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Relative effectiveness of high-dose versus standard-dose influenza vaccine against hospitalizations and mortality according to Charlson Comorbidity Index: a post-hoc analysis of the DANFLU-1 randomized trial
Get PDFPurpose: The DANFLU-1 trial suggested lower incidence of hospitalizations for pneumonia and influenza, respiratory disease and all-cause mortality among older adults receiving high-dose (HD IV) versus standard-dose (SD-IV) influenza vaccine. This study assessed the relative effectiveness of HD-IV versus SD-IV according to comorbidity in elderly individuals.
Methods: This was a post-hoc analysis of the DANFLU-1 randomized controlled feasibility trial of HD-IV versus SD-IV conducted during the 2021–2022 influenza season in adults aged 65–79 years. Outcomes assessed included influenza-related, respiratory, and cardiovascular hospitalizations, and mortality. We tested for effect modification by level of the Charlson Comorbidity Index (CCI) using ICD-10 codes up to 10 years prior to randomization.
Results: Of the 12,477 randomly assigned participants (mean age 71.7±3.9 years, 47.1% female), 8,020 (64.3%) had CCI=0, 3,560 (28.5%) had CCI=1-2 and 893 (7.2%) had CCI≥3. When comparing HD-IV with SD-IV, hazard ratios of hospitalizations for pneumonia and influenza were similar across CCI groups (HR [95%CI]: 0.15 [0.03-0.68] for CCI=0, 0.36 [0.11-1.15] for CCI=1-2, 1.00 [0.25-4.00] for CCI≥3). Comparable patterns were found for hospitalizations for respiratory disease (0.46 [0.17-1.20] for CCI=0, 0.67 [0.32-1.39] for CCI=1-2, 0.66 [0.24-1.87] for CCI≥3) and all-cause mortality (0.28 [0.09-0.86] for CCI=0, 0.70 [0.30-1.63] for CCI=1-2, 0.57 [0.24-1.36] for CCI≥3). There was no statistical evidence of effect modification by CCI for any outcome.
Conclusions: The lower incidences of clinical outcomes for HD-IV compared to SD-IV were not significantly modified by CCI. The potential benefit of HD-IV versus SD-IV may therefore be applicable regardless of comorbidity burden. Further research is required to confirm these findings
Task success in trained spiking neural network models coincides with emergence of cross-stimulus-modulated inhibition
Get PDFThe neocortex is composed of spiking neurons interconnected in a sparse, recurrent network. Spiking activity within these networks underlies the computations that transform sensory inputs into appropriate behavioral responses. In this study, we train recurrent spiking neural network (SNN) models constrained by neocortical connectivity statistics and investigate the architectural changes that enable task-relevant, spike-based computations. We employ a binary state change detection task—an experimental paradigm used in animal behavioral studies. Our SNNs consist of interconnected excitatory and inhibitory units with connection probabilities and strengths modeled after the mouse neocortex and maintained throughout training and evaluation. Following training, we find that SNNs selectively modulate firing rates based on the binary input state, and that excitatory and inhibitory connectivity within and between input and recurrent layers adjusts accordingly. Notably, inhibitory neurons in the recurrent layer that positively modulate firing rates in response to one input state strengthen their connections to recurrent units with the opposite modulation. This push-pull connectivity—where excitation and inhibition are dynamically balanced in an opponent fashion—emerges as a key computational strategy and is reminiscent of connectivity observed in primary visual cortex. Using a one-hot output encoding yields identical firing rates to both input states, yet the push-pull inhibitory motif still arises. Importantly, this motif fails to emerge when Dale’s principle is not enforced during training, and task performance also declines.Furthermore, disrupting spike timing by a few milliseconds significantly impairs task performance, highlighting the importance of precise spike time coordination for computation in sparse networks like neocortex. The emergence of push-pull inhibition through task training in spiking models underscores the crucial role of interneurons and structured inhibition in shaping neural dynamics and spike-based information processing
Large carbon dioxide emissions avoidance potential in improved commercial air transport efficiency
Get PDFAviation’s climate impact continues to grow, with little progress toward emission reductions aligned with global targets. While technological advances attract attention, operational efficiency across aircraft, airlines, airports, city pairs, and regions remains underexplored. Here we assess carbon dioxide efficiency for 27.5 million flights between 26,156 city pairs in 2023, using data from Airline Data, International Civil Aviation Organization, International Air Transport Association. Results show wide variation: 32–890 gram carbon dioxide per revenue passenger kilometres across routes and 60–360 gram carbon dioxide per revenue passenger kilometre across aircraft models. Efficiency differs by region and is lowest in Africa, Australia, and Norway, and highest in Brazil, India, and Southeast Asia. Operating all routes at their demonstrated optimum could cut emissions by 10.7%. A theoretical 50% reduction is possible with the most efficient aircraft, all-economy layouts, and 95% load factors. Efficiency-focused policy could swiftly reduce fuel use without limiting air transport capacity
PROspectiVe imaging research DEsign and coNducT (PROVIDENT): considerations for clinical trials and studies using imaging (Part II)
Get PDFObjectivesImaging is used in a wide range of contexts in clinical research projects, but adds complexity to the design, conduct and analysis. This paper is the second of two in which we use a consensus approach to combine multidisciplinary perspectives on the challenges in conducting prospective clinical trials and other research studies involving imaging. Here we consider challenges in image interpretation and quantification, quality assurance and quality control (QA/QC); scanner imaging acquisition, data flow and storage, health economics (HE) decision modelling, costings for running a trial; and commercialisation.Key findingsAvailability of scanners and staff can impact deliverability. Pre-specification of key procedures, roles and responsibilities via appropriate documentation is important; ensuring compatibility across different sites and machines is challenging and requires advance input from multiple stakeholders. Testing critical procedures, including the flow of images and derived data between participating sites and/or external legal entities, can avoid delays. Effective QA/QC is conducted at regular intervals; relevant staff should be involved at the planning stage. Identifying appropriately qualified readers and arranging for image hosting takes time; this should be done prior to image acquisition. Testing image interpretation burden informs feasibility and costings. Cost estimates for research involving imaging and HE modelling of imaging interventions can be complex due to the interplay between local and national policies, and the extent to which the research imaging is integrated with standard care.ConclusionThese considerations derived from a multidisciplinary team will be useful for funding applications, protocol design, trial implementation, conduct and commercialisation and uptake of new imaging techniques.Implications for practiceMany prospective imaging studies could be improved by the upfront awareness of potential challenges and understanding of real-world examples these considerations provide
Athenian figure-decorated pottery for whom? A view from Eastern Andalucía (Spain)
No full textAthenian pottery started to arrive in the Iberian Peninsula in significant numbers in the fifth century BCE, with a peak in the fourth century. Both black-gloss and figured-decorated pots were exported, being the first largely more popular in all the Iberian regions but one: Eastern Andalucía. Earlier scholarship has explained the preference of the native communities of that area for vases with images as a case of interpretatio iberica whereby some repetitive Athenian images were particularly favoured because they could be assimilated with concepts known in Iberian society. I now propose to look further into this question and assess whether there are any distinctive patterns in the distribution/deposition of red-figure and black-gloss pots within that region and whether the theory of prestige signalling works in contexts where red-figure pottery outnumbers black-gloss. Taking as case studies the necropoleis of Galera and Baza, in Granada, and Castellones de Céal, in Jaén, I place the “Andalusian exception” within the larger context of the consumption of Athenian pottery in Iberia and within its own local context, revealing a world fascinated with images that served the socio-political and ritual needs of the Iberians of this region in the momentous passage from life to death
Advances in Melt-Electrowriting of Fibrous Bioscaffolds: A High-Resolution Manufacturing Strategy for Tissue Regeneration
Get PDFMelt-electrowriting (MEW) is a high-resolution additive manufacturing technique that has demonstrated significant progress in recent years. Owing to its precise control over fiber deposition, MEW is especially suitable for fabricating fine structures that mimic the natural extracellular matrix (ECM), thereby presenting considerable promise for applications in tissue engineering and regeneration. This review systematically examines the fundamental design principles and recent progress in MEW-based strategies for different tissue engineering and regeneration fields. Initially, the components of the MEW system, the underlying printing mechanisms, and the role of key process parameters are introduced, thereby providing a comprehensive framework for the rational design of scaffolds that replicate both the structural and functional characteristics of native ECM. Subsequently, the selection and performance of commonly employed biomaterials are discussed, with an emphasis on the versatility for diverse tissue engineering applications. The integration of MEW with bioactive materials is further highlighted as an effective approach to enhance the biological functionality of printed constructs and extend their therapeutic potential. Finally, current challenges and future perspectives are outlined, aiming to guide ongoing research and facilitate the clinical translation of MEW-based biofabrication technologies.Graphical abstrac
Long Term Metabolic Outcomes Following Pancreatectomy and Autologous Islet Transplantation: Systematic Review and Meta‐Analysis
Get PDFThis systematic review and meta‐analysis assessed long‐term outcomes following total pancreatectomy with islet autotransplantation (TPIAT). Seventeen studies including 1332 patients were analyzed. The pooled insulin independence rate was 34%, with higher rates for non‐chronic pancreatitis indications (68%) versus chronic pancreatitis (33%). TPIAT is effective in preserving endocrine function. Further studies are needed to validate outcomes across extended indications and to standardize reporting, incorporating metabolic markers and patient‐reported quality‐of‐life endpoints over long‐term follow‐up
Virus-induced endothelial senescence as a cause and driving factor for ME/CFS and long COVID: mediated by a dysfunctional immune system
Get PDFMyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID are two post-viral diseases, which share many common symptoms and pathophysiological alterations. Yet a mechanistic explanation of disease induction and maintenance is lacking. This hinders the discovery and implementation of biomarkers and treatment options, and ultimately the establishment of effective clinical resolution. Here, we propose that acute viral infection results in (in)direct endothelial dysfunction and senescence, which at the blood-brain barrier, cerebral arteries, gastrointestinal tract, and skeletal muscle can explain symptoms. The endothelial senescence-associated secretory phenotype (SASP) is proinflammatory, pro-oxidative, procoagulant, primed for vasoconstriction, and characterized by impaired regulation of tissue repair, but also leads to dysregulated inflammatory processes. Immune abnormalities in ME/CFS and long COVID can account for the persistence of endothelial senescence long past the acute infection by preventing their clearance, thereby providing a mechanism for the chronic nature of ME/CFS and long COVID. The systemic and tissue-specific effects of endothelial senescence can thus explain the multisystem involvement in and subtypes of ME/CFS and long COVID, including dysregulated blood flow and perfusion deficits. This can occur in all tissues, but especially the brain as evidenced by findings of reduced cerebral blood flow and impaired perfusion of various brain regions, post-exertional malaise (PEM), gastrointestinal disturbances, and fatigue. Paramount to this theory is the affected endothelium, and the bidirectional sustainment of immune abnormalities and endothelial senescence. The recognition of endothelial cell dysfunction and senescence as a core element in the aetiology of both ME/CFS and Long COVID should aid in the establishment of effective biomarkers and treatment regimens
Fragmentation dynamics of CS2 dications and trications following S 2p ionization
Get PDFWe present the results from a detailed study of the fragmentation dynamics of and , formed in intense femtosecond soft x-ray pulses above the sulfur 2p edge, primarily through single core photoionization from the S 2p site, and subsequent Auger–Meitner decay(s). By combining three-dimensional velocity map imaging with covariance analysis, we determine the relative momenta of the ions produced in each two- and three-body fragmentation channel, at significantly higher ion count rates than conventional coincidence measurements. We shed new light on the wide range of fragmentation channels observed from the CS2 dication and trication, including channels that involve ionization-induced bond formation and fragmentations producing undetected neutral cofragments. In the latter case, a “native frames” approach is used to isolate contributions from concerted and sequential fragmentations and extract dynamical information about each step of a concerted fragmentation process. While dications often fragment sequentially, the trication is dominated by concerted fragmentation. The main trication fragmentation channel into S+ + C+ + S+ can be well-approximated by classical Coulombic simulations of the ground-state geometry distribution, reflecting both the nature of the trication potential energy surface and the rapid multiple ionization prior to substantial structural dynamics. This study demonstrates ways in which fundamental insights into the fragmentation dynamics of polycations following x-ray ionization may be extracted, which will be beneficial to future studies that employ time-resolved x-ray Coulomb explosion imaging to study ultrafast photochemistry