bluuebunny/crossref_metadata_2025 huggingface dataset:
Safety of phakic intraocular collamer lens implantation in 95 highly myopic special-needs children
Authors: Reynolds Margaret , Hoekel James , Tychsen Lawrence
Published: April 2021

Purpose:

To assess the safety of intraocular collamer lens (ICL) implantation in children with high ametropia by reporting rates and case specifics of perioperative and longer-term adverse events (AEs). 

Setting:

St. Louis Children's Hospital at Washington University Medical Center, St. Louis, Missouri.

Design:

Retrospective case series.

Methods:

Clinical data were collated retrospectively for 95 special-needs children (160 eyes) implanted with a Visian ICL over the past 5 years. All surgeries were performed at St Louis Children's Hospital under brief general anesthesia. The mean follow-up period was 2.0 ± 1.4 years (range, 0.5 to 5.2).

Results:

The mean age at implantation was 9.3 ± 5.2 years (range, 1.8 to 25) and mean preoperative spherical equivalent refractive error was −11.20 ± 3.90 diopters (range, 4 to 22). 62 children (62/95, 65%) had a neurodevelopmental disorder. 3 eyes (3/160, 2%) reported minor AE, consisting of steroid-response ocular hypertension, which resolved with cessation of topical steroid drops. Endothelial cell loss averaged 8.1% over 2 years, comparable with that reported in ICL-implanted adults. The most common major AE (7 eyes [7/160, 4%]) was postoperative pupillary block, requiring revision of the peripheral iridotomy. 1 child (1 eye [1/160, 0.6%]) with self-injurious behavior required repair of a wound leak. 1 child (1 eye [1/160, 0.6%]) with Down syndrome developed a cataract 2.8 years after ICL surgery, and 1 child (1 eye [1/160, 0.6%]) with severe autism spectrum disorder experienced traumatic retinal detachment 1.2 years after implantation.

Conclusions:

The most common major AE among the cohort with Visian ICL was pupillary block due to closure of the iridotomy. Overall, the AE rate was low in this higher risk, difficult-to-manage population of special-needs children.
Perceived Discrimination and Symptoms of Cognitive Dysfuntion Among Middle-Age and Older Persons Living With HIV in China: A Multicenter Cross-Sectional Study of the Mediating Role of Mental Health Symptoms and Social Isolation
Authors: Han Shuyu , Hu Yan , Wang Lina , Pei Yaolin , Zhu Zheng , Qi Xiang , Wu Bei
Published: April 2021

Perceived discrimination is associated with symptoms of cognitive dysfunction (SOCD) among middle-age and older persons living with HIV (PLWH). We aimed to explore how the association between perceived discrimination and SOCD was mediated by mental health symptoms and social isolation. The sample included 321 PLWH, ages 45 years and older, for a multicenter cross-sectional study. Structural equation modeling showed an acceptable model fit and a significant total indirect effect between perceived discrimination and SOCD. All three indirect effect pathways were significant, suggesting that perceived discrimination could influence SOCD through mental health symptoms, through social isolation, or through mental health symptoms and then social isolation. Our study demonstrates that perceived discrimination is a concern for the management of cognitive function among middle-age and older PLWH. Both mental health symptoms and social isolation are critical elements in the design and evaluation of interventions for promoting cognitive health.
The mechanical support of cardiogenic shock
Authors: Rob Daniel , Bělohlávek Jan
Published: April 2021

Purpose of review

Cardiogenic shock (CS) therapy involving catecholamines, inotropes, fluids and revascularization is often insufficient, and short-term mortality remains 50%. Different treatment algorithms and mechanical circulatory support devices (MCS) have been increasingly used in the treatment of CS. Coronavirus disease 2019 (COVID-19) pandemic is a major challenge faced by intensive care medicine providers inevitably influencing also CS management.

Recent findings

There is a lack of prospective data as well as international consensus regarding CS classification, patient risk stratification, and MCS use. Veno-arterial extracorporeal membrane oxygenation is considered the first line MCS in refractory CS and Impella the MCS of choice for the left ventricle unloading. Several ongoing randomized trials will provide much-needed evidence for MCS use in the coming years. COVID-19 infection is associated with several cardiovascular disorders complicated by CS and more data regarding the prevalence and mortality of CS during COVID-19 infection are needed.

This review summarizes current trends in the use of MCS in CS and discusses differences in CS management during the COVID-19 pandemic. Careful patient selection, early MCS initiation, and comprehensive intensive care by experienced team is key to successful outcome in patients with refractory CS.
The impact of advanced glycation end products on bone properties in chronic kidney disease
Authors: Damrath John G. , Creecy Amy , Wallace Joseph M. , Moe Sharon M.
Published: April 2021

Purpose of review

Chronic kidney disease (CKD) affects over 15% of Americans and results in an increased risk of skeletal fractures and fracture-related mortality. However, there remain great challenges in estimating fracture risk in CKD patients, as conventional metrics such as bone density assess bone quantity without accounting for the material quality of the bone tissue. The purpose of this review is to highlight the detrimental effects of advanced glycation end products (AGEs) on the structural and mechanical properties of bone, and to demonstrate the importance of including bone quality when assessing fracture risk in CKD patients.

Recent findings

Increased oxidative stress and inflammation drive the production of AGEs in CKD patients that form nonenzymatic crosslinks between type I collagen fibrils in the bone matrix. Nonenzymatic crosslinks stiffen and embrittle the bone, reducing its ability to absorb energy and resist fracture. Clinical measurement of AGEs is typically indirect and fails to distinguish the identity and properties of the various AGEs.

Accounting for the impact of AGEs on the skeleton in CKD patients may improve our estimation of overall bone quality, fracture risk, and treatments to improve both bone quantity and quality by reducing AGEs in patients with CKD merit investigation in order to improve our understanding of the etiology of increased fracture risk.
Ongoing Response in a Multiply Relapsed Metastatic Posterior Fossa Ependymoma A After Vorinostat and Concomitant Irradiation
Authors: Gorsi Hamza S. , Toll Stephanie A. , Sood Sandeep , Miler Steven , Altinok Deniz , Kumar-Sinha Chandan , Mody Rajen , Yankelevich Maxim
Published: April 2021

Posterior fossa ependymomas A confer the worst prognosis among all subtypes. They demonstrate distinct epigenetic changes, which can be targeted with epigenetic modifiers like histone deacetylase inhibitors (Vorinostat). We describe a 3-year-old male diagnosed with a posterior fossa ependymoma who had a number of recurrences requiring multimodal therapy. Molecular analysis demonstrated a BCL-6 corepressor mutation, and methylation profiling matched with posterior fossa ependymomas A. He received craniospinal irradiation and focal boost with Vorinostat. Serial imaging after irradiation revealed a progressively decreasing tumor burden with nearly complete resolution of disease at 15 months. Histone deacetylase inhibitors demonstrate promise in treatment of carefully selected cases of ependymoma.
Neonatal Hereditary Fructose Intolerance: Diagnostic Misconceptions and the Role of Genomic Sequencing
Authors: Lee Jeffrey , Arenth Joshua , Kasi Nagraj
Published: April 2021

Hereditary fructose intolerance (HFI) is a rare inborn error of metabolism due to deficiency of the enzyme aldolase B, preventing metabolism of fructose. Patients remain asymptomatic until exposed to fructose, sucrose, or sorbitol. HFI presenting as acute liver failure in the neonatal period is rare due to lack of exposure as breast milk and infant formulas are considered to be fructose free. Diagnosis can be delayed due to vague symptoms and lack of specific biomarkers. Recent advances in genetic testing have led to rapid diagnosis and favorable outcomes. We present the case of a formula-fed neonate who presented with acute liver failure where definitive diagnosis of HFI was made using expedited whole exome sequencing. Through this communication, we aim to bring attention to neonatal presentations of HFI from exposure to fructose in infant formulas and also highlight advances in rapid turnaround genomic testing in diagnosis.
Differential Diagnosis Between Perianal Crohn’s Disease and Hidradenitis Suppurativa: A Challenging Teamwork
Authors: Amhis Maya , Belarbi K Nadia , Bourrat Emmanuelle , Nassif Aude , Viala Jerome , Martinez-Vinson Christine
Published: April 2021

Hidradenitis suppurativa (HS) is a rare, debilitating skin disease characterized by the presence of recurrent tender subcutaneous nodules that develop into abscesses and fistulae. Isolated perineal Crohn’s disease (CD) is unusual, diagnosis can be difficult, and distinction from HS is a challenge for the gastroenterologist. The aim of this work was to determine the criteria that distinguish perineal CD from perineal HS. Four patients with isolated perineal CD and three with perineal HS were included. Rectal or skin biopsies of all CD patients showed granulomas. No granulomas were found for HS. Fistulae were present in 4/4 CD, extended to the anal canal. All patients with HS had gluteal abscesses. They were bilateral in all cases, superficial. Perineal lesions management should involve a multidisciplinary approach in order to make an accurate diagnosis and ultimately to give the best and most effective treatment.
Effectiveness of Buffered Lidocaine for Local Anesthesia During Liver Biopsy
Authors: Hockett Deborah , Kress Laura , Mac Donald Ryan , Krenzischek Dina A. , Maheshwari Anurag
Published: April 2021

The aim of this research study was to evaluate the effectiveness of lidocaine versus lidocaine with sodium bicarbonate in reducing anxiety and pain, using visual analog scales, in subjects receiving local anesthetic during liver biopsies. The project included 199 subjects presenting for percutaneous liver biopsy using local anesthesia. Subjects were randomized into 2 groups: the control group, which received lidocaine alone, and the experimental group, which received lidocaine buffered with sodium bicarbonate. Immediately after they received the lidocaine injection, both groups were asked to rate their preprocedure anxiety and pain using a 0–10 visual analog scale. Mean postprocedure pain was statistically significantly different between the two arms with the intervention group reporting less pain (1.65 vs. 2.27, p = .037). Change in pain scores between the two groups were also statistically significantly different with the intervention group reporting a mean change in pain score of 0.93 compared to 1.63 in the control group (p = .021). However, no differences were found for reported anxiety. This study has shown that using sodium bicarbonate with lidocaine significantly decreased pain sensation at the injection site when used for deep visceral anesthesia during percutaneous liver biopsy.
Urine Output Calculated Using Actual Body Weight May Result in Overestimation of Acute Kidney Injury for Obese Patients
Authors: Jiang Jun , Zhang Jing , Liu Ye , Xu Dongxue , Peng Zhiyong
Published: April 2021

Goal:

The derived hourly urine output (UO) indexed by body weight is one of the major criteria for the diagnosis of acute kidney injury (AKI). However, it is unclear whether actual body weight (ABW) or ideal body weight (IBW) should be used. This study aims to explore whether UO calculation based on ABW might lead to overestimation of AKI.

Method:

AKI patients identified in the Medical Information Mart for Intensive Care III database by different components of the Kidney Disease Improving Global Outcomes guidelines and different definitions of body weight were retrospectively studied. Hospital and 90-day mortality were compared to decide whether different patient groups had the same outcome.

Results:

In the cohort of 14,725 patients, AKI was identified in 4,298 (29.19%) and 3,060 (20.78%) patients respectively when ABW or IBW was used (P < 0.01). Multivariate logistic regression revealed that AKI patients identified by UO calculated from ABW had similar hospital and 90-day mortality to that of patients with no evidence of AKI. Whereas AKI patients identified by serum creatinine changes, or those identified by both ABW and IBW, had twice higher the risks of hospital death and about 1.5 times higher the risks of 90-day death compared with thoese with no evidence of AKI. Results were confirmed in two separate sensitivity analyses where patients whose admission creatinine levels were within the normal reference ranges and patients identified as sepsis were studied.

Conclusions:

Calculating hourly body weight normalized UO using ABW may lead to underestimation of UO and overestimation of AKI.
Vagus Nerve Stimulation Protects Enterocyte Glycocalyx After Hemorrhagic Shock Via the Cholinergic Anti-Inflammatory Pathway
Authors: Wu Juan , Yin Yushuang , Qin Mingzhe , Li Kun , Liu Fang , Zhou Xiang , Song Xiaoyang , Li Bixi
Published: April 2021

Introduction:

Electrical vagal nerve stimulation is known to decrease gut permeability and alleviate gut injury caused by traumatic hemorrhagic shock. However, the specific mechanism of action remains unclear. Glycocalyx, located on the surface of the intestinal epithelium, is associated with the buildup of the intestinal barrier. Therefore, the goal of our study was to explore whether vagal nerve stimulation affects enterocyte glycocalyx, gut permeability, gut injury, and remote lung injury.

Materials and methods:

Male Sprague Dawley rats were anesthetized and their cervical nerves were exposed. The rats underwent traumatic hemorrhagic shock (with maintenance of mean arterial pressure of 30–35 mmHg for 60 min) with fluid resuscitation. Vagal nerve stimulation was added to two cohorts of animals before fluid resuscitation, and one of them was injected with methyllycaconitine to block the cholinergic anti-inflammatory pathway. Intestinal epithelial glycocalyx was detected using immunofluorescence. Intestinal permeability, the degree of gut and lung injury, and inflammation factors were also assessed.

Results:

Vagal nerve stimulation alleviated the damage to the intestinal epithelial glycocalyx and decreased intestinal permeability by 43% compared with the shock/resuscitation phase (P < 0.05). Methyllycaconitine partly eliminated the effects of vagal nerve stimulation on the intestinal epithelial glycocalyx (P < 0.05). Vagal nerve stimulation protected against traumatic hemorrhagic shock/fluid resuscitation-induced gut and lung injury, and some inflammatory factor levels in the gut and lung tissue were downregulated after vagal nerve stimulation (P < 0.05).

Conclusions:

Vagal nerve stimulation could relieve traumatic hemorrhagic shock/fluid resuscitation-induced intestinal epithelial glycocalyx damage via the cholinergic anti-inflammatory pathway.
Update on neuroimaging in Alzheimer's disease
Authors: Sintini Irene , Whitwell Jennifer L.
Published: April 2021

Purpose of review

The purpose of this review was to discuss the contribution of the most recent neuroimaging studies to our understanding of the mechanisms underlying Alzheimer's disease.

Recent findings

Studies have applied cross-sectional and longitudinal positron emission tomography (PET), structural and resting-state functional magnetic resonance imaging to primarily investigate (1) how Alzheimer's disease pathological hallmarks like tau and amyloid-beta build up and spread across the brain at different disease stage and in different disease phenotypes and (2) how the spreading of these proteins is related to atrophy, to neuronal network disruption and to neuroinflammation.

The findings of these studies offer insight on the mechanisms that drive the pathological and clinical progression of Alzheimer's disease, highlighting their multifactorial nature, which is a crucial aspect for the development of disease-modifying therapeutics and can be captured with multimodal imaging approaches.
The role of childrens’ vaccination for COVID-19 - Pareto-optimal allocations of vaccines
Authors: Gavish Nir , Katriel Guy
Published: April 2021

The ultimate goal of COVID-19 vaccination campaigns is to enable the return of societies and economies to a state of normality. While vaccines have been approved for children of age 12 and older, there is an ongoing debate as to whether children should be vaccinated and at what priority, with very different policies being adopted in different countries. In this work, we use mathematical modeling and optimization to study the effect of vaccinating children on the epidemic spread. We consider Pareto-optimal allocations according to competing measures of number of infections and mortality, and systematically study the trade-offs among them. When some weight is given to the number of infections, we find that it is optimal to allocate vaccines to adolescents in age group 10-19, even when they are assumed to be less susceptible than adults. Additionally, we find that in a broad range of scenarios, optimal allocations of vaccines do not include vaccination of age-group 0-9.

Author summary

One of the acute questions public health experts and policymakers currently confront is whether children of age 12 and older, and eventually perhaps younger children, should be vaccinated against COVID-19, and at what priority. Different countries have adopted diverse policies on this issue, while others remain undecided. One of the key considerations in this debate is the impact of children’s vaccination on the epidemic spread. In this work, we use mathematical and computational methods to study this question in a systematic, quantitative way. We compute optimal vaccination allocations, under different criteria for optimality, both including and not including children. To explore tradeoffs among different goals, such as reducing number of infections and reducing mortality, we use the idea of Pareto optimization, which is novel in this field. Our results show that, under a wide range of conditions, optimal vaccine allocations include vaccination of age group 10-19, while the vaccination of age group 0-9 is of lower priority than the vaccination of other age group.
Pathway-specific Polygenic Risk Scores (PRS) identify OSA-related pathways differentially moderating genetic susceptibility to CAD
Authors: Goodman Matthew O , Cade Brian E , Shah Neomi , Huang Tianyi , Dashti Hassan S , Saxena Richa , Rutter Martin K , Libby Peter , Sofer Tamar , Redline Susan
Published: April 2021

Background

Obstructive sleep apnea (OSA) and its features, such as chronic intermittent hypoxia (IH), may differentially affect specific molecular pathways and processes in the pathogenesis of coronary artery disease (CAD) and influence the subsequent risk and severity of CAD events. In particular, competing adverse (e.g. inflammatory) and protective (e.g. increased coronary collateral blood flow) mechanisms may operate, but remain poorly understood. We hypothesize that common genetic variation in selected molecular pathways influences the likelihood of CAD events differently in individuals with and without OSA, in a pathway-dependent manner.

Methods

We selected a cross-sectional sample of 471,877 participants from the UK Biobank, among whom we ascertained 4,974 to have OSA, 25,988 to have CAD, and 711 to have both. We calculated pathway-specific polygenic risk scores (PS-PRS) for CAD, based on 6.6 million common variants evaluated in the CARDIoGRAMplusC4D genome-wide association study (GWAS), annotated to specific genes and pathways using functional genomics databases. Based on prior evidence of involvement with IH and CAD, we tested PS-PRS for the HIF-1, VEGF, NFκB and TNF signaling pathways.

Results

In a multivariable-adjusted logistic generalized additive model, elevated PS-PRSs for the KEGG VEGF pathway (39 genes) associated with protection for CAD in OSA (interaction odds ratio 0.86,p= 6E-04). By contrast, the genome-wide CAD PRS did not show evidence of statistical interaction with OSA.

Conclusions

We find evidence that pathway-specific genetic risk of CAD differs between individuals with and without OSA in a qualitatively pathway-dependent manner, consistent with the previously studied phenomena whereby features of OSA may have both positive and negative effects on CAD. These results provide evidence that gene-by-environment interaction influences CAD risk in certain pathways among people with OSA, an effect that is not well-captured by the genome-wide PRS. These results can be followed up to study how OSA interacts with genetic risk at the molecular level, and potentially to personalize OSA treatment and reduce CAD risk according to individual pathway-specific genetic risk profiles.
Host-pathogen dynamics in longitudinal clinical specimens from patients with COVID-19
Authors: Lin Michelle J. , Rachleff Victoria M. , Xie Hong , Shrestha Lasata , Lieberman Nicole A.P. , Peddu Vikas , Addetia Amin , Casto Amanda M. , Breit Nathan , Mathias Patrick C. , Huang Meei-Li , Jerome Keith R. , Greninger Alexander L. , Roychoudhury Pavitra
Published: April 2021

Background

Rapid dissemination of SARS-CoV-2 sequencing data to public repositories has enabled widespread study of viral genomes, but studies of longitudinal specimens from infected persons are relatively limited. Analysis of longitudinal specimens enables understanding of how host immune pressures drive viral evolutionin vivo.

Methods and findings

Here we performed sequencing of 49 longitudinal SARS-CoV-2-positive samples from 20 patients in Washington State collected between March and September of 2020. Viral loads declined over time with an average increase in RT-PCR cycle threshold (Ct) of 0.87 per day. We found that there was negligible change in SARS-CoV-2 consensus sequences over time, but identified a number of nonsynonymous variants at low frequencies across the genome. We observed enrichment for a relatively small number of these variants, all of which are now seen in consensus genomes across the globe at low prevalence. In one patient, we saw rapid emergence of various low-level deletion variants at the N-terminal domain of the spike glycoprotein, some of which have previously been shown to be associated with reduced neutralization potency from sera. In a subset of samples that were sequenced using metagenomic methods, differential gene expression analysis showed a downregulation of cytoskeletal genes that was consistent with a loss of ciliated epithelium during infection and recovery. We also identified co-occurrence of bacterial species in samples from multiple hospitalized individuals.

Conclusions

These results demonstrate that the intrahost genetic composition of SARS-CoV-2 is dynamic during the course of COVID-19, and highlight the need for continued surveillance and deep sequencing of minor variants.
Real-world experience with tofacitinib in ulcerative colitis - a systematic review and meta-analysis
Authors: Lucaciu L , Constantine-Cooke N , Plevris N , Siakavellas S , Derikx LAAP , Jones GR , Lees CW
Published: April 2021

Background and aims

Evidence on the outcomes of tofacitinib therapy in real world ulcerative colitis (UC) patients is needed, as a number of these patients would not match the inclusion criteria for clinical trials. We have therefore summarised data derived from observational, real-world evidence (RWE) studies on the effectiveness and safety of tofacitinib in moderate to severe ulcerative colitis (UC) patients.

Methods

We searched the PubMed, EMBASE, Scopus, Web of Science and Cochrane databases for observational studies on the use of tofacitinib in UC patients, published between 30/05/2018 and 24/01/2021. Pooled induction (8-14 weeks) and maintenance (16-26 weeks) clinical response and remission rates were calculated, as well as the proportion of reported adverse events using random effects models.

Results

Nine studies were included, comprising 830 patients, of which 81% were previously treated with anti-TNF and 57% with vedolizumab. Induction of clinical response and remission were achieved in 51% (95% CI 41-60%) and 37% (26-45%) of patients, after a median follow-up of 8 weeks. At the end of a median follow-up of 24 weeks, maintenance of clinical response and remission were met in 40% (31-50%) and 29% (23-36%) of patients, respectively. Thirty-two percent of the patients had at least one adverse event, the most commonly reported being mild infection (13%) and worsening of UC, requiring colectomy (13%). A third of the patients (35%) discontinued tofacitinib, most frequently due to primary non-response (51%).

Conclusions

Tofacitinib is a safe and effective therapy in real-world UC patients, as previously reported by clinical trials.

WHAT YOU NEED TO KNOW

Background

Tofacitinib is the first Janus kinase inhibitor (JAKi) approved for the treatment of moderate to severe ulcerative colitis (UC). Real-world data is needed to understand clinical effectiveness of new therapies.

Findings

Clinical response rates were consistent with those reported by OCTAVE Induction trials, showing clinical efficacy similar in real-world and controlled clinical trial cohorts. There were no major safety concerns reported.

Implications for patient care

The results of this meta-analysis confirm the effectiveness and acceptable safety profile of tofacitinib in a real-world, highly refractory UC population, and further support its use in clinical practice.
Real-world effectiveness of Ad26.COV2.S adenoviral vector vaccine for COVID-19
Authors: Corchado-Garcia Juan , Puyraimond-Zemmour David , Hughes Travis , Cristea-Platon Tudor , Lenehan Patrick , Pawlowski Colin , Bade Sairam , O’Horo John C. , Gores Gregory J. , Williams Amy W. , Badley Andrew D. , Halamka John , Virk Abinash , Swift Melanie D. , Wagner Tyler , Soundararajan Venky
Published: April 2021

In light of the massive and rapid vaccination campaign against COVID-19, continuous real-world effectiveness and safety assessment of the FDA-authorized vaccines is critical to amplify transparency, build public trust, and ultimately improve overall health outcomes. In this study, we leveraged large-scale longitudinal curation of electronic health records (EHRs) from the multi-state Mayo Clinic health system (MN, AZ, FL, WN, IA). We compared the infection rate of 2,195 individuals who received a single dose of the Ad26.COV2.S vaccine from Johnson & Johnson (J&J) to the infection rate of 21,950 unvaccinated, propensity-matched individuals between February 27th and April 14th 2021. Of the 1,779 vaccinated individuals with at least two weeks of follow-up, only 3 (0.17%) tested positive for SARS-CoV-2 15 days or more after vaccination compared to 128 of 17,744 (0.72%) unvaccinated individuals (4.34 fold reduction rate). This corresponds to a vaccine effectiveness of 76.7% (95% CI: 30.3-95.3%) in preventing SARS-CoV-2 infection with onset at least two weeks after vaccination. This data is consistent with the clinical trial-reported efficacy of Ad26.COV2.S in preventing moderate to severe COVID-19 with onset at least 14 days after vaccine administration (66.9%; 95% CI: 59.0-73.4%). Due to the recent authorization of the Ad26.COV2.S vaccine, there are not yet enough hospitalizations, ICU admissions, or deaths within this cohort to robustly assess the effect of vaccination on COVID-19 severity, but these outcomes will be continually assessed in near-real-time with our platform. Collectively, this study provides further evidence that a single dose of Ad26.COV2.S is highly effective in preventing SARS-CoV-2 infection and reaffirms the urgent need to continue mass vaccination efforts globally.
Head and body dyskinesia during gait in tactical athletes with vestibular deficit following concussion
Authors: Fraser John J. , VanDehy Jacob , Bodell Dawn M. , Gottshall Kim R. , Sessoms Pinata H.
Published: April 2021

Background

Vestibular deficit is common following concussion and may affect gait. The purpose of this study was to investigate differences in head and pelvic center of mass (COM) movement during gait in tactical athletes with and without concussion-related central vestibular impairment.

Material & Methods

24 patients with post-concussion vestibular impairment (20 males, 4 females; age: 31.7±7.9 years; BMI: 27.3±3.3) and 24 matched controls (20 males, 4 females; age: 31.8±6.4 years; BMI: 27.2±2.6) were included in the analyses. Three-dimensional head and pelvic COM displacement and velocities were collected at a 1.0 m/s standardized treadmill walking speed and assessed using Statistical Parametric Mapping t-tests. Maximum differences (dmax) between groups were reported for all significant kinematic findings.

Results

The Vestibular group demonstrated significantly diminished anteroposterior head excursions (dmax=2.3 cm, p=0.02;) and slower anteroposterior (dmax=0.37 m/s, p=0.01), mediolateral (dmax=0.47 m/s, p=0.02) and vertical (dmax=0.26 m/s, p<0.001) velocities during terminal stance into pre-swing phases compared to the Control group. Vertical pelvic COM excursion was significantly increased in midstance (dmax=2.4 cm, p=0.03) and mediolaterally during pre-to initial-swing phases (dmax=7.5 cm, p<0.001) in the Vestibular group. In addition, Pelvic COM velocities of the Vestibular group were higher mediolaterally during midstance (dmax=0.19 m/s, p=0.02) and vertically during post-initial contact (dmax=0.14 m/s, p<0.001) and pre-swing (dmax=0.16 m/s, p<0.001) compared to the Control group.

Significance

The Vestibular group demonstrated a more constrained head movement strategy during gait compared with Controls, a finding that is likely attributed to a neurological impairment of visual-vestibular-somatosensory integration.
Racial and ethnic disparities for SARS-CoV-2 positivity in the United States: a generalizing pandemic
Authors: Ferguson Jacqueline M. , Justice Amy C. , Osborne Thomas F. , Magid Hoda S. Abdel , Purnell Amanda L. , Rentsch Christopher T.
Published: April 2021

The coronavirus pandemic has disproportionally impacted racial and ethnic minority communities in the United States. These disparities may be changing over time as outbreaks occur in different communities. Using electronic health record data from the Department of Veterans Affairs, we estimated odds ratios, stratified by region and time period, for testing positive for SARS-CoV-2 among 951,408 individuals tested for SARS-CoV-2 between February 12, 2020 and February 12, 2021. Our study found racial and ethnic disparities for testing positive were most pronounced at the beginning of the pandemic and decreased over time. A key finding was that the disparity among Hispanic individuals attenuated but remained elevated over the entire study period. We identified variation in racial and ethnic disparities in SARS-CoV-2 positivity by time and region independent of underlying health status and other key factors in a nationwide cohort, which provides important insight for strategies to contain and prevent further outbreaks.
An in silico integrative analysis of hepatocellular carcinoma omics databases shows the dual regulatory role of microRNAs either as tumor suppressors or as oncomirs
Authors: Tolba Mahmoud M. , Soliman Bangli , Jabbar Abdul , Nasser HebaT'Allah , Elhefnawi Mahmoud
Published: April 2021

MicroRNAs are well known as short RNAs bases, 22 nucleotides, binding directly to 3'untranslated region (3'UTR) of the messenger RNA to repress their functions. Recently, microRNAs have been widely used as a therapeutic approach for various types of Cancer. MicroRNA is categorized into tumor suppressor and oncomirs. Tumor suppressor microRNAs can repress the pathologically causative oncogenes of the hallmarks of Cancer. However, based on the fact that miRNA has no proper fidelity to bind specific mRNAs due to binding to off-targets, it results in a kind of inverse biological activity. Here, we have executed an in-silico integrative analysis of GEO/TCGA-LIHC of genes/microRNAs expression analysis in HCC, including (446 HCC vs. 146 normal specimens for miRNAs expression ) ad 488 specimens for genes expression. It virtually shows that microRNAs could have an ability to target both oncogenes and tumor suppressor genes that contribute to its dual activity role as a tumor suppressor and oncomirs via miRNA-lncRNA-TFs-PPI Crosstalk. Seven resultant microRNAs show a putative dual role in HCC. It enhances our concluded suggestion of using combination therapy of tumor suppressor genes activators with microRNAs.
The causal effects of chronic air pollution on the intensity of COVID-19 disease: Some answers are blowing in the wind
Authors: Conte Marc N. , Gordon Matthew , Swartwood Nicole A. , Wilwerding Rachel , Yu Chu A. (Alex)
Published: April 2021

The threats posed by COVID-19 have catalyzed a search by researchers across multiple disciplines for policy-relevant findings about critical risk factors. We contribute to this effort by providing causal estimates of the link between increased chronic ambient pollutant concentrations and the intensity of COVID-19 disease, as measured by deaths and hospitalizations in New York City from March through August, 2020. Given concerns about unobservable characteristics that contribute to both ambient air pollutant concentrations and the impacts of COVID-19 disease, we instrument for pollutant concentrations using the time spent downwind of nearby highways and estimate key causal relationships using two-stage least squares models. The causal links between increases in concentrations of our traffic-related air pollutants (PM2.5, NO2, and NO) and COVID-19 deaths are much larger than the correlations presented in recent observational studies. We find that a 0.16 μg/m3 increase in average ambient PM2.5 concentration leads to an approximate 30% increase in COVID-19 deaths. This is the change in concentration associated with being downwind of a nearby highway. We see that this effect is mostly driven by residents with at least 75 years of age. In addition to emphasizing the importance of searching for causal relationships, our analysis highlights the value of increasing the density of pollution-monitoring networks and suggests potential benefits of further tightening of Clean Air Act amendments, as our estimated effects occur at concentrations well below thresholds set by the National Ambient Air Quality Standards.
Coherent activity at three major lateral hypothalamic neural outputs controls the onset of motivated behavior responses
Authors: Martianova Ekaterina , Pageau Alicia , Pausic Nikola , Gentiletti Tommy Doucet , Leblanc Danahe , Proulx Christophe D.
Published: April 2021

The lateral hypothalamus (LH) plays an important role in motivated behavior. However, it is not known how LH neural outputs dynamically signal to major downstream targets to organize behavior. We used multi-fiber photometry to show that three major LH neural outputs projecting to the dorsal raphe nucleus (DRN), ventral tegmental area (VTA), and lateral habenula (LHb) exhibit significant coherent activity in mice engaging motivated responses, which decrease during immobility. Mice engaging active coping responses exhibit increased activity at LH axon terminals that precedes an increase in the activity of serotonin neurons and dopamine neurons, indicating that they may play a role in initiating active responses stemming from LH signal transmissions. The optogenetic activation of LH axon terminals in either the DRN, VTA, or LHb was sufficient to increase mobility but had different effects on passive avoidance and sucrose consumption, suggesting that LH outputs use complementary mechanisms to control behavioral responses. Our results support the notion that the three LH neural outputs play complementary roles in initiating motivated behaviors.
Sleep-dependent upscaled excitability, saturated neuroplasticity, and modulated cognition in the human brain
Authors: Salehinejad Mohammad Ali , Ghanavati Elham , Reinders Joerg , Hengstler Jan G. , Kuo Min-Fang , Nitsche Michael A.
Published: April 2021

Sleep strongly affects synaptic strength, making it critical for cognition, especially learning, and memory formation. Whether andhowsleep deprivation modulates human brain physiology and cognition is not well understood. Here we examined how overnight sleep deprivation vs sufficient sleep affects (a) cortical excitability, as measured by transcranial magnetic stimulation (TMS), (b) inducibility of LTP-and-LTD-like plasticity via transcranial direct current stimulation (tDCS), and (c) learning, memory and attention. The results suggest that sleep deprivation upscales cortical excitability due to enhanced glutamate-related cortical facilitation and decreased and/or reversed GABAergic cortical inhibition. Furthermore, tDCS-induced LTP-like plasticity abolishes while LTD-like plasticity converts to excitatory LTP-like plasticity under sleep deprivation. This is associated with increased EEG theta activity, which is related to sleep pressure. Finally, we show that learning and memory formation, behavioral counterparts of plasticity, and working memory and attention, which rely on cortical excitability, are impaired during sleep deprivation. Our data suggest that upscaled brain excitability, and altered plasticity, due to sleep deprivation, are associated with impaired cognitive performance.
Gut IgA Enhances Systemic IgG Responses to Pneumococcal Vaccines Through the Commensal Microbiota
Authors: Gutzeit Cindy , Grasset Emilie K. , Matthews Dean B. , Maglione Paul J. , Magri Giuliana , Britton Graham J. , Tomalin Lewis , Pybus Marc , Vaquero Sonia Tejedor , Veeramreddy Pavan K. , Tachó-Piñot Roser , Nalda Andrea Martín , Prat Marina García , Gallo Monica Martinez , Dieli-Crimi Romina , Clemente José C. , Mehandru Saurabh , Suarez-Farina Mayte , Faith Jeremiah J. , Cunningham-Rundles Charlotte , Cerutti Andrea
Published: April 2021

The gut microbiota enhances systemic immunoglobulin G (IgG) responses to vaccines. However, it is unknown whether this effect involves IgA, a mucosal antibody that coats intestinal microbes. Here we found that gut IgA increased peripheral IgG responses to pneumococcal vaccines, as these responses were profoundly impaired in mice with global or mucosa-restricted IgA deficiency. The positive effect of IgA on vaccine-induced IgG production implicated gut bacteria. Indeed, IgG responses to pneumococcal vaccines were also defective in ex-germ free mice recolonized with gut microbes from mouse or human IgA-deficient donors. IgA exerted this IgG-enhancing effect by constraining the systemic translocation of intestinal commensal antigens, which caused chronic immune activation, including T cell overexpression of programmed death-1. This immune inhibitory receptor hindered vaccine-specific IgG production by eliciting functional B cell unresponsiveness, which was reverted by anti-programmed death-1 treatment. Thus, gut IgA is functionally interconnected with systemic IgG via intestinal microbes.
Sex differences in behaviour and molecular pathology in the 5XFAD model
Authors: Sil Annesha , Erfani Arina , Lamb Nicola , Copland Rachel , Riedel Gernot , Platt Bettina
Published: April 2021

Background

The prevalence of Alzheimer’s Disease (AD) is greater in women compared to men, but the reasons for this remain unknown. This sex difference has been widely neglected in experimental studies using transgenic mouse models of AD.

Objective

Here, we studied behaviour and molecular pathology of 5-month-old 5XFAD mice, which express mutated human amyloid precursor protein and presenilin-1 on a C57BL/6J background, vs. their wild-type littermate controls, to compared both sex- and genotype-dependent differences.

Methods

A novel behavioural paradigm was utilised (OF-NO-SI), comprising activity measures (Open Field, OF) arena, followed by Novel Object exploration (NO) and Social Interaction (SI) of a sex-matched conspecific. Each segment consisted of two repeated trials to assess between-trial habituation. Subsequently, brain pathology (amyloid load, stress response and inflammation markers, synaptic integrity, trophic support) was assessed using qPCR and Western blotting.

Results

Female 5XFAD mice had higher levels of human APP and beta-amyloid (Aβ) and heightened inflammation vs males. These markers correlated with hyperactivity observed in both sexes, yet only female 5XFAD mice presented with deficits in object and social exploration. Male animals had higher expression of stress markers and neurotrophic factors irrespective of genotype, this correlated with cognitive performance.

Conclusion

The impact of sex on AD-relevant phenotypes is in line with human data and emphasises the necessity of appropriate study design and reporting. Differential molecular profiles observed in male vs. female mice offer insights into possible protective mechanisms, and hence treatment strategies.
SmProt: A Reliable Repository with Comprehensive Annotation of Small Proteins Identified from Ribosome Profiling
Authors: Li Yanyan , Zhou Honghong , Chen Xiaomin , Zheng Yu , Kang Quan , Hao Di , Zhang Lili , Song Tingrui , Luo Huaxia , Hao Yajing , Chen Yiwen , Chen Runsheng , Zhang Peng , He Shunmin
Published: April 2021

Small proteins specifically refer to proteins consisting of less than 100 amino acids translated from small open reading frames (sORFs), which were usually missed in previous genome annotation. The significance of small proteins has been revealed in current years, along with the discovery of their diverse functions. However, systematic annotation of small proteins is still insufficient. SmProt was specially developed to provide valuable information on small proteins for scientific community. Here we present the update of SmProt, which emphasizes reliability of translated sORFs, genetic variants in translated sORFs, disease-specific sORFs translation events or sequences, and significantly increased data volume. More components such as non-AUG translation initiation, function, and new sources are also included. SmProt incorporated 638,958 unique small proteins curated from 3,165,229 primary records, which were computationally predicted from 419 ribosome profiling (Ribo-seq) datasets and collected from the literature and other sources originating from 370 cell lines or tissues in 8 species (Homo sapiens,Mus musculus,Rattus norvegicus,Drosophila melanogaster,Danio rerio,Saccharomyces cerevisiae,Caenorhabditis elegans, andEscherichia coli). In addition, small protein families identified from human microbiomes were collected. All datasets in SmProt are free to access, and available for browse, search, and bulk downloads athttp://bigdata.ibp.ac.cn/SmProt/.
Extracellular adenosine induces hypersecretion of IL-17A by T-helper 17 cells through the adenosine A2a receptor to promote neutrophilic inflammation
Authors: Tokano Mieko , Matsushita Sho , Takagi Rie , Yamamoto Toshimasa , Kawano Masaaki
Published: April 2021

Extracellular adenosine, produced from ATP secreted by neuronal or immune cells, may play a role in endogenous regulation of inflammatory responses. However, the underlying molecular mechanisms are largely unknown. Here, we show that adenosine primes hypersecretion of interleukin (IL)-17A by CD4+T cells via T cell receptor activation. This hypersecretion was also induced by an adenosine A2a receptor (A2aR) agonist, PSB0777. In addition, an A2aR antagonist (Istradefylline), and inhibitors of adenyl cyclase, protein kinase A, and cAMP response element binding protein (which are signaling molecules downstream of the Gs protein coupled with the A2aR), suppressed IL-17A production, suggesting that activation of A2aR induces IL-17A production by CD4+T cells. Furthermore, immune subset studies revealed that adenosine induced hypersecretion of IL-17A by T-helper (Th)17 cells. These results indicate that adenosine is an endogenous modulator of neutrophilic inflammation. Administration of an A2aR antagonist to mice with experimental autoimmune encephalomyelitis led to marked amelioration of symptoms, suggesting that suppression of adenosine-mediated IL-17A production is an effective treatment for Th17-related autoimmune diseases.
Bacteriophages encoding human immune evasion factors adapt to livestock-associated MRSA through rounds of integration and excision
Authors: Leinweber Helena , Sieber Raphael , Larsen Jesper , Stegger Marc , Ingmer Hanne
Published: April 2021

In recent years there has been an increase in human infections with methicillin-resistantStaphylococcus aureus(MRSA) originating from livestock and strains carrying bacterial viruses of the Sa3int-family have disseminated into the community. Sa3int phages express immune evasion factors and are common in human staphylococcal strains. As the bacterial attachment site (attB) for Sa3int phages is mutated in livestock-associated strains, the integration frequency is low and a key question is how the phages are established. Here we show that Sa3int phages adapt to alternative bacterial integration sites by mutating the phage attachment sequence,attP, leading to enhanced integration at these sites. Using a model strain carrying the mutatedattBLAof livestock-associated strains we find that once established, the Sa3int phage, Φ13 is inducible with release of heterogenous phage populations carrying mutations inattPthat in part increase homology to alternative integration sites orattBLA. Compared to the original phage, the adaptive mutations increase phage integration in new rounds of infection. Also, Sa3int phages induced from livestock-associated outbreak strains reveal mutatedattPsequences. We suspect that promiscuity of the phage-encoded recombinase allows this adaptation and propose it may explain how phages mediate “host jumps” that are regularly observed for staphylococcal lineages.
NEU1 and NEU3 enzymes alter CD22 organization on B cells
Authors: Tran Hanh-Thuc Ton , Li Caishun , Chakraberty Radhika , Cairo Christopher W.
Published: April 2021

The B cell membrane expresses sialic acid binding Immunoglobulin-like lectins, also called Siglecs, that are important for modulating immune response. Siglecs have interactions with sialoglycoproteins found on the same membrane (cis ligands) that result in homotypic and heterotypic receptor clusters. The regulation and organization of these clusters, and their effect on cell activation, is not clearly understood. We investigated the role of human neuraminidase enzymes, NEU1 and NEU3, on the clustering of CD22 on B cells using confocal microscopy. We observed that native NEU1 and NEU3 activity influence the cluster size of CD22. Using single-particle tracking, we observed that NEU3 activity increased the lateral mobility of CD22, which was in contrast to the effect of exogenous bacterial NEU enzymes. Moreover, we show that native NEU1 and NEU3 activity influenced cellular Ca2+levels, supporting a role for these enzymes in regulating B cell activation. Our results establish a role for native NEU activity in modulating CD22 organization and function on B cells.