Identification of an early survival prognostic gene signature for localized osteosarcoma patients.

Osteosarcoma is the most prevalent bone tumor in pediatric patients. Neoadjuvant chemotherapy has improved osteosarcoma patient survival, however the 5-year survival rate for localized osteosarcoma is 75% with a 30-50% recurrence rate. We, therefore, sought to identify a prognostic gene signature which could predict poor prognosis in localized osteosarcoma patients. Using the TARGET osteosarcoma transcriptomic dataset, we identified a 13-hub gene signature associated with overall survival and time to death of localized osteosarcoma patients, with the high-risk group showing a 22% and the low-risk group showing 100% overall survival. Furthermore, network analysis identified five modules of co-expressed genes that significantly correlated with survival, and identified 65 pathways enriched across 3 modules, including Hedgehog signaling, which includes 2 of the 13 genes, IHH and GLI1. Subsequently, we demonstrated that GLI antagonists inhibited growth of a recurrent localized PDX-derived cell line with elevated IHH and GLI1 expression, but not a non-relapsed cell line with low pathway activation. Finally, we show that our signature outperforms previously reported signatures in predicting poor prognosis and death within 3 years in patients with localized osteosarcoma.

Machine Learning in Cardiovascular Risk Prediction and Precision Preventive Approaches.

PURPOSE OF REVIEW: In this review, we sought to provide an overview of ML and focus on the contemporary applications of ML in cardiovascular risk prediction and precision preventive approaches. We end the review by highlighting the limitations of ML while projecting on the potential of ML in assimilating these multifaceted aspects of CAD in order to improve patient-level outcomes and further population health. RECENT FINDINGS: Coronary artery disease (CAD) is estimated to affect 20.5 million adults across the USA, while also impacting a significant burden at the socio-economic level. While the knowledge of the mechanistic pathways that govern the onset and progression of clinical CAD has improved over the past decade, contemporary patient-level risk models lag in accuracy and utility. Recently, there has been renewed interest in combining advanced analytic techniques that utilize artificial intelligence (AI) with a big data approach in order to improve risk prediction within the realm of CAD. By virtue of being able to combine diverse amounts of multidimensional horizontal data, machine learning has been employed to build models for improved risk prediction and personalized patient care approaches. The use of ML-based algorithms has been used to leverage individualized patient-specific data and the associated metabolic/genomic profile to improve CAD risk assessment. While the tool can be visualized to shift the paradigm toward a patient-specific care, it is crucial to acknowledge and address several challenges inherent to ML and its integration into healthcare before it can be significantly incorporated in the daily clinical practice.

One- versus two-specimen Xpert strategy to discontinue airborne isolation in suspected pulmonary tuberculosis: systematic review and meta-analysis.

BACKGROUND: Evaluation of a patient with suspected pulmonary tuberculosis (TB) involves initiation of airborne infection isolation (AII). However, guidelines detailing discontinuation of AII utilizing the Xpert MTB/RIF provide little clarity between use of one-specimen (1-Xpert') versus two-specimens (2-Xpert'). OBJECTIVES: To evaluate the diagnostic accuracy of one-Xpert versus two-Xpert strategy in guiding discontinuation of AII. METHODS: Data sources: PubMed, Embase, and EBSCO databases. STUDY ELIGIBILITY CRITERIA: Studies providing diagnostic accuracy data for one- versus two-Xperts in discontinuation of AII. PARTICIPANTS: Adult patients with suspected TB. TESTS: Xpert MTB/RIF on one- versus two-sputum specimens. Reference standard: Solid and liquid culture media. Assessment of risk of bias: Quality Assessment of Diagnostic Accuracy Studies tool was used. Methods of data synthesis: Meta-analysis was performed to calculate the pooled sensitivities and specificities using Stata 17.2. RESULTS: Four studies were included involving 1776 patients. A total of 68% were males, 36% were HIV positive, and 80% participants belonged to the United States. In patients with suspected pulmonary TB, 7% (95% CI, 6-9%) participants were found to have culture-positive MTB. For one-Xpert strategy, the pooled sensitivity was 86% (95% CI, 75-92%; I2, 1.05%) and specificity was 100% (95% CI, 99-100%; I2, 36%). Two-Xpert strategy had a pooled sensitivity of 92% (95% CI, 84-96%; I2, 16%) and a specificity of 100% (95% CI, 98-100%; I2, 27%). There was statistically significant difference between sensitivities of one-Xpert and two-Xpert strategies (p 0.05) with no statistically significant difference in their specificities. DISCUSSION: The results of this review must be interpreted in the context of a predominantly low-TB prevalence setting. Two-Xpert strategy has an incrementally higher sensitivity when compared with one-Xpert strategy with similar specificities between the two. Obtaining a second Xpert is crucial for individuals with a continued high suspicion for TB or those at a high risk of morbidity/mortality from TB.

Loss of cytochrome P450 (CYP)1B1 mitigates hyperoxia response in adult mouse lung by reprogramming metabolism and translation.

Oxygen supplementation is life saving for premature infants and for COVID-19 patients but can induce long-term pulmonary injury by triggering inflammation, with xenobiotic-metabolizing CYP enzymes playing a critical role. Murine studies showed that CYP1B1 enhances, while CYP1A1 and CYP1A2 protect from, hyperoxic lung injury. In this study we tested the hypothesis that Cyp1b1-null mice would revert hyperoxia-induced transcriptomic changes observed in WT mice at the transcript and pathway level. Wild type (WT) C57BL/6J and Cyp1b1-null mice aged 8-10 weeks were maintained in room air (21% O2) or exposed to hyperoxia (>95% O2) for 48h. Transcriptomic profiling was conducted using the Illumina microarray platform. Hyperoxia exposure led to robust changes in gene expression and in the same direction in WT, Cyp1a1-, Cyp1a2-, and Cyp1b1-null mice, but to different extents for each mouse genotype. At the transcriptome level, all Cyp1-null murine models reversed hyperoxia effects. Gene Set Enrichment Analysis identified 118 hyperoxia-affected pathways mitigated only in Cyp1b1-null mice, including lipid, glutamate, and amino acid metabolism. Cell cycle genes Cdkn1a and Ccnd1 were induced by hyperoxia in both WT and Cyp1b1-null mice but mitigated in Cyp1b1-null O2 compared to WT O2 mice. Hyperoxia gene signatures associated positively with bronchopulmonary dysplasia (BPD), which occurs in premature infants (with supplemental oxygen being one of the risk factors), but only in the Cyp1b1-null mice did the gene profile after hyperoxia exposure show a partial rescue of BPD-associated transcriptome. Our study suggests that CYP1B1 plays a pro-oxidant role in hyperoxia-induced lung injury.

Differential co-expression networks of the gut microbiota are associated with depression and anxiety treatment resistance among psychiatric inpatients.

BACKGROUND: Comorbid anxiety and depression are common and are associated with greater disease burden than either alone. Our recent efforts have identified an association between gut microbiota dysfunction and severity of anxiety and depression. In this follow-up, we applied Differential Co-Expression Analysis (DiffCoEx) to identify potential gut microbiota biomarker(s) candidates of treatment resistance among psychiatric inpatients. METHODS: In a sample of convenience, 100 psychiatric inpatients provided clinical data at admission and discharge; fecal samples were collected early during the hospitalization. Whole genome shotgun sequencing methods were used to process samples. DiffCoEx was used to identify clusters of microbial features significantly different based on treatment resistance status. Once overlapping features were identified, a knowledge-mining tool was used to review the literature using a list of microbial species/pathways and a select number of medical subject headlines (MeSH) terms relevant for depression, anxiety, and brain-gut-axis dysregulation. Network analysis used overlapping features to identify microbial interactions that could impact treatment resistance. RESULTS: DiffCoEx analyzed 10,403 bacterial features: 43/44 microbial features associated with depression treatment resistance overlapped with 43/114 microbial features associated with anxiety treatment resistance. Network analysis resulted in 8 biological interactions between 16 bacterial species. Clostridium perfringens evidenced the highest connection strength (0.95). Erysipelotrichaceae bacterium 6_1_45 has been most widely examined, is associated with inflammation and dysbiosis, but has not been associated with depression or anxiety. CONCLUSION: DiffCoEx potentially identified gut bacteria biomarker candidates of depression and anxiety treatment-resistance. Future efforts in psychiatric microbiology should examine the mechanistic relationship of identified pro-inflammatory species, potentially contributing to a biomarker-based algorithm for treatment resistance.

Increased DNA methylation, cellular senescence and premature epigenetic aging in guinea pigs and humans with tuberculosis.

BACKGROUND: Tuberculosis (TB) is the archetypical chronic infection, with patients having months of symptoms before diagnosis. In the two years after successful therapy, survivors of TB have a three-fold increased risk of death. METHODS: Guinea pigs were infected with Mycobacterium tuberculosis (Mtb) for 45 days, followed by RRBS DNA methylation analysis. In humans, network analysis of differentially expressed genes across three TB cohorts were visualized at the pathway-level. Serum levels of inflammation were measured by ELISA. Horvath (DNA methylation) and RNA-seq biological clocks were used to investigate shifts in chronological age among humans with TB. RESULTS: Guinea pigs with TB demonstrated DNA hypermethylation and showed system-level similarity to humans with TB (p-value = 0.002). The transcriptome in TB in multiple cohorts was enriched for DNA methylation and cellular senescence. Senescence associated proteins CXCL9, CXCL10, and TNF were elevated in TB patients compared to healthy controls. Humans with TB demonstrate 12.7 years (95% CI: 7.5, 21.9) and 14.38 years (95% CI: 10.23-18.53) of cellular aging as measured by epigenetic and gene expression based cellular clocks, respectively. CONCLUSIONS: In both guinea pigs and humans, TB perturbs epigenetic processes, promoting premature cellular aging and inflammation, a plausible means to explain the long-term detrimental health outcomes after TB.

Gene expression signatures identify biologically and clinically distinct tuberculosis endotypes.

BACKGROUND: In vitro, animal model and clinical evidence suggests that tuberculosis is not a monomorphic disease, and that host response to tuberculosis is protean with multiple distinct molecular pathways and pathologies (endotypes). We applied unbiased clustering to identify separate tuberculosis endotypes with classifiable gene expression patterns and clinical outcomes. METHODS: A cohort comprised of microarray gene expression data from microbiologically confirmed tuberculosis patients was used to identify putative endotypes. One microarray cohort with longitudinal clinical outcomes was reserved for validation, as were two RNA-sequencing (seq) cohorts. Finally, a separate cohort of tuberculosis patients with functional immune responses was evaluated to clarify stimulated from unstimulated immune responses. RESULTS: A discovery cohort, including 435 tuberculosis patients and 533 asymptomatic controls, identified two tuberculosis endotypes. Endotype A is characterised by increased expression of genes related to inflammation and immunity and decreased metabolism and proliferation; in contrast, endotype B has increased activity of metabolism and proliferation pathways. An independent RNA-seq validation cohort, including 118 tuberculosis patients and 179 controls, validated the discovery results. Gene expression signatures for treatment failure were elevated in endotype A in the discovery cohort, and a separate validation cohort confirmed that endotype A patients had slower time to culture conversion, and a reduced cure rate. These observations suggest that endotypes reflect functional immunity, supported by the observation that tuberculosis patients with a hyperinflammatory endotype have less responsive cytokine production upon stimulation. CONCLUSION: These findings provide evidence that metabolic and immune profiling could inform optimisation of endotype-specific host-directed therapies for tuberculosis.

MicroRNA-mRNA networks are dysregulated in opioid use disorder postmortem brain: Further evidence for opioid-induced neurovascular alterations.

Introduction: To understand mechanisms and identify potential targets for intervention in the current crisis of opioid use disorder (OUD), postmortem brains represent an under-utilized resource. To refine previously reported gene signatures of neurobiological alterations in OUD from the dorsolateral prefrontal cortex (Brodmann Area 9, BA9), we explored the role of microRNAs (miRNA) as powerful epigenetic regulators of gene function. Methods: Building on the growing appreciation that miRNAs can cross the blood-brain barrier, we carried out miRNA profiling in same-subject postmortem samples from BA9 and blood tissues. Results: miRNA-mRNA network analysis showed that even though miRNAs identified in BA9 and blood were fairly distinct, their target genes and corresponding enriched pathways overlapped strongly. Among the dominant enriched biological processes were tissue development and morphogenesis, and MAPK signaling pathways. These findings point to robust, redundant, and systemic opioid-induced miRNA dysregulation with a potential functional impact on transcriptomic changes. Further, using correlation network analysis, we identified cell-type specific miRNA targets, specifically in astrocytes, neurons, and endothelial cells, associated with OUD transcriptomic dysregulation. Finally, leveraging a collection of control brain transcriptomes from the Genotype-Tissue Expression (GTEx) project, we identified a correlation of OUD miRNA targets with TGF beta, hypoxia, angiogenesis, coagulation, immune system, and inflammatory pathways. Discussion: These findings support previous reports of neurovascular and immune system alterations as a consequence of opioid abuse and shed new light on miRNA network regulators of cellular response to opioid drugs.

Extranodal Involvement of the Anorectal Region in an HIV-Positive Patient With Plasmablastic Lymphoma: A Case Report.

Plasmablastic lymphoma (PbL) is a rare type of aggressive B-cell malignancy that has an extremely poor prognosis without chemotherapeutic treatment, requiring a high degree of suspicion for an early and accurate diagnosis. It has been classically described in patients infected with the human immunodeficiency virus (HIV). However, it accounts for only 2.6% of acquired immunodeficiency syndrome (AIDS)-related lymphomas. Extranodal involvement is most commonly seen within the oral cavity (44%). Involvement of the gastrointestinal tract (14%) is rare and can often be confused with other malignancies with plasmablastic features. We present a rare case of PbL in a 55-year-old male with HIV-AIDS (CD4 (cluster of differentiation 4) cell count of 128), who presented for evaluation of incidentally detected multiple liver masses and lytic lesions in the ribs. Further workup revealed evidence of a lesion with increased uptake in the anorectal region with fine needle aspiration (FNA) biopsy identifying the lesion as plasmablastic lymphoma.

Disseminated histoplasmosis leading to end stage liver failure in immunocompetent patient: case report and review of literature.

Histoplasmosis is the fungal infection caused by Histoplasma capsulatum fungus. It is commonly found in a few endemic areas in the United States, where there is a large number of birds or bats and can spread through their droppings. Disseminated histoplasmosis is a severe manifestation of the fungal infection which is commonly seen in individuals with underlying immunosuppression. Our case is an unusual case of disseminated histoplasmosis in a 60-year-old, immunocompetent male patient with a history of significant alcohol abuse, which led to end stage liver failure. While the patient showed some signs of improvement initially upon beginning the treatment, he ultimately continued to deteriorate despite treatment due to an overwhelming histoplasmosis infection. This case demonstrates the importance of keeping a high index of suspicion even amongst immunocompetent patients with no obvious exposure to risk factors. It also shows that timely diagnosis with a high index of suspicion is required with an integrated treatment approach.

A survey of knowledge and variables influencing perceptions about clinical research: A cross-sectional study from Mumbai.

PURPOSE: Clinical research in India has been besieged by controversies. While studies have addressed other stakeholders, few have addressed the patient. The present study was conducted to assess the extent of awareness and understanding about the nature and conduct of CR among people of Mumbai. METHODS: Institutional Ethics Committee approval was taken (EC/OA-12/15) and written informed consent was obtained. Adults who were residents of Mumbai were enrolled. A prevalidated and published 48-item questionnaire based on six themes, namely awareness and participation, voluntariness and autonomy, compensation, confidentiality, safety, and involvement in CR were administered. Perception based on themes and association of variables such as age, gender, socioeconomic class, and education on this perception was assessed. Descriptive statistics along with Chi-square test/Chi-square test for trend and crude odds ratio (cOR) were assessed. RESULTS: Of the 453 participants approached, 400 (age 32 [18-96]) consented. Only 210/400 (52.5%) were aware of CR and 194/400 (48.5%) said they needed permission for participation. Only 226/400 (56.5%) were aware of their rights and 111/400 (27.75%) felt that clinical trial participants received compensation. The socioeconomic class influenced awareness of CR (P < 0.00001; r 2= 0.495) as did the age (P < 0.0001; r 2= 0.82). Men were less likely to need permission to participate relative to women (cOR [95% confidence interval (CI)] 2.47 [1.6, 3.6] [P < 0.00001]). Those who had heard of CR were twice more willing to participate (cOR [95% CI] 1.72 (1.2, 2.6); P = 0.008). CONCLUSIONS: There is a greater need to improve awareness, especially about safety, compensation, and confidentiality in CR.

Demographic, clinical, and geographical factors associated with lack of receipt of physician recommended chemotherapy in women with breast cancer in Texas.

PURPOSE: Identifying demographic, clinical, and geographical factors that contribute to disparities in the receipt of physician recommended chemotherapy in breast cancer patients. METHODS: The Texas Cancer Registry was used to identify women aged ≥ 18 years with invasive breast cancer diagnosed from 2007 to 2011 who received a recommendation for chemotherapy. Multivariable logistic regression was performed to determine associations between demographic and clinical factors and the receipt of chemotherapy. Cox proportional regression was used to estimate the hazard ratio (HR) for overall survival. Spatial analysis was conducted using Poisson models for breast cancer mortality and receipt of chemotherapy. RESULTS: Age ≥ 65 years, residence in areas with > 20% poverty index, and early disease stage were associated with lack of receipt of chemotherapy (all p < 0.001). Lack of receipt of chemotherapy was associated with decreased overall survival (HR 1.33, 95% CI 1.12-1.59, p = 0.001). A 38-county cluster in West Texas had lower receipt of chemotherapy (relative risk 0.88, p = 0.02) and increased breast cancer mortality (p = 0.03) compared to the rest of Texas. CONCLUSION: Older age, increased poverty and rural geographical location are barriers to the receipt of chemotherapy. Interventions that target these barriers may reduce health disparities and improve breast cancer survival.