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The Genesis 12-19 (G1219) Study is an ongoing longitudinal study of a sample of UK twin pairs, non-twin sibling pairs, and their parents. G1219 was initially designed to examine the role of gene-environment interplay in adolescent depression. However, since then data have continued to be collected from both parents and their offspring into young adulthood. This has allowed for longitudinal analyses of depression and has enabled researchers to investigate multiple phenotypes and to ask questions about intermediate mechanisms. The study has primarily focused on emotional development, particularly depression and anxiety, which have been assessed at multiple levels of analysis (symptoms, cognitions, and relevant environmental experiences). G1219 has also included assessment of a broader range of psychological phenotypes ranging from antisocial behaviors and substance use to sleep difficulties, in addition to multiple aspects of the environment. DNA has also been collected. The first wave of data collection began in the year 1999 and the fifth wave of data collection will be complete before the end of 2012. In this article, we describe the sample, data collection, and measures used. We also summarize some of the key findings to date. [ABSTRACT FROM AUTHOR]

RATIONALE: Angiogenesis is a prominent feature of remodeling in asthma. Many proangiogenic factors are up-regulated in asthma, but little is known about levels of endogenous antiangiogenic agents. Collagen IV is decreased in the airway basement membrane in asthma. It has six alpha chains, of which the noncollagenous domain-1 domains have endogenous antiangiogenic properties. OBJECTIVES: To study the expression of the noncollagenous domain-1 of the alpha3 chain of collagen IV, tumstatin, in the airways of subjects with and without asthma and to examine the potential for tumstatin to regulate angiogenesis and inflammation. METHODS: We used immunohistochemistry and dot blots to examine the expression of tumstatin in bronchial biopsies, bronchoalveolar lavage fluid, and serum. We then used an in vitro angiogenesis assay and a murine model of allergic airways disease to explore tumstatin's biological function. MEASUREMENTS AND MAIN RESULTS: The level of tumstatin is decreased 18-fold in the airways of patients with asthma but not in subjects without asthma, including those with chronic obstructive pulmonary disease, cystic fibrosis, and bronchiectasis. In vitro, recombinant tumstatin inhibited primary pulmonary endothelial cell tube formation. In a mouse model of chronic allergic airways disease, tumstatin suppressed angiogenesis, airway hyperresponsiveness, inflammatory cell infiltration, and mucus secretion and decreased levels of vascular endothelial growth factor and IL-13. CONCLUSIONS: The observation that tumstatin is decreased in asthmatic airways and inhibits airway hyperresponsiveness and angiogenesis demonstrates the potential use of antiangiogenic agents such as tumstatin as a therapeutic intervention in diseases that are characterized by aberrant angiogenesis and tissue remodeling, such as asthma. [ABSTRACT FROM AUTHOR]

BACKGROUND: It is uncertain whether aspirin therapy should be continued after endoscopic hemostatic therapy in patients who develop peptic ulcer bleeding while receiving low-dose aspirin. OBJECTIVE: To test that continuing aspirin therapy with proton-pump inhibitors after endoscopic control of ulcer bleeding was not inferior to stopping aspirin therapy, in terms of recurrent ulcer bleeding in adults with cardiovascular or cerebrovascular diseases. DESIGN: A parallel randomized, placebo-controlled noninferiority trial, in which both patients and clinicians were blinded to treatment assignment, was conducted from 2003 to 2006 by using computer-generated numbers in concealed envelopes. (ClinicalTrials.gov registration number: NCT00153725) SETTING: A tertiary endoscopy center. PATIENTS: Low-dose aspirin recipients with peptic ulcer bleeding. INTERVENTION: 78 patients received aspirin, 80 mg/d, and 78 received placebo for 8 weeks immediately after endoscopic therapy. All patients received a 72-hour infusion of pantoprazole followed by oral pantoprazole. All patients completed follow-up. MEASUREMENTS: The primary end point was recurrent ulcer bleeding within 30 days confirmed by endoscopy. Secondary end points were all-cause and specific-cause mortality in 8 weeks. RESULTS: 156 patients were included in an intention-to-treat analysis. Three patients withdrew from the trial before finishing follow-up. Recurrent ulcer bleeding within 30 days was 10.3% in the aspirin group and 5.4% in the placebo group (difference, 4.9 percentage points [95% CI, -3.6 to 13.4 percentage points]). Patients who received aspirin had lower all-cause mortality rates than patients who received placebo (1.3% vs. 12.9%; difference, 11.6 percentage points [CI, 3.7 to 19.5 percentage points]). Patients in the aspirin group had lower mortality rates attributable to cardiovascular, cerebrovascular, or gastrointestinal complications than patients in the placebo group (1.3% vs. 10.3%; difference, 9 percentage points [CI, 1.7 to 16.3 percentage points]). LIMITATIONS: The sample size is relatively small, and only low-dose aspirin, 80 mg, was used. Two patients with recurrent bleeding in the placebo group did not have further endoscopy. CONCLUSION: Among low-dose aspirin recipients who had peptic ulcer bleeding, continuous aspirin therapy may increase the risk for recurrent bleeding but potentially reduces mortality rates. Larger trials are needed to confirm these findings. [ABSTRACT FROM AUTHOR]

Background: Use of proton-pump inhibitors in the management of peptic ulcer bleeding is controversial because discrepant results have been reported in different ethnic groups.Objective: To determine whether intravenous esomeprazole prevents recurrent peptic ulcer bleeding better than placebo in a multiethnic patient sample.Design: Randomized trial conducted between October 2005 and December 2007; patients, providers, and researchers were blinded to group assignment.Setting: 91 hospital emergency departments in 16 countries.Patients: Patients 18 years or older with peptic ulcer bleeding from a single gastric or duodenal ulcer showing high-risk stigmata.Intervention: Intravenous esomeprazole bolus, 80 mg, followed by 8-mg/h infusion, over 72 hours or matching placebo, each given after successful endoscopic hemostasis. Intervention was allocated by computer-generated randomization. After infusion, both groups received oral esomeprazole, 40 mg/d, for 27 days.Measurements: The primary end point was rate of clinically significant recurrent bleeding within 72 hours. Recurrent bleeding within 7 and 30 days, death, surgery, endoscopic re-treatment, blood transfusions, hospitalization, and safety were also assessed.Results: Of 767 patients randomly assigned, 764 provided data for an intention-to-treat analysis (375 esomeprazole recipients and 389 placebo recipients). Fewer patients receiving intravenous esomeprazole (22 of 375) had recurrent bleeding within 72 hours than those receiving placebo (40 of 389) (5.9% vs. 10.3%; difference, 4.4 percentage points [95% CI, 0.6% to 8.3%]; P = 0.026). The difference in bleeding recurrence remained significant at 7 days and 30 days (P = 0.010). Esomeprazole also reduced endoscopic re-treatment (6.4% vs. 11.6%; difference, 5.2 percentage points [95% CI of difference, 1.1 percentage points to 9.2 percentage points]; P = 0.012), surgery (2.7% vs. 5.4%), and all-cause mortality rates (0.8% vs. 2.1%) more than placebo, although differences for the latter 2 comparisons were not significant. About 10% and 40% of patients in both groups reported serious and nonserious adverse events, respectively.Limitation: Endoscopic therapy was not completely standardized; some patients received epinephrine injection, thermal coagulation, or hemoclips alone, whereas others received combination therapy, but there were similar proportions with single therapy in each group.Conclusion: High-dose intravenous esomeprazole given after successful endoscopic therapy to patients with high-risk peptic ulcer bleeding reduced recurrent bleeding at 72 hours and had sustained clinical benefits for up to 30 days.Primary Funding Source: AstraZeneca Research and Development. [ABSTRACT FROM AUTHOR]

BACKGROUND: Transgastric access to the peritoneal cavity presents new opportunities for novel endoscopic surgery. Secure closure of the gastrotomy site is critical to the success of transgastric endoscopic surgery. OBJECTIVE: To study the safety and efficacy of closure of a gastrotomy by using the Eagle Claw VII endoscopic suturing device after transgastric bilateral tubal ligation. DESIGN: A prospective survival study in a porcine model with ten 30-kg pigs. INTERVENTIONS: The gastrotomies were made by using a needle-knife and balloon dilation. Bilateral fallopian tube ligation was performed with detachable snares, and the tubes were transected by using the needle-knife. The gastrotomies were closed with endoscopic suturing by using the Eagle Claw VII. MAIN OUTCOME MEASUREMENTS: Included the survival of the pigs, security of the closure, number of plicating sutures used, operative time, peritoneal contamination, and histopathologic confirmation of the full-thickness healing of the gastrotomy. RESULTS: Transgastric fallopian-tube ligation was performed in 10 pigs, and all of the gastrotomies were successfully closed by using the Eagle Claw VII endoscopic suturing device. The operative time for bilateral tubal ligation was 38.2 minutes (range 18-50 minutes), whereas, the operative time for gastrotomy closure was 25.5 minutes (range 15-35 minutes). Three endoscopic sutures were necessary to achieve a secure gastrotomy closure. All the pigs survived and tolerated a full diet 24 hours after the operation. A postmortem confirmed full-thickness healing for all gastrotomies, with no evidence of leakage. One pig had an overtube-related esophageal perforation, which was successfully managed with endoscopic clip closure. LIMITATIONS: The porcine gastric wall is thicker than the human gastric wall, and the posterior wall of the porcine stomach becomes the anterior-inferior wall after gaseous distention. Hence, all the gastrotomies were made through the posterior wall. The tissue tolerance and healing of the porcine stomach may be different from that of the human stomach. CONCLUSIONS: Endoscopic suturing by using the Eagle Claw VII device is a feasible method for gastrotomy closure after a natural orifice transluminal endoscopic surgery procedure. [ABSTRACT FROM AUTHOR]

BACKGROUND: The use of intravenous (IV) proton pump inhibitors (PPI) before an endoscopy in upper-GI bleeding (UGIB) was shown to reduce the need of endoscopic therapy and shorten hospital stay. OBJECTIVE: To investigate whether preemptive use of a PPI in UGIB is a cost-effective strategy. DESIGN: A decision analysis model that represents treatment pathways for patients with UGIB was constructed and structuralized by 30-day outcomes. Direct costs of medical treatment, diagnostic and therapeutic endoscopy, endoscopic re-treatment, surgery, and hospitalization were analyzed. SETTING: Prince of Wales Hospital, Hong Kong. PATIENTS: A total of 631 patients were recruited. Sixty patients (19.1%) in the PPI group and 90 patients (28.4%) in the placebo group required endoscopic hemostasis at index endoscopy. MAIN OUTCOME MEASUREMENTS: The primary measurements were cost-effectiveness ratios and incremental cost-effectiveness ratios (ICER) to avert endoscopic therapy between PPI and placebo treatment. Sensitivity analyses were conducted by varying the cost of endoscopy, hospitalization, the incidence rate of endoscopic therapy, and the proportion of bleeding peptic ulcers. RESULTS: The overall direct cost per patient was U.S. dollars (USD) $2813 for PPI treatment and USD $2948 for the placebo. A PPI reduced endoscopic therapy by 7.4% and resulted in a lower cost-effectiveness ratio per endoscopic therapy averted (USD $3561) than the placebo (USD $4117). The ICER value was USD -$1843, which indicated that preemptive PPI treatment is more effective and less costly for UGIB. When the proportions of patients with peptic ulcer bleeding were greater than 8.3%, the preemptive PPI treatment remained cost saving. CONCLUSIONS: Preemptive use of IV PPI before an endoscopy is a cost-effective strategy in the management of UGIB. [ABSTRACT FROM AUTHOR]

BACKGROUND: To investigate the extent to which three putative 'environmental' risk factors, maternal punitive discipline (MPD), paternal punitive discipline (PPD) and negative life events (NLEs), share genetic influences with, and moderate the heritability of, externalizing behavior.MethodThe sample consisted of 2647 participants, aged 12-19 years, from the G1219 and G1219Twins longitudinal studies. Externalizing behavior was measured using the Youth Self-Report, MPD, PPD and exposure to NLEs were assessed using the Negative Sanctions Scale and the Life Event Scale for Adolescents respectively.ResultGenetic influences overlapped for externalizing behavior and each 'environmental' risk, indicating gene-environment correlation. When controlling for the gene-environment correlation, genetic variance decreased, and both shared and non-shared environmental influences increased, as a function of MPD. Genetic variance increased as a function of PPD, and for NLEs the only interaction effect was on the level of non-shared environment influence unique to externalizing behavior.ConclusionThe magnitude of the influence of genetic risk on externalizing behavior is contextually dependent, even after controlling for gene-environment correlation. [ABSTRACT FROM AUTHOR]

Long noncoding RNAs (lncRNAs) are increasingly appreciated for their important functions in mammalian cells. However, how their functional capacities are encoded in their sequences and manifested in their structures remains largely unknown. Some lncRNAs bind to and modulate the availability of RNA-binding proteins, but the structural principles that underlie this mode of regulation are unknown. The NORAD lncRNA is a known decoy for Pumilio proteins, which modulate the translation and stability of hundreds of messenger RNAs and, consequently, a regulator of genomic stability and aging. Here we probed the RNA structure and long-range RNA-RNA interactions formed by human NORAD inside cells under different stressful conditions. We discovered a highly modular structure consisting of well-defined domains that contribute independently to NORAD function. Following arsenite stress, most structural domains undergo relaxation and form interactions with other RNAs that are targeted to stress granules. We further revealed a unique structural organization that spatially clusters the multiple Pumilio binding sites along NORAD and consequently contributes to the derepression of Pumilio targets. We then applied these structural principles to design an effective artificial decoy for the let-7 microRNA. Our work demonstrates how the sequence of a lncRNA spatially clusters its function into separated domains and how structural principles can be employed for the rational design of lncRNAs with desired activities., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background and study aims Percutaneous transhepatic cholangioscopy (PTCS) is a management option for patients in whom peroral cholangioscopy or endoscopic retrograde cholangiopancreatography (ERCP) fail. We conducted a case series on the efficacy and safety of PTCS using a cholangiopancreatoscope cleared by the US Food and Drug Administration in 2020. Patients and methods Fifty adult patients scheduled for PTCS or other cholangioscopic procedure were enrolled at seven academic medical centers and followed for 30 days after the index procedure. The primary efficacy endpoint was achievement of clinical intent by 30 days after the index PTCS procedure. Secondary endpoints included technical success, procedure time, endoscopist ratings of device attributes on a scale of 1 to 10 (best), and serious adverse events (SAEs) related to the device or procedure. Results Patients had a mean age of 64.7±15.9 years, and 60.0% (30/50) were male. Forty-four patients (88.0%) achieved clinical intent by 30 days post-procedure. The most common reasons for the percutaneous approach were past (38.0%) or anticipated (30.0%) failed ERCP. The technical success rate was 96.0% (48/50), with a mean procedure time of 37.6 minutes (SD, 25.1; range 5.0-125.0). The endoscopist rated the overall ability of the cholangioscope to complete the procedure as a mean 9.2 (SD, 1.6; range 1.0-10.0). Two patients (4.0%) experienced related SAEs, one of whom had a fatal periprocedure aspiration. Conclusions PTCS is an important endoscopic option for selected patients with impossible retrograde access or in whom ERCP fails. Because of the associated risk, this technique should be practiced by highly trained endoscopists at high-volume centers. (ClinicalTrials.gov number, NCT04580940)., Competing Interests: Conflict of Interest Ivo Boskoski: Consultant for Apollo Endosurgery, Boston Scientific, Cook Medical, Nitinotes, Erbe Elektromedizin, Pentax Medical, Fractyl Health, and Lecturer for Microteach. Torsten Beyna: (Competing interests relevant to this publication) paid consultancy for Olympus, Boston Scientific, Microtech Endoscopy. James Lau: Consultant for Boston Scientific. Arnaud Lemmers: Research grants from Boston Scientific and Medtronic Mehran Fotoohi: No disclosures. Mohan Ramchandani: No disclosures. Valerio Pontecorvi: No disclosures. Joyce A. Peetermans: Full-time employee of Boston Scientific. Eran Shlomovitz: Consultant for Boston Scientific., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

The incidence of metabolic syndrome is significantly higher in patients with irritable bowel syndrome (IBS), but the mechanisms involved remain unclear. Gut microbiota is causatively linked with the development of both metabolic dysfunctions and gastrointestinal disorders, thus gut dysbiosis in IBS may contribute to the development of metabolic syndrome. Here, we show that human gut bacterium Ruminococcus gnavus-derived tryptamine and phenethylamine play a pathogenic role in gut dysbiosis-induced insulin resistance in type 2 diabetes (T2D) and IBS. We show levels of R. gnavus, tryptamine, and phenethylamine are positively associated with insulin resistance in T2D patients and IBS patients. Monoassociation of R. gnavus impairs insulin sensitivity and glucose control in germ-free mice. Mechanistically, treatment of R. gnavus-derived metabolites tryptamine and phenethylamine directly impair insulin signaling in major metabolic tissues of healthy mice and monkeys and this effect is mediated by the trace amine-associated receptor 1 (TAAR1)-extracellular signal-regulated kinase (ERK) signaling axis. Our findings suggest a causal role for tryptamine/phenethylamine-producers in the development of insulin resistance, provide molecular mechanisms for the increased prevalence of metabolic syndrome in IBS, and highlight the TAAR1 signaling axis as a potential therapeutic target for the management of metabolic syndrome induced by gut dysbiosis., (© 2023. Springer Nature Limited.)

Host-pathogen interactions and pathogen evolution are underpinned by protein-protein interactions between viral and host proteins. An understanding of how viral variants affect protein-protein binding is important for predicting viral-host interactions, such as the emergence of new pathogenic SARS-CoV-2 variants. Here we propose an artificial intelligence-based framework called UniBind, in which proteins are represented as a graph at the residue and atom levels. UniBind integrates protein three-dimensional structure and binding affinity and is capable of multi-task learning for heterogeneous biological data integration. In systematic tests on benchmark datasets and further experimental validation, UniBind effectively and scalably predicted the effects of SARS-CoV-2 spike protein variants on their binding affinities to the human ACE2 receptor, as well as to SARS-CoV-2 neutralizing monoclonal antibodies. Furthermore, in a cross-species analysis, UniBind could be applied to predict host susceptibility to SARS-CoV-2 variants and to predict future viral variant evolutionary trends. This in silico approach has the potential to serve as an early warning system for problematic emerging SARS-CoV-2 variants, as well as to facilitate research on protein-protein interactions in general., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Diarrhea-predominant irritable bowel syndrome (IBS-D), a globally prevalent functional gastrointestinal (GI) disorder, is associated with elevated serotonin that increases gut motility. While anecdotal evidence suggests that the gut microbiota contributes to serotonin biosynthesis, mechanistic insights are limited. We determined that the bacterium Ruminococcus gnavus plays a pathogenic role in IBS-D. Monocolonization of germ-free mice with R. gnavus induced IBS-D-like symptoms, including increased GI transit and colonic secretion, by stimulating the production of peripheral serotonin. R. gnavus-mediated catabolism of dietary phenylalanine and tryptophan generated phenethylamine and tryptamine that directly stimulated serotonin biosynthesis in intestinal enterochromaffin cells via a mechanism involving activation of trace amine-associated receptor 1 (TAAR1). This R. gnavus-driven increase in serotonin levels elevated GI transit and colonic secretion but was abrogated upon TAAR1 inhibition. Collectively, our study provides molecular and pathogenetic insights into how gut microbial metabolites derived from dietary essential amino acids affect serotonin-dependent control of gut motility., Competing Interests: Declaration of interests The authors have claimed no financial interests to declare., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Liver disease has emerged as a healthcare burden because of high hospitalization rates attributed both to steatohepatitis and to severe hepatic toxicity associated with changes of drug exposure. Early detection of hepatic insufficiency is critical to preventing long-term liver damage. The galactose single-point test is recommended by the US FDA as a sensitive means to quantify liver function, yet the conventional method used for quantitation of circulating galactose still relies on the standard colorimetric method, requiring time-consuming and labor-intensive processes, and is confined to the medical laboratory, thus limiting prevalence. To facilitate time- and cost-effective disease management particularly during a pandemic, a pocket-sized rapid quantitative device consisting of a biosensor and electrochemical detection has been developed. An in vitro validation study demonstrated that the coefficient of variation was less than 15% and deviations were between -4 and 14% in the range of 100-1500 μg/mL. The device presented good linear fit (correlation coefficient, r = 0.9750) over the range of 150-1150 µg/mL. Moreover, the device was found to be free from interference of common endogenous and exogenous substances, and deviated hematocrit, enabling a direct measurement of galactose in the whole blood without sample pre-treatment steps. The clinical validation comprising 118 subjects showed high concordance (r = 0.953) between the device and the conventional colorimetric assay. Thus, this novel miniaturized device is reliable and robust for routine assessment of quantitative liver function intended for follow-up of hepatectomy, drug dose adjustment, and screening for galactosemia, allowing timely and cost-effective clinical management of patients., (© 2022. Springer-Verlag GmbH Germany, part of Springer Nature.)

RNA homodimerization is important for various physiological processes, including the assembly of membraneless organelles, RNA subcellular localization, and packaging of viral genomes. However, understanding RNA dimerization has been hampered by the lack of systematic in vivo detection methods. Here, we show that CLASH, PARIS, and other RNA proximity ligation methods detect RNA homodimers transcriptome-wide as "overlapping" chimeric reads that contain more than one copy of the same sequence. Analyzing published proximity ligation data sets, we show that RNA:RNA homodimers mediated by direct base-pairing are rare across the human transcriptome, but highly enriched in specific transcripts, including U8 snoRNA, U2 snRNA, and a subset of tRNAs. Mutations in the homodimerization domain of U8 snoRNA impede dimerization in vitro and disrupt zebrafish development in vivo, suggesting an evolutionarily conserved role of this domain. Analysis of virus-infected cells reveals homodimerization of SARS-CoV-2 and Zika genomes, mediated by specific palindromic sequences located within protein-coding regions of N gene in SARS-CoV-2 and NS2A gene in Zika. We speculate that regions of viral genomes involved in homodimerization may constitute effective targets for antiviral therapies., (© 2022 Gabryelska et al.; Published by Cold Spring Harbor Laboratory Press.)

Objectives: This study seeks to provide an understanding of the changing experiences in caregivers of end-of-life patients in Hong Kong through exploring their caregiving journey., Methods: Using longitudinal individual qualitative interviews, a total of 14 caregivers of community-dwelling elderly patients receiving end-of-life care were recruited between 2015 and 2016. A series of in-depth interviews and observations were conducted in 14 cases during the end-of-life journey., Results: A thematic analysis revealed four sequential experiential stages, abbreviated as "CAPE" that caregivers confronted: Stage 1 Certainty, (1a) lack of certainty regarding the progression of decline at the end-stage of life (1b) feelings of despair as patients' function decreased; Stage 2 Ambivalence, (2a) feelings of ambivalence after decisions were made regarding EOL care, (2b) struggle over care responsibility within families; Stage 3 Perturbed, (3a) varied in quality of EOL care, (3b) depressed mood arisen from frequent exposure to the suffering of elderly patients; and Stage 4 Expectation, (4a) losing the caregiving role as patients showing signs of imminent death., Conclusions: These findings increase our understanding of caregivers' in-depth experience over time that arise within the structural context of end-of-life care. Our data highlights the need for end of life related knowledge and information, provision of a caring atmosphere and communication, and professional-led detachment in creating caregiving-friendly service in healthcare system, thus as to provide support and alleviate stress for caregivers with their critical responsibility and role during the course of end-of-life care.

The dynamics of SARS-CoV-2 RNA structure and their functional relevance are largely unknown. Here we develop a simplified SPLASH assay and comprehensively map the in vivo RNA-RNA interactome of SARS-CoV-2 genome across viral life cycle. We report canonical and alternative structures including 5'-UTR and 3'-UTR, frameshifting element (FSE) pseudoknot and genome cyclization in both cells and virions. We provide direct evidence of interactions between Transcription Regulating Sequences, which facilitate discontinuous transcription. In addition, we reveal alternative short and long distance arches around FSE. More importantly, we find that within virions, while SARS-CoV-2 genome RNA undergoes intensive compaction, genome domains remain stable but with strengthened demarcation of local domains and weakened global cyclization. Taken together, our analysis reveals the structural basis for the regulation of replication, discontinuous transcription and translational frameshifting, the alternative conformations and the maintenance of global genome organization during the whole life cycle of SARS-CoV-2, which we anticipate will help develop better antiviral strategies., (© 2021. The Author(s).)

The SARS-CoV-2 Delta variant has evolved as the dominant strain of the current pandemic. Studies have shown that this variant has increased infectivity/viral load, and reduced neutralization by the host antibodies from convalescent patients/vaccinees. Clinically, Delta variant infection has been observed/documented in convalescent patients/vaccinees, although with less incidence of severe diseases, but can serve as reservoir to spread the infection to the unvaccinated. The current understanding (as of 18 August 2021) on the virologic aspect (including the amino acid substitutions), clinical implications, and public health implications will be discussed in this mini review, and recommendations to health authorities will be provided., (© The Author(s) 2021. Published by Oxford University Press on behalf of the West China School of Medicine & West China Hospital of Sichuan University.)

Aberrations in stress-linked hypothalamic-pituitary-adrenal axis function have been independently associated with schizophrenia, antisocial behaviour and childhood maltreatment. In this study, we examined pituitary volume (PV) in relation to childhood maltreatment (physical abuse, sexual abuse, neglect) in men (i) with schizophrenia and a history of serious violence (n = 13), (ii) with schizophrenia but without a history of serious violence (n = 15), (iii) with antisocial personality disorder (ASPD) and a history of serious violence (n = 13), and (iv) healthy participants without a history of violence (n = 15). All participants underwent whole-brain magnetic resonance imaging. Experiences of childhood maltreatment were rated based on interviews (for all), and case history and clinical/forensic records (for patients only). There was a trend for smaller PV, on average, in schizophrenia patients (regardless of a history of violence), compared to the healthy group and the ASPD group; other group differences in PV were non-significant. Sexual abuse ratings correlated negatively with PVs in ASPD participants, but no significant association between childhood maltreatment and PV was found in schizophrenia participants. Our findings are consistent with previous evidence of smaller-than-normal PV in chronic schizophrenia patients, and suggest that illness-related influences may mask the possible sexual abuse-smaller PV association, seen here in ASPD, in this population., (Copyright © 2021. Published by Elsevier B.V.)

To assess the impact of the key non-synonymous amino acid substitutions in the RBD of the spike protein of SARS-CoV-2 variant B.1.617.1 (dominant variant identified in the current India outbreak) on the infectivity and neutralization activities of the immune sera, L452R and E484Q (L452R-E484Q variant), pseudotyped virus was constructed (with the D614G background). The impact on binding with the neutralizing antibodies was also assessed with an ELISA assay. Pseudotyped virus carrying a L452R-E484Q variant showed a comparable infectivity compared with D614G. However, there was a significant reduction in the neutralization activity of the immune sera from non-human primates vaccinated with a recombinant receptor binding domain (RBD) protein, convalescent patients, and healthy vaccinees vaccinated with an mRNA vaccine. In addition, there was a reduction in binding of L452R-E484Q-D614G protein to the antibodies of the immune sera from vaccinated non-human primates. These results highlight the interplay between infectivity and other biologic factors involved in the natural evolution of SARS-CoV-2. Reduced neutralization activities against the L452R-E484Q variant will have an impact on health authority planning and implications for the vaccination strategy/new vaccine development., (© The Author(s) 2021. Published by Oxford University Press on behalf of the West China School of Medicine & West China Hospital of Sichuan University.)

Background: Patients on dialysis are hyporesponsive to the hepatitis B virus vaccines (HBVv). We examined intradermal (ID) HBVv Sci-B-Vac, with topical Toll-like receptor 7 (TLR7) agonist imiquimod pretreatment in dialysis patients., Methods: We enrolled and prospectively followed adult patients on dialysis between January 2016 and September 2018. Eligible patients were randomly allocated (1:1:1) into 1 treatment group, topical imiquimod cream followed by ID HBVv (IMQ + ID); and 2 control groups: topical aqueous cream (placebo) followed by ID HBVv (AQ + ID) or topical aqueous cream followed by intramuscular HBVv (AQ + IM). The primary endpoint was the seroprotection rate (hepatitis B surface antibody ≥10 mIU/mL) at 52 weeks., Results: Ninety-four patients were enrolled, among which 57.4% were previous nonresponders. Seroprotection rate was significantly better at week 52 for the IMQ + ID group with 96.9% compared to 74.2% and 48.4% for AQ + ID and AQ + IM groups, respectively (P < .0001). The geometric mean concentration was significantly higher at week 52 for the IMQ + ID group: 1135 (95% confidence interval [CI], 579.4-2218.2) mIU/mL, compared to 86.9 (95% CI, 18.5-409.3) mIU/mL and 7.2 (2.0-26.5) mIU/mL for the AQ + ID and AQ + IM groups, respectively (P < .0001). IMQ + ID vaccination (odds ratio, 3.70 [95% CI, 1.16-11.81]; P = .027) was the only factor independently associated with higher 52-week seroprotection rate. Adverse reaction was infrequent., Conclusions: Pretreatment with topical imiquimod before ID HBVv Sci-B-Vac was safe with favorable seroprotection in dialysis patients., Clinical Trials Registration: NCT02621112., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)