bluuebunny/crossref_metadata_2025 huggingface dataset:
ERAP1 Controls the Interaction of the Inhibitory Receptor KIR3DL1 With HLA-B51:01 by Affecting Natural Killer Cell Function
Authors: D’Amico Silvia , D’Alicandro Valerio , Compagnone Mirco , Tempora Patrizia , Guida Giusy , Romania Paolo , Lucarini Valeria , Melaiu Ombretta , Falco Michela , Algeri Mattia , Pende Daniela , Cifaldi Loredana , Fruci Doriana
Published: December 2021

The endoplasmic reticulum aminopeptidase ERAP1 regulates innate and adaptive immune responses by trimming peptides for presentation by major histocompatibility complex (MHC) class I molecules. Previously, we have shown that genetic or pharmacological inhibition of ERAP1 on murine and human tumor cell lines perturbs the engagement of NK cell inhibitory receptors Ly49C/I and Killer-cell Immunoglobulin-like receptors (KIRs), respectively, by their specific ligands (MHC class I molecules), thus leading to NK cell killing. However, the effect of ERAP1 inhibition in tumor cells was highly variable, suggesting that its efficacy may depend on several factors, including MHC class I typing. To identify MHC class I alleles and KIRs that are more sensitive to ERAP1 depletion, we stably silenced ERAP1 expression in human HLA class I-negative B lymphoblastoid cell line 721.221 (referred to as 221) transfected with a panel of KIR ligands (i.e. HLA-B*51:01, -Cw3, -Cw4 and -Cw7), or HLA-A2 which does not bind any KIR, and tested their ability to induce NK cell degranulation and cytotoxicity. No change in HLA class I surface expression was detected in all 221 transfectant cells after ERAP1 depletion. In contrast, CD107a expression levels were significantly increased on NK cells stimulated with 221-B*51:01 cells lacking ERAP1, particularly in the KIR3DL1-positive NK cell subset. Consistently, genetic or pharmacological inhibition of ERAP1 impaired the recognition of HLA-B*51:01 by the YTS NK cell overexpressing KIR3DL1*001, suggesting that ERAP1 inhibition renders HLA-B*51:01 molecules less eligible for binding to KIR3DL1. Overall, these results identify HLA-B*51:01/KIR3DL1 as one of the most susceptible combinations for ERAP1 inhibition, suggesting that individuals carrying HLA-B*51:01-like antigens may be candidates for immunotherapy based on pharmacological inhibition of ERAP1.
Translational Clinical Strategies for the Prevention of Gastrointestinal Tract Graft Versus Host Disease
Authors: Rayasam Aditya , Drobyski William R.
Published: December 2021

Graft versus host disease (GVHD) is the major non-relapse complication associated with allogeneic hematopoietic stem cell transplantation (HSCT). Unfortunately, GVHD occurs in roughly half of patients following this therapy and can induce severe life-threatening side effects and premature mortality. The pathophysiology of GVHD is driven by alloreactive donor T cells that induce a proinflammatory environment to cause pathological damage in the skin, gastrointestinal (GI) tract, lung, and liver during the acute phase of this disease. Recent work has demonstrated that the GI tract is a pivotal target organ and a primary driver of morbidity and mortality in patients. Prevention of this complication has therefore emerged as an important goal of prophylaxis strategies given the primacy of this tissue site in GVHD pathophysiology. In this review, we summarize foundational pre-clinical studies that have been conducted in animal models to prevent GI tract GVHD and examine the efficacy of these approaches upon subsequent translation into the clinic. Specifically, we focus on therapies designed to block inflammatory cytokine pathways, inhibit cellular trafficking of alloreactive donor T cells to the GI tract, and reconstitute impaired regulatory networks for the prevention of GVHD in the GI tract.
T Cell Fitness and Autologous CAR T Cell Therapy in Haematologic Malignancy
Authors: Mehta Palak H. , Fiorenza Salvatore , Koldej Rachel M. , Jaworowski Anthony , Ritchie David S. , Quinn Kylie M.
Published: December 2021

A range of emerging therapeutic approaches for the treatment of cancer aim to induce or augment endogenous T cell responses. Chimeric antigen receptor (CAR) T cell therapy (CTT) is one such approach that utilises the patient’s own T cells, engineered ex vivo to target cell surface antigens, to eliminate haematological malignancies. Despite mediating high rates of responses in some clinical trials, this approach can be limited by dysfunctional T cells if they are present at high frequencies either in the starting material from the patient or the CAR T cell product. The fitness of an individual’s T cells, driven by age, chronic infection, disease burden and cancer treatment, is therefore likely to be a crucial limiting factor of CTT. Currently, T cell dysfunction and its impact on CTT is not specifically quantified when patients are considering the therapy. Here, we review our current understanding of T cell fitness for CTT, how fitness may be impacted by age, chronic infection, malignancy, and treatment. Finally, we explore options to specifically tailor clinical decision-making and the CTT protocol for patients with more extensive dysfunction to improve treatment efficacy. A greater understanding of T cell fitness throughout a patient’s treatment course could ultimately be used to identify patients likely to achieve favourable CTT outcomes and improve methods for T cell collection and CTT delivery.
Strategies to Improve the Antitumor Effect of Immunotherapy for Hepatocellular Carcinoma
Authors: Xing Rui , Gao Jinping , Cui Qi , Wang Qian
Published: December 2021

Hepatocellular carcinoma (HCC), one of the most fatal malignancies in the world, is usually diagnosed in advanced stages due to late symptom manifestation with very limited therapeutic options, which leads to ineffective intervention and dismal prognosis. For a decade, tyrosine kinase inhibitors (TKIs) have offered an overall survival (OS) benefit when used in a first-line (sorafenib and lenvatinib) and second-line setting (regorafenib and cabozantinib) in advanced HCC, while long-term response remains unsatisfactory due to the onset of primary or acquired resistance. Recently, immunotherapy has emerged as a promising therapy in the treatment of several solid tumors, such as melanoma and non-small cell lung cancer. Moreover, as the occurrence of HCC is associated with immune tolerance and immunosurveillance escape, there is a potent rationale for employing immunotherapy in HCC. However, immunotherapy monotherapy, mainly including immune checkpoint inhibitors (ICIs) that target checkpoints programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), and the cytotoxic T lymphocyte antigen-4 (CTLA-4), has a relatively low response rate. Thus, the multi-ICIs or the combination of immunotherapy with other therapies, like antiangiogenic drugs and locoregional therapies, has become a novel strategy to treat HCC. Combining different ICIs may have a synergistical effect attributed to the complementary effects of the two immune checkpoint pathways (CTLA-4 and PD-1/PD-L1 pathways). The incorporation of antiangiogenic drugs in ICIs can enhance antitumor immune responses via synergistically regulating the vasculature and the immune microenvironment of tumor. In addition, locoregional treatments can improve antitumor immunity by releasing the neoplasm antigens from killed tumor cells; in turn, this antitumor immune response can be intensified by immunotherapy. Therefore, the combination of locoregional treatments and immunotherapy may achieve greater efficacy through further synergistic effects for advanced HCC. This review aims to summarize the currently reported results and ongoing trials of the ICIs-based combination therapies for HCC to explore the rational combination strategies and further improve the survival of patients with HCC.
A Co-Association Network Analysis Reveals Putative Regulators for Health-Related Traits in Pigs
Authors: Crespo-Piazuelo Daniel , Ramayo-Caldas Yuliaxis , González-Rodríguez Olga , Pascual Mariam , Quintanilla Raquel , Ballester Maria
Published: December 2021

In recent years, the increase in awareness of antimicrobial resistance together with the societal demand of healthier meat products have driven attention to health-related traits in livestock production. Previous studies have reported medium to high heritabilities for these traits and described genomic regions associated with them. Despite its genetic component, health- and immunity-related traits are complex and its study by association analysis with genomic markers may be missing some information. To analyse multiple phenotypes and gene-by-gene interactions, systems biology approaches, such as the association weight matrix (AWM), allows combining genome wide association study results with network inference algorithms. The present study aimed to identify gene networks, key regulators and candidate genes associated to immunocompetence in pigs by integrating multiple health-related traits, enriched for innate immune phenotypes, using the AWM approach. The co-association network analysis unveiled a network comprised of 3,636 nodes (genes) and 451,407 edges (interactions), including a total of 246 regulators. From these, five genes (ARNT2,BRMS1L,MED12L,SUPT3HandTRIM25) were selected as key regulators as they were associated with the maximum number of genes with the minimum overlapping (1,827 genes in total). The five regulators were involved in pathways related to immunity such as lymphocyte differentiation and activation, platelet activation and degranulation, megakaryocyte differentiation, FcγR-mediated phagocytosis and response to nitric oxide, among others, but also in immunometabolism. Furthermore, we identified genes co-associated with the key regulators previously reported as candidate genes (e.g.,ANGPT1, CD4, CD36, DOCK1,PDE4B, PRKCE, PTPRCandSH2B3) for immunity traits in humans and pigs, but also new candidate ones (e.g.,ACSL3,CXADR,HBB,MMP12,PTPN6,WLS) that were not previously described. The co-association analysis revealed new regulators associated with health-related traits in pigs. This approach also identified gene-by-gene interactions and candidate genes involved in pathways related to cell fate and metabolic and immune functions. Our results shed new light in the regulatory mechanisms involved in pig immunity and reinforce the use of the pig as biomedical model.
A Comprehensive Annotation of the Channel Catfish (Ictalurus punctatus) T Cell Receptor Alpha/Delta, Beta, and Gamma Loci
Authors: Crider Jonathan , Quiniou Sylvie M. A. , Felch Kristianna L. , Showmaker Kurt , Bengtén Eva , Wilson Melanie
Published: December 2021

The complete germline repertoires of the channel catfish,Ictalurus punctatus, T cell receptor (TR) loci, TRAD, TRB, and TRG were obtained by analyzing genomic data from PacBio sequencing. The catfish TRB locus spans 214 kb, and contains 112 TRBV genes, a single TRBD gene, 31 TRBJ genes and two TRBC genes. In contrast, the TRAD locus is very large, at 1,285 kb. It consists of four TRDD genes, one TRDJ gene followed by the exons for TRDC, 125 TRAJ genes and the exons encoding the TRAC. Downstream of the TRAC, are 140 TRADV genes, and all of them are in the opposite transcriptional orientation. The catfish TRGC locus spans 151 kb and consists of four diverse V-J-C cassettes. Altogether, this locus contains 15 TRGV genes and 10 TRGJ genes. To place our data into context, we also analyzed the zebrafish TR germline gene repertoires. Overall, our findings demonstrated that catfish possesses a more restricted repertoire compared to the zebrafish. For example, the 140 TRADV genes in catfish form eight subgroups based on members sharing 75% nucleotide identity. However, the 149 TRAD genes in zebrafish form 53 subgroups. This difference in subgroup numbers between catfish and zebrafish is best explained by expansions of catfish TRADV subgroups, which likely occurred through multiple, relatively recent gene duplications. Similarly, 112 catfish TRBV genes form 30 subgroups, while the 51 zebrafish TRBV genes are placed into 36 subgroups. Notably, several catfish and zebrafish TRB subgroups share ancestor nodes. In addition, the complete catfish TR gene annotation was used to compile a TR gene segment database, which was applied in clonotype analysis of an available gynogenetic channel catfish transcriptome. Combined, the TR annotation and clonotype analysis suggested that the expressed TRA, TRB, and TRD repertoires were generated by different mechanisms. The diversity of the TRB repertoire depends on the number of TRBV subgroups and TRBJ genes, while TRA diversity relies on the many different TRAJ genes, which appear to be only minimally trimmed. In contrast, TRD diversity relies on nucleotide additions and the utilization of up to four TRDD segments.
Immunometabolites Drive Bacterial Adaptation to the Airway
Authors: Tomlinson Kira L. , Prince Alice S. , Wong Fok Lung Tania
Published: December 2021

Pseudomonas aeruginosa and Staphylococcus aureus are both opportunistic pathogens that are frequently associated with chronic lung infections. While bacterial virulence determinants are critical in initiating infection, the metabolic flexibility of these bacteria promotes their persistence in the airway. Upon infection, these pathogens induce host immunometabolic reprogramming, resulting in an airway milieu replete with immune-signaling metabolites. These metabolites are often toxic to the bacteria and create a steep selection pressure for the emergence of bacterial isolates adapted for long-term survival in the inflamed lung. In this review, we discuss the main differences in the host immunometabolic response to P. aeruginosa and S. aureus, as well as how these pathogens alter their own metabolism to adapt to airway metabolites and cause persistent lung infections.
Immune Metabolism of IL-4-Activated B Cells and Th2 Cells in the Context of Allergic Diseases
Authors: Lin Yen-Ju , Goretzki Alexandra , Schülke Stefan
Published: December 2021

Over the last decades, the frequency of allergic disorders has steadily increased. Immunologically, allergies are caused by abnormal immune responses directed against otherwise harmless antigens derived from our environment. Two of the main cell types driving allergic sensitization and inflammation are IgE-producing plasma cells and Th2 cells. The acute activation of T and B cells, their differentiation into effector cells, as well as the formation of immunological memory are paralleled by distinct changes in cellular metabolism. Understanding the functional consequences of these metabolic changes is the focus of a new research field termed “immune metabolism”. Currently, the contribution of metabolic changes in T and B cells to either the development or maintenance of allergies is not completely understood. Therefore, this mini review will introduce the fundamentals of energy metabolism, its connection to immune metabolism, and subsequently focus on the metabolic phenotypes of IL-4-activated B cells and Th2 cells.
Tcf1 Sustains the Expression of Multiple Regulators in Promoting Early Natural Killer Cell Development
Authors: Liu Juanjuan , Wang Zhao , Hao Shanshan , Wang Fang , Yao Yingpeng , Zhang Yajiao , Zhao Yanyi , Guo Wenhui , Yu Guotao , Ma Xiaohan , Liu Jingjing , Chen Feng , Yuan Shunzong , Kang Youmin , Yu Shuyang
Published: December 2021

T cell factor 1 (Tcf1) is known as a critical mediator for natural killer (NK) cell development and terminal maturation. However, its essential targets and precise mechanisms involved in early NK progenitors (NKP) are not well clarified. To investigate the role of Tcf1 in NK cells at distinct developmental phases, we employed three kinds of genetic mouse models, namely, Tcf7fl/flVavCre/+, Tcf7fl/flCD122Cre/+ and Tcf7fl/flNcr1Cre/+ mice, respectively. Similar to Tcf1 germline knockout mice, we found notably diminished cell number and defective development in BM NK cells from all strains. In contrast, Tcf7fl/flNcr1Cre/+ mice exhibited modest defects in splenic NK cells compared with those in the other two strains. By analyzing the published ATAC-seq and ChIP-seq data, we found that Tcf1 directly targeted 110 NK cell-related genes which displayed differential accessibility in the absence of Tcf1. Along with this clue, we further confirmed that a series of essential regulators were expressed aberrantly in distinct BM NK subsets with conditional ablating Tcf1 at NKP stage. Eomes, Ets1, Gata3, Ikzf1, Ikzf2, Nfil3, Runx3, Sh2d1a, Slamf6, Tbx21, Tox, and Zeb2 were downregulated, whereas Spi1 and Gzmb were upregulated in distinct NK subsets due to Tcf1 deficiency. The dysregulation of these genes jointly caused severe defects in NK cells lacking Tcf1. Thus, our study identified essential targets of Tcf1 in NK cells, providing new insights into Tcf1-dependent regulatory programs in step-wise governing NK cell development.
Sequential Analysis of Binding and Neutralizing Antibody in COVID-19 Convalescent Patients at 14 Months After SARS-CoV-2 Infection
Authors: Rosati Margherita , Terpos Evangelos , Ntanasis-Stathopoulos Ioannis , Agarwal Mahesh , Bear Jenifer , Burns Robert , Hu Xintao , Korompoki Eleni , Donohue Duncan , Venzon David J. , Dimopoulos Meletios-Athanasios , Pavlakis George N. , Felber Barbara K.
Published: December 2021

Durability of SARS-CoV-2 Spike antibody responses after infection provides information relevant to understanding protection against COVID-19 in humans. We report the results of a sequential evaluation of anti-SARS-CoV-2 antibodies in convalescent patients with a median follow-up of 14 months (range 12.4-15.4) post first symptom onset. We report persistence of antibodies for all four specificities tested [Spike, Spike Receptor Binding Domain (Spike-RBD), Nucleocapsid, Nucleocapsid RNA Binding Domain (N-RBD)]. Anti-Spike antibodies persist better than anti-Nucleocapsid antibodies. The durability analysis supports a bi-phasic antibody decay with longer half-lives of antibodies after 6 months and antibody persistence for up to 14 months. Patients infected with the Wuhan (WA1) strain maintained strong cross-reactive recognition of Alpha and Delta Spike-RBD but significantly reduced binding to Beta and Mu Spike-RBD. Sixty percent of convalescent patients with detectable WA1-specific NAb also showed strong neutralization of the Delta variant, the prevalent strain of the present pandemic. These data show that convalescent patients maintain functional antibody responses for more than one year after infection, suggesting a strong long-lasting response after symptomatic disease that may offer a prolonged protection against re-infection. One patient from this cohort showed strong increase of both Spike and Nucleocapsid antibodies at 14 months post-infection indicating SARS-CoV-2 re-exposure. These antibodies showed stronger cross-reactivity to a panel of Spike-RBD including Beta, Delta and Mu and neutralization of a panel of Spike variants including Beta and Gamma. This patient provides an example of strong anti-Spike recall immunity able to control infection at an asymptomatic level. Together, the antibodies from SARS-CoV-2 convalescent patients persist over 14 months and continue to maintain cross-reactivity to the current variants of concern and show strong functional properties.
Reactogenicity and Immunogenicity of the Pfizer and AstraZeneca COVID-19 Vaccines
Authors: Mahallawi Waleed H. , Mumena Walaa A.
Published: December 2021

Background

The relationships of the coronavirus disease 2019 (COVID-19) vaccination with reactogenicity and the humoral immune response are important to study. The current study aimed to assess the reactogenicity and immunogenicity of the Pfizer and AstraZeneca COVID-19 vaccines among adults in Madinah, Saudi Arabia.

Methods

A cross-sectional study, including 365 randomly selected adult Pfizer or AstraZeneca vaccine recipients who received a homologous prime-boost vaccination between February 1st and June 30th, 2021. Data of height and weight were collected to assess the weight status of percipients. An evaluation of seropositivity for anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies was assessed using enzyme-linked immunosorbent assay (ELISA).

Results

Among the participants, 69% (n = 250) reported at least one vaccine-related symptom. Pain at the injection site was the most frequently reported vaccine-related symptom. The mean total score for vaccine-related symptoms was significantly higher among participants who received the AstraZeneca vaccine, women, and participants with no previous COVID-19 infection (p < 0.05). Spike-specific IgG antibodies were detected in 98.9% of participants after the receipt of two vaccine doses, including 99.5% of Pfizer vaccine recipients and 98.3% of AstraZeneca vaccine recipients. Significantly, higher proportions of participants in the <35-year age group developed a humoral immune response after the first vaccine dose compared with the participants in other age groups.

Conclusion

Participants who received the Pfizer COVID-19 vaccine reported fewer vaccine-related complications compared with those who received the AstraZeneca COVID-19 vaccine, but no serious side effects were reported in response to either vaccine. Health status and age were factors that may influence COVID-19 vaccine effectiveness for the generation of antibodies against the SARS-CoV-2 spike protein.
Monocyte Trajectories Endotypes Are Associated With Worsening in Septic Patients
Authors: Bodinier Maxime , Peronnet Estelle , Brengel-Pesce Karen , Conti Filippo , Rimmelé Thomas , Textoris Julien , Vedrine Christophe , Quemeneur Laurence , Griffiths Andrew D. , Tan Lionel K. , Venet Fabienne , Maucort-Boulch Delphine , Monneret Guillaume ,   the REALISM study group
Published: December 2021

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. The immune system plays a key role in sepsis onset and remains dysregulated over time in a heterogeneous manner. Here, we decipher the heterogeneity of the first week evolution of the monocyte HLA-DR (mHLA-DR) surface protein expression in septic patients, a key molecule for adaptive immunity onset. We found and verified four distinctive trajectories endotypes in a discovery (n = 276) and a verification cohort (n = 102). We highlight that 59% of septic patients exhibit low or decreasing mHLA-DR expression while in others mHLA-DR expression increased. This study depicts the first week behavior of mHLA-DR over time after sepsis onset and shows that initial and third day mHLA-DR expression measurements is sufficient for an early risk stratification of sepsis patients. These patients might benefit from immunomodulatory treatment to improve outcomes. Going further, our study introduces a way of deciphering heterogeneity of immune system after sepsis onset which is a first step to reach a more comprehensive landscape of sepsis.
Anti-Human Herpesvirus 6 A/B Antibodies Titers Correlate With Multiple Sclerosis-Associated Retrovirus Envelope Expression
Authors: Pérez-Pérez Silvia , Domínguez-Mozo María I. , García-Martínez M. Ángel , García-Frontini M. Celeste , Villarrubia Noelia , Costa-Frossard Lucienne , Villar Luisa M. , Arroyo Rafael , Álvarez-Lafuente Roberto
Published: December 2021

Human endogenous retrovirus W family envelope proteins (pHERV-W ENV/syncytin-1) have been repeatedly associated with multiple sclerosis (MS). Here, we have focused on the study of pHERV-W ENV/syncytin-1 expression levels in MS patients (relapsing and progressive forms) and in healthy donors (HD) and on exploring their possible relationship with Epstein-Barr virus (EBV) and human herpesvirus-6A/B (HHV-6A/B). We included blood samples from 101 MS patients and 37 HD to analyze antiviral antibody titers by ELISA and pHERV-W ENV/syncytin-1 expression levels by flow cytometry as well as by qPCR. Patients with relapsing MS forms showed significantly higher pHERV-W ENV/syncytin-1 protein and gene expression levels than HD. Progressive MS patients also showed significantly higher protein and gene expression levels than both HD and relapsing MS patients. Regarding antiviral antibodies titers, anti-HHV-6A/B IgM levels were positively correlated with pHERV-W ENV/syncytin-1 protein expression levels in patients with relapsing MS, while in the progressive forms patients this correlation was found with anti-HHVA/B IgG levels. Therefore, pHERV-W ENV could be involved in MS pathogenesis, playing a role in relapsing and progressive forms. Besides, anti-HHV-6A/B antibodies positively correlated with pHERV-W ENV expression. Further studies are needed to better understand this possible relationship.
Pollen Source Richness May Be a Poor Predictor of Bumblebee (Bombus terrestris) Colony Growth
Authors: Watrobska Cecylia M. , Ramos Rodrigues Ana , Arce Andres N. , Clarke Jessica , Gill Richard J.
Published: December 2021

Agricultural intensification has drastically altered foraging landscapes for bees, with large-scale crop monocultures associated with floral diversity loss. Research on bumblebees and honeybees has shown individuals feeding on pollen from a low richness of floral sources can experience negative impacts on health and longevity relative to higher pollen source richness of similar protein concentrations. Florally rich landscapes are thus generally assumed to better support social bees. Yet, little is known about whether the effects of reduced pollen source richness can be mitigated by feeding on pollen with higher crude protein concentration, and importantly how variation in diet affects whole colony growth, rearing decisions and sexual production. Studying queen-right bumblebee (Bombus terrestris) colonies, we monitored colony development under a polyfloral pollen diet or a monofloral pollen diet with 1.5–1.8 times higher crude protein concentration. Over 6 weeks, we found monofloral colonies performed better for all measures, with no apparent long-term effects on colony mass or worker production, and a higher number of pupae in monofloral colonies at the end of the experiment. Unexpectedly, polyfloral colonies showed higher mortality, and little evidence of any strategy to counteract the effects of reduced protein; with fewer and lower mass workers being reared, and males showing a similar trend. Our findings (i) provide well-needed daily growth dynamics of queenright colonies under varied diets, and (ii) support the view that pollen protein content in the foraging landscape rather than floral species richness per se is likely a key driver of colony health and success.
Mesozooplankton Community Dynamics and Grazing Potential Across Algal Bloom Cycles in a Subtropical Estuary
Authors: Sweat L. Holly , Alexander Hunter , Phlips Edward J. , Johnson Kevin B.
Published: December 2021

Mesozooplankton, as abundant grazers of microalgae in coastal systems, have the potential to prevent or mitigate harmful algal blooms (HABs) and their effects. The Indian River Lagoon (IRL) is a subtropical estuary in eastern Florida (United States) where repeated blooms, dominated by the toxic dinoflagellatePyrodinium bahamense, the brown tide speciesAureoumbra lagunensis, pico/nano planktonic cyanobacteria and other nano-eukaryotes, have highlighted the need to better understand fluctuations in the grazing potential of mesozooplankton populations across bloom cycles. Mesozooplankton and abiotic environmental data were collected at five sites in the northern IRL system at 6-week intervals from November 2013 through June 2016. A total of 107 taxa from 14 phyla were detected. Communities varied across sites, dates and between bloom and non-bloom periods, with densities up to 338 individuals L–1. Eight taxa comprising 85–94% of the total population at each site were identified as primary potential grazers, including barnacle nauplii, cladocerans, adult copepods, gastropod veligers, larvaceans, and polychaete metatrochophores. Although abundant, the estimated grazing potential of the primary taxa, calculated from their measured densities and previously published grazing rates, suggest that mesozooplankton lack the capacity to suppress phytoplankton once they reach bloom levels. These findings illustrate the utility of monitoring data and underscore the importance of systematically evaluating algal bloom controls with a consideration for the dynamic conditions of each unique ecosystem.
High-Resolution Reanalysis of the Mediterranean Sea Biogeochemistry (1999–2019)
Authors: Cossarini Gianpiero , Feudale Laura , Teruzzi Anna , Bolzon Giorgio , Coidessa Gianluca , Solidoro Cosimo , Di Biagio Valeria , Amadio Carolina , Lazzari Paolo , Brosich Alberto , Salon Stefano
Published: December 2021

Ocean reanalyses integrate models and observations to provide a continuous and consistent reconstruction of the past physical and biogeochemical ocean states and variability. We present a reanalysis of the Mediterranean Sea biogeochemistry at a 1/24° resolution developed within the Copernicus Marine Environment Monitoring Service (CMEMS) framework. The reanalysis is based on the Biogeochemical Flux Model (BFM) coupled with a variational data assimilation scheme (3DVarBio) and forced by the Nucleus for European Modeling of the Ocean (NEMO)–OceanVar physical reanalysis and European Centre for medium-range weather forecasts (ECMWF) reanalysis ERA5 atmospheric fields. Covering the 1999–2019 period with daily means of 12 published and validated biogeochemical state variables, the reanalysis assimilates surface chlorophyll data and integrates EMODnet data as initial conditions, in addition to considering World Ocean Atlas data at the Atlantic boundary, CO2 atmospheric observations, and yearly estimates of riverine nutrient inputs. With the use of multiple observation sources (remote, in situ, and BGC-Argo), the quality of the biogeochemical reanalysis is qualitatively and quantitatively assessed at three validation levels including the evaluation of 12 state variables and fluxes and several process-oriented metrics. The results indicate an overall good reanalysis skill in simulating basin-wide values and variability in the biogeochemical variables. The uncertainty in reproducing observations at the mesoscale and weekly temporal scale is satisfactory for chlorophyll, nutrient, oxygen, and carbonate system variables in the epipelagic layers, whereas the uncertainty increases for a few variables (i.e., oxygen and ammonium) in the mesopelagic layers. The vertical dynamics of phytoplankton and nitrate are positively evaluated with specific metrics using BGC-Argo data. As a consequence of the continuous increases in temperature and salinity documented in the Mediterranean Sea over the last 20 years and atmospheric CO2 invasion, we observe basin-wide biogeochemical signals indicating surface deoxygenation, increases in alkalinity, and dissolved inorganic carbon concentrations, and decreases in pH at the surface. The new, high-resolution reanalysis, open and freely available from the Copernicus Marine Service, allows users from different communities to investigate the spatial and temporal variability in 12 biogeochemical variables and fluxes at different scales (from the mesoscale to the basin-wide scale and from daily to multiyear scales) and the interaction between physical and biogeochemical processes shaping Mediterranean marine ecosystem functioning.
An Integrative Assessment Combining Deep-Sea Net Sampling, in situ Observations and Environmental DNA Analysis Identifies Cabo Verde as a Cephalopod Biodiversity Hotspot in the Atlantic Ocean
Authors: Merten Véronique , Bayer Till , Reusch Thorsten B. H. , Puebla Oscar , Fuss Janina , Stefanschitz Julia , Lischka Alexandra , Hauss Helena , Neitzel Philipp , Piatkowski Uwe , Czudaj Stephanie , Christiansen Bernd , Denda Anneke , Hoving Henk-Jan T.
Published: December 2021

The deep sea is among the largest, most biologically diverse, yet least-explored ecosystems on Earth. Baseline information on deep-sea biodiversity is crucial for understanding ecosystem functioning and for detecting community changes. Here, we established a baseline of cephalopod community composition and distribution off Cabo Verde, an archipelago in the eastern tropical Atlantic. This baseline served to test the hypothesis that Cabo Verde is biogeographically separated from other Macaronesian archipelagos and allowed the identification of cephalopod species which may play a role in the Macaronesian carbon cycle and oceanic food web. To investigate cephalopod community composition, this study used 746 individual cephalopods obtained by nets (0–1000 m) and 52 cephalopod encounters during video surveys with either towed camera (0–2500 m) or manned submersible (0–375 m). Additionally, environmental DNA (eDNA) metabarcoding on 105 seawater samples (50–2500 m), using an 18S rRNA universal cephalopod primer pair, and a species-specific primer pair for Taningia danae resulted in the detection of 32 cephalopod taxa. When combined, the three methods detected a total of 87 taxa, including 47 distinct species. Each method contributed between 7 and 54% of taxa that were not detected by the other methods, indicating that multiple methodological approaches are needed for optimal deep-sea cephalopod biodiversity assessments. This study documents the occurrences of six species and three genera for the first time in waters surrounding Cabo Verde. Video surveys and eDNA analysis detected Taningia danae recurrently (100–2500 m). eDNA metabarcoding proved to be a powerful tool for cephalopod biodiversity monitoring and complementary to traditional sampling methods. When also including literature records, Cabo Verde hosts at least 102 cephalopod taxa including 30 families and 64 benthic and pelagic species. The total number and species composition of Cabo Verde cephalopods is similar to the Canary Islands and Azores, two known cephalopod biodiversity hotspots, but the Cabo Verde octopus fauna seems to differ. Due to a range of life history characteristics, we hypothesize that the squids Taningia danae (Octopoteuthidae) and Sthenoteuthis pteropus (Ommastrephidae) are important in the carbon cycle of Macaronesia. As a cephalopod biodiversity hotspot Cabo Verde could function as a model region to investigate cephalopod biology and ecology in a rapidly changing Atlantic Ocean.
Accuracy of Intraocular Lens Power Calculation Formulas in Pediatric Cataract Patients: A Systematic Review and Meta-Analysis
Authors: Zhong Yueyang , Yu Yibo , Li Jinyu , Lu Bing , Li Su , Zhu Yanan
Published: December 2021

Background: Among the various intraocular lens (IOL) power calculation formulas available in clinical settings, which one can yield more accurate results is still inconclusive. We performed a meta-analysis to compare the accuracy of the IOL power calculation formulas used for pediatric cataract patients.

Methods: Observational cohort studies published through April 2021 were systematically searched in PubMed, Web of Science, and EMBASE databases. For each included study, the mean differences of the mean prediction error and mean absolute prediction error (APE) were analyzed and compared using the random-effects model.

Results: Twelve studies involving 1,647 eyes were enrolled in the meta-analysis, and five formulas were compared: Holladay 1, Holladay 2, Hoffer Q, SRK/T, and SRK II. Holladay 1 exhibited the smallest APE (0.97; 95% confidence interval [CI]: 0.92–1.03). For the patients with an axial length (AL) less than 22 mm, SRK/T showed a significantly smaller APE than SRK II (mean difference [MD]: −0.37; 95% CI: −0.63 to −0.12). For the patients younger than 24 months, SRK/T had a significantly smaller APE than Hoffer Q (MD: −0.28; 95% CI: −0.51 to −0.06). For the patients aged 24–60 months, SRK/T presented a significantly smaller APE than Holladay 2 (MD: −0.60; 95% CI: −0.93 to −0.26).

Conclusion: Due to the rapid growth and high variability of pediatric eyes, the formulas for IOL calculation should be considered according to clinical parameters such as age and AL. The evidence obtained supported the accuracy and reliability of SRK/T under certain conditions.

Systematic Review Registration: PROSPERO, identifier: INPLASY202190077.
ATMP Environmental Exposure Assessment in European Healthcare Settings: A Systematic Review of the Literature
Authors: Damerval Margaux , Fagnoni-Legat Christine , Louvrier Aurélien , Fischer Sarah , Limat Samuel , Clairet Anne-Laure , Nerich Virginie , Madelaine Isabelle , Kroemer Marie
Published: December 2021

Since 2007, a new class of biologic products for human use called “advanced therapy medicinal products (ATMP)” have been legally integrated in the European Medical Agency. They consist of recombinant nucleic acid, engineered cells, cells, or tissues. In the United States, ATMP fall under the regulatory framework of biological products and the term “cell and gene therapy product” is used in the legislative and regulatory documents. Potential clinical applications are broad, particularly, in the field of cancer, inherited genetic disease, and regenerative medicine. Indeed, the benefit conferred by CD19 chimeric antigen receptor T cells led to the first engineered cell therapy products to be approved by the Food and Drug Administration (FDA) in 2017. Gene therapy products to treat orphan diseases are also extensively developed with many clinical trials ongoing in the world. Nevertheless, the use of these therapeutic products is complex and requires careful considerations in the terms of regulatory and hospital setting requirements, such as storage, handling, administration, and disposal which justify the implementation of a secured medication circuit. Through this systematic review of the literature, the authors wanted to compile data on the assessment of environmental exposure related to the use of ATMP in healthcare setting to secure their medication circuit. A literature search was conducted on PubMed and Web of Science, and 32 publications dealing with environmental exposure assessment and ATMP were selected. In addition, marketed ATMPs were identified and data regarding the environmental concerns were extracted from product information sections from European Public Assessment Reports (EPAR). The environmental contamination assessments were mainly addressed in the reviews rather than in original articles related to the use of ATMP. Most of the product information sections from EPAR suggested precautions rather than requirements when dealing with environmental consideration following ATMP handling. Nevertheless, these precautions usually remain elusive especially concerning waste disposal and the detection of biological material on the work surfaces, and mainly relate to the genetically modified organisms (GMO) over non-GMO cellular products. Pharmaceutical oversight and adherence to the good preparation practices and good clinical practices are essential to ensure the safe use in term of environmental concern of these new therapeutic products in healthcare setting.
Prognostic Value of C4d Immunolabelling in Adult Patients With IgA Vasculitis
Authors: Romero Anais , Drieux Fanny , François Arnaud , Dervaux Alexandra , Xu Xiao Li , Titeca-Beauport Dimitri , Bertrand Dominique , Guerrot Dominique
Published: December 2021

Background and Objectives: Glomerular C4d deposits are associated the severity and outcomes of IgA nephropathy. Whether this holds true in immunoglobulin A vasculitis (IgAV) is not known. The main objective of the study was to analyze the prognostic value of glomerular C4d immunolabelling on kidney impairment in adults with IgAV.

Design, Setting, Participants, Measurements: This retrospective cohort study included 120 adults with IgAV and a kidney biopsy performed between 1995 and 2018 in two French university hospital centers. All paraffin-embedded biopsies were reassessed according to Oxford classification. Immunofluorescence for C4d was performed in all cases. For analysis, patients were grouped according to positivity for C4d in the glomerular area. The main outcome was a composite endpoint of 50% increase in 24 h-proteinuria, or eGFR decrease by 50%, or kidney replacement therapy.

Results: The median follow-up was 28.3 months. Twenty-three patients met the composite endpoint, 12 for kidney replacement therapy, 6 for an eGFR decrease >50% and 5 for a >50% increase in proteinuria. At time of biopsy, the median proteinuria was 1.9 g/24 h and the median eGFR 73.5 mL/min/1.73 m2. Among the 102 patients evaluable for C4d, 24 were positive on >30% glomeruli, mainly with a parieto-mesangial pattern. In this group, the initial proteinuria was more frequently nephrotic than in the C4d– group (60% vs. 33%, P = 0.039). Mesangial hypercellularity was more frequent in the C4d+ group (42% vs. 13%; P = 0.006) whereas macroscopic hematuria was more frequent in the C4d– group (18% vs. 0%; P = 0.03). After a median follow-up of 28 months, kidney survival did not differ according to C4d status.

Conclusion: In a population of adult IgAV patients, glomerular positivity for C4d was associated with the severity of the kidney disease at presentation, but not with subsequent renal function deterioration.
Clinical Characteristics, Diagnosis, Treatment, and Mortality Rate of TB/COVID-19 Coinfectetd Patients: A Systematic Review
Authors: Koupaei Maryam , Naimi Adel , Moafi Narges , Mohammadi Paria , Tabatabaei Faezeh Sadat , Ghazizadeh Soroosh , Heidary Mohsen , Khoshnood Saeed
Published: December 2021

Introduction: Novel coronavirus (COVID-19) and tuberculosis (TB) are the newest and one of the oldest global threats, respectively. In the COVID-19 era, due to the health system's focus on the COVID-19 epidemic, the national TB control program received less attention, leading to a worsening of the global TB epidemic. In this study, we will review the characteristics of TB patients coinfected with COVID-19.

Material and Methods: Using Scopus, PubMed/Medline, Embase, and Web of Science databases, a systematic search was performed. Case reports and case series on TB/COVID-19 coinfection published from January 1, 2019 to February 24, 2021 were collected. There were no limitations regarding publication language.

Results: Eleven case series and 20 case reports were identified from 18 countries, with the majority them being from India (N = 6) and China (N = 4). Overall, 146 patients (114 men and 32 women) coinfected with TB and COVID-19 enrolled. Smoking (15.1%), diabetes (14.4%), and hypertension (8.9%) were the most frequent comorbidities among these patients. The COVID-19 patients with TB mainly suffered fever (78.8%), cough (63.7%), and respiratory distress (22.6%). Hydroxychloroquine (64.0%) and lopinavir/ritonavir (39.5%) were the most common treatments for them. The mortality rate was 13.0% and the rate of discharged patients was 87.0%.

Conclusion: Global prevalence of COVID-19-related deaths is 6.6%. Our results showed that 13.0% of patients with TB/COVID-19 died. Thus, this study indicated that coinfection of TB and COVID-19 can increase the mortality. The respiratory symptoms of TB and COVID-19 are very similar, and this causes them to be misdiagnosed. In addition, TB is sometimes diagnosed later than COVID-19 and the severity of the disease worsens, especially in patients with underlying conditions. Therefore, patients with TB should be screened regularly in the COVID-19 era to prevent the spread of the TB/COVID-19 coinfection.
Case Report: SARS-CoV-2 Infection—Are We Redeemed? A Report of Candida Spondylodiscitis as a Late Complication
Authors: Moreno-Gómez Luis Miguel , Esteban-Sinovas Olga , García-Pérez Daniel , García-Posadas Guillermo , Delgado-Fernández Juan , Paredes Igor
Published: December 2021

Background:We describe a case of candida spondylodiscitis secondary to coronavirus disease (COVID-19).

Case report:A 47-year-old man diagnosed with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) required prolonged admission to the intensive care unit (ICU). Four months later, he was diagnosed with thoracic candida spondylodiscitis. Medical management was insufficient, so he eventually underwent surgery.

Discussions:Fungal infections seem to be more likely in patients with COVID-19, but it is unknown whether they are directly attributed to COVID-19 or other surrounding factors. Regardless of the answer, the diagnosis is complicated, and the mortality rate is high.

Lessons:COVID-19 is posing a challenge to the society, and new and unexpected diseases that had once disappeared have risen again. It is our duty to suspect them and to treat them in the most effective way possible.
Suspension of Care for Patients With Spasticity During COVID-19 Pandemic: Ethical and Medico-Legal Point of View Starting From an Italian Study
Authors: De Donno Antonio , Acella Adriano , Angrisani Carmelinda , Gubinelli Giulia , Musci Gianluca , Gravili Gianluca , Ciritella Chiara , Santamato Andrea
Published: December 2021

The COVID-19 pandemic has revolutionized the habits of entire communities, having even more profound negative effects on assistance for the chronically ill. The sudden demand for extraordinary resources caught all worldwide countries unprepared, highlighting shortages in provision of care services. This applies to all patients, affected by COVID-19 or not, as many need continuing access to chronic diseases treatments. Almost all of the energy available has been directed toward care of COVID-19 patients, and almost nothing has been done to continue therapy for patients with spasticity. This study builds on a recent article and discusses its results as a basis for highlighting the ethical dilemmas and unintended consequences of health systems changing their priorities during the pandemic. The above mentioned study has shown increased patient-perceived spasticity during lockdown (72.2%) with reductions in perceived quality of life (70.9%). Telemedicine tools have proved insufficient, with access by only 7.3% of these patients. Despite the health emergency, it cannot be denied that this situation is a violation of these patients' rights and dignity. The healthcare system will also have to bear increased costs in the future to recover the loss of previous therapies benefits, because of their interruption. The real challenge will be to exploit the critical issues emerged during the pandemic, and to resolve the measures needed to take the care to the patient, and not vice versa. This applies particularly to fragile patients, to respect their dignity and right to care.
The Glomerular Filtration Rate: From the Diagnosis of Kidney Function to a Public Health Tool
Authors: Cusumano Ana Maria , Tzanno-Martins Carmen , Rosa-Diez Guillermo Javier
Published: December 2021

The prevalence of chronic kidney disease (CKD) continues to increase worldwide, as well as the associated morbidity and mortality and the consequences on the patients' quality of life and countries' economies. CKD often evolves without being recognized by patients and physicians, although the diagnosis is based on two simple laboratory data: the estimated glomerular filtration rate (eGFR) and urine analysis. To measure GFR, the knowledge about the physiologic processes at the nephron level, the concept of clearance, and the identification of creatinine as a suitable endogenous marker for measuring the creatinine clearance (CrCl) had to be previously developed. On those bases, different equations to calculate CrCl (Cockcroft and Gault, 1976), or estimated GFR (four variables MDRD, 1999; CKD-Epi, 2009, among others) were generated. They all include creatinine and some demographic data, such as sex and age. However, to compare results throughout life or among laboratories, the creatinine determination must be standardized. In addition, the accuracy of these equations remains controversial in certain subgroups of patients. For these reasons, other mathematical models to improve CrCl estimation have been developed, such as when urine cannot be collected, in debilitated elderly patients and patients with trauma, diabetes, or obesity. Currently, eGFR in adults can be measured and reported immediately, using isotope dilution mass spectrometry traceable creatinine-based equations. In conclusion, based on knowledge obtained from renal physiology, eGFR can be used in the clinic for the diagnosis and early treatment of CKD, as well as a public instrument to estimate the prevalence.