Pediatric Traumatic Brain Injury Outcomes and Disparities During the COVID-19 Pandemic.

BACKGROUND: To study the impact of the COVID-19 pandemic on traumatic brain injury (TBI) patient demographic, clinical and trauma related characteristics, and outcomes. METHODS: Retrospective chart review was conducted on pediatric TBI patients admitted to a Level I Pediatric Trauma Center between January 2015 and June 2022. The pre-COVID era was defined as January 1, 2015, through March 12, 2020. The COVID-19 era was defined as March 13, 2020, through June 30, 2022. Bivariate analysis and logistic regression were performed. RESULTS: Four hundred-thirty patients were treated for pediatric TBI in the pre-COVID-19 period, and 166 patients during COVID-19. In bivariate analyses, the racial/ethnic makeup, age, and sex varied significantly across the two time periods (p < 0.05). Unwitnessed TBI events increased during the COVID-19 era. Logistic regression analyses also demonstrated significantly increased odds of death, severe disability, or vegetative state during COVID-19 (AOR 7.23; 95 % CI 1.43, 36.41). CONCLUSION: During the COVID-19 pandemic, patients admitted with pediatric TBI had significantly different demographics with regards to age, sex, and race/ethnicity when compared to patients prior to the pandemic. There was an increase in unwitnessed events. In the COVID period, patients had a higher odds ratio of severe morbidity and mortality despite adjustment for confounding factors. LEVEL OF EVIDENCE AND STUDY TYPE: Level II, Prognosis.

GCRS: A hybrid graph convolutional network for risk stratification in multiple myeloma cancer patients.

In this study, we present an efficient Graph Convolutional Network based Risk Stratification system (GCRS) for cancer risk-stage prediction of newly diagnosed multiple myeloma (NDMM) patients. GCRS is a hybrid graph convolutional network consisting of a fusion of multiple connectivity graphs that are used to learn the latent representation of topological structures among patients. This proposed risk stratification system integrates these connectivity graphs prepared from the clinical and laboratory characteristics of NDMM cancer patients for partitioning them into three cancer risk groups: low, intermediate, and high. Extensive experiments demonstrate that GCRS outperforms the existing state-of-the-art methods in terms of C-index and hazard ratio on two publicly available datasets of NDMM patients. We have statistically validated our results using the Cox Proportional-Hazards model, Kaplan-Meier analysis, and log-rank test on progression-free survival (PFS) and overall survival (OS). We have also evaluated the contribution of various clinical parameters as utilized by the GCRS risk stratification system using the SHapley Additive exPlanations (SHAP) analysis, an interpretability algorithm for validating AI methods. Our study reveals the utility of the deep learning approach in building a robust system for cancer risk stage prediction.

The burden of non-alcoholic steatohepatitis: A systematic review of health-related quality of life and patient-reported outcomes.

Background & Aims: Non-alcoholic steatohepatitis (NASH) is associated with increased mortality and a high clinical burden. NASH adversely impacts patients' health-related quality of life (HRQoL), but published data on the humanistic burden of disease are limited. This review aimed to summarise and critically evaluate studies reporting HRQoL or patient-reported outcomes (PROs) in populations with NASH and identify key gaps for further research. Methods: Medline, EMBASE, the Cochrane Library and PsycINFO were searched for English-language publications published from 2010 to 2021 that reported HRQoL/PRO outcomes of a population or subpopulation with NASH. Results: Twenty-five publications covering 23 unique studies were identified. Overall, the data showed a substantial impact of NASH on HRQoL, particularly in terms of physical functioning and fatigue, with deterioration of physical and mental health as NASH progresses. Prevalent symptoms, including fatigue, abdominal pain, anxiety/depression, cognition problems, and poor sleep quality, adversely impact patients' ability to work and perform activities of daily living and the quality of relationships. However, some patients fail to attribute symptoms to their disease because of a lack of patient awareness and education. NASH is associated with high rates of comorbidities such as obesity and type 2 diabetes, which contribute to reduced HRQoL. Studies were heterogeneous in terms of diagnostic methods, population, outcomes, follow-up time, and measures of HRQoL/utility. Most studies were rated 'moderate' at quality assessment, and all evaluable studies had inadequate control of confounders. Conclusions: NASH is associated with a significant HRQoL burden that begins early in the disease course and increases with disease progression. More robust studies are needed to better understand the humanistic burden of NASH, with adequate adjustment for confounders that could influence outcomes. Lay summary: Non-alcoholic steatohepatitis (NASH) has a significant impact on quality of life, with individuals experiencing worse physical and mental health compared with the general population. NASH and its symptoms, which include tiredness, stomach pain, anxiety, depression, poor focus and memory, and impaired sleep, affect individuals' relationships and ability to work and perform day-to-day tasks. However, not all patients are aware that their symptoms may be related to NASH. Patients would benefit from more education on their disease, and the importance of good social networks for patient health and well-being should be reinforced. More studies are needed to better understand the patient burden of NASH.

Sprouty proteins are negative regulators of interferon (IFN) signaling and IFN-inducible biological responses.

Interferons (IFNs) have important antiviral and antineoplastic properties, but the precise mechanisms required for generation of these responses remain to be defined. We provide evidence that during engagement of the Type I IFN receptor (IFNR), there is up-regulation of expression of Sprouty (Spry) proteins 1, 2, and 4. Our studies demonstrate that IFN-inducible up-regulation of Spry proteins is Mnk kinase-dependent and results in suppressive effects on the IFN-activated p38 MAP kinase (MAPK), the function of which is required for transcription of interferon-stimulated genes (ISGs). Our data establish that ISG15 mRNA expression and IFN-dependent antiviral responses are enhanced in Spry1,2,4 triple knock-out mouse embryonic fibroblasts, consistent with negative feedback regulatory roles for Spry proteins in IFN-mediated signaling. In other studies, we found that siRNA-mediated knockdown of Spry1, Spry2, or Spry4 promotes IFN-inducible antileukemic effects in vitro and results in enhanced suppressive effects on malignant hematopoietic progenitors from patients with polycythemia vera. Altogether, our findings demonstrate that Spry proteins are potent regulators of Type I IFN signaling and negatively control induction of Type I IFN-mediated biological responses.

Nuclear cyclin D1/CDK4 kinase regulates CUL4 expression and triggers neoplastic growth via activation of the PRMT5 methyltransferase.

Cyclin D1 elicits transcriptional effects through inactivation of the retinoblastoma protein and direct association with transcriptional regulators. The current work reveals a molecular relationship between cyclin D1/CDK4 kinase and protein arginine methyltransferase 5 (PRMT5), an enzyme associated with histone methylation and transcriptional repression. Primary tumors of a mouse lymphoma model exhibit increased PRMT5 methyltransferase activity and histone arginine methylation. Analyses demonstrate that MEP50, a PRMT5 coregulatory factor, is a CDK4 substrate, and phosphorylation increases PRMT5/MEP50 activity. Increased PRMT5 activity mediates key events associated with cyclin D1-dependent neoplastic growth, including CUL4 repression, CDT1 overexpression, and DNA rereplication. Importantly, human cancers harboring mutations in Fbx4, the cyclin D1 E3 ligase, exhibit nuclear cyclin D1 accumulation and increased PRMT5 activity.

Genotoxic stress-induced cyclin D1 phosphorylation and proteolysis are required for genomic stability.

While mitogenic induction of cyclin D1 contributes to cell cycle progression, ubiquitin-mediated proteolysis buffers this accumulation and prevents aberrant proliferation. Because the failure to degrade cyclin D1 during S-phase triggers DNA rereplication, we have investigated cellular regulation of cyclin D1 following genotoxic stress. These data reveal that expression of cyclin D1 alleles refractory to phosphorylation- and ubiquitin-mediated degradation increase the frequency of chromatid breaks following DNA damage. Double-strand break-dependent cyclin D1 degradation requires ATM and GSK3beta, which in turn mediate cyclin D1 phosphorylation. Phosphorylated cyclin D1 is targeted for proteasomal degradation after ubiquitylation by SCF(Fbx4-alphaBcrystallin). Loss of Fbx4-dependent degradation triggers radio-resistant DNA synthesis, thereby sensitizing cells to S-phase-specific chemotherapeutic intervention. These data suggest that failure to degrade cyclin D1 compromises the intra-S-phase checkpoint and suggest that cyclin D1 degradation is a vital cellular response necessary to prevent genomic instability following genotoxic insult.

Nuclear accumulation of cyclin D1 during S phase inhibits Cul4-dependent Cdt1 proteolysis and triggers p53-dependent DNA rereplication.

Deregulation of cyclin D1 occurs in numerous human cancers through mutations, alternative splicing, and gene amplification. Although cancer-derived cyclin D1 mutants are potent oncogenes in vitro and in vivo, the mechanisms whereby they contribute to neoplasia are poorly understood. We now provide evidence derived from both mouse models and human cancer-derived cells revealing that nuclear accumulation of catalytically active mutant cyclin D1/CDK4 complexes triggers DNA rereplication, resulting from Cdt1 stabilization, which in turn triggers the DNA damage checkpoint and p53-dependent apoptosis. Loss of p53 through mutations or targeted deletion results in increased genomic instability and neoplastic growth. Collectively, the data presented reveal mechanistic insights into how uncoupling of critical cell cycle regulatory events will perturb DNA replication fidelity, thereby contributing to neoplastic transformation.

Development of a candidate DNA/MVA HIV-1 subtype C vaccine for India.

Development of a vaccine against human immunodeficiency virus type-1 (HIV-1) is the mainstay for controlling the AIDS pandemic. An ideal HIV vaccine should induce neutralizing antibodies, CD4+ helper T cells, and CD8+ cytotoxic T cells. While the induction of broadly neutralizing antibodies remains a highly challenging goal, there are a number of technologies capable of inducing potent cell-mediated responses in animal models, which are now starting to be tested in humans. Naked DNA immunization is one of them. The present study focuses on the stimulation cell-mediated and humoral immune responses by recombinant DNA-MVA vaccines, the areas where this technology might assist either alone or as a part of more complex vaccine formulations in the HIV vaccine development. Candidate recombinant DNA-MVA vaccine formulations expressing the human immunodeficiency virus-1 env and gagprotease genes from HIV-1 Indian subtype C were constructed and characterized. A high level of expression of the respective recombinant MVA (rMVA) constructs was demonstrated in BHK-21 cells followed by the robust humoral as well as cell mediated immune (CMI) responses in terms of magnitude and breadth. The response to a single inoculation of the rDNA vaccine was boosted efficiently by rMVA in BALB/c mice. This is the first reported candidate HIV-1 DNA/MVA vaccine employing the Indian subtype C sequences and constitutes a part of a vaccine scheduled to enter a preclinical non-human primate evaluation in India.

Augmentation of HIV-1 subtype C vaccine constructs induced immune response in mice by CpG motif 1826-ODN.

The greatest biomedical challenge of this century is to develop a preventive vaccine against Human Immunodeficiency Virus (HIV-1). For an HIV vaccine to be effective, it appears logical to develop new strategies that enhance the level of the immune response as well as steer it towards the desirable cellular type. In view of this, there is a need for rational inclusion of biological adjuvants into the HIV-1 vaccination strategies that could potentiate the immune responses both qualitatively and quantitatively. The adjuvant may include the immunostimulatory oligonucleotides containing CpG motifs, whose immunomodulatory characters are well established and represent the basis for an effective vaccine adjuvant. In our study, we investigated the use of an immunostimulatory oligonucleotide (or CpG motif), 1826-ODN to augment the immune response elicited by plasmid DNA vaccine constructs containing Indian subtype C HIV-1 envelope gp120 and gag-protease genes in Balb/c mouse model system. A dose of 2-microg CpG motifs/mouse was found to be optimum when co-administered with the DNA vaccine constructs with the peak level of humoral and cell mediated immune responses at 6 weeks post immunization. Murine IFN-gamma ELISpot assay demonstrated that the use of 1826-ODN led to a broad based and long term recognition of the subtype C envelope and gag peptides. The use of CpG motifs has been effective in augmenting the immune responses generated by the DNA constructs. Taken together, these results are an important advancement towards the design of future preclinical and clinical trials of these vaccine constructs.