Protocol of the IntenSify-Trial: An open-label phase I trial of the CYP3A inhibitor cobicistat and the cytostatics gemcitabine and nab-paclitaxel in patients with advanced stage or metastatic pancreatic ductal adenocarcinoma to evaluate the combination's pharmacokinetics, safety, and efficacy.

Expression of CYP3A5 protein is a basal and acquired resistance mechanism of pancreatic ductal adenocarcinoma cells conferring protection against the CYP3A and CYP2C8 substrate paclitaxel through metabolic degradation. Inhibition of CYP3A isozymes restores the cells sensitivity to paclitaxel. The combination of gemcitabine and nab-paclitaxel is an established regimen for the treatment of metastasized or locally advanced inoperable pancreatic cancer. Cobicistat is a CYP3A inhibitor developed for the pharmacoenhancement of protease inhibitors. The addition of cobicistat to gemcitabine and nab-paclitaxel may increase the antitumor effect. We will conduct a phase I dose escalation trial with a classical 3 + 3 design to investigate the safety, tolerability, and pharmacokinetics (PKs) of gemcitabine, nab-paclitaxel, and cobicistat. Although the doses of gemcitabine (1000 mg/m2 ) and cobicistat (150 mg) are fixed, three dose levels of nab-paclitaxel (75, 100, and 125 mg/m2 ) will be explored to account for a potential PK drug interaction. After the dose escalation phase, we will set the recommended dose for expansion (RDE) and treat up to nine patients in an expansion part of the trial. The trial is registered under the following identifiers EudraCT-Nr. 2019-001439-29, drks.de: DRKS00029409, and ct.gov: NCT05494866. Overcoming resistance to paclitaxel by CYP3A5 inhibition may lead to an increased efficacy of the gemcitabine and nab-paclitaxel regimen. Safety, efficacy, PK, and RDE data need to be acquired before investigating this combination in a large-scale clinical study.

Assessing the impact of the Royal Canadian Mounted Police (RCMP) protocol and Emotional Resilience Skills Training (ERST) among diverse public safety personnel.

BACKGROUND: Public safety personnel (PSP; e.g., border services personnel, correctional workers, firefighters, paramedics, police, public safety communicators) are frequently exposed to potentially psychologically traumatic events. Such events contribute to substantial and growing challenges from posttraumatic stress injuries (PTSIs), including but not limited to posttraumatic stress disorder. METHODS: The current protocol paper describes the PSP PTSI Study (i.e., design, measures, materials, hypotheses, planned analyses, expected implications, and limitations), which was originally designed to evaluate an evidence-informed, proactive system of mental health assessment and training among Royal Canadian Mounted Police for delivery among diverse PSP (i.e., firefighters, municipal police, paramedics, public safety communicators). Specifically, the PSP PTSI Study will: (1) adapt, implement, and assess the impact of a system for ongoing (i.e., annual, monthly, daily) evidence-based assessments; (2) evaluate associations between demographic variables and PTSI; (3) longitudinally assess individual differences associated with PTSI; and, (4) assess the impact of providing diverse PSP with a tailored version of the Emotional Resilience Skills Training originally developed for the Royal Canadian Mounted Police in mitigating PTSIs based on the Unified Protocol for the Transdiagnostic Treatment of Emotional Disorders. Participants are assessed pre- and post-training, and then at a follow-up 1-year after training. The assessments include clinical interviews, self-report surveys including brief daily and monthly assessments, and daily biometric data. The current protocol paper also describes participant recruitment and developments to date. DISCUSSION: The PSP PTSI Study is an opportunity to implement, test, and improve a set of evidence-based tools and training as part of an evidence-informed solution to protect PSP mental health. The current protocol paper provides details to inform and support translation of the PSP PTSI Study results as well as informing and supporting replication efforts by other researchers. TRIAL REGISTRATION: Hypotheses Registration: aspredicted.org, #90136. Registered 7 March 2022-Prospectively registered. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05530642. Registered 1 September 2022-Retrospectively registered. The subsequent PSP PTSI Study results are expected to benefit the mental health of all participants and, ultimately, all PSP.

Terrestrial forcing of marine biodiversification.

The diversification of the three major marine faunas during the Phanerozoic was intimately coupled to the evolution of the biogeochemical cycles of carbon and nutrients via nutrient runoff from land and the diversification of phosphorus-rich phytoplankton. Nutrient input to the oceans has previously been demonstrated to have occurred in response to orogeny and fueling marine diversification. Although volcanism has typically been associated with extinction, the eruption of continental Large Igneous Provinces (LIPs) is also a very significant, but previously overlooked, source of phosphorus involved in the diversification of the marine biosphere. We demonstrate that phosphorus input to the oceans peaked repeatedly following the eruption and weathering of LIPs, stimulating the diversification of nutrient-rich calcareous and siliceous phytoplankton at the base of marine food webs that in turn helped fuel diversification at higher levels. These developments were likely furthered by the evolution of terrestrial floras. Results for the Meso-Cenozoic hold implications for the Paleozoic Era. Early-to-middle Paleozoic diversity was, in contrast to the Meso-Cenozoic, limited by nutrient-poor phytoplankton resulting from less frequent tectonism and poorly-developed terrestrial floras. Nutrient runoff and primary productivity during the Permo-Carboniferous likely increased, based on widespread orogeny, the spread of deeper-rooting forests, the fossil record of phytoplankton, and biogeochemical indices. Our results suggest that marine biodiversity on geologic time scales is unbounded (unlimited), provided sufficient habitat, nutrients, and nutrient-rich phytoplankton are also available in optimal amounts and on optimal timescales.