There are no plasma biomarkers specific for GVHD of the gastrointestinal (GI) tract, the GVHD target organ most associated with nonrelapse mortality (NRM) following hematopoietic cell transplantation ...(HCT). Using an unbiased, large-scale, quantitative proteomic discovery approach to identify candidate biomarkers that were increased in plasma from HCT patients with GI GVHD, 74 proteins were increased at least 2-fold; 5 were of GI origin. We validated the lead candidate, REG3α, by ELISA in samples from 1014 HCT patients from 3 transplantation centers. Plasma REG3α concentrations were 3-fold higher in patients at GI GVHD onset than in all other patients and correlated most closely with lower GI GVHD. REG3α concentrations at GVHD onset predicted response to therapy at 4 weeks, 1-year NRM, and 1-year survival (P ≤ .001). In a multivariate analysis, advanced clinical stage, severe histologic damage, and high REG3α concentrations at GVHD diagnosis independently predicted 1-year NRM, which progressively increased with higher numbers of onset risk factors present: 25% for patients with 0 risk factors to 86% with 3 risk factors present (P < .001). REG3α is a plasma biomarker of GI GVHD that can be combined with clinical stage and histologic grade to improve risk stratification of patients.
In the inductive power transfer systems (IPTSs) of wireless electric vehicles (WEV), the electromagnetic field (EMF) should be lowered for the safety of pedestrians. In general, the EMF should be ...canceled for every space, time, and load condition of interest. Three generalized design methods for cancelling the EMF of WEV are proposed in this paper. By adding active EMF cancel coils to each primary main coil and secondary main coil, respectively, the EMF generated from each main coil can be independently cancelled by their corresponding cancel coils. Moreover, the EMF can be successfully mitigated if a dominant EMF source only is cancelled with 3-dB margin, which can be applied to any resonant type wireless power transfer systems. Furthermore, no significant power drop may occur if the cancel coils are placed aside from magnetic coupling path. Design examples are shown for U-type and W-type IPTS as well as a wireless stationary EV charger. Experimental verifications are shown for a recently developed I-type IPTS, which has a narrow rail width structure with alternating magnetic polarity along with a roadway. The proposed design methods have been demonstrated, without the loss of generality, to only the secondary coil where relatively large EMF is generated due to high ampere turns. An optimum spacing for cancel coils from main coils and an optimum number of turns are determined. Through experiments, additional EMF mitigation techniques such as the magnetic mirror method, separating pick-up rectifiers, and passive Al plate are provided. Thus, the EMF at 1 m distance from the center of a pick-up becomes under 44 mG even for the maximum power of 12 kW.
Following the inauguration, the Trump administration authorized a series of anti-immigrant policies, including modifications to the public charge regulation. This study analyzed the effect of the ...publication of a proposed public charge rule in 2018 on the risk of preterm birth between uninsured and privately insured Latinx birthing people in the United States by using natality files from the National Center for Health Statistics. In total, 1,375,580 Latinx birthing people reported private insurance as their primary source of delivery from 2014 to 2019, while 317,056 Latinx birthing people reported self-pay as their primary source of delivery during the same period. After the publication of the proposed public charge rule in 2018, the odds of preterm birth among uninsured foreign-born Latinx birthing people increased by 6.2% compared with privately insured foreign-born Latinx birthing people (OR: 1.062; 95% CI: 1.016, 1.110). On the other hand, the odds of preterm births among uninsured US-born Latinx birthing people did not significantly increase after the publication of the proposed rule compared with privately insured US-born Latinx birthing people. These findings suggest the publication of the public charge rule proposed in 2018 may be associated with adverse birth outcomes among uninsured foreign-born Latinx birthing people in the United States.
Pre-synaptic nerve terminals (synaptosomes) require ATP for neurotransmitter exocytosis and recovery and for ionic homeostasis, and are consequently abundantly furnished with mitochondria. ...Pre-synaptic mitochondrial dysfunction is implicated in a variety of neurodegenerative disorders, although there is no precise definition of the term 'dysfunction'. In this study, we test the hypothesis that partial restriction of electron transport through Complexes I and II in synaptosomes to mimic possible defects associated with Parkinson's and Huntington's diseases respectively, sensitizes individual terminals to mitochondrial depolarization under conditions of enhanced proton current utilization, even though these stresses are within the respiratory capacity of the synaptosomes when averaged over the entire population. We combine two novel techniques, firstly using a modification of a plate-based respiration and glycolysis assay that requires only microgram quantities of synaptosomal protein, and secondly developing an improved method for fluorescent imaging and statistical analysis of single synaptosomes. Conditions are defined for optimal substrate supply to the in situ mitochondria within mouse cerebrocortical synaptosomes, and the energetic demands of ion cycling and action-potential firing at the plasma membrane are additionally determined.
Serum levels of an interleukin-1 receptor family member called suppressor of tumorigenicity 2 (ST2) predict response to therapy for graft-versus-host disease (GVHD) and improve on clinical grading in ...assessing the risk of death without relapse after allogeneic transplantation.
Although mortality related to graft-versus-host disease (GVHD) after allogeneic hematopoietic stem-cell transplantation has been reduced,
1
,
2
acute GVHD remains a major complication of allogeneic transplantation, occurring in approximately half the transplant recipients.
3
,
4
High-dose systemic glucocorticoids remain the first-line therapy for GVHD,
5
–
9
although just half of patients have complete resolution of GVHD by day 28 after therapy initiation.
6
Patients who do not have a response to GVHD therapy are at high risk for death without relapse of the primary disease for which the transplantation was performed within 6 months after therapy initiation.
10
–
13
We previously reported that a model . . .
In response to the opioid epidemic in the United States, the federal and state governments have initiated various public health responses to mitigate the problem. Among others, Drug-Induced Homicide ...Laws (DIHL) have been introduced to disrupt opioid supply by imposing unconventionally punitive sanctions against sales and distribution. The purpose of this study was to examine whether DIHL had an impact on opioid-related deaths, while controlling for other laws and socioeconomic indices. A dynamic panel model was used with cases from 92 counties across 10 states and the District of Columbia between 2013 and 2018. The findings suggest that DIHL implementation has curtailed the rate of opioid mortality. Supply-interruption approaches may have merits and should be further evaluated.
Given its heterogeneity and diverse clinical outcomes, precise subclassification of BCLC-C hepatocellular carcinoma (HCC) is required for appropriately determining patient prognosis and selecting ...treatment.
We recruited 2,626 patients with BCLC-C stage HCC from multiple centers, comprising training/test (n=1,693) and validation cohorts (n=933). The XGBoost was chosen for maximum performance among the machine learning (ML) models. Patients were categorized into low-/intermediate-/high-/very high-risk subgroups which were based on the estimated prognosis, and this subclassification was named the CLAssification via Machine learning of BCLC-C (CLAM-C).
The areas under the receiver operating characteristic curve of the CLAM-C for predicting the 6-/12-/24-month survival of patients with BCLC-C were 0.800/0.831/0.715, respectively-significantly higher than those of the conventional models, which was consistent in the validation cohort. The four subgroups had significantly different median overall survivals, and this difference was maintained among various patient subgroups and treatment modalities. Immune-checkpoint inhibitors and transarterial therapies were associated with significantly better survival than tyrosine kinase inhibitors (TKIs) in the low- and intermediate-risk subgroups. In cases with first-line systemic therapy, the CLAM-C identified atezolizumab-bevacizumab as the best therapy particularly in the high-risk group. In cases with later-line systemic therapy, nivolumab had better survival than TKIs in the low-to-intermediate-risk subgroup, whereas TKIs had better survival in the high-to-very high-risk subgroup.
ML modeling effectively subclassified patients with BCLC-C HCC, potentially aiding treatment allocation. Our study underscores the potential utilization of ML modeling in terms of prognostication and treatment allocation in patients with BCLC-C HCC.
Severe (grade 3-4) acute graft-versus-host disease (AGVHD) is a major cause of death after unrelated-donor (URD) hematopoietic cell transplant (HCT), resulting in particularly high mortality after ...HLA-mismatched transplantation. There are no approved agents for AGVHD prevention, underscoring the critical unmet need for novel therapeutics. ABA2 was a phase II trial to rigorously assess safety, efficacy, and immunologic effects of adding T-cell costimulation blockade with abatacept to calcineurin inhibitor (CNI)/methotrexate (MTX)-based GVHD prophylaxis, to test whether abatacept could decrease AGVHD.
ABA2 enrolled adults and children with hematologic malignancies under two strata: a randomized, double-blind, placebo-controlled stratum (8/8-HLA-matched URD), comparing CNI/MTX plus abatacept with CNI/MTX plus placebo, and a single-arm stratum (7/8-HLA-mismatched URD) comparing CNI/MTX plus abatacept versus CNI/MTX CIBMTR controls. The primary end point was day +100 grade 3-4 AGVHD, with day +180 severe-AGVHD-free-survival (SGFS) a key secondary end point. Sample sizes were calculated using a higher type-1 error (0.2) as recommended for phase II trials, and were based on predicting that abatacept would reduce grade 3-4 AGVHD from 20% to 10% (8/8s) and 30% to 10% (7/8s). ABA2 enrolled 142 recipients (8/8s, median follow-up = 716 days) and 43 recipients (7/8s, median follow-up = 708 days).
In 8/8s, grade 3-4 AGVHD was 6.8% (abatacept) versus 14.8% (placebo) (
= .13, hazard ratio = 0.45). SGFS was 93.2% (CNI/MTX plus abatacept) versus 82% (CNI/MTX plus placebo,
= .05). In the smaller 7/8 cohort, grade 3-4 AGVHD was 2.3% (CNI/MTX plus abatacept, intention-to-treat population), which compared favorably with a nonrandomized matched cohort of CNI/MTX (30.2%,
< .001), and the SGFS was better (97.7%
58.7%,
< .001). Immunologic analysis revealed control of T-cell activation in abatacept-treated patients.
Adding abatacept to URD HCT was safe, reduced AGVHD, and improved SGFS. These results suggest that abatacept may substantially improve AGVHD-related transplant outcomes, with a particularly beneficial impact on HLA-mismatched HCT.
This study analyzed the effects of the announcement and publication of the 2019 Public Charge Rule on participation of the special supplemental nutrition program for women, infants, and children ...(WIC) among pregnant immigrants. A difference-in-differences approach was used to analyze the changes in prenatal WIC participation before and after the 2019 Public Charge Rule announcement and publication among immigrants relative to US natives. We identified 17,623,683 live singletons born in a hospital from 2015 to 2019. Compared to US natives, the odds of prenatal WIC participation among immigrants were 11.4% lower after the 2019 Public Charge Rule announcement, and 19% lower after the final rule was published. The results of this study suggest that pregnant immigrants may decide not to participate in the WIC program due to the fear of jeopardizing their immigration status after the announcement and publication of the 2019 Public Charge Rule.
Nicotinamide adenine dinucleotide (NAD) exists in an oxidized form (NAD+) and a reduced form (NADH). NAD+ plays crucial roles in cancer metabolism, including in cellular signaling, energy production ...and redox regulation. However, it remains unclear whether NAD(H) pool size (NAD+ and NADH) could be used as biomarker for colon cancer progression. Here, we showed that the NAD(H) pool size and NAD+/NADH ratio both increased during colorectal cancer (CRC) progression due to activation of the NAD+ salvage pathway mediated by nicotinamide phosphoribosyltransferase (NAMPT). The NAMPT expression was upregulated in adenoma and adenocarcinoma tissues from CRC patients. The NADH fluorescence intensity measured by two‐photon excitation fluorescence (TPEF) microscopy was consistently increased in CRC cell lines, azoxymethane/dextran sodium sulfate (AOM/DSS)‐induced CRC tissues and tumor tissues from CRC patients. The increases in the NAD(H) pool inhibited the accumulation of excessive reactive oxygen species (ROS) levels and FK866, a specific inhibitor of NAMPT, treatment decreased the CRC nodule size by increasing ROS levels in AOM/DSS mice. Collectively, our results suggest that NAMPT‐mediated upregulation of the NAD(H) pool protects cancer cells against detrimental oxidative stress and that detecting NADH fluorescence by TPEF microscopy could be a potential method for monitoring CRC progression.
NAD(H) pool size increased during colorectal cancer (CRC) progression due to activation of the enzymes in the salvage pathway of NAD+ synthesis, especially NAMPT. The increases in the NAD(H) pool promoted colon cancer progression by decreasing excessive ROS levels. Detection of NADH fluorescence by TPEF microscopy could be a potential method for monitoring CRC progression.
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