The 15th International dsRNA Virus Symposium was held in Porto, Portugal from November 3-7, 2025. This triennial conference, previously held in Banff, Alberta, Canada in 2022, brought together a global community of dsRNA virologists to describe and discuss advances in the field over the last three years. Emerging themes across dsRNA viruses include continued study of biomolecular condensates (by liquid-liquid phase separation) in the formation of viral replication complexes; structures of viral proteins and their effect on function; mechanisms of genome recombination and reassortment that result in the epidemiological diversity of subsets of dsRNA viruses; and the diverse host cell responses to infection that influence pathogenesis. The field continues to be greatly facilitated by the broader development and implementation of reverse genetics systems to study these viruses. The keynote address, entitled "The Odyssey of the HIV-1 Capsid: From Assembly to Nuclear Entry," was delivered by Peijun Zhang, Professor of Structural Biology at Oxford University, and described the use of sophisticated imaging techniques to study various stages of virus replication in host cells. The Jean Cohen Memorial Lecture at this meeting, entitled "The Magnificent Reovirus Replication Factories," was given by Terence Dermody, Vira I. Heinz Distinguished Professor and Chair of Pediatrics at the University of Pittsburgh School of Medicine. Dr. Dermody presented recent unpublished data on the role of reovirus non-structural proteins in scaffolding replication complexes and the implications of these mechanisms for the efficient translation of nonpolyadenylated RNAs.
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Balancing ischemic versus bleeding complications following percutaneous coronary intervention (PCI) remains challenging. However, the optimal dose of unfractionated heparin (UFH) for elective PCI is currently unclear. A Randomized Trial of Higher versus Lower Dose Heparin for PCI (HD-PCI) is a multicenter, randomized, controlled, registry-based, open-label, cluster crossover trial of a lower-dose (70 units/kg) versus higher-dose (100 units/kg) UFH dosing hospital-level policy for elective PCI conducted in 11 centres in Ontario, Canada. The primary efficacy outcome was defined as a composite of all-cause death, myocardial infarction or target vessel revascularization; the key safety outcome was defined as major bleeding; and the key net benefit outcome was defined as the composite of all-cause death, myocardial infarction, target vessel revascularization or major bleeding. All outcomes were evaluated within 30 days of the index PCI. HD-PCI is a large cluster randomized crossover trial that will inform the ischemic and bleeding effects of lower-dose (70 units/kg) versus higher-dose (100 units/kg) in patients undergoing elective PCI. ClinicalTrials.gov Identifier NCT04049591.
Large-scale double-digest RAD sequencing (ddRADseq) datasets generated for genotyping are increasingly available in aquaculture, yet their unmapped reads remain largely unexplored for pathogen surveillance. Here, we evaluated the utility and limitations of repurposing unmapped ddRADseq reads to examine pathogen-associated and disease-associated microbiome-pathobiome patterns during scale drop disease (SDD) outbreaks in farmed barramundi (Lates calcarifer). Using fin clips ddRADseq datasets from 4593 barramundi across four commercial sea-cages, we profiled bacterial and viral communities by taxonomic classification of unmapped reads. Fish sampled during active outbreaks consistently exhibited strong enrichment of scale drop disease virus (SDDV-associated signals; 76.3%-80.5%), frequently co-occurrence with infectious spleen and kidney necrosis virus (ISKNV; 0%-13.4%), along with a marked microbial shift towards Vibrio-dominated bacterial communities, particularly reads classified within the Vibrio harveyi clade. In contrast, clinically healthy post-outbreak fish showed consistently low viral signals and were characterized by distinct, more diverse microbial profiles dominated by Alphanudivirus, Cyvirus, Stenotrophomonas and Burkholderia, indicating a comparatively stable microbiome state in the absence of active disease outbreaks. Treating normalized pathogen read counts as proxy traits, exploratory quantitative genetic analyses indicated low overall heritability estimates for SDDV-associated signal (h2 = 0.08), with higher cohort-specific estimates (up to 0.23), consistent with strong environmental or co-infection effects and complex co-infection dynamics in open-sea farming systems. While ddRADseq-based pathogen detection is inherently biased by restriction-enzyme site representation, host-DNA dominance and the lack of absolute quantification, consistent patterns observed across thousands of fish tissues across multiple cohorts and outbreak stages provide biological meaningful population-level insights into farm-associated microbiome and pathobiome dynamics. Together, our results support that the use of unmapped ddRADseq reads as a cost-effective, complementary tool for retrospective pathogen screening and hypothesis generation in aquaculture, alongside targeted surveillance and diagnostic approaches.
This post hoc subgroup analysis was conducted using pooled data from three US-based clinical trials to compare efficacy and safety of rimegepant 75 mg versus placebo in acute migraine in adults who are Black or African American. Migraine, characterized by recurring moderate-to-severe unilateral head pain, affects approximately 13% of the population and in the United States affects Black or African American and White populations at similar rates. Despite this, there is stark underrepresentation of Black or African American patients in clinical trials. Rimegepant, an oral small molecule calcitonin gene-related peptide receptor blocker or antagonist, is approved for acute migraine treatment in the United States; however, treatment has not previously been analyzed in Black or African American adults. Using pooled data from three US-based, double-blind, randomized, placebo-controlled, multicenter clinical trials (ClinicalTrials.gov, NCT03235479; NCT03237845; NCT03461757), efficacy analyses were conducted on a modified intent-to-treat population including all participants who received study medication, had a migraine attack of moderate or severe pain intensity at the time of dosing, and provided ≥1 efficacy datapoint after receiving study treatment. Trials were conducted July 2017 to January 2018 (NCT03235479, NCT03237845) or February 2018 to October 2018 (NCT03461757). The coprimary efficacy endpoints of each trial were freedom from pain (score 0 = none on a 4-point pain scale) and freedom from most bothersome symptom (MBS) at 2 h post dose. Safety was assessed through reported on-treatment adverse events, defined as events occurring on or after treatment was received. Analyses were performed in the Black or African American population, in the White population, and in the overall pooled study population (including Black or African American, White, Asian, American Indian or Alaskan Native, Native Hawaiian or other Pacific Islander, and multiple races). Overall, 3551 treated participants were in the pooled population; 696 (19.6%) were Black or African American; 2700 (76.0%) were White. In the Black or African American population, rimegepant showed improvements versus placebo in the two coprimary endpoints. For pain freedom 2 h post dose, the stratified risk was 24.4% (88/359) for rimegepant and 18.2% (59/323) for placebo in Black or African American participants; risk difference was 6.2% (95% confidence interval [CI]: 0.1, 12.3; p = 0.047). For MBS freedom 2 h post dose, the stratified risk was 43.1% (155/359) for rimegepant and 35.5% (115/323) for placebo in Black or African American participants; risk difference was 7.6% (95% CI: 0.3, 14.9; p = 0.041). The risk difference was similar in White participants: 7.9% (95% CI: 5.2, 10.6; p < 0.001) for pain freedom 2 h post dose and 9.9% (95% CI: 6.5, 13.4; p < 0.001) for MBS freedom 2 h post dose. Adverse event rates among Black or African American participants treated with rimegepant were 10.7% (39/365) and 7.9% (26/331) in participants receiving placebo. This pooled analysis showed rimegepant 75 mg was effective and well tolerated for migraine treatment in Black or African American adult participants. Migraine affects Black or African American people at a similar rate as White people; however, medical studies for migraine therapies often do not include many Black or African American people. We conducted this analysis using data from three separate studies of the drug rimegepant (a drug approved for treating acute migraine) to see how safe and effective it is for Black or African American people. This analysis shows that rimegepant is better than placebo (a tablet that contains no drug) in improving migraine pain and other related symptoms in Black or African American people with migraine.
Translation initiation in eukaryotic cells is usually driven by recognition of a 5' cap and a 3' poly(A) tail, which cooperate through interactions with eukaryotic initiation factors (eIFs) and poly(A)-binding protein (PABP) to promote mRNA circularization and efficient ribosome recruitment. However, many viral RNAs lack one or both of these canonical features and must use alternative strategies to access the host translational machinery. Diverse mechanisms are used to bypass cap dependence, including internal ribosome entry sites that recruit ribosomal subunits with variable requirements for canonical initiation factors as well as viral protein genome-linked strategies that functionally substitute for the cap by engaging components of the eIF4F complex. For viral mRNAs lacking poly(A) tails, translation can be supported by long-range RNA-RNA interactions that mediate 5'-3' communication and viral or host proteins that replace PABP to facilitate closed-loop formation. Emerging examples, including host protein ATXN2L during reovirus infection, illustrate how viruses use or mimic cellular factors to promote selective translation. Collectively, these strategies reveal fundamental principles of mRNA circularization and translational control, highlighting the dynamic interplay between viral and host machinery in regulating protein synthesis.
Compromises to the integrity of articular cartilage, whether genetic, post-traumatic or age-related, lead to debilitating chronic degenerative diseases including osteoarthritis. In this study, our objective was to leverage multiomic and spatial transcriptomic datasets to identify gene regulatory networks that drive human articular cartilage cell fate, and build a foundation from which novel therapeutics to overcome degenerative disease could be developed. We jointly profiled the transcriptome and open chromatin regions in individual nuclei recovered from distal femora at 2 fetal timepoints and performed high-definition spatial transcriptomics at an additional timepoint. We established a human pluripotent stem cell platform to interrogate the function of computationally predicted transcription factors during human chondrocyte differentiation. We computationally predicted gene regulatory networks governing chondrocyte subsets comprising the human distal femur during development. Following functional analysis of two transcription factors predicted to function in the superficial zone, CREB5 and NFATC2, using our in vitro experimental platform, we found both have the potential to reprogram growth plate cartilage and induce features of articular cartilage. We further identified new biological roles for CREB5 related to ECM organization and taxis. We expect new regulatory networks we uncovered to be important for promoting cartilage health and treating disease, and our platform to be a useful tool for studying cartilage development and homeostasis in vitro. The ability to reprogram chondrocytes toward an articular-like fate has significant therapeutic potential to treat degenerative joint diseases.
5-HT2A receptors have been shown to play critical roles in regulating neuronal signalling networks and brain plasticity. They have become important targets for treatment of resistant forms of mental health disorders such as depression, anxiety and post-traumatic stress disorder. Like many G protein-coupled receptors (GPCRs), signalling downstream of 5-HT2A depends on where the receptor is in the cell. Events and signalling pathways modulated by the cell surface pool of receptors may be distinct from those regulated by an internal pool of receptors. In this review, we parse out how the cell organizes and regulates this location bias and explore approaches to target the distinct receptor pools pharmacologically.
What is this summary about?Rimegepant is a treatment used by people in several countries to prevent migraine attacks. It is taken by mouth (orally). Several other oral treatments used to prevent migraine attacks were not designed for this purpose. They are commonly used for other conditions, such as high blood pressure, seizures, or depression. Many people have found these other oral treatments to not work well in preventing their migraine attacks. Rimegepant differs from these oral preventive treatments because it was specifically designed to stop the cause of migraine.This summary explains findings from the first study testing if rimegepant can reduce the frequency of migraine attacks in people who have found these other oral treatments not to work well. This was because the other treatments had taken too long to work, did not work well enough, or had too many side effects. Some people are not recommended to take the other oral treatments because they have a higher chance of severe side effects.What were the main results?During the study, participants took either rimegepant or a placebo every other day for 3 months.Participants who took rimegepant had a larger reduction in the number of migraine days per month than participants who took the placebo. Participants who took rimegepant also had larger reductions in the number of migraine days per month with moderate to severe pain, and larger improvements in their quality of life than participants who took the placebo. A similar proportion of participants who took rimegepant or the placebo reported side effects.What do the results mean?Rimegepant reduced the frequency of migraine attacks in participants who had found several types of oral preventive treatments not to work well or not be suitable. Researchers concluded that rimegepant might be an alternative treatment to prevent migraine attacks in this group.Clinical trial number: NCT05518123.
The temporal sequence of lumbar spine degeneration (trajectory) is difficult to characterize due to limited availability of longitudinal imaging data. The aim of this cross-sectional study was to discover degeneration trajectories and their clinical relevance by applying an innovative computational approach to an extensive dataset from chronic low back pain patients. Clinical MRI exams from 423 patients in the comeBACK study were graded for disc degeneration, facet osteoarthritis, and other pathoanatomical features. We then trained an event-based model, which is specifically designed to infer longitudinal trajectories from cross-sectional data, to model spine degeneration trajectory subtypes. The clinical significance of the identified trajectories was assessed using propensity score matching of trajectory subtypes and subsequent generalized linear mixed-effects modeling. Pain characteristics included the Fear-Avoidance Beliefs Questionnaire, neuropathic pain (painDETECT), pain impact score, and chronic widespread pain (CWP). Two distinct trajectories were identified. A "disc-first" subtype (n = 260, 61%) was characterized by a high prevalence of disc herniation and disc degeneration that was more severe than facet osteoarthritis. Conversely, a "facet-first" subtype (n = 146, 39%) was characterized by a greater severity of facet osteoarthritis than disc degeneration. The disc-first subtype was associated with more CWP (p = 0.030), while the facet-first subtype had higher neuropathic pain (painDETECT scores) (p = 0.039). We identified two distinct trajectories of lumbar spine degeneration related to differing clinical presentations. After replication with other large datasets, this method could be used to characterize and stage spinal degeneration of individual patients. Ultimately, this new information would help clarify degeneration mechanisms and risk factors and support treatment optimization.
Pathogenic bacteria posed a serious threat to water ecosystems and might even have triggered disease outbreaks. In this study, a carbon-doped polymer carbon nitride (C-PCN) composed of numerous interwoven and stacked ultrathin lamellar units was fabricated via a simple stepwise calcination strategy. Compared with the polymer carbon nitride (PCN), C-PCN exhibited more remarkable photocatalytic performance for the Providencia alcalifaciens (P. alcalifaciens) isolated from a local hospital's waste water. C-PCN with a concentration of 0.4 mg mL-1 killed 7.07 log P. alcalifaciens within 100 min, whereas PCN could only inactivate 2.38 log P. alcaliphilus under the same conditions. Moreover, C-PCN could remove 99.87% antibiotic-resistance genes (ARGs) QnrS2 within 6 h. We addressed the gap in the existing research on inactivated P. alcalifaciens, and the fragmentation pathway of circular plasmids during photocatalysis reaction was observed via atomic force microscopy (AFM). The incorporation of carbon enhanced the visible light absorption capability of C-PCN and promoted more efficient charge separation. Mechanism investigation revealed that ˙O2 - and ˙OH were the vital reactive oxygen species (ROS) for antibiotic-resistance bacteria (ARB) inactivation and ARG degradation. ROS could induce cell rupture by damaging cellular membranes and disrupt metabolic processes by affecting enzyme activity. Additionally, a small-scale continuous-flow device could inactivate bacteria in hospital wastewater in 2.5 h under natural light irradiation, thus laying a foundation for advanced hospital wastewater treatment.
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Prolonged exposure (PE) is an evidence-based treatment for PTSD. However, the imaginal exposure portion of PE can be distressing for patients, and despite many service members reporting multiple traumatic events, traditional PE focuses solely on the most distressing event. This article evaluates a modified version of PE that considers the need for distress-reduction in trauma-focused treatments. We compared distress during two methods of imaginal exposure: (1) standard exposure, where participants focused on their most distressing event; and (2) graduated exposure, where participants focused on their top three most distressing events, from third most distressing to most distressing. Mean peak subjective units of distress scores (SUDS) were compared across groups. Participants were 199 active duty personnel and veterans (79.9% men; mean age 38.5 years). There was a significant overall effect of group on peak SUDS, F(3,359) = 12.46, p < .001. Participants receiving standard exposure reported an average peak SUDS of 88.1/100 (SD = 13.4), compared to 75.2 (SD = 22.5) for graduated imaginal exposure participant's most distressing event. Participants in the graduated group also reported significantly lower peak SUDS for their second (M = 72.23, SD = 20.6; t(183) = 5.49, p < .001, d = .81) and third most distressing events (M = 74.63, SD = 21.1; t(183) = 466, p < .001, d = .69) compared to mean SUDS rating for the standard exposure group. Incorporating a graduated approach appears to mitigate average peak distress from participating in the imaginal exposure component of PE.Trial registration These data were collected as part of a larger, randomized clinical trial that was registered with ClinicalTrials.gov (Identifier NCT03529435).
Visual discomfort or visual stress is an uncomfortable subjective experience that occurs in response to specific visual stimuli. It affects a large proportion of the population to various degrees, disproportionately impacting those with heightened sensory sensitivities, particularly neurodivergent individuals. We argue that this might stem from a mismatch between the statistical properties of visual stimuli in human-made environments and those in natural environments that the visual system can process efficiently. We discuss the inefficiency with which images with certain spatial, chromatic and temporal characteristics are processed by the visual system and propose a cerebral mechanism to account for the discomfort they induce. The mechanism offers a potential explanation for the large individual differences in susceptibility to discomfort. We highlight two avenues for intervention: (1) environmental modifications aimed at reducing the prevalence of visually stressing stimuli in urban settings, and (2) individual-level strategies, such as personalised optical treatments. Addressing these challenges requires an interdisciplinary effort bridging neuroscience, vision science, interior and urban design and typography to create visually accessible and inclusive environments.
Virtual ward (VW) is a hospital-led alternative to inpatient care enabled by technology where patients are looked after in their usual residence. Such a service may not be familiar to many. This survey aims to explore the views and acceptability of VW among hospitalised patients. This study was conducted among patients aged ≥18 years admitted to medical wards of a tertiary hospital in Malaysia. The survey questions were adapted from existing questionnaires and piloted before use. Participants were provided with a clinical vignette and description of a VW service before completing the questionnaire. It collated data on respondents' demographics, admission details, VW acceptability and their views on VW-related telehealth. The next of kin or main caregiver provided responses if the person was unable to participate. Responses were collected from 120 participants (95 patients, 25 caregivers), of which 108 respondents (90.0%) agreed to be managed by a VW service if such a service was available and able to meet their needs. Being at home, supported by family members, and the ability to maintain independence were the most common reasons cited for its acceptance. Among those unwilling, participants preferred to have the medical and nursing team close by. In terms of telehealth readiness, 95% of patients have internet access, and 97.5% possess the appropriate devices for video consultation. However, only 20% of patients have utilised online video consultations before to seek medical advice. The majority of people surveyed were willing to accept a virtual ward service. The findings provide useful information towards the planning of virtual ward programmes in Malaysia.
Definitive chemoradiation (CRT) is standard for patients with medically inoperable esophageal cancer. OBP-301 is a modified adenovirus that adds a human telomerase reverse transcriptase gene promoter, replicating only in tumor cells to cause lysis. In this phase 1 study, OBP-301 was added to carboplatin/paclitaxel and radiation therapy (RT) (50.4 Gy). Patients received intratumoral OBP-301 via endoscopy 3 days prior to and then at days 12 and 26 of RT. The primary endpoint was protocol-defined dose-limiting toxicity. Secondary endpoints included clinical complete response (cCR) rate, number alive and alive without progression at 1 year. From June 2020 to July 2024, 15 evaluable patients were enrolled. Fourteen patients (93%) received all planned OBP-301 injections and 50.4 Gy RT. No dose-limiting toxicities were observed. The most common treatment-related grade 3/4 toxicities were neutropenia (40%) and lymphopenia (33%). Two patients died prior to restaging: 1 patient developed grade 5 respiratory failure 6 weeks after CRT (suspected RT pneumonitis), whereas a second patient had unrecognized airway involvement at baseline, which led to a tracheoesophageal fistula during Week 3 of CRT. The cCR rate for patients undergoing restaging (n = 13) was 100% (95% CI, 77-100), and 87% (95% CI, 62-96) for all 15 patients. At 1 year, 9 (60%) out of 15 patients are still alive and 8 (53%) are alive without progression. OBP-301 administration before and during CRT is feasible and safe, resulting in a very promising cCR rate. A randomized study is being planned to further evaluate safety and efficacy.
What is this summary about?Rimegepant is a new medicine that can be used to prevent migraine attacks or stop a migraine attack that has already started. Many people with migraine have tried a type of medicine called a ‘triptan’ to stop an attack that has already started. Some people find triptans to work well for the treatment of migraine. This summary describes findings from a study that looked to see if rimegepant could stop a migraine attack in people who have found triptans not to provide enough symptom relief, to cause bothersome side effects, or are not recommended to use triptans because of other conditions they have or medicines they take.What were the main results?People in this study took rimegepant or a placebo to treat a single migraine attack that caused them moderate or severe pain. People who took rimegepant had more relief from migraine pain and other symptoms than people who took the placebo. They were also more able to do their daily activities normally. Fewer people who took rimegepant needed to take additional medicines to treat their migraine pain and other symptoms than people who took the placebo. Similar proportions of people who took rimegepant or the placebo reported side effects.What do the results mean?Researchers found rimegepant can relieve the pain and other symptoms of a migraine attack in people who have found triptans not to provide enough symptom relief, to cause bothersome side effects, or are not recommended to use triptans.Clinical trial number: NCT05509400.
Although technology has been widely implemented in Parkinson's disease (PD) research, little is known about its efficacy on participants' psychosocial domains. This study assessed the potential effect and usability of the Voice-Activated Intelligent Personal Assistant (VIPA) on participants' sense of coherence and psychosocial well-being. This single-blinded, 2-arm pilot randomised controlled trial, with 7 post-intervention interviews, recruited 48 participants. Intervention group participants received a user protocol for their 8-week VIPA usage, while the control group received usual care. Primary outcome was the Sense of Coherence 13-item scale (SOC-13). Other outcomes were Mental Health Continuum-Short Form (MHC-SF), UCLA Three-Item Loneliness Scale, Parkinson's Disease Questionnaire-8, Brief Resilient Coping Scale, and System Usability Scale. Generalized Estimating Equation (GEE) was selected as the primary analysis, with multiple imputation performed as sensitivity analysis. A significant reduction of positive emotion in IG was identified for the MHC-SF emotional well-being at post-intervention (β = -1.69, p = 0.028) but not at week 12 follow-up (β = -0.96, p = 0.31). Exploratory effect sizes were identified for SOC-13 meaningfulness (d = 0.27), manageability (d = 0.19), and MHC-SF psychological well-being (d = 0.27). Interviewee reportedly internalised their failed interaction attempts into speech characteristics, and it resembled being ignored by a real person. The study identified preliminary trends of improvements in participants' meaningfulness domain and psychological well-being. The decrease in emotional well-being could be attributed to the reported technical difficulties and VIPA's fair usability. A future VIPA redesign is required to avoid similar adverse effects.