A multi-subgroup predictive model based on clinical parameters and laboratory biomarkers to predict in-hospital outcomes of plasma exchange-centered artificial liver treatment in patients with hepatitis B virus-related acute-on-chronic liver failure

BackgroundPostoperative risk stratification is challenging in patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) who undergo artificial liver treatment. This study characterizes patients’ clinical parameters and laboratory biomarkers with different in-hospital outcomes. The purpose was to establish a multi-subgroup combined predictive model and analyze its predictive capability.MethodsWe enrolled HBV-ACLF patients who received plasma exchange (PE)-centered artificial liver support system (ALSS) therapy from May 6, 2017, to April 6, 2022. There were 110 patients who died (the death group) and 110 propensity score-matched patients who achieved satisfactory outcomes (the survivor group). We compared baseline, before ALSS, after ALSS, and change ratios of laboratory biomarkers. Outcome prediction models were established by generalized estimating equations (GEE). The discrimination was assessed using receiver operating characteristic analyses. Calibration plots compared the mean predicted probability and the mean observed outcome.ResultsWe built a multi-subgroup predictive model (at admission; before ALSS; after ALSS; change ratio) to predict in-hospital outcomes of HBV-ACLF patients who received PE-centered ALSS. There were 110 patients with 363 ALSS sessions who survived and 110 who did not, and 363 ALSS sessions were analyzed. The univariate GEE models revealed that several parameters were independent risk factors. Clinical parameters and laboratory biomarkers were entered into the multivariate GEE model. The discriminative power of the multivariate GEE models was excellent, and calibration showed better agreement between the predicted and observed probabilities than the univariate models.ConclusionsThe multi-subgroup combined predictive model generated accurate prognostic information for patients undergoing HBV-ACLF patients who received PE-centered ALSS

Functional genomic screening identifies dual leucine zipper kinase as a key mediator of retinal ganglion cell death

Glaucoma, a major cause of blindness worldwide, is a neurodegenerative optic neuropathy in which vision loss is caused by loss of retinal ganglion cells (RGCs). To better define the pathways mediating RGC death and identify targets for the development of neuroprotective drugs, we developed a high-throughput RNA interference screen with primary RGCs and used it to screen the full mouse kinome. The screen identified dual leucine zipper kinase (DLK) as a key neuroprotective target in RGCs. In cultured RGCs, DLK signaling is both necessary and sufficient for cell death. DLK undergoes robust posttranscriptional up-regulation in response to axonal injury in vitro and in vivo. Using a conditional knockout approach, we confirmed that DLK is required for RGC JNK activation and cell death in a rodent model of optic neuropathy. In addition, tozasertib, a small molecule protein kinase inhibitor with activity against DLK, protects RGCs from cell death in rodent glaucoma and traumatic optic neuropathy models. Together, our results establish a previously undescribed drug/drug target combination in glaucoma, identify an early marker of RGC injury, and provide a starting point for the development of more specific neuroprotective DLK inhibitors for the treatment of glaucoma, nonglaucomatous forms of optic neuropathy, and perhaps other CNS neurodegenerations

Expert Consensus on Microtransplant for Acute Myeloid Leukemia in Elderly Patients -Report From the International Microtransplant Interest Group

Recent studies have shown that microtransplant (MST) could improve outcome of patients with elderly acute myeloid leukemia (EAML). To further standardize the MST therapy and improve outcomes in EAML patients, based on analysis of the literature on MST, especially MST with EAML from January 1st, 2011 to November 30th, 2022, the International Microtransplant Interest Group provides recommendations and considerations for MST in the treatment of EAML. Four major issues related to MST for treating EAML were addressed: therapeutic principle of MST (1), candidates for MST (2), induction chemotherapy regimens (3), and post-remission therapy based on MST (4). Others included donor screening, infusion of donor cells, laboratory examinations, and complications of treatment

Stable foraminifer isotope composition of ODP Site 184-1143, South China Sea

Site 1143 is located at 9°21.72'N, 113°17.11'E, at a water depth of 2772 m within a basin on the southern continental margin of the South China Sea. Three holes were cored at the site and combined into a composite (spliced) stratigraphic section that documents complete recovery for the upper 190.85 meters composite depth, the interval of advanced piston coring (Wang, Prell, Blum, et al., 2000, doi:10.2973/odp.proc.ir.184.2000; Wang et al., 2001, doi:10.1007/BF02907085). The early Pliocene to Holocene sediment sequence provided abundant and well-preserved calcareous microfossils and offered an excellent opportunity to establish foraminiferal stable isotope records. Here, we present benthic and planktonic d18O and d13C records that cover the last 5 m.y. These data sets will provide an important basis for upcoming studies to generate an orbitally tuned oxygen isotope stratigraphy and examine long- and short-term changes in deep and surface water mass signatures (temperature, salinity, and nutrients) with an average sample spacing of ~2.9 k.y. for the benthic and ~2.6 k.y. for the planktonic records

Age model and Plio-Pleistocene benthic stable oxygen isotope ratios of ODP Site 184-1143 in the Sourh China Sea

Based on benthic foraminiferal delta18O from ODP Site 1143, a 5-Myr astronomical timescale for the West Pacific Plio-Pleistocene was established using an automatic orbital tuning method. The tuned Brunhes/Matuyama paleomagnetic polarity reversal age agrees well with the previously published age of 0.78 Ma. The tuned ages for several planktonic foraminifer bio-events also agree well with published dates, and new ages for some other bio-events in the South China Sea were also estimated. The benthic delta18O from Site 1143 is highly coherent with the Earth's orbit (ETP) both at the obliquity and precession bands for the last 5 Myr, and at the eccentricity band for the last 2 Myr. In general, the 41-kyr cycle was dominant through the Plio-Pleistocene although the 23-kyr cycle was also very strong. The 100-kyr cycle became dominant only during the last 1 Myr. A comparison of the benthic delta18O between the Atlantic (ODP 659) and the East and West Pacific (846 and 1143) reveals that the Atlantic-Pacific benthic oxygen isotope difference ratio (Delta delta18OAtl-Pac) displays an increasing trend in three time intervals: 3.6-2.7 Ma, 2.7-2.1 Ma and 1.5-0.25 Ma. Each of the intervals begins with a rapid negative shift in Delta delta18OAtl-Pac, followed by a long period with an increasing trend, corresponding to the growth of the Northern Hemisphere ice sheet. This means that all three intervals of ice sheet growth in the Northern Hemisphere were accompanied at the beginning by a rapid relative warming of deep water in the Atlantic as compared to that of the Pacific, followed by its gradual relative cooling. This general trend, superimposed on the frequent fluctuations with glacial cycles, should yield insights into the processes leading to the boreal glaciation. Cross-spectral analyses of the Delta delta18OAtl-Pac with the Earth's orbit suggests that after the initiation of Northern Hemisphere glaciation at about 2.5 Ma, obliquity rather than precession had become the dominant force controlling the vertical structure or thermohaline circulation in the paleo-ocean