bluuebunny/crossref_metadata_2025 huggingface dataset:
Sound Pressure Distribution in the Ear After Radical Mastoidectomy With Meatoplasty
Authors: Lee Chia-Fone , Hsu Ken-Hao , Chen Chin-Kuo
Published: July 2022

Objective

We aimed to identify the sound pressure distribution along the external auditory canal after radical mastoidectomy with meatoplasty by combining real ear measurements and measurements obtained using a finite-element model.

Study Design

Case series with chart review.

Setting

Tertiary care university hospital.

Patients

We evaluated 16 patients who had undergone radical mastoidectomy with meatoplasty in one ear and had intact nonoperated contralateral ears, which served as the control group.

Intervention (Diagnostic)

Real ear measurements testing at specific frequencies were performed postoperatively.

Main Outcome Measure

Sound pressure gains were measured at five different depths along the external auditory canal, and a validated finite-element model was used to simulate the sound pressure distributions along the external auditory canals of the operated and nonoperated ears.

Results

The average peak resonant frequency near the tympanic membrane in operated ears was significantly lesser than that in nonoperated ears (2434.4 ± 616.4 versus 2935.9 ± 602.2 Hz; Wilcoxon signed-rank test, p < 0.05). The average peak resonant amplitude near the tympanic membrane showed no significant intergroup difference (paired-sample t test, p > 0.05). The peak resonant frequencies at different depths of the external auditory canal varied in the nonoperated ears (Kruskal-Wallis rank-sum test, 2880.9 ± 581.7 Hz, p = 0.02) but did not differ significantly in the operated ears (Kruskal-Wallis rank-sum test, 2464.4 ± 670.3 Hz, p = 0.75). In the finite-element model, the peak resonant frequencies along the depth of the external auditory canal varied in the normal ear and were homogeneous in the operated ear.

Conclusion

Radical mastoidectomy with meatoplasty altered the sound distribution in the external auditory canal. Our finite-element model successfully simulated the postoperative sound distribution in the external auditory canal and will facilitate development of wearable equipment for these patients.
Trends in Pediatric Acute Otitis Media Burden During the First COVID-19 Year
Authors: Marom Tal , Schwarz Yehuda , Gluck Ofer , Ginzburg Gabriel , Tamir Sharon Ovnat
Published: July 2022

Objective

To study the changes in acute otitis media (AOM) pediatric emergency department (PED) visits and pediatric admission before and during the first coronavirus disease 2019 (COVID-19) year.

Study Design

Retrospective case review.

Setting

Secondary care center.

Patients

Children younger than 18 years with all-cause and AOM-related PED visits and pediatric admissions for 3 years (March 1, 2018–January 28, 2021) were identified. Children were categorized according to age (0–2, 2–6, and 6–18 yr) and their date of presentation: pre–COVID-19 (yearly average of visits/admissions during the 2 prepandemic years: March 1, 2018–February 28, 2019 and March 1, 2019–February 29, 2020) or COVID-19 year (visits/admissions between March 1, 2020–February 28, 2021).

Intervention

Pre– and post–COVID-19 emergence, alternating lockdowns, kindergarten and school closures, and increased hygiene measures.

Main Outcome Measure

Post– versus pre–COVID-19 AOM PED visit and pediatric admission incidence rate ratios (IRRs), using a generalized estimating equation model with a negative binomial regression calculation, while controlling for monthly fluctuations.

Results

Annual AOM visits/admissions during the pre–COVID-19 and COVID-19 years were 517 and 192 and 256 and 94, respectively (p < 0.05 for both). For children aged 0 to 2 years, AOM visits/admissions significantly decreased during the first COVID-19 year, compared with the pre-COVID years (β = −1.11 [IRR, 0.33; 95% confidence interval [CI], 0.26–0.42; p < 0.005] and β = −1.12 [IRR, 0.33; 95% CI, 0.25–0.42; p < 0.005]). Relatively to all-cause of children aged 0 to 2 years, AOM visits/admissions decreased during the first COVID-19 year versus the pre–COVID-19 years (β = −2.14 [IRR, 0.12; 95% CI, 0.08–0.17; p < 0.005] and β = −1.36 [IRR, 0.26; 95% CI, 0.23–0.29; p < 0.005]) and had monthly fluctuations coinciding with the lockdown/relaxation measures. For children aged 2 to 6 years, the reduction in AOM admissions was significant (β = −1.70, IRR, 0.18; 95% CI, 0.09–0.37; p < 0.005). No significant differences were observed for children aged 6 to 18 years because of the small sample size.

Conclusion

Pediatric AOM burden substantially decreased during the first COVID-19 year.
Are Speech Perception Scores in Cochlear Implant Recipients Consistent Across Different Tests?
Authors: Andresen Nicholas S. , Vohra Varun , Galaiya Deepa J. , Carver Courtney L. , Marsiglia Dawn D. , Yeagle Jennifer D. , Creighton Francis X. , Wang Nae-Yuh , Bowditch Stephen P. , Della Santina Charles C. , Sun Daniel Q.
Published: July 2022

Objective

Cochlear implant (CI) candidacy and postoperative outcomes are assessed using sets of speech perception tests that vary from center to center, limiting comparisons across institutions and time periods. The objective of this study was to determine if scores on one speech perception test could be reliably predicted from scores on another test.

Study Design

Arizona Biomedical (AzBio) Sentence Test, Consonant-Nucleus-Consonant word (CNCw), and Hearing in Noise Test (HINT) scores in quiet for the implanted ear were collected for individuals who received a CI between 1985 and 2019. Scores collected during the same testing session were analyzed using Bland-Altman plots to assess agreement between testing methods. Simple linear regression with logit transformation was used to generate predictive functions and 95% confidence intervals for expected mean and individual scores.

Setting

Single academic medical center.

Patients

A total of 1,437 individuals with a median age of 59.9 years (range, 18–95 yr) and 46% (654 of 1,437) male.

Interventions

N.A.

Main Outcome Measures

Agreement as a function of test score, mean, variance, and correlation coefficients.

Results

A total of 2,052 AzBio/CNCw, 525 AzBio/HINT, and 7,187 CNCw/HINT same-session score pairings were identified. Pairwise test comparisons demonstrated limited agreement between different tests performed in the same session, and a score correlation between different speech tests revealed large variances.

Conclusion

Transformation functions between test batteries were predictive of mean scores but performed poorly for prediction of individual scores. Point-wise comparisons of scores across CI test batteries should be used with caution in clinical and research settings.
Otologic Manifestations of Psoriasis: A Systematic Review and Meta-Analysis
Authors: Jeong Seth S. , Shih Michael C. , Rizk Habib G. , Lambert Paul R.
Published: July 2022

Introduction

Psoriatic skin lesions are often seen in the auricle and external auditory canal, but middle ear and inner ear manifestations are not easily identified. Several studies have indicated hearing loss and vestibular dysfunction with psoriasis, but the extent of association has not been well defined.

Methods

A systematic search of PubMed, CINAHL, Scopus, and Cochrane Library was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Included studies described audiometric or vestibular assessment of psoriasis patients. Meta-analysis was represented with odds ratios (ORs) or mean difference (MD) with 95% confidence intervals.

Results

A total of 13 studies with 589 psoriasis patients and 617 healthy controls were included. Age did not significantly differ between psoriasis patients (47.1 [12.4] yr) and healthy controls (45.4 [11.2] yr). Psoriasis area and severity index score was 9.9 (8.4), and body surface area scores was 7.9 (14.7). Pure-tone audiometry analysis showed higher mean hearing thresholds in psoriasis patients compared with healthy controls across all frequencies, with the greatest difference at 4000 Hz (MD, 7.70 [4.46–10.94]; p < 0.00001). Speech reception thresholds were worse with psoriasis (MD, 3.53 [1.56–5.49]; p < 0.0001). Abnormal stapedial reflex was more common in psoriasis (OR, 5.19 [1.68–15.99]; p = 0.004). Abnormal vestibular testing was more common in psoriasis for caloric testing (OR, 13.12 [2.88–59.84]; p < 0.0001). Two additional studies of 41,681 psoriasis patients and 80,273 healthy controls found that psoriasis patients were at higher risk for sudden sensorineural hearing loss (OR, 1.50 [1.25–1.80]; p < 0.0001).

Conclusion

Our study shows that psoriasis is associated with hearing loss and vestibular dysfunction, but clinical significance remains undefined. The trends noted in our study require more investigation, and the pathophysiologic mechanisms need to be defined.
Single-Center Experience Evaluating Clinical Outcomes of a Novel-Guided Drill System for Percutaneous Bone-Anchored Hearing Implant
Authors: Shoman Nael M.
Published: July 2022

Objective

Evaluate intraoperative and postoperative outcomes of a novel guided drill system for percutaneous bone-anchored hearing implants.

Methods

Between January 2016 and February 2021, patients age ≥18 years deemed potential candidates for a bone-anchored hearing device, were formally assessed for candidacy and counseling. Those that qualified and opted to proceed were added to a prospectively maintained database, including demographic, clinical, and audiologic data. Intraoperative findings were reported, as were clinical outcomes at 7 days, 4 weeks, 3 months and 6 months postoperatively. The Holgers index was used to grade soft tissue reactions.

Results

One hundred patients underwent the procedure. There were 56 women, and mean age was 54 years (18–84 yr). Ninety-six were done under local anesthetic. Mean surgical time was 13 minutes (9–27 min). No significant intraoperative events were noted. There were nine cases of implant loss, all in the first 50 cases. Mean duration of implant loss was 3.6 weeks (range, 2–5 wk). At the first postoperative visit, 82 had Holgers 0, 16 Holgers 1, 2 Holgers 2, and none Holgers 3. At the second postoperative visit, excluding the 9 with implant loss, 83 (91%) had Holgers 0, 6 (7%) Holgers 1, and 2 (2%) Holgers 2. None were Holgers 3.

Conclusions

The current study represents, to our knowledge, the largest series on the novel guided drill technique. Results show it is safe and efficient with low soft tissue complication rates. Drill bit design and technical modifications may have helped lower implant loss rate in this series over time.
The Impact of the Location of Chorda Tymapni Nerve Origin on the Round Window Accessibility During Pediatric Cochlear Implantation: A Radioclinical Assessment
Authors: Elzayat Saad , Mandour Mahmoud , Elfarargy Haitham H. , Lotfy Rasha , Margani Valerio , Covelli Edoardo , Barbara Maurizio
Published: July 2022

Objectives

This study assessed the impact of the location of the chorda tympani nerve (CTN) origin on the round window (RW) accessibility during pediatric cochlear implantation (CI). We also tried to validate the radiologic method to measure the length between the origin of the CTN from the facial nerve to the stylomastoid foramen (CF-SM).

Study Design

It was a prospective observational case-series study.

Settings

The included CI surgeries were performed at tertiary referral institutions from November 2018 to August 2021.

Subjects

We included 146 pediatric patients who were candidates for CI.

Intervention

We measured the CF-SM length in the parasagittal cut of the preoperative high-resolution computed tomography. We also classified the intraoperative RW according to the accessibility through the ordinary posterior tympanotomy approach into accessible or inaccessible.

Main Outcome Measure

We correlated the preoperative radiologic CF-SM length with the intraoperative RW accessibility.

Results

The radiologic CF-SM length ranged from 2.9 to 7.4 mm with a mean of 4.9 ± 1.03 mm. The RW was accessible in 107 patients and inaccessible in 39 patients. Spearman’s correlation coefficient revealed a significant relationship between the location of CTN origin and the RW accessibility as the p value was less than 0.0001.

Conclusions

We found a precise method to measure the CF-SM length in the parasagittal cut of the high-resolution computed tomography. We also found a significant impact of the location of the CTN origin on intraoperative RW accessibility. The radiologic CF-SM length of more than 5.4 mm had a powerful prediction capability of the RW inaccessibility.
First-Time Mothers' Invisible Presence Using Social Networking Sites
Authors: Elliott Gail M. C. , Letvak Susan , Côté-Arsenault Denise , Wallace Debra C. , Smith Julia Mendez
Published: July 2022

Purpose:

To describe first-time mothers' experiences with online social networking sites in the early postpartum period, explore how mothers use them to gain support, and to evaluate how their use can aid or hinder maternal role transition.

Study Design:

Qualitative descriptive study.

Methods:

This qualitative descriptive study, using convenience and snowball sampling, first-time mothers in the early postpartum period were recruited through social media. Semistructured interviews were conducted virtually where mothers were asked to describe their experiences with online social networking. Thematic analysis methods were used to develop themes from participant interviews.

Results:

Twelve first-time mothers ranging from 4 to 12 weeks postpartum participated in the study. Thematic analysis revealed four themes: 1) Habits of first-time mom using social networking sites, 2) New purpose online, 3) Taking it to the moms, and 4) Impact on motherhood.

Clinical Implications:

Maternal child nurses have opportunities to further customize support for first-time mothers online. Awareness of habits, trends, implications of early mothering during COVID-19, and the role social networking sites can play in supporting mothers in the early postpartum period offers new ways for nurses to support and empower the motherhood collective.
The Clonal Relationship Between the Ductal and Lobular Components of Mixed Ductal-Lobular Carcinomas Suggested a Ductal Origin in Most Tumors
Authors: Pérez-Mies Belén , Caniego-Casas Tamara , Carretero-Barrio Irene , Biscuola Michele , López-García María A. , Hardisson David , Rosas Marta , López Rodríguez María J. , Cristóbal Eva , Pizarro David , Rosa-Rosa Juan M. , Palacios José
Published: July 2022

The relationship between the ductal and lobular components of invasive ductolobular carcinomas (IDLC) has not been fully elucidated. In this study, the molecular alterations of both components were analyzed in a series of 20 IDLC that were selected, not only by morphologic criteria, but also by the loss of E-cadherin expression in the lobular component. We found that 80% of tumors shared alterations of driver genes in both components, being PIK3CA the most common alteration. In addition, 45% of IDLC carried CDH1 mutations in their lobular component that were absent in the ductal component. Fluorescent in situ hybridization analysis of the CDH1 gene excluded homozygous CDH1 loss as a frequent cause of E-cadherin loss in tumors without CDH1 mutations. In addition, no pathogenic mutations of catenin genes were detected in this series of tumors. In 25% of tumors, actionable mutations in PIK3CA, AKT1, and ERBB2 were found in only 1 component. Altogether, our results confirm that most IDLC derive from invasive carcinoma of no special type, in which a population of cells lose E-cadherin and acquire a lobular phenotype. The frequency of CDH1 mutations in IDLC appears to be lower than in conventional invasive lobular carcinomas, suggesting the implication of alternative mechanisms of E-cadherin loss. Moreover, molecular heterogeneity between ductal and lobular areas suggests the need for molecular characterization of both components to guide targeted therapies.
Acute Alcohol Intoxication in Pediatric Emergencies
Authors: Castro-Rodríguez Cristina , Lorente-Romero Jorge , Rivas-García Arístides , García-Loygorri Clara Ferrero , Vázquez-López Paula , Marañón Rafael
Published: July 2022

Introduction

Alcohol intoxication in pediatrics is a growing problem in our environment. The objectives of this study are to define the prevalence of acute alcohol intoxication in the pediatric emergency department (PED) and to describe the associated symptoms and their relationship with potential risk factors.

Methods and Material

This cross-sectional study includes patients younger than 16 years with a diagnosis of acute alcohol intoxication between March 2010 and October 2018 in the PED of a tertiary hospital. Patients with concomitant intoxication by other substances were excluded. The association between qualitative variables was determined using the χ2 or Fisher exact test and quantitative with the Student t, Mann-Whitney U test, and simple linear regression.

Results

There were 136 episodes of alcohol intoxication, which represents a prevalence of 24.1/100,000 emergencies. After excluding 10 patients because of positive screening for other drugs, 126 patients with a mean age of 14.5 years (SD, 1.2 years) were included, 57.9% of whom were women. A total of 25.4% of the patients were younger than 14 years. Ethanolemia was determined in 88.9%, and its mean concentration was 195.7 mg/dL (SD, 56.5 mg/dL), with potentially serious levels (>300 mg/dL) being found in 3.6% of the patients. A relationship was found between the Glasgow Coma Scale score and ethanolemia (B = −12.7; 95% confidence interval, −8.1 to −17.4; P < 0.001), as well as with potassium (B = −31, 9; 95% confidence interval, −6.6 to −57.3; P = 0.014). No patient had seizures or hypoglycemia. A total of 10.3% of the patients required admission.

Conclusions

Alcohol intoxication is a rare consultation reason in the PED. They usually present with mild and self-limited symptoms, being the decrease in the level of consciousness and hypokalemia the most frequent symptom and analytical alteration.
Use of Minimally Invasive Radiofrequency-assisted Lipolysis as a Novel Treatment of Grade 2 and Grade 3 Cellulite.
Authors: Peters Mark H.
Published: July 2022

Background:

Cellulite is a common condition and laxity in the superficial fascial system (SFS) contributes significantly to its appearance in the thigh and buttock areas. Components of the SFS such as the fibrous septae and adipose tissue are targets for an effective treatment to improve the appearance of cellulite. This preliminary report demonstrates the use of radiofrequency-assisted lipolysis (RFAL) as a novel treatment approach to improve the appearance of cellulite by tightening the SFS.

Methods:

Ten female patients with Grade II and Grade III cellulite of the thighs or buttocks were included in this study. Minimally invasive application of bipolar radiofrequency energy to the affected areas was performed. Predetermined internal thermal endpoints at multiple tissue levels and different directions were reached in the treated tissues. Aspiration of the coagulated adipose tissue was performed using a small diameter cannula to minimize damage to the connective tissues. Pre-treatment and 6 months post-operative photos of 70 different body areas were randomized and scored by five blinded evaluators.

Results:

Using the Photonumeric Cellulite Severity Scale (CSS), scoring of preoperative and postoperative photographs revealed statistically significant differences in all body area comparisons. The magnitude of the differences in all scored body areas were considered large and mean differences were all positive indicating an improvement across time.

Conclusions:

Grade 2 and Grade 3 cellulite of the thighs and buttocks can be effectively treated using RFAL technology to decrease the laxity of the SFS.
Lymph Node Fibroblastic Reticular Cells Attenuate Immune Responses Through Induction of Tolerogenic Macrophages at Early Stage of Transplantation
Authors: Liu Beichen , Liu Huihui , Liu Siwei , Qin Chenchen , He Xiaoya , Song Zhengyang , Dong Yujun , Ren Hanyun
Published: July 2022

Background.

Fibroblastic reticular cells (FRCs) are a type of stromal cells located in the T zone in secondary lymphoid organs. Previous studies showed that FRCs possess the potential to promote myeloid differentiation. We aim to investigate whether FRCs in lymph nodes (LNs) could induce tolerogenic macrophage generation and further influence T-cell immunity at an early stage of allogeneic hematopoietic stem cell transplantation (allo-HSCT).

Methods.

LNs were assayed to confirm the existence of proliferating macrophages after allo-HSCT. Ex vivo—expanded FRCs and bone marrow cells were cocultured to verify the generation of macrophages. Real-time quantitative PCR and ELISA assays were performed to observe the cytokines expressed by FRC. Transcriptome sequencing was performed to compare the difference between FRC-induced macrophages (FMs) and conventional macrophages. Mixed lymphocyte reaction and the utilization of FMs in acute graft-versus-host disease (aGVHD) mice were used to test the inhibitory function of FMs in T-cell immunity in vitro and in vivo.

Results.

We found a large number of proliferating macrophages near FRCs in LNs with tolerogenic phenotype under allo-HSCT conditions. Neutralizing anti–macrophage colony-stimulating factor receptor antibody abolished FMs generation in vitro. Phenotypic analysis and transcriptome sequencing suggested FMs possessed immunoinhibitory function. Mixed lymphocyte reaction proved that FMs could inhibit T-cell activation and differentiation toward Th1/Tc1 cells. Injection of FMs in aGVHD mice effectively attenuated aGVHD severity and mortality.

Conclusions.

This study has revealed a novel mechanism of immune regulation through the generation of FRC-induced tolerogenic macrophages in LNs at an early stage of allo-HSCT.
Reemergence of pathogenic, autoantibody-producing B cell clones in myasthenia gravis following B cell depletion therapy
Authors: Fichtner Miriam L. , Hoehn Kenneth B. , Ford Easton E. , Mane-Damas Marina , Oh Sangwook , Waters Patrick , Payne Aimee S. , Smith Melissa L. , Watson Corey T. , Losen Mario , Martinez-Martinez Pilar , Nowak Richard J. , Kleinstein Steven H. , O’Connor Kevin C.
Published: July 2022

Myasthenia gravis (MG) is an autoantibody-mediated autoimmune disorder of the neuromuscular junction. In a subset of patients with MG, muscle-specific tyrosine kinase (MuSK) autoantibodies are present. MuSK MG patients respond well to CD20-mediated B cell depletion therapy (BCDT); most achieve complete stable remission. However, relapse often occurs. To further understand the immunomechanisms underlying relapse, we sought to study autoantibody-producing B cells over the course of BCDT. We developed a fluorescently labeled antigen to enrich for MuSK-specific B cells, which was validated with a novel Nalm6 cell line engineered to express a human MuSK-specific B cell receptor. B cells (≅ 2.6 million) from 12 different samples collected from nine MuSK MG patients were screened for MuSK specificity. We successfully isolated two MuSK-specific IgG4 subclass-expressing plasmablasts from two of these patients, who were experiencing a relapse after a BCDT-induced remission. Human recombinant MuSK mAbs were then generated to validate binding specificity and characterize their molecular properties. Both mAbs were strong MuSK binders, they recognized the Ig1-like domain of MuSK, and showed pathogenic capacity when tested in an AChR clustering assay. The presence of persistent clonal relatives of these MuSK-specific B cell clones was investigated through B cell receptor repertoire tracing of 63,977 unique clones derived from longitudinal samples collected from these two patients. Clonal variants were detected at multiple timepoints spanning more than five years and reemerged after BCDT-mediated remission, predating disease relapse by several months. These results indicate that a reservoir of rare pathogenic MuSK autoantibody-expressing B cell clones survive BCDT and reemerge into circulation prior to manifestation of clinical relapse. This study provides both a mechanistic understanding of MuSK MG relapse and a valuable candidate biomarker for relapse prediction.
Age- or lifestyle-induced accumulation of genotoxicity is associated with a generalized shutdown of long gene transcription
Authors: Ibañez-Solé Olga , Izeta Ander
Published: July 2022

A causative role for DNA damage as a molecular driver of aging has long been advocated. Transcription-blocking lesions (TBLs) accumulate with age in a stochastic manner. Thus, gene expression data might reflect the gene length-dependent accumulation of TBLs. Here we present an analysis of gene expression as a function of gene length in several independent single-cell RNA sequencing datasets of mouse and human aging. We found a pervasive age-associated downregulation of long gene expression, which is seen across species, datasets, sexes, tissues and cell types. Furthermore, long gene downregulation was also observed in premature aging models such as UV-radiation and smoke exposure, and in gene expression data from progeroid diseases Cockayne syndrome and trichothiodystrophy. Finally, we analyzed the length of differentially expressed genes associated to age in both mice and humans. Downregulated genes were significantly longer than upregulated genes. These data highlight a previously undetected hallmark of cellular aging and provide strong support for age-associated accumulation of genotoxic damage inducing a generalized shutdown of RNA polymerase II-mediated long gene transcription.

Abstract Figure
Waning and boosting of functional humoral immunity to SARS-CoV-2
Authors: Tong X. , McNamara R.P. , Avendaño M.J. , Serrano E.F. , García-Salum T. , Pardo-Roa C. , Levican J. , Poblete E. , Salina E. , Muñoz A. , Riquelme A. , Alter G. , Medina R.A.
Published: July 2022

Since the emergence of the SARS-CoV-2 virus, we have witnessed a revolution in vaccine development with the rapid emergence and deployment of both traditional and novel vaccine platforms. The inactivated CoronaVac vaccine and the mRNA-based Pfizer/BNT162b2 vaccine are among the most widely distributed vaccines, both demonstrating high, albeit variable, vaccine effectiveness against severe COVID-19 over time. Beyond the ability of the vaccines to generate neutralizing antibodies, antibodies can attenuate disease via their ability to recruit the cytotoxic and opsinophagocytic functions of the immune response. However, whether Fc-effector functions are induced differentially, wane with different kinetics, and are boostable, remains unknown. Here, using systems serology, we profiled the Fc-effector profiles induced by the CoronaVac and BNT162b2 vaccines, over time. Despite the significantly higher antibody functional responses induced by the BNT162b2 vaccine, CoronaVac responses waned more slowly, albeit still found at levels below those present in the systemic circulation of BNT162b2 immunized individuals. However, mRNA boosting of the CoronaVac vaccine responses resulted in the induction of significantly higher peak antibody functional responses with increased humoral breadth, including to Omicron. Collectively, the data presented here point to striking differences in vaccine platform-induced functional humoral immune responses, that wane with different kinetics, and can be functionally rescued and expanded with boosting.
The burden of human coronavirus infection in children hospitalised with lower respiratory tract infection in Cape Town, South Africa
Authors: Aliyu Abdulmumuni S. , Masu Adelaide N. , Kagina Benjamin M. , Muloiwa Rudzani
Published: July 2022

Introduction

Human coronaviruses (HCoV) NL63, HKU, OC43 and 229E are known to cause various respiratory infections including croup, pneumonia, and bronchitis in young children. The role of these four HCoV strains in the aetiology of pneumonia is little described in South Africa.

Methods

We used data collected between September 2012 – September 2013 from children aged <13 years with lower respiratory illness at Red Cross War Memorial Children’s Hospital. Respiratory samples including a nasopharyngeal swab (NP) and induced sputum (IS) were taken and tested for the four strains of coronaviruses using FTD33 multiplex real-time PCR.

Results

A total of 460 respiratory samples were analysed. Of these, 258 (56.0%) were male and 19 (4.1%) HIV infected. The median age of the children was 8 (IQR 4-18) months.

Nasopharyngeal (NP) samples were obtained from 460 children while induced sputum (IS) was not available for six children due to sample loss prior to analysis, leaving 454 available for analysis. A total of 42 (9.1%, 95% CI 6.7-12.1%) participants tested positive for HCoV in at least one of the two specimens. PCR was able to detect a total of 35 (7.7%) cases from the 454 tested IS specimens compared to 23 (5.0%) detected out of 460 NP samples.

The commonest detected HCoVs were coronavirus OC43 with 20 (4.3%) detected from either specimen followed by coronavirus NL63 or coronavirus HKU detected in 14 (3.0%) and 10 (2.2%) of positive test samples, respectively. The least common virus detected HCoV was coronavirus 229E detected in both positive test samples of one participant.

Overall HCoVs were detected in 23 (8.9%) of boys compared to 19 (9.1%) of the girls who returned a positive test; p=0.856. The overall age distribution of children with PCR detected HCoVs was similar to that of children with a negative result with median age of 10 (IQR 5-16) months and median of 8 (IQR 4-19) months, respectively; p=0.535. Prevalence of HCoV was 11/192 (5.7%), 23/153 (15.0%) and 8/115 (7.0%) in children <6 months old, 6-18 months and over 18 months respectively; p=0.008.

Conclusion

Children aged 6 to 18 months had double the risk of other age groups.
Reduced Olfactory Bulb Volume Accompanies Olfactory Dysfunction After Mild SARS-CoV-2 Infection
Authors: Petersen Marvin , Becker Benjamin , Schell Maximilian , Mayer Carola , Nägele Felix L. , Petersen Elina , Twerenbold Raphael , Thomalla Götz , Cheng Bastian , Betz Christian , Hoffmann Anna S.
Published: July 2022

Background

Despite its high prevalence, the determinants of smelling impairment in COVID-19 remain not fully understood. In this work, we aimed to examine the association between olfactory bulb volume and the clinical trajectory of COVID-19-related smelling impairment in a large-scale magnetic resonance imaging (MRI) analysis.

Methodology/Principal

Data of non-vaccinated COVID-19 convalescents recruited within the framework of the Hamburg City Health Study COVID Program between March and December 2020 were analyzed. On average 8 months after recruitment,, participants underwent MRI and neuropsychological testing as well as a structured questionnaire for olfactory function. Between March and April 2022 olfactory function was assessed at an additional timepoint including quantitative olfactometric testing with Sniffin’ Sticks.

Results

This study included 233 individuals recovered from mainly mild to moderate SARS-CoV-2 infections. Longitudinal assessment demonstrated a declining prevalence of olfactory dysfunction from 67.1% at acute infection, 21.0% at baseline examination and 17.5% at follow-up. Participants with post-acute olfactory dysfunction had a significantly lower olfactory bulb volume at scan-time than normally smelling individuals. Olfactory bulb volume predicted olfactometric scores at follow-up. Performance in neuropsychological testing was not significantly associated with the olfactory bulb volume.

Conclusions

Our work demonstrates an association of long-term smelling dysfunction and olfactory bulb integrity in a sample of individuals recovered from mainly mild to moderate COVID-19. Collectively, our results highlight olfactory bulb volume as a surrogate marker that may inform diagnosis and guide rehabilitation strategies in COVID-19.
Translation in the cell under fierce competition for shared resources: a mathematical model
Authors: Katz Rami , Attias Elad , Tuller Tamir , Margaliot Michael
Published: July 2022

During the process of translation the mRNAs in the cell “compete” for shared resources like tRNA molecules and ribosomes. This creates an indirect and intricate coupling between the mRNAs. For example, if ribosomal “traffic jams” evolve on some mRNA then the abundance of free ribosomes may decrease leading to lower initiation rates in the other mRNAs. When the shared resources are abundant the coupling between mRNAs due to this competition is weak. However, when the resources are scarce, e.g., when the pool of free ribosomes is starved, the competition may have a dramatic effect on the dynamics of translation in the cell. This scenario may be relevant for example under stress conditions or during a high yield viral infection, where the viral mRNAs “hijack” components of the translation machinery. Fierce competition for shared resources may also take place in synthetic or engineered systems such as cell free systems or in the case of high-throughput heteroglougs gene expression.

We study this scenario using a mathematical model that includes a network ofmribosome flow models (RFMs) interconnected via a pool of free ribosomes. Each RFM is a non-linear dynamical model for ribosome flow along a single mRNA molecule, and the interconnection via the pool encapsulates the competition for shared resources. We analyze the case wheremis large, i.e., a there is a large number of mRNAs. This implies that many ribosomes are attached to the mRNAs and thus the pool is starved.

Our model allows quantitative and qualitative analysis of the network steady state when the pool is starved. Our analysis results show that adding an mRNA to the network always decreases the steady state pool density. This makes sense, as every new mRNA “consumes” ribosomes. We also show that adding an mRNA has an intricate effect on the total protein production in the network: on the one-hand, the new mRNA produces new proteins. On the other-hand, the other mRNAs produce less proteins, as the pool that feeds these mRNAs now has a smaller abundance of ribosomes. Our analysis yields an explicit bound for the total production rate of the network when the number of RFMIOs is very large. In particular, we analyze how the total density of ribosomes in the network bounds the total production rate. This bound demonstrates that when the number of mRNAs increases, the marginal utility of adding another mRNA diminishes, and the total protein production rate saturates to a limiting value. We demonstrate our analysis approach using an example of producing insulin in a cell free system.
Beyond the limits of the unassigned protist microbiome: inferring large-scale spatio-temporal patterns of marine parasites
Authors: Rizos Iris , Debeljak Pavla , Finet Thomas , Klein Dylan , Ayata Sakina-Dorothée , Not Fabrice , Bittner Lucie
Published: July 2022

Marine protists are major components of the oceanic microbiome that remain largely unrepresented in culture collections and genomic reference databases. The exploration of this uncharted protist diversity in oceanic communities relies essentially on studying genetic markers from the environment as taxonomic barcodes. Here we report that across 6 large scale spatio-temporal planktonic surveys, half of the genetic barcodes remain taxonomically unassigned at the genus level, preventing a fine ecological understanding for numerous protist lineages. Among them, parasitic Syndiniales (Dinoflagellata) appear as the least described protist group. We have developed a computational workflow, integrating diverse 18S rDNA gene metabarcoding datasets, in order to infer large-scale ecological patterns at 100% similarity of the genetic marker, overcoming the limitation of taxonomic assignment. From a spatial perspective, we identified 2 171 unassigned clusters exclusively shared between the Tropical/Subtropical Ocean and the Mediterranean Sea among all Syndiniales orders and 25 ubiquitous clusters shared within all the studied marine regions. From a temporal perspective, over 3 time-series, we highlighted 38 unassigned clusters that follow rhythmic patterns of recurrence and are the best indicators of parasite community’s variation. These clusters withhold potential as ecosystem change indicators, mirroring their associated host community responses. Our results underline the importance of Syndiniales in structuring planktonic communities through space and time, raising questions regarding host-parasite association specificity and the trophic mode of persistent Syndiniales, while providing an innovative framework for prioritizing unassigned protist taxa for further description.
The host range and the role of O-antigen in P1 transduction with its alternative S’ tail fibre
Authors: Huan Yang W. , Fa-arun Jidapha , Wang Baojun
Published: July 2022

Enterobacteria phage P1 expresses two types of tail fibre, S and S’. Despite the wide usage of phage P1 for transduction, the host range and the receptor for its alternative S’ tail fibre was never determined. Here, a ΔS-cin Δpac E. coli P1 lysogenic strain was generated to allow packaging of phagemid DNA into P1 phage having either S or S’ tail fibre. P1(S’) could transduce phagemid DNA into Shigella flexneri 2a 2457O, Shigella flexneri 5a M90T and Escherichia coli O3 efficiently. Mutational analysis of the O-antigen assembly genes and LPS inhibition assays indicated that P1(S’) transduction requires at least one O-antigen unit. E. coli O111:B4 LPS produced a high neutralising effect against P1(S’) transduction, indicating that this E. coli strain could be a host for P1(S’). Mutations in the O-antigen modification genes of S. flexneri 2a 2457O and S. flexneri 5a M90T did not cause significant changes to P1(S’) transduction efficiency. A higher transduction efficiency of P1(S’) improved the delivery of a cas9 antimicrobial phagemid into both S. flexneri 2457O and M90T. These findings provide novel insights into P1 tropism-switching, by identifying the host range of P1(S’) and demonstrating its potential for delivering a sequence-specific Cas9 antimicrobial into clinically relevant S. flexneri.
Efficient in vivo neuronal genome editing in the mouse brain using nanocapsules containing CRISPR-Cas9 ribonucleoproteins
Authors: Metzger Jeanette M. , Wang Yuyuan , Neuman Samuel S. , Snow Kathy J. , Murray Stephen A. , Lutz Cathleen M. , Bondarenko Viktoriya , Felton Jesi , Gimse Kirstan , Xie Ruosen , Zhao Yi , Flowers Matthew T. , Simmons Heather A. , Roy Subhojit , Saha Krishanu , Levine Jon , Emborg Marina E. , Gong Shaoqin
Published: July 2022

Genome editing of somatic cells via clustered regularly interspaced short palindromic repeats (CRISPR) offers promise for new therapeutics to treat a variety of genetic disorders, including neurological diseases. However, the dense and complex parenchyma of the brain and the post-mitotic state of neurons make efficient genome editing challenging. In vivo delivery systems for CRISPR-Cas proteins and single guide RNA (sgRNA) include both viral vectors and non-viral strategies, each presenting different advantages and disadvantages for clinical application. We developed non-viral and biodegradable PEGylated nanocapsules (NCs) that deliver preassembled Cas9-sgRNA ribonucleoproteins (RNPs). Here, we show that the RNP NCs led to robust genome editing in neurons following intracerebral injection into the mouse striatum. Genome editing was predominantly observed in medium spiny neurons (>80%), with occasional editing in cholinergic, calretinin, and parvalbumin interneurons. Glial activation was minimal and was localized along the needle tract. Our results demonstrate that the RNP NCs are capable of safe and efficient neuronal genome editing in vivo.

SIGNIFICANCE STATEMENT

Modifying the DNA of cells in the brain could present opportunities for new treatments of neurological diseases. In this report, we describe a nanocapsule system designed to deliver the elements needed to modify the DNA of brain cells, also known as genome editing. These nanocapsules are created by chemically encapsulating the genome editing components, such that the nanocapsules are stable when prepared and biodegradable to release their payload upon entering cells. When injected into the mouse brain, our research shows that the nanocapsules lead to safe and efficient editing of DNA in neurons.
Stiffness-dependent active wetting enables optimal collective cell durotaxis
Authors: Pallarès Macià-Esteve , Pi-Jaumà Irina , Fortunato Isabela Corina , Grazu Valeria , Gómez-González Manuel , Roca-Cusachs Pere , de la Fuente Jesus M , Alert Ricard , Sunyer Raimon , Casademunt Jaume , Trepat Xavier
Published: July 2022

The directed migration of cellular clusters enables morphogenesis, wound healing, and collective cancer invasion. Gradients of substrate stiffness are known to direct the migration of cellular clusters in a process called collective durotaxis, but underlying mechanisms remain unclear. Here, we unveil a connection between collective durotaxis and the wetting properties of cellular clusters. We show that clusters of cancer cells dewet soft substrates and wet stiff ones. At intermediate stiffness, at the crossover from low to high wettability, clusters on uniform-stiffness substrates become maximally motile, and clusters on stiffness gradients exhibit optimal durotaxis. Durotactic velocity increases with cluster size, stiffness gradient, and actomyosin activity. We demonstrate this behavior on substrates coated with the cell-cell adhesion protein E-cadherin and then establish its generality on substrates coated with extracellular matrix. We develop a physical model of three-dimensional active wetting that explains this mode of collective durotaxis in terms of a balance between in-plane active traction and tissue contractility, and out-of-plane surface tension. Finally, we show that the distribution of cluster displacements has a heavy tail, with infrequent but large cellular hops that contribute to durotactic migration. Our study demonstrates a physical mechanism of collective durotaxis, through both cell-cell and cell-substrate adhesion ligands, based on the wetting properties of active droplets.
Mouse primary visual cortex neurons respond to the illusory “darker than black” in neon color spreading
Authors: Saeedi Alireza , Wang Kun , Nikpourian Ghazaleh , Bartels Andreas , Totah Nelson K. , Logothetis Nikos K. , Watanabe Masataka
Published: July 2022

Illusions are a powerful tool for studying the single neuron correlates of perception. Here, we introduce the neon color spreading (NCS) illusion in mice and report the neuronal correlates of illusory brightness, which has heretofore only been studied using human fMRI. We designed a novel NCS paradigm to evoke the percept of an illusory drifting grating and analyzed the activity of 520 single units in the mouse primary visual cortex (V1). A substantial proportion of V1 single units (60.5%) responded to illusory gratings with direction tuning matched to their preferred direction, which was determined using physically presented luminance-defined gratings (LDG). Moreover, by presenting LDG gratings with a 180° phase shift relative to NCs gratings, we show that spatial phase tuning shifted 180° for most single units. This finding conclusively demonstrates that V1 single units respond to illusory brightness. Using this novel mouse paradigm, we show that responses to illusory gratings have a lower magnitude and are delayed relative to physical gratings. We determined where V1 single units fell in the V1 cellular hierarchy (based on their susceptibility to surround suppression, their putative classification as interneuron or pyramidal neuron, and designation as a simple or complex cell) and found that higher-level V1 single units are more responsive to NCS stimuli. These findings resolve the debate of whether V1 is involved in illusory brightness processing and reveal a V1 hierarchical organization in which higher-level neurons are pivotal to the processing of illusory qualities, such as brightness.
A survey of transcriptomic datasets identifies ABA-responsive factors as regulators of photomorphogenesis inArabidopsis
Authors: Stafen Cássia Fernanda , Souza Iara , de Oliveira Ben Hur , de Oliveira-Busatto Luísa Abruzzi , Dalmolin Rodrigo Juliani Siqueira , Sánchez Oscar Lorenzo , Maraschin Felipe dos Santos
Published: July 2022

Following germination, seedlings grown in light show a photomorphogenic development with open and green cotyledons and a robust root system. The light perception by the photoreceptors activate autotrophic photosynthetic metabolism to sustain growth of the whole plant. Several studies have evaluated transcriptional responses to light signals. Nevertheless, evaluating a single source experiment might bias the identificationof general, reproducible light responses. In order to identify widespread light-dependent signaling events that control early seedling photomorphogenesis we performed a survey comparing commonly regulated genes in transcriptomic public datasets derived from etiolated seedlings exposed to short light treatments. By compiling commonly regulated genes from different datasets, we obtained broadly representative regulated processes concerning general light transcriptional response. Our analysis shows that light primarly affects shoot gene expression promoting the assembly of photosynthetic machinery, signaling and redox responses. We observed that Transcriptograms allowed a better comparison among different experiments than DEseq analysis. We also identified that, transcriptional regulation of early light response is centered in the transcription factor ABA-Insensitive5 (ABI5) along with other bZIP transcription factors suggesting a mechanism by which dark expressed transcription factors guide the activation of early photomorphogenic genes.

Key Message

Comparative analisys of seedling deetiolation transcriptomic datasets identified ABA-responsive bZIP transcription factors as central regulators of early photomorphogenesis
Digitally Predicting Protein Localization and Manipulating Protein Activity in Fluorescence Images Using Four-dimensional Reslicing GAN
Authors: Jiao Yang , Weng Mo , Gu Lingkun , Jiang Yingtao , Yang Mei
Published: July 2022

Motivation

While multi-channel fluorescence microscopy is a vital imaging method in biological studies, the number of channels that can be imaged simultaneously is limited by technical and hardware limitations such as emission spectra cross-talk. One feasible solution is using deep neural networks to model the localization relationship between two proteins so that the localization of a protein can be digitally predicted. Furthermore, the input and predicted localization implicitly reflects the modeled relationship. Accordingly, observing the predictions via repeatedly manipulating input localizations is an explainable and feasible way to analyze the modeled relationships between the input and the predicted proteins.

Results

We propose a Protein Localization Prediction (PLP) method using a cGAN named Four-dimensional Reslicing Generative Adversarial Network (4DR-GAN) to digitally generate additional channels. 4DR-GAN models the joint probability distribution of imaged and target proteins by simultaneously incorporating the protein localization signals in four dimensions including space and time. Because protein localization often correlates with protein activation state, with accurate PLP, we further propose two novel tools: digital activation (DA) and digital inactivation (DI) to digitally activate and inactivate a protein and observe the response of the predicted protein localization. Compared with genetic approaches, these tools allow precise spatial and temporal control. A comprehensive experiment on four groups of proteins shows that 4DR-GAN achieves higher-quality PLP than Pix2Pix and the DA and DI responses are consistent with the known protein functions. The proposed PLP method helps simultaneously visualize additional proteins and DA and DI provide guidance to study localization-based protein functions.

Availability and Implementation

The open-source code is athttps://github.com/YangJiaoUSA/4DR-GAN.