Obstetrical complications, often referred to as the "great obstetrical syndromes," are among the most common global causes of mortality and morbidity in young women and their infants. However,... Show moreObstetrical complications, often referred to as the "great obstetrical syndromes," are among the most common global causes of mortality and morbidity in young women and their infants. However, treatments for these syndromes are underdeveloped compared with other fields of medicine and are urgently needed. This current paucity of treatments for obstetrical complications is a reflection of the challenges of drug development in pregnancy. The appetite of pharmaceutical companies to invest in research for obstetrical syndromes is generally reduced by concerns for maternal, fetal, and infant safety, poor definition, and high-risk regulatory paths toward product approval. Notably, drug candidates require large investments for development with an unguaranteed return on investment. Furthermore, the discovery of promising drug candidates is hampered by a poor understanding of the pathophysiology of obstetrical syndromes and their uniqueness to human pregnancies. This limits translational extrapolation and de-risking strategies in preclinical studies, as available for other medical areas, compounded with limited fetal safety monitoring to capture early prenatal adverse reactions. In addition, the ethical review committees are reluctant to approve the inclusion of pregnant women in trials, and in the absence of regulatory guidance in obstetrics, clinical development programs are subject to unpredictable regulatory paths. To develop effective and safe drugs for pregnancy complications, substantial commitment, and investment in research for innovative therapies are needed in parallel with the creation of an enabling ethical, legislative, and guidance framework. Solutions are proposed to enable stakeholders to work with a common set of expectations to facilitate progress in this medical discipline. Addressing this significant unmet need to advance maternal and possibly perinatal health requires the involvement of all stakeholders and specifically patients, couples, and cli-nicians facing pregnancy complications in the dearth of appropriate therapies. This paper focused on the key pharmaceutical research and development challenges to achieve effective and safe treatments for obstetrical syndromes. Show less
Roos-Blom, M.J.; Dongelmans, D.; Stilma, W.; Spijkstra, J.J.; Jonge, E. de; Keizer, N. de 2020
Purpose: Half of the patients experience pain during their ICU slay which is known to influence their outcomes. Nurses and physicians encounter organizational barriers towards pain assessment and... Show morePurpose: Half of the patients experience pain during their ICU slay which is known to influence their outcomes. Nurses and physicians encounter organizational barriers towards pain assessment and treatment. We aimed to evaluate the association between adequate pain management and nurse to patient ratio, bed occupancy rale, and fulltime presence of an intensivist.Materials and methods: We performed unadjusted and case-mix adjusted mixed-effect logistic regression modeling on data from thirteen Dutch ICUs to investigate the association between ICU organizational characteristics and adequate pain management, i.e. patient-shift observations in which patients' pain was measured and acceptable, or unacceptable and normalized within 1 h.All ICU patients admitted between December 2017 and June 2018 were included, excluding patients who were delirious, comatose or had a Glasgow coma score < 8 at the first day of ICU admission.Results: Case-mix adjusted nurse to patient ratios of 0.70 to 0.80 and over 0.80 were significantly associated with adequate pain management (OR [95% confidence interval] of respectively 1.14 [1.07-121] and 1.1611.08-1.24]). Bed occupancy rate and intensivist presence showed no association.Conclusion: Higher nurse to patient ratios increase the percentage of patients with adequate pain management especially in medical and mechanically ventilated patients. (C) 2019 Elsevier Inc. All rights reserved. Show less
Background The effect of risk-reducing salpingo-oophorectomy (RRSO) on breast cancer risk for BRCA1 and BRCA2 mutation carriers is uncertain. Retrospective analyses have suggested a protective... Show moreBackground The effect of risk-reducing salpingo-oophorectomy (RRSO) on breast cancer risk for BRCA1 and BRCA2 mutation carriers is uncertain. Retrospective analyses have suggested a protective effect but may be substantially biased. Prospective studies have had limited power, particularly for BRCA2 mutation carriers. Further, previous studies have not considered the effect of RRSO in the context of natural menopause. Methods A multi-centre prospective cohort of 2272 BRCA1 and 1605 BRCA2 mutation carriers was followed for a mean of 5.4 and 4.9 years, respectively; 426 women developed incident breast cancer. RRSO was modelled as a time-dependent covariate in Cox regression, and its effect assessed in premenopausal and postmenopausal women. Results There was no association between RRSO and breast cancer for BRCA1 (HR = 1.23; 95% CI 0.94-1.61) or BRCA2 (HR = 0.88; 95% CI 0.62-1.24) mutation carriers. For BRCA2 mutation carriers, HRs were 0.68 (95% CI 0.40-1.15) and 1.07 (95% CI 0.69-1.64) for RRSO carried out before or after age 45 years, respectively. The HR for BRCA2 mutation carriers decreased with increasing time since RRSO (HR = 0.51; 95% CI 0.26-0.99 for 5 years or longer after RRSO). Estimates for premenopausal women were similar. Conclusion We found no evidence that RRSO reduces breast cancer risk for BRCA1 mutation carriers. A potentially beneficial effect for BRCA2 mutation carriers was observed, particularly after 5 years following RRSO. These results may inform counselling and management of carriers with respect to RRSO. Show less
Roos-Blom, M.J.; Gude, W.T.; Spijkstra, J.J.; Jonge, E. de; Dongelmans, D.; Keizer, N.F. de 2019
