Distortional effects of separate accounting and formula apportionment on factor allocation.

Unlabelled: We examine distortions caused by tax base allocation systems-separate accounting (SA) or formula apportionment (FA)-with respect to the allocation of assets and workforce within multinational entities (MNEs). The effects of both systems are intensively debated by EU Member States as they are striving to implement a European tax system. Its introduction would lead to a switch from SA to FA.

Real-world burden of systemic lupus erythematosus in the USA: a comparative cohort study from the Medical Expenditure Panel Survey (MEPS) 2016-2018.

Objective: SLE is a chronic, multiorgan, autoimmune disease; however, current prevalence estimates are dated and often from non-generalisable patient populations, and quality of life and patient-reported outcomes in the real-world SLE population are not well-published. The present study used the Medical Expenditure Panel Survey (MEPS), a generalisable US data source encompassing a representative sample of regions/payers, to estimate SLE prevalence and characterise disease burden compared with non-SLE respondents.

Methods: Retrospective population-based survey data weighted to the full US population from MEPS for the calendar years 2016-2018, pooled over the full study period, was used.

Efficacy of baricitinib in patients with moderate-to-severe rheumatoid arthritis with 3 years of treatment: results from a long-term study.

Objective: To evaluate the long-term efficacy of once-daily baricitinib 4 mg in patients with active RA who were either naïve to DMARDs or who had inadequate response (IR) to MTX.

Methods: Analyses of data from two completed 52-week, phase III studies, RA-BEGIN (DMARD-naïve) and RA-BEAM (MTX-IR), and one ongoing long-term extension (LTE) study (RA-BEYOND) were performed (148 total weeks). At week 52, DMARD-naïve patients treated with MTX monotherapy or baricitinib 4 mg+MTX in RA-BEGIN were switched to open-label baricitinib 4 mg monotherapy; MTX-IR patients treated with adalimumab (+MTX) in RA-BEAM were switched to open-label baricitinib 4 mg (+MTX) in the LTE.

COVID-19 and investor behavior.

How do retail investors respond to the outbreak of COVID-19? We use transaction-level trading data to show that investors significantly increase their trading activities as the COVID-19 pandemic unfolds, both at the extensive and at the intensive margin. Investors, on average, increase their brokerage deposits and open more new accounts. The average weekly trading intensity increases by 13.

Comparison of baricitinib, upadacitinib, and tofacitinib mediated regulation of cytokine signaling in human leukocyte subpopulations.

Background: The in vitro pharmacology of baricitinib, upadacitinib, and tofacitinib was evaluated to understand differences among these JAK inhibitors (JAKis) at the cellular level.

Methods: Peripheral blood mononuclear cells from healthy donors were incubated with different JAKis, levels of phosphorylated signal transducer and activator of transcription (pSTAT) were measured following cytokine stimulation, and half maximum inhibitory concentration (IC) values were calculated in phenotypically gated leukocyte subpopulations. Therapeutic dose relevance of the in vitro analysis was assessed using calculated mean concentration-time profiles over 24 h obtained from JAKi-treated subjects.

Low rates of radiographic progression of structural joint damage over 2 years of baricitinib treatment in patients with rheumatoid arthritis.

Objectives: To evaluate radiographic progression of structural joint damage over 2 years in patients with rheumatoid arthritis from baricitinib clinical trials who were disease-modifying antirheumatic drug (DMARD)-naïve or had an inadequate response to conventional synthetic DMARDs (csDMARD-IR).

Methods: Patients had completed one of three phase III studies and entered a long-term extension (LTE) study, continuing on the same baricitinib dose as at originating study completion. At 52 weeks, DMARD-naïve patients receiving methotrexate (MTX) or combination therapy (baricitinib 4 mg+MTX) were switched to baricitinib 4 mg monotherapy (±MTX per investigator opinion); MTX-IR patients receiving adalimumab were switched to baricitinib 4 mg on background MTX.

Clinical outcomes in patients switched from adalimumab to baricitinib due to non-response and/or study design: phase III data in patients with rheumatoid arthritis.

Objective: To evaluate clinical outcomes in patients who changed treatment from adalimumab to baricitinib, an oral Janus kinase (JAK)1/JAK2 inhibitor, during a phase III programme.

Methods: In phase III RA-BEAM, patients were randomised 3:3:2 to placebo, baricitinib 4 mg once daily, or adalimumab 40 mg biweekly. At week 16 or subsequent visits, non-responders were rescued to open-label baricitinib 4 mg.

Insecticidal Effects of Plasma Treated Water.

The efficacy of plasma-treated tap water (PTW) for the possible treatment of a mealybug () infestation was studied under laboratory conditions. Mealybugs growing on have been treated using PTW after being transferred to Petri dishes, thus avoiding possible buffering effects that might occur in an in-situ study. When treating tap water with a dielectric barrier discharge for several minutes (1, 3, 5 and 10 min) a distinct acidification of the water can be determined, resulting in a pH value of 1.

FR-900098, an antimalarial development candidate that inhibits the non-mevalonate isoprenoid biosynthesis pathway, shows no evidence of acute toxicity and genotoxicity.

FR-900098 is an inhibitor of 1-deoxy-d-xylulose-5-phosphate (DXP) reductoisomerase, the second enzyme in the non-mevalonate isoprenoid biosynthesis pathway. In previous studies, FR-900098 was shown to possess potent antimalarial activity in vitro and in a murine malaria model. In order to provide a basis for further preclinical and clinical development, we studied the acute toxicity and genotoxicity of FR-900098.

Efficacy and safety of tabalumab, an anti-BAFF monoclonal antibody, in patients with moderate-to-severe rheumatoid arthritis and inadequate response to TNF inhibitors: results of a randomised, double-blind, placebo-controlled, phase 3 study.

Background: Tabalumab is a human monoclonal antibody that neutralises B-cell activating factor.

Objectives: To evaluate tabalumab efficacy and safety in patients with rheumatoid arthritis (RA).

Methods: This phase 3, randomised, double-blind, placebo-controlled study evaluated 456 patients with active RA after 24-week treatment with subcutaneous tabalumab (120 mg every 4 weeks (120/Q4W) or 90 mg every 2 weeks (90/Q2W)) versus placebo, with loading doses (240 or 180 mg) at week 0.

Evaluation of immunogenicity of LY2963016 insulin glargine compared with Lantus® insulin glargine in patients with type 1 or type 2 diabetes mellitus.

Aims: To compare the immunogenicity profiles and the potential effects on clinical outcomes of LY2963016 insulin glargine (LY IGlar) and Lantus® insulin glargine (IGlar), products with identical primary amino acid sequences, in patients with type 1 or type 2 diabetes mellitus (T1DM or T2DM).

Methods: To assess immunogenicity, anti-insulin glargine antibodies (measured as percent binding) were compared between treatments in 52-week (open-label) and 24-week (double-blind) randomized studies in total study populations of patients with T1DM (N = 535) and T2DM (N = 756), respectively, and two subgroups of patients with T2DM: insulin-naïve patients and those reporting prestudy IGlar treatment (prior IGlar). Relationships between insulin antibody levels and clinical outcomes were assessed using analysis of covariance and partial correlations.

Efficacy and safety of tabalumab, an anti-B-cell-activating factor monoclonal antibody, in patients with rheumatoid arthritis who had an inadequate response to methotrexate therapy: results from a phase III multicentre, randomised, double-blind study.

Objectives: Randomised, double-blind, placebo-controlled study to evaluate efficacy and safety of tabalumab in patients with rheumatoid arthritis (RA) with inadequate responses to methotrexate (MTX-IR).

Methods: 1041 patients with moderate-severe RA despite ongoing MTX enrolled in a 52-week study evaluating subcutaneous tabalumab 120 mg every four weeks (120/Q4W) or 90 mg every two weeks (90/Q2W) versus placebo. Primary endpoints were American College of Rheumatology 20% (ACR20) response rate and Health Assessment Questionnaire-Disability Index change from baseline at 24 weeks and modified Total Sharp Score (mTSS) change at 52 weeks.

The antimalarial pipeline--an update.

There are quite a number of antimalarial compounds in different states of preclinical and clinical development. Among those in advanced stages, combinations of known drugs or new substances from drug classes already used in antimalarial therapy are predominant. More compounds with novel or even unknown mechanism of action are found among those compounds which are in less advanced stages of development.

Resistance of the Burkholderia cepacia complex to fosmidomycin and fosmidomycin derivatives.

The Burkholderia cepacia complex (BCC) is a group of 17 closely related opportunistic pathogens that are able to infect the respiratory tract of cystic fibrosis patients. BCC bacteria are intrinsically resistant to many antibiotics and are therefore difficult to eradicate. Fosmidomycin could be a new therapeutic agent to treat BCC infections as it inhibits 1-deoxy-d-xylulose-5-phosphate reductoisomerase (Dxr), a key enzyme in the non-mevalonate pathway essential in BCC bacteria for isoprenoid synthesis.

The second-generation active Aβ immunotherapy CAD106 reduces amyloid accumulation in APP transgenic mice while minimizing potential side effects.

Immunization against amyloid-β (Aβ) can reduce amyloid accumulation in vivo and is considered a potential therapeutic approach for Alzheimer's disease. However, it has been associated with meningoencephalitis thought to be mediated by inflammatory T-cells. With the aim of producing an immunogenic vaccine without this side effect, we designed CAD106 comprising Aβ1-6 coupled to the virus-like particle Qβ.

2-Acylamino-5-chlorobenzophenones with enhanced selectivity towards malaria parasites.

Previously we described a series of 5-acylaminobenzophenones with considerable antimalarial activity. Unfortunately, most compounds also displayed high cytotoxicity resulting in low selectivity towards malaria parasites. Through the replacement of the 5-acylamino moiety by simple chlorine and further modifications of the 2-acylamino residue we could obtain inhibitors with improved selectivity towards malaria parasites combined with an acceptable reduction of antimalarial activity.

Antimalarial and antitrypanosomal activity of a series of amide and sulfonamide derivatives of a 2,5-diaminobenzophenone.

Here, we describe a series of readily obtainable benzophenone derivatives with antimalarial and antitrypanosomal activity. The most active compounds display submicromolar activity against Plasmodium falciparum. Micromolar activity is obtained against Trypanosoma brucei.

Structure-based optimization of aldose reductase inhibitors originating from virtual screening.

Diabetes mellitus is a universal health problem. The World Health Organization (WHO) estimates that 150 million people suffer from diabetes mellitus worldwide in 2005. Long-term complications are a serious problem in the treatment of diabetes, manifesting in macrovascular and microvascular complications.

Development of benzophenone-based farnesyltransferase inhibitors as novel antimalarials.

The development of farnesyltransferase inhibitors directed against Plasmodium falciparum is a strategy towards new drugs against malaria. Previously, we described benzophenone-based farnesyltransferase inhibitors with high in vitro antimalarial activity but no in vivo activity. Through the introduction of a methylpiperazinyl moiety, farnesyltransferase inhibitors with in vivo antimalarial activity were obtained.

Studies addressing the importance of charge in the binding of fosmidomycin-like molecules to deoxyxylulosephosphate reductoisomerase.

Fosmidomycin and its homologue FR900098 are inhibitors of 1-deoxy-D-xylulose-5-phosphate reductoisomerase, which is part of the mevalonate-independent isoprenoid biosynthetic pathway. Replacement of the phosphonate moiety by uncharged sulfone or sulfonamide partial structures resulted in complete loss of activity. Dropping one of the two negative charges resulted in a marked decrease in activity.

Synoviolin promotes IRE1 ubiquitination and degradation in synovial fibroblasts from mice with collagen-induced arthritis.

The E3 ubiquitin ligase synoviolin (SYVN1) functions as an anti-apoptotic factor that is responsible for the outgrowth of synovial cells during the development of rheumatoid arthritis. The molecular mechanisms underlying SYVN1 regulation of cell death are largely unknown. Here, we report that elevated SYVN1 expression correlates with decreased levels of the protein inositol-requiring enzyme 1 (IRE1)-a pro-apoptotic factor in the endoplasmic reticulum (ER)-stress-induced apoptosis pathway-in synovial fibroblasts from mice with collagen-induced arthritis (CIA).

Synthesis of beta- and gamma-oxa isosteres of fosmidomycin and FR900098 as antimalarial candidates.

To expand the structure-activity relationships of fosmidomycin and FR900098, two potent antimalarials interfering with the MEP-pathway, we decided to replace a methylene group in beta-position of the phosphonate moiety of these leads by an oxygen atom. beta-oxa-FR900098 (11) proved equally active as the parent compound. When applied to 4-[hydroxyl(methyl)amino]-4-oxobutyl phosphonic acid, featuring a hydroxamate instead of the retrohydroxamate moiety, a beta-oxa modification yielded a derivative (13) with superior activity against the Plasmodium falciparum 3D7 strain than fosmidomycin, while a gamma-oxa modification resulted in less active derivatives.

Double ester prodrugs of FR900098 display enhanced in-vitro antimalarial activity.

Fosmidomycin and FR900098 are inhibitors of the 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR; IspC), a key enzyme of the mevalonate-independent isoprenoid biosynthesis pathway. We have determined the in-vitro antimalarial activity of two double ester prodrugs 2, 3 in direct comparison with the unmodified FR900098 1 against intraerythrocytic forms of Plasmodium falciparum. Temporarily masking the polar properties of the phosphonate moiety of the DXR inhibitor FR900098 1 enhanced not only its oral bioavailability but also the intrinsic activity of this series against the parasites.