bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Lactobacillus plantarum on growth traits, slaughter performance, serum markers and intestinal bacterial community of Daheng broilers
Authors: Song Xiaoyan , Lin Zhongzhen , Yu Chunlin , Qiu Mohan , Peng Han , Jiang Xiaosong , Du Huarui , Li Qingyun , Liu Yiping , Zhang Zengrong , Ren Peng , Yang Chaowu
Published: August 2021

Probiotics are expected to be an ideal alternative for antibiotics in the poultry industry. This study aimed to investigate the effect of Lactobacillus plantarum on growth traits, slaughter performance, serum markers and intestinal bacterial community of Daheng broilers. A total of 2400 healthy one‐day‐old Daheng broilers were randomly divided into 5 groups with 6 replicates per group and 40 individuals per replicate. Birds in control group were fed a basal diet, and others were fed basal diets supplemented with 105, 106, 107 and 108 CFU/kg Lactobacillus plantarum, respectively. It turned out that adding Lactobacillus plantarum to diet could significantly improve the serum immune performance of broilers (p < 0.05), enhance the antioxidant capacity to a certain extent (p > 0.05), but had no significant effect on growth traits and slaughter performance. Moreover, Lactobacillus plantarum could improve the diversity of intestinal bacterial community, but with the increase of addition concentration, the diversity would gradually decrease. In conclusion, Lactobacillus plantarum can be used as feed additive in broiler production, but whether it is more effective than antibiotics needs further investigation.
Pilot evaluation of a consumer wearable device to assess sleep in a clinical polysomnography trial of suvorexant for treating insomnia in patients with Alzheimer's disease
Authors: Svetnik Vladimir , Wang Ting‐Chuan , Ceesay Paulette , Snyder Ellen , Ceren Omar , Bliwise Donald , Budd Kerry , Hutzelmann Jill , Stevens Joanne , Lines Christopher , Michelson David , Herring W. Joseph
Published: August 2021

The orexin receptor antagonist suvorexant was previously reported to significantly improve total sleep time (TST), by 28 min per night versus placebo after 4 weeks, in a sleep laboratory polysomnography (PSG) study of patients with Alzheimer's disease and insomnia. The study included an exploratory evaluation of a consumer‐grade wearable “watch” device for assessing sleep that we report on here. Participants who met diagnostic criteria for both probable Alzheimer's disease dementia and insomnia were randomized to suvorexant 10–20 mg (N = 142) or placebo (N = 143) in a double‐blind, 4‐week trial. Patients were provided with a consumer‐grade wearable watch device (Garmin vívosmart® HR) to be worn continuously. Overnight sleep laboratory PSG was performed on three nights: screening, baseline and Night 29 (last dose). Watch treatment effects were assessed by change‐from‐baseline in watch TST at Week 4 (average TST per night). We also analysed Night 29 data only, with watch data restricted to the PSG recording time. In the 193 participants included in the Week 4 watch analysis (suvorexant = 97, placebo = 96), the suvorexant–placebo difference in watch TST was 4 min (p = .622). In patients with usable data for both assessments at the baseline and Night 29 PSG (suvorexant = 57, placebo = 50), the watch overestimated TST compared to PSG (e.g., placebo baseline = 412 min for watch and 265 min for PSG) and underestimated change‐from‐baseline treatment effects: the suvorexant–placebo difference was 20 min for watch TST (p = .405) and 35 min for PSG TST (p = .057). These findings show that the watch was less sensitive than PSG for evaluating treatment effects on TST.
The debate around the access to vaccine and licensing amidst second wave of COVID‐19 in India
Authors: Sharma Sparsh
Published: August 2021

The guardian of global health signified a “global response” to contain COVID 19 utilising the platform of World Health Organization when the novel virus strain was spreading. The nature of “waves,” that is, variable epidemiological patterns and peaks in trajectory, have been inconsistent and myriad in different regions and countries. Many researchers and scholars have deliberated on the possible ways forward to curb or mitigate the effects of the virus; and one such means is through universal vaccination. Hence, this article explores the positions to achieve that goal by looking at the licensing aspect and IP waiver debate and suggests a fine‐tuning which balances all the interests, amidst the second wave in India.
The Meloidogyne javanica effector Mj2G02 interferes with jasmonic acid signalling to suppress cell death and promote parasitism in Arabidopsis
Authors: Song Handa , Lin Borong , Huang Qiuling , Sun Tianlin , Wang Wenjun , Liao Jinling , Zhuo Kan
Published: August 2021

Plant‐parasitic nematodes can cause devastating damage to crops. These nematodes secrete effectors that suppress the host immune responses to enhance their survival. In this study, Mj2G02, an effector from Meloidogyne javanica, is described. In situ hybridization and transcriptional analysis showed that Mj2G02 was highly expressed in the early infection stages and exclusively expressed in the nematode subventral oesophageal gland cells. In planta RNA interference targeting Mj2G02 impaired M. javanica parasitism, and Mj2G02‐transgenic Arabidopsis lines displayed more susceptibility to M. javanica. Using an Agrobacterium‐mediated transient expression system and plant immune response assays, we demonstrated that Mj2G02 localized in the plant cell nuclei and could suppress Gpa2/RBP‐1‐induced cell death. Moreover, by RNA‐Seq and quantitative reverse transcription PCR analyses, we showed that Mj2G02 was capable of interfering with the host jasmonic acid (JA) signalling pathway. Multiple jasmonate ZIM‐domain (JAZ) genes were significantly upregulated, whereas the JAR1 gene and four JA‐responsive genes, MYC3, UPI, THI2.1, and WRKY75, were significantly downregulated. In addition, HPLC analysis showed that the endogenous jasmonoyl‐isoleucine (JA‐Ile) level in Mj2G02‐transgenic Arabidopsis lines was significantly decreased compared to that in wildtype plants. Our results indicate that the M. javanica effector Mj2G02 suppresses the plant immune response, therefore facilitating nematode parasitism. This process is probably mediated by a JA‐Ile reduction and JAZ enhancement to repress JA‐responsive genes.
Pharmacogenomics fail to explain proton pump inhibitor refractory esophagitis in pediatric esophageal atresia
Authors: Yasuda Jessica L. , Staffa Steven J. , Nurko Samuel , Kane Madeline , Wall Stephanie , Mougey Edward B. , Franciosi James P. , Manfredi Michael A. , Rosen Rachel
Published: August 2021

Background

Esophagitis is prevalent in patients with esophageal dysmotility despite acid suppression, likely related to poor esophageal clearance. Esophageal atresia (EA) is a classic model of dysmotility where this observation holds true. In adult non‐dysmotility populations, failure of esophagitis to respond to proton pump inhibitors (PPI) has been linked to variants in CYP2C19 that influence the activity of the encoded enzyme. It is unknown if CYP2C19 metabolizer phenotype contributes to PPI‐refractory, non‐allergic esophagitis in EA.

Methods

We performed a cross‐sectional study of 314 children with (N = 188) and without (N = 126) EA who were on PPI therapy at the time of endoscopy to evaluate for possible gastroesophageal reflux disease. Patients with eosinophilic esophagitis and/or fundoplication were excluded. Clinical and histology data were collected. Genomic DNA from biopsy samples was genotyped for polymorphisms in CYP2C19.

Results

CYP2C19 metabolizer phenotypes were not associated with presence or severity of esophagitis (P = 0.994). In a multivariate logistic regression adjusted for potential confounders, EA was the strongest and only significant predictor of esophagitis (odds ratio 2.72, P = 0.023). Using negative binomial regression, we found that CYP2C19 phenotype was not a significant predictor of eosinophil count in children with PPI‐refractory esophagitis.

Conclusions

Patients with EA are significantly more likely to experience PPI‐refractory, non‐allergic esophagitis than controls regardless of CYP2C19 metabolizer phenotype, suggesting that factors other than CYP2C19 genetics, including dysmotility, are the primary drivers of esophagitis in EA. CYP2C19 genotype failed to predict PPI‐refractory, non‐allergic esophagitis in both EA and non‐EA children.
Stigma experiences of patients living with gastroparesis
Authors: Taft Tiffany H. , Craven Meredith R. , Adler Emerald P. , Simons Madison , Nguyen Linda
Published: August 2021

Introduction

Stigmatization toward chronic digestive diseases is well documented. Patients perceive others hold negative stereotypes toward their disease and may internalize these beliefs as true. Because of this, stigmatization is associated with poor outcomes across disease‐related and psychosocial domains. No study to date evaluates stigmatization toward patients living with gastroparesis (GP), a poorly understood disease affecting gastric motility. We aimed to gain deep understanding of stigma in patients living with gastroparesis.

Methods

Patients with GP were recruited from two university‐based gastroenterology practices as well as patient advocacy support groups. Participants underwent a semi‐structured qualitative interview about their experiences with stigma related to their GP diagnosis, which were audio‐recorded and transcribed to text for analysis using a grounded theory approach. Major themes with representative quotations were documented.

Results

Twenty‐three patients participated. The majority were White, female, with idiopathic GP under the care of a gastroenterologist. All patients reported stigma related to GP. Seven major themes were found: stigma from healthcare providers, stigma within interpersonal relationships, GP as an invisible disease, blame, unsolicited suggestions on how to manage disease, disclosure, and stigma resistance.

Conclusions

This is the first study to describe stigma experiences in patients with GP. The results suggest patients experience considerable stigmatization toward their condition from multiple sources. Patients also demonstrated resistance to negative beliefs, which can serve as a protective factor for the negative effects of disease stigma. Clinicians should be aware of stigma in GP patients, including their own potential internal biases and behaviors.
Comparison of synchronization between left bundle branch and his bundle pacing in atrial fibrillation patients: An intra‐patient‐controlled study
Authors: Sheng Xia , Pan Yi‐Wen , Yu Chan , Wang Bei , Zhang Pei , Li Jing , Zhang Jie‐Fang , Chen Shi‐Quan , Wang Min , Sun Ya‐Xun , Jiang Dong‐Mei , Yang Ying , Ye Yang , Cha Yong‐Mei , Fu Guo‐Sheng
Published: August 2021

Background

His bundle pacing (HBP) is a physiological pacing strategy to preserve the electrical synchrony of ventricular conduction and left ventricular (LV) function. Left bundle branch pacing (LBBP) has emerged as an alternative physiological pacing technique.

Objective

To evaluate cardiac electrical and mechanical synchrony comparing LBBP and HBP in patients with permanent atrial fibrillation (AF).

Methods

Consecutive patients with symptomatic bradycardia and AF were enrolled from January to June of 2019. The cardiac electrical and mechanical synchrony in different pacing mode were evaluated at baseline and after implantation.

Results

Both HBP and LBBP were performed in 20 patients. LBBP significantly widened the QRS duration compared with the intrinsic conduction (113.2 ± 14.5  vs. 96.5 ± 16.2 ms; p = .01), while HBP did not (104.5 ± 22.3  vs. 96.5 ± 16.2 ms; p = .12). Both LBBP and HBP patients had similar LV myocardial strain measurements for the mechanical synchrony evaluation without significant change compared with baseline. There was no significant difference in right ventricular synchrony measurement between LBBP and HBP. Compared to HBP, LBBP had less interventricular synchrony (IMVD, 14.7 ± 9.2  vs. 3.1 ± 12.7 ms, p < .01; Ts‐LV‐RV, 37.9 ± 10.7  vs. 18.5 ± 10.8 ms, p < .001).

Conclusions

Although LBBP's a physiological pacing mode can achieve a similar cardiac electrical and mechanical synchronization when compared to HBP, LBBP results in modest delay in RV activation, and the clinical implication remains to be studied.
TH2 sensitization in the skin‐gut‐brain axis: How early‐life Th2‐mediated inflammation may negatively perpetuate developmental and psychologic abnormalities
Authors: Jackson‐Cowan LaDonya , Cole Emily F. , Arbiser Jack L. , Silverberg Jonathan I. , Lawley Leslie P.
Published: August 2021

We recently reported children with comorbid atopic dermatitis (AD), asthma, allergic rhinitis, and food allergies displaying a 2.7‐fold increase in developmental delays.2 To this end, we hypothesize unregulated increases in T helper‐2 (Th2)–driven inflammation, such as those seen in atopic diseases, can exert deleterious effects on the developing brain. Recognizing that available information is incomplete and that many potential associations are not firmly established, we speculate these effects underlie the association between Th2 sensitization and cognitive dysfunction in children. In this review, we explore the role of Th2 sensitization in the skin‐gut‐brain axis and explain how it can lead to reduced connectivity and transmission in the developing brain. With a focus on AD, we explore the association between Th2 sensitization and developmental abnormalities such as developmental delays, memory impairment, autism spectrum disorder (ASD), and epilepsy/seizures. As such, we review the available literature to examine the impact of increased IL‐4 exposure in early life on the brain. We explore the possible association between Th2 sensitization and psychologic dysfunction such as attention‐deficit/hyperactivity disorder (ADHD), depression, anxiety, and suicidal ideation. We also examine the impact that increased exposure to glucocorticoids and neurotrophins in early life exerts on the developing brain. Last, we discuss future directions for the advancement of our knowledge as a scientific community including possible interventions to reduce developmental and psychologic aberrations in children.
Access as equity: Addressing the distribution of the pediatric dermatology workforce
Authors: Ugwu‐Dike Pearl , Nambudiri Vinod E.
Published: August 2021

While overall shortages in the pediatric dermatologist workforce have been well‐documented, recent evidence indicates a geographic maldistribution of providers, which can further exacerbate health disparities for children. Wide geographic gaps in access to pediatric care constitute a critical public health issue and impede upon a child's right to access care. In this review, we examine the issue of geographic maldistribution of pediatric dermatologists through the lens of health equity: describing the problem, exploring the enablers of and barriers to change, and offering potential solutions.
Perinatal‐lethal Gaucher disease presenting with blueberry muffin lesions
Authors: Rosanio Francesco Maria , D’Acunzo Ida , Mozzillo Filomena , Di Pinto Rosita , Tornincasa Chiara , Amabile Sonia , Piccirillo Alessandro , Roma Vincenzina , Giordano Lucio
Published: August 2021

“Blueberry muffin baby” is an expression applied to newborns displaying a generalized purpuric rash caused by dermal erythropoiesis. This presentation is typically associated with TORCH (toxoplasmosis, other, rubella, cytomegalovirus, and herpesvirus) complex infections. However, alternative diagnoses should be considered, including other infections, neoplastic diseases, congenital vascular lesions, and metabolic diseases. We report a case of perinatal‐lethal‐type Gaucher disease presenting with cholestasis, hepatosplenomegaly, persistent thrombocytopenia, and blueberry muffin‐like skin lesions.
Immunological features and complications in patients with glycogen storage disease 1b after living donor liver transplantation
Authors: Shimizu Seiichi , Sakamoto Seisuke , Yamada Masaki , Fukuda Akinari , Yanagi Yusuke , Uchida Hajime , Mimori Kotaro , Shoji Kensuke , Funaki Takanori , Miyairi Isao , Nakano Noriyuki , Haga Chizuko , Yoshioka Takako , Imadome Ken‐Ichi , Horikawa Reiko , Kasahara Mureo
Published: August 2021

Background

LT is an elective treatment choice for children diagnosed with GSD1b that can improve their quality of life and stabilize their glucose intolerance. However, careful attention should be paid to immunosuppression after LT due to the susceptibility to infection because of neutropenia and neutrophil dysfunction in GSD1b patients. This study revealed the immunological features and complications in the early post‐LT period.

Methods

We compared findings between 11 (1.9%) children with GSD1b and 273 children with BA. Analyses using the PSM were performed to overcome selection bias.

Results

Despite persistent low tacrolimus trough levels in GSD1b patients, none of these children developed TCMR within 1 month after LDLT (GSD1b: 0/11 [0%] vs. BA: 86/273 [31.5%], p = .038). This result was also confirmed in PSM. The incidence of bloodstream infections was higher in GSD1b patients than in BA patients in the early phase of the post‐transplant period (GSD1b: 4/11 [36.4%] vs. BA: 33/273 [12.1%], p = .041), but not reach statistical significance in PSM. In a phenotypic analysis, the ratio of CD8+ T cells in GSD1b recipients' peripheral blood mononuclear cell samples was lower than in recipients with BA through the first month after LDLT.

Conclusions

We found that GSD1b recipients were more likely to develop postoperative bloodstream infection than recipients with BA but did not experience TCMR despite low tacrolimus levels in the early post‐LDLT period. A tailored immunosuppression protocol should be prepared for GSD1b recipients after LDLT.
Positive allosteric modulation of NMDA receptors: mechanisms, physiological impact and therapeutic potential
Authors: Geoffroy Chloé , Paoletti Pierre , Mony Laetitia
Published: August 2021

NMDA receptors (NMDARs) are glutamate‐gated ion channels that play key roles in synaptic transmission and plasticity. Both hyper‐ and hypo‐activation of NMDARs are deleterious to neuronal function. In particular, NMDAR hypofunction is involved in a wide range of neurological and psychiatric conditions like schizophrenia, intellectual disability, age‐dependent cognitive decline, or Alzheimer's disease. While early medicinal chemistry efforts were mostly focused on the development of NMDAR antagonists, the last 10 years have seen a boom in the development of NMDAR positive allosteric modulators (PAMs). Here we review the currently developed NMDAR PAMs, their pharmacological profiles and mechanisms of action, as well as their physiological effects in healthy animals and animal models of NMDAR hypofunction. In light of the complexity of physiological outcomes of NMDAR PAMs in vivo, we discuss the remaining challenges and questions that need to be addressed to better grasp and predict the therapeutic potential of NMDAR positive allosteric modulation.

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Recent Developments in Air Pumps for Thermal Management of Electronics
Authors: Wen Tsrong-Yi , Ye Jia-Cheng
Published: August 2021

For electronics, poor thermal management could cause severe mechanical and electrical failures. Forced convective air cooling, i.e., flowing air over a hot surface, is one of the most efficient and economical solutions to manage thermal issues of electronics. Air pump is used to initiate and sustain airflow required in forced convection. This paper reviews both the mechanical and the nonmechanical air pumps that have been using widely in current electronics or have a great potential in future electronics. The mechanical pumps include axial fans, blowers, beam fans, and diaphragm pumps, while the nonmechanical pump specifically focuses on electrohydrodynamic pumps. This paper presents the working principle first and then the recent developments, including the pump itself (design, characteristics, etc.) and the applications in thermal management (placement, integration, etc.). In the end, this paper conducts the strength analysis (flow rate, pressure, noise, flexibility, and reliability) among the reviewed five types of air pumps.
Effects of Sleeve Parameters on Cavitation Control Performance in Steam Trap Valves
Authors: Qiu Chang , Gao Zhi-xin , Jin Zhi-jiang , Qian Jin-yuan
Published: August 2021

The steam trap valve is used in thermal power systems to pour out condensate water and keep steam inside. While flowing through steam trap valves, the condensate water can easily reach cavitation, which may cause serious damage to the piping system. In this paper, in order to control cavitation inside steam trap valves, effects of sleeve parameters, including orifice diameter, installation angle and thickness, are investigated using a cavitation model. The pressure, velocity, and vapor distribution inside valves are analyzed and compared for different sleeve geometrical parameters. The total vapor volumes are also predicted and compared. The results show that the sleeve parameters have a significant influence on the cavitation intensity and cavitation vapor distributions. Specifically, the orifice diameter of the sleeve has much larger effect on each aspect than that of other two geometrical parameters of the sleeve. The improved geometrical parameters of the sleeve are determined to suppress the cavitation inside the valve. The sleeve with smaller diameter orifices, higher installation angle (maximum 80 deg), and higher thickness is recommended in practice for better anticavitation performance. The work is of significance for cavitation control and the optimization design of steam trap valves.
Some Reflections on Sparrow's Work on Similarity Solutions for Laminar Film Condensation on a Vertical Plate
Authors: Dhir Vijay K.
Published: August 2021

In this contribution in honor of the late Prof. E. M. Sparrow, we reflect on the pioneering work of Sparrow and Gregg on the development of similarity solutions for laminar film condensation on a vertical plate. Dhir and Lienhard, using this work as a basis, developed a generalized solution for isothermal curved surfaces on which gravitational acceleration varied along the surface and for variable gravity situations. Subsequently, nonisothermal surfaces were also considered. These studies were publisher earlier in the Journal of Heat Transfer.
High-Dimensional Reliability Method Accounting for Important and Unimportant Input Variables
Authors: Yin Jianhua , Du Xiaoping
Published: August 2021

Reliability analysis is a core element in engineering design and can be performed with physical models (limit-state functions). Reliability analysis becomes computationally expensive when the dimensionality of input random variables is high. This work develops a high-dimensional reliability analysis method through a new dimension reduction strategy so that the contributions of unimportant input variables are also accommodated after dimension reduction. Dimension reduction is performed with the first iteration of the first-order reliability method (FORM), which identifies important and unimportant input variables. Then a higher order reliability analysis is performed in the reduced space of only important input variables. The reliability obtained in the reduced space is then integrated with the contributions of unimportant input variables, resulting in the final reliability prediction that accounts for both types of input variables. Consequently, the new reliability method is more accurate than the traditional method which fixes unimportant input variables at their means. The accuracy is demonstrated by three examples.
Cinnamaldehyde adsorption and thermal decomposition on copper surfaces
Authors: Chen Bo , Ponce Rodrigo , Guerrero-Sánchez Jonathan , Takeuchi Noboru , Zaera Francisco
Published: August 2021

The uptake and thermal chemistry of cinnamaldehyde on Cu(110) single-crystal surfaces were characterized by temperature-programmed desorption and x-ray photoelectron spectroscopy (XPS). Adsorption at 85 K appears to be initiated by low-temperature decomposition to form styrene, which desorbs at 190 K, followed by the sequential buildup of a molecular monolayer and then a condensed molecular film. Molecular desorption from the monolayer occurs at 410 K, corresponding to a desorption energy of approximately 98 kJ/mol, and further decomposition to produce styrene (again) and other fragmentation products is seen at 550 K. The molecular nature and the quantitation of the low-temperature uptake were corroborated by the XPS data, which also provided hints about the adsorption geometry adopted by the unsaturated aldehyde on the surface. Density functional theory calculations, used to estimate adsorption energies as a function of coverage and coordination mode, pointed to possible η1-O binding, at least at high coverages, and to a stabilizing effect on the surface by the aromatic ring of cinnamaldehyde. Finally, coadsorption of oxygen on the surface was found to weaken the binding of cinnamaldehyde to the Cu substrate at high coverages without enhancing its uptake, but to not modify the decomposition mechanism or energetics in any significant way.
Mitochondria as a Potential Target for the Development of Prophylactic and Therapeutic Drugs against Schistosoma mansoni Infection
Authors: Talaam Keith Kiplangat , Inaoka Daniel Ken , Hatta Takeshi , Tsubokawa Daigo , Tsuji Naotoshi , Wada Minoru , Saimoto Hiroyuki , Kita Kiyoshi , Hamano Shinjiro
Published: August 2021

The emergence of parasites resistant to praziquantel, the only therapeutic agent, and its ineffectiveness as a prophylactic agent (inactive against the migratory/juvenile
Schistosoma mansoni
), make the development of new antischistosomal drugs urgent. The parasite’s mitochondrion is an attractive target for drug development, because this organelle is essential for survival throughout the parasite’s life cycle.
Building Optimal Three-Drug Combination Chemotherapy Regimens To Eradicate Mycobacterium tuberculosis in Its Slow-Growth Acid Phase
Authors: Kim Sarah , Yamada Walter M. , Duncanson Brandon , Nole Jocelyn , Rogers Stephanie , Parker Sarah , Bacci Meredith , Mtchedlidze Nino , Peloquin Charles A. , Louie Arnold , Schmidt Stephan , Drusano George L. , Neely Michael N.
Published: August 2021

Mycobacterium tuberculosis
metabolic state affects the response to therapy. Quantifying the effect of antimicrobials in the acid and nonreplicating metabolic phases of
M. tuberculosis
growth will help to optimize therapy for tuberculosis.
Genotoxic Agents Produce Stressor-Specific Spectra of Spectinomycin Resistance Mutations Based on Mechanism of Action and Selection in Bacillus subtilis
Authors: Korry Benjamin J. , Lee Stella Ye Eun , Chakrabarti Amit K. , Choi Ashley H. , Ganser Collin , Machan Jason T. , Belenky Peter
Published: August 2021

Mutagenesis is integral for bacterial evolution and the development of antibiotic resistance. Environmental toxins and stressors are known to elevate the rate of mutagenesis through direct DNA toxicity, known as stress-associated mutagenesis, or via a more general stress-induced process that relies on intrinsic bacterial pathways.
Murine Irgm Paralogs Regulate Nonredundant Functions To Execute Host Defense to Toxoplasma gondii
Authors: Dockterman Jacob , Fee Brian E. , Taylor Gregory A. , Coers Jörn
Published: August 2021

Gamma interferon (IFN-γ)-induced immunity-related GTPases (IRGs) confer cell-autonomous immunity to the intracellular protozoan pathogen
Toxoplasma gondii
. Effector IRGs are loaded onto the
Toxoplasma
-containing parasitophorous vacuole (PV), where they recruit ubiquitin ligases, ubiquitin-binding proteins, and IFN-γ-inducible guanylate-binding proteins (Gbps), prompting PV lysis and parasite destruction.
The Gut-Lung Axis in Cystic Fibrosis
Authors: Price Courtney E. , O’Toole George A.
Published: August 2021

Cystic fibrosis (CF) is a heritable, multiorgan disease that impacts all tissues that normally express cystic fibrosis transmembrane conductance regulator (CFTR) protein. While the importance of the airway microbiota has long been recognized, the intestinal microbiota has only recently been recognized as an important player in both intestinal and lung health outcomes for persons with CF (pwCF).
Can Science Help Resolve the Controversy on the Origins of the SARS-CoV-2 Pandemic?
Authors: Casadevall Arturo , Weiss Susan R. , Imperiale Michael J.
Published: August 2021

The origins of the calamitous SARS-CoV-2 pandemic are now the subject of vigorous discussion and debate between two competing hypotheses for how it entered the human population: (i) direct infection from a feral source, likely a bat and possibly with an intermediate mammalian host, and (ii) a lab accident whereby bat isolates infected a researcher, who then passed it to others. Here, we ask whether the tools of science can help resolve the origins question and conclude that while such studies can provide important information, these are unlikely to provide a definitive answer.
Early detection of neovascular age-related macular degeneration: an economic evaluation based on data from the EDNA study
Authors: Hernandez Rodolfo , Kennedy Charlotte , Banister Katie , Goulao Beatriz , Cook Jonathan , Sivaprasad Sobha , Hogg Ruth , Azuara-Blanco Augusto , Heimann Heinrich , Dimitrova Maria , Gale Richard , Porteous Mia , Ramsay Craig R , Chakravarthy Usha , Scotland Graham S
Published: August 2021

Background/aims

To evaluate the cost-effectiveness of non-invasive monitoring tests to detect the onset of neovascular age-related macular degeneration (nAMD) in the unaffected second eye of patients receiving treatment for unilateral nAMD in a UK National Health Service (NHS) hospital outpatient setting.

Methods

A patient-level state transition model was constructed to simulate the onset, detection, and treatment of nAMD in the second eye. Five index tests were compared: self-reported change in visual function, Amsler test, clinic measured change in visual acuity from baseline, fundus assessment by clinical examination or colour photography, and spectral domain optical coherence tomography (SD-OCT). Diagnosis of nAMD was confirmed by fundus fluorescein angiography (FFA) before prompt initiation of antivascular endothelial growth factor treatment. Quality-adjusted life-years (QALYs) and costs of health and social care were modelled over a 25-year time horizon.

Results

SD-OCT generated more QALYs (SD-OCT, 5.830; fundus assessment, 5.787; Amsler grid, 5.736, patient’s subjective assessment, 5.630; and visual acuity, 5.600) and lower health and social care costs (SD-OCT, £19 406; fundus assessment, £19 649; Amsler grid, £19 751; patient’s subjective assessment, £20 198 and visual acuity, £20 444) per patient compared with other individual monitoring tests. Probabilistic sensitivity analysis indicated a high probability (97%–99%) of SD-OCT being the preferred test across a range of cost-effectiveness thresholds (£13 000–£30 000) applied in the UK NHS.

Conclusions

Early treatment of the second eye following FFA confirmation of SD-OCT positive findings is expected to maintain better visual acuity and health-related quality of life and may reduce costs of health and social care over the lifetime of patients.
Five-year outcomes of eyes initially enrolled in the 2-year BEVORDEX trial of bevacizumab or dexamethasone implants for diabetic macular oedema
Authors: Cornish Elisa E , Teo Kelvin YC , Gillies Mark C , Lim Lyndell L , Nguyen Vuong , Wickremasinghe Sanjeewa , Mehta Hemal , McAllister Ian L , Fraser-Bell Samantha
Published: August 2021

Background

The BEVORDEX trial compared outcomes of eyes with diabetic macular oedema (DMO) randomised to receive either intravitreal dexamethasone (DEX-) implant or bevacizumab over 2 years. We assessed long-term efficacy and safety outcomes 5 years from enrolment.

Methods

Patients received standard clinical care after they finished the study. Their files were reviewed for visual and anatomical outcomes, post-trial treatments and complications.

Results

Three-year and five-year data were available for 82% and 59% of eyes enrolled in the BEVORDEX study, respectively. Visual acuity gains at end of trial were generally lost by both treatment groups at 5 years but the macular thickness did not change from end of trial to 5 years. A similar proportion of eyes from each treatment group gained ≥10 letters at 5 years from enrolment in the BEVORDEX trial.

Eyes that were initially randomised to the DEX-implant group had significantly fewer treatments but were more likely to develop proliferative diabetic retinopathy (PDR) over the 5-year period compared with eyes initially randomised to bevacizumab. The proportion of eyes that had cataract surgery by 5 years was similar between initial treatment groups.

Conclusions

Eyes in the BEVORDEX trial had similar 5-year rates of cataract surgery, however, more eyes converted to PDR in the group initially treated with DEX-implant. Eyes that were initially treated for 2 years with either intravitreal DEX-implant of bevacizumab followed by standard of care had similar visual and anatomical outcomes at 5 years.
Plasminogen activator inhibitor is significantly elevated in liver transplant recipients with decompensated NASH cirrhosis
Authors: Rivas Gloriany , Hummer-Bair Breianna , Bezinover Dmitri , Kadry Zakiyah , Stine Jonathan
Published: August 2021

Background

Non-alcoholic fatty liver disease is a prohaemostatic state with abnormal primary, secondary and tertiary haemostasis. Plasminogen activator inhibitor (PAI)-1 is the best-established marker for prohaemostasis in non-alcoholic fatty liver disease. While epidemiological studies demonstrate decompensated non-alcoholic steatohepatitis (NASH) cirrhosis patients have increased rates of venous thromboembolism, including portal vein thrombosis, mechanistic studies have focused exclusively on patients without or with compensated cirrhosis. We aimed to characterizecharacterise PAI-1 levels in decompensated NASH cirrhosis.

Methods

PAI-1 level was measured in consecutive adult liver transplant recipients immediately prior to liver transplantation. Multivariable models were constructed using linear regression to assess factors related to PAI-1 level.

Results

Forty-six subjects with mean age 57 (IQR 53–62) years and Model for Endstage Liver Disease (MELD) score of 34 (IQR 30–40) were enrolled. Baseline characteristics were similar between NASH (n=10) and non-NASH (n=36) subjects except for rates of diabetes and hyperlipidaemia. Mean PAI-1 level was greater in NASH (53.9, 95% CI 33.3 to 74.5 mg/mL) when compared with non-NASH (36.1, 95% CI 28.7 to 43.5), p=0.040. NASH remained independently predictive of PAI-1 level prior to transplant on adjusted multivariable modelling (β 40.13, 95% CI 14.41 to 65.86, p=0.003). Conclusions: PAI-1 level is significantly elevated in decompensated NASH cirrhosis independent of other pro-haemostatic factors. This may explain the greater rates of venous thromboembolism in decompensated NASH cirrhosis. Future study focusing on prevention of venous thromboembolism in this population is paramount to improve patient-oriented outcomes given the high morbidity and mortality of venous thromboembolism and the significant impact it has on transplant candidacy.
The genomic epidemiology of multi-drug resistant invasive non-typhoidalSalmonellain selected sub-Saharan African countries
Authors: Park Se Eun , Pham Duy Thanh , Pak Gi Deok , Panzner Ursula , Maria Cruz Espinoza Ligia , von Kalckreuth Vera , Im Justin , Mogeni Ondari D. , Schütt-Gerowitt Heidi , Crump John A , Breiman Robert F , Adu-Sarkodie Yaw , Owusu-Dabo Ellis , Rakotozandrindrainy Raphaël , Bassiahi Soura Abdramane , Aseffa Abraham , Gasmelseed Nagla , Sooka Arvinda , Keddy Karen H , May Jürgen , Aaby Peter , Biggs Holly M , Hertz Julian T , Montgomery Joel M , Cosmas Leonard , Olack Beatrice , Fields Barry , Sarpong Nimako , Razafindrabe Tsiriniaina Jean Luco , Raminosoa Tiana Mirana , Kabore Leon Parfait , Sampo Emmanuel , Teferi Mekonnen , Yeshitela Biruk , El Tayeb Muna Ahmed , Krumkamp Ralf , Dekker Denise Myriam , Jaeger Anna , Tall Adama , Gassama Amy , Niang Aissatou , Bjerregaard-Andersen Morten , Løfberg Sandra Valborg , Deerin Jessica Fung , Park Jin Kyung , Konings Frank , Carey Megan E , Van Puyvelde Sandra , Ali Mohammad , Clemens John , Dougan Gordon , Baker Stephen , Marks Florian
Published: August 2021

Background

Invasive non-typhoidalSalmonella(iNTS) is one of the leading causes of bacteraemia in sub-Saharan Africa. We aimed to provide a better understanding of the genetic characteristics and transmission patterns associated with multi-drug resistant (MDR) iNTS serovars across the continent.

Methods

A total of 166 iNTS isolates collected from a multi-centre surveillance in 10 African countries (2010–2014) and a fever study in Ghana (2007–2009) were genome sequenced to investigate the geographical distribution, antimicrobial genetic determinants and population structure of iNTS serotypes–genotypes. Phylogenetic analyses were conducted in the context of the existing genomic frameworks for various iNTS serovars. Population-based incidence of MDR-iNTS disease was estimated in each study site.

Results

SalmonellaTyphimurium sequence-type (ST) 313 andSalmonellaEnteritidis ST11 were predominant, and both exhibited high frequencies of MDR;SalmonellaDublin ST10 was identified in West Africa only. Mutations in thegyrAgene (fluoroquinolone resistance) were identified inS. Enteritidis andS. Typhimurium in Ghana; an ST313 isolate carryingblaCTX-M-15was found in Kenya. International transmission of MDR ST313 (lineage II) and MDR ST11 (West African clade) was observed between Ghana and neighbouring West African countries. The incidence of MDR-iNTS disease exceeded 100/100 000 person-years-of-observation in children aged <5 years in several West African countries.

Conclusions

We identified the circulation of multiple MDR iNTS serovar STs in the sampled sub-Saharan African countries. Investment in the development and deployment of iNTS vaccines coupled with intensified antimicrobial resistance surveillance are essential to limit the impact of these pathogens in Africa.
Efficacy and safety of diuretics in heart failure with preserved ejection fraction: a scoping review
Authors: Singh Arushi , Agarwal Anubha , Wafford Q. Eileen , Shah Sanjiv J , Huffman Mark , Khan Sadiya
Published: August 2021

Objective

Diuretics reduce congestion in patients with heart failure with preserved ejection fraction (HFpEF). However, comparison of clinical effects across diuretic classes or combinations of diuretics in patients with HFpEF are not well described. Therefore, we sought to conduct a scoping review to map trial data of diuretic efficacy and safety in patients with HFpEF.

Review methods and results

We searched multiple bibliometric databases for published literature and ClinicalTrials.gov, and hand searched unpublished studies comparing different classes of diuretics to usual care or placebo in patients with HFpEF. We included randomised controlled trials or quasi-experimental studies. Two authors independently screened and extracted key data using a structured form. We identified 13 published studies on diuretics in HFpEF, with 1 evaluating thiazide use, 7 on mineralocorticoid receptor antagonists (MRAs) and 5 on sodium-glucose co-transporter 2 inhibitors (SGLT2i). There remain 17 ongoing trials evaluating loop diuretics (n=1), MRAs (n=5), SGLT2i (n=10) and a polydiuretic (n=1), including 2 well-powered trials of SGLT2i that will be completed in 2021.

Conclusions

The limited number of published trials evaluating different classes of diuretics in patients with HFpEF have been generally small and short term. Ongoing and emerging trials of single or combination diuretics with greater power will be useful to better define their safety and efficacy.

Scoping review registration

doi:10.18131/g3-dejv-tm77.
THADA drives Golgi residency and upregulation of PD-L1 in cancer cells and provides promising target for immunotherapy
Authors: Li Chushu , Chi Hao , Deng Shouyan , Xu Ke , Wang Huanbin , Yao Han , Wang Yungang , Chen Dawei , Guo Xun , Fang Jing-Yuan , He Fang , Xu Jie
Published: August 2021

Background

The abnormal upregulation of programmed death-ligand 1 (PD-L1) in cancer cells inhibits T cell-mediated cytotoxicity, but the molecular mechanisms that drive and maintain PD-L1 expression are still incompletely understood.

Methods

Combined analyses of genomes and proteomics were applied to find potential regulators of PD-L1. In vitro experiments were performed to investigate the regulatory mechanism of PD-L1 by thyroid adenoma associated gene (THADA) using human colorectal cancer (CRC) cells. The prevalence of THADA was analyzed using CRC tissue microarrays by immunohistochemistry. T cell killing assay, programmed cell death 1 binding assay and MC38 transplanted tumor models in C57BL/6 mice were developed to investigate the antitumor effect of THADA.

Results

THADA is critically required for the Golgi residency of PD-L1, and this non-redundant, coat protein complex II (COPII)-associated mechanism maintains PD-L1 expression in tumor cells. THADA mediated the interaction between PD-L1 as a cargo protein with SEC24A, a module on the COPII trafficking vesicle. Silencing THADA caused absence and endoplasmic reticulum (ER) retention of PD-L1 but not major histocompatibility complex-I, inducing PD-L1 clearance through ER-associated degradation. Targeting THADA substantially enhanced T cell-mediated cytotoxicity, and increased CD8+ T cells infiltration in mouse tumor tissues. Analysis on clinical tissue samples supported a potential role of THADA in upregulating PD-L1 expression in cancer.

Conclusions

Our data reveal a crucial cellular process for PD-L1 maturation and maintenance in tumor cells, and highlight THADA as a promising target for overcoming PD-L1-dependent immune evasion.
Age-specific atrial fibrillation incidence, attributable risk factors and risk of stroke and mortality: results from the MORGAM Consortium
Authors: Morseth Bente , Geelhoed Bastiaan , Linneberg Allan , Johansson Lars , Kuulasmaa Kari , Salomaa Veikko , Iacoviello Licia , Costanzo Simona , Söderberg Stefan , Niiranen Teemu J , Vishram-Nielsen Julie K K , Njølstad Inger , Wilsgaard Tom , Mathiesen Ellisiv B , Løchen Maja-Lisa , Zeller Tanja , Blankenberg Stefan , Ojeda Francisco M , Schnabel Renate B
Published: August 2021

Background

The main aim was to examine age-specific risk factor associations with incident atrial fibrillation (AF) and their attributable fraction in a large European cohort. Additionally, we aimed to examine risk of stroke and mortality in relation to new-onset AF across age.

Methods

We used individual-level data (n=66 951, 49.1% men, age range 40–98 years at baseline) from five European cohorts of the MOnica Risk, Genetics, Archiving and Monograph Consortium. The participants were followed for incident AF for up to 10 years and the association with modifiable risk factors from the baseline examinations (body mass index (BMI), hypertension, diabetes, daily smoking, alcohol consumption and history of stroke and myocardial infarction (MI)) was examined. Additionally, the participants were followed up for incident stroke and all-cause mortality after new-onset AF.

Results

AF incidence increased from 0.9 per 1000 person-years at baseline age 40–49 years, to 17.7 at baseline age ≥70 years. Multivariable-adjusted Cox models showed that higher BMI, hypertension, high alcohol consumption and a history of stroke or MI were associated with increased risk of AF across age groups (p<0.05). Between 30% and 40% of the AF risk could be attributed to BMI, hypertension and a history of stroke or MI. New-onset AF was associated with a twofold increase in risk of stroke and death at ages≥70 years (p≤0.001).

Conclusion

In this large European cohort aged 40 years and above, risk of AF was largely attributed to BMI, high alcohol consumption and a history MI or stroke from middle age. Thus, preventive measures for AF should target risk factors such as obesity and hypertension from early age and continue throughout life.
A quantum moat barrier, realized with a finite square well
Authors: Ibrahim A. , Marsiglio F.
Published: August 2021

The notion of a double well potential typically involves two regions of space separated by a repulsive potential barrier. The ground state is a wave function that is suppressed in the barrier region and localized in the two surrounding regions. We illustrate that an attractive potential well (a quantum moat) with a finite nonzero width also acts as a barrier, using a simple square well model. We also show how the pseudopotential method both explains the role of the well as a barrier, and greatly improves the efficiency of constructing wave functions for this system using matrix diagonalization. With this simplified model we provide an introduction to the ideas typically used to simplify calculations in solids, where in place of the double well potential, multiple potentials occur in a periodic array.
Spin correlations in final-state parton showers and jet observables
Authors: Karlberg Alexander , Salam Gavin P. , Scyboz Ludovic , Verheyen Rob
Published: August 2021

As part of a programme to develop parton showers with controlled logarithmic accuracy, we consider the question of collinear spin correlations within the PanScales family of parton showers. We adapt the well-known Collins–Knowles spin-correlation algorithm to PanScales antenna and dipole showers, using an approach with similarities to that taken by Richardson and Webster. To study the impact of spin correlations, we develop Lund-declustering based observables that are sensitive to spin-correlation effects both within and between jets and extend the MicroJets collinear single-logarithmic resummation code to include spin correlations. Together with a 3-point energy correlation observable proposed recently by Chen, Moult and Zhu, this provides a powerful set of constraints for validating the logarithmic accuracy of our shower results. The new observables and their resummation further open the pathway to phenomenological studies of these important quantum mechanical effects.
A critical assessment of black hole solutions with a linear term in their redshift function
Authors: Gregoris Daniele , Ong Yen Chin , Wang Bin
Published: August 2021

Different theories of gravity can admit the same black hole solution, but the parameters usually have different physical interpretations. In this work we study in depth the linear term$$\beta r$$βrin the redshift function of black holes, which arises in conformal gravity, de Rham–Gabadadze–Tolley (dRGT) massive gravity,f(R) gravity (as approximate solution) and general relativity. Geometrically we quantify the parameter$$\beta $$βin terms of the curvature invariants. Astrophysically we found that$$\beta $$βcan be expressed in terms of the cosmological constant, the photon orbit radius and the innermost stable circular orbit (ISCO) radius. The metric degeneracy can be broken once black hole thermodynamics is taken into account. Notably, we show that under Hawking evaporation, different physical theories with the same black hole solution (at the level of the metric) can lead to black hole remnants with different values of their physical masses with direct consequences on their viability as dark matter candidates. In particular, the mass of the graviton in massive gravity can be expressed in terms of the cosmological constant and of the formation epoch of the remnant. Furthermore the upper bound of remnant mass can be estimated to be around$$0.5 \times 10^{27}$$0.5×1027kg.