Capillary malformation-arteriovenous malformation (CM-AVM) is an autosomal dominant blood vascular (BV) disorder characterized by CM and fast flow BV lesions. Inactivating mutations of the RASA1 gene ...are the cause of CM-AVM in most cases. RASA1 is a GTPase-activating protein that acts as a negative regulator of the Ras small GTP-binding protein. In addition, RASA1 performs Ras-independent functions in intracellular signal transduction. Whether CM-AVM results from loss of an ability of RASA1 to regulate Ras or loss of a Ras-independent function of RASA1 is unknown. To address this, we generated Rasa1 knockin mice with an R780Q point mutation that abrogates RASA1 catalytic activity specifically. Homozygous Rasa1(R780Q/R780Q) mice showed the same severe BV abnormalities as Rasa1-null mice and died midgestation. This finding indicates that BV abnormalities in CM-AVM develop as a result of loss of an ability of RASA1 to control Ras activation and not loss of a Ras-independent function of this molecule. More important, findings indicate that inhibition of Ras signaling is likely to represent an effective means of therapy for this disease.
Benthic macroalgae must attach firmly to the substrate to prevent being detached and washed away by water motion. The success of the bioadhesion system can be strongly influenced by surface chemistry ...and so this should be optimized for large-scale cultivation. This is especially important during the early stage of cultivation when the juveniles have little thigmotactic attachment, which is needed to interlock with surface rugosity. Juvenile sporophytes of Saccharina latissima (Phaeophyceae) were directly applied onto polymer films of varied surface composition to determine how the attachment force of the developing holdfast was influenced by surface chemistry. Eight polymer chemistries were examined: polyamide (PA), polyethylene (PE), polyester (PES), polypropylene (PP), polymethylacrylate (PMA), polyvinylalcohol (PVA), polyvinylchloride (PVC) and thermoplastic polyurethane (TPU). The PP and PE were also examined as three grades: commercial grade with additives, pure polymer, or pure polymer following a corona treatment. Additive inclusion and corona significantly reduced the water contact angle (p < 0.0001), indicating an increase in the surface free energy available for bioadhesion. After 6 weeks, the attachment force was greatest on PVA, PA and PVC (0.19-0.33 N), correlating strongly with the achieved biomass (R
2
= 0.68). Additives and corona treatment improved holdfast attachment force, particularly corona treated PE (0.28 ± 0.08 N: 0 N without corona). Generally, attachment force appeared greatest on chemistries with a contact angle of 60-75°. These results confirm that the bioadhesion of the phaeophyte holdfast is strongly influenced by the surface free energy of the substrate chosen. Through alteration of the additive composition, attachment could be improved to create bespoke cultivation substrates. Corona treatment is highlighted as a very suitable method for improving holdfast attachment force during cultivation.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, GIS, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The grazing lands of the High Atlas are vulnerable to climate change and the decline of traditional management practices. However, prior to the mid-20th century, there is little information to ...examine historical environmental change and resilience to past climate variability. Here, we present a new pollen, non-pollen palynomorph (NPP) and microcharcoal record from a sub-alpine marsh (pozzine) at Oukaïmeden, located in the Marrakech High Atlas, Morocco. The record reveals a history of grazing impacts with diverse non-arboreal pollen assemblages dominant throughout the record as well as recurrent shifts between wetter and drier conditions. A large suite of radiocarbon dates (
n
= 22) constrains the deposit to the last ~ 1,000 years although multiple reversed ages preclude development of a robust age-depth model for all intervals. Between relatively dry conditions during the Medieval period and in the 20th century, intervening wet conditions are observed, which we interpret as a locally enhanced snowpack during the Little Ice Age. Hydrological fluctuations evidenced by wetland pollen and NPPs are possibly associated with centennial-scale precipitation variability evidenced in regional speleothem records. The pollen record reveals an herbaceous grassland flora resilient against climatic fluctuations through the last millennium, possibly supported by sustainable collective management practices (
agdal
), with grazing indicators suggesting a flourishing pastoral economy. However, during the 20th century, floristic changes and increases in charcoal accumulation point to a decline in management practices, diversification of land-use (including afforestation) and intensification of human activity.
Background & Aims
The phase 2, FOURward study (NCT02175966) investigated short‐duration therapy (4/6 weeks) with four direct‐acting antivirals (DAAs) with distinct mechanisms of action in patients ...infected with hepatitis C virus (HCV) genotype‐1.
Methods
Non‐cirrhotic patients were randomized 1:1 to DCV‐TRIO (fixed‐dose daclatasvir 30 mg, asunaprevir 200 mg and beclabuvir 75 mg) twice‐daily + sofosbuvir 400 mg once‐daily for 4 or 6 weeks. The primary endpoint was sustained virological response at post‐treatment Week 12 (SVR12). Patients without SVR12 were offered retreatment based on the DAA resistance profile at failure; patients with resistance to ≤1 DCV‐TRIO component received DCV‐TRIO + RBV for 12 weeks.
Results
Twenty‐eight patients with HCV genotype‐1 were enrolled; 79% had genotype‐1a infection and median baseline HCV‐RNA levels were high (9 × 106 IU/mL). Most patients had undetectable HCV‐RNA at end of treatment (96% n=27/28); however, relapse occurred in 77% (n=10/13) and 43% (n=6/14) treated for 4 and 6 weeks, leading to SVR12 rates of 29% (n=4/14) and 57% (n=8/14) respectively. SVR12 was higher in patients with lower baseline HCV‐RNA (<2 million IU/mL, 71% n=5/7; ≥2 million IU/mL, 33% n=7/21). None of the 16 non‐SVR12 patients had NS3 or NS5B resistance‐associated substitutions (RAS) detected at failure. All 15 patients retreated with DCV‐TRIO + RBV for 12 weeks achieved SVR12. All regimens were well tolerated.
Conclusions
Short‐duration treatment with four DAAs with distinct mechanisms of action was insufficient for most patients with genotype‐1 infection and high baseline viraemia. Non‐SVR12 was not associated with emergence of NS3 or NS5B RAS and retreatment with DCV‐TRIO + RBV for 12 weeks led to SVR in all patients.
Large glaciers and ice caps formed in the Mediterranean mountains during the cold stages of the Pleistocene and some small glaciers remain today. Here we review 157 outputs that include radiometric ...dates on glacial deposits or outwash in the Mediterranean published between 1975 and 2020. The last decade has seen a striking increase in the use of terrestrial cosmogenic nuclide (TCN) dating and this has revolutionised our understanding of the Late Pleistocene glacial record. Our meta-analysis of 1663 radiometric ages highlights much greater complexity in the timing of Pleistocene glaciation across the region than hitherto recognised. Evidence from multiple dating methods, in a range of depositional settings, confirms that the Mediterranean glacial record extends through all of the Late Pleistocene and deep into the Middle Pleistocene. Evidence of Early Pleistocene glacial activity has been recognised from outwash deposits in the Julian Alps of Slovenia. The most extensive glaciations occurred during the Middle Pleistocene: their ages have been established primarily by using 40Ar/39Ar in the Italian Apennines and U-series dating in the glaciokarst of the Balkans. The Late Pleistocene glacial geochronologies are based on optically stimulated luminescence (OSL), radiocarbon and TCN dating. TCN dating is now the dominant method for dating Late Pleistocene glacial landforms. It is now clear that glaciers were present throughout the Late Pleistocene and, in most parts of the Mediterranean, they were at or near their maximum extent before the global last glacier maximum (27.5–23.3 ka). The outwash record in river valleys downstream of the glaciated terrains confirms that glaciers were important agents of landscape change throughout this period. Deglaciation in the Mediterranean mountains was punctuated by glacier stabilisations as well as some readvances towards the very end of the Pleistocene. The deglacial trend has continued throughout the Holocene with rapid change in recent decades due to rising global temperatures. Some small glaciers remain today due to the influence of locally favourable topoclimatic factors. For much of the Quaternary Period conditions in the Mediterranean mountains involved much more extensive glaciation than recorded at any time in the Holocene.
Phaeophyte macroalgae of the genus Sargassum, including Sargassum muticum, are under investigation as a cultivation crop. Overgrowth or grazing reduces the value and productivity of the crop. This ...can occur both in the hatchery and during growth at sea, although juvenile stages are especially vulnerable. A decontamination protocol could be used to prevent this. Following a screening procedure, sodium hypochlorite (NaClO) and potassium iodide (KI) were selected for further study. The lethal concentrations for protozoans associated with S. muticum zygotes were 1 % KI, 0.75 % NaClO or a combination of 0.5 % KI and 0.38 % NaClO. A 3-min exposure to these treatments was able to eliminate protozoa from branchlets 20–80 % of the time. NaClO caused large reductions in the operating efficiency of photosystem II (Fq ’/Fₘ ’), particularly in juveniles (74 ± 17 %), which had still not fully recovered after 17 days. This also halved juvenile density and caused negative growth. One percent KI reduced Fq ’/Fₘ ’ in adults by 29 ± 11 %, with recovery by day 10. In juveniles, growth was reduced by 65 % and Fq ’/Fₘ ’ by 61 ± 11 % with recovery after 17 days. A combined treatment of 0.5 % KI and 0.38 % NaClO had far milder effects: reducing adult and juveniles Fq ’/Fₘ ’ by 6 ± 3 and 34 ± 9 % respectively, with full recovery by day 10. A reduction in juvenile growth was also seen between day 0–10 (32 %); however, size was no different to the control by day 20. This combined treatment is therefore suitable for decontamination of both juveniles and adult S. muticum tissue.
IMPORTANCE: The antiviral activity of all-oral, ribavirin-free, direct-acting antiviral regimens requires evaluation in patients with chronic hepatitis C virus (HCV) infection. OBJECTIVE: To ...determine the rates of sustained virologic response (SVR) in patients receiving the 3-drug combination of daclatasvir (a pan-genotypic NS5A inhibitor), asunaprevir (an NS3 protease inhibitor), and beclabuvir (a nonnucleoside NS5B inhibitor). DESIGN, SETTING, AND PARTICIPANTS: This was an open-label, single-group, uncontrolled international study (UNITY-1) conducted at 66 sites in the United States, Canada, France, and Australia between December 2013 and August 2014. Patients without cirrhosis who were either treatment-naive (n = 312) or treatment-experienced (n = 103) and had chronic HCV genotype 1 infection were included. INTERVENTIONS: Patients received a twice-daily fixed-dose combination of daclatasvir, 30 mg; asunaprevir, 200 mg; and beclabuvir, 75 mg. MAIN OUTCOMES AND MEASURES: The primary study outcome was SVR12 (HCV-RNA <25 IU/mL at posttreatment week 12) in patients naive to treatment. A key secondary outcome was SVR12 in the treatment-experienced cohort. RESULTS: Baseline characteristics were comparable between the treatment-naive and treatment-experienced cohorts. Patients were 58% male, 26% had IL28B (rs12979860) CC genotype, 73% were infected with genotype 1a, and 27% were infected with genotype 1b. Overall, SVR12 was observed in 379 of 415 patients (91.3%; 95% CI, 88.6%-94.0%): 287 of 312 treatment-naive patients (92.0%; 95% CI, 89.0%-95.0%) and 92 of 103 treatment-experienced patients (89.3%; 95% CI, 83.4%-95.3%). Virologic failure occurred in 34 patients (8%) overall. One patient died at posttreatment week 3; this was not considered related to study medication. There were 7 serious adverse events, all considered unrelated to study treatment, and 3 adverse events (<1%) leading to treatment discontinuation, including 2 grade 4 alanine aminotransferase elevations. The most common adverse events (in ≥10% of patients) were headache, fatigue, diarrhea, and nausea. CONCLUSIONS AND RELEVANCE: In this open-label, nonrandomized, uncontrolled study, a high rate of SVR12 was achieved in treatment-naive and treatment-experienced noncirrhotic patients with chronic HCV genotype 1 infection who received 12 weeks of treatment with the oral fixed-dose regimen of daclatasvir, asunaprevir, and beclabuvir. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01979939
Background
Schizophrenia is a chronic mental disorder associated with substantial morbidity and mortality affecting 0.25–1.6% of adults in the USA. Antipsychotic treatment is the standard of care for ...schizophrenia, but real-world treatment patterns and associated costs have not been systematically reviewed.
Objective
We conducted a systematic review to summarize treatment patterns and associated costs related to oral antipsychotic treatment of patients with schizophrenia in the USA.
Data Sources
We searched Medline (via PubMed) and Embase to identify relevant observational studies published from January 1, 2008, to June 1, 2018; costs were converted to 2018 US dollars.
Study Eligibility
Observational, real-world studies reporting on patterns of treatment and/or associated costs for adult patients with schizophrenia treated with oral antipsychotics in the USA were included.
Results
Eighty-one studies were identified. Frequently prescribed oral second-generation antipsychotics were olanzapine (up to 50.9%), risperidone (up to 40.0%), and quetiapine (up to 30.7%). Suboptimal adherence was common across studies. Antipsychotic switching occurred in about half of patients, while antipsychotic combination therapy occurred in nearly 30%; all were associated with increased medication-related costs. Mean annual direct medical costs differed by treatment, with reported costs of $17,115 to $26,138 for patients treated with olanzapine, $18,395 for risperidone, and $17,656 to $28,101 for quetiapine.
Limitations
This systematic review is limited by the variations in definitions of schizophrenia-related clinical terms used between studies and by the inclusion of studies focused on only the US health care system.
Conclusions
In the treatment of schizophrenia, suboptimal adherence, antipsychotic switching, and antipsychotic augmentation were all associated with high costs of care in comparison to patients who were adherent and did not require antipsychotic switching or augmentation. These findings illustrate the need for the development of new treatments that address efficacy and adherence challenges of currently available therapies.
Plain Language Summary
Schizophrenia is a debilitating mental disorder that affects up to 1.6% of adults in the USA. Antipsychotic medications reduce symptoms of the disease, but many patients with schizophrenia are not fully adherent or choose to discontinue treatment entirely, increasing their risk of hospitalization. In others, efforts to achieve better symptom control or to avoid intolerable side effects may result in switching antipsychotic medications or adding additional medications, leading to higher medical treatment costs. The magnitude of these cost increases is unclear. This study sought to assess medical costs associated with antipsychotic treatment adherence, switching, and adding additional antipsychotics. We reviewed 81 studies published from January 2008 through June 2018 examining treatment adherence in patients with schizophrenia. We calculated rates of adherence, switching, and adding antipsychotics, as well as associated medical costs. Overall adherence to antipsychotic treatment was less than 50%, with up to 50% of patients switching medications and up to 29% adding an additional antipsychotic medication to their current treatment. Patients who were not treatment adherent incurred annual medical costs of $10,316 compared with $5723 in patients who were adherent. The costs of immediate or delayed switching of antipsychotic medications ranged from $21,922 to $28,232, while costs of adding an additional antipsychotic ranged from $24,045 to $29,344. These data suggest that suboptimal medication adherence, along with high rates of patient discontinuation and medication switching, lead to higher treatment costs in the management of patients with schizophrenia.
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