A Simple Approach to Adjust for Case-Mix When Comparing Institutional Cesarean Birth Rates.

OBJECTIVE: This study aimed to develop a validated model to predict intrapartum cesarean in nulliparous women and to use it to adjust for case-mix when comparing institutional laboring cesarean birth (CB) rates. STUDY DESIGN: This multicenter retrospective study used chart-abstracted data on nulliparous, singleton, term births over a 7-year period. Prelabor cesareans were excluded. Logistic regression was used to predict the probability of CB for individual pregnancies. Thirty-five potential predictive variables were evaluated including maternal demographics, prepregnancy health, pregnancy characteristics, and newborn weight and gender. Models were trained on 21,017 births during 2011 to 2015 (training cohort), and accuracy assessed by prediction on 15,045 births during 2016 to 2017 (test cohort). RESULTS: Six variables delivered predictive success equivalent to the full set of 35 variables: maternal weight, height, and age, gestation at birth, medically-indicated induction, and birth weight. Internal validation within the training cohort gave a receiver operator curve with area under the curve (ROC-AUC) of 0.722. External validation using the test cohort gave ROC-AUC of 0.722 (0.713-0.731 confidence interval). When comparing observed and predicted CB rates at 16 institutions in the test cohort, five had significantly lower than predicted rates and three had significantly higher than predicted rates. CONCLUSION: Six routine clinical variables used to adjust for case-mix can identify outliers when comparing institutional CB rates.

VTX-2337 is a novel TLR8 agonist that activates NK cells and augments ADCC.

PURPOSE: We aim to characterize VTX-2337, a novel Toll-like receptor (TLR) 8 agonist in clinical development, and investigate its potential to improve monoclonal antibody-based immunotherapy that includes the activation of natural killer (NK) cells. EXPERIMENTAL DESIGN: HEK-TLR transfectants were used to compare the selectivity and potency of VTX-2337, imiquimod, CpG ODN2006, and CL075. The ability of VTX-2337 to induce cytokine and chemokine production from human peripheral blood mononuclear cells (PBMC) and activation of specific immune cell subsets was examined. The potential for VTX-2337 to activate NK cell activity through direct and indirect mechanisms was also investigated. Finally, we tested the potential for VTX-2337 to augment antibody-dependent cell-mediated cytotoxicity (ADCC), especially in individuals with low-affinity FcγR3A single-nucleotide polymorphism (SNP). RESULTS: VTX-2337 selectively activates TLR8 with an EC(50) of about 100 nmol/L and stimulates production of TNFα and interleukin (IL)-12 from monocytes and myeloid dendritic cells (mDC). VTX-2337 stimulates IFNγ production from NK cells and increases the cytotoxicity of NK cells against K562 and ADCC by rituximab and trastuzumab. Effects of VTX-2337 on NK cells were, in part, from direct activation as increased IFNγ production and cytotoxic activity were seen with purified NK cells. Finally, VTX-2337 augments ADCC by rituximab in PBMCs with different FcγR3A genotypes (V/V, V/F, and F/F at position 158). CONCLUSIONS: VTX-2337 is a novel small-molecule TLR8 agonist that activates monocytes, DCs, and NK cells. Through the activation of NK cells, it has the potential to augment the effectiveness of monoclonal antibody treatments where a polymorphism in FcγR3A limits clinical efficacy.