bluuebunny/crossref_metadata_2025 huggingface dataset:
Learning Pediatric Point-of-Care Ultrasound
Authors: Kwan Charisse , Weerdenburg Kirstin , Pusic Martin , Constantine Erika , Chen Aaron , Rempell Rachel , Herman Joshua E. , Boutis Kathy
Published: April 2021

Objectives

Using an education and assessment tool, we examined the number of cases necessary to achieve a performance benchmark in image interpretation of pediatric soft tissue, cardiac, lung, and focused assessment with sonography for trauma (FAST) point-of-care ultrasound (POCUS) applications. We also determined interpretation difficulty scores to derive which cases provided the greatest diagnostic challenges.

Methods

Pediatric emergency physicians participated in web-based pediatric POCUS courses sponsored by their institution as a credentialing priority. Participants deliberately practiced cases until they achieved diagnostic interpretation scores of combined 90% accuracy, sensitivity, and specificity.

Results

Of the 463 who enrolled, 379 (81.9%) completed cases. The median (interquartile range) number of cases required to achieve the performance benchmark for soft tissue was 94 (68–128); cardiac, 128 (86–201); lung, 87 (25–118); and FAST, 93 (68–133) (P < 0001). Specifically, cases completed to achieve benchmark were higher for cardiac relative to other applications (P < 0.0001 for all comparisons). In soft tissue cases, a foreign body was more difficult to diagnose than cobblestoning and hypoechoic collections (P = 0.036). Poor cardiac function and abnormal ventricles were more difficult to interpret with accuracy than normal (P < 0.0001) or pericardial effusion cases (P = 0.01). The absence of lung sliding was significantly more difficult to interpret than normal lung cases (P = 0.028). The interpretation difficulty of various FAST imaging findings was not significantly different.

Conclusions

There was a significant variation in number of cases required to reach a performance benchmark. We also identified the specific applications and imaging findings that demonstrated the greatest diagnostic challenges. These data may inform future credentialing guidelines and POCUS learning interventions.
Point-of-Care Ultrasound Findings in Multisystem Inflammatory Syndrome in Children
Authors: Kennedy Thomas M. , Dessie Almaz , Kessler David O. , Malia Laurie , Rabiner Joni E. , Firnberg Maytal T. , Ng Lorraine
Published: April 2021

Objectives

Multisystem inflammatory syndrome in children (MIS-C) associated with coronavirus disease 2019 is a novel pediatric condition with significant morbidity and mortality. The primary objective of this investigation was to describe the point-of-care ultrasound (POCUS) findings in patients evaluated in the emergency department (ED) who were diagnosed with MIS-C.

Methods

A retrospective cross-sectional study was conducted including patients <21-years-old who had POCUS performed for clinical care in a pediatric ED and were diagnosed with MIS-C. Point-of-care ultrasound studies were performed by pediatric emergency medicine attending physicians or fellows. Data abstracted by chart review included patient demographics, clinical history, physical examination findings, diagnostic test results, the time POCUS studies and echocardiograms were performed, therapies administered, and clinical course after admission.

Results

For the 24 patients included, 17 focused cardiac ultrasound, 9 lung POCUS, 7 pediatric modified rapid ultrasound for shock and hypotension, 1 focused assessment with sonography for trauma, 1 POCUS for suspected appendicitis, and 1 ocular POCUS were performed by 13 physicians. Point-of-care ultrasound identified impaired cardiac contractility in 5 patients, large intraperitoneal free fluid with inflamed bowel in 1 patient, and increased optic nerve sheath diameters with elevation of the optic discs in 1 patient. Trace or small pericardial effusions, pleural effusions, and intraperitoneal free fluid were seen in 3 patients, 6 patients, and 4 patients, respectively.

Conclusions

This study demonstrates the spectrum of POCUS findings in MIS-C. Prospective studies are needed to help delineate the utility of incorporating POCUS into an ED management pathway for patients with suspected MIS-C.
Efficacy of Fecal Calprotectin Combined With Stool Hemoglobin in Differentiating Bacterial Origin in Acute Gastroenteritis
Authors: Kim Hyun Jin
Published: April 2021

Objectives

Differentiating bacterial origin in acute gastroenteritis (AGE) is important to improve outcomes. Fecal calprotectin is a sensitive screening tool for gut mucosal inflammation. This study aimed to evaluate the diagnostic efficacy and cutoff level of fecal calprotectin in distinguishing bacterial origin in pediatric AGE.

Methods

Patients who were diagnosed with AGE at 1 to 18 years between January 2015 and January 2020 were retrospectively analyzed. A polymerase chain reaction test was applied to stool samples to detect viruses and bacteria. The level of fecal calprotectin was determined using an enzyme-linked immunosorbent assay test.

Results

Eighty patients were enrolled in this study. The most common viral pathogen was norovirus, and bacterial pathogen was Clostridium perfringens. The median fecal calprotectin level was 686 μg/g (interquartile range [IQR], 140–1192 μg/g) in all patients, 560 μg/g (IQR, 60–669 μg/g) in patients with viral pathogens, and 985 μg/g (IQR, 272–1984 μg/g) in those with bacterial pathogens (P = 0.019). The stool hemoglobin concentration (337.29 vs 84.83 ng/mL, P = 0.016) and C-reactive protein (4.06 vs 0.45 mg/dL, P = 0.082) levels were higher in patients with bacterial pathogens than in those with viral pathogens. For identifying bacterial pathogens, the area under the receiver operating characteristic curve of fecal calprotectin was 0.739 (95% confidence interval, 0.584–0.894); combination with stool hemoglobin improved diagnostic efficacy, and the area under the receiver operating characteristic curve was 0.870. The optimal cutoff values of fecal calprotectin and stool hemoglobin were 815 μg/g and 158 ng/mL, respectively.

Conclusions

The combination of stool hemoglobin and fecal calprotectin may be a useful marker for detecting bacterial etiology in pediatric AGE.
Association of Placental Mesenchymal Dysplasia With a Live Female Fetus and Complete Hydatidiform Mole: Report of a Challenging Case Confirmed by Molecular Genotyping Analysis
Authors: Hamard Aymeric , Heitzmann Anne , Ceccaldi Claire , Descriaud Céline , Mauduit Claire , Gaillot-Durand Lucie , Hajri Touria , Massardier Jérôme , Vinas Roselyne , Allias Fabienne
Published: April 2021

Placental mesenchymal dysplasia (PMD) and complete hydatidiform mole (CHM) with a coexisting fetus are 2 rare placental abnormalities characterized by lacunar placenta and presence of an embryo on ultrasound examination. We report the case of a 34-yr-old woman referred at 32.6 weeks of gestation because of a multicystic placenta. A caesarean section was performed at 39.1 weeks of gestation giving birth to a 2905 g normal female infant. Pathological examination revealed macroscopic and microscopic morphological, and immunohistological features of PMD in the main placenta, and features of CHM in a separate placental mass. Fluorescent in situ hybridization and molecular genotyping analyses showed diandric diploidy in the CHM component and androgenetic/biparental mosaicism in the PMD component, confirming the association of PMD and CHM with a live infant. There was no progression to gestational trophoblastic neoplasia during follow-up for the mother, or any sign of Beckwith-Wiedemann syndrome or hepatic tumor in the child.
Tele-Rehabilitation with Virtual Reality
Authors: Cornejo Thumm Pablo , Giladi Nir , Hausdorff Jeffrey M. , Mirelman Anat
Published: April 2021

Physical training in Parkinson disease improves motor performance, alleviates nonmotor symptoms, and enhances cognition and quality of life. Nonetheless, adherence to exercise is low and travel costs and time may limit participation and compliance. Training at home can help avoid these burdens and, as needed during the recent global pandemic (COVID-19), reinforce social distancing and reduce the risk of infection. However, training at home requires motivation and self-control and telerehabilitation is time-consuming for both patient and therapist. In recent years, there is growing use of virtual reality and exergaming to increase motivation and adherence for exercising with evidence of improvements in mobility and balance after using virtual reality in the clinic. Here, a novel telerehabilitation training program using a treadmill–virtual reality system for simultaneous training of two patients with Parkinson disease in their homes is described. Remote monitoring software enabled visual and auditory communication with the two patients, allowing the trainer to adapt the settings remotely and provide feedback. Participants received weekly training sessions over 1 yr. The findings show high adherence to training, increased walking duration throughout the sessions, and increased patient confidence, gait speed, and mobility. Training multiple participants simultaneously was feasible, enabling an individualized treatment approach while conserving therapist time.
Ambulatory Virtual Care During a Pandemic: Patient Safety Considerations
Authors: Mullur Jyotsna , Chen Yih-Chieh , Wickner Paige , Licurse Adam , Desai Sonali
Published: April 2021

Background

The COVID-19 pandemic prompted sudden and fundamental changes in health care, including a rapid rise in the utilization of telehealth services in the ambulatory setting. With the unprecedented and significant decline in traditional office-based visits and procedures, novel patient safety risks and challenges emerged.

Methods

The ambulatory practices at our quaternary care, academic medical center experienced a 200-fold increase in virtual visit volume between February and April 2020. We convened a multidisciplinary working group dedicated to evaluating quality and safety when providing virtual visits during a pandemic. Our primary outcome was patient experience with virtual care delivery, which was assessed by leveraging patient complaint data and patient satisfaction survey data.

Results

For our main focus of patient experience and satisfaction, survey data were analyzed from the approximately 76,616 virtual visit encounters that occurred between March 1, 2020, and April 21, 2020. During this period, 5 patient complaints were filed to the Patient Advocacy Department. Overall, patient satisfaction with telehealth remained stable and high at >93% from February to May 2020. As we assessed these data each month, our working group developed risk mitigation strategies in response to the novel challenges presented by the use of telemedicine due to the COVID-19 pandemic while working to maintain patient satisfaction with care. We identified quality and safety issues around patient factors including optimal triage of patients and use of technology. We also evaluated accessibility to virtual platforms and logistics such as coordination of care for diagnostic testing. Finally, a guidance document was created and communicated to our diverse ambulatory practices to support clinicians.

Conclusions

Ambulatory virtual care delivery requires a dynamic, flexible model of care through continuous rapid-cycle process improvement to mitigate patient safety risks during a pandemic, incorporating both provider and patient perspectives.
Realizing the Power of Text Mining and Natural Language Processing for Analyzing Patient Safety Event Narratives: The Challenges and Path Forward
Authors: Fong Allan
Published: April 2021

Patient safety event (PSE) reports are a useful lens to understand hazards and patient safety risks in healthcare systems. However, patient safety officers and analysts in healthcare systems and safety organizations are challenged to make sense of the ever-increasing volume of PSE reports, including the free-text narratives. As a result, there is a growing emphasis on applying text mining and natural language processing (NLP) approaches to assist in the processing and understanding of these narratives. Although text mining and NLP in healthcare have advanced significantly over the past decades, the utility of the resulting models, ontologies, and algorithms to analyze PSE narratives are limited given the unique difference and challenges in content and language between PSE narratives and clinical documentation. To promote the application of text mining and NLP for PSE narratives, these unique challenges must be addressed. Improving data access, developing NLP resources to practically use contributing factor taxonomies, and developing and adopting shared specifications for interoperability will help create an infrastructure and environment that unlocks the collaborative potential between patient safety, research, and machine learning communities, in the development of reproducible and generalizable methods and models to better understand and improve patient safety and patient care.
PET/CT Imaging for Langerhans Cell Histiocytosis Involving Only Posterior Elements of the Cervical Vertebra
Authors: Zhang Wenjie , Xie Hangyu , Su Minggang
Published: April 2021

Langerhans cell histiocytosis only involving the posterior elements of the spine is rare. We report the case of a 7-year-old boy who has pain and restricted motion of his neck. 18F-FDG PET/CT revealed an osteolytic lesion in the posterior elements of the fourth cervical vertebra. The lesion has high 18F-FDG uptake with an SUVmax of 8.01. An operation was performed, and the final pathological finding revealed Langerhans cell histiocytosis.
18F-FET PET/CT in Early Subventricular Zone Recurrence of Adult Glioblastoma
Authors: Dissaux Gurvan , Dissaux Brieg , Bourhis David , Schick Ulrike , Querellou Solène
Published: April 2021

Glioma stem cells (GSCs) are the source of tumor recurrence in glioblastoma and are capable of whole tumor regeneration once the treatment has concluded. Compelling evidence from the last decade suggests that GSC may arise from neural stem cells residing in the adult subventricular zone (SVZ). We report the findings of an 18F-FET PET/CT showing pathological uptake in SVZ with a tumor-background ratio of greater than 1.6, giving evidence for glioblastoma recurrence. This case highlights the particular attention to be paid to the SVZ given the possible development of GSC.
Breast Metastasis of Primary Peritoneal Carcinoma Demonstrated on FDG PET/CT
Authors: Gungor Serkan , Girgin Rabia Burcin
Published: April 2021

Primary serous peritoneal carcinomas (PSPCs) are rare, and dissemination other than intraperitoneal implantation is even rarer. Breast is an extremely unusual location of metastasis for PSPC. The distinction of breast metastasis of PSPC from primary breast cancer is crucial because the treatment and the prognosis are entirely different. Here we present a case of breast and axillary lymph node metastases from PSPC that were identified on staging FGD PET/CT.
Introduction of Transnasal Endoscopy to a Scottish District General Hospital
Authors: McColl Gillian , Yeap Elaine , Stirling Lynn , Sharp Catherine , Robertson Kevin
Published: April 2021

Esophagogastroduodenoscopy can be uncomfortable and distressing with many patients opting for conscious sedation over topical local anesthetic spray. Transnasal endoscopy is an alternative and we sought to assess how easily it could be introduced to a district general hospital and how acceptable patients found it. Selected patients requiring diagnostic endoscopy were offered transnasal endoscopy with topical nasal anesthetic by clinicians new to transnasal endoscopy but competent at esophagogastroduodenoscopy. Postal feedback questionnaires were used to assess comfort, distress, recollection of periprocedural consultation, and overall experience (visual analog scale 1-10). A total of 213 transnasal endoscopy procedures were undertaken with 207 completed successfully (97.2%). Two patients (0.9%) had self-limiting epistaxis and no patient required admission. One hundred (47%) questionnaires were returned including 98 from those with completed transnasal endoscopy. Thirty-three (33%) had previous esophagogastroduodenoscopy and 28 (85%) reported a preference for transnasal endoscopy. Fifty-eight patients (59%) found transnasal endoscopy comfortable (visual analog scale >6) with 17 reporting discomfort (visual analog scale <5). Seventeen patients found the procedure distressing (visual analog scale >6) but 70 (73%) did not (visual analog scale <5). Eighty-four patients (85.7%) had clear recollection of their procedure (visual analog scale >6) and overall satisfaction was reported as good (visual analog scale >6) by 94.7%. Transnasal endoscopy can be adopted by clinicians competent with conventional esophagogastroduodenoscopy with expectation of high procedure completion rate and low complication rate. Our patients reported high levels of satisfaction with few reporting distress. Perhaps as a consequence, most patients had a clear recollection of their procedure.
The Effect of Zolpidem on Language Function of Patients With Nonfluent Variant of Frontotemporal Dementia: A Pilot Study
Authors: Sayadnasiri Mohammad , Dieji Bahamn , Noroozi Mehdi , Rezaei Omid
Published: April 2021

Objective

Primary progressive aphasia (PPA), as the language variant of frontotemporal dementia, is a neurodegenerative disease with an insidious course that has no appropriate treatment yet. The present study evaluated the effect of zolpidem on improving language function in patients with nonfluent variant PPA (nfv-PPA).

Methods

In this interventional pilot study, patients diagnosed with nfv-PPA were evaluated for language function through the Persian Aphasia Test. Patients were then treated with zolpidem with a maximum dose of 10 mg twice daily and reevaluated after 6 weeks using the Persian Aphasia Test. Data were compared by paired samples t test. Values of P ≤ 0.05 were considered significant.

Results

Thirteen (8 men) patients completed the study. The mean age of the patients was 58.5 ± 4.5 years. Changes were statistically significant in none of the 6 subtests including spontaneous speech content, speech fluency, auditory comprehension, sequential command comprehension, repetition, and naming.

Conclusion

The study showed that zolpidem did not affect the improvement of language function in patients with nfv-PPA. Thus, traditional language structures do not seem to be sensitive to the modulatory effects of zolpidem. Studies with larger sample sizes will help support this hypothesis.
A novel variant of interest of SARS-CoV-2 with multiple spike mutations detected through travel surveillance in Africa
Authors: de Oliveira Tulio , Lutucuta Silvia , Nkengasong John , Morais Joana , Paixão Joana Paula , Neto Zoraima , Afonso Pedro , Miranda Julio , David Kumbelembe , Inglês Luzia , Raisa Rivas Carralero Amilton Pereira Agostinho Paulo , Freitas Helga Reis , Mufinda Franco , Tessema Sofonias Kifle , Tegally Houriiyah , San Emmanuel James , Wilkinson Eduan , Giandhari Jennifer , Pillay Sureshnee , Giovanetti Marta , Naidoo Yeshnee , Katzourakis Aris , Ghafari Mahan , Singh Lavanya , Tshiabuila Derek , Martin Darren , Lessells Richard J
Published: April 2021

At the end of 2020, the Network for Genomic Surveillance in South Africa (NGS-SA) detected a SARS-CoV-2 variant of concern (VOC) in South Africa (501Y.V2 or PANGO lineage B.1.351)1. 501Y.V2 is associated with increased transmissibility and resistance to neutralizing antibodies elicited by natural infection and vaccination2,3. 501Y.V2 has since spread to over 50 countries around the world and has contributed to a significant resurgence of the epidemic in southern Africa. In order to rapidly characterize the spread of this and other emerging VOCs and variants of interest (VOIs), NGS-SA partnered with the Africa Centres for Disease Control and Prevention and the African Society of Laboratory Medicine through the Africa Pathogen Genomics Initiative to strengthen SARS-CoV-2 genomic surveillance across the region.
“Maternal and offspring genetic risk score (GRS) analyses of fetal alcohol exposure and ADHD risk in offspring”
Authors: Haan Elis , Sallis Hannah M. , Ystrom Eivind , Njølstad Pål Rasmus , Andreassen Ole A. , Reichborn-Kjennerud Ted , Munafò Marcus R. , Havdahl Alexandra , Zuccolo Luisa
Published: April 2021

Background

Studies investigating the effects of prenatal alcohol exposure on childhood ADHD symptoms using conventional observational designs have reported inconsistent findings, which may be affected by unmeasured confounding and maternal and fetal ability to metabolise alcohol. We used genetic variants from alcohol metabolising genes (alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH)) as proxies for fetal alcohol exposure to investigate their association with offspring ADHD risk around age 7-8.

Methods

We used data from three longitudinal pregnancy cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC), Generation R study (GenR) and the Norwegian Mother, Father and Child Cohort study (MoBa). Genetic risk scores (GRS) for alcohol use and metabolism using 36 single nucleotide polymorphisms (SNPs) from ADH/ALDH genes were calculated for mothers (NALSPAC=8,196; NMOBA=13,614), fathers (NMOBA=13,935) and offspring (NALSPAC=8,237; NMOBA=14,112; NGENR=2,661). Associations between maternal GRS and offspring ADHD risk were tested in the full sample to avoid collider bias. Offspring GRS analyses were stratified by maternal drinking status. Results: The pooled estimate in maternal GRS analyses adjusted for offspring GRS in ALSPAC and MoBa was OR=0.99, 95%CI 0.97-1.02. The pooled estimate in offspring GRS analyses stratified by maternal drinking status across the cohorts was: ORDRINKING=0.98, 95%CI 0.94-1.02; ORNO DRINKING=0.99, 95%CI 0.97-1.02. These findings remained similar after accounting for maternal genotype data in ALSPAC and maternal and paternal genotype data in MoBa.

Conclusions

We did not find evidence for a causal effect of fetal alcohol exposure on ADHD risk in offspring. The results may be affected by low power and outcome assessment.
Characterizing the countrywide epidemic spread of influenza A(H1N1)pdm09 virus in Kenya between 2009 and 2018
Authors: Owuor D. Collins , de Laurent Zaydah R. , Kikwai Gilbert K. , Mayieka Lillian M. , Ochieng Melvin , Müller Nicola F. , Otieno Nancy A. , Emukule Gideon O. , Hunsperger Elizabeth N. , Garten Rebecca , Barnes John R. , Chaves Sandra S. , Nokes D. James , Agoti Charles N.
Published: April 2021

Background

The spatiotemporal patterns of spread of influenza A(H1N1)pdm09 viruses on a countrywide scale are unclear in many tropical/subtropical regions mainly because spatiotemporally representative sequence data is lacking.

Methods

We isolated, sequenced, and analyzed 383 influenza A(H1N1)pdm09 viral genomes isolated from hospitalized patients between 2009 and 2018 from seven locations across Kenya. Using these genomes and contemporaneously sampled global sequences, we characterized the spread of the virus in Kenya over several seasons using phylodynamic methods.

Results

The transmission dynamics of influenza A(H1N1)pdm09 virus in Kenya was characterized by: (i) multiple virus introductions into Kenya over the study period, although these were remarkably few, with only a few of those introductions instigating seasonal epidemics that then established local transmission clusters; (ii) persistence of transmission clusters over several epidemic seasons across the country; (iii) seasonal fluctuations in effective reproduction number (Re) associated with lower number of infections and seasonal fluctuations in relative genetic diversity after an initial rapid increase during the early pandemic phase, which broadly corresponded to epidemic peaks in the northern and southern hemispheres; (iv) high virus genetic diversity with greater frequency of seasonal fluctuations in 2009-11 and 2018 and low virus genetic diversity with relatively weaker seasonal fluctuations in 2012-17; and (v) virus migration from multiple geographical regions to multiple geographical destinations in Kenya.

Conclusion

Considerable influenza virus diversity circulates within Africa, as demonstrated in this report, including virus lineages that are unique to the region, which may be capable of dissemination to other continents through a globally migrating virus population. Further knowledge of the viral lineages that circulate within understudied low-to-middle income tropical and subtropical regions is required to understand the full diversity and global ecology of influenza viruses in humans and to inform vaccination strategies within these regions.
Increased household secondary attacks rates with Variant of Concern SARS-CoV-2 index cases
Authors: Buchan Sarah A. , Tibebu Semra , Daneman Nick , Whelan Michael , Vanniyasingam Thuva , Murti Michelle , Brown Kevin A.
Published: April 2021

IMPORTANCE

Higher secondary attack rates related to variant of concern (VOC) index cases have been reported, but have not been explored within households, which continue to be an important source of coronavirus disease 2019 (COVID-19) transmission

OBJECTIVE

To compare secondary attack rates in households with VOC versus non-VOC index cases.

DESIGN

A retrospective cohort study of household index cases reported from February 7 – 27, 2021. A propensity-score matched cohort was derived to calculate adjusted estimates.

SETTING

Ontario, Canada.

PARTICIPANTS

A population-based cohort of all private households with index cases. We excluded cases in congregate settings, as well as households with one individual or with >1 case with the same earliest symptom onset date.

EXPOSURE

VOC status, defined as either individuals confirmed as B.1.1.7 using whole genome sequencing or those that screened positive for the N501Y mutation using real-time PCR.

MAIN OUTCOME AND MEASURE

Household secondary attack rate, defined as the number of household secondary cases that occurred 1-14 days after the index case divided by the total number of household secondary contacts.

RESULTS

We included 1,259 index VOC and non-VOC cases in the propensity score-matched analysis. The secondary attack rate for VOC index cases in this matched cohort was 1.31 times higher than non-VOC index cases (RR=1.31, 95%CI 1.14-1.49), similar to the unadjusted estimate. In stratified analyses, the higher secondary attack rate for VOC compared to non-VOC index cases was accentuated for asymptomatic index cases (RR=1.91, 95% CI 0.96-3.80) and presymptomatic cases (RR=3.41, 95%CI 1.13-10.26)

CONCLUSIONS AND RELEVANCE

This study provides strong evidence of increased transmissibility in households due to VOCs and suggests that asymptomatic and pre-symptomatic transmission may be of particular importance for VOCs. Our study suggests that more aggressive public health measures will be needed to control VOCs and that ongoing research is needed to understand mechanisms of VOC transmissibility to curb their associated morbidity and mortality.
HBACopy Number and Kidney Disease Risk among Black Americans: a Longitudinal Cohort Study
Authors: Ruhl A. Parker , Jeffries Neal , Yang Yu , Naik Rakhi P. , Patki Amit , Pecker Lydia H. , Mott Bryan T. , Zakai Neil A. , Winkler Cheryl A. , Kopp Jeffrey B. , Lange Leslie A. , Irvin Marguerite R. , Gutierrez Orlando M. , Cushman Mary , Ackerman Hans C.
Published: April 2021

Background

Alpha globin gene (HBA)copy number is variable among people of African descent.HBAlimits endothelial nitric oxide signaling and variation in gene copy number could modify kidney disease risk in this population.

Objective

To examine the association ofHBAcopy number with chronic kidney disease (CKD) and end-stage kidney disease (ESKD). We hypothesized that higherHBAcopy number would be associated with greater CKD prevalence and ESKD incidence.

Design

Prospective, longitudinal cohort from the REasons for Geographic and Racial Differences in Stroke (REGARDS) study which enrolled participants from 2003 through 2007 and conducted follow-up through June 2014. Data were analyzed from January 2018 through January 2021.

Setting

Community-dwelling participants enrolled throughout the contiguous United States

Participants

Black Americans age 45 years and older

Measurements

HBAcopy number was measured using droplet-digital PCR on genomic DNA; copy number ranged from 2 to ≥ 5 copies. The prevalence ratio (PR) of CKD and relative risk (RR) of incident reduced estimated glomerular filtration rate (eGFR) were calculated using modified Poisson multivariable regression employing a log-linear effect ofHBAallele count. The hazard ratio (HR) of incident ESKD was calculated using Cox proportional hazards multivariable regression.

Results

Among 9,918 participants,HBAgene copy number frequencies were 4%, 28%, 67%, and 1% for 2, 3, 4, and ≥5 copies, respectively. After adjusting for demographic, clinical, and genetic risk factors, each additional copy ofHBAwas associated with 14% greater prevalence of CKD (PR = 1.14, 95% CI 1.07 to 1.21;P< 0.0001). While there was no significant association with incident reduced eGFR (RR = 1.06, 95% CI 0.94 to 1.18; p = 0.36), the hazard of incident ESKD was 28% higher for each additional copy ofHBA(HR = 1.28, 95% CI 1.01 to 1.61;P= 0.04).

Limitations

This study did not identify the mechanism by whichHBAcopy number modifies kidney disease risk. This study focused on Black Americans, a population with a high frequency of the 3.7 kb gene deletion; it is unknown whetherHBAmodifies kidney disease risk in other populations with the 3.7 kb deletion.

Conclusions

IncreasingHBAcopy number was associated with greater prevalent CKD and incident ESKD in a national longitudinal study of Black Americans.

Funding Source

National Institutes of Health
Validity and cultural generalisability of a 5-minute AI-based, computerised cognitive assessment in Mild Cognitive Impairment and Alzheimer’s Dementia
Authors: Modarres Hadi , Kalafatis Chris , Apostolou Panos , Marefat Haniye , Khanbagi Mahdiyeh , Karimi Hamed , Vahabi Zahra , Aarsland Dag , Khaligh-Razavi Seyed-Mahdi
Published: April 2021

INTRODUCTION

Early detection and monitoring of mild cognitive impairment (MCI) and Alzheimer’s Disease (AD) patients are key to tackling dementia and providing benefits to patients, caregivers, healthcare providers and society. We developed the Integrated Cognitive Assessment (ICA); a 5-minute, language independent computerised cognitive test that employs an Artificial Intelligence (AI) model to improve its accuracy in detecting cognitive impairment. In this study, we aimed to evaluate the generalisability of the ICA in detecting cognitive impairment in MCI and mild AD patients.

METHODS

We studied the ICA in a total of 230 participants. 95 healthy volunteers, 80 MCI, and 55 participants with mild AD completed the ICA, the Montreal Cognitive Assessment (MoCA) and Addenbrooke’s Cognitive Examination (ACE) cognitive tests.

RESULTS

The ICA demonstrated convergent validity with MoCA (Pearson r = 0.58, p<0.0001) and ACE (r = 0.62, p<0.0001). The ICA AI model was able to detect cognitive impairment with an AUC of 81% for MCI patients, and 88% for mild AD patients. The AI model demonstrated improved performance with increased training data and showed generalisability in performance from one population to another. The ICA correlation of 0.17 (p=0.01) with education years is considerably smaller than that of MoCA (r=0.34, p<0.0001) and ACE (r=0.41, p<0.0001) which displayed significant correlations. In a separate study the ICA demonstrated no significant practice effect observed over the duration of the study.

DISCUSSION

The ICA can support clinicians by aiding accurate diagnosis of MCI and AD and is appropriate for large-scale screening of cognitive impairment. The ICA is unbiased by differences in language, culture and education.
Dorsomedial striatal activity tracks completion of behavioral sequences
Authors: Vandaele Youna , Ottenheimer David J , Janak Patricia H
Published: April 2021

For proper execution of goal-directed behaviors, individuals require both a general representation of the goal and an ability to monitor their own progress toward that goal. Here, we examine how dorsomedial striatum (DMS), a region pivotal for forming associations among stimuli, actions, and outcomes, encodes the execution of goal-directed action sequences that require self-monitoring of behavior. We trained rats to complete a sequence of at least 5 consecutive lever presses (without visiting the reward port) to obtain a reward and recorded the activity of individual cells in DMS while rats performed the task. We found that the pattern of DMS activity gradually changed during the execution of the sequence, permitting accurate decoding of sequence progress from neural activity at a population level. Moreover, this sequence-related activity was blunted on trials where rats did not complete a sufficient number of presses. Overall, these data suggest a link between DMS activity and the execution of behavioral sequences that require monitoring of ongoing behavior.
Endoplasmic reticulum phospholipid scramblase activity revealed after protein reconstitution into giant unilamellar vesicles containing a photostable lipid reporter
Authors: Mathiassen Patricia P. M. , Menon Anant K. , Günther Pomorski Thomas
Published: April 2021

Transbilayer movement of phospholipids in biological membranes is mediated by a diverse set of lipid transporters. Among them are scramblases that facilitate a rapid bi-directional movement of lipids without metabolic energy input. Here, we established a new fluorescence microscopy-based assay for detecting phospholipid scramblase activity of membrane proteins upon their reconstitution into giant unilamellar vesicles formed from proteoliposomes by electroformation. The assay is based on chemical bleaching of fluorescence of a photostable ATTO-dye labeled phospholipid with the membrane-impermeant reductant sodium dithionite. We demonstrate that this new methodology is suitable for the study of the scramblase activity of the yeast endoplasmic reticulum at single vesicle level.
Ultrapotent bispecific antibodies neutralize emerging SARS-CoV-2 variants
Authors: Cho Hyeseon , Gonzales-Wartz Kristina Kay , Huang Deli , Yuan Meng , Peterson Mary , Liang Janie , Beutler Nathan , Torres Jonathan L. , Cong Yu , Postnikova Elena , Bangaru Sandhya , Talana Chloe Adrienna , Shi Wei , Yang Eun Sung , Zhang Yi , Leung Kwanyee , Wang Lingshu , Peng Linghang , Skinner Jeff , Li Shanping , Wu Nicholas C. , Liu Hejun , Dacon Cherrelle , Moyer Thomas , Cohen Melanie , Zhao Ming , Lee F. Eun-Hyung , Weinberg Rona S. , Douagi Iyadh , Gross Robin , Schmaljohn Connie , Pegu Amarendra , Mascola John R. , Holbrook Michael , Nemazee David , Rogers Thomas F. , Ward Andrew B. , Wilson Ian A. , Crompton Peter D. , Tan Joshua
Published: April 2021

The emergence of SARS-CoV-2 variants that threaten the efficacy of existing vaccines and therapeutic antibodies underscores the urgent need for new antibody-based tools that potently neutralize variants by targeting multiple sites of the spike protein. We isolated 216 monoclonal antibodies targeting SARS-CoV-2 from plasmablasts and memory B cells of COVID-19 patients. The three most potent antibodies targeted distinct regions of the RBD, and all three neutralized the SARS-CoV-2 variants B.1.1.7 and B.1.351. The crystal structure of the most potent antibody, CV503, revealed that it binds to the ridge region of SARS-CoV-2 RBD, competes with the ACE2 receptor, and has limited contact with key variant residues K417, E484 and N501. We designed bispecific antibodies by combining non-overlapping specificities and identified five ultrapotent bispecific antibodies that inhibit authentic SARS-CoV-2 infection at concentrations of <1 ng/mL. Through a novel mode of action three bispecific antibodies cross-linked adjacent spike proteins using dual NTD/RBD specificities. One bispecific antibody was >100-fold more potent than a cocktail of its parent monoclonalsin vitroand prevented clinical disease in a hamster model at a 2.5 mg/kg dose. Notably, six of nine bispecific antibodies neutralized B.1.1.7, B.1.351 and the wild-type virus with comparable potency, despite partial or complete loss of activity of at least one parent monoclonal antibody against B.1.351. Furthermore, a bispecific antibody that neutralized B.1.351 protected against SARS-CoV-2 expressing the crucial E484K mutation in the hamster model. Thus, bispecific antibodies represent a promising next-generation countermeasure against SARS-CoV-2 variants of concern.
Rab40/Cullin5 complex regulates EPLIN and actin cytoskeleton dynamics during cell migration and invasion
Authors: Linklater Erik S , Duncan Emily D , Han Ke-Jun , Kaupinis Algirdas , Valius Mindaugas , Lyons Traci R , Prekeris Rytis
Published: April 2021

Rab40b is a SOCS box containing protein that regulates the secretion of MMPs to facilitate extracellular matrix remodeling during cell migration. Here we show that Rab40b interacts with Cullin5 via the Rab40b SOCS domain. We demonstrate that loss of Rab40b/Cullin5 binding decreases cell motility and invasive potential, and show that defective cell migration and invasion stem from alteration to the actin cytoskeleton, leading to decreased invadopodia formation, decreased actin dynamics at the leading edge, and an increase in stress fibers. We also show that these stress fibers anchor at less dynamic, more stable focal adhesions. Mechanistically, changes in the cytoskeleton and focal adhesion dynamics are mediated in part by EPLIN, which we demonstrate to be a binding partner of Rab40b and a target for Rab40b/Cullin5 dependent localized ubiquitylation and degradation. Thus, we propose a model where the Rab40b/Cullin5 dependent ubiquitylation regulates EPLIN localization to promote cell migration and invasion by altering focal adhesion and cytoskeletal dynamics.
High performance microbial opsins for spatially and temporally precise perturbations of large neuronal networks
Authors: Sridharan Savitha , Gajowa Marta , Ogando Mora B. , Jagadisan Uday , Abdeladim Lamiae , Sadahiro Masato , Bounds Hayley , Hendricks William D. , Tayler Ian , Gopakumar Karthika , Antón Oldenburg Ian , Brohawn Stephen G. , Adesnik Hillel
Published: April 2021

Patterned optogenetic activation of defined neuronal populations in the intact brain can reveal fundamental aspects of the neural codes of perception and behavior. The biophysical properties of existing optogenetic tools, however, constrain the scale, speed, and fidelity of precise optical control. Here we use structure-guided mutagenesis to engineer opsins that exhibit very high potency while retaining fast kinetics. These new opsins enable large-scale, temporally and spatially precise control of population neural activityin vivoandin vitro. We benchmark these new opsins against existing optogenetics tools with whole-cell electrophysiology and all-optical physiology and provide a detailed biophysical characterization of a diverse family of microbial opsins under two-photon illumination. This establishes a toolkit and a resource for matching the optimal opsin to the goals and constraints of patterned optogenetics experiments. Finally, by combining these new opsins with optimized procedures for cell-specific holographic photo-stimulation, we demonstrate the simultaneous co-activation of several hundred spatially defined neurons with a single hologram, and nearly double that number by temporally interleaving holograms at fast rates. These newly engineered opsins substantially extend the capabilities of patterned illumination optogenetic paradigms for addressing neural circuits and behavior.
COVID-associated pediatric hospitalization and ICU admission trends across a multi-state health system and the broader US population
Authors: Venkatakrishnan AJ , Pawlowski Colin , O’Horo John C. , Badley Andrew , Halamka John , Soundararajan Venky
Published: April 2021

Public health concerns are emerging based on reports of new SARS-CoV-2 variant strains purportedly triggering a rise in COVID-associated hospitalizations and ICU admissions, particularly in younger patients and the pediatric population. However, analyzing health records of COVID patients from the electronic health records (EHRs) of a multi-state US healthcare system, we find that there is actually a significant drop in COVID-associated hospitalization rates and ICU admission rates in March 2021 compared to February 2021. We further triangulate these EHR-derived insights with the official US government epidemiological data sets to show that during this same time period, there is no apparent nation-wide spike in pediatric hospitalizations. Our study motivates the need to develop a real-time system that integrates various COVID hospitalization and ICU monitoring efforts from the EHR databases of various health systems together with national epidemiological data sets. By infusing SARS-CoV-2 genomic sequencing data to flag potentially new or emergent viral strains, as well as county-level COVID vaccine rollout rates and shifts in SARS-CoV-2 PCR positivity rates into such a real-time monitoring system, public health policies and media reporting can be more effectively informed through the rigor of holistic biomedical data sciences.
XAV-19, a swine glyco-humanized polyclonal antibody against SARS-CoV-2 Spike receptor-binding domain, targets multiple epitopes and broadly neutralizes variants
Authors: Vanhove Bernard , Marot Stéphane , So Ray T. , Gaborit Benjamin , Evanno Gwénaëlle , Malet Isabelle , Lafrogne Guillaume , Mevel Edwige , Ciron Carine , Royer Pierre-Joseph , Lheriteau Elsa , Raffi François , Bruzzone Roberto , Pun Mok Chris Ka , Duvaux Odile , Marcelin Anne-Geneviève , Calvez Vincent
Published: April 2021

Amino acid substitutions and deletions in Spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants can reduce the effectiveness of monoclonal antibodies (mAbs). In contrast, heterologous polyclonal antibodies raised against S protein, through the recognition of multiple target epitopes, have the potential to maintain neutralization capacities. XAV-19 is a swine glyco-humanized polyclonal neutralizing antibody raised against the receptor binding domain (RBD) of the Wuhan-Hu-1 Spike protein of SARS-CoV-2. XAV-19 target epitopes were found distributed all over the RBD and particularly cover the receptor binding motives (RBM), in direct contact sites with the Angiotensin Converting Enzyme-2 (ACE-2). Therefore, in Spike/ACE2 interaction assays, XAV-19 showed potent neutralization capacities of the original Wuhan Spike and of the United Kingdom (Alpha/B.1.1.7) and South African (Beta/B.1.351) variants. These results were confirmed by cytopathogenic assays using Vero E6 and live virus variants including the Brazil (Gamma/P.1) and the Indian (Delta/B.1.617.2) variants. In a selective pressure study with the Beta strain on Vero E6 cells conducted over 1 month, no mutation was associated with addition of increasing doses XAV-19. The potential to reduce viral load in lungs was confirmed in a human ACE2 transduced mouse model. XAV-19 is currently evaluated in patients hospitalized for COVID-19-induced moderate pneumonia in a phase 2a-2b (NCT04453384) where safety was already demonstrated and in an ongoing 2/3 trial (NCT04928430) to evaluate the efficacy and safety of XAV-19 in patients with moderate-to-severe COVID-19. Owing to its polyclonal nature and its glyco-humanization, XAV-19 may provide a novel safe and effective therapeutic tool to mitigate the severity of coronavirus disease 2019 (Covid-19) including the different variants of concern identified so far.
A realistic touch-transfer method reveals low risk of transmission for SARS-CoV-2 by contaminated coins and bank notes
Authors: Todt Daniel , Meister Toni Luise , Tamele Barbora , Howes John , Paulmann Dajana , Becker Britta , Brill Florian H. , Wind Mark , Schijven Jack , Mhlekude Baxolele , Goffinet Christine , Krawczyk Adalbert , Steinmann Jörg , Pfaender Stephanie , Brüggemann Yannick , Steinmann Eike
Published: April 2021

The current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has created a significant threat to global health. While respiratory aerosols or droplets are considered as the main route of human-to-human transmission, secretions expelled by infected individuals can also contaminate surfaces and objects, potentially creating the risk of fomite-based transmission. Consequently, frequently touched objects such as paper currency and coins have been suspected as a potential transmission vehicle. To assess the risk of SARS-CoV-2 transmission by banknotes and coins, we examined the stability of SARS-CoV-2 and bovine coronavirus (BCoV), as surrogate with lower biosafety restrictions, on these different means of payment and developed a touch transfer method to examine transfer efficiency from contaminated surfaces to skin. Although we observed prolonged virus stability, our results, including a novel touch transfer method, indicate that the transmission of SARS-CoV-2 via contaminated coins and banknotes is unlikely and requires high viral loads and a timely order of specific events.
An emerging SARS-CoV-2 mutant evading cellular immunity and increasing viral infectivity
Authors: Motozono Chihiro , Toyoda Mako , Zahradnik Jiri , Ikeda Terumasa , Saito Akatsuki , Tan Toong Seng , Ngare Isaac , Nasser Hesham , Kimura Izumi , Uriu Keiya , Kosugi Yusuke , Torii Shiho , Yonekawa Akiko , Shimono Nobuyuki , Nagasaki Yoji , Minami Rumi , Toya Takashi , Sekiya Noritaka , Fukuhara Takasuke , Matsuura Yoshiharu , Schreiber Gideon ,   The Genotype to Phenotype Japan (G2P-Japan) consortium, Nakagawa So , Ueno Takamasa , Sato Kei
Published: April 2021

During the current SARS-CoV-2 pandemic that is devastating the modern societies worldwide, many variants that naturally acquire multiple mutations have emerged. Emerging mutations can affect viral properties such as infectivity and immune resistance. Although the sensitivity of naturally occurring SARS-CoV-2 variants to humoral immunity has recently been investigated, that to human leukocyte antigen (HLA)-restricted cellular immunity remains unaddressed. Here we demonstrate that two recently emerging mutants in the receptor binding domain of the SARS-CoV-2 spike protein, L452R (in B.1.427/429) and Y453F (in B.1.298), can escape from the HLA-24-restricted cellular immunity. These mutations reinforce the affinity to viral receptor ACE2, and notably, the L452R mutation increases protein stability, viral infectivity, and potentially promotes viral replication. Our data suggest that the HLA-restricted cellular immunity potentially affects the evolution of viral phenotypes, and the escape from cellular immunity can be a further threat of the SARS-CoV-2 pandemic.

Graphical Abstract
Mixed selectivity coding of sensory and motor social signals in the thalamus of a weakly electric fish
Authors: Wallach Avner , Melanson Alexandre , Longtin André , Maler Leonard
Published: April 2021

Recent studies have shown that high-level neural activity often exhibits mixed selectivity to multivariate signals. How such representations arise and how they modulate natural behavior is poorly understood. The social behavior of weakly electric fish is relatively low-dimensional and easily reproduced in the laboratory. Here we show how electrosensory signals related to courtship and rivalry inApteronotus leptorhynchusare represented in the preglomerular nucleus, the thalamic region exclusively connecting the midbrain with the pallium. We show that preglomerular cells convert their midbrain inputs into a mixed selectivity code that includes corollary discharge of outgoing communication signals. We discuss how the preglomerular pallial targets might use these inputs to control social behavior and determine dominance in male-male competition and female mate selection during courtship. Our results showcase the potential of the electrocommunication system as an accessible model for studying the neural substrates of social behavior and principles of multi-dimensional neural representation.