Miracle-dz/UniFAR-FTUs huggingface dataset:
Impact of Direct Antiviral Agents (DAAs) on B-cell Non Hodgkin's Lymphoma in patients with chronic hepatitis C.

The relationship between HCV infection and extrahepatic manifestations has been demonstrated by epidemiological, clinical, immunological and pathological studies. Patients with HCV infection have an increased risk of morbidity and mortality related to these non-liver diseases. For these reasons, HCV chronic infection should be considered a systemic disease in which extrahepatic manifestations increase the severity of the disease. HCV-extrahepatic manifestations may severely affect the overall prognosis, while viral eradication significantly reduces non-liver related deaths. Over the past 5 years, treatment of chronic HCV infection in patients with hematologic malignancies has evolved rapidly and effective and safe direct-acting antivirals (DAAs) have become the standardof-care treatment. The choice of regimens with DAAs should be individualized after thorough assessment for potential hematologic toxic effects and drug-drug interactions. Elimination of HCV from infected cancer patients confers virologic, hepatic, and oncologic benefits.
Ready-to-Use Micronized Human Acellular Dermal Matrix to Accelerate Wound Healing in Diabetic Foot Ulcers: A Prospective Randomized Pilot Study

ABSTRACT OBJECTIVE To examine and report clinical outcomes of a ready-to-use micronized dermal matrix for diabetic foot ulcers (DFUs) and compare it to treatment with conventional negative-pressure wound therapy (NPWT) only. METHODS The researchers randomly allocated 30 DFUs Wagner grade 2 or higher from 30 adult patients into two groups. The control group (n = 15) was treated with conventional NPWT, and the experimental group (n = 15) was treated with micronized dermal matrix and NPWT. The researchers evaluated the following outcomes: granulation tissue formation, proportion of patients with closed or granulated wounds at 42 and 120 days, achievement of complete wound healing in the 6 months of follow-up, and intervals from enrollment to final surgical procedures. RESULTS All 15 wounds treated with the micronized matrix showed healthy granulation tissue without noticeable complications during follow-up. At 42 days, 46.7% of wounds in the experimental group had closed compared with 28.6% in the conventional NPWT group (P = .007). At 120 days, 86.7% of the experimental group had completely closed wounds, compared with 57.1% in the conventional therapy group (P = .040). During the 6-month follow-up period, 93.3% of the experimental group achieved complete wound healing compared with 85.7% of the conventional therapy group (P = .468). CONCLUSIONS The healing outcomes for DFUs in the experimental group were superior when micronized matrix treatment was combined with NPWT.
Leadership for a climate resilient, net-zero health system: Transforming supply chains to the circular economy

The global pandemic has taught us that we can focus the attention of the healthcare system on a clear intention when there is a looming threat. Climate action is required from multiple stakeholders particularly private sector suppliers in order to achieve the net-zero carbon emission by 2050 goal established by the Canadian government. Also building climate resilience among healthcare institutions and their supply chains is urgently needed, as they are already affected by a changing climate. By adopting a circular economy framework, the industry can move away from the current damaging take, make waste economic model and adopt a more sustainable model characterized by designing out waste and pollution, keeping products and materials in use, and regenerating natural systems. Health leaders can adopt sharing platforms, view product as a service, reduce single use products, encourage extended producer responsibility, and encourage value-based procurement in order to further these aims.
Bone Marrow-Derived SH-SY5Y Neuroblastoma Cells Infected with Kaposi’s Sarcoma-Associated Herpesvirus Display Unique Infection Phenotypes and Growth Properties

Our study has provided evidence that neuronal SH-SY5Y cells displayed unique cellular responses upon KSHV infection. Unlike other infected cells, this neuronal cell line displayed a higher growth rate upon infection and can spontaneously transition back and forth between latent and lytic phases of infection. ABSTRACT Kaposi’s sarcoma-associated herpesvirus (KSHV) is an important oncogenic virus previously shown to be neurotropic, but studies on neuronal cell infection and pathogenesis are still very limited. Here, we characterized the effects of KSHV infection on neuronal SH-SY5Y cells by the recombinant virus rKSHV.219, which expresses both green fluorescent protein (GFP) and red fluorescent protein (RFP) to reflect the latent and lytic phases of infection. We demonstrated that infected cells have a higher growth rate and that KSHV infection can be sustained. Interestingly, the infected cells can transition spontaneously back and forth between lytic and latent phases of infection, producing progeny viruses but without any adverse effects on cell growth. In addition, transcriptome analysis of viral and cellular genes in latent and lytic cells showed that unlike other infected cell lines, the latently infected cells expressed both latent and most, but not all, of the lytic genes required for infectious virion production. The viral genes uniquely expressed by the lytic cells were mainly involved in the early steps of virus binding. Some of the cellular genes that were deregulated in both latently and lytically infected cells are involved in cell adhesion, cell signal pathways, and tumorigenesis. The downregulated cellular CCDN1, PAX5, and NFASC and upregulated CTGF, BMP4, YAP1, LEF1, and HLA-DRB1 genes were found to be associated with cell adhesion molecules (CAMs), hippo signaling, and cancer. These deregulated genes may be involved in creating an environment that is unique in neuronal cells to sustain cell growth upon KSHV infection and not observed in other infected cell types. IMPORTANCE Our study has provided evidence that neuronal SH-SY5Y cells displayed unique cellular responses upon KSHV infection. Unlike other infected cells, this neuronal cell line displayed a higher growth rate upon infection and can spontaneously transition back and forth between latent and lytic phases of infection. Unlike other latently infected cells, a number of lytic genes were also expressed in the latent phase of infection in addition to the established latent viral genes. They may play a role in deregulating a number of host genes that are involved in cell signaling and tumorigenesis in order to sustain the infection and growth advantages for the cells. Our study has provided novel insights into KSHV infection of neuronal cells and a potential new model for further studies to explore the underlying mechanism in viral and host interactions for neuronal cells and the association of KSHV with neuronal diseases.
The deubiquitinase TRABID stabilizes the K29/K48-specific E3 ubiquitin ligase HECTD1

Ubiquitin is a versatile posttranslational modification, which is covalently attached to protein targets either as a single moiety or as a ubiquitin chain. In contrast to K48 and K63-linked chains, which have been extensively studied, the regulation and function of most atypical ubiquitin chains are only starting to emerge. The deubiquitinase TRABID/ZRANB1 is tuned for the recognition and cleavage of K29 and K33-linked chains. Yet, substrates of TRABID and the cellular functions of these atypical ubiquitin signals remain unclear. We determined the interactome of two TRABID constructs rendered catalytic dead either through a point mutation in the catalytic cysteine residue or through removal of the OTU catalytic domain. We identified 50 proteins trapped by both constructs and which therefore represent candidate substrates of TRABID. The E3 ubiquitin ligase HECTD1 was then validated as a substrate of TRABID and used UbiCREST and Ub-AQUA proteomics to show that HECTD1 preferentially assembles K29- and K48-linked ubiquitin chains. Further in vitro autoubiquitination assays using ubiquitin mutants established that while HECTD1 can assemble short homotypic K29 and K48-linked chains, it requires branching at K29/K48 in order to achieve its full ubiquitin ligase activity. We next used transient knockdown and genetic knockout of TRABID in mammalian cells in order to determine the functional relationship between TRABID and HECTD1. This revealed that upon TRABID depletion, HECTD1 is readily degraded. Thus, this study identifies HECTD1 as a mammalian E3 ligase that assembles branched K29/K48 chains and also establishes TRABID-HECTD1 as a DUB/E3 pair regulating K29 linkages.
Electronic Geriatric Assessment: Is It Feasible in a Multi-Institutional Study That Included a Notable Proportion of Older African American Patients? (Alliance A171603).

PURPOSE This study determined whether an electronic version of the geriatric assessment is feasible in a multi-institutional, diverse setting. METHODS Ten sites within the Alliance for Clinical Trials in Oncology participated. Patients who had active cancer or a history of cancer and were 65 years of age or older were eligible. The geriatric assessment was completed with an electronic data capture system that had been loaded onto iPads. Feasibility was defined a priori as completion in at least 70% of patients either with or without help. To enhance racial diversity, the original sample size was later changed and augmented by 50% with the intention of increasing enrollment of older minority patients. RESULTS A total of one hundred fifty-four patients were registered with a median age of 72 years (range, 65-91 years). Forty-three (28%) identified themselves as African American or Black. One hundred forty-one patients (92%) completed the electronic geriatric assessment. Feasibility was observed across all subgroups, regardless of race, education, performance status, comorbidities, and cognition; 124 patients (81%) completed the geriatric assessment without help. Reasons for not completing the geriatric assessment are as follows: clinic visit did not occur (n = 6), no iPad connection to the Internet (n = 3), patient declined (n = 2), prolonged hospitalization (n = 1), and patient died (n = 1). Reasons for needing help, as reported by study personnel, were as follows: the patient preferred that research personnel ask the questions (n = 9), vision problem (n = 3), lack of comfort with the iPad (n = 2), questions were not clear (n = 1), less proficient in English (n = 1), and challenge in pressing the green button to go to the next question (n = 1). CONCLUSION The electronic geriatric assessment is feasible in a multi-institutional setting that includes a notable proportion of African American or Black patients.
Prazoles Targeting Tsg101 Inhibit Release of Epstein-Barr Virus following Reactivation from Latency

Production of virions is necessary for the ubiquitous Epstein-Barr virus (EBV) to persist in humans and can set the stage for development of EBV cancers in at-risk individuals. In our attempts to identify inhibitors of the EBV lytic phase, we previously found that a prazole proton pump inhibitor, known to block the interaction of ubiquitin with the ESCRT-1 factor Tsg101, blocks production of EBV. ABSTRACT Epstein-Barr virus (EBV) is a ubiquitous herpesvirus responsible for several diseases, including cancers of lymphoid and epithelial cells. EBV cancers typically exhibit viral latency; however, the production and release of EBV through its lytic phase are essential for cancer development. Antiviral agents that specifically target EBV production do not currently exist. Previously, we reported that the proton pump inhibitor tenatoprazole, which blocks the interaction of ubiquitin with the ESCRT-1 factor Tsg101, inhibits production of several enveloped viruses, including EBV. Here, we show that three structurally distinct prazoles impair mature particle formation postreactivation and identify the impact on stages of replication. The prazoles did not impair expression of lytic genes representative of the different kinetic classes but interfered with capsid maturation in the nucleus as well as virion transport from the nucleus. Replacement of endogenous Tsg101 with a mutant Tsg101 refractory to prazole-mediated inhibition rescued EBV release. These findings directly implicate Tsg101 in EBV nuclear egress and identify prazoles as potential therapeutic candidates for conditions that rely on EBV replication, such as chronic active EBV infection and posttransplant lymphoproliferative disorders. IMPORTANCE Production of virions is necessary for the ubiquitous Epstein-Barr virus (EBV) to persist in humans and can set the stage for development of EBV cancers in at-risk individuals. In our attempts to identify inhibitors of the EBV lytic phase, we previously found that a prazole proton pump inhibitor, known to block the interaction of ubiquitin with the ESCRT-1 factor Tsg101, blocks production of EBV. We now find that three structurally distinct prazoles impair maturation of EBV capsids and virion transport from the nucleus and, by interfering with Tsg101, prevent EBV release from lytically active cells. Our findings not only implicate Tsg101 in EBV production but also identify widely used prazoles as candidates to prevent development of posttransplant EBV lymphomas.
Alpha-synuclein seeds in olfactory mucosa of patients with isolated REM sleep behaviour disorder.

Isolated REM sleep behaviour disorder (RBD) is an early-stage α-synucleinopathy in most, if not all, affected subjects. Detection of pathological α-synuclein in peripheral tissues of patients with isolated RBD may identify those progressing to Parkinson's disease, dementia with Lewy bodies or multiple system atrophy, with the ultimate goal of testing preventive therapies. Real-time quaking-induced conversion (RT-QuIC) provided evidence of α-synuclein seeding activity in CSF and olfactory mucosa of patients with α-synucleinopathies. The aim of this study was to explore RT-QuIC detection of α-synuclein aggregates in olfactory mucosa of a large cohort of subjects with isolated RBD compared to patients with Parkinson's disease and control subjects. This cross-sectional case-control study was performed at the Medical University of Innsbruck, Austria, the Hospital Clinic de Barcelona, Spain, and the University of Verona, Italy. Olfactory mucosa samples obtained by nasal swab in 63 patients with isolated RBD, 41 matched Parkinson's disease patients and 59 matched control subjects were analysed by α-synuclein RT-QuIC in a blinded fashion at the University of Verona, Italy. Median age of patients with isolated RBD was 70 years, 85.7% were male. All participants were tested for smell, autonomic, cognitive and motor functions. Olfactory mucosa was α-synuclein RT-QuIC positive in 44.4% isolated RBD patients, 46.3% Parkinson's disease patients and 10.2% control subjects. While the sensitivity for isolated RBD plus Parkinson's disease versus controls was 45.2%, specificity was high (89.8%). Among isolated RBD patients with positive α-synuclein RT-QuIC, 78.6% had olfactory dysfunction compared to 21.4% with negative α-synuclein RT-QuIC (P < 0.001). The extent of olfactory dysfunction was more severe in isolated RBD patients positive than negative for olfactory mucosa a-synuclein RT-QuIC (P < 0.001). We provide evidence that the α-synuclein RT-QuIC assay enables the molecular detection of neuronal α-synuclein aggregates in olfactory mucosa of patients with isolated RBD and Parkinson's disease. Although the overall sensitivity was moderate in this study, nasal swabbing is attractive as a simple, non-invasive test and might be useful as part of a screening battery to identify subjects in the prodromal stages of α-synucleinopathies. Further studies are needed to enhance sensitivity, and better understand the temporal dynamics of α-synuclein seeding in the olfactory mucosa and spreading to other brain areas during the progression from isolated RBD to overt α-synucleinopathy, as well the impact of timing, disease subgroups and sampling technique on the overall sensitivity.
EXTRACOLONIC FINDINGS—IDENTIFICATION AT LOW-DOSE CTC

Abstract In contrast to optical colonoscopy, computed tomography colonography (CTC) has the ability to reveal pathology outside of the colon. While identification of colorectal lesions at CTC requires only limited radiation dose, the detection of abnormalities in extracolonic soft tissue requires more radiation. The purpose of this study was to investigate the influence of ultra-low-dose (ULD) CTC on the detection and characterisation of extracolonic findings. In a prospective study 49 patients with colorectal symptoms were examined with CTC adding a ULD series (mean effective dose 0.9 ± 0.4 mSv) to the normal unenhanced standard dose (SD) series (mean effective dose 3.6 ± 1.2 mSv). Five radiologists individually and blindly evaluated the ULD, followed by evaluation of the SD after ≥9 weeks (median 35 weeks). A ViewDEX-based examination protocol was used, including a confidence scale and a graded assessment of need for follow-up according to the CTC Reporting and Data System (C-RADS E0–E4). The reference findings comprised the combined information from CTC (ULD, SD and contrast-enhanced CTC series) and a 4-year radiological and clinical follow-up. For the overall detection of reference findings (E2–E4) we found a statistically significant difference in favour of SD. This, however, was not the case when looking at classification of possibly important/important reference findings (E3–E4). Our results suggest that CTC with ULD (0.9 mSv) is comparable to SD (3.6 mSv) for identification of clinically relevant extracolonic pathology, but there is a large inter-observer variability.
Comparing Psychometric Properties of the NIH Toolbox Cognition Battery to Gold-Standard Measures in Socioeconomically Diverse Older Adults.

OBJECTIVE The National Institutes of Health Toolbox-Cognition Battery (NIHTB-CB) is an efficient computerized neuropsychological battery. This study investigated its psychometric properties in terms of sociodemographic characteristics and technology use in adults aged 57-87 (with an average age of 70). METHODS Community-based participatory research procedures were used to enhance enrollment of adults with lower education and income backgrounds. Study procedures replicated work that compared the NIHTB-CB Crystallized and Fluid composites to analogous gold-standard (GS) measures and extended it by investigation of socioeconomic status and technology use-related differences in performance. RESULTS The high correlations among the NIHTB-CB and GS analogous Crystallized and Fluid composites suggested good convergent validity. There was no evidence of significant education- or economic-related group differences in these associations. However, caution is needed as Cronbach's alpha that indicated the NIHTB-CB Fluid composite had questionable internal item consistency. The NIHTB-CB and GS measures demonstrated poor discriminant validity in the high school but not college-educated groups. Regression analyses found that comfort with technology use, income, education, and age predicted better cognitive test performance on the computerized and paper-pencil measures. CONCLUSIONS There is an urgent need to improve the understanding of socioeconomic disparities influence on test scores and brain health. Lack of discriminant validity in the cognitive tests indicates that these measures could result in diagnostic errors within noncollege-educated older adults. These findings reduce confidence in the use of the NIHTB-CB Fluid composite in older adults and support that there is a significant socioeconomic-related digital divide in comfort with technology use.
Symptom clusters in cancer patients: An Italian survey to validate and describe unwarranted clinical variation, inequality in access to healthcare, knowledge, and risk of malpractice

Background and aims: The perceptions of professionals involved in cancer care regarding the importance of their symptoms-specific knowledge, unwarranted clinical variation (UCV), and inequalities in access to healthcare are still underdescribed. This study aims to confirm the construct validity of a previously initially developed questionnaire and describe nurses’ perceptions about the relevance of their knowledge referred to cancer symptoms management, the UCV, the inequalities in access to healthcare, and malpractice risk. Method: A cross-sectional pan-national study was conducted using a convenience sample, collecting data through a previously initially validated questionnaire. Construct validity was corroborated through confirmatory factor analysis, and descriptive statistics were employed for summarizing the questionnaire’s scores. The scores between the nurses working in accredited cancer centers and nurses employed in general hospitals were inferentially compared. Results: The sample comprised 810 nurses, 480 were nurses working in accredited cancer centers, and 330 were nurses working in general hospitals. The questionnaire showed adequate construct validity and reliability. Nurses perceived the cluster of psychosocial symptoms with a greater risk of UCV and inequalities in access to cancer services than the cluster of physical symptoms. Discussion and conclusions: A paradigm shift aimed at integrating psychosocial cancer symptoms in the care paths emerged as pivotal for improving cancer care in Italy.
The impact of identity by descent on fitness and disease in dogs

Significance Dogs and humans have coexisted together for thousands of years, but it was not until the Victorian Era that humans practiced selective breeding to produce the modern standards we see today. Strong artificial selection during the breed formation period has simplified the genetic architecture of complex traits and caused an enrichment of identity-by-descent (IBD) segments in the dog genome. This study demonstrates the value of IBD segments and utilizes them to infer the recent demography of canids, predict case-control status for complex traits, locate regions of the genome potentially linked to inbreeding depression, and to identify understudied breeds where there is potential to discover new disease-associated variants. Domestic dogs have experienced population bottlenecks, recent inbreeding, and strong artificial selection. These processes have simplified the genetic architecture of complex traits, allowed deleterious variation to persist, and increased both identity-by-descent (IBD) segments and runs of homozygosity (ROH). As such, dogs provide an excellent model for examining how these evolutionary processes influence disease. We assembled a dataset containing 4,414 breed dogs, 327 village dogs, and 380 wolves genotyped at 117,288 markers and data for clinical and morphological phenotypes. Breed dogs have an enrichment of IBD and ROH, relative to both village dogs and wolves, and we use these patterns to show that breed dogs have experienced differing severities of bottlenecks in their recent past. We then found that ROH burden is associated with phenotypes in breed dogs, such as lymphoma. We next test the prediction that breeds with greater ROH have more disease alleles reported in the Online Mendelian Inheritance in Animals (OMIA). Surprisingly, the number of causal variants identified correlates with the popularity of that breed rather than the ROH or IBD burden, suggesting an ascertainment bias in OMIA. Lastly, we use the distribution of ROH across the genome to identify genes with depletions of ROH as potential hotspots for inbreeding depression and find multiple exons where ROH are never observed. Our results suggest that inbreeding has played a large role in shaping genetic and phenotypic variation in dogs and that future work on understudied breeds may reveal new disease-causing variation.