Impact of the Thompson method on breastfeeding exclusivity and duration: Multi-method design.

BACKGROUND: How hospital clinicians facilitate breastfeeding in the first 48-72 h is critical to breastfeeding exclusivity and duration. Mothers who discharge hospital directly breastfeeding are more likely to continue exclusively breastfeeding at 3-months. OBJECTIVE: To assess the impact of facility-wide implementation of a physiological breastfeeding method (the Thompson method) on direct breastfeeding at hospital discharge and exclusive breastfeeding at 3-months of age. DESIGN: Multi-method design using interrupted time series analysis and surveys. SETTING(S): An Australian tertiary maternity hospital. PARTICIPANTS: 13,667 mother-baby pairs (interrupted time series analysis) and 495 postnatal mothers (surveys). METHODS: The Thompson method includes cradle position and hold, alignment of mouth-to-nipple, baby-led connection and seal, maternal fine-tuning for symmetry, and leisurely duration. We used a large pre-post implementation dataset and conducted interrupted time series analysis using a 24-month baseline period (January 2016 - December 2017); and a 15-month post-implementation period (April 2018 - June 2019). We recruited a sub-sample of women to complete surveys at hospital discharge and 3-months postpartum. Surveys were primarily used to measure impact of Thompson method on exclusive breastfeeding at 3-months, compared with a baseline survey conducted in same setting. RESULTS: Following implementation of the Thompson method, the declining trend in direct breastfeeding at hospital discharge was significantly averted by 0.39% each month relative to baseline (95% CI: 0.03% to 0.76%; p = 0.037). While the 3-month exclusive breastfeeding rate in the Thompson group was 3 percentage points higher than the baseline group; this result did not reach statistical significance. However, a subgroup analysis of women who discharged hospital exclusively breastfeeding revealed the relative odds of exclusive breastfeeding at 3-months in the Thompson group was 0.25 (95% CI: 0.17 to 0.38; p < 0.001), significantly better than the baseline group (Z = 3.23, p < 0.01) where the relative odds was only 0.07 (95% CI: 0.03 to 0.19; p < 0.001). CONCLUSIONS: Implementation of the Thompson method for well mother-baby pairs improved direct breastfeeding trends at hospital discharge. For women who discharged hospital exclusively breastfeeding, exposure to the Thompson method reduced the risk of exclusive breastfeeding discontinuation by 3-months. The positive impact of the method was potentially confounded by partial implementation and a parallel rise in birth interventions which undermine breastfeeding. We recommend strategies to strengthen clinician buy-in to the method, and future research using a cluster randomised trial design. TWEETABLE ABSTRACT: Facility-wide implementation of the Thompson method improves direct breastfeeding at hospital discharge and predicts breastfeeding exclusivity at 3-months.

Structure-based design of novel class II c-Met inhibitors: 2. SAR and kinase selectivity profiles of the pyrazolone series.

As part of our effort toward developing an effective therapeutic agent for c-Met-dependent tumors, a pyrazolone-based class II c-Met inhibitor, N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (1), was identified. Knowledge of the binding mode of this molecule in both c-Met and VEGFR-2 proteins led to a novel strategy for designing more selective analogues of 1. Along with detailed SAR information, we demonstrate that the low kinase selectivity associated with class II c-Met inhibitors can be improved significantly. This work resulted in the discovery of potent c-Met inhibitors with improved selectivity profiles over VEGFR-2 and IGF-1R that could serve as useful tools to probe the relationship between kinase selectivity and in vivo efficacy in tumor xenograft models. Compound 59e (AMG 458) was ultimately advanced into preclinical safety studies.

Naphthamides as novel and potent vascular endothelial growth factor receptor tyrosine kinase inhibitors: design, synthesis, and evaluation.

A series of naphthyl-based compounds were synthesized as potential inhibitors of vascular endothelial growth factor (VEGF) receptors. Investigations of structure-activity relationships led to the identification of a series of naphthamides that are potent inhibitors of the VEGF receptor tyrosine kinase family. Numerous analogues demonstrated low nanomolar inhibition of VEGF-dependent human umbilical vein endothelial cell (HUVEC) proliferation, and of these several compounds possessed favorable pharmacokinetic (PK) profiles. In particular, compound 48 demonstrated significant antitumor efficacy against established HT29 human colon adenocarcinoma xenografts implanted in athymic mice. A full account of the preparation, structure-activity relationships, pharmacokinetic properties, and pharmacology of analogues within this series is presented.

Design, synthesis, and evaluation of orally active benzimidazoles and benzoxazoles as vascular endothelial growth factor-2 receptor tyrosine kinase inhibitors.

Inhibition of the VEGF signaling pathway has become a valuable approach in the treatment of cancers. Guided by X-ray crystallography and molecular modeling, a series of 2-aminobenzimidazoles and 2-aminobenzoxazoles were identified as potent inhibitors of VEGFR-2 (KDR) in both enzymatic and HUVEC cellular proliferation assays. In this report we describe the synthesis and structure-activity relationship of a series of 2-aminobenzimidazoles and benzoxazoles, culminating in the identification of benzoxazole 22 as a potent and selective VEGFR-2 inhibitor displaying a good pharmacokinetic profile. Compound 22 demonstrated efficacy in both the murine matrigel model for vascular permeability (79% inhibition observed at 100 mg/kg) and the rat corneal angiogenesis model (ED(50) = 16.3 mg/kg).

Total synthesis of (+/-)-momilactone A.

The first total synthesis of (+/-)-momilactone A was accomplished using a highly diastereoselective transannular Diels-Alder reaction on a trans-trans-cis macrocyclic triene.