Patient-Reported and Clinical Outcomes Among Patients With Calciphylaxis.

Objective: To describe the pain intensity among hospitalized patients with calciphylaxis, elucidate the factors associated with pain improvement, and examine the link between pain improvement and clinical outcomes. Patients and Methods: Patients were identified from the Partners Research Patient Data Registry and the Partners Calciphylaxis Registry and Biorepository (Clinicaltrials.gov ID: NCT03032835). Those with calciphylaxis requiring hospitalization for at least 14 consecutive days during the study period from May 2016 through December 2021 were included. Pain intensity was assessed using patient-reported pain scores on numerical rating scales from 0 to 10. Associations between pain improvement and clinical outcomes, including lesion improvement, amputation, and mortality, were examined using univariate and multivariate regression models. Results: Our analysis included 111 patients (age, 58±14 years; men, 40%; on maintenance dialysis, 79%). No significant improvement of pain intensity was observed over the 14 days of hospitalization (mean difference, -0.71; P=.08). However, among 49 (44.1%) patients who showed at least 1-point improvement in the pain score, there was an association with surgical debridement during hospitalization (odds ratio, 3.37; 95% CI, 1.17-9.67; P=.02). Hyperbaric oxygen therapy was associated with pain improvement (odds ratio, 5.38; 95% CI, 1.14-25.50; P=.03) in patients on maintenance dialysis. Pain improvement was associated with lower rates of subsequent amputation at 6 months of follow up (6% vs 13%; P<.05) but did not predict lesion improvement or survival. Conclusion: Pain control remains a challenge among hospitalized patients with calciphylaxis. Surgical debridement and hyperbaric oxygen therapy may improve pain intensity. Pain improvement predicted a lower risk of future amputation.

Human Evaluation of Models Built for Interpretability.

Recent years have seen a boom in interest in interpretable machine learning systems built on models that can be understood, at least to some degree, by domain experts. However, exactly what kinds of models are truly human-interpretable remains poorly understood. This work advances our understanding of precisely which factors make models interpretable in the context of decision sets, a specific class of logic-based model. We conduct carefully controlled human-subject experiments in two domains across three tasks based on human-simulatability through which we identify specific types of complexity that affect performance more heavily than others-trends that are consistent across tasks and domains. These results can inform the choice of regularizers during optimization to learn more interpretable models, and their consistency suggests that there may exist common design principles for interpretable machine learning systems.

Etoposide-induced DNA damage affects multiple cellular pathways in addition to DNA damage response.

DNA damage response (DDR) coordinates lesion repair and checkpoint activation. DDR is intimately connected with transcription. However, the relationship between DDR and transcription has not been clearly established. We report here RNA-sequencing analyses of MCF7 cells containing double-strand breaks induced by etoposide. While etoposide does not apparently cause global changes in mRNA abundance, it altered some gene expression. At the setting of fold alteration ≥ 2 and false discovery rate (FDR) ≤ 0.001, FDR < 0.05, or p < 0.05, etoposide upregulated 96, 268, or 860 genes and downregulated 41, 133, or 503 genes in MCF7 cells. Among these differentially expressed genes (DEGs), the processes of biogenesis, metabolism, cell motility, signal transduction, and others were affected; the pathways of Ras GTPase activity, RNA binding, cytokine-mediated signaling, kinase regulatory activity, protein binding, and translation were upregulated, and those pathways related to coated vesicle, calmodulin binding, and microtubule-based movement were downregulated. We further identified RABL6, RFTN2, FAS-AS1, and TCEB3CL as new DDR-affected genes in MCF7 and T47D cells. By metabolic labelling using 4-thiouridine, we observed dynamic alterations in the transcription of these genes in etoposide-treated MCF7 and T47D cells. During 0-2 hour etoposide treatment, RABL6 transcription was robustly increased at 0.5 and 1 hour in MCF7 cells and at 2 hours in T47D cells, while FAS-AS1 transcription was dramatically and steadily elevated in both cell lines. Taken together, we demonstrate dynamic alterations in transcription and that these changes affect multiple cellular processes in etoposide-induced DDR.

Effects of Soft Drinks on Resting State EEG and Brain-Computer Interface Performance.

Motor imagery-based (MI based) brain-computer interface (BCI) using electroencephalography (EEG) allows users to directly control a computer or external device by modulating and decoding the brain waves. A variety of factors could potentially affect the performance of BCI such as the health status of subjects or the environment. In this study, we investigated the effects of soft drinks and regular coffee on EEG signals under resting state and on the performance of MI based BCI. Twenty-six healthy human subjects participated in three or four BCI sessions with a resting period in each session. During each session, the subjects drank an unlabeled soft drink with either sugar (Caffeine Free Coca-Cola), caffeine (Diet Coke), neither ingredient (Caffeine Free Diet Coke), or a regular coffee if there was a fourth session. The resting state spectral power in each condition was compared; the analysis showed that power in alpha and beta band after caffeine consumption were decreased substantially compared to control and sugar condition. Although the attenuation of powers in the frequency range used for the online BCI control signal was shown, group averaged BCI online performance after consuming caffeine was similar to those of other conditions. This work, for the first time, shows the effect of caffeine, sugar intake on the online BCI performance and resting state brain signal.

Soft drink effects on sensorimotor rhythm brain computer interface performance and resting-state spectral power.

Brain-computer interface (BCI) systems allow users to directly control computers and other machines by modulating their brain waves. In the present study, we investigated the effect of soft drinks on resting state (RS) EEG signals and BCI control. Eight healthy human volunteers each participated in three sessions of BCI cursor tasks and resting state EEG. During each session, the subjects drank an unlabeled soft drink with either sugar, caffeine, or neither ingredient. A comparison of resting state spectral power shows a substantial decrease in alpha and beta power after caffeine consumption relative to control. Despite attenuation of the frequency range used for the control signal, caffeine average BCI performance was the same as control. Our work provides a useful characterization of caffeine, the world's most popular stimulant, on brain signal frequencies and their effect on BCI performance.

Acetylation of the c-MYC oncoprotein is required for cooperation with the HTLV-1 p30(II) accessory protein and the induction of oncogenic cellular transformation by p30(II)/c-MYC.

The human T-cell leukemia retrovirus type-1 (HTLV-1) p30(II) protein is a multifunctional latency-maintenance factor that negatively regulates viral gene expression and deregulates host signaling pathways involved in aberrant T-cell growth and proliferation. We have previously demonstrated that p30(II) interacts with the c-MYC oncoprotein and enhances c-MYC-dependent transcriptional and oncogenic functions. However, the molecular and biochemical events that mediate the cooperation between p30(II) and c-MYC remain to be completely understood. Herein we demonstrate that p30(II) induces lysine-acetylation of the c-MYC oncoprotein. Acetylation-defective c-MYC Lys→Arg substitution mutants are impaired for oncogenic transformation with p30(II) in c-myc(-/-) HO15.19 fibroblasts. Using dual-chromatin-immunoprecipitations (dual-ChIPs), we further demonstrate that p30(II) is present in c-MYC-containing nucleoprotein complexes in HTLV-1-transformed HuT-102 T-lymphocytes. Moreover, p30(II) inhibits apoptosis in proliferating cells expressing c-MYC under conditions of genotoxic stress. These findings suggest that c-MYC-acetylation is required for the cooperation between p30(II)/c-MYC which could promote proviral replication and contribute to HTLV-1-induced carcinogenesis.

(-)-Phenserine attenuates soman-induced neuropathology.

Organophosphorus (OP) nerve agents are deadly chemical weapons that pose an alarming threat to military and civilian populations. The irreversible inhibition of the critical cholinergic degradative enzyme acetylcholinesterase (AChE) by OP nerve agents leads to cholinergic crisis. Resulting excessive synaptic acetylcholine levels leads to status epilepticus that, in turn, results in brain damage. Current countermeasures are only modestly effective in protecting against OP-induced brain damage, supporting interest for evaluation of new ones. (-)-Phenserine is a reversible AChE inhibitor possessing neuroprotective and amyloid precursor protein lowering actions that reached Phase III clinical trials for Alzheimer's Disease where it exhibited a wide safety margin. This compound preferentially enters the CNS and has potential to impede soman binding to the active site of AChE to, thereby, serve in a protective capacity. Herein, we demonstrate that (-)-phenserine protects neurons against soman-induced neuronal cell death in rats when administered either as a pretreatment or post-treatment paradigm, improves motoric movement in soman-exposed animals and reduces mortality when given as a pretreatment. Gene expression analysis, undertaken to elucidate mechanism, showed that (-)-phenserine pretreatment increased select neuroprotective genes and reversed a Homer1 expression elevation induced by soman exposure. These studies suggest that (-)-phenserine warrants further evaluation as an OP nerve agent protective strategy.