Limitations of current high-throughput sequencing technologies lead to biased expression estimates of endogenous retroviral elements.

Human endogenous retroviruses (HERVs), the remnants of ancient germline retroviral integrations, comprise almost 8% of the human genome. The elucidation of their biological roles is hampered by our inability to link HERV mRNA and protein production with specific HERV loci. To solve the riddle of the integration-specific RNA expression of HERVs, several bioinformatics approaches have been proposed; however, no single process seems to yield optimal results due to the repetitiveness of HERV integrations. The performance of existing data-bioinformatics pipelines has been evaluated against real world datasets whose true expression profile is unknown, thus the accuracy of widely-used approaches remains unclear. Here, we simulated mRNA production from specific HERV integrations to evaluate second and third generation sequencing technologies along with widely used bioinformatic approaches to estimate the accuracy in describing integration-specific expression. We demonstrate that, while a HERV-family approach offers accurate results, per-integration analyses of HERV expression suffer from substantial expression bias, which is only partially mitigated by algorithms developed for calculating the per-integration HERV expression, and is more pronounced in recent integrations. Hence, this bias could erroneously result into biologically meaningful inferences. Finally, we demonstrate the merits of accurate long-read high-throughput sequencing technologies in the resolution of per-locus HERV expression.

Immunogenicity, Immunological Memory and Monitoring of Disease Activity Following an Anamnestic Immunization With the 13-Valent Pneumococcal Conjugate Vaccine in Children With Idiopathic Nephrotic Syndrome.

Anamnestic 13-valent pneumococcal conjugate vaccine immunization did not affect the relapse risk in pediatric idiopathic nephrotic syndrome. Pneumococcal serotype (PS)-specific antibody titers increased significantly in all groups. Children receiving immunomodulatory treatments (IMTs) displayed significantly lower levels of PS-specific antibodies for 3/8 serotypes tested. PS-specific B-cell counts significantly increased only in healthy controls and patients receiving corticosteroids.

Length of hospital stay in involuntary admissions in Greece: a 10-year retrospective observational study.

PURPOSE: The treatment of mental disorders has shifted from inpatient wards to community-based settings in recent years, but some patients may still have to be admitted to inpatient wards, sometimes involuntarily. It is important to maintain the length of hospital stay (LoS) as short as possible while still providing adequate care. The present study aimed to explore the factors associated with the LoS in involuntarily admitted psychiatric patients. METHODS: A ten-year retrospective chart review of 332 patients admitted involuntarily to the inpatient psychiatric ward of the General University Hospital of Ioannina, Northwestern Greece, between 2008 and 2017 was conducted. RESULTS: The mean LoS was 23.8 (SD = 33.7) days and was relatively stable over the years. Longer-stay hospitalization was associated with schizophrenia-spectrum disorder diagnosis, previous hospitalizations and the use of mechanical restraint, whereas patients in residential care experienced significantly longer LoS (52.6 days) than those living with a caregiver (23.5 days) or alone (19.4 days). Older age at disease onset was associated with shorter LoS, whereas no statistically significant differences were observed with regard to gender. CONCLUSION: While some of our findings were in line with recent findings from other countries, others could not be replicated. It seems that multiple factors influence LoS and the identification of these factors could help clinicians and policy makers to design more targeted and cost-effective interventions. The optimization of LoS in involuntary admissions could improve patients' outcomes and lead to more efficient use of resources.

HERVs: Expression Control Mechanisms and Interactions in Diseases and Human Immunodeficiency Virus Infection.

Human endogenous retroviruses (HERVs) are the result of retroviral infections acquired millions of years ago; nowadays, they compose around 8% of human DNA. Multiple mechanisms have been employed for endogenous retroviral deactivation, rendering replication and retrotransposition defective, while some of them have been co-opted to serve host evolutionary advantages. A pleiad of mechanisms retains the delicate balance of HERV expression in modern humans. Thus, epigenetic modifications, such as DNA and histone methylation, acetylation, deamination, chromatin remodeling, and even post-transcriptional control are recruited. In this review, we aim to summarize the main HERV silencing pathways, revisit paradigms of human disease with a HERV component, and emphasize the human immunodeficiency virus (HIV) and HERV interactions during HIV infection.

The interaction of human immunodeficiency virus-1 and human endogenous retroviruses in patients (primary cell cultures) and cell line models.

IMPORTANCE: In this work, we demonstrated that human immunodeficiency virus (HIV) infection leads to the modification of the human endogenous retrovirus (HERV) expression. Differential expression of multiple HERVs was found in peripheral blood mononuclear cells derived from HIV-infected patients compared to healthy donors and HIV-infected T cell cultures compared to non-infected. The effect of HIV presence on HERV expression appears to be more restricted in cells of monocytic origin, as only deregulation of HERV-W and HERV-K (HML-6) was found in these cell cultures after their infection with HIV. Multiple factors contribute to this aberrant HERV expression, and its levels appear to be modified in a time-dependent manner. Further studies and the development of optimized in vitro protocols are warranted to elucidate the interactions between HIV and HERVs in detail.

Can Sulfonylureas for Agricultural Use Cause Diabetes? A Report of Three Cases.

Sulfonylureas (SUs) are commonly used as herbicides. Many farmers and other professionals use SUs for cereal, strawberry, and grape crops. This study examines the possible association between exposure to SUs herbicides and the risk of developing type 2 diabetes (T2D). The study presents three cases of unrelated agronomists who had used SUs for more than three decades and developed T2D. The objective was to investigate the association between occupational dermal and inhalation exposure to herbicides and T2D. Further studies with a larger sample size are needed to determine the association and to help develop prevention strategies.

The Underappreciated Role of Secretory IgA in IBD.

Eighty percent of antibody secreting cells (ASCs) are found in the intestine, where they produce grams of immunoglobulin (Ig) A daily. immunoglobulin A is actively transcytosed into the lumen, where it plays a critical role in modulating the gut microbiota. Although loss of immune tolerance to bacterial antigens is the likely trigger of the dysregulated immune response that characterizes inflammatory bowel disease (IBD), little effort has been placed on understanding the interface between B cells, IgA, and the microbiota during initiation or progression of disease. This may be in part due to the misleading fact that IgA-deficient humans are mostly asymptomatic, likely due to redundant role of secretory (S) IgM. Intestinal B cell recruitment is critically dependent on integrin α4ß7-MAdCAM-1 interactions, yet antibodies that target α4ß7 (ie, vedolizumab), MAdCAM-1 (ie, ontamalimab), or both ß7 integrins (α4ß7 and αE [CD103] ß7; etrolizumab) are in clinical use or development as IBD therapeutics. The effect of such interventions on the biology of IgA is largely unknown, yet a single dose of vedolizumab lowers SIgA levels in stool and weakens the oral immunization response to cholera vaccine in healthy volunteers. Thus, it is critical to further understand the role of these integrins for the migration of ASC and other cellular subsets during homeostasis and IBD-associated inflammation and the mode of action of drugs that interfere with this traffic. We have recently identified a subset of mature ASC that employs integrin αEß7 to dock with intestinal epithelial cells, predominantly in the pericryptal region of the terminal ileum. This role for the integrin had not been appreciated previously, nor the αEß7-dependent mechanism of IgA transcytosis that it supports. Furthermore, we find that B cells more than T cells are critically dependent on α4ß7-MAdCAM-1 interactions; thus MAdCAM-1 blockade and integrin-ß7 deficiency counterintuitively hasten colitis in interleukin-10-deficient mice. In both cases, de novo recruitment of IgA ASC to the intestinal lamina propria is compromised, leading to bacterial overgrowth, dysbiosis, and lethal colitis. Thus, despite the safe and effective use of anti-integrin antibodies in patients with IBD, much remains to be learned about their various cell targets.

Loss of immune tolerance to bacterial antigens represents the likely trigger of the dysregulated immune response that characterizes IBD, yet the interface between B cells, IgA, and the microbiota during initiation and progression of disease has been understudied. Here we review important aspects of the biology of IgA, its role on the control of the microbiota in mouse models, and its potential role on the pathogenesis of IBD.

Who is coercively admitted to psychiatric wards? Epidemiological analysis of inpatient records of involuntary psychiatric admissions to a University General Hospital in Greece for the years 2008-2017.

BACKGROUND: Involuntary psychiatric admissions are a widely used practice despite ethical concerns about coercion. There are particular concerns that vulnerable groups, such as single, unemployed or racial minorities, may be more subjected to such practices. AIM: We aimed to investigate the social patterns of involuntary psychiatric admissions from 2008 to 2017 at University General Hospital in Ioannina, Greece. METHOD: We retrospectively assessed inpatient records from 2008 to 2017 of patients admitted to the Department of Psychiatry of the Ioannina University General Hospital, Northwestern Greece. Alternative patients of alternative years were selected for inclusion; this yielded 332 patients involuntarily admitted, corresponding to 28.5% of total involuntary psychiatric admissions. RESULTS: Over the 10-year period, the overall numbers of annual involuntary psychiatric admissions remained relatively stable, as did the length of hospital stay (mean = 23.8 days). The most common disorder upon admission was schizophrenia spectrum disorders, accounting for approximately two-thirds of all admissions, followed by mood disorders (about 20%). There was evidence that people who lacked social support or experienced financial hardship were more greatly represented among those admitted: 70.2% of admitted patients were single and 64.8% were unemployed. Most patients had been admitted to the psychiatric ward in the past (64.2%). CONCLUSION: Our study indicates potentially worrisome evidence that patients who are in vulnerable positions are at elevated likelihood of being involuntarily admitted to psychiatric wards. Future research is needed to evaluate the socio-demographic patterning of involuntary admissions in other European countries.

Human endogenous retroviruses in cancer: Oncogenesis mechanisms and clinical implications.

Human Endogenous Retroviruses (HERVs) are viral sequences integrated into the human genome, resulting from the infection of human germ-line cells by ancient exogenous retroviruses. Despite losing their replication and retrotransposition abilities, HERVs appear to have been co-opted in human physiological functions while their aberrant expression is linked to human disease. The role of HERVs in multiple malignancies has been demonstrated, however, the extent to which HERV activation and expression participate in the development of cancer is not yet fully comprehended. In this review article, we discuss the presumed role of HERVs in carcinogenesis and their promising diagnostic and prognostic implications. Additionally, we explore recent data on the HERVs in cancer therapeutics, either through the manipulation of their expression, to induce antitumor innate immunity responses or as cancer immunotherapy targets. Finally, more precise and higher resolution high-throughput sequencing approaches will further elucidate HERV participation in human physiological and pathological processes.

Neonatal Sepsis Caused by Streptococcus gallolyticus Complicated with Pulmonary Hypertension: A Case-Report and a Systematic Literature Review.

Streptococcus gallolyticus (S. gallolyticus) has been linked to the development of infections in adults; however, in neonates S. gallolyticus sepsis is very rare and resembles Group B Streptococcal infections. In this case report, we present the case of a full-term neonate who developed early-onset sepsis due to S. gallolyticus. A systematic review of the literature was also conducted. The neonate had good APGAR scores at 1' and 5'. At 5 h postnatally, the neonate developed poor feeding and respiratory distress. She received oxygen in a head box, and a complete blood count and biochemistry, blood, CSF and body surface cultures were obtained. Empiric intravenous antibiotics (ampicillin and tobramycin) were initiated, and she was transferred to a tertiary NICU for further treatment. The neonate was mechanically ventilated and received dopamine and colloid fluids for circulatory support. A cardiology consultation revealed pulmonary hypertension on day one. S. gallolyticus was isolated in the blood culture. Central nervous system ultrasonography, brainstem auditory evoked potentials, and a second cardiology evaluation were normal on day three. Clinical and laboratory improvement was noted on day three, and the baby was discharged after a 12-day hospitalization. Follow-up visits were scheduled for reevaluation.

Diagnostic and Therapeutic Challenges in a Patient with Ureteral Metastases from a Triple Negative Breast Cancer.

Metastatic ureteral tumors arising from a primary breast carcinoma are extremely rare. They present with hematuria and radiological findings compatible with obstructive ureteral phenomena. We present a case of an 87-year-old woman with a history of lymphoma and triple negative breast cancer (TNBC), during an emergency admission for peptic ulcer, developed macroscopic hematuria. Radiologic and endoscopic investigations revealed a remarkable stenosis at the lower segment of the right ureter, attributed to metastases from her breast carcinoma. We report this case with the aim to make both oncologists and urologists aware of this rare condition.

The immunopathogenesis of idiopathic nephrotic syndrome: a narrative review of the literature.

Idiopathic nephrotic syndrome (INS) is a common glomerular disease in childhood, and the immunological involvement in the pathogenesis of non-genetic INS, although not fully elucidated, is evident. This narrative review aims to offer a concise and in-depth view of the current knowledge on the immunological mechanisms of the development of INS as well as the role of the immunological components of the disease in the responsiveness to treatment. T cell immunity appears to play a major role in the INS immunopathogenesis and has been the first to be linked to the disease. Various T cell immunophenotypes are implicated in INS, including T-helper-1, T-helper-2, T-helper-17, and T regulatory cells, and various cytokines have been proposed as surrogate biomarkers of the disease; however, no distinct T helper or cytokine profile has been conclusively linked to the disease. More recently, the recognition of the role of B cell mediated immunity and the various B cell subsets that are dysregulated in patients with INS have led to new hypotheses on the underlying immunological causes of INS. Finally, the disambiguation of the exact mechanisms of the INS development in the future may be the key to the development of more targeted personalized approaches in managing INS. CONCLUSIONS: INS demonstrates particularly interesting immunopathogenetic pathways, in which multiple interactions between T cell and B cell immunity and the podocyte are involved. The disambiguation of these pathways will provide promising novel therapeutic targets in INS. WHAT IS KNOWN: • INS is the most common glomerular disease in the paediatric population, and its onset and relapses have been linked to various immunological triggers. • Multiple immunological mechanisms have been implicated in the pathogenesis of INS; however, no single distinct immunological profile has been recognized. WHAT IS NEW: • Th17 cells and Treg cells play an important role in the immune dysregulation in INS. • Transitional B cell levels as well as the transitional/memory B cell ratio have been correlated to nephrotic relapses and have been proposed as biomarkers of INS relapses in SSNS patients.

Systematic review with meta-analysis: COVID-19 outcomes in patients receiving anti-TNF treatments.

BACKGROUND: Accumulating evidence suggests a beneficial effective of tumour necrosis factor-alpha (TNF-α) inhibitors on the outcomes of COVID-19 disease, which, however is not validated by all studies. AIMS: To perform a systematic review and meta-analysis of existing reports to investigate the impact of anti-TNF treatments on the clinical outcomes of COVID-19 patients. METHODS: A systematic search at PubMed and SCOPUS databases using specific keywords was performed. All reports of COVID-19 outcomes for patients receiving anti-TNF therapy by September 2021 were included. Pooled effect measures were calculated using a random-effects model. The Newcastle Ottawa Scale for observational studies was used to assess bias. Studies that were not eligible for meta-analysis were described qualitatively. RESULTS: In total, 84 studies were included in the systematic review, and 35 were included in the meta-analysis. Patients receiving anti-TNF treatment, compared to non-anti-TNF, among COVID-19 cases had a lower probability of hospitalisation (eight studies, 2555 patients, pooled OR = 0.53, 95% CI: 0.42-0.67, I2  = 0) and severe disease defined as intensive care unit admission or death (two studies, 1823 patients, pooled OR = 0.63, 95% CI: 0.41-0.96, I2  = 0), after adjustment for validated predictors of adverse disease outcomes. No difference was found for the risk for hospitalisation due to COVID-19 in populations without COVID-19 for patients receiving anti-TNF treatment compared to non-anti-TNF (three studies, 5 994 958 participants, pooled risk ratio = 0.97, 95% CI: 0.68-1.39, I2  = 20) adjusted for age, sex and comorbidities. CONCLUSIONS: TNF-α inhibitors are associated with a lower probability of hospitalisation and severe COVID-19 when compared to any other treatment for an underlying inflammatory disease.

Viral Causality of Human Cancer and Potential Roles of Human Endogenous Retroviruses in the Multi-Omics Era: An Evolutionary Epidemiology Review.

Being responsible for almost 12% of cancers worldwide, viruses are among the oldest known and most prevalent oncogenic agents. The quality of the evidence for the in vivo tumorigenic potential of microorganisms varies, thus accordingly, viruses were classified in 4 evidence-based categories by the International Agency for Research on Cancer in 2009. Since then, our understanding of the role of viruses in cancer has significantly improved, firstly due to the emergence of high throughput sequencing technologies that allowed the "brute-force" recovery of unknown viral genomes. At the same time, multi-omics approaches unravelled novel virus-host interactions in stem-cell biology. We now know that viral elements, either exogenous or endogenous, have multiple sometimes conflicting roles in human pathophysiology and the development of cancer. Here we integrate emerging evidence on viral causality in human cancer from basic mechanisms to clinical studies. We analyze viral tumorigenesis under the scope of deep-in-time human-virus evolutionary relationships and critically comment on the evidence through the eyes of clinical epidemiology, firstly by reviewing recognized oncoviruses and their mechanisms of inducing tumorigenesis, and then by examining the potential role of integrated viruses in our genome in the process of carcinogenesis.

Upregulation of Human Endogenous Retroviruses in Bronchoalveolar Lavage Fluid of COVID-19 Patients.

Severe COVID-19 pneumonia has been associated with the development of intense inflammatory responses during the course of infections with SARS-CoV-2. Given that human endogenous retroviruses (HERVs) are known to be activated during and participate in inflammatory processes, we examined whether HERV dysregulation signatures are present in COVID-19 patients. By comparing transcriptomes of bronchoalveolar lavage fluid (BALF) of COVID-19 patients and healthy controls, and peripheral blood monocytes (PBMCs) from patients and controls, we have shown that HERVs are intensely dysregulated in BALF of COVID-19 patients compared to those in BALF of healthy control patients but not in PBMCs. In particular, upregulation in the expression of specific HERV families was detected in BALF samples of COVID-19 patients, with HERV-FRD being the most highly upregulated family among the families analyzed. In addition, we compared the expression of HERVs in human bronchial epithelial cells (HBECs) without and after senescence induction in an oncogene-induced senescence model in order to quantitatively measure changes in the expression of HERVs in bronchial cells during the process of cellular senescence. This apparent difference of HERV dysregulation between PBMCs and BALF warrants further studies in the involvement of HERVs in inflammatory pathogenetic mechanisms as well as exploration of HERVs as potential biomarkers for disease progression. Furthermore, the increase in the expression of HERVs in senescent HBECs in comparison to that in noninduced HBECs provides a potential link for increased COVID-19 severity and mortality in aged populations. IMPORTANCE SARS-CoV-2 emerged in late 2019 in China, causing a global pandemic. Severe COVID-19 is characterized by intensive inflammatory responses, and older age is an important risk factor for unfavorable outcomes. HERVs are remnants of ancient infections whose expression is upregulated in multiple conditions, including cancer and inflammation, and their expression is increased with increasing age. The significance of this work is that we were able to recognize dysregulated expression of endogenous retroviral elements in BALF samples but not in PBMCs of COVID-19 patients. At the same time, we were able to identify upregulated expression of multiple HERV families in senescence-induced HBECs in comparison to that in noninduced HBECs, a fact that could possibly explain the differences in disease severity among age groups. These results indicate that HERV expression might play a pathophysiological role in local inflammatory pathways in lungs afflicted by SARS-CoV-2 and their expression could be a potential therapeutic target.

Prevalence and associated factors of anxiety and depression in students at a Greek university during COVID-19 lockdown.

BACKGROUND: Restrictions on movement and lockdown are measures taken in many nations, in response to the COVID-19 pandemic. University students are additionally burdened by the transition to distance e-learning. The aims of the study were to investigate the prevalence of anxiety and depression in university students and to identify associated risk factors. DESIGN AND METHODS: An online questionnaire was administered to 2,009 students in the University of Patras, Greece, during the national lockdown. Socio-demographic, academic data, and the forced disruption of daily life were assessed along with the Greek version of the Hospital Anxiety and Depression Scale. RESULTS:  Anxiety and depression prevalence was 35.8% and 51.2% respectively. Age, school of study, financial status, self-perceived health status, level of satisfaction with the state's and university's response and specific aspects in the daily routine were associated with both anxiety and depression scores. At higher odds of both depression and anxiety were students with low income, bad health status, annoyed at staying home and those who encountered difficulties with the online education system. Additional risk factors for depression were studies in humanities and social sciences, and low satisfaction with the university's response, while for anxiety were studies in agricultural sciences and absence of information about COVID-19. CONCLUSIONS: The proportion of Greek students showing depression and anxiety, during the restrictive measures, is alarming. Mental health in university students should be monitored. Mitigation strategies should focus on specific personal, academic and social variables that have been identified as protective factors.