Effectiveness and safety of glecaprevir/pibrentasvir for 8 weeks in the treatment of patients with acute hepatitis C: A single-arm retrospective study.

BACKGROUND AND AIMS: No direct-acting antiviral is currently approved for acute HCV infection, delaying treatment. We investigated the effectiveness and safety of 8-week glecaprevir/pibrentasvir (G/P) in patients with acute HCV infection. APPROACH AND RESULTS: This noninterventional, single-arm, retrospective chart review was designed to enroll adults/adolescents with acute HCV infection. Analyses were conducted on a full analysis set (FAS; all enrolled) and modified FAS (FAS excluding nonvirologic failures). The primary end point (modified FAS) was sustained virologic response at posttreatment week 12 (SVR12) with superiority to 92.6% threshold determined by historic chronic HCV G/P SVR12 rates. Secondary end points (FAS) included SVR12, on-treatment virologic failure, posttreatment relapse, and reinfection. Adverse events and safety laboratory values were assessed.Overall, 202 adults were enrolled; in the modified FAS, 150/151 (99.3%; 95% CI: 96.3-99.9) achieved SVR12, demonstrating superiority to efficacy threshold. In the FAS, the SVR12 rate was 74.3% and the on-treatment virologic failure rate was 0%. Relapse and reinfection rates after the final treatment visit (FAS) were 0.5% and 3%, respectively; 39 patients had missing SVR12 data. No on-treatment alanine aminotransferase elevations > 3 × upper limit of normal with total bilirubin > 2 × upper limit of normal were reported. All 53 patients with alanine aminotransferase Grade ≥ 2 at baseline improved to Grade 0/1 on treatment. No adverse eventss of hepatic decompensation/failure or leading to G/P discontinuation occurred. Two patients had serious adverse events unrelated to G/P. CONCLUSIONS: Eight-week G/P therapy was effective and well-tolerated in patients with acute HCV infection. Data support further investigation of G/P in acute HCV to shorten care cascades, reduce transmission, and support HCV elimination.

Improved synthesis and application of an alkyne-functionalized isoprenoid analogue to study the prenylomes of motor neurons, astrocytes and their stem cell progenitors.

Protein prenylation is one example of a broad class of post-translational modifications where proteins are covalently linked to various hydrophobic moieties. To globally identify and monitor levels of all prenylated proteins in a cell simultaneously, our laboratory and others have developed chemical proteomic approaches that rely on the metabolic incorporation of isoprenoid analogues bearing bio-orthogonal functionality followed by enrichment and subsequent quantitative proteomic analysis. Here, several improvements in the synthesis of the alkyne-containing isoprenoid analogue C15AlkOPP are reported to improve synthetic efficiency. Next, metabolic labeling with C15AlkOPP was optimized to obtain useful levels of metabolic incorporation of the probe in several types of primary cells. Those conditions were then used to study the prenylomes of motor neurons (ES-MNs), astrocytes (ES-As), and their embryonic stem cell progenitors (ESCs), which allowed for the identification of 54 prenylated proteins from ESCs, 50 from ES-MNs, and 84 from ES-As, representing all types of prenylation. Bioinformatic analysis revealed specific enriched pathways, including nervous system development, chemokine signaling, Rho GTPase signaling, and adhesion. Hierarchical clustering showed that most enriched pathways in all three cell types are related to GTPase activity and vesicular transport. In contrast, STRING analysis showed significant interactions in two populations that appear to be cell type dependent. The data provided herein demonstrates that robust incorporation of C15AlkOPP can be obtained in ES-MNs and related primary cells purified via magnetic-activated cell sorting allowing the identification and quantification of numerous prenylated proteins. These results suggest that metabolic labeling with C15AlkOPP should be an effective approach for investigating the role of prenylated proteins in primary cells in both normal cells and disease pathologies, including ALS.

Plant periderm as a continuum in structural organisation: a tracheophyte-wide survey and hypotheses on evolution.

Periderm is a well-known structural feature with vital roles in protection of inner plant tissues and wound healing. Despite its importance to plant survival, knowledge of periderm occurrences outside the seed plants is limited and the evolutionary origins of periderm remain poorly explored. Here, we review the current knowledge of the taxonomic distribution of periderm in its two main forms - canonical periderm (periderm formed as a typical ontogenetic stage) and wound periderm (periderm produced as a self-repair mechanism) - with a focus on major plant lineages, living and extinct. We supplement the published occurrences with data based on our own observations and experiments. This updated body of data reveals that the distribution of wound periderm is more widespread taxonomically than previously recognized and some living and extinct groups are capable of producing wound periderm, despite canonical periderm being absent from their normal developmental program. A critical review of canonical and wound periderms in extant and fossil lineages indicates that not all periderms are created equal. Their organisation is widely variable and the differences can be characterised in terms of variations in three structural features: (i) the consistency in orientation of periclinal walls within individual files of periderm cells; (ii) the lateral coordination of periclinal walls between adjacent cell files; and (iii) whether a cambial layer and conspicuous layering of inward and outward derivatives can be distinguished. Using a new system of scoring periderm structure based on these criteria, we characterise the level of organisation of canonical and wound periderms in different lineages. Looking at periderms through the lens provided by their level of organisation reveals that the traditional image of periderm as a single generalised feature, is best viewed as a continuum of structural configurations that are all predicated by the same basic process (periclinal divisions), but can fall anywhere between very loosely organized (diffuse periclinal growth) to very tightly coordinated (organized periclinal growth). Overall, wound periderms in both seed plants and seed-free plants have lower degrees of organisation than canonical periderms, which may be due to their initiation in response to inherently disruptive traumatic events. Wound and canonical periderms of seed plants have higher degrees of organisation than those of seed-free plants, possibly due to co-option of the programs responsible for organizing their vascular cambial growth. Given the importance of wound periderm to plant survival, its widespread taxonomic distribution, and its early occurrence in the fossil record, we hypothesise that wound periderm may have had a single origin in euphyllophytes and canonical periderm may have originated separately in different lineages by co-option of the basic regulatory toolkit of wound periderm formation. In one evolutionary scenario, wound periderm regulators activated initially by tissue tearing due to tensional stresses elicited by woody growth underwent heterochronic change that switched their activation trigger from tissue tearing to the tensional stresses that precede it, with corresponding changes in the signalling that triggered the regulatory cascade of periderm development from tearing-induced signals to signalling induced by tension in cells.

Drug-Induced Liver Injury in the Elderly: Consensus Statements and Recommendations from the IQ-DILI Initiative.

The elderly demographic is the fastest-growing segment of the world's population and is projected to exceed 1.5 billion people by 2050. With multimorbidity, polypharmacy, susceptibility to drug-drug interactions, and frailty as distinct risk factors, elderly patients are especially vulnerable to developing potentially life-threatening safety events such as serious forms of drug-induced liver injury (DILI). It has been a longstanding shortcoming that elderly individuals are often a vulnerable population underrepresented in clinical trials. As such, an improved understanding of DILI in the elderly is a high-priority, unmet need. This challenge is underscored by recent documents put forward by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) that encourage data collection in the elderly and recommend improved practices that will facilitate a more inclusive approach. To establish what is already known about DILI in the elderly and pinpoint key gaps of knowledge in this arena, a working definition of "elderly" is required that accounts for both chronologic and biologic ages and varying states of frailty. In addition, it is critical to characterize the biological role of aging on liver function, as well as the different epidemiological factors such as polypharmacy and inappropriate prescribing that are common practices. While data may not show that elderly people are more susceptible to DILI, DILI due to specific drugs might be more common in this population. Improved characterization of DILI in the elderly may enhance diagnostic and prognostic capabilities and improve the way in which liver safety is monitored during clinical trials. This summary of the published literature provides a framework to understand and evaluate the risk of DILI in the elderly. Consensus statements and recommendations can help to optimize medical care and catalyze collaborations between academic clinicians, drug manufacturers, and regulatory scientists to enable the generation of high-quality research data relevant to the elderly population.

Perception of environmental issues in the head-and-neck surgery room: A preliminary study.

OBJECTIVES: To assess the perception of environmental issues in head-and-neck surgery rooms and to compare the perception of priority environmental issues according to health professionals' age-group, initial training and role in the operating room. METHODS: A multicenter descriptive observational study was conducted in January 2023, contacting health professionals working in the operating rooms of 5 French centers. An anonymous online questionnaire explored the perception of environmental issues according to age, initial training and role in the operating room. RESULTS: Sixty-nine percent of the 387 persons contacted (267/387) completed the entire questionnaire. Ninety-six percent of respondents (256/267) said that they felt concerned about climate change issues and 85% (226/267) felt well-informed. Ninety-three percent (251/267) were willing to make environmental efforts in the operating room. Priorities were to improve waste recycling and reduce the amount of waste for 95% (251/267) and 97% (259/267) of respondents respectively. Those under 40 years of age tended to feel better informed about climate issues (76% [75/99] versus 60% [100/168]; P=0.010). CONCLUSION: Our study showed that the vast majority of health professionals working in head-and-neck surgery rooms in France felt concerned about climate issues and were ready to make an effort. Nevertheless, it seems important to carry out information campaigns dedicated to these environmental issues.

Perception of endoscopic endonasal surgery training by French otolaryngology residents: A STROBE analysis of expectations.

OBJECTIVES: To analyze the perception of endoscopic endonasal surgery training by French otolaryngology residents. MATERIAL AND METHODS: A multicenter retrospective observational study was conducted from March to April 2023. Otolaryngology residents from 7 French regions filled out a 27-item questionnaire on their training in endoscopic endonasal surgery. RESULTS: Out of 283 residents contacted, 126 (45%) filled out the questionnaire. Seventy-four (59%) had already partially or completely performed the surgeries specified in their diploma course. The level of mastery of the main steps of endonasal surgery and the level of autonomy were higher in the consolidation stage group than in the basic and advanced stages. Seventy residents (56%) felt they had gaps in their level of training. To improve training, 94 (75%) wished for more dissection sessions, surgical skills assessments each semester and simulation sessions. Eighty-nine (71%) felt they needed to find their own teaching aids and other methods to complete their training. One hundred and thirteen (90%) felt that the lack of funding available for congresses and training courses was detrimental. CONCLUSION: This study highlighted the overall satisfaction of residents with their training in endoscopic endonasal surgery. They expressed a desire for more dissection, simulation and evaluation.

Evaluation of hyaluronic acid-polymacrolactone hydrogels with 3D printing capacity.

The implementation of personalized patches, tailored to individual genetic profiles and containing specific amounts of bioactive substances, has the potential to produce a transformative impact within the medical sector. There are several methods of designing scaffolds in the context of personalized medicine, with three-dimensional (3D) printing emerging as a pivotal technique. This innovative approach can be used to construct a wide variety of pharmaceutical dosage forms, characterized by variations in shape, release profile, and drug combinations, allowing precise dose individualization and the incorporation of multiple therapeutic agents. To expand the potential and applicability of personalized medicine, particularly with regards to indomethacin (IND), a drug necessitating individualized dosing, this study proposes the development of new transdermal delivery systems for IND based on hyaluronic acid and a polylactone synthesized within our research group, namely poly(ethylene brasilate-co-squaric acid) (PEBSA). The obtained systems were characterized in terms of their swelling capacity, rheological behavior, and morphological characteristics that highlighted the formation of stable three-dimensional networks. To impart specific shape and geometry to the structures, multi-component systems based on PEBSA, HA, and methacrylate gelatin were obtained. The scaffolds were loaded with IND and subsequently 3D printed. The release capacity of IND and its dependence on the relative ratios of the components comprising the scaffold composition were highlighted. The cytocompatibility studies revealed the successful development of biocompatible and noncytotoxic systems.

Thinking outside the CaaX-box: an unusual reversible prenylation on ALDH9A1.

Protein lipidation is a post-translational modification that confers hydrophobicity on protein substrates to control their cellular localization, mediate protein trafficking, and regulate protein function. In particular, protein prenylation is a C-terminal modification on proteins bearing canonical motifs catalyzed by prenyltransferases. Prenylated proteins have been of interest due to their numerous associations with various diseases. Chemical proteomic approaches have been pursued over the last decade to define prenylated proteomes (prenylome) and probe their responses to perturbations in various cellular systems. Here, we describe the discovery of prenylation of a non-canonical prenylated protein, ALDH9A1, which lacks any apparent prenylation motif. This enzyme was initially identified through chemical proteomic profiling of prenylomes in various cell lines. Metabolic labeling with an isoprenoid probe using overexpressed ALDH9A1 revealed that this enzyme can be prenylated inside cells but does not respond to inhibition by prenyltransferase inhibitors. Site-directed mutagenesis of the key residues involved in ALDH9A1 activity indicates that the catalytic C288 bears the isoprenoid modification likely through an NAD+-dependent mechanism. Furthermore, the isoprenoid modification is also susceptible to hydrolysis, indicating a reversible modification. We hypothesize that this modification originates from endogenous farnesal or geranygeranial, the established degradation products of prenylated proteins and results in a thioester form that accumulates. This novel reversible prenoyl modification on ALDH9A1 expands the current paradigm of protein prenylation by illustrating a potentially new type of protein-lipid modification that may also serve as a novel mechanism for controlling enzyme function.

Surgical and instrumental options for chronic rhinitis: A systematic review and PRISMA meta-analysis.

BACKGROUND: There is no consensus on the role of surgery in the treatment of chronic rhinitis (CR). Should it be considered when nasal symptoms are not controlled by medical treatment? Various targets (turbinates and secretory nerves) and techniques (surgical, laser, cryotherapy, radiofrequency and phototherapy) have been reported, but benefit varies between reports. The aim of this systematic review and meta-analysis was to evaluate results of surgical and instrumental procedures in CR care. METHODS: Two systematic reviews of the US National Library of Medicine, Cochrane Library, Web of Science and Embase databases were conducted in October 15, 2021 (registration numbers CRD42021284257 and CRD42021295227). A database watch was performed until submission of the manuscript. The review focuses on total nasal symptom score (TNSS) and quality of life (QoL) after treatment. All controlled studies reporting nasal surgery/instrumental procedures in adult patients with CR were included. RESULTS: The database search yielded a total of 5628 articles; after eligibility screening, 2091 patients were included from 21 studies. QoL results favored surgery/instrumental procedures over medical treatment (SMD -1.27; 95% CI [-2.38; -0.16]; I2=97%), as did TNSS (SMD -1.40; 95% CI [-2.30; -0.50]; I2=98%). The small number of studies and their heterogeneity did not allow meta-regression to be performed. CONCLUSION: This systematic review supports the use of surgical/instrumental procedures to improve nasal symptom score and QoL of adult patients with CR poorly controlled by medical treatment.

Dating the evolution of the complex thalloid liverworts (Marchantiopsida): total-evidence dating analysis supports a Late Silurian-Early Devonian origin and post-Mesozoic morphological stasis.

Divergence times based on molecular clock analyses often differ from those derived from total-evidence dating (TED) approaches. For bryophytes, fossils have been excluded from previous assessments of divergence times, and thus, their utility in dating analyses remains unexplored. Here, we conduct the first TED analyses of the complex thalloid liverworts (Marchantiopsida) that include fossils and evaluate macroevolutionary trends in morphological 'diversity' (disparity) and rates. Phylogenetic analyses were performed on a combined dataset of 130 discrete characters and 11 molecular markers (sampled from nuclear, plastid and mitochondrial genomes). Taxon sampling spanned 56 extant species - representing all the orders within Marchantiophyta and extant genera within Marchantiales - and eight fossil taxa. Total-evidence dating analyses support the radiation of Marchantiopsida during Late Silurian-Early Devonian (or Middle Ordovician when the outgroup is excluded) and that of Ricciaceae in the Middle Jurassic. Morphological change rate was high early in the history of the group, but it barely increased after Late Cretaceous. Disparity-through-time analyses support a fast increase in diversity until the Middle Triassic (c. 250 Ma), after which phenotypic evolution slows down considerably. Incorporating fossils in analyses challenges previous assumptions on the affinities of extinct taxa and indicates that complex thalloid liverworts radiated c. 125 Ma earlier than previously inferred.

Mosaic assembly of regulatory programs for vascular cambial growth: a view from the Early Devonian.

Evidence for secondary growth extends into the Early Devonian, 407 million years ago, raising questions about tempo and mode of origination of this key developmental feature. To address such questions, we analyze anatomy in the four oldest fossil plants with well-characterized woody tissues; one of these represents a new genus, described here formally. The new fossil is documented using the cellulose acetate peel technique and associated methods. We use the paradigm of structural fingerprints to identify developmental components of cambial growth based on fossil anatomy. We integrate developmental inferences within a theoretical framework of modular regulation of secondary growth. The fossils possess structural fingerprints consistent with four different combinations of regulatory mechanisms (modules) acting in cambial growth, representing four distinct modes of secondary growth. The different modes of secondary growth demonstrate that cambial growth is an assemblage of regulatory modules whose deployment followed a mosaic pattern across woody plants, which may represent ancestors of younger lineages that exhibit woody growth. The diverse modes of wood development occupy a wide morphospace in the anatomy of wood in the Early Devonian, suggesting that the origins of secondary growth and of its modular components pre-date this interval.

Complex wound response mechanisms and phellogen evolution - insights from Early Devonian euphyllophytes.

We analyze the oldest fossil occurrences of wound-response periderm to characterize the development of wound responses in early tracheophytes. The origin of periderm production by a cambium (phellogen), an innovation with key roles in protection of inner plant tissues, is poorly explored; understanding periderm development in early tracheophytes can illuminate key aspects of this process. Anatomy of wound-response tissues is characterized in serial sections in a new Early Devonian (Emsian; c. 400 Ma) euphyllophyte from Quebec (Canada) - Nebuloxyla mikmaqiana sp. nov. - and compared to previously described euphyllophyte periderm from the same fossil locality to reconstruct periderm development. Characterizing development in these oldest periderm occurrences allows us to propose a model for the development of wound-response periderm in early tracheophytes: by phellogen activity that is poorly coordinated laterally but bifacial, producing secondary tissues initially outwardly and subsequently inwardly. The earliest occurrences of wound periderm pre-date the oldest known periderm produced systemically as a regular ontogenetic stage (canonical periderm), suggesting that periderm evolved initially as a wound-response mechanism. We hypothesize that canonical periderm evolved by exaptation of this wound sealing mechanism, whose deployment was triggered by tangential tensional stresses induced in the superficial tissues by vascular cambial growth from within.

Transcriptomic reprogramming for neuronal age reversal.

Aging is a progressive multifaceted functional decline of a biological system. Chronic age-related conditions such as neurodegenerative diseases are leading causes of death worldwide, and they are becoming a pressing problem for our society. To address this global challenge, there is a need for novel, safe, and effective rejuvenation therapies aimed at reversing age-related phenotypes and improving human health. With gene expression being a key determinant of cell identity and function, and in light of recent studies reporting rejuvenation effects through genetic perturbations, we propose an age reversal strategy focused on reprogramming the cell transcriptome to a youthful state. To this end, we suggest using transcriptomic data from primary human cells to predict rejuvenation targets and develop high-throughput aging assays, which can be used in large perturbation screens. We propose neural cells as particularly relevant targets for rejuvenation due to substantial impact of neurodegeneration on human frailty. Of all cell types in the brain, we argue that glutamatergic neurons, neuronal stem cells, and oligodendrocytes represent the most impactful and tractable targets. Lastly, we provide experimental designs for anti-aging reprogramming screens that will likely enable the development of neuronal age reversal therapies, which hold promise for dramatically improving human health.

Deterioration experienced by French otolaryngology residents in their training during the COVID-19 pandemic: A STROBE analysis.

OBJECTIVE: To evaluate the impact of the first three waves of COVID-19 on the academic and surgical training of ENT and Head and Neck Surgery residents in France. MATERIAL AND METHODS: Observational, retrospective study. A 55-item survey of academic education and surgical training was sent to ENT residents in five major French regions (Île-de-France, Rhône-Alpes Auvergne, Occitanie, Grand Est, Grand Ouest) from August to October 2021. RESULTS: Eighty-nine out of 135 residents (66%) responded. Two-thirds considered that surgical training was more affected than academic education, with reductions evaluated of 50-75%, 25-50% and 0-25% for the first three waves, respectively. Residents in Île-de-France, Rhône-Alpes Auvergne and Grand Est were the most affected by the first wave (75-100% reduction in surgical activity, in parallel to increased admissions). Otology, rhinology and functional exploration were the most affected, whereas pediatrics and oncology were spared. Seventy-one of the 89 residents (79.7%) felt that the first wave impacted their career, while this proportion decreased to 39.3% and 44.9% for the second and third waves, respectively. CONCLUSION: The first wave of COVID-19, compared to the following two waves, severely impacted the surgical training of French ENT residents, especially in regions severely impacted by the pandemic, while academic education was relatively safeguarded by the implementation of e-learning alternatives.

New Hydrogels Based on Agarose/Phytagel and Peptides.

Short aromatic peptide derivatives, i.e., peptides or amino acids modified with aromatic groups, such as 9-fluorenylmethoxycarbonyl (Fmoc), can self-assemble into extracellular matrix-like hydrogels due to their nanofibrillar architecture. Among different types of amino acids, lysine (Lys) and glycine (Gly) are involved in multiple physiological processes, being key factors in the proper growth of cells, carnitine production, and collagen formation. The authors have previously successfully presented the possibility of obtaining supramolecular gels based on Fmoc-Lys-Fmoc and short peptides such as Fmoc-Gly-Gly-Gly in order to use them as a substrate for cell cultures. This paper investigates how the introduction of a gelling polymer can influence the properties of the network as well as the compatibility of the resulting materials with different cell types. A series of hydrogel compositions consisting of combinations of Fmoc-Lys-Fmoc and Fmoc-Gly-Gly-Gly with Agarose and Phytagel are thus obtained. All compositions form structured gels as shown by rheological studies and scanning electron microscopy. Fourier transform infrared spectroscopy analysis evidences the formation of H-bonds between the polysaccharides and amino acids or short peptides. Moreover, all gels exhibit good cell viability on fibroblasts as demonstrated by a live-dead staining test and good in vivo biocompatibility, which highlights the great potential of these biomaterials for biomedical applications.

An early snapshot of plant-herbivore interactions: Psilophyton diakanthon sp. nov. from the Early Devonian of Gaspé (Quebec, Canada).

PREMISE: Trimerophytes are a plexus of early tracheophytes that form the base of the euphyllophyte clade and, thus, represent the link between the earliest land plants and modern-day ferns, sphenophytes, and seed plants. As the best-characterized trimerophyte, the genus Psilophyton occupies a key position in the euphyllophyte fossil record. We describe a new Psilophyton species that has implications for the evolution of plant-animal interactions. METHODS: The fossil material is preserved by permineralization in the Lower Devonian (Emsian) Battery Point Formation (Québec, Canada) and was studied in serial sections using the cellulose acetate peel technique. RESULTS: Psilophyton diakanthon sp. nov. differs from other Psilophyton species in possessing fibers that form a discontinuous layer in the inner cortex and two distinct types of spinescent emergences whose anatomy and morphology are consistent with roles in anti-herbivore defense. CONCLUSIONS: Psilophyton diakanthon adds another species to an already diverse genus. Its two morphologically distinct types of spinescence suggest that herbivory was rampant in plant-animal interactions and demonstrate that anti-herbivory defenses had reached a previously unrecognized level of sophistication by 400 million years ago, in the Early Devonian.

French health insurance data for chronic rhinosinusitis with nasal polyps between 2011 and 2018: A STROBE-compliant analysis.

AIMS: The main aim of the present study was to report the annual volume of surgeries performed for chronic rhinosinusitis with nasal polyps (CRSwNP) in France, based on health insurance data. The secondary objectives were to describe the different characteristics of the surgeries and their complications, and to estimate the number of patients eligible for biotherapy. MATERIAL AND METHODS: This was a descriptive observational retrospective study using data from French national health insurance databases for the period 2011-2018. Inclusion criteria comprised all hospital stays with procedures related to CRSwNP according to the French Common Classification of Medical Acts and consistent with French practices. RESULTS: Ninety-two thousand one hundred and fourty one patients (92,141) for 92,884 admissions for CRSwNP surgery were analyzed, providing an accurate representation of CRSwNP surgery in France between 2011 and 2018. The revision surgery rate for patients operated on in 2011 was 13.0% (1,457/11,212), corresponding to an average annual rate of 1.86% over 7 years. In the 11,750 sinus surgery admissions in 2018, the complications rate was only 0.65% (77/11,750). CONCLUSION: Sinus surgery is safe (0.65% complications) and reliable (estimated revision rate, 5.5%: 5,078/92,884). This study provides the first evaluation of the target population for biotherapy in France.