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Phase 3 studies in patients with chronic hepatitis B have shown tenofovir alafenamide to have non-inferior efficacy to tenofovir disoproxil fumarate, with improved renal and bone safety. We conducted this study to evaluate the safety and efficacy of switching to tenofovir alafenamide in participants with chronic hepatitis B and renal or hepatic impairment.

Direct-acting antivirals (DAAs) for hepatitis C virus (HCV) infection have delivered high response rates (>95%) and simplified the management of HCV treatment, permitting non-specialists to manage patients without advanced liver disease. We collected and reviewed global data on the registration and reimbursement (government subsidised) of HCV therapies, including restrictions on reimbursement. Primary data collection occurred between Nov 15, 2021, and July 24, 2023, through the assistance of a global network of 166 HCV experts. We retrieved data for 160 (77%) of 209 countries and juristrictions. By mid-2023, 145 (91%) countries had registered at least one of the following DAA therapies: sofosbuvir–velpatasvir, sofosbuvir–velpatasvir–voxilaprevir, glecaprevir–pibrentasvir, sofosbuvir–daclatasvir, or sofosbuvir. 109 (68%) countries reimbursed at least one DAA therapy. Among 102 low-income and middle-income countries (LMICs), 89 (87%) had registered at least one HCV DAA therapy and 53 (52%) reimbursed at least one DAA therapy. Among all countries with DAA therapy reimbursement (n=109), 66 (61%) required specialist prescribing, eight (7%) had retreatment restrictions, seven (6%) had an illicit drug use restriction, five (5%) had an alcohol use restriction, and three (3%) had liver disease restrictions. Global access to DAA reimbursement remains uneven, with LMICs having comparatively low reimbursement compared with high-income countries. To meet WHO goals for HCV elimination, efforts should be made to assist countries, particularly LMICs, to increase access to DAA reimbursement and remove reimbursement restrictions—especially prescriber-type restrictions—to ensure universal access.

The aim of the COSMIC-312 trial was to evaluate cabozantinib plus atezolizumab versus sorafenib in patients with previously untreated advanced hepatocellular carcinoma. In the initial analysis, cabozantinib plus atezolizumab significantly prolonged progression-free survival versus sorafenib. Here, we report the pre-planned final overall survival analysis and updated safety and efficacy results following longer follow-up.

Programmed cell death protein 1 (PD-1) inhibitors have modest efficacy as a monotherapy in hepatocellular carcinoma (HCC). A personalized therapeutic cancer vaccine (PTCV) may enhance responses to PD-1 inhibitors through the induction of tumor-specific immunity. We present results from a single-arm, open-label, phase 1/2 study of a DNA plasmid PTCV (GNOS-PV02) encoding up to 40 neoantigens coadministered with plasmid-encoded interleukin-12 plus pembrolizumab in patients with advanced HCC previously treated with a multityrosine kinase inhibitor. Safety and immunogenicity were assessed as primary endpoints, and treatment efficacy and feasibility were evaluated as secondary endpoints. The most common treatment-related adverse events were injection-site reactions, observed in 15 of 36 (41.6%) patients. No dose-limiting toxicities or treatment-related grade ≥3 events were observed. The objective response rate (modified intention-to-treat) per Response Evaluation Criteria in Solid Tumors 1.1 was 30.6% (11 of 36 patients), with 8.3% (3 of 36) of patients achieving a complete response. Clinical responses were associated with the number of neoantigens encoded in the vaccine. Neoantigen-specific T cell responses were confirmed in 19 of 22 (86.4%) evaluable patients by enzyme-linked immunosorbent spot assays. Multiparametric cellular profiling revealed active, proliferative and cytolytic vaccine-specific CD4+and CD8+effector T cells. T cell receptor β-chain (TCRβ) bulk sequencing results demonstrated vaccination-enriched T cell clone expansion and tumor infiltration. Single-cell analysis revealed posttreatment T cell clonal expansion of cytotoxic T cell phenotypes. TCR complementarity-determining region cloning of expanded T cell clones in the tumors following vaccination confirmed reactivity against vaccine-encoded neoantigens. Our results support the PTCV’s mechanism of action based on the induction of antitumor T cells and show that a PTCV plus pembrolizumab has clinical activity in advanced HCC. ClinicalTrials.gov identifier: NCT04251117.

Strongly attractive forces act between superhydrophobic surfaces across water due to the formation of a bridging gas capillary. Upon separation, the attraction can range up to tens of micrometers as the gas capillary grows, while gas molecules accumulate in the capillary. We argue that most of these molecules come from the pre-existing gaseous layer found at and within the superhydrophobic coating. In this study, we investigate how the capillary size and the resulting capillary forces are affected by the thickness of the gaseous layer. To this end, we prepared superhydrophobic coatings with different thicknesses by utilizing different numbers of coating cycles of a liquid flame spraying technique. Laser scanning confocal microscopy confirmed an increase in gas layer thickness with an increasing number of coating cycles. Force measurements between such coatings and a hydrophobic colloidal probe revealed attractive forces caused by bridging gas capillaries, and both the capillary size and the range of attraction increased with increasing thickness of the pre-existing gas layer. Hence, our data suggest that the amount of available gas at and in the superhydrophobic coating determines the force range and capillary growth.

Introduction: In March 2020, a pandemic state was declared due to SARS-COV-2 (COVID-19). Patients with kidney disease, especially those on replacement therapies, proved more susceptible to severe infection. This rapid literature review aims to help understand how the pandemic impacted patient experience of kidney care. Methods: It was conducted in accordance with Cochrane Rapid Review interim guidance. Search terms, ‘coronavirus’, ‘kidney care’, and ‘patient-reported experience’ and terms with similar semantic meaning, identified 1,117 articles in Medline, Scopus, and Worldwide Science. Seventeen were included in the narrative synthesis. Results: The findings were summarised into three themes: remote consultation and telemedicine (n= 9); psychosocial impact (n= 2); and patient satisfaction and patient-reported experience (n= 6). Patients were mostly satisfied with remote consultations, describing them as convenient and allowing avoidance of hospital visits. Anxieties included missing potentially important clinical findings due to lack of physical examination, poor digital literacy, and technical difficulties. Psychosocial impact differed between treatment modalities—transplant recipients expressing feelings of instability and dread of having to return to dialysis, and generally, were less satisfied, citing reduced ability to work and difficulty accessing medications. Those on home dialysis treatments tended to feel safer. Findings focused on aspects of patient experience of kidney care during the pandemic rather than a holistic view. Conclusions: There was little direct evaluation of modality differences and limited consideration of health inequalities in care experiences. A fuller understanding of these issues would guide policy agendas to support patient experience during future public health crises. Graphical abstract:

Skeletal muscle stem and progenitor cells including those derived from human pluripotent stem cells (hPSCs) offer an avenue towards personalized therapies and readily fuse to form human–mouse myofibres in vivo. However, skeletal muscle progenitor cells (SMPCs) inefficiently colonize chimeric stem cell niches and instead associate with human myofibres resembling foetal niches. We hypothesized competition with mouse satellite cells (SCs) prevented SMPC engraftment into the SC niche and thus generated an SC ablation mouse compatible with human engraftment. Single-nucleus RNA sequencing of SC-ablated mice identified the absence of a transient myofibre subtype during regeneration expressing Actc1. Similarly, ACTC1+human myofibres supporting PAX7+SMPCs increased in SC-ablated mice, and after re-injury we found SMPCs could now repopulate into chimeric niches. To demonstrate ACTC1+myofibres are essential to supporting PAX7 SMPCs, we generated caspase-inducible ACTC1 depletion human pluripotent stem cells, and upon SMPC engraftment we found a 90% reduction in ACTC1+myofibres and a 100-fold decrease in PAX7 cell numbers compared with non-induced controls. We used spatial RNA sequencing to identify key factors driving emerging human niche formation between ACTC1+myofibres and PAX7+SMPCs in vivo. This revealed that transient regenerating human myofibres are essential for emerging niche formation in vivo to support PAX7 SMPCs.

No adjuvant treatment has been established for patients who remain at high risk for hepatocellular carcinoma recurrence after curative-intent resection or ablation. We aimed to assess the efficacy of adjuvant atezolizumab plus bevacizumab versus active surveillance in patients with high-risk hepatocellular carcinoma.

A fundamental understanding of the interactions between mineral surfaces and amphiphilic surface modification agents is needed for better control over the production and uses of mineral fillers. Here, we controlled the carboxylic acid layer formation conditions on calcite surfaces with high precision via vapor deposition. The properties of the resulting carboxylic acid layers were analyzed using surface-sensitive techniques, such as atomic force microscopy (AFM), contact angle measurements, angle resolved X-ray photoelectron spectroscopy (XPS), and vibrational sum-frequency spectroscopy. A low wettability was achieved with long hydrocarbon chain carboxylic acids such as stearic acid. The stearic acid layer formed by vapor deposition is initially patchy, but with increasing vapor exposure time, the patches grow and condense into a homogeneous layer with a thickness close to that expected for a monolayer as evaluated by AFM and XPS. The build-up process of the layer occurs more rapidly at higher temperatures due to the higher vapor pressure. The stability of the deposited fatty acid layer in the presence of a water droplet increases with the chain length and packing density in the adsorbed layer. Vibrational sum frequency spectroscopy data demonstrate that the stearic acid monolayers on calcite have their alkyl chains in an all-trans conformation and are anisotropically distributed on the plane of the surface, forming epitaxial monolayers. Vibrational spectra also show that the stearic acid molecules interact with the calcite surface through the carboxylic acid headgroup in both its protonated and deprotonated forms. The results presented provide new molecular insights into the properties of adsorbed carboxylic acid layers on calcite.

Critical care outreach teams support ward staff to manage patients who are seriously ill or after discharge from the intensive care unit (ICU). Respiratory deterioration is a common reason for (re)admission to the ICU. Physiotherapists are health professionals with skills to address acute respiratory concerns. Experienced respiratory physiotherapists play a role in supporting junior clinicians, particularly in managing deteriorating patients on the ward.

Introduction:Intratumoral administration of pexa-vec (pexastimogene devacirepvec), an oncolytic and immunotherapeutic vaccinia virus, given to patients with hepatocellular carcinoma (HCC), is associated with both local and distant tumor responses. We hypothesized subsequent treatment with sorafenib could demonstrate superior efficacy. Methods:This random phase III open-label study evaluated the sequential treatment with pexa-vec followed by sorafenib compared to sorafenib in patients with advanced HCC and no prior systemic treatment. The primary endpoint is overall survival (OS). Key secondary endpoints included time to progression (TTP), progression-free survival, overall response rate (ORR), and disease control rate (DCR). Safety was assessed in all patients who received ≥1 dose of study treatment. Results:The study was conducted at 142 sites in 16 countries. From December 30, 2015, to the interim analysis on August 2, 2019, 459 patients were randomly assigned (pexa-vec plus sorafenib: 234, sorafenib: 225). At the interim analysis, the median OS was 12.7 months (95% CI: 9.89, 14.95) in the pexa-vec plus sorafenib arm and 14.0 months (95% CI: 11.01, 18.00) in the sorafenib arm. This led to the early termination of the study. The median TTP was 2.0 months (95% CI: 1.77, 2.96) and 4.2 months (95% CI: 2.92, 4.63); ORR was 19.2% (45 patients) and 20.9% (47 patients); and DCR was 50.0% (117 patients) and 57.3% (129 patients) in the pexa-vec plus sorafenib and sorafenib arms, respectively. Serious adverse events were reported in 117 (53.7%) patients in the pexa-vec plus sorafenib and 77 (35.5%) patients in the sorafenib arm. Liver failure was the most frequently reported in both groups. Conclusion:Sequential pexa-vec plus sorafenib treatment did not demonstrate increased clinical benefit in advanced HCC and fared worse compared to sorafenib alone. The advent of the added value of checkpoint inhibitors should direct any further development of oncolytic virus therapy strategies.

Since the release of the first global hepatitis elimination targets in 2016, and until the COVID-19 pandemic started in early 2020, many countries and territories were making progress toward hepatitis C virus (HCV) elimination. This study aims to evaluate HCV burden in 2020, and forecast HCV burden by 2030 given current trends.

ObjectivesTo determine the impact of a 12-week ergonomic/exercise programme compared with an ergonomic/health education programme on the development of neck pain in office workers over 12 months.MethodsThis cluster-randomised trial prospectively recruited office workers from public and private organisations. Only non-neck pain cases at baseline were included (n=484). All participants received an ergonomic workstation review then randomly allocated to receive a neck/shoulder progressive exercise programme (20 min, 3 ×/week; intervention group) or health education sessions (60 min, 1 ×/week; active control) for 12 weeks. Generalised estimating equations evaluated group differences in the point prevalence of neck pain cases (defined as those with a neck pain score of ≥3 on a 0 (no pain) to 9 (worst pain) scale) over time (3, 6, 9 and 12 months) with cumulative incidence of neck pain cases evaluated descriptively.ResultsWhile no significant group × time interaction was evident, the 12-month point prevalence of neck pain cases in the intervention group (10%) was half that of the active control group (20%) (adjusted OR 0.46, 95% CI 0.21 to 1.01, p=0.05). Lower cumulative incidence of neck pain cases was observed in the intervention (17%) compared with active control group (30%) over the 12 months.ConclusionsA combined ergonomics and exercise intervention may have more benefits in preventing neck pain cases in office workers than an ergonomic and health education intervention. Group differences were modest and should be interpreted with caution when considering strategies for primary prevention of neck pain in the office worker population.Trial registrationACTRN12612001154897

A profound understanding of the properties of unmodified and saturated fatty acid-modified calcite surfaces is essential for elucidating their resistance and stability in the presence of water droplets. Additional insights can be obtained by also studying the effects of carboxylic acid-saturated aqueous solutions. We elucidate surface wettability, structure, and nanomechanical properties beneath and at the edge of a deposited droplet after its evaporation. When calcite was coated by a highly packed monolayer of stearic acid, a hydrophilic region was found at the three-phase contact line. In atomic force microscopy mapping, this region is characterized by low adhesion and a topographical hillock. The surface that previously was covered by the droplet demonstrated a patchy structure of about 6 nm height, implying stearic acid reorganization into a patchy bilayer-like structure. Our data suggest that during droplet reverse dispensing and droplet evaporation, pinning of the three-phase contact line leads to the transport of dissolved fatty carboxylic acid and possibly calcium bicarbonate Ca(HCO3)2molecules to the contact line boundary. Compared to the surface of intrinsically hydrophobic materials, such as polystyrene, the changes in contact angle and base diameter during droplet evaporation on stearic acid-modified calcite are strikingly different. This difference is due to stearic acid reorganization on the surface and transport to the water–air interface of the droplet. An effect of the evaporating droplet is also observed on unmodified calcite due to dissolution and recrystallization of the calcite surface in the presence of water. In the case where a water droplet saturated with octanoic acid is used instead of water, the stearic acid-coated calcite remains considerably more stable. Our findings are discussed in terms of the coffee-ring effect.

Chronic rhinosinusitis with nasal polyps affects approximately 2–4% of the general population, and long-term use of systemic corticosteroids is associated with adverse effects. The aim of this study was to assess the efficacy and safety of mepolizumab in adults with recurrent, refractory severe bilateral chronic rhinosinusitis with nasal polyps.

Increasing beach sediment loss from erosion and high levels of crab Ocypodespp. predation are threatening turtle nests and nesting habitat. The 900 m long beach on Cousine Island, Seychelles, supports a nesting population of approximately 70–130 hawksbill turtle Eretmochelys imbricatanests each season. Seasonal and storm-related erosion and accretion cycles on Cousine Island have the potential of destroying 50% or more of all turtle egg clutches on the island in a single nesting season. Observed crab predation rates had reached 90–100% in preferred nesting beach zones in previous years. This has resulted in intensive management measures to minimise turtle egg and nest losses. We investigated the distribution and population density of ghost crabs and the morphology of the beach across the different beach area zones and across the turtle-nesting season during 2014–2015. Crab burrow numbers varied between beach zone areas and across the season and were highest on the backshore. Crab density correlated negatively with available beach area, and we found that crab density increased in the presence of turtle nests. When examining beach dynamics, we found them to be cyclical and found the nesting beach prone to higher levels of erosion than accretion with significant changes in beach width throughout the season. The mean vertical beach elevation drop on Cousine Island was higher than what hawksbill turtles have been reported to prefer. We suggest the continuation of beach elevation monitoring and management to use the beach morphology data to assist with hawksbill turtle nest translocations to minimise nest losses and maximise hatchling recruitment success.

RO7049389, a hepatitis B virus (HBV) core protein allosteric modulator being developed for the treatment of chronic HBV infection, was found to be safe and well tolerated in healthy participants (part 1 of this study). The objective of this proof-of-mechanism study (part 2) was to evaluate the safety, pharmacokinetics, and antiviral activity of RO7049389 in patients with chronic HBV infection.

Understanding the wear of mineral fillers is crucial for controlling industrial processes, and in the present work, we examine the wear resistance and nanomechanical properties of bare calcite and stearic acid-modified calcite surfaces under dry and humid conditions at the nanoscale. Measurements under different loads allow us to probe the situation in the absence and presence of abrasive wear. The sliding motion is in general characterized by irregular stick-slip events that at higher loads lead to abrasion of the brittle calcite surface. Bare calcite is hydrophilic, and under humid conditions, a thin water layer is present on the surface. This water layer does not affect the friction force. However, it slightly decreases the wear depth and strongly influences the distribution of wear particles. In contrast, stearic acid-modified surfaces are hydrophobic. Nevertheless, humidity affects the wear characteristics by decreasing the binding strength of stearic acid at higher humidity. A complete monolayer coverage of calcite by stearic acid results in a significant reduction in wear but only a moderate reduction in friction forces at low humidity and no reduction at 75% relative humidity (RH). Thus, our data suggest that the wear reduction does not result from a lowering of the friction force but rather from an increased ductility of the surface region as offered by the stearic acid layer. An incomplete monolayer of stearic acid on the calcite surface provides no reduction in wear regardless of the RH investigated. Clearly, the wear properties of modified calcite surfaces depend crucially on the packing density of the surface modifier and also on the air humidity.

Les différentes études sur les complications de l'AMP sont plutôt rassurantes et montrent des taux de complications relativement faibles, mais seules quelques études ont été menées à partir de registres exhaustifs et le dispositif d'AMP vigilance n'étant pas une source d'information exhaustive, il ne permet pas d'avoir une vue complète des complications post-AMP.

En France, en 2021, 162 441 tentatives d'assistance médicale à la procréation (AMP) ont été réalisées. On observe une augmentation du nombre de femmes prises en charges et du nombre d'enfants nés d'AMP. Le suivi à long terme de l'état de santé de ces populations représente un enjeu majeur de santé publique. Le Système national des données de santé français (SNDS) permet de réaliser un suivi à long terme de cette population. Notre objectif est de décrire les populations de la cohorte FERTICOH.

Background Pharmacokinetics and safety of JNJ-64530440, a hepatitis B virus capsid assembly modulator producing normal empty capsids (CAM-N), in healthy volunteers were evaluated.Methods This Phase I study (NCT03439488) was a double-blind, randomised, placebo-controlled study. Adults (n= 10/cohort, five Asian/five non-Asian), randomised 4:1, received single-ascending doses of oral JNJ-64530440 (first- and second-generation formulations) or placebo under fasted (50, 150, 300 and 900 mg) or fed (300, 750, 1,000, 2000 and 4000 mg) conditions. Multiple-ascending doses of 750 or 2000 mg once daily and 750 mg twice daily JNJ-64530440 (second-generation formulation) for 7 days were evaluated. Pharmacokinetic parameters were estimated from plasma concentrations. Safety was assessed throughout.Results Less than dose-proportional increases in maximum plasma concentrations (Cmax) and area under the plasma concentration–time curves (AUCs) were observed across the doses. Mean plasma half-lives ranged from 9.3 to 14.5 h. Cmaxand AUC were ∼two fold higher under fed versus fasting conditions and slightly higher in Asians versus Caucasians. JNJ-64530440 doses ≥750 mg achieved plasma levels higher than protein-binding adjusted concentrations demonstrating in vitroantiviral activity. No serious adverse events (AEs), treatment discontinuations or dose-limiting toxicities were seen. AE frequency/severity did not increase with dose.Conclusions Single (up to 4000 mg) and multiple doses (up to 2000 mg for 7 days) of JNJ-64530440 were well tolerated in healthy volunteers. Multiple doses ≥750 mg/day achieved plasma concentrations expected to have antiviral activity that may lower hepatitis B surface antigen. No clinically relevant differences in tolerability or pharmacokinetic parameters were seen between Asians versus Caucasians.

The rheological behavior of aqueous suspensions of lignocellulose nanofibrils (LCNFs) is investigated systematically by considering the coupled effect of residual lignin and LCNF morphology. The LCNF was obtained by high-energy fluidization of TEMPO-oxidized mechanical fibers, followed by size fractionation (fibril widths of ∼5, ∼9, and ∼18 nm). The nanofibril width and the corresponding fibril–fibril interactions are strongly influenced by the presence and distribution of lignin in the respective fractions, either retained on the fibril surface or as free structures present in the finest size fraction. All samples containing lignin display dilatancy, typifying gel suspensions with aggregated hydrophobic particles. Fine fractionated samples display strong gel behavior. The coarse fractionated sample, by contrast, shows a greater tendency to flocculate viaentanglement and displays less gel-like characteristics; hence, it dewaters more freely.

There is a medical need for highly effective, safe, and well tolerated treatments for patients infected with hepatitis C virus (HCV) with severe renal impairment. We investigated the safety and efficacy of sofosbuvir with ribavirin or ledipasvir combined with sofosbuvir in a prospective study of patients with genotype 1 or 3 HCV infection and stage 4–5 chronic kidney disease (creatinine clearance by Cockcroft-Gault ≤30 mL/min) who were not on dialysis.

The COVID-19 pandemic has spread rapidly worldwide. It is common to encounter patients with COVID-19 with abnormal liver function, either in the form of hepatitis, cholestasis, or both. The clinical implications of liver derangement might be variable in different clinical scenarios. With growing evidence of its clinical significance, it would be clinically helpful to provide practice recommendations for various common clinical scenarios of liver derangement during the COVID-19 pandemic. The Asia-Pacific Working Group for Liver Derangement during the COVID-19 Pandemic was formed to systematically review the literature with special focus on the clinical management of patients who have been or who are at risk of developing liver derangement during this pandemic. Clinical scenarios covering the use of pharmacological treatment for COVID-19 in the case of liver derangement, and assessment and management of patients with chronic hepatitis B or hepatitis C, non-alcoholic fatty liver disease, liver cirrhosis, and liver transplantation during the pandemic are discussed.

Mycosis fungoides (MF) is a slowly progressive cutaneous T-cell lymphoma (CTCL) for which there is no cure. In the early plaque stage, the disease is indolent, but development of tumors heralds an increased risk of metastasis and death. Previous research into the genomic landscape of CTCL revealed a complex pattern of >50 driver mutations implicated in more than a dozen signaling pathways. However, the genomic mechanisms governing disease progression and treatment resistance remain unknown. Building on our previous discovery of the clonotypic heterogeneity of MF, we hypothesized that this lymphoma does not progress in a linear fashion as currently thought but comprises heterogeneous mutational subclones. We sequenced exomes of 49 cases of MF and identified 28 previously unreported putative driver genes. MF exhibited extensive intratumoral heterogeneity (ITH) of a median of 6 subclones showing a branched phylogenetic relationship pattern. Stage progression was correlated with an increase in ITH and redistribution of mutations from stem to clades. The pattern of clonal driver mutations was highly variable, with no consistent mutations among patients. Similar intratumoral heterogeneity was detected in leukemic CTCL (Sézary syndrome). Based on these findings, we propose a model of MF pathogenesis comprising divergent evolution of cancer subclones and discuss how ITH affects the efficacy of targeted drug therapies and immunotherapies for CTCL.

Mycosis fungoides (MF) is a slowly progressive cutaneous T-cell lymphoma (CTCL) for which there is no cure. In the early plaque stage, the disease is indolent, but development of tumors heralds an increased risk of metastasis and death. Previous research into the genomic landscape of CTCL revealed a complex pattern of >50 driver mutations implicated in more than a dozen signaling pathways. However, the genomic mechanisms governing disease progression and treatment resistance remain unknown. Building on our previous discovery of the clonotypic heterogeneity of MF, we hypothesized that this lymphoma does not progress in a linear fashion as currently thought but comprises heterogeneous mutational subclones. We sequenced exomes of 49 cases of MF and identified 28 previously unreported putative driver genes. MF exhibited extensive intratumoral heterogeneity (ITH) of a median of 6 subclones showing a branched phylogenetic relationship pattern. Stage progression was correlated with an increase in ITH and redistribution of mutations from stem to clades. The pattern of clonal driver mutations was highly variable, with no consistent mutations among patients. Similar intratumoral heterogeneity was detected in leukemic CTCL (Sézary syndrome). Based on these findings, we propose a model of MF pathogenesis comprising divergent evolution of cancer subclones and discuss how ITH affects the efficacy of targeted drug therapies and immunotherapies for CTCL.

Background Selgantolimod is a novel oral, selective Toll-like receptor 8 (TLR8) agonist in development for the treatment of chronic hepatitis B (CHB). TLR8 is an endosomal innate immune receptor and a target for treatment of viral infections. This first-in-human study investigated the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of selgantolimod in healthy volunteers.Methods Of 71 subjects enrolled, 59 received a single dose of selgantolimod (0.5, 1.5, 3 or 5 mg) or placebo, and 12 were evaluated for food effect. Safety, PK and PD activity by induction of cytokines, chemokines and acute phase proteins were assessed. PK/PD analyses were conducted.Results Single doses of 0.5–5 mg were generally safe. No serious adverse events (AEs) or AEs leading to discontinuation were reported, and most were Grade 1 in severity. Selgantolimod displayed rapid absorption and dose-proportional PK and PD activity. Food had minimal effect on PK but resulted in diminished PD activity. In PK/PD analyses, near-saturation of induction for most evaluated biomarkers occurred at the 5-mg dose.Conclusions Single doses of up to 5 mg selgantolimod were safe and induced dose-dependent PD responses. These data support evaluation of selgantolimod in combination with other agents in future clinical studies of CHB. Australian New Zealand Clinical Trials Registration: ACTRN12616001646437.

Hornworts comprise a bryophyte lineage that diverged from other extant land plants >400 million years ago and bears unique biological features, including a distinct sporophyte architecture, cyanobacterial symbiosis and a pyrenoid-based carbon-concentrating mechanism (CCM). Here, we provide three high-quality genomes of Anthoceroshornworts. Phylogenomic analyses place hornworts as a sister clade to liverworts plus mosses with high support. The Anthocerosgenomes lack repeat-dense centromeres as well as whole-genome duplication, and contain a limited transcription factor repertoire. Several genes involved in angiosperm meristem and stomatal function are conserved in Anthocerosand upregulated during sporophyte development, suggesting possible homologies at the genetic level. We identified candidate genes involved in cyanobacterial symbiosis and found that LCIB, a ChlamydomonasCCM gene, is present in hornworts but absent in other plant lineages, implying a possible conserved role in CCM function. We anticipate that these hornwort genomes will serve as essential references for future hornwort research and comparative studies across land plants.

Plants are the foundation of terrestrial ecosystems, and their colonization of land was probably facilitated by mutualistic associations with arbuscular mycorrhizal fungi. Following this founding event, plant diversification has led to the emergence of a tremendous diversity of mutualistic symbioses with microorganisms, ranging from extracellular associations to the most intimate intracellular associations, where fungal or bacterial symbionts are hosted inside plant cells. Here, through analysis of 271 transcriptomes and 116 plant genomes spanning the entire land-plant diversity, we demonstrate that a common symbiosis signalling pathway co-evolved with intracellular endosymbioses, from the ancestral arbuscular mycorrhiza to the more recent ericoid and orchid mycorrhizae in angiosperms and ericoid-like associations of bryophytes. By contrast, species forming exclusively extracellular symbioses, such as ectomycorrhizae, and those forming associations with cyanobacteria, have lost this signalling pathway. This work unifies intracellular symbioses, revealing conservation in their evolution across 450 million yr of plant diversification.

Therapies with novel mechanisms of action against hepatitis B virus (HBV) infection are being explored with the goal of achieving a functional cure (sustained off-treatment response) without requiring lifelong therapy. We aimed to evaluate the pharmacokinetics, safety, and antiviral activity of ABI-H0731, an investigational inhibitor of the HBV core protein.

Mounting evidence suggests that terrestrialization of plants started in streptophyte green algae, favoured by their dual existence in freshwater and subaerial/terrestrial environments. Here, we present the genomes of Mesostigma virideand Chlorokybus atmophyticus, two sister taxa in the earliest-diverging clade of streptophyte algae dwelling in freshwater and subaerial/terrestrial environments, respectively. We provide evidence that the common ancestor of M. virideand C. atmophyticus(and thus of streptophytes) had already developed traits associated with a subaerial/terrestrial environment, such as embryophyte-type photorespiration, canonical plant phytochrome, several phytohormones and transcription factors involved in responses to environmental stresses, and evolution of cellulose synthase and cellulose synthase-like genes characteristic of embryophytes. Both genomes differed markedly in genome size and structure, and in gene family composition, revealing their dynamic nature, presumably in response to adaptations to their contrasting environments. The ancestor of M. viridepossibly lost several genomic traits associated with a subaerial/terrestrial environment following transition to a freshwater habitat.

BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease which presents a grave prognosis for diagnosed patients. Nintedanib (a triple tyrosine kinase inhibitor) and pirfenidone (unclear mechanism of action) are the only approved therapies for IPF, but have limited efficacy. The pathogenic mechanisms of this disease are not fully elucidated; however, a role for mast cells (MCs) has been postulated.ObjectivesThe aim of this work was to investigate a role for MCs in IPF and to understand whether nintedanib or pirfenidone could impact MC function.Methods and resultsMCs were significantly elevated in human IPF lung and negatively correlated with baseline lung function (FVC). Importantly, MCs were positively associated with the number of fibroblast foci, which has been linked to increased mortality. Furthermore, MCs were increased in the region immediately surrounding the fibroblast foci, and co-culture studies confirmed a role for MC–fibroblast crosstalk in fibrosis. Nintedanib but not pirfenidone inhibited recombinant stem cell factor (SCF)–induced MC survival. Further evaluation of nintedanib determined that it also inhibited human fibroblast-mediated MC survival. This was likely via a direct effect on ckit (SCF receptor) since nintedanib blocked SCF-stimulated ckit phosphorylation, as well as downstream effects on MC proliferation and cytokine release. In addition, nintedanib ablated the increase in lung MCs and impacted high tissue density frequency (HDFm) in a rat bleomycin model of lung fibrosis.ConclusionNintedanib inhibits MC survival and activation and thus provides a novel additional mechanism by which this drug may exert anti-fibrotic effects in patients with IPF.

Background Physical activity has health benefits for adults with acquired brain injury, but it is a challenge to increase physical activity during inpatient rehabilitation. The objectives of this pilot study were to determine whether a physiotherapy-supervised inpatient walking program was feasible and able to improve physical activity and sedentary behaviour in the short and medium term. Methods Adults with acquired brain injury receiving inpatient rehabilitation undertook twice-weekly supervised walks plus behavioural therapy for 4 weeks. Feasibility was measured via recruitment, participation and drop out rates, adverse events and intervention delivery costs. Physical activity and sedentary behaviour were measured with an activPAL. Assessments were conducted at baseline, post-intervention and 3–6 months post-intervention. Results The program was safe to deliver (no adverse events), recruitment rate was 55% (16/29) and the participation rate for eligible individuals was high (14/19, 74%). However, the program had a high drop out rate (7/16, 44%) and physical activity and sedentary behaviour did not significantly change during the 4-week intervention. Costs were AU$427.71/participant. Physical activity and sedentary behaviour did improve 3–6 months after the intervention (vs baseline, on average: +3913 steps per day, 95% CI: 671, 7156). Conclusion This pilot study demonstrated a supervised physiotherapy walking program is safe and feasible to recruit in an inpatient setting. However, drop out during the study was high and behaviour change did not occur. More work is required to boost physical activity during sub-acute rehabilitation for acquired brain injury.

Mycosis fungoides (MF) is a mature T-cell lymphoma currently thought to develop primarily in the skin by a clonal expansion of a transformed, resident memory T cell. However, this concept does not explain the key characteristics of MF, such as the debut with multiple, widespread skin lesions or inability of skin-directed therapies to provide cure. The testable inference of the mature T-cell theory is the clonality of MF with respect to all rearranged T-cell receptor (TCR) genes. Here, we used a whole-exome sequencing approach to detect and quantify TCR-a, ß, and ? clonotypes in tumor cell clusters microdissected from MF lesions. This method allowed us to calculate the tumor cell fraction of the sample and therefore an unequivocal identification of the TCR clonotypes as neoplastic. Analysis of TCR sequences from 29 patients with MF stage I to IV proved the existence of multiple T-cell clones within the tumor cell fraction, with a considerable variation between patients and between lesions from the same patient (median, 11 clones; range, 2-80 clones/sample). We have also detected multiple neoplastic clones in the peripheral blood in all examined patients. Based on these findings, we propose that circulating neoplastic T-cell clones continuously replenish the lesions of MF, thus increasing their heterogeneity by a mechanism analogous to the consecutive tumor seeding. We hypothesize that circulating neoplastic clones might be a promising target for therapy and could be exploited as a potential biomarker in MF.

Mycosis fungoides (MF) is a mature T-cell lymphoma currently thought to develop primarily in the skin by a clonal expansion of a transformed, resident memory T cell. However, this concept does not explain the key characteristics of MF, such as the debut with multiple, widespread skin lesions or inability of skin-directed therapies to provide cure. The testable inference of the mature T-cell theory is the clonality of MF with respect to all rearranged T-cell receptor (TCR) genes. Here, we used a whole-exome sequencing approach to detect and quantify TCR-α, β, and γ clonotypes in tumor cell clusters microdissected from MF lesions. This method allowed us to calculate the tumor cell fraction of the sample and therefore an unequivocal identification of the TCR clonotypes as neoplastic. Analysis of TCR sequences from 29 patients with MF stage I to IV proved the existence of multiple T-cell clones within the tumor cell fraction, with a considerable variation between patients and between lesions from the same patient (median, 11 clones; range, 2-80 clones/sample). We have also detected multiple neoplastic clones in the peripheral blood in all examined patients. Based on these findings, we propose that circulating neoplastic T-cell clones continuously replenish the lesions of MF, thus increasing their heterogeneity by a mechanism analogous to the consecutive tumor seeding. We hypothesize that circulating neoplastic clones might be a promising target for therapy and could be exploited as a potential biomarker in MF.

Superhydrophobic surfaces in the Cassie–Baxter wetting state retain an air layer at the surface which prevents liquid water from reaching into the porous surface structure. In this work we explore how addition of ethanol, which reduces the surface tension, influences the wetting properties of superhydrophobic and smooth hydrophobic surfaces. Wetting properties are measured by dynamic contact angles, and the air layer at the superhydrophobic surface is visualized by laser scanning confocal microscopy. Colloidal probe atomic force microscopy measurements between a hydrophobic microsphere and the macroscopic surfaces showed that the presence of ethanol strongly affects the interaction forces. When the macroscopic surface is superhydrophobic, attractive forces extending up to a few micrometers are observed on retraction in water and in 20 vol % ethanol, signifying the presence of a large and growing gas capillary. Submicrometer attractive forces are observed between the probe particle and a smooth hydrophobic surface, and in this case a smaller gas capillary is formed. Addition of ethanol results in markedly different effects between superhydrophobic and hydrophobic surfaces. In particular, we show that the receding contact angle on the superhydrophobic surface is of paramount importance for describing the interaction forces.

On one hand, a large class of inequality measures, which includes the generalized entropy, the Atkinson, the Gini, etc., for example, has been introduced in P.D. Mergane, G.S. Lo, Appl. Math. 4 (2013), 986–1000. On the other hand, the influence function (IF) of statistics is an important tool in the asymptotics of a nonparametric statistic. This function has been and is being determined and analyzed in various aspects for a large number of statistics. We proceed to a unifying study of the IFof all the members of the so-called Theil-like family and regroup those IF’s in one formula. Comparative studies become easier.

In the two previous papers of this series, the main results on the asymptotic behaviors of empirical divergence measures based on wavelets theory have been established and particularized for important families of divergence measures like Rényi and Tsallis families and for the Kullback-Leibler measures. While the proofs of the results in the second paper may be skipped, the proofs of those in paper 1 are to be thoroughly proved since they serve as a foundation to the whole structure of results. We prove them in this last paper of the series. We will also address the applicability of the results to usual distribution functions.

Nano-lignocellulose (NLC) and lignin-free nanocellulose (nano-holocellulose, NHC) were used in paper coating to investigate their effect on coating layer quality and offset printing. The NLC was produced by microfluidisation of unbleached secondary fibres while the reference NHC was obtained from the same fibre source after lignin removal (OHEPH bleaching), following the same mechanical process. TEMPO-mediated oxidation of the fibres prior to microfluidisation was applied to increase the electrostatic charge and hydrophilicity of the nanofibrils. The coatings, displaying given surface morphology and energy, were applied on Kraft, printing-grade papers at three grammage levels. The structure of the coated and uncoated (reference) papers were accessed (SEM and AFM) and IGT printing was carried out to determine the print density, print gloss, rub-off resistance, surface energy, roughness, ink transfer, dry pick resistance, water interference and set-off. The results highlight the important effect of residual lignin or type of nanocellulose on the coating layer and the development of offset printing properties. It was observed that roughness was a key factor leading to a deterioration of the print properties, predominantly affecting the NLC coating. Considering the lower hydrophilicity of NLC, an alternative dispersion with water-alcohol mixtures is proposed. By using this dispersing medium, tailorable surface coverage, surface smoothness, ink acceptance and improved printability was achieved. We show that under these conditions and compared to NHC, NLC is equally effective as a coating layer.

Mycosis fungoides (MF), the most common type of cutaneous T-cell lymphoma, is believed to represent a clonal expansion of a transformed skin-resident memory T cell. T-cell receptor (TCR) clonality (ie, identical sequences of rearranged TCRα, TCRβ, and TCRγ), the key premise of this hypothesis, has been difficult to document conclusively because malignant cells are not readily distinguishable from the tumor-infiltrating reactive lymphocytes that contribute to the TCR clonotypic repertoire of MF. Here, we have successfully adopted targeted whole-exome sequencing (WES) to identify the repertoire of rearranged TCR genes in tumor-enriched samples from patients with MF. Although some of the investigated MF biopsies had the expected frequency of monoclonal rearrangements of TCRγ corresponding to that of tumor cells, the majority of the samples presented multiple TCRγ, TCRα, and TCRβ clonotypes by WES. Our findings are compatible with the model in which the initial malignant transformation in MF does not occur in mature memory T cells but rather at the level of T-lymphocyte progenitors before TCRβ or TCRα rearrangements. We have also shown that WES can be combined with whole-transcriptome sequencing in the same sample, which enables comprehensive characterization of the TCR repertoire in relation to tumor content. WES/whole-transcriptome sequencing might be applicable to other types of T-cell lymphomas to determine clonal dominance and clonotypic heterogeneity in these malignancies.

Mycosis fungoides (MF), the most common type of cutaneous T-cell lymphoma, is believed to represent a clonal expansion of a transformed skin-resident memory T cell. T-cell receptor (TCR) clonality (ie, identical sequences of rearranged TCRα, TCRβ, and TCRγ), the key premise of this hypothesis, has been difficult to document conclusively because malignant cells are not readily distinguishable from the tumor-infiltrating reactive lymphocytes that contribute to the TCR clonotypic repertoire of MF. Here, we have successfully adopted targeted whole-exome sequencing (WES) to identify the repertoire of rearranged TCR genes in tumor-enriched samples from patients with MF. Although some of the investigated MF biopsies had the expected frequency of monoclonal rearrangements of TCRγ corresponding to that of tumor cells, the majority of the samples presented multiple TCRγ, TCRα, and TCRβ clonotypes by WES. Our findings are compatible with the model in which the initial malignant transformation in MF does not occur in mature memory T cells but rather at the level of T-lymphocyte progenitors before TCRβ or TCRα rearrangements. We have also shown that WES can be combined with whole-transcriptome sequencing in the same sample, which enables comprehensive characterization of the TCR repertoire in relation to tumor content. WES/whole-transcriptome sequencing might be applicable to other types of T-cell lymphomas to determine clonal dominance and clonotypic heterogeneity in these malignancies.

Effective and well tolerated nucleos(t)ide analogue treatment exists for patients with chronic hepatitis B, although treatment is generally anticipated to be life-long, with concomitant costs and treatment-related side-effects. We aimed to characterise the outcomes of patients with persistent viral suppression who discontinued nucleotide analogue use after extended treatment.

ABSTRACTThe mechanisms of efficacy for fecal microbiota transplantation (FMT) in treating recurrent Clostridioides difficileinfection (rCDI) remain poorly defined, with restored gut microbiota-bile acid interactions representing one possible explanation. Furthermore, the potential implications for host physiology of these FMT-related changes in gut bile acid metabolism are also not well explored. In this study, we investigated the impact of FMT for rCDI upon signalling through the farnesoid X receptor (FXR)-fibroblast growth factor (FGF) pathway. Herein, we identify that in addition to restoration of gut microbiota and bile acid profiles, FMT for rCDI is accompanied by a significant, sustained increase in circulating levels of FGF19 and reduction in FGF21. These FGF changes were associated with weight gain post-FMT, to a level not exceeding the pre-rCDI baseline. Collectively, these data support the hypothesis that the restoration of gut microbial communities by FMT for rCDI is associated with an upregulated FXR-FGF pathway, and highlight the potential systemic effect of FMT.

The formation of a bridging gas meniscus viacavitation or nanobubbles is considered the most likely origin of the submicrometer long-range attractive forces measured between hydrophobic surfaces in aqueous solution. However, the dynamics of the formation and evolution of the gas meniscus is still under debate, in particular, in the presence of a thin air layer on a superhydrophobic surface. On superhydrophobic surfaces the range can even exceed 10 μm. Here, we report microscopic images of the formation and growth of a gas meniscus during force measurements between a superhydrophobic surface and a hydrophobic microsphere immersed in water. This is achieved by combining laser scanning confocal microscopy and colloidal probe atomic force microscopy. The configuration allows determination of the volume and shape of the meniscus, together with direct calculation of the Young–Laplace capillary pressure. The long-range attractive interactions acting on separation are due to meniscus formation and volume growth as air is transported from the surface layer.

Viral hepatitis is a major public health threat and a leading cause of death worldwide. Annual mortality from viral hepatitis is similar to that of other major infectious diseases such as HIV and tuberculosis. Highly effective prevention measures and treatments have made the global elimination of viral hepatitis a realistic goal, endorsed by all WHO member states. Ambitious targets call for a global reduction in hepatitis-related mortality of 65% and a 90% reduction in new infections by 2030. This Commission draws together a wide range of expertise to appraise the current global situation and to identify priorities globally, regionally, and nationally needed to accelerate progress. We identify 20 heavily burdened countries that account for over 75% of the global burden of viral hepatitis. Key recommendations include a greater focus on national progress towards elimination with support given, if necessary, through innovative financing measures to ensure elimination programmes are fully funded by 2020. In addition to further measures to improve access to vaccination and treatment, greater attention needs to be paid to access to affordable, high-quality diagnostics if testing is to reach the levels needed to achieve elimination goals. Simplified, decentralised models of care removing requirements for specialised prescribing will be required to reach those in need, together with sustained efforts to tackle stigma and discrimination. We identify key examples of the progress that has already been made in many countries throughout the world, demonstrating that sustained and coordinated efforts can be successful in achieving the WHO elimination goals.

ObjectiveSorafenib is the standard systemic therapy for advanced hepatocellular carcinoma (HCC). Survival benefits of resection/local ablation for early HCC are compromised by 70% 5-year recurrence rates. The phase 3 STORM trial comparing sorafenib with placebo as adjuvant treatment did not achieve its primary endpoint of improving recurrence-free survival (RFS). The biomarker companion study BIOSTORM aims to define (A) predictors of recurrence prevention with sorafenib and (B) prognostic factors with B level of evidence.DesignTumour tissue from 188 patients randomised to receive sorafenib (83) or placebo (105) in the STORM trial was collected. Analyses included gene expression profiling, targeted exome sequencing (19 known oncodrivers), immunohistochemistry (pERK, pVEGFR2, Ki67), fluorescence in situ hybridisation (VEGFA) and immunome. A gene signature capturing improved RFS in sorafenib-treated patients was generated. All 70 RFS events were recurrences, thus time to recurrence equalled RFS. Predictive and prognostic value was assessed using Cox regression models and interaction test.ResultsBIOSTORM recapitulates clinicopathological characteristics of STORM. None of the biomarkers tested (related to angiogenesis and proliferation) or previously proposed gene signatures, or mutations predicted sorafenib benefit or recurrence. A newly generated 146-gene signature identifying 30% of patients captured benefit to sorafenib in terms of RFS (p of interaction=0.04). These sorafenib RFS responderswere significantly enriched in CD4+T, B and cytolytic natural killer cells, and lacked activated adaptive immune components. Hepatocytic pERK (HR=2.41; p=0.012) and microvascular invasion (HR=2.09; p=0.017) were independent prognostic factors.ConclusionIn BIOSTORM, only hepatocytic pERK and microvascular invasion predicted poor RFS. No mutation, gene amplification or previously proposed gene signatures predicted sorafenib benefit. A newly generated multigene signature associated with improved RFS on sorafenib warrants further validation.Trial registration numberNCT00692770.