bluuebunny/crossref_metadata_2025 huggingface dataset:
The Development of Ovine Gastric and Intestinal Organoids for Studying Ruminant Host-Pathogen Interactions
Authors: Smith David , Price Daniel R. G. , Burrells Alison , Faber Marc N. , Hildersley Katie A. , Chintoan-Uta Cosmin , Chapuis Ambre F. , Stevens Mark , Stevenson Karen , Burgess Stewart T. G. , Innes Elisabeth A. , Nisbet Alasdair J. , McNeilly Tom N.
Published: September 2021

Gastrointestinal (GI) infections in sheep have significant implications for animal health, welfare and productivity, as well as being a source of zoonotic pathogens. Interactions between pathogens and epithelial cells at the mucosal surface play a key role in determining the outcome of GI infections; however, the inaccessibility of the GI tract in vivo significantly limits the ability to study such interactions in detail. We therefore developed ovine epithelial organoids representing physiologically important gastric and intestinal sites of infection, specifically the abomasum (analogous to the stomach in monogastrics) and ileum. We show that both abomasal and ileal organoids form self-organising three-dimensional structures with a single epithelial layer and a central lumen that are stable in culture over serial passage. We performed RNA-seq analysis on abomasal and ileal tissue from multiple animals and on organoids across multiple passages and show the transcript profile of both abomasal and ileal organoids cultured under identical conditions are reflective of the tissue from which they were derived and that the transcript profile in organoids is stable over at least five serial passages. In addition, we demonstrate that the organoids can be successfully cryopreserved and resuscitated, allowing long-term storage of organoid lines, thereby reducing the number of animals required as a source of tissue. We also report the first published observations of a helminth infecting gastric and intestinal organoids by challenge with the sheep parasitic nematode Teladorsagia circumcincta, demonstrating the utility of these organoids for pathogen co-culture experiments. Finally, the polarity in the abomasal and ileal organoids can be inverted to make the apical surface directly accessible to pathogens or their products, here shown by infection of apical-out organoids with the zoonotic enteric bacterial pathogen Salmonella enterica serovar Typhimurium. In summary, we report a simple and reliable in vitro culture system for generation and maintenance of small ruminant intestinal and gastric organoids. In line with 3Rs principals, use of such organoids will reduce and replace animals in host-pathogen research.
Computed Tomography-Based Assessment of Transvalvular Pressure Gradient in Aortic Stenosis
Authors: Franke Benedikt , Brüning Jan , Yevtushenko Pavlo , Dreger Henryk , Brand Anna , Juri Benjamin , Unbehaun Axel , Kempfert Jörg , Sündermann Simon , Lembcke Alexander , Solowjowa Natalia , Kelle Sebastian , Falk Volkmar , Kuehne Titus , Goubergrits Leonid , Schafstedde Marie
Published: September 2021

Background: In patients with aortic stenosis, computed tomography (CT) provides important information about cardiovascular anatomy for treatment planning but is limited in determining relevant hemodynamic parameters such as the transvalvular pressure gradient (TPG).

Purpose: In the present study, we aimed to validate a reduced-order model method for assessing TPG in aortic stenosis using CT data.

Methods: TPGCT was calculated using a reduced-order model requiring the patient-specific peak-systolic aortic flow rate (Q) and the aortic valve area (AVA). AVA was determined by segmentation of the aortic valve leaflets, whereas Q was quantified based on volumetric assessment of the left ventricle. For validation, invasively measured TPGcatheter was calculated from pressure measurements in the left ventricle and the ascending aorta. Altogether, 84 data sets of patients with aortic stenosis were used to compare TPGCT against TPGcatheter.

Results: TPGcatheter and TPGCT were 50.6 ± 28.0 and 48.0 ± 26 mmHg, respectively (p = 0.56). A Bland–Altman analysis revealed good agreement between both methods with a mean difference in TPG of 2.6 mmHg and a standard deviation of 19.3 mmHg. Both methods showed good correlation with r = 0.72 (p < 0.001).

Conclusions: The presented CT-based method allows assessment of TPG in patients with aortic stenosis, extending the current capabilities of cardiac CT for diagnosis and treatment planning.
Off-Label Underdosing or Overdosing of Non-vitamin K Antagonist Oral Anticoagulants in Patients With Atrial Fibrillation: A Meta-Analysis
Authors: Wu Xiaojuan , Hu Linyan , Liu Jinjin , Gu Qiuping
Published: September 2021

Background: Several studies have investigated the role of off-label non-vitamin K antagonist oral anticoagulants (NOACs) in patients with atrial fibrillation (AF). We aimed to compare the effectiveness and safety outcomes between off-label underdose or overdose vs. on-label dose of NOACs in AF patients.

Methods: The PubMed database was systematically searched until August 2021. Observational cohorts were included if they compared the outcomes of off-label underdose or overdose with on-label dose of NOACs in AF patients. The risk ratios (RRs) and 95% confidence intervals (CIs) were pooled using a fixed-effects model (I2 ≤ 50%) or a random-effects model (I2 > 50%).

Results: A total of 15 observational studies were included. Compared with on-label dose of NOACs, off-label underdose of NOACs was associated with increased risks of stroke or systemic embolism (RR = 1.09, 95% CI 1.02–1.16), and all-cause death (RR = 1.29, 95% CI 1.10–1.52) but not ischemic stroke (RR = 1.34, 95% CI 0.76–2.36), myocardial infarction (RR = 1.08, 95% CI 0.92–1.28), major bleeding (RR = 0.97, 95% CI 0.89–1.05), intracranial hemorrhage (RR = 1.12, 95% CI 0.90–1.40), and gastrointestinal bleeding (RR = 0.96, 95% CI 0.85–1.07), whereas off-label overdose of NOACs was associated with increased risks of SSE (RR = 1.20, 95% CI 1.05–1.36), all-cause death (RR = 1.22, 95% CI 1.06–1.39), and major bleeding (RR = 1.33, 95% CI 1.16–1.52) but not gastrointestinal bleeding (RR = 1.18, 95% CI 0.99–1.42) and myocardial infarction (RR = 0.98, 95% CI 0.75–1.30).

Conclusion: Compared with on-label dose of NOACs, off-label underdose was associated with increased risks of stroke or systemic embolism and all-cause death, whereas off-label overdose of NOACs was associated with increased risks of stroke or systemic embolism, all-cause death, and major bleeding.
Magma Migration at Shallower Levels and Lava Fountains Sequence as Revealed by Borehole Dilatometers on Etna Volcano
Authors: Bonaccorso Alessandro , Carleo Luigi , Currenti Gilda , Sicali Antonino
Published: September 2021

A main challenge in open conduit volcanoes is to detect and interpret the ultra-small strain (<10–6) associated with minor but critical eruptions such as the lava fountains. Two years after the flank eruption of December 2018, Etna generated a violent and spectacular eruptive sequence of lava fountains. There were 23 episodes from December 13, 2020 to March 31, 2021, 17 of which in the brief period 16 February to 31 March with an intensified occurrence rate. The high-precision borehole dilatometer network recorded significant strain changes in the forerunning phase of December 2020 accompanying the final magma migration at the shallower levels, and also during the single lava fountains and during the entire sequence. The source modeling provided further information on the shallow plumbing system. Moreover, the strain signals also gave useful information both on the explosive efficiency of the lava fountains sequence and the estimate of erupted volume. The high precision borehole dilatometers confirm to be strategic and very useful tool, also to detect and interpret ultra-small strain changes associated with explosive eruptions, such as lava fountains, in open conduit volcanoes.
Striking the Balance: GLP-1/Glucagon Co-Agonism as a Treatment Strategy for Obesity
Authors: Hope David C. D. , Vincent Matthew L. , Tan Tricia M. M.
Published: September 2021

Obesity and Type 2 diabetes represent global health challenges, and there is an unmet need for long-lasting and effective pharmacotherapies. Although long-acting glucagon-like peptide-1 (GLP-1) analogues are now in routine use for diabetes and are now being utilised for obesity per se, the need for ever better treatments has driven the development of co-agonists, with the theoretical advantages of improved efficacy by targeting multiple pathways and reduced adverse effects. In this review, we highlight the past and present progress in our understanding and development of treatments based on GLP-1/glucagon co-agonism. We also reflect on the divergent effects of varying the GLP-1:glucagon activity and ratio in the context of pre-clinical and human clinical trial findings. In particular, the multiple metabolic actions of glucagon highlight the importance of understanding the contributions of individual hormone action to inform the safe, effective and tailored use of GLP-1/glucagon co-agonists to target weight loss and metabolic disease in the future.
Association Between Neonatal Thyroid Function and Anogenital Distance from Birth to 48 Months of Age
Authors: Luan Min , Liang Hong , Fang Guanghong , Wang Ziliang , Su Xiujuan , Chen Aimin , Miao Maohua , Yuan Wei
Published: September 2021

Background

Evidence from animal studies has indicated that neonatal thyroid function is vital for the reproductive development. Anogenital distance (AGD), a sensitive biomarker of the fetal hormonal milieu, can be used to predict adult reproductive disorders. However, few human studies have examined the association between neonatal thyroid function and AGD. We aimed to explore their associations in a birth cohort study.

Methods

Concentrations of thyroid stimulating hormone (TSH) and thyroid hormones (THs), including total triiodothyronine (TT3), total thyroxine (TT4), free triiodothyronine (FT3), and free thyroxine (FT4) were measured in cord plasma in the Shanghai-Minhang Birth Cohort. The offspring AGD (AGDAP [anus–penis] and AGDAS [anus–scrotum] for boys and AGDAC [anus–clitoris] and AGDAF [anus–fourchette] for girls), body weight and anogenital index (AGI = AGD/weight [mm/kg]) were obtained at each follow-up visit. In total, 344 children (194 boys and 150 girls) with cord plasma concentrations of THs and TSH and at least one AGD measurement at birth and at 6, 12, and 48 months of age were included. Multiple linear regression and generalized estimating equation (GEE) models were used to examine the associations of cord plasma concentrations of THs and TSH with AGI.

Results

Multiple linear regression models showed inverse associations of TT4, FT3, and FT4 with female AGI, although statistical significance was only reached at birth, 6 and 48 months of age. These associations were also found in GEE models: higher TT4 and FT4 concentrations were associated with lower AGIAC (TT4: β = -0.27, 95% CI: -0.50, -0.03 for middle vs. lowest tertile; FT4: β = -0.38, 95% CI: -0.61, -0.16 for middle and β = -0.30, 95% CI: -0.55, -0.04 for highest vs. lowest tertile). Besides, girls with the highest tertile of FT3 concentrations had lower AGIAF than those with the lowest tertile (the highest vs. lowest tertile: β = -0.22, 95% CI: -0.36, -0.08). Positive associations between TSH and AGI at birth and at 12 months of age were observed in boys.

Conclusions

This study provides further evidence on the effects of neonatal thyroid function on reproductive development at an early life stage.
Egg Cannibalism Varies With Sex, Reproductive Status, and Egg and Nymph Ages in Arma custos (Hemiptera: Asopinae)
Authors: Wu Shaolong , Zeng Weiai , Deng Wan , Li Mi , Hu Wei , Cai Hailin , Li Youzhi , Xie Pengfei , Tan Lin , Zhou Zhicheng
Published: September 2021

Background: Egg cannibalism is common in nature. In China, Arma custos (Hemiptera: Asopinae) has been widely used as a natural enemy to control agricultural and forestry pests. A previous study showed that adult A. custos devour their eggs. However, no research has investigated the interaction between A. custos cannibalism and egg development. Clarifying the mechanisms involved in egg cannibalism by A. custos improves our understanding of the evolutionary relationships to enable more efficient mass rearing and biological control systems.

Results: Virgin females showed a lower egg cannibalism inclination than gravid females. Both virgin and mated females showed a higher egg cannibalism inclination than virgin and mated males. The first and second instar nymphs did not devour eggs. The third, fourth, and fifth instar nymphs devoured eggs. Younger eggs were more readily eaten than older eggs. Neither A. custos nymphs nor female adults consumed all the available eggs, allowing an emergence ratio of >70%.

Conclusion:Arma custos females exhibit a higher tendency for egg cannibalism than males. Egg cannibalism varies not only with the developmental stage of the eggs and nymphs but also with sex and reproductive status of A. custos females. These findings help us to better understand the evolutionary relationships in egg cannibalism by A. custos and contribute to the efficient mass rearing and realization of A. custos in biological control systems.
Common Threads: Aphidicolin-Inducible and Folate-Sensitive Fragile Sites in the Human Genome
Authors: Lokanga Rachel Adihe , Kumari Daman , Usdin Karen
Published: September 2021

The human genome has many chromosomal regions that are fragile, demonstrating chromatin breaks, gaps, or constrictions on exposure to replication stress. Common fragile sites (CFSs) are found widely distributed in the population, with the largest subset of these sites being induced by aphidicolin (APH). Other fragile sites are only found in a subset of the population. One group of these so-called rare fragile sites (RFSs) is induced by folate stress. APH-inducible CFSs are generally located in large transcriptionally active genes that are A + T rich and often enriched for tracts of AT-dinucleotide repeats. In contrast, all the folate-sensitive sites mapped to date consist of transcriptionally silenced CGG microsatellites. Thus, all the folate-sensitive fragile sites may have a very similar molecular basis that differs in key ways from that of the APH CFSs. The folate-sensitive FSs include FRAXA that is associated with Fragile X syndrome (FXS), the most common heritable form of intellectual disability. Both CFSs and RFSs can cause chromosomal abnormalities. Recent work suggests that both APH-inducible fragile sites and FRAXA undergo Mitotic DNA synthesis (MiDAS) when exposed to APH or folate stress, respectively. Interestingly, blocking MiDAS in both cases prevents chromosome fragility but increases the risk of chromosome mis-segregation. MiDAS of both APH-inducible and FRAXA involves conservative DNA replication and POLD3, an accessory subunit of the replicative polymerase Pol δ that is essential for break-induced replication (BIR). Thus, MiDAS is thought to proceed via some form of BIR-like process. This review will discuss the recent work that highlights the similarities and differences between these two groups of fragile sites and the growing evidence for the presence of many more novel fragile sites in the human genome.
Identification of New Genes and Loci Associated With Bone Mineral Density Based on Mendelian Randomization
Authors: Liu Yijun , Jin Guang , Wang Xue , Dong Ying , Ding Fupeng
Published: September 2021

Bone mineral density (BMD) is a complex and highly hereditary trait that can lead to osteoporotic fractures. It is estimated that BMD is mainly affected by genetic factors (about 85%). BMD has been reported to be associated with both common and rare variants, and numerous loci related to BMD have been identified by genome-wide association studies (GWAS). We systematically integrated expression quantitative trait loci (eQTL) data with GWAS summary statistical data. We mainly focused on the loci, which can affect gene expression, so Summary data-based Mendelian randomization (SMR) analysis was implemented to investigate new genes and loci associated with BMD. We identified 12,477 single-nucleotide polymorphisms (SNPs) regulating 564 genes, which are associated with BMD. The genetic mechanism we detected could make a contribution in the density of BMD in individuals and play an important role in understanding the pathophysiology of cataclasis.
Generation of Pure Highly Functional Human Anti-Tumor Specific Cytotoxic T Lymphocytes With Stem Cell-Like Memory Features for Melanoma Immunotherapy
Authors: Hamieh Mohamad , Chatillon Jean-François , Dupel Estelle , Bayeux Florence , Fauquembergue Emilie , Maby Pauline , Drouet Aurelie , Duval-Modeste Anne-Bénédicte , Adriouch Sahil , Boyer Olivier , Latouche Jean-Baptiste
Published: September 2021

Adoptive immunotherapy based on the transfer of anti-tumor cytotoxic T lymphocytes (CTLs) is a promising strategy to cure cancers. However, rapid expansion of numerous highly functional CTLs with long-lived features remains a challenge. Here, we constructed NIH/3T3 mouse fibroblast-based artificial antigen presenting cells (AAPCs) and precisely evaluated their ability to circumvent this difficulty. These AAPCs stably express the essential molecules involved in CTL activation in the HLA-A*0201 context and an immunogenic HLA-A*0201 restricted analogue peptide derived from MART-1, an auto-antigen overexpressed in melanoma. Using these AAPCs and pentamer-based magnetic bead-sorting, we defined, in a preclinical setting, the optimal conditions to expand pure MART-1-specific CTLs. Numerous highly purified MART-1-specific CTLs were rapidly obtained from healthy donors and melanoma patients. Both TCR repertoire and CDR3 sequence analyses revealed that MART-1-specific CTL responses were similar to those reported in the literature and obtained with autologous or allogeneic presenting cells. These MART-1-specific CTLs were highly cytotoxic against HLA-A*0201+MART-1+tumor cells. Moreover, they harbored a suitable phenotype for immunotherapy, with effector memory, central memory and, most importantly, stem cell-like memory T cell features. Notably, the cells harboring stem cell-like memory phenotype features were capable of self-renewal and of differentiation into potent effector anti-tumor T cells. These “off-the-shelf” AAPCs represent a unique tool to rapidly and easily expand large numbers of long-lived highly functional pure specific CTLs with stem cell-like memory T cell properties, for the development of efficient adoptive immunotherapy strategies against cancers.
Presence of Anti-Thyroid Antibodies Correlate to Worse Outcome of Anti-NMDAR Encephalitis
Authors: Chen Zhongyun , Zhang Yan , Cui Lili , Huang Huijin , Chen Weibi , Su Yingying
Published: September 2021

Objective

To investigate the characteristics and prognosis of anti-NMDAR encephalitis with the prevalence of anti-thyroid antibodies (ATAbs).

Methods

The clinical data of anti-NMDAR encephalitis patients admitted to Xuanwu Hospital from January 2012 to August 2018 was prospectively analyzed, and the patients were followed up for 24 months.

Results

A total of 120 patients were enrolled, of which 34.2% (41/120) were positive for ATAbs. The antibodies were more frequent in patients with severe disease compared to the non-severe group (51.4% vs. 25.6%, P=0.008). In addition, prevalence of ATAbs correlated with a higher incidence of disturbed consciousness, autonomic dysfunction, central hypoventilation and mechanical ventilation. The ATAbs-positive patients were also more likely to receive intravenous gamma immunoglobulin and immunosuppressor compared to the ATAbs-negative cases (P=0.006; P=0.035). Although the presence of ATAbs was associated with longer hospital stays and worse prognosis at 6 months (P=0.006; P=0.038), it had no impact on long-term patient prognosis. Positive status of anti-thyroglobulin antibody was an independent risk factor for worse prognosis at 6 months [odds ratio (OR)= 3.907, 95% CI: 1.178-12.958, P=0.026].

Conclusion

ATAbs are prevalent in patients with anti-NMDAR encephalitis, especially in severe cases, and correlate with poor prognosis and impaired short-term neurological recovery.
Characterization by Quantitative Serum Proteomics of Immune-Related Prognostic Biomarkers for COVID-19 Symptomatology
Authors: Villar Margarita , Urra José Miguel , Rodríguez-del-Río Francisco J. , Artigas-Jerónimo Sara , Jiménez-Collados Natalia , Ferreras-Colino Elisa , Contreras Marinela , de Mera Isabel G. Fernández , Estrada-Peña Agustín , Gortázar Christian , de la Fuente José
Published: September 2021

The COVID-19 pandemic caused by SARS-CoV-2 challenges the understanding of factors affecting disease progression and severity. The identification of prognostic biomarkers and physiological processes associated with disease symptoms is relevant for the development of new diagnostic and therapeutic interventions to contribute to the control of this pandemic. To address this challenge, in this study, we used a quantitative proteomics together with multiple data analysis algorithms to characterize serum protein profiles in five cohorts from healthy to SARS-CoV-2-infected recovered (hospital discharge), nonsevere (hospitalized), and severe [at the intensive care unit (ICU)] cases with increasing systemic inflammation in comparison with healthy individuals sampled prior to the COVID-19 pandemic. The results showed significantly dysregulated proteins and associated biological processes and disorders associated to COVID-19. These results corroborated previous findings in COVID-19 studies and highlighted how the representation of dysregulated serum proteins and associated BPs increases with COVID-19 disease symptomatology from asymptomatic to severe cases. The analysis was then focused on novel disease processes and biomarkers that were correlated with disease symptomatology. To contribute to translational medicine, results corroborated the predictive value of selected immune-related biomarkers for disease recovery [Selenoprotein P (SELENOP) and Serum paraoxonase/arylesterase 1 (PON1)], severity [Carboxypeptidase B2 (CBP2)], and symptomatology [Pregnancy zone protein (PZP)] using protein-specific ELISA tests. Our results contributed to the characterization of SARS-CoV-2–host molecular interactions with potential contributions to the monitoring and control of this pandemic by using immune-related biomarkers associated with disease symptomatology.
Immune Landscape of CMV Infection in Cancer Patients: From “Canonical” Diseases Toward Virus-Elicited Oncomodulation
Authors: El Baba Ranim , Herbein Georges
Published: September 2021

Human Cytomegalovirus (HCMV) is an immensely pervasive herpesvirus, persistently infecting high percentages of the world population. Despite the apparent robust host immune responses, HCMV is capable of replicating, evading host defenses, and establishing latency throughout life by developing multiple immune-modulatory strategies. HCMV has coexisted with humans mounting various mechanisms to evade immune cells and effectively win the HCMV-immune system battle mainly through maintaining its viral genome, impairing HLA Class I and II molecule expression, evading from natural killer (NK) cell-mediated cytotoxicity, interfering with cellular signaling, inhibiting apoptosis, escaping complement attack, and stimulating immunosuppressive cytokines (immune tolerance). HCMV expresses several gene products that modulate the host immune response and promote modifications in non-coding RNA and regulatory proteins. These changes are linked to several complications, such as immunosenescence and malignant phenotypes leading to immunosuppressive tumor microenvironment (TME) and oncomodulation. Hence, tumor survival is promoted by affecting cellular proliferation and survival, invasion, immune evasion, immunosuppression, and giving rise to angiogenic factors. Viewing HCMV-induced evasion mechanisms will play a principal role in developing novel adapted therapeutic approaches against HCMV, especially since immunotherapy has revolutionized cancer therapeutic strategies. Since tumors acquire immune evasion strategies, anti-tumor immunity could be prominently triggered by multimodal strategies to induce, on one side, immunogenic tumor apoptosis and to actively oppose the immune suppressive microenvironment, on the other side.
Long-Term Clinical and Immunological Impact of Severe COVID-19 on a Living Kidney Transplant Recipient – A Case Report
Authors: Qiu Liru , Zhang Ji , Huang Yafei , Chen Gen , Chen Zhishui , Ming Changsheng , Lu Xia , Gong Nianqiao
Published: September 2021

The long-term impact of COVID-19 on transplant recipients remains unknown. We describe the case of a 30-year-old male kidney transplant recipient from Wuhan, China that was treated for severe COVID-19 in February 2020. He suffered an acute lung and renal injury and required systemic treatment including adjustment of his immunosuppressant regime. He was followed up to 1-year after discharge. No chronic lung fibrosis or deterioration of his pulmonary function was observed. Despite COVID-19 mediated damage to his renal tubular cells, no transplant rejection occurred. His immunological profile demonstrated both cellular anti-SARS-CoV-2 reactivity and specific humoral immunity, indicating that it is beneficial for the transplanted patients to be immunized with SARS-CoV-2 virus vaccine. This case will help guide clinical decision making for immunocompromised individuals that become infected with SARS-CoV-2.
Improper Diving Behavior Affects Physiological Responses of Acropora hyacinthus and Porites cylindrica
Authors: Zhang Yu , Huang Jianzhong , Li Xinke , Song Cuiping , Xia Jingquan , Ren Yuxiao , Wang Aimin , Li Xiubao
Published: September 2021

Human activities beyond ecosystem capacity have resulted in serious effects on corals worldwide. Nowadays, many studies have focused on the influence of diving activities on coral communities, while the knowledge of physiological changes under corresponding environmental stresses remains largely undetermined. In the study, we aimed to investigate the physiological effects of touching, ammonia nitrogen enrichment (5 μmol⋅L–1), and sediment cover (particle size of less than 0.3 mm), which simulated improper self-contained underwater breathing apparatus (SCUBA) diving behaviors, on Acropora hyacinthus and Porites cylindrica in Wuzhizhou Island, the South China Sea. For A. hyacinthus, continuous touching caused the tentacles to shrink and secrete mucus, which consumed energy and dissolved oxygen. The skeletal growth rate was decreased by 72% compared with the control group. There was a rapid decline of Fv/Fm and alpha under the dual impacts of high ammonia nitrogen and touching, while the Chl a concentration and tissue biomass were decreased by 36 and 28% compared with touching alone, respectively. High ammonia nitrogen and touching increased the concentrations of lipid and protein. Nevertheless, zooxanthellae density was increased by 23% to relieve the effects of a lower concentration of Chl a in a high nutrient environment. Constant touching and sediment cover in diving areas with elevated ammonia content affected the photosynthesis and respiration of corals, and a significant decrease was observed for lipid, zooxanthellae density, and Chl a concentration. Coral bleaching occurred on day 7. For P. cylindrica, the decreasing magnitude of Fv/Fm and alpha under different stresses in the subsequent phase was less compared with A. hyacinthus. The contents of carbohydrate and protein under continuous touching were decreased by 7 and 15% compared with the control group, respectively, causing negative growth. Under the dual influences of high ammonia nitrogen and continuous touching, all energy reserves were significantly lower. Repeated touching and sediment cover in diving areas containing high ammonia content increased the concentrations of lipid and protein compared with the touching and high nutrient treatment group likely because that Porites associated with C15 zooxanthella increased heterotrophic feeding to compensate for restricted symbiodiniaceae photosynthesis. Additionally, P. cylindrica produced mucus to aid the removal of sediment, so that corals didn’t obviously bleach during the experiment. Collectively, P. cylindrica was more resistant to diving activities than A. hyacinthus which only relies on photoautotrophy. To ensure the sustainable development of coral reef dive tourism, it is necessary to strengthen the supervision of diving behaviors, rotate the diving areas, and conduct regular assessments on the coral status.
Surface-Layer Circulations in Suruga Bay Induced by Intrusions of Kuroshio Branch Water
Authors: Toyoda Takahiro , Sakamoto Kei , Usui Norihisa , Hirose Nariaki , Tanaka Kiyoshi , Katsumata Takaaki , Takahashi Daisuke , Niki Masato , Kutsuwada Kunio , Miyama Toru , Nakano Hideyuki , Urakawa L. Shogo , Komatsu Kensuke K. , Kawakami Yuma , Yamanaka Goro
Published: September 2021

The water mass structure in Suruga Bay is strongly influenced by open-ocean water. In particular, it is suggested that intermittent intrusions of the Kuroshio water generate characteristic circulations in the surface layer of the bay. In this study, we investigated the processes of the intrusions of open-ocean water into the bay and related generation of bay-scale cyclonic and anti-cyclonic circulation patterns. In doing so, we used an ocean simulation product with observational data constraint on meso and larger scales and with a resolution fine enough to resolve the smaller-scale intrusion structure. Cyclonic and anti-cyclonic circulation patterns as suggested by previous observational studies were detected as positive and negative first leading empirical orthogonal function (EOF) modes of the velocity field in Suruga Bay. The time scale of occurrences of these patterns was estimated as about 1 month, which was consistent with short-term Kuroshio fluctuations as reported in previous studies. Conditions favorable for generating these patterns were analyzed for three typical Kuroshio path periods individually. As suggested by previous studies, relatively strong northward flow to the west of Zeni-su generally promoted the open-ocean water intrusions into the eastern bay mouth, leading the cyclonic circulation in Suruga Bay. Our results showed that the correlation of this relation was significant for each Kuroshio path period. The open-ocean water intrusion increased the surface-layer temperature in Suruga Bay by about 0.7°C on average. On the other hand, the anti-cyclonic circulation pattern in Suruga Bay tended to be generated with relatively weak northward flow to the west of Zeni-su during the large meander Kuroshio path period, whereas this relation was rather weak during other periods. These results were mostly supported by available observations and would be useful for integrating our understanding of the influences of the western boundary current fluctuations on the circulation and temperature variations in proximal bays.
A Multi-Institutional Randomized Controlled Trial to Investigate Whether Zoledronate Prevents Bone Loss After Discontinuation of Denosumab: The Study Protocol of Denosumab Sequential Therapy (DST) Trial
Authors: Lee Chia-Che , Wang Chen-Yu , Hung Chih-Chien , Huang Chuan-Ching , Li Chung-Yi , Chen Hsuan-Yu , Chang Yun-Liang , Tseng Wo-Jan , Wang Ting-Ming , Yang Rong-Sen , Wong Tze-Hong , Fu Shau-Huai
Published: September 2021

Background: Though denosumab is an effective treatment for osteoporosis, the rebound effect after discontinuation has drawn investigators' attention. It includes a dramatic loss of gained bone mineral density (BMD) and an increased risk of vertebral fractures. This prospective multi-institutional randomized controlled trial aims to investigate whether zoledronate prevents loss of BMD after discontinuation of denosumab. The trial was registered as Denosumab Sequential Therapy (DST) trial in March 2019 at clinicaltrials.gov, with the identifier NCT03868033.

Methods: The study is conducted at National Taiwan University Hospital and its branches. Patients who have continuously received denosumab treatment for two or more years are surveyed for eligibility. Baseline characteristics and questionnaires of life quality are recorded after recruitment. BMD, circulating levels of bone turnover markers (BTMs), including serum N-terminal propeptide of type 1 collagen (P1NP) and C-terminal telopeptide (CTX), are checked before the stratified randomization to 4 groups. Biological sex and the T-scores are used to create 4 strata. The participants in group 1 adhere to regular denosumab therapy for another 2 years. All the other patients receive on-time zoledronate treatment in the first year. The participants in group 2, 3, and 4 have on-time denosumab, on-time zoledronate and drug holiday in the second year, respectively. BMDs are checked annually. Pre-scheduled checkpoints of BTMs are also arranged. For patient safety, rescue treatment with another injection of zoledronate will be applied to the patients on drug holiday if the CTX levels raise above the pre-specified threshold, 0.573 ng/mL for women and 0.584 ng/mL for men. The primary outcomes are the percentage changes of BMDs in lumbar spine, total hip and femoral neck. The secondary outcomes include the changes of serum level of the BTMs, new osteoporotic fractures, extra zoledronate injections needed in group 4 and the differences of quality of life.

Discussion: We aim to provide evidence whether zoledronate prevents bone loss after denosumab cessation. To our knowledge, the study has the largest sample size. No other randomized controlled study included all the three different treatment strategies and a positive control. It is also the first associated randomized controlled trial outside Europe.
Combined Use of Serum Uromodulin and eGFR to Estimate Mortality Risk
Authors: Yazdani Babak , Delgado Graciela E. , Scharnagl Hubert , Krämer Bernhard K. , Drexel Heinz , März Winfried , Scherberich Jürgen E. , Leiherer Andreas , Kleber Marcus E.
Published: September 2021

Serum uromodulin (sUmod) shows a strong direct correlation with eGFR in patients with impaired kidney function and an inverse association with mortality. However, there are patients in whom only one of both markers is decreased. Therefore, we aimed to investigate the effect of marker discordance on mortality risk. sUmod and eGFR were available in 3,057 participants of the Ludwigshafen Risk and Cardiovascular Health study and 529 participants of the VIVIT study. Both studies are monocentric prospective studies of patients that had been referred for coronary angiography. Participants were categorized into four groups according to the median values of sUmod (LURIC: 146 ng/ml, VIVIT: 156) and eGFR (LURIC: 84 ml/min/1.73 m2, VIVIT: 87). In 945 LURIC participants both markers were high (UHGH), in 935 both were low (ULGL), in 589 only eGFR (UHGL), and in 582 only sUmod (ULGH) was low. After balancing the groups for cardiovascular risk factors, hazard ratios (95%CI) for all-cause mortality as compared to UHGH were 2.03 (1.63–2.52), 1.43 (1.13–1.81), and 1.32 (1.03–1.69) for ULGL, UHGL, and ULGH, respectively. In VIVIT, HRs were 3.12 (1.38–7.08), 2.38 (1.01–5.61), and 2.06 (0.81–5.22). Adding uromodulin to risk prediction models that already included eGFR as a covariate slightly increased the Harrell's C and significantly improved the AUC in LURIC. In UHGL patients, hypertension, heart failure and upregulation of the renin-angiotensin-aldosterone-system seem to be the driving forces of disease development, whereas in ULGH patients metabolic disturbances might be key drivers of increased mortality. In conclusion, SUmod/eGFR subgroups mirror distinct metabolic and clinical patterns. Assessing sUmod additionally to creatinine or cystatin C has the potential to allow a more precise risk modeling and might improve risk stratification.
Capturing Salmonella SspH2 Host Targets in Virus-Like Particles
Authors: De Meyer Margaux , Fijalkowski Igor , Jonckheere Veronique , De Sutter Delphine , Eyckerman Sven , Van Damme Petra
Published: September 2021

In the context of host-pathogen interactions, gram-negative bacterial virulence factors, such as effectors, may be transferred from bacterial to eukaryotic host cytoplasm by multicomponent Type III protein secretion systems (T3SSs). Central to Salmonella enterica serovar Typhimurium (S. Typhimurium) pathogenesis is the secretion of over 40 effectors by two T3SSs encoded within pathogenicity islands SPI-1 and SPI-2. These effectors manipulate miscellaneous host cellular processes, such as cytoskeleton organization and immune signaling pathways, thereby permitting host colonization and bacterial dissemination. Recent research on effector biology provided mechanistic insights for some effectors. However, for many effectors, clearly defined roles and host target repertoires—further clarifying effector interconnectivity and virulence networks—are yet to be uncovered. Here we demonstrate the utility of the recently described viral-like particle trapping technology Virotrap as an effective approach to catalog S. Typhimurium effector-host protein complexes (EH-PCs). Mass spectrometry-based Virotrap analysis of the novel E3 ubiquitin ligase SspH2 previously shown to be implicated in modulating actin dynamics and immune signaling, exposed known host interactors PFN1 and−2 besides several putative novel, interconnected host targets. Network analysis revealed an actin (-binding) cluster among the significantly enriched hits for SspH2, consistent with the known localization of the S-palmitoylated effector with actin cytoskeleton components in the host. We show that Virotrap complements the current state-of-the-art toolkit to study protein complexes and represents a valuable means to screen for effector host targets in a high-throughput manner, thereby bridging the knowledge gap between effector-host interplay and pathogenesis.
Sex Differences in Adverse Reactions to an Inactivated SARS-CoV-2 Vaccine Among Medical Staff in China
Authors: Zhu Jian-Sheng , Zhang Mei-Xian , Chien Ching-Wen , Yang Wei-Ying , Shi Gui-Feng , Qiu Shulin , Tung Tao-Hsin , Chen Hai-Xiao
Published: September 2021

Objective: We investigated whether there were sex differences in adverse reactions to an inactivated SARS-CoV-2 vaccine among medical staff in China.

Methods: From 24 February to 7 March 2021 an online cross-sectional survey was conducted with a self-administered COVID-19 vaccine questionnaire among medical staff in Taizhou, China. In total, 1397 interviewees (1,107 women and 290 men) participated in the survey.

Results: In our study, 178 (16.1%) women and 23 (7.9%) men reported adverse reactions following their first vaccination, and 169 (15.3%) women and 35 (12.1%) men reported adverse reactions following their second vaccination. After adjusting for confounding factors, adverse reactions to other vaccines, worry about adverse reactions, knowledge of the inactivated vaccine being used in the hospital, taking the vaccine for one's family proactively and receiving an influenza vaccination were significantly related to adverse reactions to both injections in women. In contrast, in men, concerns about adverse reactions independently increased the risk of adverse reactions following either vaccination, and a history of adverse reactions to other vaccines also increased the risk of adverse reactions to both injections.

Conclusions: Sex differences in the frequency of reported adverse reactions to an inactivated SARS-CoV-2 vaccine and potential factors were demonstrated in a sample of medical staff.
Age-Adjusted Endothelial Activation and Stress Index for Coronavirus Disease 2019 at Admission Is a Reliable Predictor for 28-Day Mortality in Hospitalized Patients With Coronavirus Disease 2019
Authors: Pérez-García Felipe , Bailén Rebeca , Torres-Macho Juan , Fernández-Rodríguez Amanda , Jiménez-Sousa Maria Ángeles , Jiménez Eva , Pérez-Butragueño Mario , Cuadros-González Juan , Cadiñanos Julen , García-García Irene , Jiménez-González María , Ryan Pablo , Resino Salvador
Published: September 2021

Background: Endothelial Activation and Stress Index (EASIX) predict death in patients undergoing allogeneic hematopoietic stem cell transplantation who develop endothelial complications. Because coronavirus disease 2019 (COVID-19) patients also have coagulopathy and endotheliitis, we aimed to assess whether EASIX predicts death within 28 days in hospitalized COVID-19 patients.

Methods: We performed a retrospective study on COVID-19 patients from two different cohorts [derivation (n = 1,200 patients) and validation (n = 1,830 patients)]. The endpoint was death within 28 days. The main factors were EASIX [(lactate dehydrogenase * creatinine)/thrombocytes] and aEASIX-COVID (EASIX * age), which were log2-transformed for analysis.

Results: Log2-EASIX and log2-aEASIX-COVID were independently associated with an increased risk of death in both cohorts (p < 0.001). Log2-aEASIX-COVID showed a good predictive performance for 28-day mortality both in the derivation cohort (area under the receiver-operating characteristic = 0.827) and in the validation cohort (area under the receiver-operating characteristic = 0.820), with better predictive performance than log2-EASIX (p < 0.001). For log2 aEASIX-COVID, patients with low/moderate risk (<6) had a 28-day mortality probability of 5.3% [95% confidence interval (95% CI) = 4–6.5%], high (6–7) of 17.2% (95% CI = 14.7–19.6%), and very high (>7) of 47.6% (95% CI = 44.2–50.9%). The cutoff of log2 aEASIX-COVID = 6 showed a positive predictive value of 31.7% and negative predictive value of 94.7%, and log2 aEASIX-COVID = 7 showed a positive predictive value of 47.6% and negative predictive value of 89.8%.

Conclusion: Both EASIX and aEASIX-COVID were associated with death within 28 days in hospitalized COVID-19 patients. However, aEASIX-COVID had significantly better predictive performance than EASIX, particularly for discarding death. Thus, aEASIX-COVID could be a reliable predictor of death that could help to manage COVID-19 patients.
Measurement of the Total Lung Volume Using an Adjusted Single-Breath Helium Dilution Method in Patients With Obstructive Lung Disease
Authors: Liu Qing , Zhou Lingxiao , Feng Peiling , Liu Jinkai , Shen Bin , Huang Lili , Wang Yingying , Zou Yimin , Xia Yang , Huang Gang
Published: September 2021

Background: Whole-body plethysmography (WBP) is the gold standard for measuring lung volume, but its clinical application is limited as it requires expensive equipment and is not simple to use. Studies have shown that the single-breath helium dilution (SBHD) method, which is commonly used in clinical practice, significantly underestimates lung volume in patients with obstructive lung disease (OLD). By comparing the differences in lung volume measured using SBHD and WBP, we aimed to establish a correction equation for the SBHD method to determine the total lung volume in patients with OLD of different severities.

Methods: From 628 patients with OLD simultaneously subjected to SBHD and WBP, 407 patients enrolled between January 2018 and November 2019 were in the training group and 221 enrolled between December 2019 and December 2020 were in the prospective verification cohort. The multiple linear regression equation was used for data in the training group to establish a correction equation for SBHD to determine the total lung volume, and this was validated in the prospective validation cohort.

Results: There was a moderate positive correlation between total lung capacity (TLC) determined using the SBHD [TLC (SBHD)] and WBP methods [TLC (WBP)] (r = 0.701; P < 0.05), and the differences between TLC (SBHD) and TLC (WBP) (ΔTLC) were related to the severity of obstruction. As the severity of obstruction increased, the TLC was underestimated by the SBHD method. We established the following correction equation: TLC (adjusted SBHD) (L) = −0.669 + 0.756*TLC(SBHD)(L) – 0.047*FEV1FVC+0.039*height (cm)–0.009*weight(kg)(r2 = 0.753 and adjusted r2 = 0.751). Next, we validated this equation in the validation cohort. With the correction equation, no statistical difference was observed between TLC (adjusted SBHD) and TLC (WBP) among the obstruction degree groups (P > 0.05).

Conclusions: The SBHD method is correlated with WBP to measure the total lung volume, but the SBHD method presents limitations in determining the total lung volume in patients with obstructive lung disease. Here, we established an effective and reliable correction equation in order to accurately assess the total lung volume of patients with OLD using the SBHD method.
Design and Rationale of a Prospective International Follow-Up Study on Intensive Care Survivors of COVID-19: The Long-Term Impact in Intensive Care Survivors of Coronavirus Disease-19–AFTERCOR
Authors: Wildi Karin , Li Bassi Gianluigi , Barnett Adrian , Panigada Mauro , Colombo Sebastiano M. , Bandera Alessandra , Muscatello Antonio , McNicholas Bairbre , Laffey John G. , Battaglini Denise , Robba Chiara , Torres Antoni , Motos Ana , Luna Carlos M. , Rainieri Fernando , Hodgson Carol , Burrell Aidan J. C. , Buscher Hergen , Dalton Heidi , Cho Sung-Min , Choi Huimahn Alex , Thomson David , Suen Jacky , Fraser John F.
Published: September 2021

Background: In a disease that has only existed for 18 months, it is difficult to be fully informed of the long-term sequelae of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Evidence is growing that most organ systems can be affected by the virus, causing severe disabilities in survivors. The extent of the aftermath will declare itself over the next 5–10 years, but it is likely to be substantial with profound socio-economic impact on society.

Methods: This is an international multi-center, prospective long-term follow-up study of patients who developed severe coronavirus disease-2019 (COVID-19) and were admitted to Intensive Care Units (ICUs). The study will be conducted at international tertiary hospitals. Patients will be monitored from time of ICU discharge up to 24 months. Information will be collected on demographics, co-existing illnesses before ICU admission, severity of illness during ICU admission and post-ICU quality of life as well as organ dysfunction and recovery. Statistical analysis will consist of patient trajectories over time for the key variables of quality of life and organ function. Using latent class analysis, we will determine if there are distinct patterns of patients in terms of recovery. Multivariable regression analyses will be used to examine associations between baseline characteristics and severity variables upon admission and discharge in the ICU, and how these impact outcomes at all follow-up time points up to 2 years.

Ethics and Dissemination: The core study team and local principal investigators will ensure that the study adheres to all relevant national and local regulations, and that the necessary approvals are in place before a site may enroll patients.

Clinical Trial Registration:anzctr.org.au: ACTRN12620000799954.