bluuebunny/crossref_metadata_2025 huggingface dataset:
Morphologic and Immunophenotypic Differences in Juvenile Myelomonocytic Leukemias With CBL and Other Canonical RAS-pathway Gene Mutations: A Single Institutional Experience
Authors: Mariani Rachel A. , Jennings Lawrence , Zhang Shanxiang , Bhat Rukhmi , Gong Shunyou
Published: March 2021

The diagnostic criteria for juvenile myelomonocytic leukemia have recently been revised to include clinical findings and RAS-pathway gene mutations per the 2016 World Health Organization Classification of Tumors of Hematopoietic and Lymphoid Tissues. Differing clinical behaviors have been observed in cases with CBL versus other RAS-pathway gene (RAS-p) mutations, notably the patients with CBL mutations can be self-limiting with spontaneous resolution. Additional clinical characteristics and histopathologic findings between these subsets are less well-described. We performed a retrospective search and identified cases with either CBL or RAS-p mutations, as per targeted and/or massively parallel sequencing. Eight patients had sufficient material for review, including cytogenetic studies and peripheral blood, bone marrow aspirate, and/or biopsy with flow cytometry analyses. Three patients showed CBL mutations and lower percentages of hemoglobin F and peripheral blood absolute monocyte counts, lesser degrees of leukocytosis compared with the RAS-p cohort, and normal megakaryocyte morphology and myeloblast immunophenotypes. Two of these patients were managed with observation only and experienced resolution of their disease. The patients with RAS-p mutations had severe thrombocytopenia, moderate to severe anemia, and experienced variable clinical outcomes. Abnormal megakaryocyte morphology and decreased numbers of megakaryocytes were seen in cases with RAS-p mutations. In addition, 3 of 4 cases with flow cytometry data demonstrated aberrant CD7 expression in myeloblasts. Our study is the first to identify morphologic and immunophenotypic differences between juvenile myelomonocytic leukemia cases with CBL or RAS-p mutations, and further supports previous reports of significantly different clinical behaviors between these subsets of patients.
Preparing Teaching Assistants in Nursing
Authors: Heitkemper Elizabeth M. , Hafermann Kelly A. , Honig Judy C. , Smaldone Arlene
Published: March 2021

Background

Teaching assistants (TAs) serve an important role in schools of nursing, but their educational needs are poorly understood.

Purpose

To better prepare TAs, our School of Nursing identified and evaluated current TA practices to create tailored educational materials.

Methods

A 16-item survey captured how faculty used TAs. Focus groups with current faculty and former TAs explored the TA role and identified areas to target for future training. Focus groups were analyzed using thematic content analysis.

Results

Survey response rate was high (88%). Most faculty meet with TAs before the semester, and typical TA duties included attending lecture (71%) and facilitating examination review sessions (64%). Qualitative themes focused on faculty/TA communication, faculty guidance, knowing the policies, and TA/student boundary negotiation.

Conclusions

Findings demonstrate the importance of preparing TAs. Since this study, the university and school of nursing have each developed educational materials to better prepare TAs and faculty.
Prognostic and Theranostic Biomarkers in Ovarian Clear Cell Carcinoma
Authors: Wiedemeyer Katharina , Wang Linyuan , Kang Eun Young , Liu Shuhong , Ou Young , Kelemen Linda E. , Feil Lukas , Anglesio Michael S. , Glaze Sarah , Ghatage Prafull , Nelson Gregg S. , Köbel Martin
Published: March 2021

In this study, we aimed to test whether prognostic biomarkers can achieve a clinically relevant stratification of patients with stage I ovarian clear cell carcinoma (OCCC) and to survey the expression of 10 selected actionable targets (theranostic biomarkers) in stage II to IV cases. From the population-based Alberta Ovarian Tumor Type study, 160 samples of OCCC were evaluated by immunohistochemistry and/or silver-enhanced in situ hybridization for the status of 5 prognostic (p53, p16, IGF2BP3, CCNE1, FOLR1) and 10 theranostic biomarkers (ALK, BRAF V600E, ERBB2, ER, MET, MMR, PR, ROS1, NTRK1-3, VEGFR2). Kaplan-Meier survival analyses were performed. Cases with abnormal p53 or combined p16/IFG2BP3 abnormal expression identified a small subset of patients (6/54 cases) with stage I OCCC with an aggressive course (5-yr ovarian cancer-specific survival of 33.3%, compared with 91.5% in the other stage I cases). Among theranostic targets, ERBB2 amplification was present in 11/158 (7%) of OCCC, while MET was ubiquitously expressed in OCCC similar to a variety of normal control tissues. ER/PR showed a low prevalence of expression. No abnormal expression was detected for any of the other targets. We propose a combination of 3 biomarkers (p53, p16, IGF2BP3) to predict prognosis and the potential need for adjuvant therapy for patients with stage I OCCC. This finding requires replication in larger cohorts. In addition, OCCC could be tested for ERBB2 amplification for inclusion in gynecological basket trials targeting this alteration.
Bacterial RTX toxins and host immunity
Authors: Ahmad Jawid Nazir , Sebo Peter
Published: March 2021

Purpose of review

RTX toxin action often defines the outcome of bacterial infections. Here, we discuss the progress in understanding the impacts of RTX toxin activities on host immunity.

Recent findings

Bordetella pertussis CyaA activity paralyzes sentinel phagocytic cells by elevating cellular cAMP levels and blocks differentiation of infiltrating monocytes into bactericidal macrophages, promoting also de-differentiation of resident alveolar macrophages into monocyte-like cells. Vibrio cholerae multifunctional autoprocessing repeats-in-toxins (MARTX), through Rho inactivating and α/β-hydrolase (ABH) domain action blocks mitogen-activated protein kinase signaling in epithelial cells and dampens the inflammatory responses of intestinal epithelia by blocking immune cell recruitment. The action of actin crosslinking effector domain and Ras/Rap1-specific endopeptidase (RRSP) domains of MARTX compromises the phagocytic ability of macrophages. Aggregatibacter actinomycetemcomitans LtxA action triggers neutrophil elastase release into periodontal tissue, compromising the epithelial barrier and promoting bacterial spreads into deeper tissue.

Action of RTX toxins enables bacterial pathogens to cope with the fierce host immune defenses. RTX toxins often block phagocytosis and bactericidal reactive oxygen species and NO production. Some RTX toxins can reprogram the macrophages to less bactericidal cell types. Autophagy is hijacked for example by the activity of the V. cholerae ABH effector domain of the MARTX protein. Subversion of immune functions by RTX toxins thus promotes bacterial survival and proliferation in the host.
Features and Strategies in the Management of Choanal Atresia: A 6-Year Retrospective Analysis
Authors: Kalentakis Zacharias , Stamataki Sofia , Chalkiadakis Vasileios , Papapetropoulos Nektarios
Published: March 2021

Introduction:

Choanal atresia although rare, is the most common inborn nasal deformity and an important cause of newborn airway obstruction. This study aims to describe a single-center experience in the management of choanal atresia and emphasize the ambiguous issues regarding its surgical repair.

Patients and Methods:

The authors retrospectively analyzed the treatment strategy of 18 patients with choanal atresia and their outcomes during the follow-up period.

Results:

Bilateral choanal atresia was diagnosed in 9 patients, 6 of those had mixed bony-membranous type (67% versus 33% who had pure bony type). Almost half of the 18 patients had a mixed bony-membranous type of atresia (56%). Interestingly, 89% of patients with bilateral atresia underwent transnasal endoscopic repair with stenting, compared to 44% of those with unilateral atresia (P = 0.04). A trend to preference of stent procedure in patients with bony type was also observed, in comparison with mixed bony-membranous type (89% versus 50%, P = 0.09). No significant difference in the need for revision treatment was noticed among the two treatment groups.

Conclusions:

Both in our data and literature there is no clear supremacy of stenting. Considering the high incidence of re-stenosis, all patients should be under close follow up for a long-term period. Inevitably, further investigation is necessary to establish an ideal surgical procedure.
Clinical Staging, Angioarchitecture Type, and Surgical Treatment of Arteriovenous Malformations in the Head and Neck: A Single-Center Retrospective Analysis
Authors: Sheng Bin , Wang Min , Xu Yuan , Chen Yong , Yuan Si-Ming
Published: March 2021

Objective:

Head and neck are the predilection sites of arteriovenous malformations (AVMs). Although embolization is the first-line treatment for AVMs, complete surgical removal of the lesion still has its value due to the best outcome with low recurrence rate. Here, the authors made a retrospective analysis on the surgical treatment of AVMs in the head and neck.

Methods:

From January 2006 to December 2019, a total of 18 patients with AVMs in the head and neck were enrolled in this study, including 10 males. The Schobinger clinical staging, Yakes’ angioarchitecture type, and surgical treatment were analyzed. The follow-up data were collected. Then, individual treatment strategies were summarized.

Results:

According to Schobinger clinical classification system, 6 patients were at stage I, 7 patients at stage II, and 5 patients at stage III. According to Yakes’ AVM classification system, 3 Type I, 4 Type II, 5 Type III, and 3 Type IV were confirmed. 3 patients cannot be confirmed due to lacking of arteriographic data. Surgical treatments included simple surgical excision (8 patients), dilator therapy (6 patients), and skin grafting after surgical excision (4 patients). In the follow-up period, 2 patients had recurrence and accepted operation again. All patients were satisfied with the appearance.

Conclusions:

Individual surgical treatment based on the clinical stage and angioarchitecture type can achieve satisfactory results in AVMs in the head and neck.
The Evolution of Unilateral Cleft Lip Repair
Authors: Raghuram Anjali C. , Jacob Laya , Wlodarczyk Jordan R. , Munabi Naikhoba C.O. , Tomaro Micaela , Nagengast Eric , Chong David K. , Yao Caroline A. , Magee William P.
Published: March 2021

The understanding of cleft lip etiology and approaches for surgical repair have evolved over time, allowing for improved ability to restore form and function. The variability of cleft lip presentations has necessitated a nuanced surgical approach with multidisciplinary cleft care. The earliest documentation of unilateral cleft lip repair predates the 19th century, with crude outcomes observed before the advent of curved incisions and advancement flaps. In the 20th century, straight line, quadrilateral flap, and triangular flap repairs were introduced to mitigate post-repair surgical scarring, increase lip length, and restore the symmetry of the Cupid's bow. Towards the latter part of the century, the development of rotation-advancement principles allowed for improved functional and aesthetic outcomes. Future technical improvements will continue to address the goals of lip and nasal symmetry, muscular continuity, precise scar concealment, and improved patient satisfaction in an increasing range of cleft phenotypes and during subsequent years of growth.
Evaluation of the Clinical Features Accompanied by the Gene Mutations
Authors: Eryilmaz Isil E. , Bakar Mustafa , Egeli Unal , Cecener Gulsah , Yurdacan Beste , Colak Dilara K. , Tunca Berrin
Published: March 2021

Introduction:

Early-onset Alzheimer disease (EOAD) is an earlier Alzheimer disease form which is characterized by the mutations in the amyloid precursor protein, presenilin-1/2 (PSEN1/2), and triggering receptor expressed on myeloid cells 2 (TREM2). However, it is still necessary to report mutational screening in multiethnic groups to improve the genetic background of EOAD due to the variant classification challenge.

Methods:

We performed targeted sequencing for the amyloid precursor protein, PSEN1, PSEN2, and TREM2 genes in 74 patients and 1 family diagnosed with EOAD.

Results:

Among the detected variants, 8 were coding and 6 were noncoding in 15 of 74 patients. In PSEN1, 2 pathogenic coding variants (T274K and L364P) detected in 2 patients were novel and 3 coding variants (G183V, E318G, and L219P) detected in 2 patients were previously reported. We found 4 patients with the compound heterozygosity for the PSEN2 A23= and N43= and a family with the coexistence of them, and 1 patient with TREM2 Y38C. The coding variation frequency was 12.1%. In silico analysis indicated pathogenic potentials and clinical interpretations of the detected variants.

Conclusion:

Our study reveals the rare gene variants including novel ones from the Turkish EOAD cohort and provides to clinicians the list of detected variants in the screened genes, which may also be useful for accurate genetic counseling.
A small number of early introductions seeded widespread transmission of SARS-CoV-2 in Québec, Canada
Authors: Lía Murall Carmen , Fournier Eric , Galvez Jose Hector , N’Guessan Arnaud , Reiling Sarah J. , Quirion Pierre-Olivier , Naderi Sana , Roy Anne-Marie , Chen Shu-Huang , Stretenowich Paul , Bourgey Mathieu , Bujold David , Gregoire Romain , Lepage Pierre , St-Cyr Janick , Willet Patrick , Dion Réjean , Charest Hugues , Lathrop Mark , Roger Michel , Bourque Guillaume , Ragoussis Jiannis , Shapiro B. Jesse , Moreira Sandrine
Published: March 2021

Using genomic epidemiology, we investigated the arrival of SARS-CoV-2 to Québec, the Canadian province most impacted by COVID-19, with >280,000 positive cases and >10,000 deaths in a population of 8.5 million as of March 1st, 2021. We report 2,921 high-quality SARS-CoV-2 genomes in the context of >12,000 publicly available genomes sampled globally over the first pandemic wave (up to June 1st, 2020). By combining phylogenetic and phylodynamic analyses with epidemiological data, we quantify the number of introduction events into Québec, identify their origins, and characterize the spatio-temporal spread of the virus. Conservatively, we estimated at least 500 independent introduction events, the majority of which happened from spring break until two weeks after the Canadian border closed for non-essential travel. Subsequent mass repatriations did not generate large transmission lineages (>50 cases), likely due to mandatory quarantine measures in place at the time. Consistent with common spring break and ‘snowbird’ destinations, most of the introductions were inferred to have originated from Europe via the Americas. Fewer than 100 viral introductions arrived during spring break, of which 5-10 led to the largest transmission lineages of the first wave (accounting for 36-58% of all sequenced infections). These successful viral transmission lineages dispersed widely across the province, consistent with founder effects and superspreading dynamics. Transmission lineage size was greatly reduced after March 11th, when a quarantine order for returning travelers was enacted. While this suggests the effectiveness of early public health measures, the biggest transmission lineages had already been ignited prior to this order. Combined, our results reinforce how, in the absence of tight travel restrictions or quarantine measures, fewer than 100 viral introductions in a week can ensure the establishment of extended transmission chains.
Cash transfers may increase the no-show rate for surgical patients in low-resource settings: A randomized trial
Authors: Shrime Mark G. , Harter Elizabeth A. , Handforth Becky , Phillips Christine L. , Bos Hendrika W.C. , Hamer Mirjam , Alcorn Dennis , Bennette Tirzah , Millimouno Etienne Faya , Nieba Jacqueline , Oumar Barry Alpha , Zogbe Koko Madeline
Published: March 2021

Background

Over two-thirds of the world’s population cannot access surgery when needed. Interventions to address this gap have primarily focused on surgical training and ministry-level surgical planning. However, patients more commonly cite cost— rather than governance or surgeon availability—as their primary access barrier. We undertook a randomized, controlled trial (RCT) to evaluate the effect on compliance with scheduled surgical appointments of addressing this barrier through a cash transfer.

Methods

453 patients who were deemed surgical candidates by a nursing screening team in Guinea, West Africa, were randomized into three study arms: control, conditional cash transfer, and labeled unconditional cash transfer. Arrival to a scheduled surgical appointment was the primary outcome. The study was performed in conjunction with Mercy Ships.

Results

The overall no-show rate was five-fold lower in Guinea than previously published estimates, leading to an underpowered study. In a post-hoc analysis, which included non-randomized patients, patients in the control group and the conditional cash transfer group demonstrated no effect from the cash transfer. Patients in the unconditional cash transfer group were significantly less likely to arrive for their scheduled appointment. Subgroup analysis suggested that actual receipt of the unconditional cash transfer, instead of a lapse in the transfer mechanism, was associated with failure to show.

Conclusion

We find that cash transfers are feasible for surgical patients in a low-resource setting, but that unconditional transfers may have negative effects on compliance. Although demand-side barriers are large for surgical patients in low-resource settings, interventions to address them must be designed with care.
Serological profiles of pan-coronavirus-specific responses in COVID-19 patients using a multiplexed electro-chemiluminescence-based testing platform
Authors: Chaudhury Sidhartha , Hutter Jack , Bolton Jessica S , Hakre Shilpa , Mose Evelyn , Wooten Amy , O’Connell William , Hudak Joseph , Krebs Shelly J. , Darden Janice M. , Regules Jason A. , Murray Clinton K. , Modjarrad Kayvon , Scott Paul , Peel Sheila , Bergmann-Leitner Elke S.
Published: March 2021

Serological assessment of SARS-CoV-2 specific responses are an essential tool for determining the prevalence of past SARS-CoV-2 infections in the population especially when testing occurs after symptoms have developed and limited contact tracing is in place. The goal of our study was to test a new 10-plex electro-chemiluminescence-based assay to measure IgM and IgG responses to the spike proteins from multiple human coronaviruses including SARS-CoV-2, assess the epitope specificity of the SARS-CoV-2 antibody response against full-length spike protein, receptor-binding domain and N-terminal domain of the spike protein, and the nucleocapsid protein. We carried out the assay on samples collected from three sample groups: subjects diagnosed with COVID-19 from the U.S. Army hospital at Camp Humphreys in Pyeongtaek, South Korea; healthcare administrators from the same hospital but with no reported diagnosis of COVID-19; and pre-pandemic samples. We found that the new CoV-specific multiplex assay was highly sensitive allowing plasma samples to be diluted 1:30,000 with a robust signal. The reactivity of IgG responses to SARS-CoV-2 nucleocapsid protein and IgM responses to SARS-CoV-2 spike protein could distinguish COVID-19 samples from non-COVID-19 and pre-pandemic samples. The data from the three sample groups also revealed a unique pattern of cross-reactivity between SARS-CoV-2 and SARS-CoV-1, MERS-CoV, and seasonal coronaviruses HKU1 and OC43. Our findings show that the CoV-2 IgM response is highly specific while the CoV-2 IgG response is more cross-reactive across a range of human CoVs and also showed that IgM and IgG responses show distinct patterns of epitope specificity. In summary, this multiplex assay was able to distinguish samples by COVID-19 status and characterize distinct trends in terms of cross-reactivity and fine-specificity in antibody responses, underscoring its potential value in diagnostic or serosurveillance efforts.
A standardized analytics pipeline for reliable and rapid development and validation of prediction models using observational health data
Authors: Khalid Sara , Yang Cynthia , Blacketer Clair , Duarte-Salles Talita , Fernández-Bertolín Sergio , Kim Chungsoo , Park Rae Woong , Park Jimyung , Schuemie Martijn , Sena Anthony , Suchard Marc A. , You Seng Chan , Rijnbeek Peter , Reps Jenna
Published: March 2021

Background and Objective

As a response to the ongoing COVID-19 pandemic, several prediction models have been rapidly developed, with the aim of providing evidence-based guidance. However, no COVID-19 prediction model in the existing literature has been found to be reliable. Models are commonly assessed to have a risk of bias, often due to insufficient reporting, use of non-representative data, and lack of large-scale external validation. In this paper, we present the Observational Health Data Sciences and Informatics (OHDSI) analytics pipeline for patient-level prediction as a standardized approach for rapid yet reliable development and validation of prediction models. We demonstrate how our analytics pipeline and open-source software can be used to answer important prediction questions while limiting potential causes of bias (e.g., by validating phenotypes, specifying the target population, performing large-scale external validation and publicly providing all analytical source code).

Methods

We show step-by-step how to implement the pipeline for the question: ‘In patients hospitalized with COVID-19, what is the risk of death 0 to 30 days after hospitalization’. We develop models using six different machine learning methods in a US claims database containing over 20,000 COVID-19 hospitalizations and externally validate the models using data containing over 45,000 COVID-19 hospitalizations from South Korea, Spain, and the US.

Results

Our open-source tools enabled us to efficiently go end-to-end from problem design to reliable model development and evaluation. When predicting death in patients hospitalized for COVID-19 adaBoost, random forest, gradient boosting machine, and decision tree yielded similar or lower internal and external validation discrimination performance compared to L1-regularized logistic regression, whereas the MLP neural network consistently resulted in lower discrimination. L1-regularized logistic regression models were well calibrated.

Conclusion

Our results show that following the OHDSI analytics pipeline for patient-level prediction can enable the rapid development towards reliable prediction models. The OHDSI tools and pipeline are open source and available to researchers around the world.
Importance of serological testing in the convalescence phase in patients with pulmonary impairment due to COVID 19 - a health care workers analysis
Authors: Pereira José Rodrigues , Santoro Ilka Lopes , Santos Maria Silvia Biagioni , de Toledo Andreia Padilha , Copelli Greice Elen , de França Caroline Villela Galvão , Caboclo Edmundo Di Giaimo
Published: March 2021

1

Since its discovery, more than 37 million people have been infected by SARS-CoV-2 with deaths around 1 million worldwide. The prevalence is not known because infected individuals may be asymptomatic. In addition, the use of specific diagnostic tests is not always conclusive, raising doubts about the etiology of the disease.

The best diagnostic method and the ideal time of collection remains the subject of study. The gold standard for diagnosing COVID 19 is the RT PCR molecular test, usually using an oropharynx and nasopharynx swab. Its sensitivity is 70% and drops significantly after the second week of symptoms. Serological tests, in turn, have increased sensitivity after 14 days, and can contribute to the diagnosis when SARS-CoV-2 infection is suspected, even with negative RT PCR.

Our study showed sensitivity and specificity of 100% of the serological test (ELISA method) for cases of viral pneumonia caused by the new coronavirus, suggesting that this test could assist in the diagnosis of pulmonary interstitial changes that have not yet been etiologically clarified. We found a greater immune response in men, regardless of the severity of symptoms. The greater the severity, the higher the levels of IgA and IgG, mainly found in patients with multilobar impairment and in need for oxygen. We concluded that the serological test collected around 30 days after the onset of symptoms is the best diagnostic tool in the convalescence phase, not only for epidemiological purposes, but also for the etiological clarification of pulmonary changes that have not yet been diagnosed.
Dynamic Data-Driven Algorithm to Predict the Cumulative COVID-19 Infected Cases Using Susceptible-Infected-Susceptible Model
Authors: Anand Abhinav , Kumar Saurabh , Ghosh Palash
Published: March 2021

In recent times, researchers have used Susceptible-Infected-Susceptible (SIS) model to understand the spread of pandemic COVID-19. The SIS model has two compartments, susceptible and infected. In this model, the interest is to determine the number of infected people at a given time point. However, it is also essential to know the cumulative number of infected people at a given time point, which is not directly available from the SIS model’s present structure. In this work, we propose a modified structure of the SIS model to determine the cumulative number of infected people at a given time point. We develop a dynamic data-driven algorithm to estimate the model parameters based on an optimally chosen training phase to predict the same. We demonstrate the proposed algorithm’s prediction performance using COVID-19 data from Delhi, India’s capital city.
Prediction of Procedural Pain during Endometrial Biopsy
Authors: Jeong Hye Gyeong , Kim Jooyoung , Choo Sung il , Kim Kidong , Lee Banghyun , Ahn Soyeon
Published: March 2021

Background/Objective

Endometrial (EM) biopsy is a commonly-performed gynecological procedure that is associated with side effects such as discomfort and pain. The aim of the current study was to predict procedural pain during EM biopsy.

Methods

We retrospectively reviewed the medical records of 100 women who underwent EM biopsy between July 2014 and November 2015 in an outpatient clinic of our hospital. Eighty-one patients were included in the final analysis after excluding those who lacked pain data and those who were sedated with midazolam. We examined the association of patient and clinician characteristics with procedural pain, and created a prediction model using characteristics via multiple linear regression analysis.

Results

Eighty-one women underwent EM biopsy (dilatation and curettage, EM sampling). In univariable analysis, history of EM biopsy, endometrial thickness (EMT) and training year of operator (TY) were significantly associated with procedural pain. The initial multivariable model was fitted with significant predictors in a univariable analysis. The p-value of EMT and TY was below the pre-defined threshold (0.2) and the final pain prediction model included EMT and TY. Furthermore, pain during the procedure was calculated by the following equation: pain score (numeric rating scale) = 7.364 + (−0.872) * EM thickness (cm) + (−1.033)*TY.

Conclusion

Both endometrial thickness and training year of operator were useful predictors of the severity of EM biopsy-related pain.
COVID-19 Vaccination Prioritization Based on Cardiovascular Risk Factors and Number-Needed-to-Vaccinate to Prevent Death
Authors: Leong Darryl P. , Banerjee Amitava , Yusuf Salim
Published: March 2021

The supply limitations of COVID-19 vaccines have led to the need to prioritize vaccine distribution. Obesity, diabetes and hypertension have been associated with an increased risk of severe COVID-19 infection. Approximately half as many individuals with a cardiovascular risk factor need to be vaccinated against COVID-19 to prevent related death as compared with individuals without a risk factor. Our analysis suggests that prioritizing adults with these cardiovascular risk factors for vaccination is likely to be an efficient way to reduce population COVID-19 mortality.
Latino children’s obesity risk varies by place of birth: Findings from New York City public school youth, 2006-2017
Authors: Flórez Karen R. , Day Sophia E. , Huang Terry T.-K. , Konty Kevin J. , D’Agostino Emily M.
Published: March 2021

Introduction

Research showing Place of Birth (POB) predicts excess weight gain and obesity risk among Latino adults has not prompted similar research in Latino children, although childhood is a critical period for preventing obesity.

Methods

Longitudinal cohort observational study on public school children self-identified by parent/guardian as Latino in grades K-12 for school years 2006-07 through 2016-17 with measured weight and height (n= 570,172students; 3,10,3642observations). POB reported by parent/guardian was categorized as continental US (not NYC) (n=295,693), NYC (n=166,361), South America (n=19,452), Central America (n=10,241), Dominican Republic (n=57,0880), Puerto Rico (n=9,687) and Mexico (n=9,647). Age- and sex-specific BMI percentiles were estimated based on established growth charts. Data were analyzed in 2020.

Results

Prevalence of obesity was highest among US (non-NYC)-born girls (21%) and boys (27%), followed by NYC-born girls (19%) and boys (25%). Among girls, South Americans (9%) had the lowest prevalence of all levels of obesity, while Puerto Ricans (19%) and Dominicans (15%) had the highest prevalence. Among boys, South Americans also had the lowest prevalence of all levels of obesity (15%), while Puerto Ricans (22%) and Mexicans (21%) had the highest. In adjusted models, obesity risk was highest in US (non-NYC)-born children, followed by children born in NYC (p<0.001). Immigrant Latino children exhibited an advantage, particularly Dominicans, South Americans and Puerto Ricans, and even after controlling for individual and neighborhood sociodemographic features including linguistic isolation and poverty.

Conclusions

The heterogeneity of obesity risk among Latino children highlights the importance of POB.
Interoception of breathing and its relationship with anxiety
Authors: Harrison Olivia K. , Köchli Laura , Marino Stephanie , Luechinger Roger , Hennel Franciszek , Brand Katja , Hess Alexander J. , Frässle Stefan , Iglesias Sandra , Vinckier Fabien , Petzschner Frederike , Harrison Samuel J. , Stephan Klaas E.
Published: March 2021

Interoception, the perception of internal bodily states, is thought to be inextricably linked to affective qualities such as anxiety. While interoception spans sensory to metacognitive processing, it is not clear whether anxiety is differentially related to these processing levels. Here we investigated this question in the domain of breathing, using computational modelling and high-field (7 Tesla) fMRI to assess brain activity relating to dynamic changes in inspiratory resistance of varying predictability. Notably, the anterior insula was associated with both breathing-related prediction certainty and prediction errors, suggesting an important role in representing and updating models of the body. Individuals with low vs. moderate anxiety traits showed differential anterior insula activity for prediction certainty. Multimodal analyses of data from fMRI, computational assessments of breathing-related metacognition, and questionnaires demonstrated that anxiety-interoception links span all levels from perceptual sensitivity to metacognition, with strong effects seen at higher levels of interoceptive processes.
Prenatal smoking, alcohol and caffeine exposure and maternal reported ADHD symptoms in childhood: triangulation of evidence using negative control and polygenic risk score analyses
Authors: Haan Elis , Sallis Hannah M. , Zuccolo Luisa , Labrecque Jeremy , Ystrom Eivind , Reichborn-Kjennerud Ted , Andreassen Ole , Havdahl Alexandra , Munafò Marcus R.
Published: March 2021

Background and aims

Studies have indicated that maternal prenatal substance use may be associated with offspring attention deficit hyperactivity disorder (ADHD) via intrauterine effects. We measured associations between prenatal smoking, alcohol and caffeine consumption with childhood ADHD symptoms accounting for shared familial factors.

Design

First, we used a negative control design comparing maternal and paternal substance use. Three models were used for negative control analyses: unadjusted (without confounders), adjusted (including confounders) and mutually adjusted (including confounders and partner’s substance use). The results were meta-analysed across the cohorts. Second, we used polygenic risk scores (PRS) as proxies for exposures. Maternal PRS for smoking, alcohol and coffee consumption were regressed against ADHD symptoms. We triangulated the results across the two approaches to infer causality. Setting: We used data from three longitudinal pregnancy cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC) in the UK, Generation R study (GenR) in the Netherlands and Norwegian Mother, Father and Child Cohort study (MoBa) in Norway.

Participants

Phenotype data available for children was: NALSPAC=5,455-7,751; NGENR=1,537-3,119; NMOBA=28,053-42,206. Genotype data available for mothers was: NALSPAC=7,074; NMOBA=14,583. Measurements: A measure of offspring ADHD symptoms at age 7-8 years was derived by dichotomising scores from questionnaires and parental self-reported prenatal substance use was measured at the 2nd pregnancy trimester.

Findings

The pooled estimate for maternal prenatal substance use showed an association with total ADHD symptoms (odds ratio (OR)SMOKING=1.11, 95% confidence interval (CI) 1.00-1.23; ORALCOHOL=1.27, 95%CI 1.08-1.49; ORCAFFEINE=1.05, 95%CI 1.00-1.11), while not for fathers (ORSMOKING=1.03, 95%CI 0.95-1.13; ORALCOHOL=0.83, 95%CI 0.47-1.48; ORCAFFEINE=1.02, 95%CI 0.97-1.07). However, maternal associations did not persist in sensitivity analyses (substance use before pregnancy, adjustment for maternal ADHD symptoms in MoBa). The PRS analyses were inconclusive for an association in ALSPAC or MoBa.

Conclusions

There appears to be no causal intrauterine effect of maternal prenatal substance use on offspring attention-deficit hyperactivity disorder symptoms.
Geographically-targeted COVID-19 vaccination is more equitable than age-based thresholds alone
Authors: Wrigley-Field Elizabeth , Kiang Mathew V , Riley Alicia R , Barbieri Magali , Chen Yea-Hung , Duchowny Kate A , Matthay Ellicott C , Van Riper David , Jegathesan Kirrthana , Bibbins-Domingo Kirsten , Leider Jonathon P
Published: March 2021

COVID-19 mortality increases dramatically with age and is also substantially higher among Black, Indigenous, and People of Color (BIPOC) populations in the United States. These two facts introduce tradeoffs because BIPOC populations are younger than white populations. In analyses of California and Minnesota--demographically divergent states--we show that COVID vaccination schedules based solely on age benefit the older white populations at the expense of younger BIPOC populations with higher risk of death from COVID-19. We find that strategies that prioritize high-risk geographic areas for vaccination at all ages better target mortality risk than age-based strategies alone, although they do not always perform as well as direct prioritization of high-risk racial/ethnic groups.

One-sentence summary

Age-based COVID-19 vaccination prioritizes white people above higher-risk others; geographic prioritization improves equity.
Using proper mean generation intervals in modelling of COVID-19
Authors: Tang Xiujuan , Musa Salihu S. , Zhao Shi , He Daihai
Published: March 2021

In susceptible-exposed-infectious-recovered (SEIR) epidemic models, with the exponentially distributed duration of exposed/infectious statuses, the mean generation interval (GI, time lag between infections of a primary case and its secondary case) equals the mean latent period (LP) plus the mean infectious period (IP). It was widely reported that the GI for COVID-19 is as short as 5 days. However, many works in top journals used longer LP or IP with the sum (i.e., GI), e.g., > 7 days. This discrepancy will lead to overestimated basic reproductive number, and exaggerated expectation of infectious attack rate and control efficacy, since all these quantities are functions of basic reproductive number. We argue that it is important to use suitable epidemiological parameter values.
Understanding the effectiveness of government interventions in Europe’s second wave of COVID-19
Authors: Sharma Mrinank , Mindermann Sören , Rogers-Smith Charlie , Leech Gavin , Snodin Benedict , Ahuja Janvi , Sandbrink Jonas B. , Monrad Joshua Teperowski , Altman George , Dhaliwal Gurpreet , Finnveden Lukas , Norman Alexander John , Oehm Sebastian B. , Sandkühler Julia Fabienne , Mellan Thomas , Kulveit Jan , Chindelevitch Leonid , Flaxman Seth , Gal Yarin , Mishra Swapnil , Brauner Jan Markus , Bhatt Samir
Published: March 2021

As European governments face resurging waves of COVID-19, non-pharmaceutical interventions (NPIs) continue to be the primary tool for infection control. However, updated estimates of their relative effectiveness have been absent for Europe’s second wave, largely due to a lack of collated data that considers the increased subnational variation and diversity of NPIs. We collect the largest dataset of NPI implementation dates in Europe, spanning 114 subnational areas in 7 countries, with a systematic categorisation of interventions tailored to the second wave. Using a hierarchical Bayesian transmission model, we estimate the effectiveness of 17 NPIs from local case and death data. We manually validate the data, address limitations in modelling from previous studies, and extensively test the robustness of our estimates. The combined effect of all NPIs was smaller relative to estimates from the first half of 2020, indicating the strong influence of safety measures and individual protective behaviours--such as distancing--that persisted after the first wave. Closing specific businesses was highly effective. Gathering restrictions were highly effective but only for the strictest limits. We find smaller effects for closing educational institutions compared to the first wave, suggesting that safer operation of schools was possible with a set of stringent safety measures including testing and tracing, preventing mixing, and smaller classes. These results underscore that effectiveness estimates from the early stage of an epidemic are measured relative to pre-pandemic behaviour. Updated estimates are required to inform policy in an ongoing pandemic.
Estimation of the Reproduction Number for COVID-19 Based on Latest Vaccination Results and the Timing for Herd-Immunity: Prospect for 2021
Authors: Zhu Steven Suan , Iboi Enahoro
Published: March 2021

This study examined four countries Israel, United States, United Kingdom, and Serbia and present their possible vaccination trajectories into 2021. We found that populations in all the four countries are relaxing and taking the advantage of the benefit of an increasingly immunized community hence, experiencing a rising phase of ℛ c(t). The United States is of particular concern, due to its fast rising ℛc(t) in comparison to other countries, potentially generating another wave of infection. Due to aggressive vaccination program, continued implementation of restrictive measures, or both, in all countries we analyzed, present a cautiously optimistic outlook at controlling the pandemic toward the latter part of 2021. We also found that despite a significant fraction of the population in selected countries being immunized, no countries other than Israel has its ℛc(t) reached its intrinsic ℛ0 value. Based on our proposed methodology for deriving ℛ0, our prediction shows that Israel’s indigenous COVID-19 daily ℛ0 is approximately 2.2 based on its latest data.
Low grade inflammation in the epileptic hippocampus contrasts with explosive inflammation occurring in the acute phase followingstatus epilepticusin rats: translation to patients with epilepsy
Authors: Gasmi Nadia , Navarro Fabrice P. , Ogier Michaël , Belmeguenaï Amor , Lieutaud Thomas , Georges Béatrice , Bodennec Jacques , Guénot Marc , Streichenberger Nathalie , Ryvlin Philippe , Rheims Sylvain , Bezin Laurent
Published: March 2021

There is still a lack of robust data, acquired identically and reliably from tissues either surgically resected from patients with mesial temporal lobe epilepsy (mTLE) or collected in animal models, to answer the question of whether the degree of inflammation of the hippocampus differs between mTLE patients, and between epilepsy and epileptogenesis. Here, using highly calibrated RTqPCR, we show that neuroinflammatory marker expression was highly variable in the hippocampus and the amygdala of mTLE patients. This variability was not associated with gender, age, duration of epilepsy, seizure frequency, and anti-seizure drug treatments. In addition, it did not correlate between the two structures and was reduced when the inflammatory status was averaged between the two structures. We also show that brain tissue not frozen within minutes after resection had significantly decreased housekeeping gene transcript levels, precluding the possibility of using post-mortem tissues to assess physiological baseline transcript levels in the hippocampus. We thus used rat models of mTLE, induced by status epilepticus (SE), that have the advantage of providing access to physiological baseline values. They indisputably indicated that inflammation measured during the chronic phase of epilepsy was much lower than the explosive inflammation occurring after SE, and was only detected when epilepsy was associated with massive neurodegeneration and gliosis. Comparison between the inter-individual variability measured in patients and that established in all epileptic and control rats suggests that some mTLE patients may have very low inflammation in the hippocampus, close to control values. However, the observation of elevated inflammation in the amygdala of some patients indicates that inflammation should be studied not only at the epileptic hippocampus, but also in the associated brain structures in order to have a more integrated view of the degree of inflammation present in brain networks involved in mesial temporal lobe epilepsy.
Cytostatic hypothermia and its impact on glioblastoma and survival
Authors: Enam Syed Faaiz , Kilic Cem Y. , Huang Jianxi , Kang Brian J. , Chen Reed , Tribble Connor S. , Ilich Ekaterina , Betancur Martha I. , Blocker Stephanie J. , Owen Steven J. , Buckley Anne F. , Lyon Johnathan G. , Bellamkonda Ravi V.
Published: March 2021

Novel therapeutic approaches are needed for patients with glioblastoma (GBM) who otherwise have limited options. Here we studied and deployed non-freezing ‘cytostatic’ hypothermia to stunt GBM growth. This contrasts with ablative, cryogenic hypothermia: a double-edged sword against tumors infiltrating otherwise healthy tissue. We investigated three grades of hypothermiain vitroand identified a cytostatic window of 20–25°C. For some glioma lines, 18 h/d of cytostatic hypothermia was sufficient to halt divisionin vitro. Cytostatic hypothermia induced cell cycle arrest, reduced metabolite production and consumption, and reduced inflammatory cytokine synthesis. Next, we fabricated an experimental device to test local cytostatic hypothermiain vivoin two rodent models of GBM: utilizing the rat F98 and the human U-87 MG lines. Hypothermia more than doubled the median survival of F98 bearing rats from 3.9 weeks to 9.7 weeks and two rats survived through 12 weeks. All U-87 MG bearing rats that successfully received cytostatic hypothermia survived their study period. Thus, this approach lengthened survival without chemical interventions. Unlike targeted therapeutics that are successful in preclinical models but fail in clinical trials, cytostatic hypothermia affects multiple cellular processes simultaneously. This, alongside reduced cellular division, suggests that opportunities for tumor evolution are reduced and the likelihood of translation to larger species may be more likely. In addition, based on our work, designs, and the literature, engineering a patient-centric device is tangible. Taken together, cytostatic hypothermia could be a novel approach to cancer therapy and eventually serve a valuable role to patients with GBM.

One Sentence Summary

Hypothermia influences multiple cellular pathways, can be a safe and effective approach to halt glioblastoma growth, and holds translational promise.
Localized phosphorylation of RNA Polymerase II by G1 cyclin-Cdk promotes cell cycle entry
Authors: Kõivomägi Mardo , Swaffer Matthew P. , Turner Jonathan J. , Marinov Georgi , Skotheim Jan M.
Published: March 2021

The cell cycle is thought to be initiated by cyclin-dependent kinases (Cdk) inactivating transcriptional inhibitors of cell cycle gene-expression(1, 2). In budding yeast, the G1 cyclin Cln3-Cdk1 complex is thought to directly phosphorylate Whi5, thereby releasing the transcription factor SBF and committing cells to division(3-7). Here, we report that Cln3-Cdk1 does not phosphorylate Whi5, but instead phosphorylates the RNA Polymerase II subunit Rpb1’sC-terminaldomain (CTD) on S5of its heptapeptide repeats. Cln3-Cdk1 binds SBF-regulated promoters(8)and Cln3’s function can be performed by the canonical S5kinase(9)Ccl1-Kin28 when synthetically recruited to SBF. Thus, Cln3-Cdk1 triggers cell division by phosphorylating Rpb1 at SBF-regulated promoters to activate transcription. Our findings blur the distinction between cell cycle and transcriptional Cdks to highlight the ancient relationship between these processes.
Invasive dedifferentiated melanoma cells inhibit JAK1-STAT3-driven actomyosin contractility of human fibroblastic reticular cells of the lymph node
Authors: Rovera Christopher , Berestjuk Ilona , Lecacheur Margaux , Diazzi Serena , Mallavialle Aude , Albrengues Jean , Gaggioli Cédric , Girard Christophe , Passeron Thierry , Deckert Marcel , Tartare-Deckert Sophie , Prod’homme Virginie
Published: March 2021

Fibroblastic reticular cells (FRC) are immunologically specialized fibroblasts controlling the size and microarchitecture of the lymph node (LN), partly through their contractile properties. Swelling is a hallmark of tumor-draining LN in lymphophilic cancers such as cutaneous melanoma, a very aggressive and heterogeneous tumor with high risk of early metastasis. Melanoma cells can dynamically switch between melanocytic proliferative and dedifferentiated mesenchymal-like invasive phenotypes, which are characterized by distinct transcriptional signatures. Melanoma secreted cues, such as extracellular vesicles, growth factors or proinflammatory cytokines, promote LN stroma remodeling and metastatic spreading. But how FRC integrate these pro-metastatic signals and modulate their contractile functions remains poorly characterized. Here, we show that factors secreted by dedifferentiated melanoma cells, but not by melanocytic cells, strongly inhibit FRC actomyosin-dependent contractile forces by decreasing the activity of the RHOA-ROCK pathway and the mechano-responsive transcriptional co-activator YAP, leading to a decrease in F-actin stress fibers and cell elongation. Transcriptional profiling and biochemical analyses indicate that FRC actomyosin cytoskeleton relaxation is driven by inhibition of JAK1 and its downstream transcription factor STAT3, and is associated with increased FRC proliferation and activation. Interestingly, dedifferentiated melanoma cells reduce FRC contractilityin vitroindependently of extracellular vesicle secretion. These data show that FRC are specifically modulated by proteins secreted by invasive dedifferentiated melanoma cells and suggest that melanoma-derived cues could modulate the biomechanical properties of distant LN before metastatic invasion. They also highlight that JAK1-STAT3 and YAP signaling pathways contribute to the maintenance of the spontaneous contractility of resting human FRC.