Regulation of NKB pathways and their roles in the control of Kiss1 neurons in the arcuate nucleus of the male mouse.

Kisspeptin (Kiss1) and neurokinin B (NKB) (encoded by the Kiss1 and Tac2 genes, respectively) are indispensable for reproduction. In the female of many species, Kiss1 neurons in the arcuate nucleus (ARC) coexpress dynorphin A and NKB. Such cells have been termed Kiss1/NKB/Dynorphin (KNDy) neurons, which are thought to mediate the negative feedback regulation of GnRH/LH secretion by 17beta-estradiol. However, we have less knowledge about the molecular physiology and regulation of Kiss1/Kiss1-expressing neurons in the ARC of the male. Our work focused on the adult male mouse, where we sought evidence for coexpression of these neuropeptides in cells in the ARC, assessed the role of Kiss1 neurons in negative feedback regulation of GnRH/LH secretion by testosterone (T), and investigated the action of NKB on KNDy and GnRH neurons. Results showed that 1) the mRNA encoding Kiss1, NKB, and dynorphin are coexpressed in neurons located in the ARC; 2) Kiss1 and dynorphin A mRNA are regulated by T through estrogen and androgen receptor-dependent pathways; 3) senktide, an agonist for the NKB receptor (neurokinin 3 receptor, encoded by Tacr3), stimulates gonadotropin secretion; 4) KNDy neurons express Tacr3, whereas GnRH neurons do not; and 5) senktide activates KNDy neurons but has no discernable effect on GnRH neurons. These observations corroborate the putative role for KNDy neurons in mediating the negative feedback effects of T on GnRH/LH secretion and provide evidence that NKB released from KNDy neurons is part of an auto-feedback loop that generates the pulsatile secretion of Kiss1 and GnRH in the male

Improving surgical quality in low-income and middle-income countries: why do some health facilities perform better than others?

BACKGROUND: Evidence on heterogeneity in outcomes of surgical quality interventions in low-income and middle-income countries is limited. We explored factors driving performance in the Safe Surgery 2020 intervention in Tanzania's Lake Zone to distil implementation lessons for low-resource settings. METHODS: We identified higher (n=3) and lower (n=3) performers from quantitative data on improvement from 14 safety and teamwork and communication indicators at 0 and 12 months from 10 intervention facilities, using a positive deviance framework. From 72 key informant interviews with surgical providers across facilities at 1, 6 and 12 months, we used a grounded theory approach to identify practices of higher and lower performers. RESULTS: Performance experiences of higher and lower performers differed on the following themes: (1) preintervention context, (2) engagement with Safe Surgery 2020 interventions, (3) teamwork and communication orientation, (4) collective learning orientation, (5) role of leadership, and (6) perceived impact of Safe Surgery 2020 and beyond. Higher performers had a culture of teamwork which helped them capitalise on Safe Surgery 2020 to improve surgical ecosystems holistically on safety practices, teamwork and communication. Lower performers prioritised overhauling safety practices and began considering organisational cultural changes much later. Thus, while also improving, lower performers prioritised different goals and trailed higher performers on the change continuum. CONCLUSION: Future interventions should be tailored to facility context and invest in strengthening teamwork, communication and collective learning and facilitate leadership engagement to build a receptive climate for successful implementation of safe surgery interventions