bluuebunny/crossref_metadata_2025 huggingface dataset:
Robust HIV-specific CD4+ and CD8+ T-cell responses distinguish elite control in adolescents living with HIV from viremic nonprogressors
Authors: Vieira Vinicius A. , Millar Jane , Adland Emily , Muenchhoff Maximilian , Roider Julia , Guash Claudia Fortuny , Peluso Denise , Thomé Beatriz , Garcia-Guerrero Maria C. , Puertas Mari C. , Bamford Alasdair , Brander Christian , Carrington Mary , Martinez-Picado Javier , Frater John , Tudor-Williams Gareth , Goulder Philip
Published: September 2021

Background:

Elite controllers are therapy-naive individuals living with HIV capable of spontaneous control of plasma viraemia for at least a year. Although viremic nonprogressors are more common in vertical HIV-infection than in adults’ infection, elite control has been rarely characterized in the pediatric population.

Design:

We analyzed the T-cell immunophenotype and the HIV-specific response by flow cytometry in four pediatric elite controllers (PECs) compared with age-matched nonprogressors (PNPs), progressors and HIV-exposed uninfected (HEUs) adolescents.

Results:

PECs T-cell populations had lower immune activation and exhaustion levels when compared with progressors, reflected by a more sustained and preserved effector function. The HIV-specific T-cell responses among PECs were characterized by high-frequency Gag-specific CD4+ T-cell activity, and markedly more polyfunctional Gag-specific CD8+ activity, compared with PNPs and progressors. These findings were consistently observed even in the absence of protective HLA-I molecules such as HLA-B∗27/57/81.

Conclusion:

Pediatric elite control is normally achieved after years of infection, and low immune activation in PNPs precedes the increasing ability of CD8+ T-cell responses to achieve immune control of viraemia over the course of childhood, whereas in adults, high immune activation in acute infection predicts subsequent CD8+ T-cell mediated immune control of viremia, and in adult elite controllers, low immune activation is therefore the consequence of the rapid CD8+ T-cell mediated immune control generated after acute infection. This distinct strategy adopted by PECs may help identify pathways that facilitate remission in posttreatment controllers, in whom protective HLA-I molecules are not the main factor.
Distinct antibody profiles in HLA-B ∗ 57 + , HLA-B ∗ 57 − HIV controllers and chronic progressors
Authors: Klingler Jéromine , Paul Nicodème , Laumond Géraldine , Schmidt Sylvie , Mayr Luzia M. , Decoville Thomas , Lambotte Olivier , Autran Brigitte , Bahram Seiamak , Moog Christiane
Published: September 2021

Objective:

Spontaneous control of HIV replication without treatment in HIV-1 controllers (HICs) was associated with the development of an efficient T-cell response. In addition, increasing data suggest that the humoral response participates in viral clearance.

Design:

In-depth characterization of Ab response in HICs may help to define new parameters associated with this control.

Methods:

We assessed the levels of total and HIV-specific IgA and IgG subtypes induction and their functional potencies – that is, neutralization, phagocytosis, antibody-dependent cellular cytotoxicity (ADCC), according to the individual's major histocompatibility complex class I (HLA)-B∗57 status, and compared it with nontreated chronic progressors.

Results:

We found that despite an undetectable viral load, HICs displayed HIV-specific IgG levels similar to those of chronic progressors. Interestingly, our compelling multifunctional analysis demonstrates that the functional Ab profile, by itself, allowed to discriminate HLA-B∗57

+
HICs from HLA-B∗57

−
HICs and chronic progressors.

Conclusion:

These results show that HICs display a particular HIV-specific antibody (Ab) profile that may participate in HIV control and emphasize the relevance of multifunctional Ab response analysis in future Ab-driven vaccine studies.
Retroperitoneal Recurrence of Melanotic Schwannoma on 18F-FDG PET/CT
Authors: OuYang Xiangliu , Zheng Lichun , Zhang Xiaoming
Published: September 2021

Melanotic schwannoma is an uncommon nerve sheath neoplasm. Only 10% of melanotic schwannoma are malignant whereas metastases from melanotic schwannoma are much less common. Hereby we present FDG PET/CT findings of recurrent left retroperitoneal melanotic schwannoma with widespread metastases in a 50-year-old man.
Successful Delayed Neurolysis of the Median Nerve in a Teenager 7 years After Supracondylar Fracture
Authors: Choong Jia , Baldrighi Carla , Oestreitch Kerstin , Jester Andrea
Published: September 2021

Supracondylar humeral fractures are the commonest elbow fractures in childhood, associated with a high rate of neurological complications. We present the case of a 14-year-old adolescent girl with persisting daily pain, lack of sensation, and strength to her left hand after a displaced supracondylar fracture 7 years earlier. At the time of the fracture, she underwent closed reduction and percutaneous Kirschner wire fixation. During revision surgery, half of the median nerve was found embedded in bone at the level consistent with the healed fracture site. Neurolysis of the fascicles adherent to the bone was performed. Postoperatively, the patient had complete recovery of sensation, reduced pain, and a 2.5-fold improvement of grip strength. This case shows that there is a role for delayed neurolysis in children.
Sequential Treatment of Extreme Maxillary Hypoplasia: A Historical Patient Report of an Edentulous Adult Patient With Ankyloglossia
Authors: Saint-Denis Louis , Simon Etienne , Brix Muriel
Published: September 2021

Introduction:

The management of multiple dimensions in orthognathic surgery often requires careful planning. Too large discrepancies could require a sequential procedure to make alignment of the archs possible.

Report of case:

The authors report a case of a 30-year-old partially edentulous man with severe maxillary hypoplasia caused by an untreated ankyloglossia. The transverse deficiency was estimated at more than 15 mm and the sagittal discrepancy shows a negative overjet of 11.5 mm. These wide deficits needed a 2-step surgery and the use of computed-aided design/computed-aided manufacturing. The first step was a palatal expansion by a fan-shaped Le Fort I osteotomy. The second step treated sagittal discrepancy and re-expanded the maxilla.

At the end, the sagittal dimension got normal and the maxilla have been widened to almost 7 mm.

Conclusion:

Custom-made surgery is very useful for uncommon cases, in particular for toothless patients. It facilitates complex operations and allows precise results.
Bilateral Petrous Apex Cephalocele Associated with a Wide Sella
Authors: Doğan Emrah , Özgür Erdoğan
Published: September 2021

Petrous apex cephalocele (PAC) is a rare type of cephalocele. It is usually asymptomatic. It can be unilateral or bilateral. Bilateral cases are less common. They are etiologically and clinically different entities from unilateral ones. A 56-year-old female patient presented to the hospital with the complaint of a severe nonspecific headache. She has been examined in ear nose throat, ophthalmology, and finally neurology clinics. Bilateral PAC was incidentally found in magnetic resonance imaging (MRi) examination. Headache was associated with PAC because no additional pathology could explain the clinical symptomatology. There is a proven relationship between empty sella and PAC. Regarding PAC less than 50 cases are known. Our paper aims to contribute to the literature by exhibiting etiologic and clinic differences between unilateral and bilateral PAC. It highlights the relationship between PAC and broad sella that is a different entity from empty sella and shows this remarkable radiological appearance. The authors presented our case accompanied by clinical and MRi findings.
Application of Various Methods to Evaluate the Postoperative Characteristics of Expanded Pedicled Deltopectoral Flap for Large Facial Scars
Authors: Wang Zhantong , Ding Jianke , Tang Yinke , Su Yingjun , Cheng Xiaoxi , Yu Zhou , Ma Xianjie
Published: September 2021

The expanded pedicled deltopectoral flap (EPDF) has been widely used to repair large facial scars. Although doctors and patients are usually satisfied with the outcomes, the actual functional recovery and cosmetic effects of EPDF are still unknown. It is, therefore, necessary to objectively investigate the effect of transferred EPDF by using a variety of methods. From January 2008 to December 2018, 52 patients who underwent EPDF surgery at Xijing Hospital were enrolled. Sense of touch, static 2-point discrimination, elasticity, and color were measured. Thermesthesia and algesthesia were also tested. Postoperative scars were evaluated using the patient and observer scar assessment scale. Satisfaction of patients, doctors, and laypersons was investigated. The algaesthesis, thalposis, and rhigosis scores were 4.7 ± 0.7, 3.7 ± 0.9, and 4.5 ± 0.8, respectively. The tactile score was 0.3 ± 0.2 mN, and 2-point discrimination was 10.1 ± 4.8 mm. L∗, a∗ hemoglobin, and melanin content of the flaps were significantly different when compared with normal skin (P 
< 0.05). The satisfaction of doctors, patients, and laypersons was 88.5%, 71.2%, and 67.3%, respectively. The higher satisfaction of patients was mainly associated with the smaller color difference between the flap and the surrounding skin, and lower patient and observer scar assessment scale score. These results confirm that excellent functional recovery and reliable cosmetic effects are observed when facial scars are repaired with EPDF. The methods used in this study can be applied to the evaluation of functional recovery and cosmetic outcomes of transferred flaps, which may provide a more comprehensive understanding of flap assessment.
Association of Relative Handgrip Strength With Anthropometric Measures and Lipid Profiles in Individuals With Cardiovascular Disease
Authors: Pasdar Yahya , Khamoushi Firoozeh , Rezaeian Shahab , Darbandi Mitra , Najafi Farid , Hamzeh Behrooz
Published: September 2021

The present study was conducted to assess the relationship between relative handgrip strength (RHGS) and cardiovascular risk factors in individuals with cardiovascular disease (CVD) and healthy subjects. This study was based on a cross-sectional analysis of 883 participants aged 35 to 65 years among those with CVD and healthy subjects from Ravansar Non-Communicable Disease (RaNCD) cohort study. There was a significant inverse association between body fat percentage, body fat mass, waist circumference, hip circumference, and waist-to-hip ratio with RHGS in both groups (P < .001). There was no significant association between RHGS and total cholesterol, triglycerides, low-density lipoprotein, and high-density lipoprotein of the 2 groups (P > .05). Increased RHGS may be associated with improved body composition in individuals with CVD and individuals with no CVD, which requires further longitudinal studies.
Pseudonocardia abyssalis sp. nov. and Pseudonocardia oceani sp. nov., two novel actinomycetes isolated from the deep Southern Ocean
Authors: Parra Jonathan , Soldatou Sylvia , Rooney Liam M. , Duncan Katherine R.
Published: September 2021

The actinomycetes strains KRD168T and KRD185T were isolated from sediments collected from the deep Southern Ocean and, in this work, they are described as representing two novel species of the genus

Pseudonocardia

through a polyphasic approach. Despite sharing >99 % 16S rRNA gene sequence similarity with other members of the genus, comparative genomic analysis allowed species delimitation based on average nucleotide identity and digital DNA–DNA hybridization. The KRD168T genome is characterized by a size of 6.31 Mbp and a G+C content of 73.44 mol%, while the KRD185T genome has a size of 6.82 Mbp and a G+C content of 73.98 mol%. Both strains contain meso-diaminopimelic acid as the diagnostic diamino acid, glucose as the major whole-cell sugar, MK-8(H4) as a major menaquinone and iso-branched hexadecanoic acid as a major fatty acid. Biochemical and fatty acid analyses also revealed differences between these strains and their phylogenetic neighbours, supporting their status as distinct species. The names Pseudonocardia abyssalis sp. nov. (type strain KRD168T=DSM 111918T=NCIMB 15270T) and Pseudonocardia oceani (type strain KRD185T=DSM 111919T=NCIMB 15269T) are proposed.
Detection of Somatic Copy Number Deletion of the CDKN2A Gene by Quantitative Multiplex PCR for Clinical Practice
Authors: Tian Yuan , Zhou Jing , Qiao Juanli , Liu Zhaojun , Gu Liankun , Zhang Baozhen , Lu Youyong , Xing Rui , Deng Dajun
Published: September 2021

Background

While the amplification of oncogenes (such as EGFR, c-ERBB2, c-MYC, and c-MET) are increasingly driving decision-making for precise cancer treatments, a feasible method to detect somatic copy number deletion (SCND) of tumor suppressor genes is still absent to date.

Methods

The genomic coordinates of gene deletion fragments were analyzed using the Catalogue Of Somatic Mutation In Cancer (COSMIC) datasets. Interstitial base-resolution deletion/fusion coordinates for CDKN2A were extracted from published articles and our whole genome sequencing (WGS) datasets. The copy number of the CDKN2A gene was measured with a multiplex quantitative PCR assay P16-Light and confirmed with whole genome sequencing (WGS).

Results

Estimated common deletion regions (CDRs) were observed in many tumor suppressor genes, such as ATM, CDKN2A, FAT1, miR31HG, PTEN, and RB1, in the SNP array-based COSMIC datasets. A 5.1-kb base-resolution CDR could be identified in >90% of cancer samples with CDKN2A deletion by sequencing. The CDKN2A CDR covers exon-2, which is essential for P16INK4A and P14ARF synthesis. Using the true CDKN2A CDR as a PCR target, a multiplex quantitative PCR assay P16-Light was programmed to detect CDKN2A gene copy number with a lower detection limit of 20%. P16-Light was further confirmed with WGS as the gold standard among cancer tissue samples from 139 patients.

Conclusion

CDRs are common in many tumor suppressor genes. The 5.1-kb CDKN2A CDR was found in >90% of cancers containing CDKN2A deletion. The CDKN2A CDR was used as a potential target for developing the P16-Light assay to detect CDKN2A SCND and amplification for routine clinical practices.
The Kinetics of COVID-19 Vaccine Response in a Community Vaccinated Population
Authors: Tu Michael , Chiang Samantha , Bender Richard , Wong David T.W. , Strom Charles
Published: September 2021

We used a noninvasive electrochemical quantitative assay for IgG antibodies to SARS-CoV-2 S1 in saliva to investigate the kinetics of antibody response in a community-based population who had received either the Pfizer or Moderna mRNA-based vaccines. Samples were received from a total of 97 individuals including a subset of 42 individuals who collected samples twice-weekly for 3 months or longer. In all, 840 samples were collected and analyzed. In all individuals, salivary antibody levels rose sharply in the 2-week period following their second vaccination, with peak antibody levels being at 10-20 days post-vaccination. We observed that 20%, 10% and 2.4% of individuals providing serial samples had a 90%, 95%, and 99% drop respectively from peak levels during the duration of monitoring and two patients fell to pre-vaccination levels (5%). The use of non-invasive quantitative salivary antibody measurement can allow widespread, cost-effective monitoring of vaccine response.

Article Summary Line

COVID-19 antibodies were measured in saliva and 20% of vaccinated subjects experienced a 90% drop in peak antibody levels over the course of monitoring.
Unrecognized introductions of SARS-CoV-2 into the state of Georgia shaped the early epidemic
Authors: Babiker Ahmed , Martin Michael A. , Marvil Charles E. , Bellman Stephanie , Petit Robert A. , Bradley Heath L. , Stittleburg Victoria D. , Ingersoll Jessica M. , Kraft Colleen S. , Read Timothy D. , Waggoner Jesse J. , Koelle Katia , Piantadosi Anne
Published: September 2021

In early 2020, as SARS-CoV-2 diagnostic and surveillance responses ramped up, attention focused primarily on returning international travelers. Here, we build on existing studies characterizing early patterns of SARS-CoV-2 spread within the U.S. by analyzing detailed clinical, molecular, and viral genomic data from the state of Georgia through March 2020. We find evidence for multiple early introductions into Georgia, despite relatively sparse sampling. Most sampled sequences likely stemmed from a single introduction from Asia at least two weeks prior to the state’s first detected infection. Our analysis of sequences from domestic travelers demonstrates widespread circulation of closely-related viruses in multiple U.S. states by the end of March 2020. Our findings indicate that the early attention directed towards identifying SARS-CoV-2 in returning international travelers may have led to a failure to recognize locally circulating infections for several weeks, and points towards a critical need for rapid and broadly-targeted surveillance efforts in the future.
Basal cell carcinoma treated with HeberFERON. A real world retrospective study
Authors: Martínez-Suárez C , Roben-Aguilar Y , Reyes-Acosta O , Garcia-Vega Y , Vega-Abascal J , Sánchez-Linares V , Sotolongo-Díaz D , Piña-Rodriguez Y , Fernández-Martori M , Betancourt-Pérez A , Jimenez-Lamas M , Ballester-Caballero Y , Pérez-Morgado R , Curbelo-Alonso M , Molina-Abad A , Martínez-Borrego R , Maturell-Peraza J , Pulido-Garcia L , López-Pupo N , Ramírez-Hidalgo Y , Ramos-Trujillo M , Fernández-Ramirez I , Hernández-Colina M , Perez-Lopez A , Leon-Garcia Y , Chaya-Salgado S , La O-Ayala Y , Hernández-Rodriguez R , Duncan-Roberts Y , Bello-Rivero I
Published: September 2021

Background

Basal cell carcinoma is the most common type of skin cancer with major impact in health-related quality of life. The use of the formulation based on the combination of IFN-alpha 2b and IFN-gamma (HeberFERON) is an effective alternative in the treatment of basal cell carcinoma, immunogenic tumor, potentially responsible to immunotherapies. The aim of this report is to record, retrospectively, the effect of HeberFERON patients with BCC in the Cuban real word condition.

Methods

This is a retrospectively study of the use of HeberFERON in real world conditions. Eligible patients were adults with histologic diagnosis of single or multiple basal cell carcinoma of any skin phototype, lesions of any size, subtype, location, recurrent or not, with or without specific prior treatments. Adult patients, who signed the informed consent to receive the treatment with HeberFERON, were identified from the data bases. The evaluation of clinical effectiveness was carried out according to RECIST 1.1. Ethical committee of participating institutions approved the study.

Results

In clinical practice evaluated patients the nose was the region of higher frequency of tumors (36.3%) and the nodular clinical subtype was the predominant (45.3%). Clinical response rate differences (p=0. 000) were found, with complete response of 61.9%, and partial response of 32.7%; with an overall response rate of 94.2% The HeberFERON exerted a 100% disease control, with no progression reported in 640 treated patients. The best responder tumor subtypes to HeberFERON were the more aggressive tumors, morpheaform with complete response of 72% (overall response=96%), followed by the infiltrative with complete response of 66.7% (overall response=100%). Tumor with larger size and patients with more than four tumors had lesser response to the anti-tumor effect of HeberFERON.

Conclusions

HeberFERON was highly effective in basal cell carcinomas in real world conditions. In the context of resistance of skin tumors to hedgehog and immune check point inhibitors the combination of IFNs alpha 2b and IFN gamma appears as a plausible therapeutic option for a wide number of basal cell carcinomas.
PathProfiler: Automated Quality Assessment of Retrospective Histopathology Whole-Slide Image Cohorts by Artificial Intelligence – A Case Study for Prostate Cancer Research
Authors: Haghighat Maryam , Browning Lisa , Sirinukunwattana Korsuk , Malacrino Stefano , Alham Nasullah Khalid , Colling Richard , Cui Ying , Rakha Emad , Hamdy Freddie C. , Verrill Clare , Rittscher Jens
Published: September 2021

Research using whole slide images (WSIs) of scanned histopathology slides for the development of artificial intelligence (AI) algorithms has increased exponentially over recent years. Glass slides from large retrospective cohorts with patient follow-up data are digitised for the development and validation of AI tools. Such resources, therefore, become very important, with the need to ensure that their quality is of the standard necessary for downstream AI development. However, manual quality control of such large cohorts of WSIs by visual assessment is unfeasible, and whilst quality control AI algorithms exist, these focus on bespoke aspects of image quality, e.g. focus, or use traditional machine-learning methods such as hand-crafted features, which are unable to classify the range of potential image artefacts that should be considered.

In this study, we have trained and validated a multi-task deep neural network to automate the process of quality control of a large retrospective cohort of prostate cases from which glass slides have been scanned several years after production, to determine both the usability of the images for research and the common image artefacts present.

Using a two-layer approach, quality overlays of WSIs were generated from a quality assessment undertaken at patch-level at 5X magnification. From these quality overlays the slide-level quality scores were predicted and then compared to those generated by three specialist urological pathologists, with a Pearson correlation of 0.89 for overall ‘usability’ (at a diagnostic level), and 0.87 and 0.82 for focus and H&E staining quality scores respectively. We subsequently applied our quality assessment pipeline to the TCGA prostate cancer cohort and to a colorectal cancer cohort, for comparison.

Our model, designated as PathProfiler, indicates comparable predicted usability of images from the cohorts assessed (86-90%), and perhaps more significantly is able to predicts WSIs that could benefit from re-scanning or re-staining for quality improvement.

We have shown in this study that AI can be used to automate the process of quality control of large retrospective cohorts to maximise research outputs and conclusions.
Stress signaling and STAT1 activation characterize the keratinocytic gene expression pattern in Hidradenitis suppurativa
Authors: Frings VG , Jopp L , Srivastava M , Presser D , Goebeler M , Schmidt M
Published: September 2021

Background

The underlying pathogenetic factors generating the innate immune signal necessary for T cell activation, initiation and chronification of Hidradenitis suppurativa (HS, also known as Acne inversa) are still poorly understood. Emerging evidence suggests that defective keratinocyte function critically contributes to HS disease development and progression.

Objectives

To elucidate the role of keratinocytes in HS lesion formation, we compared the transcriptomes of isolated lesional and perilesional HS epidermis by RNA sequencing.

Methods

Lesional and perilesional HS skin samples of at least 3 different donors were obtained. Isolated epidermal keratinocytes were further processed for cell culture, protein extraction, immunostaining procedures or RNA isolation and RNA sequencing. For large scale promotor site analysis, DEGs were analyzed for overrepresented transcription factor binding sites. Functional annotation clustering for analyzing enriched functional-related gene groups was performed employing the DAVID Bioinformatics Resources.

Results

We show that HS is characterized by a strong epidermal stress state as evident by a significant overrepresentation of an AP-1-driven stress signature in the overall gene expression pattern of lesional keratinocytes and a substantial activation of the stress-activated cJun N-terminal kinase (JNK) pathway in lesional HS epidermis. Additionally, our data reveal a strong induction of STAT1 activation in lesional HS epidermis that likely results from IFNγ production and governs the expression of key inflammatory genes that coordinate activation of innate immunity and the adaptive T cell response in HS.

Conclusions

Taken together, these data implicate a new role of combined stress signaling and JAK/STAT1 pathway activation in disease progression of HS suggesting interference with JAK/STAT1 signaling as a potentially promising therapeutic approach for HS.
Multi-omics approach identifies novel age-, time- and treatment-related immunopathological signatures in MIS-C and pediatric COVID-19
Authors: Sacco Keith , Castagnoli Riccardo , Vakkilainen Svetlana , Liu Can , Delmonte Ottavia M. , Oguz Cihan , Kaplan Ian M. , Alehashemi Sara , Burbelo Peter D. , Bhuyan Farzana , de Jesus Adriana A. , Dobbs Kerry , Rosen Lindsey B. , Cheng Aristine , Shaw Elana , Vakkilainen Mikko S. , Pala Francesca , Lack Justin , Zhang Yu , Fink Danielle L. , Oikonomou Vasileios , Snow Andrew L. , Dalgard Clifton L. , Chen Jinguo , Sellers Brian A. , Montealegre Sanchez Gina A. , Barron Karyl , Rey Emma , Vial Cecilia , Poli Maria Cecilia , Licari Amelia , Montagna Daniela , Marseglia Gian Luigi , Licciardi Francesco , Ramenghi Ugo , Discepolo Valentina , Vecchio Andrea Lo , Guarino Alfredo , Eisenstein Eli M. , Imberti Luisa , Sottini Alessandra , Biondi Andrea , Mató Sayonara , Gerstbacher Dana , Truong Meng , Stack Michael A. , Magliocco Mary , Bosticardo Marita , Kawai Tomoki , Danielson Jeffrey J. , Hulett Tyler , Askenazi Manor ,   NIAID Immune Response to COVID Group,   Chile MIS-C Group,   Pavia Pediatric COVID-19 Group, Cohen Jeffrey I. , Su Helen C. , Kuhns Douglas B. , Lionakis Michail S. , Snyder Thomas M. , Holland Steven M. , Goldbach-Mansky Raphaela , Tsang John S. , Notarangelo Luigi D. ,   Members of the NIAID Immune Response to COVID Group, Barnett Jason , Cheng Xi , Kaladi Krishnaveni , Kuram Vasu , Mackey Joseph , Bansal Neha M. , Martins Andrew J. , Palterer Boaz , Matthews Helen , Mudunuri Uma , Nambiar Marshall , Oler Andrew , Rastegar Andre , Samuel Smilee , Shyu Conrad , Waingankar Varsha , Weber Sarah , Xirasagar Sandhya ,   Members of the Chile MIS-C Group, Espinosa Yazmin , Astudillo Camila ,   Members of the Pavia Pediatric COVID-19 Group, De Filippo Maria , Votto Martina , Montagna Lorenza
Published: September 2021

Pediatric COVID-19 (pCOVID-19) is rarely severe, however a minority of SARS-CoV-2-infected children may develop MIS-C, a multisystem inflammatory syndrome with significant morbidity. In this longitudinal multi-institutional study, we used multi-omics to identify novel time- and treatment-related immunopathological signatures in children with COVID-19 (n=105) and MIS-C (n=76). pCOVID-19 was characterized by enhanced type I IFN responses, and MIS-C by type II IFN- and NF-κB dependent responses, matrisome activation, and increased levels of Spike protein. Reduced levels of IL-33 in pCOVID-19, and of CCL22 in MIS-C suggested suppression of Th2 responses. Expansion of TRBV11-2 T-cell clonotypes in MIS-C was associated with inflammation and signatures of T-cell activation, and was reversed by glucocorticoids. The association of MIS-C with the combination of HLA A*02, B*35, C*04 alleles suggests genetic susceptibility. MIS-C B cells showed higher mutation load. Use of IVIG was identified as a confounding factor in the interpretation of autoantibody levels.
Effectiveness of rectal artesunate as pre-referral treatment for severe malaria in children <5 years of age
Authors: Hetzel Manuel W. , Okitawutshu Jean , Tshefu Antoinette , Omoluabi Elizabeth , Awor Phyllis , Signorell Aita , Brunner Nina C. , Kalenga Jean-Claude , Akano Babatunde , Ayodeji Kazeem , Okon Charles , Yusuf Ocheche , Athieno Proscovia , Kimera Joseph , Tumukunde Gloria , Angiro Irene , Delvento Giulia , Lee Tristan , Lambiris Mark , Kwiatkowski Marek , Cereghetti Nadja , Visser Theodoor , Napier Harriet G. , Cohen Justin M. , Buj Valentina , Burri Christian , Lengeler Christian
Published: September 2021

Background

To prevent child deaths from severe malaria, early parenteral treatment is essential. Yet, in remote rural areas, higher-level facilities offering parenteral antimalarials are often difficult to access. A randomised controlled trial found pre-referral rectal artesunate (RAS) to reduce death and disability in children who delay arriving at a referral facility. This study examined the effectiveness of pre-referral RAS treatment in established community-based health care systems.

Methods

An observational study accompanied the roll-out of RAS in the Democratic Republic of the Congo, Nigeria and Uganda. Children < 5 years presenting to a community-based health provider with a positive malaria test and signs of severe malaria were followed-up during admission and after 28 days to assess their health status and treatment history. The primary outcome was death; covariates of interest included RAS use, referral completion, and post-referral treatment.

Findings

Post-roll-out, RAS was administered to 88% of patients in DRC, 52% in Nigeria, and 70% in Uganda. The overall case fatality rate (CFR) was 6.7% (135/2011) in DRC, 11.7% (69/589) in Nigeria, and 0.5% (19/3686) in Uganda; 865/6286 patients were sick at follow-up. In all countries, the CFR was higher after RAS-roll-out (6.7 vs. 6.6% in DRC, 16.1 vs. 4.2% in Nigeria, 0.7 vs. 0.3% in Uganda). In DRC and Nigeria, children receiving RAS were more likely to die than those not receiving RAS (aOR = 3.31, 95% CI 1.43-7.65 and aOR = 2.42, 95% CI 1.25-4.70, respectively). In Uganda, RAS users were less likely to be dead or sick at follow-up (aOR = 0.61, 95% CI 0.46-0.80). Post-referral parenteral antimalarials were protective in all countries; however, the effect of ACT administration was inconsistent.

Interpretation

RAS pre-referral treatment had no beneficial effect on child survival in three highly malaria endemic settings. RAS is unlikely to reduce malaria deaths unless health system shortfalls such as referral and post-referral treatment are addressed.
Prediction of Life-threatening and Disabling Bleeding in Patients with Acute Myeloid Leukemia Receiving Intensive Induction Chemotherapy
Authors: Versluis Jurjen , Pandey Manu , Flamand Yael , Haydu J. Erika , Belizaire Roger , Vedula Rahul S. , Charles Anne , Copson Kevin M. , Shimony Shai , Rozental Alon , Bendapudi Pavan K. , Wolach Ofir , Griffiths Elizabeth A. , Thompson James E. , Stone Richard M. , DeAngelo Daniel J. , Neuberg Donna , Luskin Marlise R. , Wang Eunice S. , Lindsley R. Coleman
Published: September 2021

Bleeding in patients with acute myeloid leukemia (AML) receiving intensive induction chemotherapy is multifactorial and contributes to early death. We sought to define incidence and risk factors of grade 4 bleeding to support strategies for risk mitigation. Bleeding events were assessed according to the WHO bleeding assessment scale, which includes grade 4 bleeding as fatal, life-threatening, retinal with visual impairment, or involving the central nervous system. Using multivariable competing-risk regression analysis with grade 4 bleeding as the primary outcome, we identified risk factors in the development cohort (n=341), which were tested in an independent cohort (n=143). Grade 4 bleeding occurred in 5.9% and 9.8% of patients in the development and validation cohort, respectively. Risk factors that were independently associated with grade 4 bleeding included baseline platelet count ≤40 ×109/L compared with >40 ×109/L, and baseline PT-INR >1.5 or >1.3-1.5 compared with ≤1.3. These variables were allocated points, which allowed for stratification of patients with low- and high-risk for grade 4 bleeding. Cumulative incidence of grade 4 bleeding at day+60 was significantly higher among patients with high- versus low-risk (development: 31±7% vs. 2±1%, P<0.001, validation: 25±9% vs. 7±2%, P=0.008). In both cohorts, high bleeding risk was associated with disseminated intravascular coagulation (DIC) and proliferative disease. We developed and validated a simple risk model for grade 4 bleeding, which enables development of rational risk mitigation strategies to improve early mortality of intensive induction treatment.

KEY POINTS

Risk factors predicting grade 4 bleeding were consistent with DIC-like coagulopathy, including prolonged PT-INR and thrombocytopenia.

The grade 4 bleeding score was externally validated and allows for preventive strategies to improve early mortality in high-risk patients.
Non-invasive Vagus Nerve Stimulation for Respiratory Symptoms of COVID-19: Results From a Randomized Controlled Trial (SAVIOR I)
Authors: Tornero Carlos , Pastor Ernesto , del Mar Garzando María , Orduña Jorge , Forner MJ , Bocigas Irene , Cedeño David L. , Vallejo Ricardo , Staats Peter , Liebler Eric J.
Published: September 2021

Background

Severe coronavirus disease 2019 (COVID-19) is characterized, in part, by an excessive inflammatory response. Evidence from animal and human studies suggests that vagus nerve stimulation can lead to reduced levels of various pro-inflammatory cytokines. We conducted a prospective randomized controlled study (SAVIOR-I) to assess the feasibility, efficacy, and safety of non-invasive vagus nerve stimulation (nVNS) for the treatment of respiratory symptoms and inflammatory markers among patients who were hospitalized for COVID-19 (ClinicalTrials.gov identifier: NCT04368156).

Methods

Participants were randomly assigned in a 1:1 allocation to receive either the standard of care (SoC) alone or nVNS therapy plus the SoC. The nVNS group received 2 consecutive 2-minute doses of nVNS 3 times daily as prophylaxis. Efficacy and safety were evaluated via the incidence of specific clinical events, inflammatory biomarker levels, and the occurrence of adverse events.

Results

Of the 110 participants who were enrolled and randomly assigned, 97 (nVNS, n=47; SoC, n=50) had sufficient available data and comprised the evaluable population. C-reactive protein (CRP) levels decreased from baseline to a significantly greater degree in the nVNS group than in the SoC group at day 5 and overall (ie, all postbaseline data points collected through day 5, combined). Procalcitonin level also showed significantly greater decreases from baseline to day 5 in the nVNS group than in the SoC group. D-dimer levels were decreased from baseline for the nVNS group and increased from baseline for the SoC group at day 5 and overall, although the difference between the treatment groups did not reach statistical significance. No significant treatment differences were seen for clinical respiratory outcomes or any of the other biochemical markers evaluated. No serious nVNS-related adverse events occurred during the study.

Conclusions

nVNS therapy led to significant reductions in levels of inflammatory markers, specifically CRP and procalcitonin. Because nVNS has multiple mechanisms of action that may be relevant to COVID-19, additional research into its potential to be used earlier in the course of COVID-19 and possibly mitigate some of the symptoms associated with post-acute COVID-19 syndrome is warranted.
Screening key genes and signaling pathways in COVID-19 infection and its associated complications by integrated bioinformatics analysis
Authors: Vastrad Basavaraj , Vastrad Chanabasayya
Published: September 2021

Severe acute respiratory syndrome corona virus 2 (SARS-CoV-2)/ coronavirus disease 2019 (COVID-19) infection is the leading cause of respiratory tract infection associated mortality worldwide. The aim of the current investigation was to identify the differentially expressed genes (DEGs) and enriched pathways in COVID-19 infection and its associated complications by bioinformatics analysis, and to provide potential targets for diagnosis and treatment. Valid next-generation sequencing (NGS) data of 93 COVID 19 samples and 100 non COVID 19 samples (GSE156063) were obtained from the Gene Expression Omnibus database. Gene ontology (GO) and REACTOME pathway enrichment analysis was conducted to identify the biological role of DEGs. In addition, a protein-protein interaction network, modules, miRNA-hub gene regulatory network, TF-hub gene regulatory network and receiver operating characteristic curve (ROC) analysis were used to identify the key genes. A total of 738 DEGs were identified, including 415 up regulated genes and 323 down regulated genes. Most of the DEGs were significantly enriched in immune system process, cell communication, immune system and signaling by NTRK1 (TRKA). Through PPI, modules, miRNA-hub gene regulatory network, TF-hub gene regulatory network analysis, ESR1, UBD, FYN, STAT1, ISG15, EGR1, ARRB2, UBE2D1, PRKDC and FOS were selected as hub genes, which were expressed in COVID-19 samples relative to those in non COVID-19 samples, respectively. Among them, ESR1, UBD, FYN, STAT1, ISG15, EGR1, ARRB2, UBE2D1, PRKDC and FOS were suggested to be diagonstic factors for COVID-19. The findings from this bioinformatics analysis study identified molecular mechanisms and the key hub genes that might contribute to COVID-19 infection and its associated complications.
Effects of arm swing amplitude and lower limb asymmetry on motor variability patterns during treadmill gait
Authors: Bailey Christopher A. , Hill Allen , Graham Ryan , Nantel Julie
Published: September 2021

Motor variability is a fundamental feature of gait. Altered arm swing and lower limb asymmetry (LLA) may be contributing factors having been shown to affect the magnitude and dynamics of variability in spatiotemporal and trunk motion. However, the effects on lower limb joints remain unclear.

Full-body kinematics of 15 healthy young adults were recorded during treadmill walking using the Computer-Assisted Rehabilitation Environment system. Participants completed six trials, combining three arm swing (AS) amplitude (normal, active, held) and two LLA (symmetrical, asymmetrical) conditions. The mean standard deviation (meanSD), maximum Lyapunov exponent (λmax), detrended fluctuation analysis scaling exponent of range of motion (DFAα), and sample entropy (SaEn) were computed for tridimensional trunk, pelvis, and lower limb joint angles, and compared using repeated-measures ANOVAs.

Relative to normal AS, active AS increased meanSD of all joint angles, λmax of frontal plane hip and ankle angles, and SaEn of sagittal plane ankle angles. Active AS, however, did not affect λmax or SaEn of trunk or pelvis angles. LLA increased meanSD of sagittal plane joint angles, λmax of Euclidean norm trunk angle and of lower limb joint angles, and SaEn of ankle dorsiflexion/ plantarflexion, but decreased SaEn of tridimensional trunk angles and hip rotation in the slower moving leg.

Alterations in lower limb variability with active AS and LLA suggest that young adults actively exploit their lower limb redundancies to maintain gait. This appears to preserve trunk stability and regularity during active AS but not during LLA.
Neutron crystallography reveals novel mechanisms used by Pseudomonas aeruginosa for host-cell binding
Authors: Gajdos Lukas , Blakeley Matthew P. , Haertlein Michael , Forsyth V. Trevor , Devos Juliette M. , Imberty Anne
Published: September 2021

The opportunistic pathogen Pseudomonas aeruginosa, a major cause of nosocomial infections, uses carbohydrate-binding proteins (lectins) as part of its binding to host cells. The fucose-binding lectin, LecB, displays a unique carbohydrate-binding site that incorporates two closely located calcium ions bridging between the ligand and protein, providing specificity and unusually high affinity. Here, we investigate the mechanisms involved in binding based on neutron crystallography studies of a fully deuterated LecB/fucose/calcium complex. The neutron structure, which includes the positions of all the hydrogen atoms, reveals that the high affinity of binding may be related to the occurrence of a low barrier hydrogen bond induced by the proximity of the two calcium ions, the presence of coordination rings between the sugar, calcium and LecB, and the dynamic behaviour of bridging water molecules at room temperature. These key structural details may assist in the design of anti-adhesive compounds to combat multi-resistance bacterial infections.
Deep-learning based retinal fluid segmentation in optical coherence tomography images using a cascade of ENets
Authors: Loizillon Sophie , Meurée Cédric , Breuil Camille , Faucon Timothée , Lambert Arnaud
Published: September 2021

Optical coherence tomography (OCT) is a non-invasive, painless and reproducible examination which allows ophthalmologists to visualize retinal layers. This imaging modality is useful to detect diseases such as diabetic macular edema (DME) or age related macular degeneration (AMD), which are associated with fluid accumulations. In this paper, a cascade of deep convolutional neural networks is proposed using ENets for the segmentation of fluid accumulations in OCT B-Scans. After denoising the B-Scans, a first ENet extracts the region of interest (ROI) between the inner limiting membrane (ILM) and the Bruch’s membrane (BM), whereas the second ENet segments the fluid in the ROI. A random forest classifier was applied on the segmented fluid regions to reject false positive. Our framework was trained on three different datasets with several diseases such as diabetic retinopathy (DR) and AMD. Our method achieves an average Dice Score for fluid segmentation of 0.80, 0.83 and 0.83 on the UMN DME, UMN AMD and Kermany datasets respectively.
Regulation of membrane homeostasis by TMC1 mechanoelectrical transduction channels is essential for hearing
Authors: Ballesteros Angela , Swartz Kenton J.
Published: September 2021

The mechanoelectrical transduction (MET) channel complex of auditory hair cells converts sound into electrical signals, allowing us to hear. After decades of research, the transmembrane-like channel 1 and 2 (TMC1 and TMC2) have been recently identified as pore-forming subunits of the MET channels, but the molecular peculiarity that differentiates these two proteins and makes TMC1 essential for hearing remains elusive. Here, we show that TMC1, but not TMC2, is essential for membrane remodeling triggered by a decrease in intracellular calcium concentration. We demonstrate that inhibition of MET channels or buffering of intracellular calcium lead to pronounced phosphatidylserine externalization, membrane blebbing and ectosome release at the hair cell sensory organelle, culminating in the loss of TMC1 protein. Moreover, three TMC1 deafness-causing mutations cause constitutive phosphatidylserine externalization that correlates with the deafness phenotype, suggesting that the mechanisms of hearing loss involve alterations in membrane homeostasis.
Protein Vaccine Induces a Durable, More Broadly Neutralizing Antibody Response in Macaques than Natural Infection with SARS-CoV-2 P.1
Authors: To Albert , Wong Teri Ann S. , Lieberman Michael M. , Thompson Karen , Pessaint Laurent , Greenhouse Jack , Daham Nisrine , Cook Anthony , Narvaez Brandon , Flinchbaugh Zack , Ry Alex Van , Yalley-Ogunro Jake , Elyard Hanne Andersen , Lai Chih-Yun , Donini Oreola , Lehrer Axel T.
Published: September 2021

FDA-approved and Emergency Use Authorized (EUA) vaccines using new mRNA and viral-vector technology are highly effective in preventing moderate to severe disease, however, information on their long-term efficacy and protective breadth against SARS-CoV-2 Variants of Concern (VOCs) is currently scarce. Here we describe the durability and broad-spectrum VOC immunity of a prefusion-stabilized spike (S) protein adjuvanted with liquid or lyophilized CoVaccine HT™ in cynomolgus macaques. This recombinant subunit vaccine is highly immunogenic and induces robust spike-specific and broadly neutralizing antibody responses effective against circulating VOCs (B.1.351 [Beta], P.1 [Gamma], B.1.617 [Delta]) for at least 3 months after the final boost. Protective efficacy and post-exposure immunity were evaluated using a heterologous P.1 challenge nearly 3 months after the last immunization. Our results indicate that while immunization with both high and low S doses shorten and reduce viral loads in the upper and lower respiratory tract, a higher antigen dose is required to provide durable protection against disease as vaccine immunity wanes. Histologically, P.1 infection causes similar COVID-19-like lung pathology as seen with early pandemic isolates. Post-challenge IgG concentrations were restored to peak immunity levels and vaccine-matched and cross-variant neutralizing antibodies were significantly elevated in immunized macaques indicating an efficient anamnestic response. Only low levels of P.1-specific neutralizing antibodies with limited breadth were observed in control (non-vaccinated but challenged) macaques suggesting that natural infection may not prevent reinfection by other VOCs. Overall, these results demonstrate that a properly dosed and adjuvanted recombinant subunit vaccine can provide long-lasting and protective immunity against circulating VOCs.

One Sentence Summary

A recombinant subunit protein formulated with CoVaccine HT™ adjuvant induces superior immunity than natural infection and reduces viral load while protecting cynomolgus macaques from COVID-19-like disease caused by late SARS-CoV-2 P.1 (Gamma) challenge.
SARS-CoV-2 Transmission Potential and Policy Changes in South Carolina, February 2020 – January 2021
Authors: Davies Margaret R. , Hua Xinyi , Jacobs Terrence D. , Wiggill Gabi I. , Lai Po-Ying , Du Zhanwei , DebRoy Swati , Robb Sara Wagner , Chowell Gerardo , Hai Fung Isaac Chun
Published: September 2021

Introduction

We aimed to examine how public health policies influenced the dynamics of COVID-19 time-varying reproductive number (Rt) in South Carolina from February 26, 2020 to January 1, 2021.

Methods

COVID-19 case series (March 6, 2020 - January 10, 2021) were shifted by 9 days to approximate the infection date. We analyzed the effects of state and county policies on Rt using EpiEstim. We performed linear regression to evaluate if per-capita cumulative case count varies across counties with different population size.

Results

Rt shifted from 2-3 in March to <1 during April and May. Rt rose over the summer and stayed between 1.4 and 0.7. The introduction of statewide mask mandates was associated with a decline in Rt (−15.3%; 95% CrI, -13.6%, -16.8%), and school re-opening, an increase by 12.3% (95% CrI, 10.1%, 14.4%). Less densely populated counties had higher attack rate (p<0.0001).

Conclusion

The Rt dynamics over time indicated that public health interventions substantially slowed COVID-19 transmission in South Carolina, while their relaxation may have promoted further transmission. Policies encouraging people to stay home, such as closing non-essential businesses, were associated with Rt reduction, while policies that encouraged more movement, such as re-opening schools, were associated with Rt increase.
Induction of robust neutralizing antibodies against the COVID-19 Delta variant with ChAdOx1 nCoV-19 or BNT162b2 as a booster following a primary vaccination series with CoronaVac
Authors: Patamatamkul Samadhi , Thammawat Sutthiwan , Buranrat Benjaporn
Published: September 2021

We determined the antibody response among CoronaVac vaccinees who were boosted with either BNT162b2 or ChAdOx1 nCoV-19. Increase in anti-S-RBD antibodies and surrogate neutralizing antibodies against the Delta variant was higher in BNT162b2 recipients than in ChAdOx1 nCoV-19 recipients. High proportions of reactogenicity were seen for both booster regimens.