A model to assess the environmental and economic impacts of municipal waste management in Europe.

The Monitoring Framework proposed in the EU27 New Circular Economy Action Plan comprises two mass-based indicators, namely overall recycling rate and recycling rate for specific waste streams. Yet, to monitor and assess the impacts of circular economy, indicators cannot be limited to mass-based indicators; we argue assessments should also include environmental and economic effects. Towards this end, these impacts can be quantified by an advanced model based on life cycle thinking, entailing the use of life cycle assessment and costing (LCA/LCC). Calculating these effects for municipal waste management is challenging due to gaps in available data for estimating generated waste. We propose a methodology to estimate more finely the amounts of waste generated in the Member States, complemented with LCA/LCC. The results highlight that important inconsistencies in municipal waste data reporting exist and that recycling rates calculated from these are lower than hitherto estimated. The impacts quantification shows great performance variation across EU27, with C-footprint ranging from -490 to 539 kg CO2-eq. t-1. Potentials for improvement are substantial and can bring up to 103 Mt CO2-eq. additional annual saving, reducing costs (calculated as Full Environmental LCC) of waste management by 8.4 billion EUR and bringing 206,100 new jobs in the sector. The approach presented highlights the rationale for improved data management on waste statistics and the potential for harmonised models. It also paves the way for more sophisticated impact analyses relevant for policymaking, by bringing a richer perspective to the environmental and economic impacts of waste management on top of tracking generated, collected and recycled waste flows.

The effects of acute normobaric hypoxia on vestibular-evoked balance responses in humans.

BACKGROUND: Hypoxia influences standing balance and vestibular function. OBJECTIVE: The purpose here was to investigate the effect of hypoxia on the vestibular control of balance. METHODS: Twenty participants (10 males; 10 females) were tested over two days (normobaric hypoxia and normoxia). Participants stood on a force plate (head rotated leftward) and experienced random, continuous electrical vestibular stimulation (EVS) during trials of eyes open (EO) and closed (EC) at baseline (BL), after 5 (H1), 30 (H2) and 55-min (H3) of hypoxia, and 10-min into normoxic recovery (NR). Vestibular-evoked balance responses were quantified using cumulant density, coherence, and gain functions between EVS and anteroposterior forces. RESULTS: Oxyhemoglobin saturation, end-tidal oxygen and carbon dioxide decreased for H1-3 compared to BL; however, end-tidal carbon dioxide remained reduced at NR with EC (p≤0.003). EVS-AP force peak-to-peak amplitude was lower at H3 and NR than at BL (p≤0.01). At multiple frequencies, EVS-AP force coherence and gain estimates were lower at H3 and NR than BL for females; however, this was only observed for coherence for males. CONCLUSIONS: Overall, vestibular-evoked balance responses are blunted following normobaric hypoxia >30 min, which persists into NR and may contribute to the reported increases in postural sway.

Genomic loci associated with performance limiting equine overriding spinous processes (kissing spines).

Commonly known as "Kissing Spines" (KS), the pathological mechanisms underlying impingement and overriding of spinous processes (ORSPs) in horses are poorly understood. Thoroughbreds, Warmbloods, and stock-type breeds, including Paint Horses and Quarter Horses are at increased risk for developing clinical signs of KS. A total of 155 stock-type and Warmblood horses presented at collaborating veterinary clinics and hospitals were examined using a strict clinical and radiographical phenotyping scheme to grade each horse from 0 for unaffected controls to 4 for severe KS. Following genotyping with the Illumina Equine SNP70 array (Illumina, Inc.) a Genome Wide Association Study (GWAS) using 61,229 filtered individual Single Nucleotide Polymorphisms (SNPs) was performed to the KS grade phenotype. Two significantly associated SNPs (BIEC2-668062 and BIEC2-668013) on chromosome 25 defined a ~1.4 Gb candidate region containing approximately 17 coding genes (EquCab3) and 195 ENSEMBL annotated variants. Investigation of the best associated SNP (BIEC2-668062) on chr25 demonstrates a significant correlation with an increase in one KS grade, on average, per A allele in this population. A significant effect of breed group, age, height or sex was not observed in this population. These preliminary results demonstrate the potential for KS diagnosis and preventative measures for WB/ST individuals supported by increased genetic risk for more severe KS grade. We propose further research including other affected breeds and evaluating causative variants, as well as the effect of BIEC2-668062 in these populations.

Exploring fungal RiPPs from the perspective of chemical ecology.

Since the initial detection, in 2007, of fungal ribosomally synthesised and post-translationally modified peptides (RiPPs), this group of natural products has undergone rapid expansion, with four separate classes now recognised: amatoxins/phallotoxins, borosins, dikaritins, and epichloëcyclins. Largely due to their historically anthropocentric employment in medicine and agriculture, novel fungal proteins and peptides are seldom investigated in relation to the fungus itself. Therefore, although the benefits these compounds confer to humans are often realised, their evolutionary advantage to the fungus, the reason for their continued production, is often obscure or ignored. This review sets out to summarise current knowledge on how these small peptide-derived products influence their producing species and surrounding biotic environment.

Erector spinae plane block vs. peri-articular injection for pain control after arthroscopic shoulder surgery: a randomised controlled trial.

Interscalene brachial plexus block is the standard regional analgesic technique for shoulder surgery. Given its adverse effects, alternative techniques have been explored. Reports suggest that the erector spinae plane block may potentially provide effective analgesia following shoulder surgery. However, its analgesic efficacy for shoulder surgery compared with placebo or local anaesthetic infiltration has never been established. We conducted a randomised controlled trial to compare the analgesic efficacy of pre-operative T2 erector spinae plane block with peri-articular infiltration at the end of surgery. Sixty-two patients undergoing arthroscopic shoulder repair were randomly assigned to receive active erector spinae plane block with saline peri-articular injection (n = 31) or active peri-articular injection with saline erector spinae plane block (n = 31) in a blinded double-dummy design. Primary outcome was resting pain score in recovery. Secondary outcomes included pain scores with movement; opioid use; patient satisfaction; adverse effects in hospital; and outcomes at 24 h and 1 month. There was no difference in pain scores in recovery, with a median difference (95%CI) of 0.6 (-1.9-3.1), p = 0.65. Median postoperative oral morphine equivalent utilisation was significantly higher in the erector spinae plane group (21 mg vs. 12 mg; p = 0.028). Itching was observed in 10% of patients who received erector spinae plane block and there was no difference in the incidence of significant nausea and vomiting. Patient satisfaction scores, and pain scores and opioid use at 24 h were similar. At 1 month, six (peri-articular injection) and eight (erector spinae plane block) patients reported persistent pain. Erector spinae plane block was not superior to peri-articular injection for arthroscopic shoulder surgery.

Impact of nitrogen (N) and phosphorus (P) enrichment and skewed N:P stoichiometry on the skeletal formation and microstructure of symbiotic reef corals.

Reported divergent responses of coral growth and skeletal microstructure to the nutrient environment complicate knowledge-based management of water quality in coral reefs. By re-evaluating published results considering the taxonomy of the studied corals and the N:P stoichiometry of their nutrient environment, we could resolve some of the major apparent contradictions. Our analysis suggests that Acroporids behave differently to several other common genera and show distinct responses to specific nutrient treatments. We hypothesised that both the concentrations of dissolved inorganic N and P in the water and their stoichiometry shape skeletal growth and microstructure. We tested this hypothesis by exposing Acropora polystoma fragments to four nutrient treatments for > 10 weeks: high nitrate/high phosphate (HNHP), high nitrate/low phosphate (HNLP), low nitrate/high phosphate (LNHP) and low nitrate/low phosphate (LNLP). HNHP corals retained high zooxanthellae densities and their linear extension and calcification rates were up to ten times higher than in the other treatments. HNLP and LNLP corals bleached through loss of symbionts. The photochemical efficiency (Fv/Fm) of residual symbionts in HNLP corals was significantly reduced, indicating P-starvation. Micro-computed tomography (µCT) of the skeletal microstructure revealed that reduced linear extension in nutrient limited or nutrient starved conditions (HNLP, LNHP, LNLP) was associated with significant thickening of skeletal elements and reduced porosity. These changes can be explained by the strongly reduced linear extension rate in combination with a smaller reduction in the calcification rate. Studies using increased skeletal density as a proxy for past thermal bleaching events should consider that such an increase in density may also be associated with temperature-independent response to the nutrient environment. Furthermore, the taxonomy of corals and seawater N:P stoichiometry should be considered when analysing and managing the impacts of nutrient pollution. Supplementary Information: The online version contains supplementary material available at 10.1007/s00338-022-02223-0.

Mapping coral calcification strategies from in situ boron isotope and trace element measurements of the tropical coral Siderastrea siderea.

Boron isotopic and elemental analysis of coral aragonite can give important insights into the calcification strategies employed in coral skeletal construction. Traditional methods of analysis have limited spatial (and thus temporal) resolution, hindering attempts to unravel skeletal heterogeneity. Laser ablation mass spectrometry allows a much more refined view, and here we employ these techniques to explore boron isotope and co-varying elemental ratios in the tropical coral Siderastrea siderea. We generate two-dimensional maps of the carbonate parameters within the calcification medium that deposited the skeleton, which reveal large heterogeneities in carbonate chemistry across the macro-structure of a coral polyp. These differences have the potential to bias proxy interpretations, and indicate that different processes facilitated precipitation of different parts of the coral skeleton: the low-density columella being precipitated from a fluid with a carbonate composition closer to seawater, compared to the high-density inter-polyp walls where aragonite saturation was ~ 5 times that of external seawater. Therefore, the skeleton does not precipitate from a spatially homogeneous fluid and its different parts may thus have varying sensitivity to environmental stress. This offers new insights into the mechanisms behind the response of the S. siderea skeletal phenotype to ocean acidification.

Identification of native endophytic Trichoderma spp. for investigation of in vitro antagonism towards Armillaria mellea using synthetic- and plant-based substrates.

AIMS: To isolate endophytic Trichoderma species and investigate the potential for biological control of the root rot pathogen Armillaria mellea. METHODS AND RESULTS: In all, 40 Trichoderma isolates were obtained from a range of host plants and identities were confirmed by ITS, rpb2 and tef1 sequence. When tested in dual culture assays for antagonism against A. mellea, Trichoderma isolates overgrew the A. mellea colonies within four days and by eight days 38 Trichoderma isolates significantly reduced A. mellea colony size. Armillaria mellea was unable to be recovered from five of eight co-cultivations tested, suggesting Trichoderma had killed the A. mellea in these cases. Pre-colonized hazel disks were used to determine what happens in a more heterogeneous situation with A. mellea and a refined set of eight Trichoderma isolates. Similar to plate-based assays, Trichoderma quickly covered A. mellea stopping any further growth and two Trichoderma isolates were able to eradicate A. mellea. CONCLUSIONS: Of the Trichoderma spp. tested, endophytic isolates of Trichoderma virens and T. hamatum offered the greatest antagonism towards A. mellea. Using pre-colonized hazel disks was of great importance for this work to demonstrate the fungal interactions in plant material. SIGNIFICANCE AND IMPACT OF THE STUDY: Controlling Armillaria root rot is difficult with chemical treatments, thus an environmentally benign and cost-effective alternative is required. This study highlights the prospect of biological control as an effective, environmentally friendly alternative to chemicals.

An Assessment of Earth's Climate Sensitivity Using Multiple Lines of Evidence.

We assess evidence relevant to Earth's equilibrium climate sensitivity per doubling of atmospheric CO2, characterized by an effective sensitivity S. This evidence includes feedback process understanding, the historical climate record, and the paleoclimate record. An S value lower than 2 K is difficult to reconcile with any of the three lines of evidence. The amount of cooling during the Last Glacial Maximum provides strong evidence against values of S greater than 4.5 K. Other lines of evidence in combination also show that this is relatively unlikely. We use a Bayesian approach to produce a probability density function (PDF) for S given all the evidence, including tests of robustness to difficult-to-quantify uncertainties and different priors. The 66% range is 2.6-3.9 K for our Baseline calculation and remains within 2.3-4.5 K under the robustness tests; corresponding 5-95% ranges are 2.3-4.7 K, bounded by 2.0-5.7 K (although such high-confidence ranges should be regarded more cautiously). This indicates a stronger constraint on S than reported in past assessments, by lifting the low end of the range. This narrowing occurs because the three lines of evidence agree and are judged to be largely independent and because of greater confidence in understanding feedback processes and in combining evidence. We identify promising avenues for further narrowing the range in S, in particular using comprehensive models and process understanding to address limitations in the traditional forcing-feedback paradigm for interpreting past changes.

Proxy evidence for state-dependence of climate sensitivity in the Eocene greenhouse.

Despite recent advances, the link between the evolution of atmospheric CO2 and climate during the Eocene greenhouse remains uncertain. In particular, modelling studies suggest that in order to achieve the global warmth that characterised the early Eocene, warmer climates must be more sensitive to CO2 forcing than colder climates. Here, we test this assertion in the geological record by combining a new high-resolution boron isotope-based CO2 record with novel estimates of Global Mean Temperature. We find that Equilibrium Climate Sensitivity (ECS) was indeed higher during the warmest intervals of the Eocene, agreeing well with recent model simulations, and declined through the Eocene as global climate cooled. These observations indicate that the canonical IPCC range of ECS (1.5 to 4.5 °C per doubling) is unlikely to be appropriate for high-CO2 warm climates of the past, and the state dependency of ECS may play an increasingly important role in determining the state of future climate as the Earth continues to warm.

Ocean Carbon Storage across the middle Miocene: a new interpretation for the Monterey Event.

The Miocene Climatic Optimum (MCO, 14-17 Ma) was ~3-4 °C warmer than present, similar to estimates for 2100. Coincident with the MCO is the Monterey positive carbon isotope (δ13C) excursion, with oceans more depleted in 12C relative to 13C than any time in the past 50 Myrs. The long-standing Monterey Hypothesis uses this excursion to invoke massive marine organic carbon burial and draw-down of atmospheric CO2 as a cause for the subsequent Miocene Climate Transition and Antarctic glaciation. However, this hypothesis cannot explain the multi-Myr lag between the δ13C excursion and global cooling. We use planktic foraminiferal B/Ca, δ11B, δ13C, and Mg/Ca to reconstruct surface ocean carbonate chemistry and temperature. We propose that the MCO was associated with elevated oceanic dissolved inorganic carbon caused by volcanic degassing, global warming, and sea-level rise. A key negative feedback of this warm climate was the organic carbon burial on drowned continental shelves.

Weight bias internalization in a commercial weight management sample: prevalence and correlates.

OBJECTIVE: Weight bias internalization (WBI) is associated with poor weight-related health. The purpose of this study was to identify the prevalence and correlates of WBI in a large sample of adults in a commercial weight management programme. METHODS: WW (the new Weight Watchers) members participated in an online survey. Participants (N = 18,769) completed the 10-item Weight Bias Internalization Scale - Modified (WBIS-M) and the Weight Self-Stigma Questionnaire (WSSQ). Participants reported details about weight-stigmatizing experiences, including the onset, frequency and distress, and interpersonal sources of weight stigma. Participants self-reported their demographics, weight history, and height and weight (to compute body mass index [BMI]). RESULTS: Weight bias internalization was relatively high compared with the general population (mean WBIS-M score = 4.3 ± 1.4; mean WSSQ total score = 35.2 ± 9.7). WBI was higher among participants who were female, younger and had higher BMIs (p < 0.001) and lower among those who were Black and were widowed or had a romantic partner (p < 0.001). Onset of weight stigma in childhood and young adulthood, and recent distress due to weight stigma, predicted higher WBI. Extended family and school sources of weight stigma had weaker associations with WBI than did other interpersonal sources. CONCLUSIONS: Weight bias was internalized by a significant proportion of adults enrolled in a commercial weight management programme. A phenotype of WBI includes demographic characteristics and the timing and sources of weight stigma.

More efficient North Atlantic carbon pump during the Last Glacial Maximum.

During the Last Glacial Maximum (LGM; ~20,000 years ago), the global ocean sequestered a large amount of carbon lost from the atmosphere and terrestrial biosphere. Suppressed CO2 outgassing from the Southern Ocean is the prevailing explanation for this carbon sequestration. By contrast, the North Atlantic Ocean-a major conduit for atmospheric CO2 transport to the ocean interior via the overturning circulation-has received much less attention. Here we demonstrate that North Atlantic carbon pump efficiency during the LGM was almost doubled relative to the Holocene. This is based on a novel proxy approach to estimate air-sea CO2 exchange signals using combined carbonate ion and nutrient reconstructions for multiple sediment cores from the North Atlantic. Our data indicate that in tandem with Southern Ocean processes, enhanced North Atlantic CO2 absorption contributed to lowering ice-age atmospheric CO2.

Strategies for the Construction of Cassava Brown Streak Disease Viral Infectious Clones.

Cassava brown streak disease (CBSD) has major impacts on yield and quality of the tuberous roots of cassava in Eastern and Central Arica. At least two Potyviridae species cause the disease: Cassava brown streak virus (CBSV) and Ugandan cassava brown streak virus (UCBSV). Cloned viral genome sequences known as infectious clones (ICs) have been important in the study of other viruses, both as a means of standardising infectious material and characterising viral gene function. IC construction is often technically challenging for Potyviridae due to sequence instability in E. coli. Here, we evaluate three methods for the construction of infectious clones for CBSD. Whilst a simple IC for in vitro transcription was made for UCBSV isolate 'Kikombe', such an approach failed to deliver full-length clones for CBSV isolates 'Nampula' or 'Tanza', necessitating more complex approaches for their construction. The ICs successfully generated symptomatic infection in the model host N. benthamiana and in the natural host cassava. This shows that whilst generating ICs for CBSV is still a technical challenge, a structured approach, evaluating both in vitro and in planta transcription systems should successfully deliver ICs, allowing further study into the symptomology and virulence factors in this important disease complex.

Evaluation of PCR primers targeting the groEL gene for the specific detection of Streptococcus agalactiae in the context of aquaculture.

AIMS: The aim of this study was to design a set of primers for specific detection and identification of Streptococcus agalactiae in polymerase chain reaction (PCR) that can detect a diverse range of S. agalactiae isolates from different hosts and that it is capable of discriminating between S. agalactiae and other species that are closely related or potentially present in aquaculture environments, notably Streptococcus iniae. METHODS AND RESULTS: Primers, based on the groEL2 gene of S. agalactiae, were shown to be epidemiologically sensitive to 97 isolates of S. agalactiae, representing 11 clonal complexes derived from piscine, terrestrial and aquatic mammalian host species. The primers were tested with 10 S. iniae isolates and 22 other comparator species with no cross-reaction observed after optimization of reaction conditions. They have a high analytical sensitivity, detecting as few as 10 copies of S. agalactiae genomic DNA per reaction and are capable of detecting the target in DNA extracted from the brains of infected fish. CONCLUSIONS: The primers proved suitable for the sensitive and specific detection of S. agalactiae from dairy-, human- and fish-related origins by PCR. SIGNIFICANCE AND IMPACT OF THE STUDY: Due to the importance of S. agalactiae as a pathogen, many PCR primers have been published for this bacterium, designed largely for its detection in dairy and human samples, but many cross-reacting with S. iniae. The ability to differentiate between S. agalactiae and S. iniae in aquaculture derived samples is important as both infect fish, causing similar disease symptoms and are phenotypically similar, yet control strategies and zoonotic risk are species specific.

Implementing routine blood-borne virus testing for HCV, HBV and HIV at a London Emergency Department - uncovering the iceberg?

UK guidelines recommend routine HIV testing in high prevalence emergency departments (ED) and targeted testing for HBV and HCV. The 'Going Viral' campaign implemented opt-out blood-borne virus (BBV) testing in adults in a high prevalence ED, to assess seroprevalence, uptake, linkage to care (LTC) rates and staff time taken to achieve LTC. Diagnosis status (new/known/unknown), current engagement in care, and severity of disease was established. LTC was defined as patient informed plus ⩾1 clinic visit. A total of 6211/24 981 ED attendees were tested (uptake 25%); 257 (4.1%) were BBV positive (15 co-infected), 84 (33%) required LTC. 100/147 (68%) HCV positives were viraemic; 44 (30%) required LTC (13 new, 16 disengaged). 26/54 (48%) HBV required LTC (seven new, 11 disengaged). 16/71 (23%) HIV required LTC (10 new, five disengaged). 26/84 (31%) patients requiring LTC had advanced disease (CD4 1, Fibroscan F3/F4 or liver cancer), including five with AIDS-defining conditions and three hepatocellular carcinomas. There were five BBV-related deaths. BBV prevalence was high (4.1%); most were HCV (2.4%). HIV patients were more successfully and quickly LTC than HBV or HCV patients. ED testing was valuable as one-third of those requiring LTC (new, disengaged or unknown status patients) had advanced disease.

Impact of baseline clinical and laboratory features on the risk of thrombosis in children with acute lymphoblastic leukemia: A prospective evaluation.

BACKGROUND: Children with acute lymphoblastic leukemia (ALL) have increased risk of thromboembolism (TE). However, the predictors of ALL-associated TE are as yet uncertain. OBJECTIVE: This exploratory, prospective cohort study evaluated the effects of clinical (age, gender, ALL risk group) and laboratory variables (hematological parameters, ABO blood group, inherited and acquired prothrombotic defects [PDs]) at diagnosis on the development of symptomatic TE (sTE) in children (aged 1 to ≤18) treated on the Dana-Farber Cancer Institute ALL 05-001 study. PROCEDURES: Samples collected prior to the start of ALL therapy were evaluated for genetic and acquired PDs (proteins C and S, antithrombin, procoagulant factors VIII (FVIII:C), IX, XI and von Willebrand factor antigen levels, gene polymorphisms of factor V G1691A, prothrombin gene G20210A and methylene tetrahydrofolate reductase C677T, anticardiolipin antibodies, fasting lipoprotein(a), and homocysteine). RESULTS: Of 131 enrolled patients (mean age [range] 6.4 [1-17] years) 70 were male patients and 20 patients (15%) developed sTE. Acquired or inherited PD had no impact on the risk of sTE. Multivariable analyses identified older age (odds ratio [OR] 1.13; 95% confidence interval [CI]: 1.01, 1.26) and non-O blood group (OR 3.64, 95% CI: 1.06, 12.51) as independent predictors for development of sTE. Patients with circulating blasts had higher odds of developing sTE (OR 6.66; 95% CI: 0.82, 53.85). CONCLUSION: Older age, non-O blood group, and presence of circulating blasts, but not PDs, predicted the risk of sTE during ALL therapy. We recommend evaluation of these novel risk factors in the development of ALL-associated TE. If confirmed, these easily accessible variables at diagnosis can help develop a risk-prediction model for ALL-associated TE.

Efficacy and safety results of patients with HCV genotype 2 or 3 infection treated with ombitasvir/paritaprevir/ritonavir and sofosbuvir with or without ribavirin (QUARTZ II-III).

The efficacy and safety of an investigational combination of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) plus sofosbuvir (SOF) ± ribavirin (RBV) in patients with HCV genotype 2 or 3 infection with or without cirrhosis was evaluated. Patients with HCV genotype 3 infection without cirrhosis were randomized to receive OBV/PTV/r + SOF ± RBV for 12 weeks; OBV/PTV/r + SOF + RBV was administered to genotype 3-infected patients with cirrhosis for 12 weeks and to genotype 2-infected patients without cirrhosis for either 6 or 8 weeks. Efficacy was assessed by sustained virologic response [HCV RNA <25 IU/mL] 12 weeks post-treatment (SVR12). Safety was assessed in all treated patients. In patients with genotype 3 infection with or without cirrhosis treated with 12 weeks of OBV/PTV/r + SOF ± RBV, the overall SVR12 rate was 98% (50/51), with no virologic failures. Patients with genotype 2 infection treated with OBV/PTV/r + SOF + RBV had SVR12 rates of 90% (9/10) and 44% (4/9) following 8- and 6-week treatment durations, respectively; failure to achieve SVR12 for these patients was due to relapse without baseline or treatment-emergent resistance-associated substitutions. Thus, the investigational combination of OBV/PTV/r with SOF ± RBV was well tolerated and achieved high SVR rates with no virologic failures in patients with genotype 3 infection. Combining direct-acting antivirals with complementary mechanisms of action and different viral targets may be an effective treatment strategy that may allow for shorter durations of therapy.

Sofosbuvir and velpatasvir with or without voxilaprevir in direct-acting antiviral-naïve chronic hepatitis C: patient-reported outcomes from POLARIS 2 and 3.

BACKGROUND: Chronic hepatitis C infection leads to impairment of patient-reported outcomes (PROs). Treatment with direct-acting antiviral regimens results in short- and long-term improvement of these outcomes. AIM: To assess PROs in patients treated with a newly developed direct-acting antiviral, a fixed-dose combination of sofosbuvir/velpatasvir (SOF/VEL) with/without voxilaprevir (VOX). METHODS: The PRO data were collected from participants of POLARIS-2 and POLARIS-3 clinical trials (DAA-naïve, all HCV genotypes). Participants self-administered SF-36v2, FACIT-F, CLDQ-HCV and WPAI:SHP instruments at baseline, during treatment, and in follow-up. RESULTS: Of 1160 patients, 611 received SOF/VEL/VOX and 549 received SOF/VEL (52.8 ± 11.0 years, 55.9% male, 75.4% treatment-naïve, 33.9% cirrhotic). The sustained viral response at 12 weeks (SVR12) rates were 95%-98%. During treatment, improvements in most PRO scores were significant (all but one P < .01) and ranged from, on average, +2.3 to +15.0 points (on a 0-100 scale) by the end of treatment. These improvements were similar between SOF/VEL/VOX and SOF/VEL arms (all P > .05). After treatment discontinuation, patients treated with both regimens achieved significant and clinically meaningful PRO gains (+2.7 to +16.7 by post-treatment week 12, +3.9 to +20.1 by post-treatment week 24; all but one P < .001). Multivariate analysis showed that depression, anxiety and cirrhosis were the most consistent independent predictors of PRO impairment while no association of PROs with the treatment regimen choice was found (all P > .05). CONCLUSIONS: The pan-genotypic regimens with SOF/VEL with or without VOX not only have excellent efficacy and safety, but also significantly positively impact patients' experience both during treatment and after achieving sustained virologic response in DAA-naïve patients with HCV.

Efficacy and safety of 12 weeks of elbasvir ± grazoprevir ± ribavirin in participants with hepatitis C virus genotype 2, 4, 5 or 6 infection: The C-SCAPE study.

People with hepatitis C virus (HCV) infection other than genotype 1 represent a heterogeneous group. The aim of the phase 2 C-SCAPE study was to evaluate elbasvir/grazoprevir (EBR/GZR), with or without ribavirin (RBV), in participants with HCV genotype 2, 4, 5 or 6 infection. This was a part randomised, open-label, parallel-group study (NCT01932762; PN047-03) of treatment-naive, noncirrhotic participants. Participants with HCV genotype 2 infection received GZR 100 mg + RBV ± EBR 50 mg for 12 weeks and those with genotype 4, 5 or 6 infection were randomized to receive EBR/GZR ± RBV for 12 weeks. The primary endpoint was sustained virological response 12 weeks after completion of treatment (SVR12; HCV RNA <25 IU/mL). Among participants with genotype 2 infection, SVR12 was achieved by 80% (24/30) of those receiving EBR/GZR + RBV and 73% (19/26) of those receiving GZR + RBV. SVR rates were high in participants with HCV genotype 4 infection receiving EBR/GZR with and without RBV (100% [10/10] and 90% [9/10]; respectively). In contrast, the addition of RBV to EBR/GZR appeared to increase SVR12 in participants with genotype 5 infection (EBR/GZR, 25%; EBR/GZR + RBV 100% [4/4]). In participants with genotype 6 infection, SVR12 was 75% (3/4) in both those receiving EBR/GZR and those receiving EBR/GZR + RBV. The safety profile was similar across treatment arms, with adverse events tending to occur more frequently among participants receiving RBV. In conclusion, these data support the inclusion of participants with genotype 4 or 6 infection in the EBR/GZR phase 3 studies. EBR/GZR ± RBV was unsatisfactory for participants with genotype 2 or 5 infection.