Increased transfusion rates correlated with lengthier ICU admission (p≤0.01 regardless of blood product). Ongoing hemorrhage in women with severe PPH manifests subtly and often requires active intervention. Hemorrhage control is required to achieve physiological stabilization and minimize organ damage.Ongoing hemorrhage in women with severe PPH manifests subtly and often requires active intervention. Hemorrhage control is required to achieve physiological stabilization and minimize organ damage. 3-indoxyl sulfate (3-IS) is an indole metabolism byproduct produced by commensal gut bacteria and excreted in the urine; low urinary 3-IS has been associated with increased mortality in bone marrow transplant recipients. This study investigated urinary 3-IS and patient outcomes in the ICU. Prospective study that collected urine samples, rectal swabs, and clinical data on 78 adult ICU patients at admission and again 72h later. Urine was analyzed for 3-IS by mass spectrometry. Median urinary 3-IS levels were 17.1μmol/mmol creatinine (IQR 9.5 to 26.2) at admission and 15.6 (IQR 4.2 to 30.7) 72h later. 22% of patients had low 3-IS (≤6.9μmol/mmol) on ICU admission and 28% after 72h. Low 3-IS at 72h was associated with fewer ICU-free days (22.5 low versus 26 high, p=0.03) and with death during one year of follow-up (36% low versus 9% high 3-IS, p<0.01); there was no detectable difference in 30-day mortality (18% low versus 5% high, p=0.07). Low urinary 3-IS level 72h after ICU admission was associated with fewer ICU-free days and with increased one-year but not 30-day mortality. Further studies should investigate urinary 3-IS as an ICU biomarker.Low urinary 3-IS level 72 h after ICU admission was associated with fewer ICU-free days and with increased one-year but not 30-day mortality. Further studies should investigate urinary 3-IS as an ICU biomarker. We evaluated critical care capacity in the 15 intensive care units (ICUs) in public hospitals in Addis Ababa, Ethiopia to determine the current state of critical care in the city and inform capacity-building efforts. We conducted a cross-sectional survey of ICU medical and nursing directors or their delegates using a standardized questionnaire based on World Federation of Society of Intensive and Critical Care Medicine (WFSICCM) criteria. ICU size ranged from 3 to 15 beds. All ICUs had capacity for mechanical ventilation and vasopressor support, and 53% had intensivists on staff. Ultrasound was available in 93%, while 40% had capacity for invasive blood pressure monitoring. Identified barriers to care included a lack of essential equipment, supplies, medications and specially trained providers. Respondents considered increasing available beds and coordinating between hospitals crucial for capacity building. There is burgeoning critical care capacity in Addis Ababa, Ethiopia with 103 ICU beds in public hospitals, and the WFSICCM criteria provide a useful framework for evaluating critical care capacity and identifying priorities for capacity building. All ICUs in public hospitals in Addis Ababa were able to provide basic support for patients with life-threatening organ failure but demonstrated marked heterogeneity in critical care capacity.There is burgeoning critical care capacity in Addis Ababa, Ethiopia with 103 ICU beds in public hospitals, and the WFSICCM criteria provide a useful framework for evaluating critical care capacity and identifying priorities for capacity building. All ICUs in public hospitals in Addis Ababa were able to provide basic support for patients with life-threatening organ failure but demonstrated marked heterogeneity in critical care capacity.Madangamines are marine natural products isolated from Xestospongia ingens, and madangamine A-E with a different D-ring structure have been reported. We have reported that madangamine A has strong anti-proliferative activity against various human cancer cell lines. In this study, to clarify the anti-proliferative activity of madangamine A, we searched for molecular target of the madangamine A in human cells. selleck compound Treatment with madangamine A increased the levels of LC3-II and p62, autophagy-related proteins, concomitant with growth inhibition. Moreover, madangamine A resulted in lysosome enlargement and increase in lysosomal pH, which are same phenomena observed in chloroquine-treated cells. These results suggest that madangamine A is a novel lysosome inhibitor, and the anti-proliferative activity of madangamine A is due to the inhibition of lysosome function.Destabilizing mutations in small heat shock proteins (sHsps) are linked to multiple diseases; however, sHsps are conformationally dynamic, lack enzymatic function and have no endogenous chemical ligands. These factors render sHsps as classically "undruggable" targets and make it particularly challenging to identify molecules that might bind and stabilize them. To explore potential solutions, we designed a multi-pronged screening workflow involving a combination of computational and biophysical ligand-discovery platforms. Using the core domain of the sHsp family member Hsp27/HSPB1 (Hsp27c) as a target, we applied mixed solvent molecular dynamics (MixMD) to predict three possible binding sites, which we confirmed using NMR-based solvent mapping. Using this knowledge, we then used NMR spectroscopy to carry out a fragment-based drug discovery (FBDD) screen, ultimately identifying two fragments that bind to one of these sites. A medicinal chemistry effort improved the affinity of one fragment by ~50-fold (16 µM), while maintaining good ligand efficiency (~0.32 kcal/mol/non-hydrogen atom). Finally, we found that binding to this site partially restored the stability of disease-associated Hsp27 variants, in a redox-dependent manner. Together, these experiments suggest a new and unexpected binding site on Hsp27, which might be exploited to build chemical probes.Bromodomain and extra-terminal domain (BET) protein plays an important role in epigenetic regulation, and the regulation of disruption contributes to the pathogenesis of cancer and inflammatory disease. With the goal of discovering novel BET inhibitors, especially BRD4 inhibitors, we designed and synthesized several compounds starting from our previously reported pyrido-benzodiazepinone derivative 4 to enhance BRD4 inhibitory activity while avoiding hERG inhibition. Molecular docking studies and structure-activity relationship studies led to the identification of 9-fluorobenzo[f]pyrido[4,3-b][1,4]oxazepin-10-one derivative 43, which exhibited potent BRD4 inhibitory activity with excellent potency in imiquimod-induced psoriasis model mice.