No abstract

This study modelled the cost-effectiveness of 11 oral antipsychotics for relapse prevention among patients with remitted schizophrenia in Singapore. A network meta-analysis determined the relative efficacy and tolerability of 11 oral antipsychotics (amisulpride, aripiprazole, chlorpromazine, haloperidol, olanzapine, paliperidone, quetiapine, risperidone, sulpiride, trifluoperazine and ziprasidone). The clinical estimates were applied in a Markov model to estimate lifetime costs and quality-adjusted life-years gained. Quality-of-life data were obtained from published literature. Resource utilization and cost data were retrieved from local hospital databases. The annual direct cost of healthcare services for a patient experiencing a relapse episode was three-fold that of a patient not in relapse of schizophrenia. The most favourable pharmacological treatment for relapse prevention was olanzapine with an annual probability of relapse of 0.24 (0.13-0.38) with placebo as a reference of 0.75 (0.73-0.78). Olanzapine emerged as the dominant treatment with the highest quality-adjusted life-years gained and lowest lifetime costs. Ziprasidone, aripiprazole and paliperidone incurred higher lifetime costs compared with no treatment. Probability and cost of relapse were key drivers of cost-effectiveness in sensitivity analyses. The data can help prescribers in choosing appropriate treatment and payers in allocating resources for the clinical management of this serious psychiatric disorder.

No abstract

We investigate here how APRIL impacts immune regulatory T cells and directly contributes to the immunosuppressive multiple myeloma (MM) bone marrow (BM) microenvironment. First, APRIL receptor TACI expression is significantly higher in regulatory T cells (Tregs) than conventional T cells (Tcons) from the same patient, confirmed by upregulated Treg markers, i.e., Foxp3, CTLA-4. APRIL significantly stimulates proliferation and survival of Tregs, whereas neutralizing anti-APRIL monoclonal antibodies (mAbs) inhibit these effects. Besides TACI-dependent induction of cell cycle progression and anti-apoptosis genes, APRIL specifically augments Foxp3, IL-10, TGFβ1, and PD-L1 in Tregs to further enhance Treg-inhibited Tcon proliferation. APRIL further increases MM cell-driven Treg (iTreg) via TACI-dependent proliferation associated with upregulated IL-10, TGFβ1, and CD15s in iTreg, which further inhibits Tcons. Osteoclasts producing APRIL and PD-L1 significantly block Tcon expansion by iTreg generation, which is overcome by combined treatment with anti-APRIL and anti-PD1/PD-L1 mAbs. Finally, APRIL increases IL-10-producing B regulatory cells (Bregs) via TACI on BM Bregs of MM patients. Taken together, these results define novel APRIL actions via TACI on Tregs and Bregs to promote MM cell survival, providing the rationale for targeting APRIL/TACI system to alleviate the immunosuppressive BM milieu and improve patient outcome in MM.

To target mechanisms critical for multiple myeloma (MM) plasma cell adaptations to genomic instabilities and further sustain MM cell killing, we here specifically trigger DNA damage response (DDR) in MM cells by a novel BCMA antibody drug conjugate (ADC) delivering the DNA cross-linking PBD dimer tesirine, MEDI2228. MEDI2228, more effectively than its anti-tubulin MMAF-ADC homolog, induces cytotoxicity against MM cells regardless of drug resistance, BCMA levels, p53 status, and the protection conferred by bone marrow stromal cells and IL-6. Distinctly, prior to apoptosis, MEDI2228 activates DDRs in MM cells via phosphorylation of ATM/ATR kinases, CHK1/2, CDK1/2, and H2AX, associated with expression of DDR-related genes. Significantly, MEDI2228 synergizes with DDR inhibitors (DDRi s) targeting ATM/ATR/WEE1 checkpoints to induce MM cell lethality. Moreover, suboptimal doses of MEDI2228 and bortezomib (btz) synergistically trigger apoptosis of even drug-resistant MM cells partly via modulation of RAD51 and accumulation of impaired DNA. Such combination further induces superior in vivo efficacy than monotherapy via increased nuclear γH2AX-expressing foci, irreversible DNA damages and tumor cell death, leading to significantly prolonged host survival. These results indicate leveraging MEDI2228 with DDRi s or btz as novel combination strategies, further supporting ongoing clinical development of MEDI2228 in patients with relapsed and refractory MM.

At the current daily price sacubitril/valsartan may not represent good value for limited healthcare dollars compared to enalapril in reducing cardiovascular morbidity and mortality in HF in the Singapore healthcare setting. This study highlights the cost-benefit trade-off that healthcare professionals and patients face when considering therapy.

No abstract

Reelin is an extracellular matrix (ECM) protein that is essential for neuron