bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence of resistance mutations associated with integrase inhibitors in therapy-naive HIV-positive patients in Baoding, Hebei province, China
Authors: Fan Weiguang , Wang Xiaodong , Zhang Yuchen , Meng Juan , Su Miaomiao , Yang Xuegang , Shi Haoxi , Shi Penghui , Lu Xinli
Published: September 2022

Antiretroviral therapy (ART) regimens containing integrase strand transfer inhibitors (INSTIs) are the recommended treatment for human immunodeficiency virus type 1 (HIV-1)-infected patients in the most recent guidelines in China. In this study, we investigated INSTI resistance mutations in newly diagnosed therapy-naive HIV-positive patients in Baoding City, Hebei Province (China) to provide guidance for implementing routine INSTI-associated HIV-1 genotypic resistance testing. Plasma samples were collected from HIV-1-infected patients without treatment at Baoding People’s Hospital from January 2020 to December 2021. The part of HIV-1 pol gene encoding integrase was amplified, sequenced, and analyzed for INSTI resistance. Clinical data including demographic data, CD4+ T cell counts, HIV-RNA loads, and resistance mutations were collected. Treatment-naïve HIV-1 patients (n = 131) were enrolled. We identified ten genotypes, and the predominant genotype was CRF01_AE in 67 patients (51.15%), CRF07_ BC in 39 patients (29.77%), subtype B in 11 patients (8.40%), and other subtypes (CRF68_01B, 3.82%; CRF55_01B, 1.53%, CRF80_0107, 1.53%; URFs 1.53%; and CRF103_01B, CRF59_01B, and CRF65_cpx, 1.4% each). Four major (E138A, R263k, G140S, and S147G) and three accessory (H51Y, Q146QL, and S153F) INSTI-resistance mutations were observed (genotype CRF01_AE, three patients; genotype B, one patient; and genotype CRF07_BC, one patient), resulting in different degrees of resistance to the following five INSTIs: raltegravir, elvitegravir, dolutegravir, bictegravir, and cabotegravir. The overall resistance rate was 3.82% (5/131). All INSTI-resistant strains were cross-resistant. The primary INSTI drug resistance rate among newly diagnosed HIV-infected patients in Baoding was low, but monitoring and research on HIV INSTI resistance should be strengthened in Baoding because INSTI-based regimen prescriptions are anticipated to increase in the near future.
Nonsynonymous amino acid changes in the α-chain of complement component 5 influence longitudinal susceptibility to Plasmodium falciparum infections and severe malarial anemia in kenyan children
Authors: Raballah Evans , Wilding Kristen , Anyona Samuel B. , Munde Elly O. , Hurwitz Ivy , Onyango Clinton O. , Ayieko Cyrus , Lambert Christophe G. , Schneider Kristan A. , Seidenberg Philip D. , Ouma Collins , McMahon Benjamin H. , Cheng Qiuying , Perkins Douglas J.
Published: September 2022

Background: Severe malarial anemia (SMA; Hb < 5.0 g/dl) is a leading cause of childhood morbidity and mortality in holoendemic Plasmodium falciparum transmission regions such as western Kenya.

Methods: We investigated the relationship between two novel complement component 5 (C5) missense mutations [rs17216529:C>T, p(Val145Ile) and rs17610:C>T, p(Ser1310Asn)] and longitudinal outcomes of malaria in a cohort of Kenyan children (under 60 mos, n = 1,546). Molecular modeling was used to investigate the impact of the amino acid transitions on the C5 protein structure.

Results: Prediction of the wild-type and mutant C5 protein structures did not reveal major changes to the overall structure. However, based on the position of the variants, subtle differences could impact on the stability of C5b. The influence of the C5 genotypes/haplotypes on the number of malaria and SMA episodes over 36 months was determined by Poisson regression modeling. Genotypic analyses revealed that inheritance of the homozygous mutant (TT) for rs17216529:C>T enhanced the risk for both malaria (incidence rate ratio, IRR = 1.144, 95%CI: 1.059–1.236, p = 0.001) and SMA (IRR = 1.627, 95%CI: 1.201–2.204, p = 0.002). In the haplotypic model, carriers of TC had increased risk of malaria (IRR = 1.068, 95%CI: 1.017–1.122, p = 0.009), while carriers of both wild-type alleles (CC) were protected against SMA (IRR = 0.679, 95%CI: 0.542–0.850, p = 0.001).

Conclusion: Collectively, these findings show that the selected C5 missense mutations influence the longitudinal risk of malaria and SMA in immune-naïve children exposed to holoendemic P. falciparum transmission through a mechanism that remains to be defined.
An integrated platform for Brucella with knowledge graph technology: From genomic analysis to epidemiological projection
Authors: Ma Fubo , Xiao Ming , Zhu Lin , Jiang Wen , Jiang Jizhe , Zhang Peng-Fei , Li Kang , Yue Min , Zhang Le
Published: September 2022

Motivation:Brucella, the causative agent of brucellosis, is a global zoonotic pathogen that threatens both veterinary and human health. The main sources of brucellosis are farm animals. Importantly, the bacteria can be used for biological warfare purposes, requiring source tracking and routine surveillance in an integrated manner. Additionally, brucellosis is classified among group B infectious diseases in China and has been reported in 31 Chinese provinces to varying degrees in urban areas. From a national biosecurity perspective, research on brucellosis surveillance has garnered considerable attention and requires an integrated platform to provide researchers with easy access to genomic analysis and provide policymakers with an improved understanding of both reported patients and detected cases for the purpose of precision public health interventions.

Results: For the first time in China, we have developed a comprehensive information platform for Brucella based on dynamic visualization of the incidence (reported patients) and prevalence (detected cases) of brucellosis in mainland China. Especially, our study establishes a knowledge graph for the literature sources of Brucella data so that it can be expanded, queried, and analyzed. When similar “epidemiological comprehensive platforms” are established in the distant future, we can use knowledge graph to share its information. Additionally, we propose a software package for genomic sequence analysis. This platform provides a specialized, dynamic, and visual point-and-click interface for studying brucellosis in mainland China and improving the exploration of Brucella in the fields of bioinformatics and disease prevention for both human and veterinary medicine.
Comparative phylogenetic analysis of complete plastid genomes of Renanthera (Orchidaceae)
Authors: Xiao Tao , He Liefen , Yue Liangliang , Zhang Yonghong , Lee Shiou Yih
Published: September 2022

Owing to its attractive flower shape and color, Renanthera (Orchidaceae), comprising about 19 species, has significant ornamental value as a houseplant, in floral design and in landscape gardens. Two species of Renanthera are categorized as endangered and critically endangered in China’s Red List and international trade in these orchids is currently strictly monitored by the Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES). This paper reports on the de novo assembled and annotated plastome of four species of Renanthera; R. citrina, R. coccinea, R. imschootiana, and R. philippinensis. The length of the plastome sequences ranged from 144,673 bp (R. imschootiana) to 149,007 bp (R. coccinea) with GC content of 36.6–36.7%. The plastomes showed a typical quadripartite structure, including a large single-copy (84,241–86,404 bp), a small single-copy (11,468–12,167 bp), and a pair of inverted repeats (24,482–25,715 bp) regions. Of the 120 genes detected, 74 were protein coding, 38 were tRNA, and eight were rRNA genes. The plastome of Renanthera is rather conserved, but nucleotide variations that could distinguish them apart are noticeable—the total number of tandem repeats ranged from 62 (in R. imschootiana) to 74 (in R. citrina); while the number of long repeats ranged from 21 (in R. imschootiana and R. philippinensis) to 43 (in R. citrina). Three hypervariable regions (psbI-trnS-GCU, trnG-GCC, rpl32) were identified. Phylogenetic analyses based on the CDS using maximum likelihood (ML) and Bayesian inference (BI) revealed that Renanthera is closely related to Holcoglossum, Neofinetia, Pendulorchis, and Vanda. The relationship between the four species of Renanthera was fully resolved; a monophyletic clade was formed and R. coccinea was recorded as the first to diverge from the rest. The genetic data obtained from this study could serve as a useful resource for species identification in Renanthera as well as contribute to future research on the phylogenomics of Orchidaceae.
Cardiotoxicity of immune checkpoint inhibitors: A frequency network meta-analysis
Authors: Liu Maobai , Cheng Xitong , Ni Ruping , Zheng Bin , Huang Shunmin , Yang Jing
Published: September 2022

Immune checkpoint inhibitors (ICIs) in combination withother anti-cancer treatments have been approved for a variety of cancers. While the difference in the incidence of cardiovascular adverse events has not been fully investigated. We aimed to assess the the differences in cardiotoxicity among cancer patients receiving different ICI therapies. PubMed, Embase, Web of Science, Cochrane Library, and ClinicalTrials.gov. websites were searched for all randomized controlled trials (RCTs) of ICI. The primary outcomes were any grade cardiotoxicity and Grade 3-5 cardiotoxicity, the secondary outcomes were any grade myocarditis and Grade 3-5 myocarditis, with sub-analyses based on cancer type and does of ICI. A systematic review and frequency network meta-analysis were then performed for cardiotoxicity events. 91 RCTs (n=52247) involving 12 treatment arms were finally included. We observed that PD-L1 + CTLA-4 had the highest risk among all therapies inducing any grade cardiotoxicity, and the differences were significant except PD-1 + CTLA-4, PD-1 + TTD and PD-L1 + TTD. In addition, CTLA-4 had a higher risk of Grade 3-5 cardiotoxicity than PD-1 and anit-PD-L1. For Grade 1-5 myocarditis and Grade 3-5 myocarditis, no significant difference was found among differences therapies. No differences were observed in subgroup analyses according to does and cancer type. There were differences in the incidence of cardiotoxicity among different ICI therapies. For ICI monotherapy, CTLA-4 may be linked to Grade 3-5 cardiotoxicity than PD-1 or PD-L1. For dual therapy, the cardiotoxicity of dual ICI therapy seems to be higher than that of chemotherapy or targeted therapy.
Anti-DFS70 antibodies in systemic lupus erythematosus: Prevalence in a large Chinese cohort and an unexpected association with anti-dsDNA antibodies by a long-term follow-up
Authors: Dai Yingxin , Li Enling , Chen Dandan , Niu Xiangyu , Wang Zhiqing , Lu Liangjing , Zheng Bing
Published: September 2022

Objective

Monospecific autoantibodies to dense fine speckles 70 (DFS70) antigen are purported to aid in excluding systemic autoimmune rheumatic diseases (SARD) such as systemic lupus erythematosus (SLE). However, the non-isolated anti-DFS70 still has a certain prevalence in SLE patients, and the clinical significance remains unclear. We aimed to investigate the prevalence, clinical relevance, and value of long-term monitoring of anti-DFS70 antibodies in SLE patients.

Methods

Anti-DFS70 antibodies were measured by enzyme-linked immunosorbent assay (ELISA) in 851 SLE patients, 211 healthy individuals, and 194 patients with other SARD (except SLE). Demographic, serological, and clinical associations of anti-DFS70 antibodies were analyzed by a stepwise multivariable logistic regression model. The correlation of anti-DFS70 with anti-dsDNA, anti-C1q, and SLE Disease Activity Index 2000 (SLEDAI-2K) was analyzed. Sixty-one SLE patients with follow-up time ranging from 2 to 57 months were measured anti-DFS70 antibodies using both ELISA and line immunoassay. The dynamic variations of anti-DFS70 antibodies were evaluated with anti-dsDNA, anti-C1q, and SLEDAI-2K during the follow-up.

Results

The prevalence of anti-DFS70 was significantly higher in SLE (20.7% (176/851)) than in healthy individuals (9.5% (20/211), p = 0.0002) and other SARD (10.8% (21/194), p = 0.002). Multivariable analysis revealed that anti-DFS70-positive SLE patients were associated with younger age (odds ratio (OR) = 0.982; 95% confidence interval (CI) = 0.969, 0.995), higher frequencies of anti-dsDNA (OR 1.598; 95% CI 1.107, 2.306) and anti-PCNA (OR 6.101; 95% CI 2.534, 14.688), and higher levels of serum IgG (OR 1.097; 95% CI 1.067, 1.129) and were more likely to be accompanied by mucosal ulcers (OR 5.921; 95% CI 1.652, 21.215). The O.D. value of anti-DFS70 positively correlated with levels of anti-dsDNA (r = 0.183, p < 0.0001) and anti-C1q (r = 0.181, p < 0.0001), respectively, but not with SLEDAI-2K (p = 0.920). During the follow-up, 49 (42 negative and 7 positive) patients remained stable with anti-DFS70 levels. The other 12 patients experienced significant changes in anti-DFS70, and 83.3% (10/12) of them showed similar trends between anti-DFS70 and anti-dsDNA by evaluation of dynamic variations.

Conclusion

Anti-DFS70 antibodies seem to be prevalent in Chinese SLE patients. The positive association of anti-DFS70 with anti-dsDNA and consistent dynamic variation between anti-DFS70 and anti-dsDNA during the follow-up suggested a potential relationship between anti-DFS70 and anti-dsDNA in patients with SLE.
NOD-like receptors in asthma
Authors: Alvarez-Simon Daniel , Ait Yahia Saliha , de Nadai Patricia , Audousset Camille , Chamaillard Mathias , Boneca Ivo Gomperts , Tsicopoulos Anne
Published: September 2022

Asthma is an extremely prevalent chronic inflammatory disease of the airway where innate and adaptive immune systems participate collectively with epithelial and other structural cells to cause airway hyperresponsiveness, mucus overproduction, airway narrowing, and remodeling. The nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) are a family of intracellular innate immune sensors that detect microbe-associated molecular patterns and damage-associated molecular patterns, well-recognized for their central roles in the maintenance of tissue homeostasis and host defense against bacteria, viruses and fungi. In recent times, NLRs have been increasingly acknowledged as much more than innate sensors and have emerged also as relevant players in diseases classically defined by their adaptive immune responses such as asthma. In this review article, we discuss the current knowledge and recent developments about NLR expression, activation and function in relation to asthma and examine the potential interventions in NLR signaling as asthma immunomodulatory therapies.
Utilizing mast cells in a positive manner to overcome inflammatory and allergic diseases
Authors: Zhang Zhongwei , Ernst Peter B. , Kiyono Hiroshi , Kurashima Yosuke
Published: September 2022

Mast cells (MCs) are immune cells widely distributed in the body, accompanied by diverse phenotypes and functions. Committed mast cell precursors (MCPs) leave the bone marrow and enter the blood circulation, homing to peripheral sites under the control of various molecules from different microenvironments, where they eventually differentiate and mature. Partly attributable to the unique maturation mechanism, MCs display high functional heterogeneity and potentially plastic phenotypes. High plasticity also means that MCs can exhibit different subtypes to cope with different microenvironments, which we call “the peripheral immune education system”. Under the peripheral immune education system, MCs showed a new character from previous cognition in some cases, namely regulation of allergy and inflammation. In this review, we focus on the mucosal tissues, such as the gastrointestinal tract, to gain insights into the mechanism underlying the migration of MCs to the gut or other organs and their heterogeneity, which is driven by different microenvironments. In particular, the immunosuppressive properties of MCs let us consider that positively utilizing MCs may be a new way to overcome inflammatory and allergic disorders.
Durability of clinical and immunologic responses to extended low-dose interleukin-2 therapy in patients with refractory chronic graft-versus-host disease
Authors: Donato Veronica , Kim Haesook T. , Stowe Peter , Reynolds Carol G. , Ritz Jerome , Koreth John , Whangbo Jennifer S.
Published: September 2022

Chronic graft-versus-host disease (cGVHD) remains a frequent cause of non-relapse morbidity and mortality after allogeneic hematopoietic stem cell transplantation. In our single center trials of low-dose interleukin-2 (LD IL-2), the immunomodulatory properties of regulatory T cells (Tregs) have been harnessed to treat steroid-refractory cGVHD (SR-cGVHD) safely and effectively in adults and children. In these trials, 50-60% of patients showed clinical improvement of their cGVHD manifestations with partial responses at the primary response endpoint of 8-12 weeks. Many patients continued extended duration LD IL-2 therapy and achieved deeper clinical responses, including some complete responses. However, the durability of the clinical and immunologic improvement following IL-2 discontinuation has not been reported previously. We examined 20 adult and 2 pediatric patients who received extended duration LD IL-2 for a median of 103 weeks (range, 21-258) and had stable improvement or resolution of their cGVHD symptoms before discontinuing LD IL-2 therapy. The median follow-up after stopping IL-2 was 203 weeks (range 92-599). During this time, 16 patients (73%) were able to wean off all systemic immunosuppression without disease flare or progression. Among 13 patients with available immune cell data, the median fold change in absolute Treg count was 0.58 between 1 to 10 weeks after stopping IL-2 whereas CD4+ conventional T-cell (Tcon) and CD8+ T-cell numbers remained stable. Despite a decline in Treg numbers after IL-2 discontinuation, Treg numbers remained above the pre-treatment baseline. In addition, many patients had sustained clinical improvement after stopping IL-2, suggesting that extended IL-2 therapy can lead to immune tolerance.
Safety of autologous freshly expanded mesenchymal stromal cells for the treatment of graft-versus-host disease
Authors: Stenger Elizabeth , Giver Cynthia R. , Langston Amelia , Kota Daniel , Das Pankoj Kumar , Chinnadurai Raghavan , Galipeau Jacques , Waller Edmund K. , Qayed Muna
Published: September 2022

Despite the curative potential of hematopoietic cell transplantation (HCT) for hematologic malignancies, graft-versus-host disease (GVHD) remains a substantial cause of morbidity and mortality, particularly if treatment is refractory. Treatment with additional immunosuppression including steroids often leads to opportunistic infections and organ dysfunction. Novel therapies are greatly needed, specifically ones that lead to responses in treatment-refractory patients and are better tolerated. Mesenchymal stromal cells (MSCs) are non-hematopoietic tolerogenic cells present in normal bone marrow (BM), which can be expanded ex vivo to therapeutic doses. Their safety and efficacy have been assessed in inflammatory disorders including GVHD, but heterogeneity in clinical responses has led some to examine MSC manufacturing and administration procedures, which may impact in vivo efficacy. We hypothesized that autologous, early-passage, and culture-recovered (after freeze and thaw) MSCs would be safe and may have superior efficacy. In this phase I single-center trial, we assessed MSC safety and early efficacy of an escalating number of doses (2 × 106/kg doses; dose level 1, single dose; dose level 2, two weekly doses; dose level 3, four weekly doses) in patients aged ≥12 years with treatment-refractory acute or chronic GVHD. Eleven enrolled patients received some or all planned MSC infusions, with a median age at enrollment of 37 years. The most common primary HCT indication was leukemia, and the median time from HCT to first MSC infusion was 2.6 years. MSC infusion was well tolerated, with all severe adverse events expected and determined to be unlikely or definitely not related to the study. Thus, no dose-limiting toxicities occurred in the three dose levels. Three of four patients with acute GVHD (or overlap with acute features) had responses seen at any timepoint, ranging from partial to complete. In those with a chronic GVHD indication (n = 7), an overall response at 3 months was partial in five, stable in one, and progressive in one. No appreciable differences were seen between dose levels in peripheral blood lymphocyte subsets. In conclusion, autologous and culture-recovered MSCs were safe in the setting of refractory GVHD following HCT for hematologic malignancy, and clinical responses were most notable in patients with acute GVHD.
FcγRIV is required for IgG2c mediated enhancement of RBC alloimmunization
Authors: Qiu Annie , Miller Anabel , Zotti Flavia Dei , Santhanakrishnan Manjula , Hendrickson Jeanne E. , Tredicine Maria , Stowell Sean R. , Luckey Chance John , Zimring James C. , Hudson Krystalyn E.
Published: September 2022

Passive immunization with anti-D can prevent maternal alloimmunization to RhD thereby preventing hemolytic disease of the fetus and newborn. Unexpectedly, anti-D fails in some cases and some monoclonal anti-D preparations paradoxically enhances alloimmunization. The underlying mechanisms modulating humoral alloimmunization by anti-D are unknown. We previously reported that IgG antibody subclasses differentially regulate alloimmunity in response to red blood cell (RBC) transfusions in a mouse model; in particular, IgG2c significantly enhanced RBC alloantibody responses. Initial mechanistic studies revealed that IgG2c:RBC immune complexes were preferentially consumed by the splenic dendritic cell (DC) subsets that play a role in RBC alloimmunization. The deletion of activating Fc-gamma receptors (FcγRs) (i.e., FcγRI, FcγRIII, and FcγRIV) on DCs abrogated IgG2c-mediated enhanced alloimmunization. Because DCs express high levels of FcγRIV, which has high affinity for the IgG2c subclass, we hypothesized that FcγRIV was required for enhanced alloimmunization. To test this hypothesis, knockout mice and blocking antibodies were used to manipulate FcγR expression. The data presented herein demonstrate that FcγRIV, but not FcγRI or FcγRIII, is required for IgG2c-mediated enhancement of RBC alloantibody production. Additionally, FcγRI is alone sufficient for IgG2c-mediated RBC clearance but not for increased alloimmunization, demonstrating that RBC clearance can occur without inducing alloimmunization. Together, these data, combined with prior observations, support the hypothesis that passive immunization with an RBC-specific IgG2c antibody increases RBC alloantibody production through FcγRIV ligation on splenic conventional DCs (cDCs). This raises the question of whether standardizing antibody subclasses in immunoprophylaxis preparations is desirable and suggests which subclasses may be optimal for generating monoclonal anti-D therapeutics.
Combinatorial suicide gene strategies for the safety of cell therapies
Authors: Falcon Corey , Smith Lauren , Al-Obaidi Mustafa , Abu Zaanona Mohammed , Purvis Katelyn , Minagawa Kentaro , Athar Mohammad , Salzman Donna , Bhatia Ravi , Goldman Frederick , Di Stasi Antonio
Published: September 2022

Gene-modified cellular therapies carry inherent risks of severe and potentially fatal adverse events, including the expansion of alloreactive cells or malignant transformation due to insertional mutagenesis. Strategies to mitigate uncontrolled proliferation of gene-modified cells include co-transfection of a suicide gene, such as the inducible caspase 9 safety switch (ΔiC9). However, the activation of the ΔiC9 fails to completely eliminate all gene-modified cells. Therefore, we tested a two suicide gene system used independently or together, with the goal of complete cell elimination. The first approach combined the ΔiC9 with an inducible caspase 8, ΔiC8, which lacks the endogenous prodomain. The rationale was to use a second caspase with an alternative and complementary mechanism of action. Jurkat cells co-transduced to co-express the ΔiC8, activatable by a BB homodimerizer, and the ΔiC9 activatable by the rapamycin analog sirolimus were used in a model to estimate the degree of inducible cell elimination. We found that both agents could activate each caspase independently, with enhanced elimination with superior reduction in cell regrowth of gene-modified cells when both systems were activated simultaneously. A second approach was employed in parallel, combining the ΔiC9 with the RQR8 compact suicide gene. RQR8 incorporates a CD20 mimotope, targeted by the anti-CD20 monoclonal antibody rituxan, and the QBend10, a ΔCD34 selectable marker. Likewise, enhanced cell elimination with superior reduction in cell regrowth was observed when both systems were activated together. A dose-titration effect was also noted utilizing the BB homodimerizer, whereas sirolimus remained very potent at minimal concentrations. Furtherin vivostudies are needed to validate these novel combination systems, which may play a role in future cancer therapies or regenerative medicine.
Neutrophil extracellular traps in fungal infections: A seesaw battle in hosts
Authors: Zhong Hua , Lu Ren-Yi , Wang Yan
Published: September 2022

Fungal infections are a growing health care challenge. Neutrophils play a key role in defense against fungal infections. There are many effective ways for neutrophils to eliminate fungal invaders, such as phagocytosis, oxidative bursts, and the formation of extracellular traps. This process has received considerable attention and has made rapid progress since neutrophil extracellular traps (NETs) formation was described. Here, we describe the formation, induction, and function of NETs, as well as fungal strategies against NETs hunting. We highlight the effects of NETs on common fungal pathogens and how these pathogens survive.
Preclinical characterization of amubarvimab and romlusevimab, a pair of non-competing neutralizing monoclonal antibody cocktail, against SARS-CoV-2
Authors: Ji Yun , Zhang Qi , Cheng Lin , Ge Jiwan , Wang Ruoke , Fang Mengqi , Mucker Eric M. , Chen Peng , Ma Ji , Zhang Rui , Li Chunming , Hammond Holly , Baracco Lauren , Holbrook Michael , Frieman Matthew , Zhang Zheng , Wang Xinquan , Hooper Jay W. , Zhang Linqi , Zhu Qing
Published: September 2022

Monoclonal antibodies (mAbs) targeting the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein have demonstrated clinical efficacy in preventing or treating coronavirus disease 2019 (COVID-19), resulting in the emergency use authorization (EUA) for several SARS-CoV-2 targeting mAb by regulatory authority. However, the continuous virus evolution requires diverse mAb options to combat variants. Here we describe two fully human mAbs, amubarvimab (BRII-196) and romlusevimab (BRII-198) that bind to non-competing epitopes on the receptor binding domain (RBD) of spike protein and effectively neutralize SARS-CoV-2 variants. A YTE modification was introduced to the fragment crystallizable (Fc) region of both mAbs to prolong serum half-life and reduce effector function. The amubarvimab and romlusevimab combination retained activity against most mutations associated with reduced susceptibility to previously authorized mAbs and against variants containing amino acid substitutions in their epitope regions. Consistently, the combination of amubarvimab and romlusevimab effectively neutralized a wide range of viruses including most variants of concern and interest in vitro. In a Syrian golden hamster model of SARS-CoV-2 infection, animals receiving combination of amubarvimab and romlusevimab either pre- or post-infection demonstrated less weight loss, significantly decreased viral load in the lungs, and reduced lung pathology compared to controls. These preclinical findings support their development as an antibody cocktail therapeutic option against COVID-19 in the clinic.
MCPggaac haplotype is associated with poor graft survival in kidney transplant recipients with de novo thrombotic microangiopathy
Authors: Petr Vojtech , Csuka Dorottya , Hruba Petra , Szilágyi Ágnes , Kollar Marek , Slavcev Antonij , Prohászka Zoltán , Viklicky Ondrej
Published: September 2022

De novo thrombotic microangiopathy (TMA) is associated with poor kidney graft survival, and as we previously described, it is a recipient driven process with suspected genetic background. Direct Sanger sequencing was performed in 90 KTR with de novo TMA and 90 corresponding donors on selected regions in CFH, CD46, C3, and CFB genes that involve variations with a functional effect or confer a risk for aHUS. Additionally, 37 recipients of paired kidneys who did not develop TMA were analyzed for the MCPggaac haplotype. Three-years death-censored graft survival was assessed using Kaplan-Meier and Cox regression models. The distribution of haplotypes in all groups was in the Hardy-Weinberg equilibrium and there was no clustering of haplotypes in any group. In the TMA group, we found that MCPggaac haplotype carriers were at a significantly higher risk of graft loss compared to individuals with the wild-type genotype. Worse 3-year death-censored graft survival was associated with longer cold ischemia time (HR 1.20, 95% CI 1.06, 1.36) and recipients’ MCPggaac haplotype (HR 3.83, 95% CI 1.42, 10.4) in the multivariable Cox regression model. There was no association between donor haplotypes and kidney graft survival. Similarly, there was no effect of the MCPggaac haplotype on 3-year graft survival in recipients of paired kidneys without de novo TMA. Kidney transplant recipients carrying the MCPggaac haplotype with de novo TMA are at an increased risk of premature graft loss. These patients might benefit from therapeutic strategies based on complement inhibition.
Epstein-Barr Virus and multiple sclerosis in a Spanish cohort: A two-years longitudinal study
Authors: Domínguez-Mozo María Inmaculada , López-Lozano Lorena , Pérez-Pérez Silvia , García-Martínez Ángel , Torrejón María José , Arroyo Rafael , Álvarez-Lafuente Roberto
Published: September 2022

Objectives

1. To analyze the prevalence and levels of anti-EBNA-1 and anti-VCA IgG antibodies of Epstein-Barr virus (EBV) in a Spanish cohort of multiple sclerosis (MS) patients and their interactions with other environmental and genetic risk factors. 2. To analyze the association of the evolution of these antibodies with the clinical response to different disease modifying therapies (DMTs) after two-years of follow-up. 3. To assess their possible correlation with the class II HLA alleles as well as with several SNPs identified in GWAS related to disease susceptibility.

Materials and methods

We recruited 325 MS patients without DMT (serum samples were collected 1-3 months before starting a therapy) and 295 healthy controls (HC). For each patient we also collected serum samples 6, 12, 18 and 24 months after starting the DMT. EBNA-1 and VCA IgG titers were analyzed by ELISA; 25(OH)D levels were analyzed by immunoassay; HLA DRB1*15:01 allelic variant was analyzed by Taqman technology.

Results

1. 97.8% (318/325) vs. 87.1% (257/295) positives for EBNA-1 in MS patients and HC, respectively (p<0.0001; O.R. = 6.7); 99.7% (324/325) vs. 94.6% (279/295) for VCA in MS patients and HC, respectively (p=0.0001; O.R. = 18.6). All MS patients were positive for EBNA-1 and/or VCA IgG antibodies vs. 280/295 (94.9%) HC (p<0.0001). IgG titers were also significantly higher in MS patients than in HC. 2. We did not find any statistical correlation in the variation of the EBNA-1 and VCA IgG titers between baseline and 24 month visits with the number of relapses, progression, clinical response, NEDA-3 condition or therapeutic failure. 3. When we compared different epidemiological and clinical variables between those with genetic factors associated with lower EBNA-1 IgG titers and all other MS patients, we found MS started 3.5 years later among the first.

Conclusions

These results confirm that MS occurs rarely in absence of EBV. An intriguing association between genetic burden and lower EBNA-1 IgG titers was associated with an earlier age of disease onset. Similar studies with B-cell–targeted therapies should be performed.
Dynamics and enzymatic degradation of exopolymer particles under increasing concentrations of silver ions and nanoparticles during a marine mesocosm experiment
Authors: Scheidemann Lindsay , Pontiller Benjamin , Manna Vincenzo , Cisternas-Novoa Carolina , Celussi Mauro , Tsiola Anastasia , Pitta Paraskevi , Magiopoulos Iordanis , Engel Anja
Published: September 2022

Pollution of the marine environment is an emerging threat. Nowadays, engineered nanoparticles (<100 nm) such as zinc, copper and silver are widely used as antimicrobial agents, therefore often present in daily-life products. Consequently, the demand and production of nanoparticles are expected to increase. Here, we specifically focus on silver nanoparticles (AgNP). Once released into the environment, AgNPs pose an obvious ecotoxicological risk, potentially affecting ecosystem structure and functioning. For instance, phytoplankton-derived exudates, rich in acidic polysaccharides and amino acids, can abiotically aggregate into microgels such as transparent exopolymer particles (TEP) and Coomassie stainable particles (CSP). Hence, microgels can bridge dissolved and particulate size fractions and facilitate aggregate formation with organic and mineral particles. Both physical and chemical properties make TEP and CSP attractive nutrient hotspots for heterotrophic bacterioplankton. Bacteria, in turn, utilize extracellular enzymes to access these carbon and nitrogen pools. However, knowledge about the mechanisms by which AgNPs might interact with and affect the biogeochemical cycling of TEP and CSP is still insufficient. Therefore, we conducted a mesocosm experiment in the Eastern Mediterranean Sea and investigated the effects of environmentally relevant concentrations of silver ions (Ag+) and AgNP on the properties of TEP and CSP (i.e., area and abundance) along with enzymatic activity measurements. Our results showed that cyanobacteria were likely the primary source of CSP in the ultra-oligotrophic Mediterranean Sea. Also, CSP contributed more to the microgel pool than TEP, as indicated by a strong relationship between CSP and heterotrophic microbial dynamics. While silver (i.e., Ag+ or AgNP) had overall only marginal effects, both species affected the relationships between cell-specific LAPase activity and CSP and cell-specific APase activity and phosphate levels. Thus, Ag+ and AgNP have the potential to regulate microgel dynamics. However, future studies are needed to derive a robust understanding of the effects of silver pollution on the coupling of microgel formation and degradation and the follow-on effect on biogeochemical cycles.
Quantifying spatial extents of artificial versus natural reefs in the seascape
Authors: Steward D’amy N. , Paxton Avery B. , Bacheler Nathan M. , Schobernd Christina M. , Mille Keith , Renchen Jeffrey , Harrison Zach , Byrum Jordan , Martore Robert , Brinton Cameron , Riley Kenneth L. , Taylor J. Christopher , Kellison G. Todd
Published: September 2022

With increasing human uses of the ocean, existing seascapes containing natural habitats, such as biogenic reefs or plant-dominated systems, are supplemented by novel, human-made habitats ranging from artificial reefs to energy extraction infrastructure and shoreline installments. Despite the mixture of natural and artificial habitats across seascapes, the distribution and extent of these two types of structured habitats are not well understood but are necessary pieces of information for ocean planning and resource management decisions. Through a case study, we quantified the amount of seafloor in the southeastern US (SEUS; 103,220 km2 in the Atlantic Ocean; 10 – 200 m depth) covered by artificial reefs and natural reefs. We developed multiple data-driven approaches to quantify the extent of artificial reefs within state-managed artificial reef programs, and then drew from seafloor maps and published geological and predictive seafloor habitat models to develop three estimates of natural reef extent. Comparisons of the extent of natural and artificial reefs revealed that artificial reefs account for substantially less habitat (average of two estimates 3 km2; <0.01% of SEUS) in the region than natural reefs (average of three estimates 2,654 km2; 2.57% of SEUS) and that this pattern holds across finer regional groupings (e.g., states, depth bins). Our overall estimates suggest that artificial reef coverage is several orders of magnitude less than natural reef coverage. While expansive seafloor mapping and characterization efforts are still needed in SEUS waters, our results fill information gaps regarding the extent of artificial and natural reef habitats in the region, providing support for ecosystem-based management, and demonstrating an approach applicable to other regions.
An analytical approach to entropy production in MHD mixed convection micropolar fluid flow over an inclined porous stretching sheet
Authors: Sadighi Sina , Afshar Hossein , Jabbari Mohsen , Ahmadi Danesh Ashtiani Hossein
Published: September 2022

This analytical analysis examines the MHD micropolar fluid flow and mixed convection features using entropy production analysis of an inclined porous stretching sheet. Flow field and heat transfer analysis are presented to consider thermal radiation, heat source/sink, Lorentz, and buoyancy forces. The PDEs system is transformed by appropriate similarity variables, turned into a system of high non-linearity coupling ODEs, and then solved with the help of an analytical approach. An analytical approach can provide exact explicit solutions for the flow field, heat transport, entropy production, the local skin friction coefficient, the local couple stress coefficient, and the local Nusselt number. It is shown that the magnetic field, mixed convection, and sheet inclination effects can be incorporated together into a single parameter, which is called the magneto-buoyancy-inclination parameter here. In other words, this parameter controls the boundary layer flow. In addition, an experimental procedure called Box-Behnken design (BBD) was employed to analyze the influence of material (K), radiation (Rd), and buoyancy (Λ) parameters on entropy production in MHD micropolar fluid flow over the sheet. In order to estimate accurately the optimum entropy generation containing K, Rd, and Λ, we used a quadratic regression model. Based on the results of this investigation, the value of the entropy generation number became larger by decreasing the magneto-buoyancy-inclination parameter. Further, the magnitude of the local couple stress coefficient is reduced as the heat source parameter increases.
Optimization of anesthetic decision-making in ERAS using Bayesian network
Authors: Chen Yuwen , Zhu Yiziting , Zhong Kunhua , Yang Zhiyong , Li Yujie , Shu Xin , Wang Dandan , Deng Peng , Bai Xuehong , Gu Jianteng , Lu Kaizhi , Zhang Ju , Zhao Lei , Zhu Tao , Wei Ke , Yi Bin
Published: September 2022

Enhanced recovery after surgery (ERAS) can accelerate patient recovery. However, little research has been done on optimizing the ERAS-related measures and how the measures interact with each other. The Bayesian network (BN) is a graphical model that describes the dependencies between variables and is also a model for uncertainty reasoning. In this study, we aimed to develop a method for optimizing anesthetic decisions in ERAS and then investigate the relationship between anesthetic decisions and outcomes. First, assuming that the indicators used were independent, the effects of combinations of single indicators were analyzed based on BN. Additionally, the impact indicators for outcomes were selected with statistical tests. Then, based on the previously selected indicators, the Bayesian network was constructed using the proposed structure learning method based on Strongly Connected Components (SCC) Local Structure determination by Hill Climbing Twice (LSHCT) and adjusted according to the expert’s knowledge. Finally, the relationship is analyzed. The proposed method is validated by the real clinical data of patients with benign gynecological tumors from 3 hospitals in China. Postoperative length of stay (LOS) and total cost (TC) were chosen as the outcomes. Experimental results show that the ERAS protocol has some pivotal indicators influencing LOS and TC. Identifying the relationship between these indicators can help anesthesiologists optimize the ERAS protocol and make individualized decisions.
Adrenal crisis during pregnancy: Case report and obstetric perspective
Authors: Gardella Barbara , Gritti Andrea , Scatigno Annachiara Licia , Gallotti Anna Maria Clelia , Perotti Francesca , Dominoni Mattia
Published: September 2022

Adrenal dysfunction (AD) and, in particular, adrenal crisis are uncommon events in pregnant women, but associated with significant maternal and fetal morbidity and mortality if untreated or undiagnosed. Adrenal crisis may be confused with the common symptoms of pregnancy: the obstetricians should be able to promptly diagnose and treat it in order to avoid the adverse outcomes regarding the mother and the fetus. For this reason, AD must be treated by an expert multidisciplinary team. We presented a case report of a young pregnant woman with adrenal crisis due to tuberculosis, cocaine abuse, and massive bilateral hemorrhage with symptoms of emesis, hypotension, sudden abdominal pain, and leukocytosis. The most common issues of diagnosis and treatment are discussed and analyzed. Finally, we performed a review of the literature regarding adrenal crisis and adrenal insufficiency (AI) in pregnancy in order to clarify the management of these diseases in obstetrics setting.
The effect of first trimester body mass index on the changes in the upper lip bite test classification before and after delivery: A prospective observational study
Authors: Li Yannan , Li Yue , Chen Qufei , Hua Hanli , Jiao Jing , Zhang Le , Chen Liming , Huang Shaoqiang
Published: September 2022

Background

The difficult airway (DA) assessment and management of pregnant woman has always brought specific challenges. The aim of this study was to investigate the effect of labor on the airway by assessing changes in the upper lip bite test (ULBT) classes and to explore its correlation with the first trimester's body mass index (BMI).

Methods

According to the BMI of the first trimester, 354 full-term women were divided into low BMI group, normal BMI group and high BMI group. The ULBT class and pregnancy outcome were recorded and compared at early labor, after delivery, and 48 h after delivery.

Results

The ULBT class was increased in 75(21.1%) patients after delivery. Compared to the normal BMI group, the high BMI group had a higher probability of increasing (34.8 vs. 17.5%; P = 0.002). The number of women with ULBT class 2–3 increased to 157, which was 1.48 times that of early labor. The number of women with ULBT class 3 increased from 4 to 16, of which 7 (53.8%) were from the high BMI group. Binary logistic regression analysis showed that first trimester's BMI was associated with a significant increase in ULBT class after delivery (adjusted odds ratio [aOR] = 2.13 [0.91–4.98], P = 0.02). The ULBT classes of the three groups tended to return to their initial level 48 h after delivery (P > 0.05).

Conclusion

Labor results in an approximately one-fifth increase in ULBT class. Being overweight or obese in the first trimester is associated with an increased risk of DA during labor.

Trial registration

This study was registered in the Chinese Clinical Trial Registry (http://www.chictr.org.cn) on September 26, 2020. Registration number ChiCTR2000038643.
A bibliometric analysis of publications on burn sepsis using VOSviewer
Authors: Cao Zhi , Zhang Yu , Luo Jin-Hua , Liao Wen-Qiang , Cheng Xing , Zhan Jian-Hua
Published: September 2022

Background

Sepsis is one of the most common complications in burn patients and causes high morbidity, especially in those with severe burns. Nevertheless, there are no formal criteria for diagnosing and treating burn sepsis. Therefore, this bibliometric analysis is applied to reveal research trends in this field and predicts its possible hot spots.

Methods

We screened relevant literature on burn sepsis that met the inclusion criteria of the Web of Sciences (WOS) database and analyzed publication trends and research hot spots in related fields using VOSviewer software.

Results

From 1981 to 2022, we screened 2,486 documents that met the requirements and analyzed them bibliometrically. The American scholar Herndon DN had a much higher h-index [47] than other authors. Most published, cited, and h-indexed publications are from the USA (Np: 1193, Nc: 42154, H: 98). The second most publishing country is China, but the second most cited and h-indexed country is Germany. Burns also outperforms other journals in this field (Np: 376, Nc: 8019, H: 46). “Biomarkers” is a newly emerging keyword (cluster “clinical research,” APY was 2018.16), and clinically relevant research in burn sepsis maybe a future research trend.

Conclusions

Sepsis in burn patients has unique pathophysiological characteristics and the general diagnostic criteria for sepsis lack specificity. Consequently, we must establish a database and construct an intelligent predictive model to help achieve a more individualized and precise early diagnosis and treatment of burn sepsis. This may also be an important development direction for future research in this field.
Influence of dementia literacy and caregiving appraisal on the psychological wellbeing of informal caregivers of people with dementia: A cross-sectional study
Authors: Wang Shanshan , Shan Qiuju , Cheung Daphne Sze Ki , Xu Xinyi , Leung Isaac Sze Him , Leung Angela Yee Man
Published: September 2022

Background

Dementia informal caregiving is a global phenomenon. It is well documented that caregivers' psychological health is often affected by busy caregiving schedules. Lawton's two-factor model indicates that caregivers' psychological wellbeing is influenced by caregiving appraisal and other caregiver factors. Our review also identified the significance of dementia literacy, which was an essential caregiver factor. However, it is imperative for a clear understanding of the mechanism of how psychological wellbeing is influenced by them.

Objectives

To explore the association among dementia literacy, caregiving appraisal, and psychological wellbeing and the influencing mechanisms between them.

Methods

Two hundred and twenty-three informal caregivers of people with dementia were involved in this cross-sectional study. Dementia literacy was measured by the Alzheimer's Disease Knowledge Scale and Dementia Attitude Scale. Caregiving appraisal and psychological wellbeing were measured with the Caregiving Appraisal Scale and Ryff's Psychological wellbeing Scale, respectively. Descriptive statistics were used to describe the characteristics of participants and key outcome variables. Pearson's correlation analysis was used to analyze the correlation among the variables. Structural equation modeling was used to examine the hypothetical mediating role of caregiving appraisal in the relationship between dementia literacy (i.e., knowledge of dementia and attitude toward dementia) and caregivers' psychological wellbeing.

Results

The hypotheses were partially confirmed. Attitude toward dementia was significantly associated with caregiving appraisal (r = 0.312, p < 0.01) and psychological wellbeing (r = 0.311, p < 0.01). However, knowledge of dementia was only significantly associated with psychological wellbeing (r = 0.136, p < 0.05). The structural equation modeling fitted well (p = 0.078, CFI = 0.987, RMSEA = 0.038). In the fitted model, caregiving appraisal partially mediated the association between attitude toward dementia and psychological wellbeing. In contrast, attitude toward dementia and caregiving appraisal fully mediated the association between knowledge of dementia and psychological wellbeing.

Conclusion

Efforts can be exerted to improve dementia caregivers' caregiving appraisal and attitude toward dementia to improve their psychological wellbeing.