Abstract
In this study, we explored the role of biochar (BC) and/or urease inhibitor (UI) in mitigating ammonia (NH
3
) and nitrous oxide (N
2
O) discharge from urea fertilized wheat cultivated ...fields in Pakistan (34.01°N, 71.71°E). The experiment included five treatments control, urea (150 kg N ha
−1
), BC (10 Mg ha
−1
), urea + BC and urea + BC + UI (1 L ton
−1
), which were all repeated four times and were carried out in a randomized complete block design. Urea supplementation along with BC and BC + UI reduced soil NH
3
emissions by 27% and 69%, respectively, compared to sole urea application. Nitrous oxide emissions from urea fertilized plots were also reduced by 24% and 53% applying BC and BC + UI, respectively, compared to urea alone. Application of BC with urea improved the grain yield, shoot biomass, and total N uptake of wheat by 13%, 24%, and 12%, respectively, compared to urea alone. Moreover, UI further promoted biomass and grain yield, and N assimilation in wheat by 38%, 22% and 27%, respectively, over sole urea application. In conclusion, application of BC and/or UI can mitigate NH
3
and N
2
O emissions from urea fertilized soil, improve N use efficiency (NUE) and overall crop productivity.
Reports of ChAdOx1 vaccine-associated thrombocytopenia and vascular adverse events have led to some countries restricting its use. Using a national prospective cohort, we estimated associations ...between exposure to first-dose ChAdOx1 or BNT162b2 vaccination and hematological and vascular adverse events using a nested incident-matched case-control study and a confirmatory self-controlled case series (SCCS) analysis. An association was found between ChAdOx1 vaccination and idiopathic thrombocytopenic purpura (ITP) (0-27 d after vaccination; adjusted rate ratio (aRR) = 5.77, 95% confidence interval (CI), 2.41-13.83), with an estimated incidence of 1.13 (0.62-1.63) cases per 100,000 doses. An SCCS analysis confirmed that this was unlikely due to bias (RR = 1.98 (1.29-3.02)). There was also an increased risk for arterial thromboembolic events (aRR = 1.22, 1.12-1.34) 0-27 d after vaccination, with an SCCS RR of 0.97 (0.93-1.02). For hemorrhagic events 0-27 d after vaccination, the aRR was 1.48 (1.12-1.96), with an SCCS RR of 0.95 (0.82-1.11). A first dose of ChAdOx1 was found to be associated with small increased risks of ITP, with suggestive evidence of an increased risk of arterial thromboembolic and hemorrhagic events. The attenuation of effect found in the SCCS analysis means that there is the potential for overestimation of the reported results, which might indicate the presence of some residual confounding or confounding by indication. Public health authorities should inform their jurisdictions of these relatively small increased risks associated with ChAdOx1. No positive associations were seen between BNT162b2 and thrombocytopenic, thromboembolic and hemorrhagic events.
Summary
Background
Apremilast, an oral phosphodiesterase 4 inhibitor, regulates immune responses associated with psoriasis.
Objectives
ESTEEM 2 evaluated the efficacy and safety of apremilast 30 mg ...twice daily for moderate‐to‐severe plaque psoriasis.
Methods
This phase III, double‐blind, placebo‐controlled trial randomized adults to apremilast or placebo (2 : 1). At week 16, placebo patients switched to apremilast. At week 32, apremilast patients achieving ≥ 50% reduction in Psoriasis Area and Severity Index (PASI 50) were rerandomized (1 : 1) to continue apremilast or receive placebo. Upon loss of 50% of PASI improvement obtained at week 32, patients rerandomized to placebo resumed apremilast.
Results
The modified intention‐to‐treat population (full analysis set) included 137 placebo and 274 apremilast patients. At week 16, significantly more apremilast patients achieved PASI 75 (28·8%), PASI 50 (55·5%) and static Physician's Global Assessment score of 0 or 1 (20·4%) vs. placebo (5·8%, 19·7%, 4·4%, respectively; P < 0·001). Most patients rerandomized to apremilast at week 32 had a PASI 50 response at week 52 (80%). Patients treated with apremilast showed significant improvements in quality of life (as assessed by the Dermatology Life Quality Index) and pruritus at week 16 compared with placebo (P < 0·001). The exposure‐adjusted incidence of adverse events did not increase with continued apremilast treatment for up to 52 weeks. The most common adverse events were nausea, diarrhoea, nasopharyngitis and upper respiratory tract infection.
Conclusions
Apremilast was effective in the treatment of moderate‐to‐severe plaque psoriasis over 52 weeks.
What's already known about this topic?
Psoriasis is a chronic inflammatory disease of the skin resulting from an uncontrolled immune response, which leads to a chronic imbalance in the production of pro‐ and anti‐inflammatory cytokines.
Recent surveys show that many patients with psoriasis report discontinuing treatment with conventional systemic agents or biologics due to lack of tolerability, safety issues, lack or loss of effectiveness, burden of monitoring or injections.
What does this study add?
In ESTEEM 2, apremilast, an oral phosphodiesterase 4 inhibitor, significantly reduced the severity of moderate‐to‐severe plaque psoriasis over 16 weeks, with response generally maintained in patients continuing apremilast for 52 weeks.
Apremilast was effective in difficult‐to‐treat nail, scalp and palmoplantar psoriasis and in improving pruritus and skin discomfort/pain.
Apremilast demonstrated an acceptable safety profile; no new significant adverse events emerged with continued apremilast exposure for up to 52 weeks.
Linked Comment: Gniadecki, Br J Dermatol 2015; 173: 1355–56.
This study aims at reporting the indigenous knowledge of the medicinal flora from the inhabitants of surroundings of the World's largest artificial planted forest "Changa Manga", Pakistan. Data were ...collected by direct interviews and group meetings from 81 inhabitants including 32 local healers having information regarding the use of indigenous medicinal plants over a period of one year. Different statistical tools were applied to analyze the data including Frequency citation (FC), Relative frequency citation (RFC), Use Value, Factor of informants consensus and fidelity level. This study reported 73 plant species belonging to 37 plant families and 46 genera. The majority of plant species belong to compositae family. The most commonly used medicinal plants were P. hysterophorus L., P. dactylifera L., S. indicum L, P. harmala L., P. emblica L., and A. indica A.Juss. The greatest number of species was used to cure gastrointestinal disorders. The highest fidelity level (68.18%) was of E. helioscopia to cure gastrointestinal disorders. Maximum fresh uses (17) were reported by C. dactylon (L.) Pars. While the highest number of species reporting fresh uses in similar number was 13. In this study, five novel plants are being reported for the first time in Pakistan for their ethnomedicinal worth. Our data reflect unique usage of the medicinal plants in the study area. The statistical tools used in the study proved useful in pointing the most important and disease category specific plants. High use value plant and the new reported medicinal plants might prove an important source of the isolation of pharmacologically active compounds.
Dasatinib, a potent inhibitor of BCR-ABL in vitro, is effective for patients with chronic myelogenous leukemia (CML) resistant or intolerant to imatinib. To provide a more definitive assessment of ...dasatinib in chronic-phase (CP)-CML, we report extended follow-up of a phase II trial, presenting data for the entire patient cohort (N=387). Dasatinib (70 mg) twice daily was administered to patients with imatinib-resistant or -intolerant CP-CML. With median follow-up of 15.2 months (treatment duration, <1-18.4 months), a complete hematologic response was attained or maintained in 91% of patients. A major cytogenetic response (MCyR) was attained or maintained by 59% (52% imatinib resistant and 80% imatinib intolerant); this was complete in 49% of patients (40% imatinib resistant and 75% imatinib intolerant). Of 230 patients achieving an MCyR, 7 experienced disease progression. Fifteen-month progression-free survival was 90% while overall survival was 96%. Grade 3/4 thrombocytopenia and neutropenia were reported in 48 and 49% of patients, respectively. Non-hematologic toxicity (any grade) consisted primarily of diarrhea (37%), headache (32%), fatigue (31%), dyspnea (30%) and pleural effusion (27%). Pleural effusions were classified as grade 3 in 6% of reported events, with no incidence of grade 4. Dasatinib is associated with high response rates in patients with imatinib-resistant or -intolerant CP-CML.
The metabolite 2-hydroxyglutarate (2HG) can be produced as either a D-R- or L-S- enantiomer, each of which inhibits α-ketoglutarate (αKG)-dependent enzymes involved in diverse biologic processes. ...Oncogenic mutations in isocitrate dehydrogenase (IDH) produce D-2HG, which causes a pathologic blockade in cell differentiation. On the other hand, oxygen limitation leads to accumulation of L-2HG, which can facilitate physiologic adaptation to hypoxic stress in both normal and malignant cells. Here we demonstrate that purified lactate dehydrogenase (LDH) and malate dehydrogenase (MDH) catalyze stereospecific production of L-2HG via 'promiscuous' reduction of the alternative substrate αKG. Acidic pH enhances production of L-2HG by promoting a protonated form of αKG that binds to a key residue in the substrate-binding pocket of LDHA. Acid-enhanced production of L-2HG leads to stabilization of hypoxia-inducible factor 1 alpha (HIF-1α) in normoxia. These findings offer insights into mechanisms whereby microenvironmental factors influence production of metabolites that alter cell fate and function.
The injection and mixing of contaminant mass into the fuel in inertial confinement fusion (ICF) implosions is a primary factor preventing ignition. ICF experiments have recently achieved an ...alpha-heating regime, in which fusion self-heating is the dominant source of yield, by reducing the susceptibility of implosions to instabilities that inject this mass. We report the results of unique separated reactants implosion experiments studying pre-mixed contaminant as well as detailed high-resolution three-dimensional simulations that are in good agreement with experiments. At conditions relevant to mixing regions in high-yield implosions, we observe persistent chunks of contaminant that do not achieve thermal equilibrium with the fuel throughout the burn phase. The assumption of thermal equilibrium is made in nearly all computational ICF modeling and methods used to infer levels of contaminant from experiments. We estimate that these methods may underestimate the amount of contaminant by a factor of two or more.
The objectives of this tutorial are as follows: 1) to help students and researchers develop a basic understanding of how pulsed-power systems are used to create high-energy-density (HED) matter; 2) ...to develop a basic understanding of a new, compact, and efficient pulsed-power technology called linear transformer drivers (LTDs); 3) to understand why LTDs are an attractive technology for driving HED physics (HEDP) experiments; 4) to contrast LTDs with the more traditional Marx-generator/pulse-forming-line approach to driving HEDP experiments; and 5) to briefly review the history of LTD technology as well as some of the LTD-driven HEDP research presently underway at universities and research laboratories across the globe. This invited tutorial is part of the Mini-Course on Charged Particle Beams and High-Powered Pulsed Sources, held in conjunction with the 44th International Conference on Plasma Science in May of 2017.
Diclofenac and five of its transformation products were identified in Malir River and Lyari River water as well as in effluent samples from Karachi, Pakistan. To the best of our knowledge, this is ...the first report on the identification of 3′-hydroxydiclofenac and 8-chlorocarbazole-1-yl-ethanoic acid in environmental samples. Their estimated concentrations ranged between 0.08–0.3
μg
L
−1 and 0.03–0.4
μg
L
−1, respectively. In addition, 4′- and 5-hydroxydiclofenac as well as 1-(2,6-dichlorophenyl)-1,3-dihydro-2
H-indole-2-one were detected in the samples at concentrations between 0.4–1.8, 0.01–0.3, and 0.02–0.2
μg
L
−1, respectively. The hydroxy derivatives seem to reflect human excretions via household wastewater, while the chlorocarbazole derivative is related to abiotic photolytic transformation of diclofenac.
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