bluuebunny/crossref_metadata_2025 huggingface dataset:
INADVERTENT GLOBE PENETRATION AND SUBRETINAL INJECTION OF BOTULINUM TOXIN IN A PATIENT WITH OCULOCUTANEOUS ALBINISM
Authors: Aljohani Saud , AlJaloud Ahmad , Alsakran Wael A. , AlZaid Abdulrahman
Published: May 2021

Purpose:

To present a case of localized retinal detachment and mild vitreous hemorrhage in a patient with oculocutaneous albinism after accidental intraocular injection of botulinum toxin A.

Methods:

Botulinum toxin A injection was administered to a 5-year-old patient with oculocutaneous albinism with esotropia and resulted in an ocular penetration. Dilated fundus examination indicated a nasal retinal tear causing a mild vitreous hemorrhage and a localized retinal detachment.

Results:

No treatment was required for the retinal detachment, and we observed the patient at regular intervals. On Day 1, the detachment resolved spontaneously without sequelae. On follow-up, scarring at the lesion site was detected at one month after the incidence, and the patient's vision was stable.

Conclusion:

In this instance, observation was sufficient for our patient with complete resolution of retinal detachment and no long-term complication. Botulinum toxin A did not seem toxic to intraocular tissues. However, intramuscular botulinum toxin A injection should be administered carefully. Oculocutaneous albinism did not seem to affect the final outcome in our case.
Multiple Mini-Interview Utilization in United States Physician Assistant Program Admission Processes
Authors: James Kassidy , Mazur Ziemowit , Statler Michel , Hegmann Theresa , Landel Grace , Orcutt Venetia L.
Published: May 2021

Purpose

Health care program admission processes utilize multi-faceted approaches to evaluate cognitive and noncognitive attributes of applicants. The multiple mini-interview (MMI) was developed in response to the need for a reliable and validated tool to assess noncognitive factors and has been increasingly incorporated into the admissions process by physician assistant (PA) programs. The study's purpose was to explore the current implementation and utilization of the MMI within PA programs.

Methods

The study used a mixed-methods exploratory approach including a telephone survey and semi-structured interview of 11 PA programs using the MMI in their admissions process. Quantitative data collected included demographic information, MMI implementation characteristics, station structure, scoring, feasibility, satisfaction with MMI utilization, and MMI evaluation methods.

Results

During the 2015–2016 admissions cycle, the participating programs used from 5 to 10 stations, averaging 7 minutes per station, requiring 8 faculty, 2 staff, and 7 students per interview session. Despite variation in program size, number of applicants, and years of MMI utilization, all participating programs reported that they were satisfied with the format and would continue to utilize the MMI in the admissions process.

Conclusions

While there is substantial literature describing the use of the MMI within health care programs globally, this study represents the first characterization of its use within PA programs on a national level. Although there was variation among PA program implementation of the MMI, our results are comparable to studies within other health care professions. Additional studies are necessary to further describe the MMI and its correlation with PA program educational outcomes and the impact on diversity.
Validation of the QMon-20 oscillometric blood pressure monitor for professional office use in the general population according to the ANSI/ESH/ISO 81060–2:2018 protocol
Authors: Rico-Martín Sergio , Sánchez-Bacaicoa Marisol , Calderón-García Julián F. , Labrador-Gómez Pedro J. , De Nicolás Jiménez Jorge M. , Villa-Rincón Juan , Robles Nicolás R. , Guijarro Carlos , Iammarino Chiara , Rodilla-Salas Enrique , Sánchez Muñoz-Torrero Juan F.
Published: May 2021

Objective

we assessed the accuracy of the QMon-20 oscillometric upper-arm cuff device professional for office blood pressure (BP) in general population according to the Association for the Advancement of Medical Instrumentation/European Society of Hypertension/International Organization for Standardization (AAMI/ESH/ISO) Universal Standard (ISO 81060-2:2018).

Methods

Subjects were recruited according to AAMI/ESH/ISO Universal Standard in general population using the same arm sequential BP measurement method. Two cuffs of the test device were used for arm circumference 22–31 (medium) and 32–42 cm (large).

Results

One-hundred and fourteen subjects were recruited and 106 were analyzed. For validation criterion 1, the mean ± SD of the differences between the test device and reference BP readings was 0.8 ± 5.4/−0.5 ± 4.2 mmHg (systolic/diastolic). For criterion 2, the SD of the mean BP differences between the test device and reference BP per subject was 4.34/3.48 mmHg (systolic/diastolic).

Conclusion

The QMon-20 oscillometric device for office BPs measurement fulfilled all the requirements of the AAMI/ESH/ISO Universal Standard (ISO 81060-2:2018) in general population and can be recommended for clinical use.
Effects of SCN1A and SCN2A polymorphisms on responsiveness to valproic acid monotherapy in epileptic children
Authors: Wen Zhuangfei , Chen Jiang , Zhu Bin , Lu Yan , Chen Lijiao
Published: May 2021

Background

: The gene mutation of coding sodium channel is one of the most important mechanisms in the pathogenesis of epilepsy. There exists a large inter-individual variation in the efficacy of valproic acid (VPA) against epilepsy. What are the genetic polymorphism influences of sodium channels on VPA response is still under discussion. In this study, a meta-analysis was used to further explore the effects of SCN1A and SCN2A gene polymorphism on VPA response in children with epilepsy.

Methods

: The PubMed, EMBASE, Web of Science, Chinese National Knowledge Infrastructure, Chinese Science and Technique Journals Database, China Biology Medicine disc, and Wan Fang Database were searched up to April 2021 for appropriate studies regarding the association between SCN1A and SCN2A gene polymorphism on VPA response in children suffering from epilepsy. The meta-analysis was conducted by Review Manager 5.3 software.

Results

: The results of this meta-analysis will be submitted to a peer-reviewed journal for publication.

Conclusion

: This meta-analysis will summarize the effects of SCN1A and SCN2A gene polymorphisms on VPA response in children with epilepsy.

OSF Registration Number:

DOI 10.17605/OSF.IO/N2786.
Surgical treatment of carpal tunnel syndrome in advanced-stage upper extremity lymphedema
Authors: Kim Soo-Byn , Moon Kyung-Chul
Published: May 2021

Rationale

Despite significant advances in microsurgical techniques, simultaneous release of transverse carpal ligament (TCL) and lymphovenous anastomosis (LVA) surgeries may be effective for treatment of carpal tunnel syndrome (CTS) and advanced-stage lymphedema. This case report describes the successful treatment of lymphedema with LVA in a patient with CTS and advanced-stage lymphedema.

Patient concerns

A 60-year-old female patient was referred to our lymphedema clinic with a 12-year history of chronic, acquired, right upper extremity lymphedema and CTS following right mastectomy and axillary lymph node dissection and adjuvant chemoradiotherapy for treating breast cancer.

Diagnosis

According to the indocyanine green lymphography, magnetic resonance lymphangiography, and electromyography, the patient was diagnosed with CTS and advanced-stage lymphedema (International Society of Lymphology late stage 2).

Intervention

Release of the TCL was performed first, followed by LVA at the wrist, forearm, and antecubital area. The right arm was compressed and elevated immediately postoperatively and postoperative compression bandage therapy with 35 to 40 mm Hg pressure was instituted following surgery.

Outcomes

After 2 simultaneous surgeries, the patient had significant circumference and volume reduction of the right hand. The CTS and lymphedema symptoms have decreased following synchronous TCL release and LVA surgeries.

Lessons

Simultaneous LVA and release of the TCL may be effective and safe in patients with advanced lymphedema and CTS.
Clinical and Demographic Characteristics of Cutaneous Mastocytosis in Childhood: Single-center Experience
Authors: Yazal Erdem Arzu , Özyörük Derya , Emir Suna , Çakmakçi Selma , Güleç Ceylan Gülay , Toyran Müge , Civelek Ersoy , Dibek Misirlioğlu Emine
Published: May 2021

Introduction:

Mastocytosis is a rare and heterogenous disease, and in children it is generally limited to the skin and tends to regress spontaneously in adolescence.

Aim:

In this study, demographic, clinical, and laboratory characteristics of pediatric patients with mastocytosis, and also coexisting diseases were investigated.

Results:

A total of 61 pediatric patients were included in the study. The male-to-female ratio was 2.2, the median age was 2 years (range, 0.25 to 19 y), and the median follow-up period was 2.0 years (range, 0.25 to 19 y). Types of clinical presentation at diagnosis consisted of mainly urticaria pigmentosa (45.9%). Seven patients were further investigated with suspicion of systemic mastocytosis, they were followed up, median of 9 years (range, 2.5 to 16 y), and none of them developed systemic disease. Coexisting allergic diseases were recorded in total 5 patients (8.2%). Three patients had immunoglobulin A deficiency, 1 patient had elevated immunoglobulin E level. A patient developed mature B-cell lymphoma with a heterozygous mutation in c-KIT exon 11.

Discussion:

Cutaneous mastocytosis in children may present as a complex disease with different clinical signs and symptoms. Standardized clinical criteria and guidelines for the follow-up of children with mastocytosis are required.
When Reality and Research Collide: Guidelines Are Essential for Optimal Nutrition Care in Pediatric Oncology
Authors: Ringwald-Smith Karen , Hill Rachel , Evanoff Lisa , Martin Jenna , Sacks Nancy
Published: May 2021

Nutritional problems are common in pediatric oncology due to the side effects of the disease and treatment. Nutrition intervention can be challenging, and little is known about the current clinical practice of registered dietitian nutritionists. An online questionnaire emailed to members of the pediatric, oncology nutrition, and clinical manager practice groups of the Academy of Nutrition and Dietetics, consisted of items related to current nutrition practice. Our questionnaire results suggest that the field of pediatric oncology is employed with relatively new dietitians (62% had <5 y of experience). Many registered dietitian nutritionists (60%) are providing care across the cancer care continuum (standard therapy, transplant, and survivorship) versus specializing in a particular area. Approximately half (52%) felt that their center had inadequate staffing, many reporting little in the outpatient setting. Barriers to providing optimal patient care included inadequate staffing, lack of time for research initiatives, and lack of evidence-based guidelines. Future studies should determine follow-up guidelines and appropriate staffing ratios for nutrition care in pediatric oncology. Approaches should be developed to support less experienced dietitians. Collaboration between dietitians at different facilities will likely be key in developing essential evidence-informed guidelines.
In-hospital Mortality and Racial Disparity in Children and Adolescents With Acute Myeloid Leukemia: A Population-based Study
Authors: Castellanos Maria I. , Dongarwar Deepa , Wanser Rachelle , Caceres Ibeth , Park Charles , Rodriguez Jacquelin , Salihu Hamisu M.
Published: May 2021

Survival disparities in children and adolescents with acute myeloid leukemia (AML) are documented, however, the etiology of these disparities is understudied. Few studies have evaluated factors that predict in-hospital mortality in childhood AML and racial/ethnic disparities associated with in-hospital death. Our study aimed to investigate factors associated with the risk of in-hospital death among childhood AML hospitalizations. We conducted a retrospective study of childhood AML hospitalizations using the National Inpatient Sample (NIS) from 2003 to 2017. We estimated incidences of in-hospital death among AML hospitalizations. We performed survey logistic regression models to measure the association between patient and hospital characteristics and in-hospital mortality. We identified 71,050 hospitalizations of children with AML. Compared with non-Hispanic (NH) whites, NH-black children had a higher risk of in-hospital mortality (adjusted odds ratio: 1.41, 95% confidence interval: 1.06-1.87, P<0.02). Further, NH-black patients with hematopoietic stem cell transplant experienced the highest risk of mortality (adjusted odds ratio: 5.88, 95% confidence interval: 3.13-11.06, P<0.001) as compared with NH-black children who did not receive hematopoietic stem cell transplant. Our findings highlight that NH-black children with AML continue to experience a disproportionately higher likelihood of in-hospital mortality when compared with their NH-white counterparts. Further studies are needed to delineate the etiology of these disparities.
An Unusual Case of Posttraumatic Visual Agnosia Posing Challenges to Rehabilitation
Authors: Thakkar Prince , Thampi Suhany Baby , Keziah Stephy , Ramanathan Saraswathi
Published: May 2021

Acquired focal visuoperceptual deficits are rarely reported, and rehabilitation strategies are not well established. This is a report on visuoperceptual deficit after traumatic brain injury that initially went unnoticed. Missing visual agnosia is not unusual especially when perceptual deficits present with visual field defects, impaired insight, and inattention. This case is made more interesting because of the rarity of visual agnosia with predominant ventral pathway involvement, affecting object and face recognition. This report provides a brief discussion on visual agnosia spectrum deficits and rehabilitation measures.
Extended Neuralgic Amyotrophy Syndrome in a Confirmed COVID-19 Patient After Intensive Care Unit and Inpatient Rehabilitation Stay
Authors: Alvarez Armando , Amirianfar Edwin , Mason Marisa Carino , Huang Laura , Jose Jean , Tiu Timothy
Published: May 2021

The cause of neuralgic amyotrophy is often unknown but is commonly associated with a recent upper respiratory viral tract infection. Since the beginning of the COVID-19 pandemic, there has been a tireless effort to understand the sequelae of the virus. A 46-yr-old woman who presented after a COVID-19 hospitalization complicated by hypoxic respiratory failure requiring intubation and mechanical ventilation for 23 days was subsequently found to have lower limb sensorium changes as well as upper limb weakness. Left shoulder abduction and extension were both 3/5 in motor strength, and left hip flexion strength was 4/5 with diminished sensation to crude touch in the left lateral thigh. Nerve conduction studies and electromyography findings included a mild left median neuropathy at the wrist and motor unit recruitment pattern consistent with a chronic left upper trunk plexopathy with reinnervation. The case presented describes an extended neuralgic amyotrophy syndrome from an atraumatic mechanism in a previously diagnosed COVID-19 patient. An extended neuralgic amyotrophy syndrome has at least three immune mediated etiologies postulated (1) direct neuropathogenicity, (2) molecular mimicry, and (3) direct cytotoxic effects on peripheral nerves. As COVID-19 survivors continue to be seen in outpatient settings, practitioners should remain aware of diffuse neurological complications as sequelae of the virus persist.
Fungal Infection in Burn Patents
Authors: Tu Yiji , Lineaweaver William C. , Breland Andrew , Zhang Feng
Published: May 2021

Objectives

The aims of this study were to review recent fungal infection case reports published, evaluate the treatment regimens and clinical outcomes, and provide recommendations for future management.

Methods

A review of case reports published over the last decade was conducted. PubMed was searched to collect the relevant citations using a combination of the key words (“burn,” “burned,” “burns,” “fungal,” “fungi,” and “fungus”) in title or abstract. Case series, reviews, guidelines, and experimental and non-English studies were excluded. Statistical analyses were performed using Microsoft Excel 2019.

Results

A total of 36 case reports encompassing a total of 44 burn patients with fungal infection were included in the final analysis. Ablative surgeries, including surgical excision, debridement, skin graft, vitrectomy, teeth extraction, valve replacement, or amputation, were performed in 38 cases after the suspicion or identification of fungal infection. Twenty-nine of them were eventually discharged, yielding a survival rate of 76.3%. In the remaining 6 cases, ablative surgery was not mentioned and 3 of them eventually died, yielding a survival rate of 50%. The total mortality was 27.27%. Among the 12 death cases, 1 was infected withCandida albicans, 1 with non-albicans Candida, 2 withAspergillusspp, 2 withFusariumspp, 4 with Zygomycetes, and 2 with other fungal species.

Conclusions

The overall mortality of fungal wound infection is still high in burn patients around the world, especially those infected with non-Candidaspecies. Early diagnosis of fungal infection, early initiation of appropriate antifungal therapy, and effective surgical intervention are key measures to improve the treatment effect and reduce the mortality of fungal infection in burn patients.
Impact of the coronavirus disease 2019 pandemic on healthcare workers: systematic comparison between nurses and medical doctors
Authors: Kunz Miriam , Strasser Martina , Hasan Alkomiet
Published: May 2021

Purpose of review

The COVID-19 outbreak has had major impact on individual's psychological health and overall well being worldwide. Evidence shows that these psychological challenges are especially prominent in healthcare workers (HCW); especially in nurses. Indeed, several studies report that nurses suffer more psychologically because of the consequences of the pandemic compared with medical doctors. To further look into this, we systematically review the recent literature to see whether the psychological impact of the COVID-19 pandemic differs between medical doctors and nurses across studies and which aspects of mental health are especially affected in nurses.

Recent findings

Across studies, there is solid evidence that nurses show poorer mental health outcomes compared with medical doctors during the COVID-19 pandemic. This is especially true for symptoms of depression, anxiety and posttraumatic stress disorder (PTSD). Here, prevalence rates in nurses are often higher than 50%. In contrast, general stress levels and burnout seem to be comparable between nurses and medical doctors.

Given that nurses suffer more from depression, anxiety and PTSD symptoms during the COVID-19 pandemic, special programs addressing their needs are required.
Drought-driven wildfire impacts on structure and dynamics in a wet Central Amazonian forest
Authors: Pontes-Lopes Aline , Silva Camila V. J. , Barlow Jos , Rincón Lorena M. , Campanharo Wesley A. , Nunes Cássio A. , de Almeida Catherine T. , Silva Júnior Celso H. L. , Cassol Henrique L. G. , Dalagnol Ricardo , Stark Scott C. , Graça Paulo M. L. A. , Aragão Luiz E. O. C.
Published: May 2021

While the climate and human-induced forest degradation is increasing in the Amazon, fire impacts on forest dynamics remain understudied in the wetter regions of the basin, which are susceptible to large wildfires only during extreme droughts. To address this gap, we installed burned and unburned plots immediately after a wildfire in the northern Purus-Madeira (Central Amazon) during the 2015 El-Niño. We measured all individuals with diameter of 10 cm or more at breast height and conducted recensuses to track the demographic drivers of biomass change over 3 years. We also assessed how stem-level growth and mortality were influenced by fire intensity (proxied by char height) and tree morphological traits (size and wood density). Overall, the burned forest lost 27.3% of stem density and 12.8% of biomass, concentrated in small and medium trees. Mortality drove these losses in the first 2 years and recruitment decreased in the third year. The fire increased growth in lower wood density and larger sized trees, while char height had transitory strong effects increasing tree mortality. Our findings suggest that fire impacts are weaker in the wetter Amazon. Here, trees of greater sizes and higher wood densities may confer a margin of fire resistance; however, this may not extend to higher intensity fires arising from climate change.
When rare meets common: Treatable genetic diseases are enriched in the general psychiatric population
Authors: Sriretnakumar Venuja , Harripaul Ricardo , Kennedy James L. , So Joyce
Published: May 2021

1.1

Mental illnesses are one of the biggest contributors to the global disease burden. Despite the increased recognition, diagnosis and ongoing research of mental health disorders, the etiology and underlying molecular mechanisms of these disorders are yet to be fully elucidated. Moreover, despite many treatment options available, a large subset of the psychiatric patient population is non-responsive to standard medications and therapies. There has not been a comprehensive study to date examining the burden and impact of treatable genetic disorders (TGDs) that can present with neuropsychiatric features in psychiatric patient populations. In this study, we test the hypothesis that TGDs that present with psychiatric symptoms are more prevalent within psychiatric patient populations compared to the general population by performing targeted next-generation sequencing (NGS) of 129 genes associated with 108 TGDs in a cohort of 2301 psychiatric patients. In total, 72 putative affected and 293 putative carriers for TGDs were identified, with known or likely pathogenic variants in 78 genes. Despite screening for only 108 genetic disorders, this study showed an approximately four-fold (4.13%) enrichment for genetic disorders within the psychiatric population relative to the estimated 1% cumulative prevalence of all single gene disorders globally. This strongly suggests that the prevalence of these, and most likely all, genetic diseases are greatly underestimated in psychiatric populations. Increasing awareness and ensuring accurate diagnosis of TGDs will open new avenues to targeted treatment for a subset of psychiatric patients.
Development of a quantitative antigen assay to detect coccidioidal chitinase-1 (CTS1) in human serum
Authors: Grill Francisca J. , Grys Thomas E. , Grill Marie F. , Roeder Alexa , Blair Janis E. , Lake Douglas F.
Published: May 2021

Background

Coccidioidomycosis is often diagnosed with a collection of tests that rely on the patient’s ability to mount an immune response to the fungus (antibody-based diagnostics), making diagnosis of this infection challenging. Here we present an antigen-based assay that detects and quantifies coccidioidal chitinase-1 (CTS1) in human serum.

Methods

An inhibition-based enzyme-linked immunoassay (ELISA) was developed that utilizes a monoclonal antibody specific for coccidioidal CTS1. CTS1 was quantified in commercial antigen preparations using recombinant CTS1 as a standard. Sera from 192 individuals from an endemic area were tested which included 78 patients (40.6%) with proven or probable coccidioidomycosis.

Results

The quantity of CTS1 in diagnostic commercial antigen preparations from different suppliers varied. CTS1 antigenemia was detected in 87.2% of patients with proven or probable coccidioidomycosis. Specificity was determined to be 96.94% using serum from individuals who reside in the Phoenix, Arizona area who did not have coccidioidomycosis. Levels of CTS1 correlated with low- and high-titer serology from patients with a coccidioidomycosis diagnosis.

Conclusions

Since the CTS1 inhibition ELISA described in this report does not depend on the host immune response, it is a promising diagnostic tool to aid in diagnosis and disease monitoring of coccidioidomycosis.

Diagnosis of coccidioidomycosis often relies on the host’s ability to mount an immune response. Here we present an antigen-based assay that detects and quantifies coccidioidal chitinase-1 in human serum to diagnose coccidioidomycosis independent of host immune status.
Multilocus drug resistance mutation analysis in 148 HBV patients in northern Henan Province of China
Authors: Zhou Zexin , Chen Minglei , Li Penghua , Yang Junzheng
Published: May 2021

Objectives

To analyze the genotypes and reverse transcriptase mutations gene sites in hepatitis B (HBV) patients in northern Henan Province from 2016 to 2018, which treated by tenofovir dipivoxil(TDF), Lbivudine(LDT), adefovir(ADV), lamivudine (LAM) and entecavir(ETV) analogues, to provide evidences for rational drug use and antiviral therapy for HBV patients.

Methods

HBV patients’ serum DNA was extracted, specific primers were designed for YMDD mutation sites in conservative regions; DNA sequencing of the PCR products was carried out by PCR amplification combined with Dideoxygenation termination sequencing(DDT), and then analyzed genotype and reverse transcriptase mutations gene sites of HBV patients.

Results

We collected 148 samples of HBV patients in northern Henan Province from 2016 to 2018; 97.97% of HBV patients were genotype C and 2.03% were genotype B; there are 46 cases of LAM and FTC resistance mutation, respectively; 28 cases of LDT resistance mutation, 10 cases of ADV resistance mutation, 8 cases of ETV resistance mutation, and 1 case of TDF resistance mutation were detected; the mutation rates of drug resistance was 43.45% in HBV patients with genotype C and 33.33% in HBV patients with genotype B. There was no significant difference in the distribution rate between the two genotypes (P>0.05). The most common mutations types were M204M|V and M204M|I. The M204M|V mutation type often occurred in combination of M204M|V+L180M|L+L173V|L and M204M|V+L180M|L and M204M|V+ L180M|L+V173V|M, while M204M|I mutation type was often occurred alone, M204M|V+L180M|L combination appeared alone or in combination. N236+A181 base substitution was the dominant site in ADV resistance. ETV resistance mutation was based on LAM and ETV resistance, mainly were T184 and S202 base substitution; and LDT resistance mutation was M204M|I.

Conclusion

In this article, PCR and DDT DNA sequencing were used to detect multisite resistance mutations of HBV reverse transcriptase gene in HBV patients. It was found that most of the genotypes of HBV patients in northern Henan Province were genotype C, the combination of drug resistance mutations was complex, and the mutation rates of multidrug resistance genes was high. There was no significant difference in the distribution rate of HBV genotypes among the detected patients, those data may provide evidences for the detection and confirmation of HBV resistance and rational drug use in HBV patients in the region.
Measurement of Respiratory Rate using Wearable Devices and Applications to COVID-19 Detection
Authors: Natarajan Aravind , Su Hao-Wei , Heneghan Conor , Blunt Leanna , O’Connor Corey , Niehaus Logan
Published: May 2021

We show that heart rate enabled wearable devices can be used to measure respiratory rate. Respiration modulates the heart rate creating excess power in the heart rate variability at a frequency equal to the respiratory rate, a phenomenon known as respiratory sinus arrhythmia. We isolate this component from the power spectral density of the heart beat interval time series, and show that the respiratory rate thus estimated is in good agreement with a validation dataset acquired from sleep studies (root mean squared error = 0.648 min−1, mean absolute percentage error = 3%). Using the same respiratory rate algorithm, we investigate population level characteristics by computing the respiratory rate from 10,000 individuals over a 14 day period, with equal number of males and females ranging in age from 20 - 69 years. 90% of respiratory rate values for healthy adults fall within the range 11.8 min−119.2 min−1with a mean value of 15.4 min−1. Respiratory rate is shown to increase with nocturnal heart rate. It also varies with BMI, reaching a minimum at 25 kg/m2, and increasing for lower and higher BMI. The respiratory rate decreases slightly with age and is higher in females compared to males for age < 50 years, with no difference between females and males thereafter. The 90% range for the coefficient of variation in a 14 day period for females (males) varies from 2.3%−9.2% (2.3%−9.5%) for ages 20−24 yr, to 2.5%−16.8% (2.7%−21.7%) for ages 65−69 yr. We show that respiratory rate is often elevated in subjects diagnosed with COVID-19. In a 7 day window centered on the date when symptoms present (or the test date for asymptomatic cases), we find that 33% (18%) of symptomatic (asymptomatic) individuals had at least one measurement of respiratory rate 3 min−1higher than the regular rate.
Inhibitor screening of Spike variants reveals the heterogeneity of neutralizing antibodies to COVID-19 infection and vaccination
Authors: Zhang Xiaomei , Zheng Mei , Liang Te , Zhou Haijian , Wang Hongye , Zhang Jiahui , Ren Jing , Peng Huoying , Li Siping , Bian Haodong , Wei Chundi , Yin Shangqi , He Chaonan , Han Ying , Li Minghui , Hou Xuexin , Zhang Jie , Xie Liangzhi , Lv Jing , Kan Biao , Wang Yajie , Yu Xiaobo
Published: May 2021

Mutations of the coronavirus responsible for coronavirus disease 2019 (COVID-19) could impede drug development and reduce the efficacy of COVID-19 vaccines. Here, we developed a multiplexed Spike-ACE2 Inhibitor Screening (mSAIS) assay that can measure the neutralizing effect of antibodies across numerous variants of the coronavirus’s Spike (S) protein simultaneously. By screening purified antibodies and serum from convalescent COVID-19 patients and vaccinees against 72 S variants with the mSAIS assay, we identified new S mutations that are sensitive and resistant to neutralization. Serum from both infected and vaccinated groups with a high titer of neutralizing antibodies (NAbs) displayed a broader capacity to neutralize S variants than serum with low titer NAbs. These data were validated using serum from a large vaccinated cohort (n=104) with a tiled S peptide microarray. In addition, similar results were obtained using a SARS-CoV-2 pseudovirus neutralization assay specific for wild-type S and four prevalent S variants (D614G, B.1.1.7, B.1.351, P.1), thus demonstrating that high antibody diversity is associated with high NAb titers. Our results demonstrate the utility of the mSAIS platform in screening NAbs. Moreover, we show that heterogeneous antibody populations provide a more protective effect against S variants, which may help direct COVID-19 vaccine and drug development.

Highlights

Developed a high throughput assay to screen the neutralizing effect of antibodies across multiple SARS-CoV-2 Spike variants simultaneously.

Characterized the heterogeneity of neutralizing antibodies produced in response to COVID-19 infection and vaccination.

Demonstrated the capacity of Spike variants neutralization is associated with the diversity of anti-Spike antibodies.
Novel deterministic epidemic model considering mass vaccination and lockdown against coronavirus disease 2019 spread in Israel: A numerical study
Authors: Utamura Motoaki , Koizumi Makoto , Kirikami Seiichi
Published: May 2021

Why public health intervention by the Israeli government against coronavirus disease 2019 spread has been successful while the majority of other countries are still coping with it? To give a quantitative answer, a simple numerical epidemic model is prepared to simulate the entire trend of various infection-related variables considering the 1st and 2nd vaccination campaigns against the alpha variant and simultaneous lockdown. This model is an extension of our previously published deterministic physical model, i.e. Apparent Time Lag Model, which aims at predicting an entire trend of variables in a single epidemic. The time series data of both vaccine dose ratio and lockdown period are employed in the model. Predictions have been compared with observed data in terms of daily new cases, isolated people, infections at large and effective reproductive number, and, further, the model is verified. Moreover, parameter survey calculations for several scenarios have clarified the synergy effects of vaccination and lockdown. In particular, the key element of Israel’s success has been suggested to lie in a high-dose vaccination rate that prevents the onset of a rebound in daily new cases on the rescission of the lockdown.
Early Anakinra Treatment for COVID-19 Guided by Urokinase Plasminogen Receptor
Authors: Kyriazopoulou Evdoxia , Poulakou Garyfallia , Milionis Haralampos , Metallidis Simeon , Adamis Georgios , Tsiakos Konstantinos , Fragkou Archontoula , Rapti Aggeliki , Damoulari Christina , Fantoni Massimo , Kalomenidis Ioannis , Chrysos Georgios , Angheben Andrea , Kainis Ilias , Alexiou Zoi , Castelli Francesco , Serino Francesco Saverio , Bakakos Petros , Nicastri Emanuele , Tzavara Vassiliki , Kostis Evangelos , Dagna Lorenzo , Koufargyris Panagiotis , Dimakou Katerina , Tzatzagou Glykeria , Chini Maria , Bassetti Matteo , Katrini Konstantina , Kotsis Vasileios , Tsoukalas George , Selmi Carlo , Bliziotis Ioannis , Samarkos Michael , Doumas Michael , Ktena Sofia , Masgala Aikaterini , Papanikolaou Ilias , Argyraki Aikaterini , Cardellino Chiara Simona , Katsigianni Eleni-Ioanna , Giannitsioti Efthymia , Cingolani Antonella , Akinosoglou Karolina , Liatsis-Douvitsas Orestis , Symbardi Styliani , Mouktaroudi Maria , Ippolito Giuseppe , Florou Eleni , Kotsaki Antigone , Netea Mihai G. , Eugen-Olsen Jesper , Kyprianou Miltiades , Panagopoulos Periklis , Dalekos George N. , Giamarellos-Bourboulis Evangelos J.
Published: May 2021

Background

In a previous open-label trial, early anakinra treatment guided by elevated soluble urokinase plasminogen activator receptor (suPAR) prevented progression of COVID-19 pneumonia into respiratory failure.

Methods

In the SAVE-MORE multicenter trial, 594 hospitalized patients with moderate and severe COVID-19 pneumonia and plasma suPAR 6 ng/ml or more and receiving standard-of-care were 1:2 randomized to subcutaneous treatment with placebo or 100 mg anakinra once daily for 10 days. The primary endpoint was the overall clinical status of the 11-point World Health Organization ordinal Clinical Progression Scale (WHO-CPS) at day 28. The changes of the WHO-CPS and of the sequential organ failure assessment (SOFA) score were the main secondary endpoints.

Results

Anakinra-treated patients were distributed to lower strata of WHO-CPS by day 28 (adjusted odds ratio-OR 0.36; 95%CI 0.26-0.50; P<0.001); anakinra protected from severe disease or death (6 or more points of WHO-CPS) (OR: 0.46; P: 0.010). The median absolute decrease of WHO-CPS in the placebo and anakinra groups from baseline was 3 and 4 points respectively at day 28 (OR 0.40; P<0.0001); and 2 and 3 points at day 14 (OR 0.63; P: 0.003); the absolute decrease of SOFA score was 0 and 1 points (OR 0.63; P: 0.004). 28-day mortality decreased (hazard ratio: 0.45; P: 0.045). Hospital stay was shorter.

Conclusions

Early start of anakinra treatment guided by suPAR provides 2.78 times better improvement of overall clinical status in moderate and severe COVID-19 pneumonia.

(Sponsored by the Hellenic Institute for the Study of SepsisClinicalTrials.govidentifier,NCT04680949)
Microsimulation of SARS-CoV-2 Transmission in Society
Authors: Green Anthony Roland , Keep Daniel , Piper Ian
Published: May 2021

The outbreak of the pandemic disease, COVID-19, has shown that the approaches by different countries has resulted in a range of infection rates through their societies. This has arisen from the varying personal behaviour and tactical use of lockdown strategies within each country. We report the use of microsimulation of a simulated community in Australia, using a discrete infection model within a community of residences, places of work and recreation to demonstrate the applicability of this method to both the current pandemic and to infection more generally. Simulations without any societal intervention on infection spread provided base simulations that could be compared with social and societal controls in the future and which were compared with the initial doubling times of country outbreaks across the world. Different population sizes were represented in some simulations and in other simulations the effects of either social distancing or the use of facial masks as personal behaviours was investigated within the community. Good agreement is found between the initial doubling times for several countries and the simulations that suggests that modelling infection as a collection of individual infections provides an alternative to current epidemiological models. The variation of the basic reproductive number, R0, with time and population size, suggests that one of the fundamentals assumptions in SIR type models is wrong, but varies according to the properties of the population being modelled. Investigation of the infection spread shows that the number of super-spreaders varies with the size of the population and occurs through contacts in clubs, supermarkets, schools and theatres where the source of infection is an employee and where there are high numbers of contacts. The simulations of individual control show that the benefits of social distancing or wearing masks is only fully realised where there is considerable compliance within society to these measures.
Genome-wide association study revealed loci linked to post-drought recovery and traits related to persistence of smooth bromegrass (Bromus inermis)
Authors: Saeidnia Fatemeh , Majidi Mohammad Mahdi , Mirlohi Aghafakhr
Published: May 2021

Association analysis has been proved as a powerful tool for genetic dissection of complex traits. This study was conducted to identify marker–trait associations for recovery, persistence, and as well as finding stable associations. In this study, a diverse panel of polycross derived progenies of smooth bromegrass was phenotyped under normal and water stress, during three consecutive years. Association analysis was performed between nine important agronomic traits along with three seasonal growth activity indices based on 535 SRAP markers. Population structure analysis identified five main subpopulations possessing significant genetic differences. Association analysis using mixed linear mode1 identified 339 and 233 marker-trait associations under normal and water stress environments, respectively. Some of these markers were associated with more than one trait; which can be attributed to pleiotropic effects or to a number of tightly linked genes affecting several traits. If the effectiveness of these markers in genetic control of these traits is validated, they could be potentially used for initiation of marker-assisted selection and targeted trait introgression of smooth bromegrass under normal and water stress environments.

Highlight

In this study, stable marker-trait associations (MTAs) between years and moisture regimes (normal and water stress environments) were identified in a diverse panel of polycross derived progenies of smooth bromegrass.
Structure-based design of stabilized recombinant influenza neuraminidase tetramers
Authors: Ellis Daniel , Lederhofer Julia , Acton Oliver J. , Tsybovsky Yaroslav , Kephart Sally , Yap Christina , Gillespie Rebecca A. , Creanga Adrian , Stephens Tyler , Pettie Deleah , Murphy Michael , Borst Andrew J. , Park Young-Jun , Lee Kelly K. , Graham Barney S. , Veesler David , King Neil P. , Kanekiyo Masaru
Published: May 2021

Influenza virus neuraminidase (NA) is a major antiviral drug target and has recently reemerged as a key target of antibody-mediated protective immunity. Here we show that recombinant NAs across all non-bat subtypes adopt various tetrameric conformations, including a previously unreported “open” state that may help explain poorly understood variations in NA stability across viral strains and subtypes. We used homology-directed protein design to uncover the structural principles underlying these distinct tetrameric conformations and stabilize multiple recombinant NAs in the “closed” state. In addition to improving thermal stability, conformational stabilization improved affinity to protective antibodies elicited by viral infection, including antibodies targeting a quaternary epitope and the broadly conserved catalytic site. The stabilized NA proteins can also be integrated into viruses without affecting fitness. Our findings provide a deeper understanding of NA structure, stability, and antigenicity, as well as a roadmap towards structure-based discovery of NA-directed therapeutics and vaccines.
Synaptic targets of photoreceptors specialized to detect color and skylight polarization in Drosophila
Authors: Kind Emil , Longden Kit D. , Nern Aljoscha , Zhao Arthur , Sancer Gizem , Flynn Miriam , Laughland Connor , Gezahegn Bruck , Ludwig Henrique , Thomson Alex , Obrusnik Tessa , Alarcón Paula G. , Dionne Heather , Bock Davi D. , Rubin Gerald M. , Reiser Michael B. , Wernet Mathias F.
Published: May 2021

Color and polarization provide complementary information about the world and are detected by specialized photoreceptors. However, the downstream neural circuits that process these distinct modalities are incompletely understood in any animal. Using electron microscopy, we have systematically reconstructed the synaptic targets of the photoreceptors specialized to detect color and skylight polarization in Drosophila, and we have used light microscopy to confirm many of our findings. We identified known and novel downstream targets that are selective for different wavelengths or polarized light, and followed their projections to other areas in the optic lobes and the central brain. Our results revealed many synapses along the photoreceptor axons between brain regions, new pathways in the optic lobes, and spatially segregated projections to central brain regions. Strikingly, photoreceptors in the polarization-sensitive dorsal rim area target fewer cell types, and lack strong connections to the lobula, a neuropil involved in color processing. Our reconstruction identifies shared wiring and modality-specific specializations for color and polarization vision, and provides a comprehensive view of the first steps of the pathways processing color and polarized light inputs.
Transcriptome analysis provides genome annotation and expression profiles in the central nervous system ofLymnaea stagnalisat different ages
Authors: Rosato Martina , Hoelscher Brittany , Lin Zhenguo , Agwu Chidera , Xu Fenglian
Published: May 2021

Molecular studies of the freshwater snailLymnaea stagnalis, a unique model organism for neurobiology research, has been severely hindered by the lack of sufficient genomic information. As part of our ongoing effort studyingL. stagnalisneuronal growth and connectivity at various developmental stages, we provide the first age-specific transcriptome analysis and gene annotation of young, adult, and oldL. stagnaliscentral nervous system (CNS). RNA sequencing using Illumina NovaSeq 6000 platform produced 56-69 millions of 150 bp paired-end reads, and 74% of these reads were mapped to the draft genome ofL. stagnalis. We provide gene annotations for 32,288 coding sequences with a minimum of 100 codons, contributing to the largest number of annotated genes for theL. stagnalisgenome to date. Lastly, transcriptomic analyses reveal age-specific differentially expressed genes and enriched pathways in young, adult, and old CNS. These datasets represent the largest and most updatedL. stagnalisCNS transcriptomes.
Tafazzin regulates the function of lipopolysaccharide activated B lymphocytes in mice
Authors: Zegallai Hana M. , Abu-El-Rub Ejlal , Cole Laura K. , Field Jared , Mejia Edgard M. , Gordon Joseph W. , Marshall Aaron J. , Hatch Grant M.
Published: May 2021

B lymphocytes are responsible for humoral immunity and play a key role in the immune response. Optimal mitochondrial function is required to support B cell activity during activation. We examined how deficiency of tafazzin, a cardiolipin remodeling enzyme required for mitochondrial function, alters the metabolic activity of B cells and their response to activation by lipopolysaccharide in mice. B cells were isolated from 3 month old wild type or tafazzin knockdown mice and incubated for up to 72 h with lipopolysaccharide and cell proliferation, expression of cell surface markers, secretion of antibodies and chemokines, proteasome and immunoproteasome activities, and metabolic function determined. In addition, proteomic analysis was performed to identify altered levels of proteins involved in survival, immunogenic, proteasomal and mitochondrial processes. Compared to wild type lipopolysaccharide activated B cells, lipopolysaccharide activated tafazzin knockdown B cells exhibited significantly reduced proliferation, lowered expression of cluster of differentiation 86 and cluster of differentiation 69 surface markers, reduced secretion of immunoglobulin M antibody, reduced secretion of keratinocytes-derived chemokine and macrophage-inflammatory protein-2, reduced proteasome and immunoproteasome activities, and reduced mitochondrial respiration and glycolysis. Proteomic analysis revealed significant alterations in key protein targets that regulate cell survival, immunogenicity, proteasomal processing and mitochondrial function consistent with the findings of the above functional studies. The results indicate that the cardiolipin transacylase enzyme tafazzin plays a key role in regulating mouse B cell function and metabolic activity during activation.
Pan-cancer HLA Gene-mediated Tumor Immunogenicity and Immune Evasion
Authors: Gong Xutong , Karchin Rachel
Published: May 2021

Human Leukocyte Antigen (HLA) expression contributes to the activation of anti-tumor immunity through interactions with T cell receptors. However, pan-cancer HLA-mediated immunogenicity and immunoediting mechanisms has not been systematically studied. In a retrospective analysis of 33 tumor types from the Cancer Genome Atlas, we uncovered HLA class I and class II differential expression, which outperformed traditional clinical metrics in predicting patient survival. We also characterized the distribution of HLA supertypes across cancers and showed that patients with high HLA allelic diversity and gene expression had better prognosis. Immune microenvironments with varied survival outcomes could be predicted using a neural network model trained on HLA expression data. Furthermore, we identified a subset of tumors which upregulated HLA class I but not class II genes and exploited HLA-mediated escape strategies. Our results suggest the potential of using HLA expression data to predict patient prognosis. Taken together, we emphasize the crucial role of HLA upregulation in shaping prolonged anti-tumor immunity.

Synopsis

In a retrospective analysis of 11080 patients of 33 TCGA cancer types, we showed HLA class I and class II differential expression shape various immune microenvironments and tumor immunoediting mechanisms, predicting tumor immunogenicity and patient survival.