Single-center experience with early liver transplantation for acute alcohol-related hepatitis-Limitations of the SALT score and directions for future study.

Alcohol-related liver disease (ALD) is the leading indication for liver transplantation worldwide. Since Mathurin et al. described their experience in providing early liver transplantation for patients with ALD in 2011, other centers have followed suit with generally favorable survival outcomes. This patient population poses a unique clinical challenge given the expedited nature of the evaluation and the lack of any significant sobriety period prior to transplantation. The SALT (Sustained Alcohol Use Post-Liver Transplant) score is a standardized psychometric tool increasingly used to help stratify the risk of relapse and guide listing decisions for these challenging clinical situations. In 2018, our center introduced a protocol for early liver transplantation for acute alcohol-related hepatitis (AAH). In this article, we offer a retrospective review of 26 patients transplanted between May 2018 and May 2021, including at least 1-year follow-up, and compare outcomes to initial SALT scores; we further identify additional factors that may impact post-transplant success. As transplant committees continue to weigh the ethical dilemma of denying lifesaving treatment against the obligation to remain stewards of a limited resource, we aim to contribute to a more nuanced understanding of risk regarding early transplantation for ALD.

A Link Between Inflammatory Mechanisms and Fibromyalgia.

Fibromyalgia (FM) is a condition characterized by chronic widespread pain, which has traditionally been considered psychogenic in nature due to lack of known underlying organic pathophysiology. In more recent years, inflammation of the nervous system has become increasingly recognized as a sign of neuropsychiatric conditions, and this association may enhance our knowledge of conditions such as FM. Emerging evidence has suggested inflammation, particularly neuroinflammation, as a potential contributor underlying the etiology of FM. Studies have searched for linked biomarkers with mixed results, though the literature is beginning to point to increased systemic levels of pro-inflammatory cytokines such as IL-6 and IL-8 in patients with FM relative to healthy controls. A multicenter imaging study has also reported results suggestive of microglial activation related to the presence of FM. Given the consistency in neuroinflammatory effects implicated in "sickness behavior" characteristic of chronic systemic inflammatory conditions such as cancer or rheumatic diseases, therein springs the hypothesis for a connection between FM and neuroinflammation as discussed in this chapter.

The Diagnosis of Malingering in General Hospitals in the United States: A Retrospective Analysis of the National Inpatient Sample.

Objective: To characterize the socio-demographics and comorbid medical and psychiatric diagnoses of patients in the general hospital diagnosed with malingering. Method: We conducted a retrospective observational cohort study using data from the 2019 National Inpatient Sample, an all-payors database of acute care general hospital discharges in the United States, querying for patients aged 18 and older discharged with a diagnosis of "malingerer [conscious simulation]," ICD-10 code Z76.5. Results: 45,645 hospitalizations (95% CI: 43,503 to 47,787) during the study year included a discharge diagnosis of malingering. 56.1% were for male patients, and the median age was 43 years (IQR 33 to 54). Black patients represented 26.8% of the patients with a discharge diagnosis of malingering, compared to 14.9% of all patients sampled. Zip codes in the lowest household income quartile comprised 39.9% of malingering diagnoses. The top categories of primary discharge diagnoses of hospitalizations included medical ("Diabetes mellitus without complications"), psychiatric ("Depressive disorders"), and substance use ("Alcohol-related disorders") disorders. "Sepsis, unspecified organism," was the most common primary diagnosis. Conclusion: The striking overrepresentation of Black patients in hospitalizations with diagnosis of malingering raises concern about the roles of implicit and systemic biases in assigning this label. The disproportionate number of patients of low socioeconomic status is further suggestive of bias and disparity. Another potential contribution is that the lower health literacy in these populations results in a limited knowledge of traditional ways to meet one's needs and thus greater reliance on malingered behavior as an alternative means. Accurate description of these patients' socio-demographics and comorbid medical and psychiatric diagnoses with reliable data from large samples can lead to improved understanding of how the malingering label is applied and ultimately better patient care.

EGFR and PDGFRA co-expression and heterodimerization in glioblastoma tumor sphere lines.

Concurrent amplifications of EGFR and PDGFRA have been reported in up to 5% of glioblastoma (GBM) and it remains unclear why such independent amplification events, and associated receptor overexpression, would be adaptive during glioma evolution. Here, we document that EGFR and PDGFRA protein co-expression occurs in 37% of GBM. There is wide cell-to-cell variation in the expressions of these receptor tyrosine kinases (RTKs) in stable tumor sphere lines, frequently defining tumor cell subpopulations with distinct sensitivities to growth factors and RTK inhibitors. We also find evidence for functional transactivation of PDGFRA by EGFR and EGF-induced receptor heterodimerization, both of which are abolished by EGFR inhibitors. These results indicate that GBM growth responses to targeted therapies previously tested in clinical trials are strongly influenced by the balance of EGFR and PDGFRA activation in individual cells, which is heterogeneous at baseline.

Transcription factor Sp4 regulates expression of nervous wreck 2 to control NMDAR1 levels and dendrite patterning.

Glutamatergic signaling through N-methyl-d-aspartate receptors (NMDARs) is important for neuronal development and plasticity and is often dysregulated in psychiatric disorders. Mice mutant for the transcription factor Sp4 have reduced levels of NMDAR subunit 1 (NR1) protein, but not mRNA, and exhibit behavioral and memory deficits (Zhou et al., [2010] Human Molecular Genetics 19: 3797-3805). In developing cerebellar granule neurons (CGNs), Sp4 controls dendrite patterning (Ramos et al., [2007] Proc Natl Acad Sci USA 104: 9882-9887). Sp4 target genes that regulate dendrite pruning or NR1 levels are not known. Here we report that Sp4 activates transcription of Nervous Wreck 2 (Nwk2; also known as Fchsd1) and, further, that Nwk2, an F-BAR domain-containing protein, mediates Sp4-dependent regulation of dendrite patterning and cell surface expression of NR1. Knockdown of Nwk2 in CGNs increased primary dendrite number, phenocopying Sp4 knockdown, and exogenous expression of Nwk2 in Sp4-depleted neurons rescued dendrite number. We observed that acute Sp4 depletion reduced levels of surface, but not total, NR1, and this was rescued by Nwk2 expression. Furthermore, expression of Nr1 suppressed the increase in dendrite number in Sp4- or Nwk2- depleted neurons. We previously reported that Sp4 protein levels were reduced in cerebellum of subjects with bipolar disorder (BD) (Pinacho et al., [2011] Bipolar Disorders 13: 474-485). Here we report that Nwk2 mRNA and NR1 protein levels were also reduced in postmortem cerebellum of BD subjects. Our data suggest a role for Sp4-regulated Nwk2 in NMDAR trafficking and identify a Sp4-Nwk2-NMDAR1 pathway that regulates neuronal morphogenesis during development and may be disrupted in bipolar disorder.

ROS1 signaling regulates epithelial differentiation in the epididymis.

The initial segment (IS) of the epididymis plays an essential role in male fertility. The IS epithelium is undifferentiated and nonfunctional at birth. Prior to puberty, the epithelium undergoes differentiation that leads to the formation of a fully functional organ. However, the mechanistic details of this program are not well understood. To explore this further, we used genetic engineering to create a kinase dead allele of the ROS1 receptor tyrosine kinase in mice and studied the effects of ROS1 tyrosine kinase activity on the differentiation of the IS epithelium. We show that the expression and activation of ROS1 coincides with the onset of differentiation and is exclusively located in the IS of the maturing and adult mouse epididymides. Here we demonstrate that the differentiation of the IS is dependent on the kinase activity of ROS1 and its downstream effector MEK1/2-ERK1/2 signaling axis. Using genetic engineering, we show that germ line ablation of ROS1 kinase activity leads to a failure of the IS epithelium to differentiate, and as a consequence sperm maturation and infertility were dramatically perturbed. Pharmacological inhibition of ROS1 kinase activity in the developing epididymis, however, only delayed differentiation transiently and did not result in infertility. Our results demonstrate that ROS1 kinase activity and the ensuing MEK1/2-ERK1/2 signaling are necessary for the postnatal development of the IS epithelium and that a sustained ablation of ROS1 kinase activity within the critical window of terminal differentiation abrogate the function of the epididymis and leads to sterility.