preexisting neuromuscular conditions such as myasthenia gravis, and severe infections can lead to critical illness myopathy/polyneuropathy.

COVID-19 appears to be potentially associated with a wide range of neuromuscular manifestations and complications. Further studies are needed to examine these possible associations, understand the pathogenesis, and develop preventive and treatment strategies.
Neuroimaging in Triphasic Waves
Authors: Rahwan Mohamad , Edwards Jonathan C.
Published: June 2021

Triphasic waves can be seen in a wide range of medical conditions, particularly in metabolic encephalopathies. Neuroimaging studies provide valuable diagnostic information for neurological conditions and can also help in our understanding of anatomical substrates for these conditions. Because of practical challenges and the fact that most encephalopathies with triphasic waves are presumed to be metabolic in etiology, large studies of imaging findings associated with triphasic waves are limited. We present a summary of studies that are currently available and a discussion of insights that these studies provide.
Inequalities in initiation of COVID19 vaccination by age and population group in Israel-December 2020-April 2021
Authors: Gorelik Yanay , Edelstein Michael
Published: June 2021

Background

In Israel, COVID19 vaccination coverage varies widely by population group and age. Despite the vaccine being locally and freely available in the entire country. Comparing crude coverage between localities and population groups is misleading because of differing age structures in different population groups. In order to describe inequalities in COVID19 vaccine initiation we determined differences in age-specific dose 1 vaccine coverage between the main population groups in Israel, and characterised the influence of age on vaccine coverage within each of these groups.

Methods

We obtained daily doses administered by municipality and age from the Ministry of Health, and demographic data from the Central Bureau of Statistics. We determined whether the relative proportion of people vaccinated in each age group (15-19, 20-29, 30-39, 40-49, 50-59, 60+) changed by population group (General Jewish, Ultra-Orthodox and Arab) using ANOVA and quantified association between age, population group and vaccine coverage using binomial regression.

Results

8,507,723 individuals in 268 localities were included. Compared with the General Jewish population, vaccine coverage was lower among the Arab and Ultra-Orthodox populations and lowest in the Ultra-Orthodox population in all age groups. Gaps between population groups differed according to age group (p<0.001). In all populations, coverage decreased with decreasing age (p<0.001). The Ultra-orthodox population was the least vaccinated in all age groups relatively to those aged 60 and over

Conclusions

In all age groups, the Ultra-Orthodox population had the lowest vaccine coverage. The younger the age group, the more Ultra-Orthodox Jews are diverging from their age peers in terms of initiating COVID19 vaccination. These findings suggest generational differences in terms of vaccination behaviour in this group. Qualitative studies understanding the causes behind this divergence can inform tailored vaccination strategies.
The majority of the variation in COVID-19 rates between nations is explained by median age, obesity rate, and island status
Authors: Fraiman Joseph B. , Ludwin-Peery Ethan , Ludwin-Peery Sarah
Published: June 2021

Since the World Health Organization declared SARS-CoV-2 to be a global pandemic on March 11, 2020, nearly every nation on earth has reported infections. Incidence and prevalence of COVID-19 case rates have demonstrated extreme geospatial and temporal variability across the globe. The outbreaks in some countries are extreme and devastating, while other countries face outbreaks that are relatively minor. The causes of these differences between nations remain poorly understood, and identifying the factors that underlie this variation is critical to understand the dynamics of this disease in order to better respond to this and future pandemics.

Here, we examine four factors that we anticipated would explain much of the variation in COVID-19 rates between nations: median age, obesity rate, island status, and strength of border closure measures. Clinical evidence suggests that age and obesity increase both the likelihood of infection and transmission in individual patients, which make them plausible demographic factors. The third factor, whether or not each country is an island nation, was selected because the geographical isolation of islands is expected to influence COVID-19 transmission. The fourth factor of border closure was selected because of its anticipated interaction with island nation status.

Together, these four variables are able to explain a majority of the international variance in COVID-19 case rates. Using a dataset of 190 countries, simple modeling based on these four factors and their interactions explains more than 70% of the total variance between countries. With additional covariates, more complex modeling and higher-order interactions explains more than 80% of the variance. These novel findings offer a solution to explain the unusual global variation of COVID-19 that has remained largely elusive throughout the pandemic.
Association between overcrowded households, multigenerational households, and COVID-19: a cohort study
Authors: Ghosh Arnab K. , Venkatraman Sara , Soroka Orysya , Reshetnyak Evgeniya , Rajan Mangala , An Anjile , Chae John K. , Gonzalez Christopher , Prince Jonathan , DiMaggio Charles , Ibrahim Said , Safford Monika M. , Hupert Nathaniel
Published: June 2021

Introduction

The role of overcrowded and multigenerational households as a risk factor for COVID-19 remains unmeasured. The objective of this study is to examine and quantify the association between overcrowded and multigenerational households, and COVID-19 in New York City (NYC).

Methods

We conducted a Bayesian ecological time series analysis at the ZIP Code Tabulation Area (ZCTA) level in NYC to assess whether ZCTAs with higher proportions of overcrowded (defined as proportion of estimated number of housing units with more than one occupant per room) and multigenerational households (defined as the estimated percentage of residences occupied by a grandparent and a grandchild less than 18 years of age) were independently associated with higher suspected COVID-19 case rates (from NYC Department of Health Syndromic Surveillance data for March 1 to 30, 2020). Our main measure was adjusted incidence rate ratio (IRR) of suspected COVID-19 cases per 10,000 population. Our final model controlled for ZCTA-level sociodemographic factors (median income, poverty status, White race, essential workers), prevalence of clinical conditions related to COVID-19 severity (obesity, hypertension, coronary heart disease, diabetes, asthma, smoking status, and chronic obstructive pulmonary disease), and spatial clustering.

Results

39,923 suspected COVID-19 cases presented to emergency departments across 173 ZCTAs in NYC. Adjusted COVID-19 case rates increased by 67% (IRR 1.67, 95% CI = 1.12, 2.52) in ZCTAs in quartile four (versus one) for percent overcrowdedness and increased by 77% (IRR 1.77, 95% CI = 1.11, 2.79) in quartile four (versus one) for percent living in multigenerational housing. Interaction between both exposures was not significant (βinteraction = 0.99, 95% CI: 0.99-1.00).

Conclusions

Over-crowdedness and multigenerational housing are independent risk factors for suspected COVID-19. In the early phase of surge in COVID cases, social distancing measures that increase house-bound populations may inadvertently but temporarily increase SARS-CoV-2 transmission risk and COVID-19 disease in these populations.
Statistical tests for heterogeneity of clusters and composite endpoints
Authors: Webster Anthony J.
Published: June 2021

Clinical trials and epidemiological cohort studies often group similar diseases together into a composite endpoint, to increase statistical power. A common example is to use a 3-digit code from the International Classification of Diseases (ICD), to represent a collection of several 4-digit coded diseases. More recently, data-driven studies are using associations with risk factors to cluster diseases, leading this article to reconsider the assumptions needed to study a composite endpoint of several potentially distinct diseases. An important assumption is that the (possibly multivariate) associations are the same for all diseases in a composite endpoint (not heterogeneous). Therefore, multivariate measures of heterogeneity from meta-analysis are considered, including multi-variate versions of the I2 and Q statistics. Whereas meta-analysis offers tools to test heterogeneity of clustering studies, clustering models suggest an alternative heterogeneity test, of whether the data are better described by one, or more, clusters of elements with the same mean. The assumptions needed to model composite endpoints with a proportional hazards model are also considered. It is found that the model can fail if one or more diseases in the composite endpoint have different associations. Tests of the proportional hazards assumption can help identify when this occurs. It is emphasised that in multi-stage diseases such as cancer, some germline genetic variants can strongly modify the baseline hazard function and cannot be adjusted for, but must instead be used to stratify the data.
Train-the-Trainer as an Effective Approach to Building Global Networks of Experts in Genomic Surveillance of AMR
Authors: Abrudan Monica , Matimba Alice , Nikolic Dusanka , Hughes Darren , Argimón Silvia , Kekre Mihir , Underwood Anthony , Aanensen David ,   The NIHR Global Health Research Unit (GHRU) on Genomic Surveillance of Antimicrobial Resistance
Published: June 2021

Advanced genomics and sequencing technologies are increasingly becoming critical for global health applications such as pathogen and antimicrobial resistance (AMR) surveillance. Limited resources challenge capacity development in low- and middle-income countries (LMICs), with few countries having genomics facilities and adequately trained staff. Training research and public health experts who are directly involved in the establishment of such facilities offers an effective, but limited, solution to a growing need. Instead, training them to impart their knowledge and skills to others provides a sustainable model for scaling up the much needed capacity and capability for genomic sequencing and analysis locally with global impact. We designed and developed a Train-the-Trainer course integrating pedagogical aspects with genomic and bioinformatics activities. The course was delivered to 18 participants from 12 countries in Africa, Asia, and Latin America. A combination of teaching strategies culminating in a group project created a foundation for continued development at home institutions. Upon follow-up after 6 months, at least 40% of trainees had initiated training programs and collaborations to build capacity at local, national, and regional level. This work provides a framework for implementing a training and capacity building program for the application of genomics tools and resources in AMR surveillance.

40-word summary

This work provides a framework for implementing a training and capacity building program for the application of genomics tools and resources in AMR surveillance. We outline a Train-the-Trainer course integrating pedagogical aspects with genomic and bioinformatics activities.
Modelling, Simulations and Analysis of the First COVID-19 Epidemic in Shanghai
Authors: Min Lequan
Published: June 2021

To date, over 178 million people on infected with COVID-19. It causes more 3.8 millions deaths. Based on a previous symptomatic-asymptomatic-recoverer-dead differential equation model (SARDDE) and the clinic data of the first COVID-19 epidemic in Shanghai, this paper determines the parameters of SARDDE. Numerical simulations of SARDDE describe well the outcomes of current symptomatic individuals, recovered symptomatic individuals, and died individuals, respectively. The numerical simulations suggest that both symptomatic and asymptomatic individuals cause lesser asymptomatic spread than symptomatic spread; blocking rate of about 95.5% cannot prevent the spread of the COVID19 epidemic in Shanghai. The strict prevention and control strategies implemented by Shanghai government is not only very effective but also completely necessary. The numerical simulations suggest also that using the data from the beginning to the day after about 19 days at the turning point can estimate well the following outcomes of the COVID-19 academic. It is expected that the research can provide better understanding, explaining, and dominating for epidemic spreads, prevention and control measures.
The AMIGO1 adhesion protein activates Kv2.1 voltage sensors
Authors: Sepela R.J. , Stewart R.G. , Valencia L.A. , Thapa P. , Wang Z. , Cohen B.E. , Sack J.T.
Published: June 2021

Kv2 voltage-gated potassium channels are modulated by AMIGO neuronal adhesion proteins. Here, we identify steps in the conductance activation pathway of Kv2.1 channels that are modulated by AMIGO1 using voltage clamp recordings and spectroscopy of heterologously expressed Kv2.1 and AMIGO1 in mammalian cell lines. AMIGO1 speeds early voltage sensor movements and shifts the gating charge–voltage relationship to more negative voltages. The gating charge–voltage relationship indicates that AMIGO1 exerts a larger energetic effect on voltage sensor movement than apparent from the midpoint of the conductance–voltage relationship. When voltage sensors are detained at rest by voltage sensor toxins, AMIGO1 has a greater impact on the conductance–voltage relationship. Fluorescence measurements from voltage sensor toxins bound to Kv2.1 indicate that with AMIGO1, the voltage sensors enter their earliest resting conformation, yet this conformation is less stable upon voltage stimulation. We conclude that AMIGO1 modulates the Kv2.1 conductance activation pathway by destabilizing the earliest resting state of the voltage sensors.

Statement of Significance

Kv2 potassium channels activate a potassium conductance that shapes neuronal action potentials. The AMIGO family of adhesion proteins modulate activation of Kv2 conductances, yet, which activation steps are modified is unknown. This study finds that AMIGO1 destabilizes the earliest resting conformation of the Kv2.1 voltage sensors to promote activation of channel conductance.
Phytochrome gene expression studies: PHYE is required for FR-induced expression of PHYA and PHYD suppresses expression of PHYA
Authors: Shapulatov Umidjon , Meisenburg Mara , van Hoogdalem Mark , van Hall Alexander , van Ieperen Wim , van Wassenaar Maarten , van der Krol Alexander
Published: June 2021

Arabidopsis has five phytochrome (PHY) genes for sensing the Red:Far Red (R:FR) ratio in ambient light, of which PHYA has an established role in responses to FR. To study whether and how PHYs may influence each other’s transcription, PHY-Luciferase reporter plants (pPHYA:LUC, pPHYB:LUC, pPHYC:LUC, pPHYD:LUC and pPHYE:LUC) were constructed. Subsequently, reporter lines representative for each PHY were crossed into each of the five single phy-mutant backgrounds. Reporter activities in WT and phy mutant was studied under diurnal mixed (R, B, FR), R, FR or B LED light in seedling or rosette plants. Both pPHYA:LUC and pPHYB:LUC show strong induction under FR. Full FR upregulation of both PHYA and PHYB is dependent on PHYE, identifying PHYE as a novel sensor for FR light responses. Results also show that PHYA expression is strongly suppressed by PHYD. Results were confirmed for expression of endogenous PHYA and PHYB, albeit with different dynamics compared to the LUC reporters. Profiling of pPHYA:LUC and pPHYB:LUC reporters suggest gating of FR responses. Manipulation of PHY expression levels by FR may provide a novel basis for manipulating plant growth in controlled environments.
WEE1 kinase is a therapeutic vulnerability in CIC-DUX4 undifferentiated sarcoma
Authors: Ponce Rovingaile Kriska , Thomas Nicholas J. , Bui Nam Q. , Kondo Tadashi , Okimoto Ross A.
Published: June 2021

CIC-DUX4 rearrangements define an aggressive and chemotherapy-insensitive subset of undifferentiated sarcomas. The CIC-DUX4 fusion drives oncogenesis through direct transcriptional upregulation of cell cycle and DNA replication genes. Notably, CIC-DUX4- mediated CCNE1 upregulation compromises the G1/S transition, conferring a potential survival dependence on the G2/M cell cycle checkpoint. Through an integrative transcriptional and kinase activity screen using patient-derived specimens, we now show that CIC-DUX4 sarcomas depend on the G2/M checkpoint regulator, WEE1, as an adaptive survival mechanism. Specifically, CIC-DUX4 sarcomas depend on WEE1 activity to limit DNA damage and unscheduled mitotic entry. Consequently, genetic or pharmacologic WEE1 inhibition in vitro and in vivo leads to rapid DNA damage-associated apoptotic induction of patient-derived CIC-DUX4 sarcomas. Thus, we identify WEE1 as an actionable therapeutic vulnerability in CIC-DUX4 sarcomas.
Ecological memory of prior nutrient exposure in the human gut microbiome
Authors: Letourneau Jeffrey , Holmes Zachary C , Dallow Eric P , Durand Heather K , Jiang Sharon , Gupta Savita K , Mincey Adam C , Muehlbauer Michael J , Bain James R , David Lawrence A
Published: June 2021

Many ecosystems retain an ecological memory of past conditions that affects responses to future stimuli. However, it remains unknown what mechanisms and dynamics may govern such a memory in microbial communities. Here, in both a human dietary intervention cohort and an artificial gut, we show that the human gut microbiome encodes a memory of past carbohydrate exposures. Changes in the relative abundance of primary degraders were sufficient to enhance metabolism, and these changes were mediated by transcriptional changes within hours of initial exposure. We further found that ecological memory of one carbohydrate species impacted metabolism of others. These findings demonstrate that the human gut microbiome’s metabolic potential reflects dietary exposures over preceding days and changes within hours of exposure to a novel nutrient.

One Sentence Summary

Recent nutrient exposures are encoded into the structure and activity of human gut microbial communities, which enables more efficient future metabolic responses.