bluuebunny/crossref_metadata_2025 huggingface dataset:
The PID Principles of Care: Where Are We Now? A Global Status Report Based on the PID Life Index
Authors: Nordin Julia , Solís Leire , Prévot Johan , Mahlaoui Nizar , Chapel Helen , Sánchez-Ramón Silvia , Ali Adli , Seymour John W. , Pergent Martine
Published: November 2021

A global gold standard framework for primary immunodeficiency (PID) care, structured around six principles, was published in 2014. To measure the implementation status of these principles IPOPI developed the PID Life Index in 2020, an interactive tool aggregating national PID data. This development was combined with a revision of the principles to consider advances in the field of health and science as well as political developments since 2014. The revision resulted in the following six principles: PID diagnosis, treatments, universal health coverage, specialised centres, national patient organisations and registries for PIDs. A questionnaire corresponding to these principles was sent out to IPOPI’s national member organisations and to countries in which IPOPI had medical contacts, and data was gathered from 60 countries. The data demonstrates that, regardless of global scientific progress on PIDs with a growing number of diagnostic tools and better treatment options becoming available, the accessibility and affordability of these remains uneven throughout the world. It is not only visible between regions, but also between countries within the same region. One of the most urgent needs is medical education. In countries without immunologists, patients with PID suffer the risk of remaining undiagnosed or misdiagnosed, resulting in health implications or even death. Many countries also lack the infrastructure needed to carry out more advanced diagnostic tests and perform treatments such as hematopoietic stem cell transplantation or gene therapy. The incapacity to secure appropriate diagnosis and treatments affects the PID environment negatively in these countries. Availability and affordability also remain key issues, as diagnosis and treatments require coverage/reimbursement to ensure that patients with PID can access them in practice, not only in theory. This is still not the case in many countries of the world according to the PID Life Index. Although some countries do perform better than others, to date no country has fully implemented the PID principles of care, confirming the long way ahead to ensure an optimal environment for patients with PID in every country.
GII.P16-GII.2 Recombinant Norovirus VLPs Polarize Macrophages Into the M1 Phenotype for Th1 Immune Responses
Authors: Han Ji Cheng , Li Qiu Xuan , Fang Jin Bo , Zhang Jin Yong , Li Yi Quan , Li Shan Zhi , Cheng Cheng , Xie Chang Zhan , Nan Fu Long , Zhang He , Li Zhuo Xin , Jin Ning Yi , Zhu Guang Ze , Lu Hui Jun
Published: November 2021

Norovirus (NoV) is a zoonotic virus that causes diarrhea in humans and animals. Outbreaks in nosocomial settings occur annually worldwide, endangering public health and causing serious social and economic burdens. The latter quarter of 2016 witnessed the emergence of the GII.P16-GII.2 recombinant norovirus throughout Asia. This genotype exhibits strong infectivity and replication characteristics, proposing its potential to initiate a pandemic. There is no vaccine against GII.P16-GII.2 recombinant norovirus, so it is necessary to design a preventive vaccine. In this study, GII.P16-GII.2 type norovirus virus-like particles (VLPs) were constructed using the baculovirus expression system and used to conduct immunizations in mice. After immunization of mice, mice were induced to produce memory T cells and specific antibodies, indicating that the VLPs induced specific cellular and humoral immune responses. Further experiments were then initiated to understand the underlying mechanisms involved in antigen presentation. Towards this, we established co-cultures between dendritic cells (DCs) or macrophages (Mø) and naïve CD4+T cells and simulated the antigen presentation process by incubation with VLPs. Thereafter, we detected changes in cell surface molecules, cytokines and related proteins. The results indicated that VLPs effectively promoted the phenotypic maturation of Mø but not DCs, as indicated by significant changes in the expression of MHC-II, costimulatory factors and related cytokines in Mø. Moreover, we found VLPs caused Mø to polarize to the M1 type and release inflammatory cytokines, thereby inducing naïve CD4+ T cells to perform Th1 immune responses. Therefore, this study reveals the mechanism of antigen presentation involving GII.P16-GII.2 recombinant norovirus VLPs, providing a theoretical basis for both understanding responses to norovirus infection as well as opportunities for vaccine development.
Janus Kinase Inhibitors in the Treatment of Vitiligo: A Review
Authors: Qi Fei , Liu Fang , Gao Ling
Published: November 2021

Vitiligo is a multifactorial reversible skin disorder characterized by distinct white patches that result from melanocyte destruction. Activated CXCR3+ CD8+ T cells promote melanocyte detachment and apoptosis through interferon-gamma (IFN-γ secretion and chemokines secreted by keratinocytes through the Janus kinase (JAK)/signal transducer and activator of transcription (STAT)-1 signaling pathway results in further recruitment of CXCR3+ CD8+ T cells and the formation of a positive-feedback loop. JAK inhibitors target the JAK/STAT pathway and are now approved to treat many immune-related diseases. In the treatment of vitiligo, JAK inhibitors, including ruxolitinib, baricitinib, and tofacitinib, are effective, supporting the implication of the IFN-γ-chemokine signaling axis in the pathogenesis of vitiligo. However, more studies are required to determine the ideal dosage of JAK inhibitors for the treatment of vitiligo, and to identify other inflammatory pathways that may be implicated in the pathogenesis of this condition.
Un-‘Egg’-Plored: Characterisation of Embryonation in the Whipworm Model Organism Trichuris muris
Authors: Forman Ruth , Partridge Frederick A. , Sattelle David B. , Else Kathryn J.
Published: November 2021

Trichuris muris, is the murine parasite and widely deployed model for the human whipworm Trichuris trichiura, a parasite that infects around 500 million people globally. Trichuriasis is a classical disease of poverty with a cycle of re-infection due to the continual exposure of humans, particularly children, to infective eggs, which contaminate the soil in endemic areas. Indeed, modelling studies of trichuriasis have demonstrated that the low efficacy rate of current anthelmintics combined with the high possibility of re-infection from the reservoir of infective eggs within the environment, mean that the elimination of morbidity due to trichuriasis is unlikely to occur. Despite the importance of the infective egg stage in the perpetuation of infections, understanding the biology of the Trichuris ova has been neglected for decades. Here we perform experiments to assess the impact of temperature on the embryonation process of T. muris eggs and describe in detail the stages of larval development within these eggs. In keeping with the early works performed in the early 1900s, we show that the embryonation of T. muris is accelerated by an elevation in temperature, up to 37°C above which eggs do not fully develop and become degenerate. We extend these data to provide a detailed description of T. muris egg development with clear images depicting the various stages of development. To the best of our knowledge we have, for the first time, described the presence of birefringent granules within egg-stage larvae, as well as providing a qualitative and quantitative description of a motile larval stage prior to quiescence within the egg. These experiments are the first step towards a better understanding of the basic biology which underlies the process of egg embryonation. With the threat of elevation in global temperatures, the accelerated embryonation rate we observe at higher temperatures may have important consequences for parasite transmission rates and prospective modelling studies. In addition, a deeper understanding of the Trichuris ova may allow the development of novel control strategies targeting the egg stage of Trichuris in the environment as an adjunct to MDA.
Cetacean Strandings From Space: Challenges and Opportunities of Very High Resolution Satellites for the Remote Monitoring of Cetacean Mass Strandings
Authors: Clarke Penny J. , Cubaynes Hannah C. , Stockin Karen A. , Olavarría Carlos , de Vos Asha , Fretwell Peter T. , Jackson Jennifer A.
Published: November 2021

The study of cetacean strandings was globally recognised as a priority topic at the 2019 World Marine Mammal Conference, in recognition of its importance for understanding the threats to cetacean communities and, more broadly, the threats to ecosystem and human health. Rising multifaceted anthropogenic and environmental threats across the globe, as well as whale population recovery from exploitation in some areas, are likely to coincide with an increase in reported strandings. However, the current methods to monitor strandings are inherently biased towards populated coastlines, highlighting the need for additional surveying tools in remote regions. Very High Resolution (VHR) satellite imagery offers the prospect of upscaling monitoring of mass strandings in minimally populated/unpopulated and inaccessible areas, over broad spatial and temporal scales, supporting and informing intervention on the ground, and can be used to retrospectively analyse historical stranding events. Here we (1) compile global strandings information to identify the current data gaps; (2) discuss the opportunities and challenges of using VHR satellite imagery to monitor strandings using the case study of the largest known baleen whale mass stranding event (3) consider where satellites hold the greatest potential for monitoring strandings remotely and; (4) outline a roadmap for satellite monitoring. To utilise this platform to monitor mass strandings over global scales, considerable technical, practical and environmental challenges need to be addressed and there needs to be inclusivity in opportunity from the onset, through knowledge sharing and equality of access to imagery.
Copernicus Sea Level Space Observations: A Basis for Assessing Mitigation and Developing Adaptation Strategies to Sea Level Rise
Authors: Legeais Jean-François , Meyssignac Benoît , Faugère Yannice , Guerou Adrien , Ablain Michaël , Pujol Marie-Isabelle , Dufau Claire , Dibarboure Gérald
Published: November 2021

It is essential to monitor accurately current sea level changes to better understand and project future sea level rise (SLR). This is the basis to support the design of adaptation strategies to climate change. Altimeter sea level products are operationally produced and distributed by the E.U. Copernicus services dedicated to the marine environment (CMEMS) and climate change (C3S). The present article is a review paper that intends to explain why and to which extent the sea level monitoring indicators derived from these products are appropriate to develop adaptation strategies to SLR. We first present the main key scientific questions and challenges related to SLR monitoring. The different processing steps of the altimeter production system are presented including those ensuring the quality and the stability of the sea level record (starting in 1993). Due to the numerous altimeter algorithms required for the production, it is complex to ensure both the retrieval of high-resolution mesoscale signals and the stability of the large-scale wavelengths. This has led to the operational production of two different sea level datasets whose specificities are characterized. We present the corresponding indicators: the global mean sea level (GMSL) evolution and the regional map of sea level trends, with their respective uncertainties. We discuss how these products and associated indicators support adaptation to SLR, and we illustrate with an example of downstream application. The remaining gaps are analyzed and recommendations for the future are provided.
Variation in Coral Thermotolerance Across a Pollution Gradient Erodes as Coral Symbionts Shift to More Heat-Tolerant Genera
Authors: Naugle Melissa S. , Oliver Thomas A. , Barshis Daniel J. , Gates Ruth D. , Logan Cheryl A.
Published: November 2021

Phenotypic plasticity is one mechanism whereby species may cope with stressful environmental changes associated with climate change. Reef building corals present a good model for studying phenotypic plasticity because they have experienced rapid climate-driven declines in recent decades (within a single generation of many corals), often with differential survival among individuals during heat stress. Underlying differences in thermotolerance may be driven by differences in baseline levels of environmental stress, including pollution stress. To examine this possibility, acute heat stress experiments were conducted on Acropora hyacinthus from 10 sites around Tutuila, American Samoa with differing nutrient pollution impact. A threshold-based heat stress assay was conducted in 2014 and a ramp-hold based assay was conducted in 2019. Bleaching responses were measured by assessing color paling. Endosymbiont community composition was assessed at each site using quantitative PCR. RNA sequencing was used to compare differences in coral gene expression patterns prior to and during heat stress in 2019. In 2014, thermotolerance varied among sites, with polluted sites holding more thermotolerant corals. These differences in thermotolerance correlated with differences in symbiont communities, with higher proportions of heat-tolerant Durusdinium found in more polluted sites. By 2019, thermotolerance varied less among sites, with no clear trend by pollution level. This coincided with a shift toward Durusdinium across all sites, reducing symbiont community differences seen in 2014. While pollution and symbiont community no longer could explain variation in thermotolerance by 2019, gene expression patterns at baseline levels could be used to predict thermotolerance thresholds. These patterns suggest that the mechanisms underlying thermotolerance shifted between 2014 and 2019, though it is possible trends may have also been affected by methodological differences between heat stress assays. This study documents a shift in symbiont community over time and captures potential implications of that shift, including how it affects variation in thermotolerance among neighboring reefs. This work also highlights how gene expression patterns could help identify heat-tolerant corals in a future where most corals are dominated by Durusdinium and symbiont-driven thermotolerance has reached an upper limit.
Circadian Variation in the Median Effective Dose of Epidural Ropivacaine for Labor Analgesia
Authors: Deng Jiali , Wei Changna , Liu Lin , Qian Jing , Xiao Fei , Chen Xinzhong
Published: November 2021

Background: Labor pain perception has been demonstrated to exhibit a circadian rhythm with lower pain scores during the day compared with the night. This study aimed to determine and compare the median effective dose (ED50) of ropivacaine in parturients having epidural labor analgesia during the day vs. during the night.

Methods: The study group consisted of 60 nulliparous healthy parturients who were assigned to one of two groups according to the time they requested labor analgesia: Day Group (7:01 am to 7:00 pm) and Night Group (7:01 pm to 7:00 am). A bolus of.15% ropivacaine was administered epidurally and effective analgesia was defined as the attainment of a visual analog scale (VAS) pain score ≤ 10 mm within 30 min. The dose of ropivacaine for the first parturient in each group was 18 mg. The dose for each subsequent parturient was varied with increments or decrements of 3 mg based on the response of the previous subject. The ED50 was calculated using up-down sequential analysis. Probit regression was used to estimate the relative mean potency of ropivacaine between groups.

Results: The ED50 (mean [95% CI]) of ropivacaine was lower in the Day Group (17.9 [16.5–19.4] mg) than in the Night Group (20.9 [19.2–22.7] mg) (P = 0.003). The estimate of relative potency for ropivacaine for the Night Group vs. the Day Group was 0.85 (95% CI:0.56–0.98).

Conclusions: Under the conditions of this study, the dose requirement for epidural ropivacaine for labor analgesia was ~ 15% greater during the night than during the day.

Clinical Trials Registration: Chinese Clinical Trial Registry (No.: ChiCTR1900025269. http://www.chictr.org.cn/showprojen.aspx?proj=36993).
Plasma C-C Chemokine Concentrations in Intermediate Age-Related Macular Degeneration
Authors: Palestine Alan G. , Wagner Brandie D. , Patnaik Jennifer L. , Baldermann Rebecca , Mathias Marc T. , Mandava Naresh , Lynch Anne M.
Published: November 2021

Purpose: To determine the relationship between plasma concentrations of the C-C chemokines CCL2, CCL3, CCL4, and CCL5 and intermediate age-related macular degeneration (iAMD) patients compared with control inidividuals to further define the inflammatory pathways associated with age-related macular degeneration.

Methods: The concentrations of CCL2, CCL3, CCL4, and CCL5 were measured using multiplex assays in plasma collected from 210 patients with iAMD and 102 control individuals with no macular degeneration as defined by multi-modal imaging. Non-inflammatory data included in the analysis were: age, sex, family history of AMD, history of smoking, body mass index, presence of reticular pseudo-drusen and cardiovascular disease. Median concentrations as well as a cutoff value for each chemokine were compared between the two groups.

Results: The median concentrations of CCL2 and CCL4 did not differ between control and iAMD groups, however, CCL2 was elevated in iAMD when a cutoff comparison was used (p < 0.05). Median CCL3 and CCL5 concentrations were significantly decreased in the macular degeneration group compared with controls (p < 0.001) as well as when a cutoff value comparison was used. CCL3 and CCL5 were negatively correlated in cases and positively correlated in controls.

Conclusions: Plasma CCL3 and CCL5 concentrations were significantly decreased and CCL2 concentrations were increased in patients with iAMD compared with controls, suggesting a role for C-C chemokines in the systemic inflammatory processes associated with disease development.
Gestational Psittacosis With Secondary Hemophagocytic Syndrome: A Case Report and Literature Review
Authors: Sun Li , Li Pulin , Pang Bo , Wu Peipei , Wang Ran
Published: November 2021

Gestational psittacosis and hemophagocytic syndrome (HPS) are rare clinical diseases. In this article, a case of gestational psittacosis concomitant with secondary HPS was reported. An analysis was performed on the clinical characteristics, signs, laboratory findings, progression, diagnosis, and treatment of a patient with gestational psittacosis concomitant with secondary HPS. Besides, the literature with respect to this disease was reviewed. This patient was definitively diagnosed through metagenomic next-generation sequencing techniques, bone marrow puncture and smear examination, and the determination of sCD25 level and natural killer (NK) cell activity. Anti-infectives such as doxycycline and etoposide combined with hormone chemotherapy achieved significant improvement in cough and expectoration, a return to normal temperature, and a significant improvement in oxygenation index. In addition, chest computed tomography revealed obvious absorption of lung lesions and a return of NK cell activity and sCD25 levels to normal ranges. Chlamydia psittaci pneumonia requires a clear determination of etiology, while HPS requires bone marrow puncture and smear examination, together with the determination of sCD25 level and NK cell activity in the blood. The findings of this study suggest that metagenomic next-generation sequencing is an effective instrument in clearly identifying pathogens that cause lung infection. Clinicians should consider atypical pathogens of lung infection in patients with poor response to empirical anti-infectives, and strive to design an effective treatment strategy as per an accurate diagnosis based on the etiology. As for patients suffering from long-term high fever and poor temperature control after broad-spectrum antibiotic treatment, non-infectious fever should be taken into account. A rapid and clear diagnosis would significantly improve patient prognosis.
Rate of Cornea Endothelial Cell Loss and Biomechanical Properties in Fuchs' Endothelial Corneal Dystrophy
Authors: Reinprayoon Usanee , Jermjutitham Monthira , Kasetsuwan Ngamjit
Published: November 2021

Background: Our study aimed to determine the correlation between the clinical staging of Fuchs' endothelial corneal dystrophy (FECD), rate of endothelial cell loss, and corneal biomechanical properties.

Methods: This study combined a longitudinal retrospective/prospective analysis of corneal endothelial cell loss and a prospective cross-sectional analysis of corneal biomechanics of Fuchs' endothelial dystrophy. The trial was registered at the Thai Clinical Trials Registry as TCTR 20160927004. FECD was diagnosed by the presence of corneal guttata detected by slit lamp microscopy; the disease severity was classified into four stages using the modified Stocker's classification. In vivo confocal microscopy, Scheimpflug imaging, and Corneal Visualization Scheimpflug Technology were performed to evaluate endothelial cell count, central corneal thickness, and corneal biomechanical properties. Linear mixed modeling analyses were used to estimate the endothelial cell densities in a 4-year period. The corneal biomechanics were compared among the stages using Corvis ST parameters.

Results: Eighty eyes from eighty subjects were enrolled (42, 26, 12, and none in stages 1, 2, 3, and 4, respectively). The mean endothelial cell density was 1228.35 cells/mm2. The year-by-year reduction rate was 94.3 cells/mm2 (μEMM = −94.3, 95% CI: −115.4 to −73.2, p < 0.001). Corneal endothelial cell losses in Fuchs' endothelial dystrophy were estimated to be 7.7, 7.8, and 8.4% per year for stages 1, 2, and 3, respectively. The mean corneal thicknesses of stages 1, 2, and 3 were 556 ± 32, 623 ± 33, and 648 ± 50 mm, respectively. For the corneal biomechanical parameters, the A1-length and A1-time were significantly different between stages 1 and 3 (A1-length: mean diffstage1vs.3 = 0.10, 95% CI: < 0.001–0.15, p < 0.001, A1-time: mean diffstage1vs.3 = −0.24, 95% CI: −0.41 to −0.07, respectively).

Conclusions: In the advanced stage, corneas significantly changed their biomechanical viscoelastic behavior by decreasing resistance, as measured by a longer A1-length and shorter A1-time.
Saccharomyces boulardii Combined With Quadruple Therapy for Helicobacter pylori Eradication Decreased the Duration and Severity of Diarrhea: A Multi-Center Prospective Randomized Controlled Trial
Authors: Zhao Yuchong , Yang Yilei , Aruna  , Xiao Jun , Song Jun , Huang Tizheng , Li Shuyu , Kou Jiguang , Huang Lu , Ji Dexiong , Xiong Si , Peng Wang , Xu Sanping , Cheng Bin
Published: November 2021

Background: Whether probiotics helped the Helicobacter pylori (H. pylori) eradication was still highly controversial. The non-bacterial Saccharomyces boulardii (S. boulardii) has demonstrated its efficacy in the treatment of antibiotic-associated and infectious diarrhea. We aimed to evaluate the effects of S. boulardii combined with quadruple therapy for H. pylori eradication and associated side effects.

Methods: Three hundred and sixty H. pylori-infected patients were recruited in this multicenter, randomized controlled trial. The patients who underwent H. pylori eradication treatment were randomized in a ratio of 1:1 into two separate groups that received standard quadruple therapy (Group A) and quadruple therapy plus S. boulardii sachets (Group B) for 14 days. The everyday medication and side-effect records were collected for compliance and adverse effect analysis. All patients accepted 13C/14C-urea breath tests 4 weeks after the therapy completion.

Results:Saccharomyces boulardii and quadruple therapy-combined intervention significantly reduced the incidences of overall side effects (27.8 vs. 38.5%, p = 0.034) and diarrhea (11.2 vs. 21.2%, p = 0.012) in Group B compared with quadruple therapy alone in Group A, especially reduced the diarrhea duration (5.0 days vs. 7.7 days, p = 0.032) and incidence of severe diarrhea (4.7 vs. 10.1%, p = 0.040). Intention-to-treat (ITT) analysis and per-protocol (PP) analysis both indicated no statistical differences of eradication rate between Groups A and B (ITT: 82.7 vs. 85.8%, p = 0.426; PP: 89.7 vs. 94.2%, p = 0.146). The joint use of S. boulardii and quadruple therapy markedly improved the overall pre-eradication alimentary symptoms (hazard ratio (HR): 2.507, 95% CI: 1.449–4.338) recovery.

Conclusion:Saccharomyces boulardii ameliorated H. pylori eradication-induced antibiotic-associated side effects especially reduced the incidence of severe diarrhea and the duration of diarrhea. However, there was no significant effect of S. boulardii on the rate of H. pylori eradication.

Trial Registration: The protocol had retrospectively registered at ClinicalTrails.gov, Unique identifier: NCT03688828, date of registration: September 27, 2018; https://clinicaltrials.gov/show/NCT03688828
Bacterial Abundance, Diversity and Activity During Long-Term Colonization of Non-biodegradable and Biodegradable Plastics in Seawater
Authors: Odobel Charlene , Dussud Claire , Philip Lena , Derippe Gabrielle , Lauters Marion , Eyheraguibel Boris , Burgaud Gaëtan , Ter Halle Alexandra , Meistertzheim Anne-Leila , Bruzaud Stephane , Barbe Valerie , Ghiglione Jean-Francois
Published: November 2021

The microorganisms living on plastics called “plastisphere” have been classically described as very abundant, highly diverse, and very specific when compared to the surrounding environments, but their potential ability to biodegrade various plastic types in natural conditions have been poorly investigated. Here, we follow the successive phases of biofilm development and maturation after long-term immersion in seawater (7 months) on conventional [fossil-based polyethylene (PE) and polystyrene (PS)] and biodegradable plastics [biobased polylactic acid (PLA) and polyhydroxybutyrate-co-hydroxyvalerate (PHBV), or fossil-based polycaprolactone (PCL)], as well as on artificially aged or non-aged PE without or with prooxidant additives [oxobiodegradable (OXO)]. First, we confirmed that the classical primo-colonization and growth phases of the biofilms that occurred during the first 10 days of immersion in seawater were more or less independent of the plastic type. After only 1 month, we found congruent signs of biodegradation for some bio-based and also fossil-based materials. A continuous growth of the biofilm during the 7 months of observation (measured by epifluorescence microscopy and flow cytometry) was found on PHBV, PCL, and artificially aged OXO, together with a continuous increase in intracellular (3H-leucine incorporation) and extracellular activities (lipase, aminopeptidase, and β-glucosidase) as well as subsequent changes in biofilm diversity that became specific to each polymer type (16S rRNA metabarcoding). No sign of biodegradation was visible for PE, PS, and PLA under our experimental conditions. We also provide a list of operational taxonomic units (OTUs) potentially involved in the biodegradation of these polymers under natural seawater conditions, such as Pseudohongiella sp. and Marinobacter sp. on PCL, Marinicella litoralis and Celeribacter sp. on PHBV, or Myxococcales on artificially aged OXO. This study opens new routes for a deeper understanding of the polymers’ biodegradability in seawaters, especially when considering an alternative to conventional fossil-based plastics.
Origin and Dissemination of Altered El Tor Vibrio cholerae O1 Causing Cholera in Odisha, India: Two and Half Decade’s View
Authors: Pal Bibhuti Bhusan , Behera Dipti Ranjan , Nayak Smruti Ranjan , Nayak Ashish Kumar
Published: November 2021

The origin, spread and molecular epidemiology of altered El Tor Vibrio cholerae O1 strains isolated from cholera outbreaks/surveillance studies between 1995 and 2019 from different district of Odisha were analyzed. The stock cultures of V. cholerae O1 strains from 1995 to 2019 were analyzed through molecular analysis using different PCR assays and pulse field gel electrophoresis (PFGE) analysis. The spread map (month, year and place) was constructed to locate the dissemination of altered El Tor variants of V. cholerae O1 in this region. A total of 13 cholera outbreaks were caused by V. cholerae O1 Ogawa biotype El Tor carrying ctxB1 and ctxB7 genotypes. The ctxB1 alleles of V. cholerae O1 mostly confined to the coastal areas, whereas the ctxB7 genotypes, though originating in the coastal region of Odisha, concentrated more in the tribal areas. The positive correlation between virulence-associated genes (VAGs) was found through Pearson’s correlation model, indicative of a stronger association between the VAGs. The clonal relationship through PFGE between ctxB1 and ctxB7 genotypes of V. cholerae O1 strains exhibited 80% similarity indicating single- or multi-clonal evolution. It is evident from this study that the spread of multidrug-resistant V. cholerae O1-altered El Tor was dominant over the prototype El Tor strains in this region. The origin of altered El Tor variants of V. cholerae O1 occurred in the East Coast of Odisha established that the origin of cholera happened in the Gangetic belts of Bay of Bengal where all new variants of V. cholerae O1 might have originated from the Asian countries.
In vivo Serial Passaging of Human–Simian Immunodeficiency Virus Clones Identifies Characteristics for Persistent Viral Replication
Authors: Thippeshappa Rajesh , Polacino Patricia , Chandrasekar Shaswath S. , Truong Khanghy , Misra Anisha , Aulicino Paula C. , Hu Shiu-Lok , Kaushal Deepak , Kimata Jason T.
Published: November 2021

We previously reported that a human immunodeficiency virus type 1 with a simian immunodeficiency virus vif substitution (HSIV-vifNL4-3) could replicate in pigtailed macaques (PTMs), demonstrating that Vif is a species-specific tropism factor of primate lentiviruses. However, infections did not result in high-peak viremia or setpoint plasma viral loads, as observed during simian immunodeficiency virus (SIV) infection of PTMs. Here, we characterized variants isolated from one of the original infected animals with CD4 depletion after nearly 4years of infection to identify determinants of increased replication fitness. In our studies, we found that the HSIV-vif clones did not express the HIV-1 Vpr protein due to interference from the vpx open reading frame (ORF) in singly spliced vpr mRNA. To examine whether these viral genes contribute to persistent viral replication, we generated infectious HSIV-vif clones expressing either the HIV-1 Vpr or SIV Vpx protein. And then to determine viral fitness determinants of HSIV-vif, we conducted three rounds of serial in vivo passaging in PTMs, starting with an initial inoculum containing a mixture of CXCR4-tropic [Vpr-HSIV-vifNL4-3 isolated at 196 (C/196) and 200 (C/200) weeks post-infection from a PTM with depressed CD4 counts] and CCR5-tropic HSIV (Vpr+ HSIV-vif derivatives based NL-AD8 and Bru-Yu2 and a Vpx expressing HSIV-vifYu2). Interestingly, all infected PTMs showed peak plasma viremia close to or above 105 copies/ml and persistent viral replication for more than 20weeks. Infectious molecular clones (IMCs) recovered from the passage 3 PTM (HSIV-P3 IMCs) included mutations required for HIV-1 Vpr expression and those mutations encoded by the CXCR4-tropic HSIV-vifNL4-3 isolate C/196. The data indicate that the viruses selected during long-term infection acquired HIV-1 Vpr expression, suggesting the importance of Vpr for in vivo pathogenesis. Further passaging of HSIV-P3 IMCs in vivo may generate pathogenic variants with higher replication capacity, which will be a valuable resource as challenge virus in vaccine and cure studies.
Redox Switches in Noise-Induced Cardiovascular and Neuronal Dysregulation
Authors: Frenis Katie , Kuntic Marin , Hahad Omar , Bayo Jimenez Maria Teresa , Oelze Matthias , Daub Steffen , Steven Sebastian , Münzel Thomas , Daiber Andreas
Published: November 2021

Environmental exposures represent a significant health hazard, which cumulatively may be responsible for up to 2/3 of all chronic non-communicable disease and associated mortality (Global Burden of Disease Study and The Lancet Commission on Pollution and Health), which has given rise to a new concept of the exposome: the sum of environmental factors in every individual’s experience. Noise is part of the exposome and is increasingly being investigated as a health risk factor impacting neurological, cardiometabolic, endocrine, and immune health. Beyond the well-characterized effects of high-intensity noise on cochlear damage, noise is relatively well-studied in the cardiovascular field, where evidence is emerging from both human and translational experiments that noise from traffic-related sources could represent a risk factor for hypertension, ischemic heart disease, diabetes, and atherosclerosis. In the present review, we comprehensively discuss the current state of knowledge in the field of noise research. We give a brief survey of the literature documenting experiments in noise exposure in both humans and animals with a focus on cardiovascular disease. We also discuss the mechanisms that have been uncovered in recent years that describe how exposure to noise affects physiological homeostasis, leading to aberrant redox signaling resulting in metabolic and immune consequences, both of which have considerable impact on cardiovascular health. Additionally, we discuss the molecular pathways of redox involvement in the stress responses to noise and how they manifest in disruptions of the circadian rhythm, inflammatory signaling, gut microbiome composition, epigenetic landscape and vessel function.
Face Processing in Developmental Prosopagnosia: Altered Neural Representations in the Fusiform Face Area
Authors: Haeger Alexa , Pouzat Christophe , Luecken Volker , N’Diaye Karim , Elger Christian , Kennerknecht Ingo , Axmacher Nikolai , Dinkelacker Vera
Published: November 2021

Rationale: Face expertise is a pivotal social skill. Developmental prosopagnosia (DP), i.e., the inability to recognize faces without a history of brain damage, affects about 2% of the general population, and is a renowned model system of the face-processing network. Within this network, the right Fusiform Face Area (FFA), is particularly involved in face identity processing and may therefore be a key element in DP. Neural representations within the FFA have been examined with Representational Similarity Analysis (RSA), a data-analytical framework in which multi-unit measures of brain activity are assessed with correlation analysis.

Objectives: Our study intended to scrutinize modifications of FFA-activation during face encoding and maintenance based on RSA.

Methods: Thirteen participants with DP (23–70 years) and 12 healthy control subjects (19–62 years) participated in a functional MRI study, including morphological MRI, a functional FFA-localizer and a modified Sternberg paradigm probing face memory encoding and maintenance. Memory maintenance of one, two, or four faces represented low, medium, and high memory load. We examined conventional activation differences in response to working memory load and applied RSA to compute individual correlation-matrices on the voxel level. Group correlation-matrices were compared via Donsker’s random walk analysis.

Results: On the functional level, increased memory load entailed both a higher absolute FFA-activation level and a higher degree of correlation between activated voxels. Both aspects were deficient in DP. Interestingly, control participants showed a homogeneous degree of correlation for successful trials during the experiment. In DP-participants, correlation levels between FFA-voxels were significantly lower and were less sustained during the experiment. In behavioral terms, DP-participants performed poorer and had longer reaction times in relation to DP-severity. Furthermore, correlation levels were negatively correlated with reaction times for the most demanding high load condition.

Conclusion: We suggest that participants with DP fail to generate robust and maintained neural representations in the FFA during face encoding and maintenance, in line with poorer task performance and prolonged reaction times. In DP, alterations of neural coding in the FFA might therefore explain curtailing in working memory and contribute to impaired long-term memory and mental imagery.
Efficacy and Safety of Levetiracetam vs. Phenobarbital for Neonatal Seizures: A Systematic Review and Meta-Analysis
Authors: Qiao Meng-Yuan , Cui Hong-Tao , Zhao Ling-Zhi , Miao Jing-Kun , Chen Qi-Xiong
Published: November 2021

Background: Neonatal seizures are a common neurological emergency in newborns. Phenobarbital (PB) is the first-line antiepileptic drug (AED). However, PB has some side effects, such as hypotension and respiratory depression, and it can accelerate neuronal apoptosis in the immature brain. Levetiracetam (LEV), a new antiepileptic drug, has been used as a second-line drug for the treatment of neonatal seizures. Compared with PB, LEV has many advantages, including a low incidence of side effects and better neurodevelopmental outcomes. However, there are only a few systematic reviews of LEV for the treatment of neonatal seizures.

Objective: To evaluate the efficacy and safety of LEV for neonatal seizures and to compare the efficacy, side effects, and neurological outcomes between LEV and PB in the treatment of neonatal seizures.

Methods: The keywords LEV, PB, and neonatal seizure were searched in the MEDLINE, Cochrane Library, Web of Science, EMBASE, clinicaltrials.gov, and China National Knowledge Internet (CNKI) databases with a last update in July 2021 to collect high-quality studies. We collected studies studying the efficacy or safety of LEV and PB in the treatment of neonatal seizures applying strict inclusion and exclusion criteria. The data were extracted and outcome measures, including efficacy, side effect rate, neurological score, and mortality rate, were analyzed with RevMan 5.3 software.

Results: Ten articles were finally included in the meta-analysis. The meta-analysis showed that there was no difference in efficacy between LEV and PB in the treatment of neonatal seizures. Compared with PB, the incidence of side effects of LEV was lower. The incidence of hypotension and respiratory depression in the LEV group was significantly lower than that in the PB group. In terms of long-term neurodevelopmental outcomes, there was no significant difference in the Bayley Scales of Infant Development (BSID) scores between LEV and PB.

Conclusion: PB is still the first-line AED recommended by the WHO for the treatment of neonatal seizures. The new AEDs LEV may not have better efficacy than PB. At the same time, LEV is associated with better neurodevelopment outcomes and a lower risk of adverse effects. In addition, continuous EEG monitoring should be used to diagnose neonatal seizures to evaluate the severity of the seizures, remission, and drug efficacy.

Systematic Review Registration: PROSPERO, identifier: CRD42021279029.
Post-stroke Rehabilitation of Severe Upper Limb Paresis in Germany – Toward Long-Term Treatment With Brain-Computer Interfaces
Authors: Angerhöfer Cornelius , Colucci Annalisa , Vermehren Mareike , Hömberg Volker , Soekadar Surjo R.
Published: November 2021

Severe upper limb paresis can represent an immense burden for stroke survivors. Given the rising prevalence of stroke, restoration of severe upper limb motor impairment remains a major challenge for rehabilitation medicine because effective treatment strategies are lacking. Commonly applied interventions in Germany, such as mirror therapy and impairment-oriented training, are limited in efficacy, demanding for new strategies to be found. By translating brain signals into control commands of external devices, brain-computer interfaces (BCIs) and brain-machine interfaces (BMIs) represent promising, neurotechnology-based alternatives for stroke patients with highly restricted arm and hand function. In this mini-review, we outline perspectives on how BCI-based therapy can be integrated into the different stages of neurorehabilitation in Germany to meet a long-term treatment approach: We found that it is most appropriate to start therapy with BCI-based neurofeedback immediately after early rehabilitation. BCI-driven functional electrical stimulation (FES) and BMI robotic therapy are well suited for subsequent post hospital curative treatment in the subacute stage. BCI-based hand exoskeleton training can be continued within outpatient occupational therapy to further improve hand function and address motivational issues in chronic stroke patients. Once the rehabilitation potential is exhausted, BCI technology can be used to drive assistive devices to compensate for impaired function. However, there are several challenges yet to overcome before such long-term treatment strategies can be implemented within broad clinical application: 1. developing reliable BCI systems with better usability; 2. conducting more research to improve BCI training paradigms and 3. establishing reliable methods to identify suitable patients.
Added Value of Cognition in the Prediction of Survival in Low and High Grade Glioma
Authors: van Kessel Emma , Schuit Ewoud , Huenges Wajer Irene M. C. , Ruis Carla , De Vos Filip Y. F. L. , Verhoeff Joost J. C. , Seute Tatjana , van Zandvoort Martine J. E. , Robe Pierre A. , Snijders Tom J.
Published: November 2021

Background: Diffuse gliomas, which are at WHO grade II-IV, are progressive primary brain tumors with great variability in prognosis. Our aim was to investigate whether pre-operative cognitive functioning is of added value in survival prediction in these patients.

Methods: In a retrospective cohort study of patients undergoing awake craniotomy between 2010 and 2019 we performed pre-operative neuropsychological assessments in five cognitive domains. Their added prognostic value on top of known prognostic factors was assessed in two patient groups [low- (LGG) and high-grade gliomas (HGG]). We compared Cox proportional hazards regression models with and without the cognitive domain by means of loglikelihood ratios tests (LRT), discriminative performance measures (by AUC), and risk classification [by Integrated Discrimination Index (IDI)].

Results: We included 109 LGG and 145 HGG patients with a median survival time of 1,490 and 511 days, respectively. The domain memory had a significant added prognostic value in HGG as indicated by an LRT (p-value = 0.018). The cumulative AUC for HGG with memory included was.78 (SD = 0.017) and without cognition 0.77 (SD = 0.018), IDI was 0.043 (0.000–0.102). In LGG none of the cognitive domains added prognostic value.

Conclusions: Our findings indicated that memory deficits, which were revealed with the neuropsychological examination, were of additional prognostic value in HGG to other well-known predictors of survival.
ATG4B Inhibitor UAMC-2526 Potentiates the Chemotherapeutic Effect of Gemcitabine in a Panc02 Mouse Model of Pancreatic Ductal Adenocarcinoma
Authors: Takhsha Farnaz Sedigheh , Vangestel Christel , Tanc Muhammet , De Bruycker Sven , Berg Maya , Pintelon Isabel , Stroobants Sigrid , De Meyer Guido R. Y. , Van Der Veken Pieter , Martinet Wim
Published: November 2021

Resistance against anti-cancer therapy is one of the major challenges during treatment of multiple cancers. Gemcitabine is a standard first-line chemotherapeutic drug, yet autophagy is highly activated in the hypoxic microenvironment of solid tumors and enhances the survival of tumor cells against gemcitabine chemotherapy. Recently, we showed the add-on effect of autophagy inhibitor UAMC-2526 to prevent HT-29 colorectal tumor growth in CD1-/- Foxn1nu mice treated with oxaliplatin. In this study, we aimed to investigate the potential beneficial effects of UAMC-2526 in a syngeneic Panc02 mouse model of pancreatic ductal adenocarcinoma (PDAC). Our data showed that UAMC-2526 combined with gemcitabine significantly reduced tumor growth as compared to the individual treatments. However, in contrast to in vitro experiments with Panc02 cells in culture, we were unable to detect autophagy inhibition by UAMC-2526 in Panc02 tumor tissue, neither via western blot analysis of autophagy markers LC3 and p62, nor by transmission electron microscopy. In vitro experiments revealed that UAMC-2526 enhances the potential of gemcitabine to inhibit Panc02 cell proliferation without obvious induction of cell death. Altogether, we conclude that although the combination treatment of UAMC-2526 with gemcitabine did not inhibit autophagy in the Panc02 mouse model, it has a beneficial effect on tumor growth inhibition.
The Prognosis of Leptin rs2167270 G > A (G19A) Polymorphism in the Risk of Cancer: A Meta-Analysis
Authors: Zhang Aiqiao , Wang Shangren , Zhang Fujun , Li Wei , Li Qian , Liu Xiaoqiang
Published: November 2021

Background

Although the effect of the LEP G19A (rs2167270) polymorphism on cancers is assumed, the results of its influence have been contradictory. A meta-analysis was conducted to precisely verify the relationships between LEP G19A and the development of digestion-related cancers.

Methods

Investigators systematically searched the literature in PubMed, Embase, and Web of Science and used STATA software 14.0 for the meta−analysis. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the associations. Subgroup analyses stratified by ethnicity, cancer type, and cancer system were further conducted to assess the relationship between the LEP G19A polymorphism and digestion-related cancers.

Results

In the overall population, we found a significant relationship with overall cancer (allele comparison: OR = 0.921,p= 0.000; dominant comparison: OR = 0.923,p= 0.004; recessive comparison: OR = 0.842,p= 0.000; homozygote model: OR = 0.0843,p= 0.001). In a subgroup analysis conducted by ethnicity, we obtained significant results in Asians (Asian allele comparison: OR = 0.885,p= 0.000; dominant comparison: OR = 0.862,p= 0.000; homozygote model: OR = 0.824,p= 0.039; and heterozygote comparison: OR = 0.868,p= 0.000) but not in Caucasians. In a subgroup analysis conducted by cancer type and cancer system, we obtained significant results that the LEP G19A polymorphism may decrease the risk of colorectal cancer, esophageal cancer, digestive system cancer, and urinary system cancer.

Conclusions

This meta-analysis revealed that the LEP G19A polymorphism may decrease the risk of cancer.