Doravirine (DOR) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) with efficacy against some NNRTI resistant mutants. Although DOR resistance mutations are established for HIV-1 subtype B, it is less clear for non-B subtypes. This study investigated prevalent NNRTI resistance mutations on DOR susceptibility in HIV-1 subtype C. Prevalent drug resistance mutations were identified from a South African genotypic drug resistance testing database. Mutations, single or in combination, were introduced into replication defective pseudoviruses and assessed for DOR susceptibility in vitro. The single V106M and Y188L mutations caused high-level resistance while others didn’t significantly impact DOR susceptibility. We observed agreement between our in vitro and the Stanford HIVdb predicted susceptibilities. However, the F227L mutation was predicted to cause high-level DOR resistance but was susceptible in vitro. Combinations of mutations containing K103N, V106M or Y188L caused high-level resistance, in agreement with the predictions. These mutations are frequently observed in patients failing efavirenz or nevirapine-based first-line regimens. However, they are also observed in those failing a protease inhibitor-based second-line regimen, as we have observed in our database. Genotypic drug resistance testing is therefore vital prior to initiation on DOR-based treatment for those previously exposed to efavirenz or nevirapine.

Feline immunodeficiency virus (FIV) is a naturally-occurring retrovirus that infects domestic and non-domestic feline species, producing progressive immune depletion that results in an acquired immunodeficiency syndrome (AIDS). Much has been learned about FIV since it was first described in 1987, particularly in regard to its application as a model to study the closely related lentivirus, human immunodeficiency virus (HIV). In particular, FIV and HIV share remarkable structure and sequence organization, utilize parallel modes of receptor-mediated entry, and result in a similar spectrum of immunodeficiency-related diseases due to analogous modes of immune dysfunction. This review summarizes current knowledge of FIV infection kinetics and mechanisms of immune dysfunction in relation to opportunistic disease, specifically in regard to studying HIV pathogenesis. Furthermore, we present data which highlight changes in the oral microbiota and oral immune system during FIV infection, and outline the potential for the feline model of oral AIDS manifestations to elucidate pathogenic mechanisms of HIV-induced oral disease. Finally, we discuss advances in molecular biology, vaccine development, neurologic dysfunction, and the ability to apply pharmacologic interventions and sophisticated imaging technologies to study experimental and naturally occurring FIV, which provide an excellent, but often overlooked resource for advancing therapies and management of HIV/AIDS.

Several studies with kaempferol (KP) and linearolactone (LL) have shown antiparasitic activities. However, the toxicity of treat-ments with both active principles is unknown. Therefore, this study aimed to evaluate the toxicological effects of treatments with KP and LL on the amoebic liver abscess (ALA) model in M. auratus administered intraperitoneally (i.p.). For this, ALA in-duction was carried out in male hamsters with 1.5 x105 E. histolytica trophozoites inoculated in the left hepatic lobe. The lesion evolved for four days and the i.p. of the treatments with KP (5 mg/kg body weight/day) and LL (10 mg/kg body weight/day) was carried out for four consecutive days. For histopathological evaluation, NMR studies, paraclinical analysis, and necropsy were performed. The results revealed that the inhibition of ALA by KP and LL were similar to that metronidazole (MTZ). Biochemical parameters revealed hepatic and renal alterations in all treatment groups, mainly for KP (AST and BUN). The lesions found in the organs were those that are directly linked to the pathology. In conclusion, KP and LL decrease ALA development but have few toxicological effects. Both compounds combined with MTZ could be therapeutic alternatives for amoebiasis caused by E. histolytica.

New antiviral agents are essential to improving treatment and control of SARS-CoV-2 infections that can lead to the disease COVID-19. Antimicrobial peptoids are sequence-specific oligo-N-substituted glycine peptidomimetics that emulate the structure and function of natural antimicrobial peptides but are resistant to proteases. We demonstrate antiviral activity of a new peptoid (TM9) against the coronavirus, murine hepatitis virus (MHV), as a closely related model for the structure and antiviral susceptibility profile of SARS-CoV-2. This peptoid mimics the human cathelicidin LL-37, which has also been shown to have antimicrobial and antiviral activity. In this study TM9 was effective against three murine coronavirus strains, demonstrating the therapeutic window is large enough to allow use of TM9 for treatment. All three isolates of MHV generated infection in mice after 15 min of exposure by aerosol using the Madison aerosol chamber and all three viral strains could be isolated from the lungs throughout the 5-day observation period post-infection, with the peak titers on day 2. MHV-A59 and MHV-A59-GFP were also isolated from liver, heart, spleen, olfactory bulbs, and brain. These data demonstrate that MHV serves as a valuable natural murine model of coronavirus pathogenesis in multiple organs, including the brain.

This study delves into the dynamic field of medical education research, emphasizing the integration of research training within medical curricula. It seeks to understand the impact of such integration on the competencies of future medical professionals. The primary aim is to systematically categorize and analyze the current trends and future directions in medical education research. This involves assessing the influence of research training on medical students' skills and the methodologies used in such research. Methods: The research employs an extensive bibliographic literature review across multiple databases. It classifies studies into categories like experiential or case studies, editorials, and original research articles. This classification is based on criteria such as geographical location, research objectives, theoretical frameworks, and methodologies. Results: Findings reveal a diverse landscape in medical education research, with a significant emphasis on research training. The research showcases varying methodologies and approaches used globally, highlighting the thematic focus and geographical distribution of these studies. Conclusion: Medical education research is a globally expansive and evolving field. It underscores the importance of continuous investigation, particularly focusing on integrating research elements at curricular levels and exploring innovative educational strategies. The study also points out potential gaps in research, especially in underrepresented regions, indicating directions for future research efforts.

Elizabethkingia anophelis is an opportunistic pathogen causing lifethreatening infections in humans, particularly in immunocompromised patients, neonates and elderly. Infections caused by this species are exceptionally challenging to treat due to its multiresistance to antimicrobials. We report a case of central line-associated bloodstream infection by E. anophelis in a 2.5-year-old girl with acute lymphoblastic leukemia successfully treated with a combination of piperacillin/tazobactam and amikacin. The literature was also reviewed on paediatric infections caused by E. anophelis. Accurate identification with MALDI-TOF, or using molecular techniques, is crucial because of varying susceptibilities among species. Early, accurate diagnosis and prompt effective treatment optimize outcomes.

Vaccine antigens must present the correct conformation of viral fusion glycoproteins to elicit effective immune responses. Virus-like particles (VLPs) serve as promising vaccine platforms because they mimic the membrane-embedded conformations of fusion glycoproteins on native viruses. Here, we employed SARS-CoV-2 VLPs (SMEN) presenting ancestral, Beta, or Omicron spikes to identify the variant that elicits potent and cross-protective immune responses in the highly sensitive K18-hACE2 mouse model. A combined intranasal and intramuscular administration regimen of the SMEN vaccine generated effective immune responses and was predominantly mediated by antibodies with minor contributions from T cells. Immunization with SMEN presenting an ancestral spike resulted in 100, 75, or 0% protection against ancestral, Delta or Beta VOC-induced mortality, respectively, whereas SMEN presenting the most divergent Omicron spike provided only limited protection (50%, 0%, and 25%) against ancestral, Delta, and Beta variants, respectively. By contrast, SMEN with a Beta spike offered 100% protection against the variants used in this study. Thus, the Beta variant not only overcame the immunity produced by other variants, but also elicited diverse and effective immune response. Our findings suggest that leveraging the Beta variant spike protein can enhance SARS-CoV-2 immunity, potentially leading to a more comprehensive vaccine against emerging variants.

Psoriasis is a chronic recurrent inflammatory autoimmune pathology, with a major genetic component and several interferences of immunological cells and their cytokines. The complex orchestration of psoriasis pathogenesis is related to the synergic effect of immune cells, polygenic alterations, the presence of autoantigens and several external factors. The major act of IL-23/IL-17 axis, strongly influencing the inflammatory pattern established during the disease activity, is visible as a continuous perpetuation of the pro-inflammatory response and keratinocyte activation and proliferation leading to the development of psoriatic lesions. Genome wide association studies (GWAS) along offered a better view of psoriasis pathogenic pathways, with approximately one third of psoriasis genetic impact on psoriasis development is associated to MHC region, with genetic loci located on chromosome 6. The most eloquent genetic factor of psoriasis, PSORS1, was identified in the MHC I site. Between the several factors involved in its complex etiology, dysbiosis, due to genetic or external stimulus, exhibiting less variety and the involvement of pathogenic bacteria, cand induce a burst of proinflammatory consequences, both cutaneous and gut microbiome being involved in psoriasis pathogenic process. A complex understanding of the major pathways that interplay in order to initiate and perpetuate psoriatic diseases and its associated comorbidities can help the current clinical practice by properly evaluating completely and individualized each patient and establish the proper therapeutic management.

Bronchopulmonary dysplasia (BPD), also known as chronic lung disease, is the most common respiratory morbidity in preterm infants. "Old" or "Classic" BPD, as per the original description, is less common now. "New BPD," which presents with distinct clinical and pathological features, is more frequently observed in the current era of advanced neonatal care, where extremely premature infants are surviving due to medical advancements. The pathogenesis of BPD is complex and multifactorial and involves both genetic and environmental factors. This review provides an overview of the pathology of BPD and discusses the influence of several prenatal and postnatal factors on its pathogenesis, such as maternal factors, genetic susceptibility, ventilator-associated lung injury, oxygen toxicity, sepsis, patent ductus arteriosus (PDA), and nutritional deficiencies. This in-depth review draws on existing literature to explore these factors and their potential contribution to the development of BPD.

During HIV-1 virus assembly the genomic RNA (vRNA) is selected for packaging by the viral protein Gag because it contains a specific packaging signal, Psi. While there have been numerous studies of Gag-Psi interactions, there is almost no information on kinetic aspects of this interaction. We have investigated the kinetics of Gag binding to different RNAs using switchSENSE DRX2 technology. We measured the association rate of Gag binding to monomeric Psi, to a “Multiple Binding Site Mutant” Psi that is inactive for genome packaging in vivo, and to a scrambled Psi. We discovered that Gag binds more rapidly to Psi RNA than to the mutant or scrambled RNAs. Furthermore, rapid Gag association kinetics are retained within sub-regions of Psi: Gag associates more rapidly with RNA containing only the 3’ two of the three Psi stem-loops than with monomeric RNA containing the 5’ two stem-loops or a scrambled RNA. No differences were detectable with individual Psi stem-loops. Interestingly, the rate of binding of Gag molecules to Psi increases with increasing Gag concentration, suggesting cooperativity in binding. The results are consistent with the hypothesis that selectivity in packaging derives from kinetic differences in initiation of particle assembly.

Hereditary Hemorrhagic Telangiectasia (HHT), also known as Osler-Weber-Rendu syndrome, is a rare and inherited vascular disorder, characterized by the development of arteriovenous malformations (AVMs) in various organs and telangiectasia (small AVM) in the mucocutaneous. The majority of HHT patients have haploinsufficiency of genes involved in the transforming growth factor-beta (TGFβ) signaling pathway, including endoglin (ENG), activin receptor-like kinase 1 (ALK1, also known as ACVRL1), or SMAD4. Active angiogenesis is also required for telangiectasia and AVM development. Anti-angiogenic strategies have been tested in patients and animal models extensively. However, the exact mechanisms for telangiectasia and AVM development remain unclear. In this review, we discuss recent advances in identifying disease mechanisms, and potential therapeutic targets.

Mortality in children accounts for 15% of all AIDS-related deaths globally, with a higher burden among Cameroonian children (25%), likely due to poor virological response. We sought to evaluate viral suppression (VS) and its determinants in a nationally representative paediatric and young adult population receiving antiretroviral therapy (ART). A cross-sectional and multicentric study was conducted among Cameroonian children (

Interstitial lung disease (ILD) is one of the most serious extra-articular complications of rheu-matoid arthritis (RA), which increases the mortality of RA. Because the pathogenesis of RA-ILD remains poorly understood, appropriate therapeutic strategies and biomarkers have not yet been identified. Thus, the goal of this review was to summarize and analyze the reported data on the etiology and pathogenesis of RA-ILD. The incidence of RA-ILD increases with age, and is also generally higher in men than in women and in patients with specific genetic variations and eth-nicity. Lifestyle factors associated with an increased risk of RA-ILD include smoking and exposure to pollutants. The presence of an anti-cyclic citrullinated peptide antibody, high RA disease activity, and rheumatoid factor positivity also increase the risk of RA-ILD. We also explored the roles of biological processes (e.g., fibroblast–myofibroblast transition, epithelial–mesenchymal transition, and immunological processes), signaling pathways (e.g., JAK/STAT and PI3K/Akt), and the his-topathology of RA involved in RA-ILD pathogenesis based on published preclinical and clinical models of RA-ILD in animal and human studies.

The African continent has the highest prevalence of hypertension globally, with South Africa reporting the highest prevalence in Southern Africa. While the influence of genetic variability in the pathogenesis of hypertension is well described internationally, limited reports are available for African populations. This study aimed to assess the association of genetic variants and essential hypertension in a cohort of two ethnic South African population groups. Two hundred and seventy-seven hypertensive and one hundred and seventy-six normotensive individuals were genotyped for 79 variants. Genotyping was performed using the Illumina GoldenGate Assay and allele-specific polymerase chain reaction. The association of variants was assessed using the Fisher Exact test under the additive and allelic genetic models, while multivariate logistic regression was used to predict the development of hypertension. Five variants (CYP11B2 rs179998, AGT rs5051 and rs699, AGTR1 rs5186 and ACE rs4646994) were significantly associated with essential hypertension in the cohort under study. Furthermore, AGTR1 rs5186 and AGT rs699 were identified as risk factors for the development of hypertension in both ethnic groups. In two ethnic South African populations an association was observed between Renin-Angiotensin-Aldosterone System (RAAS) related genes and the development of hypertension.

Preeclampsia is a complex pregnancy-related hypertensive disorder which poses significant risks for both maternal and fetal health. Preeclampsia affects 5-8% of the pregnancies in the United States, causing a significant public health and economic burden. Despite extensive research, the etiology and pathogenesis of preeclampsia remain elusive, but have been correlated with maternal conditions such as obesity. In the past decades, the incidence of preeclampsia increased along with the prevalence of obesity among women of reproductive age. Maternal obesity has been shown to negatively affect pregnancy in almost all aspects. However, the precise mechanisms by which obesity influences preeclampsia are unclear. Ankyrin repeat and SOCS Box Containing protein 4 (ASB4) is an E3 ubiquitin ligase that can promote the degradation of a wide range of target proteins. ASB4-null mice display a full spectrum of preeclampsia-like phenotypes during pregnancy including hypertension, proteinuria, and decreased litter size. Furthermore, maternal obesity induced by a high fat diet aggravates preeclampsia-like phenotypes in pregnant mice lacking ASB4. Variants in the ASB4 gene have been associated with obesity in humans, and a functional connection between the ASB4 gene and obesity has been established in mice. This review discusses the connections between preeclampsia, obesity, and ASB4.

A great deal of studies have assessed the expression of noncoding RNAs (ncRNAs) as well as their relevant molecular functions and biological mechanisms in the individuals of alcohol dependence. Alcohol dependence is one of the most prevalent neuropsychological disorders worldwide, and its pathogenesis is intricate and inadequately understood. There is considerable evidence demonstrating substantial links between multiple genetic factors and the development of alcohol dependence. Critical roles of ncRNAs have been emphasized in the pathophysiology of mental diseases including alcohol dependence. In the comprehension of ncRNAs action and their mechanisms of modification, they have emerged as therapeutic targets for a variety of psychiatric illness including alcohol dependence. Worth mentioning, dysregulated expression of ncRNAs has been regularly detected in individuals of alcohol dependence. An in-depth knowledge of roles of ncRNAs and m6A modification may be valuable for the development of a novel treatment against alcohol dependence. In general, a deeper comprehension of functional roles ncRNAs may make significant contributions to the precise diagnosis and/or actual treatment of alcohol dependence. Here in this review, we mostly focused on the up-to-date knowledge regarding alterations and/or modifications in the expression of ncRNAs in alcohol dependence, and then, presented their prospects for future research and therapeutic application with a novel concept of engram-system.

Immunosuppressed individuals, such as people living with HIV (PLWH), remain vulnerable to severe COVID-19. We analyzed the persistence of specific SARS-CoV-2 humoral and cellular immune responses in a retrospective, cross-sectional study in PLWH on antiretroviral therapy. Among 104 participants, 70.2% had anti-S IgG antibodies and 55.8% had significant neutralizing activity against the Omicron variant in a surrogate virus neutralization test. Only 38.5% were vaccinated (8.76 ± 4.1 months prior), all displaying anti-S IgG, 75% with neutralizing antibodies and anti-S IgA. 29.8% had no SARS-CoV-2 serologic markers and displayed significantly lower CD4 counts and HIV viral load. Severe immunosuppression (present in 12.5% of participants) was linked to lower levels of detectable anti-S IgG (0.0003), anti-S IgA (p < 0.0001) and lack of neutralizing activity against Omicron variant (p < 0.0001). T-cell responses were present in 86.7% of tested participants, even in those lacking serological markers. In PLWH without severe immunosuppression, neutralizing antibodies and T-cell responses persisted for up to 9 months post-infection or vaccination. Advanced immunosuppression led to diminished humoral immunity, but retained cellular immune.

Acquired immunodeficiency syndrome (AIDS) has transitioned from a progressive, fatal disease to a chronic, manageable disease thanks to better defining of antiretroviral therapy, hence contributing to increased life expectancy. In parallel, a growing number of subjects without overt clinical signs of disease but living with chronic HIV infection (people living with HIV, PLWH) are experiencing early cardiovascular disease worldwide. However, a progressive increase in the prevalence of multiple comorbid diseases has been reported as these patients age, including cardiovascular disease (CVD). Cardiovascular mortality can be either directly related to the viral infection, a progressive reduction of response to the antiretroviral therapy, chronic inflammation or lifestyle-related. Cardiovascular ageing represents a relevant issue in the management of HIV-infected patients. Although the exact pathophysiological mechanism that leads PLWH to develop cardiovascular disease is not entirely understood, there is substantial evidence that they accumulate age-related conditions earlier than the general population. Furthermore, since the proportion of PLWH growing older than 50 years has progressively increased, this results in a complex interaction between disease-related pathophysiology and the exposition of a growing burden of cardiovascular risk factors. For this reason, we performed a systematic review of the genes most frequently associated with ageing in HIV-infected subjects, followed by a bioinformatic analysis to explore the biological impact of the genes related to ageing.

The objective of this study was to analyze the epidemiological links of HIV, HCV and HIV-HCV coinfections to less studied types of transmission in certain populations. We performed an observational, prospective study on 903 patients aged between 15-87 years who took part in the Open Test Project. They were divided into two subgroups: general population and individuals from prisons, and questioned about multiple risk factors. Chi-Square Independence Test was used to establish correlations between the risk factors and the results of the screening tests. Logistic regression was used to calculate the probability of a reactive screening test based on each independent risk factor and age. HIV was very strongly associated with unprotected sexual intercourse with HIV-positive partners (the strongest association), unprotected sexual intercourse with sex workers, newly diagnosed sexually transmitted diseases (STDs), intravenous drug use (IDUs) and sharing injecting materials. In the case of HCV reactive tests, very strong associations have been established with injecting drug use (the strongest association), unprotected sexual intercourse with IDUs and sharing injecting materials. Our study indicates the need for implementing targeted public health programs, tailored to the local epidemiology that can ultimately lead to micro-elimination of hepatitis and HIV infections in this area.

HIV-associated cardiovascular diseases remain a leading cause of death in people living with HIV/AIDS (PLWHA). Although antiretroviral drugs suppress the viral load, they fail to remove the virus entirely. HIV-1 Nef protein is known to play a role in viral virulence and HIV latency. Expression of Nef protein can be detected in different organs, including cardiac tissue. Despite the established role of Nef protein in HIV-1 replication, its impact on organ function inside the human body is not clear. To understand the effect of Nef at the organ level, we created a new Nef transgenic (Nef-TG) mouse that expresses Nef protein in the heart. Our study found that Nef expression caused inhibition of cardiac function and pathological changes in the heart with increased fibrosis, leading to heart failure and early mortality. Further, we found that cellular autophagy is significantly inhibited in cardiac tissue of Nef-TG mice. Mechanistically, we found that Nef protein causes the accumulation of Bcl2 and Beclin-1 protein in the tissue, which may affect the cellular autophagy system. Additionally, we found Nef expression causes upregulation of cellular senescence marker p21, and senescence-associated -galactosidase expression. Our findings suggested that Nef-mediated inhibition of autophagy and induction of senescence markers may promote aging in the PLWHA. Our mouse model could help us to understand the effect of Nef protein on organ function during latent HIV infection.

Malignant lymphoma is an unusual form of gallbladder neoplasm. Almost all of these tumors are diffuse large B-cell lymphomas or mucosa-associated lymphoid tissue-type lymphomas. Herein, we report a rare case of a gallbladder Burkitt’s lymphoma (BL) in a child living with HIV. As far as we are concerned, this is the secondfirst report in the pediatric population and the first one in an individual living with HIV. The patient (a five-year-old black female child) attended the Federal Hospital of Lagoa, Rio de Janeiro, Brazil, underwent cholecystectomy and the postoperative pathological analysis of the gallbladder revealed a diagnosis of BL (EBV-positive). Also, HIV serology was performed and returned positive. She was transferred to the Martagão Gesteira Institute of Pediatrics and Childcare for oncological treatment, dying from sepsis and disease progression about 18 months later. Patient did not undergo ART/cART. Previous cases of gallbladder BL were herein described and analyzed to characterize the clinicopathological features and possible similarities. BL can occur in the gallbladder both in the context of HIV infection and in the pediatric population. Biopsy is mandatory in cases with suggestive findings of lymphoma, and an early diagnosis can change the course of the disease. Furthermore, the case highlights the importance of an early initiation of ART/cART in people living with HIV (PLWH).

Polycystic ovary syndrome (PCOS) is a complex disorder that impacts both the endocrine and metabolic systems. The gut microbiota plays a crucial role in in metabolism regulation and immune responses through its interaction with the external environment. This article explores the intricate interplay between intestinal flora and the pathogenesis of PCOS, focusing on the pivotal role of microbial metabolites, specifically short-chain fatty acids (SCFAs). SCFA levels in fecal and blood samples from women with PCOS (n=69) and healthy controls (n=18) were analyzed using Gas Chromatography-Mass Spectrometry (GC/MS) for precise measurement. The results revealed that women with PCOS exhibited a significant reduction in beneficial bacteria alongside a notable overgrowth of opportunistic microorganisms. An overproduction of acetic acid (AA) and valeric acid (VA) in fecal samples suggests a link between elevated SCFAs and the development of obesity and PCOS. Interestingly, AA in the bloodstream might offer a protective effect against PCOS by ameliorating key symptoms such as high body mass index (BMI), insulin resistance (IR), and chronic inflammation. This finding points to the potential therapeutic value of maintaining optimal AA levels in the blood. Although serum SCFA levels showed non-significant changes following metformin treatment, the normalization of AA in the gut underscores that metformin exerts a more pronounced effect locally within the gastrointestinal tract. This treatment also led to an increase in beneficial gut bacteria and a reduction in opportunistic pathogens, suggesting a restoration of gut microbial balance. Furthermore, the study identified the most effective model for predicting the success of metformin therapy, based on serum concentrations of butyric acid (BA) and VA, achieving a 91% accuracy rate, 100% sensitivity, and 80% specificity. These promising findings highlight the potential for developing targeted interventions and personalized treatments, ultimately improving clinical outcomes for women with PCOS.

HIV early detection (CD4 counts ≥350 cells/μL) is correlated with higher life expectancy among people living with HIV (PLHIV). Several factors including physical, cultural, structural, and financial barriers have contributed to HIV late detection. This is the first-of-its-kind study on the regional differences in early detection of HIV within Tajikistan and any country in the Central Asia region. Utilizing Tajikistan Ministry of Health's national HIV data (N=10,700) spanning 2010 to 2023, we developed median regression models with median CD4 cell count as the outcome and as predictors: time (years), region, age, gender, and area (urban/rural status). Individuals younger than 19 years old are more likely to be detected early for HIV, whereas those older than 39 years are more prone to late detection. Given their active engagement in age-related and sexual activities, those older than 39 years face a higher risk of HIV transmission to others if diagnosed late. Therefore, they require further attention and targeted interventions. Females are detected earlier compared to their male counterparts, regardless of region of residence. Rural populations are detected earlier in most years compared to their urban counterparts. The COVID-19 pandemic accelerated HIV early detection in 2021 but most regions have returned to near pre-pandemic levels of detection in 2022 and 2023. These fluctuations in early detection may signify a shift in attention and resource allocation, potentially affecting efforts to address access gaps during the initial year of the COVID-19 pandemic. There are significant health inequities among different demographic and geographic groups which warrant further attention.

Vaccination represents the historical milestone in medical sciences, which has been saving millions of lives. Nonetheless, continued outbreaks of emergent infectious diseases are swamping from every coast to every border all over the world. Modern vaccines are our most powerful arsenals to defend the public health of a global population ever since 1796. As unexpected, modern vaccination approaches have brought out all sorts of unwelcome pathogenic disorders to varying extents. Pathogenic viruses have also continued to evolve to defeat elaborate arsenals devised by human intelligence. In this review, we have covered a variety of vaccination approaches along with their sophisticated materials from the past to the most recent development. Furthermore, we discuss varied serious pathogenic outcomes elicited by contemporary vaccination programmes involving novel materials in real clinical trials. The complex immune mediators will be discussed in the context to tackle the complication of vaccine-induced pathogenesis. We will offer the insight into the intractable discrepancy of vaccine-associated pathology. The precision approach bestowed with evolutionary concepts will be considered as a feasible option to confront various issues of pathogenic complicacy.

Psoriasis is a lifelong, systemic, immune mediated inflammatory skin condition, affecting 1-3% of the world’s population, with an impact on quality of life similar to diseases like cancer or diabetes. Genetics are the single largest risk factor in psoriasis, with GWAS studies showing that many psoriasis risk genes lie along the IL23/Th17 axis. Potential psoriasis risk genes determined through GWAS can be annotated and characterised using functional genomics, allowing the identification of novel drug targets and the repurposing of existing drugs. The pathogenesis of psoriasis is complex and focusing on the IL23/Th17 axis can provide insight into key cell types, cytokines and intracellular signaling pathways involved. Examination of currently available biological treatments, time to relapse post drug withdrawal and rates of drug primary/secondary drug failure show the need for greater understanding of the underlying genetic mechanisms of psoriasis and how they can impact treatment. This could allow for patient stratification towards the treatment most likely reduce dis-ease burden for the longest period possible.

Periodontitis is a chronic inflammatory disease affecting the tissues that surround and support the teeth. In the U. S., approximately 65 million people are affected by this condition. Its occurrence is also associated with many important systemic diseases such as cardiovascular disease, rheumatoid arthritis, and Alzheimer’s disease. Among the most important etiologies of periodontitis is Porphyromonas gingivalis, a keystone bacterial pathogen. Keystone pathogens can orchestrate inflammatory disease by remodeling a normally benign microbiota causing imbalance between normal and pathogenic microbiota (dysbiosis). The important characteristics of P. gingivalis causing dysbiosis are its virulence factors that cause effective subversion of host defenses to its advantage [1], allowing other pathogens to grow. However, the mechanisms involving these processes are poorly understood. However, various microbial strategies target host sialoglycoproteins for immune dysregulation. In addition, the enzymes that break down sialoglycoproteins/sialoglycans are the “sialoglycoproteases”, resulting in exposed terminal sialic acid. This process could lead to pathogen-toll like receptor (TLR) interactions mediated through sialic acid receptor–ligand mechanisms. By assessing the function of P. gingivalis sialoglycoproteases, could pave the way to designing carbohydrate analogues and sialic acid mimetics to serve as drug targets.

Alcoholic liver disease (ALD) is a major cause of chronic liver disease. This term covers a broad spectrum of liver lesions, from simple steatosis to alcoholic hepatitis and cirrhosis. The patho-genesis of ALD is multifactorial and not fully elucidated due to complex mechanisms related to direct ethanol toxicity with subsequent hepatic and systemic inflammation. The accumulation of pro-inflammatory cytokines and the reduction of anti-inflammatory cytokines promote the development and progression of ALD. To date, there are no targeted therapies to counteract disease progression and prevent acute liver failure. Corticosteroids reduce mortality by acting on the hepatic-systemic inflammation. On the other hand, several studies analyzed the effect of the inhibition of pro-inflammatory cytokines and the stimulation of anti-inflammatory cytokines as potential therapeutic targets in ALD. This narrative review aims to clarify the role of the cy-tokines in the pathogenesis and treatment of ALD.

Drug-resistant tuberculosis (DR-TB) and HIV-coinfection present a conundrum to public health globally, and the achievement of the global END TB strategy in 2035. A descriptive, retrospective review of medical records of patients diagnosed with DR-TB who received treatment was conducted. Student’s t-test was performed to assess differences between two means and ANOVA between groups. Either the Chi-square test with and without trend or Fischer’s exact test was used to test the degree of association of categorical variables. Logistic regression was used to determine predictors of DR-TB treatment outcomes. Also, a decision tree classifier, which is a supervised machine learning algorithm was used. Python version 3.8. and R version 4.1.1 software were used for data analysis. A p-value of 0.05 with a 95% confidence interval (CI) was used to determine statistical significance. A total of 456 DR-TB patients were included in the study with more male patients (n = 256, 56.1%) than female patients (n = 200, 43.9%). The overall treatment success rate was 61.4%. There was a significant decrease in the % of patients cured during the Covid-19 pandemic compared to the pre-pandemic period. Our findings showed that machine learning can be used to predict TB patients' treatment outcomes.

Both bacteria product flagellin and macrophages are implicated in HIV infection/disease progression. However, the impact of their interaction on HIV infection and the associated mechanisms remain to be determined. We thus examined the effect of the flagellins on HIV infection of primary human macrophages. We observed that the pretreatment of macrophages with the flagellins from the different bacteria significantly inhibited HIV infection. The mechanistic investigation showed that the flagellin treatment of macrophages downregulated the major HIV entry receptors (CD4 and CCR5) and upregulated the CC chemokines (MIP-1α, MIP-1β, and RANTES), the ligands of CCR5. These effects of the flagellin could be compromised by a toll like receptor 5 (TLR5) antagonist. Given the important role of flagellin as a vaccine adjuvant in TLR5 activation-mediated immune regulation and in HIV infection of macrophages, future investigations are necessary to determine the in vivo impact of flagellin-TLR5 interaction on macrophage-mediated innate immunity against HIV infection and the effectiveness of flagellin adjuvant-based vaccines studies.

Most cervical cancer cases are a result of persistent high-risk Human papillomavirus (HPV) infections. Cervical cancer is prevalent in LMICs especially in SSA where it is second most prevalent cancer. In South Africa, it is the second most common cancer affecting women aged between 15 and 44 years. The host immune response has been shown as an important factor in controlling the progression or regression of high-risk HPV infection of the cervix to cervical cancer. The risk of cervical cancer is known to be influenced by the host's genetic diversity, particularly by immune response-regulating genes such as the Human Leukocyte Antigen (HLA) class I and II genes. HLA class I genes present viral peptides to CD8+ T cells which are restricted and pre-programmed for cytotoxic functions. There is very little known about the HLA genes of South African women and how these influence outcome of HPV infections. This review aims to understand the role and influence of HLA class I genes in HPV clearance, persistence, and CD8+ T cell mediated immunity in African women by examining existing literature in this area. Understanding this role can influence and inform therapeutic vaccine design that is population specific.

The DEAD-box RNA helicase DDX3X is a multifunctional protein involved in RNA metabolism and stress responses. In this study, we investigated the role of RG/RGG motifs in the dynamic process of liquid-liquid phase separation (LLPS) of DDX3X using cell-free assays and explored their potential link to cancer development through bioinformatic analysis. Our results demonstrate that the number, location, and composition of RG/RGG motifs significantly influence the ability of DDX3X to undergo phase separation and form self-aggregates. Mutational analysis revealed that the spacing between RG/RGG motifs and the number of glycine residues within each motif are critical factors in determining the extent of phase separation. Bioinformatic analysis of cancer genomic datasets uncovered a significant enrichment of DDX3X mutations in RG/RGG motifs across multiple cancer types, particularly in the N-terminal region of the protein. Furthermore, we found that DDX3X is co-expressed with the stress granule protein G3BP1 in several cancer types and can undergo co-phase separation with G3BP1 in a cell-free system, suggesting a potential functional interaction between these proteins in phase-separated structures. DDX3X and G3BP1 may interact through their RG/RGG domains and subsequently exert important cellular functions under stress situation. Collectively, our findings provide novel insights into the role of RG/RGG motifs in modulating DDX3X phase separation and their potential contribution to cancer pathogenesis.

In the intricate dance between viruses and host cells, RNA-binding proteins (RBPs) serve as crucial orchestrators of gene expression and cellular processes. We will delve into the riveting realm of viral hijacking, where viruses deftly exploit host RBPs to manipulate cellular machinery for their replication and pathogenesis. Through a masterstroke of molecular subterfuge, viruses co-opt RBPs involved in various facets of RNA metabolism - from transcription to degradation - to promote viral gene expression and evade host immune defenses. This manipulation leads to global alterations in cellular RNA metabolism, impacting essential host genes vital for immune responses and homeostasis.Unveiling this clandestine alliance between viruses and RBPs is not just a scientific pursuit, but a critical imperative for devising innovative antiviral strategies to disrupt these interactions. By unraveling the intricate interplay between viral proteins and host RBPs throughout the viral life cycle - from entry to assembly - researchers aim to identify vulnerabilities that can be targeted for therapeutic intervention. Strategies such as disrupting viral protein-RBP interactions hold promise for inhibiting viral replication and curbing pathogenesis, offering a beacon of hope in the battle against viral infections.Our manuscript elucidates the indispensable roles played by RBPs in viral replication, translation, and pathogenesis, shedding light on the molecular mechanisms driving viral success. Delving deeper, it explores how viruses intricately entwine with host RBPs, manipulating cellular signaling pathways to create a hospitable environment for viral spread. By dissecting these manipulative tactics, researchers uncover new targets for antiviral therapy, envisioning a future where tailored interventions disrupt viral-host RBP interactions with precision and efficacy.As the narrative unfolds, the therapeutic implications of targeting RBPs or their interactions with viral proteins emerge as a promising frontier in the fight against viral infections. From small molecule inhibitors to RNA-based therapeutics, innovative approaches are on the horizon, offering new avenues for combatting viral diseases. We set the stage for future research, beckoning researchers to delve deeper into the molecular intricacies of viral hijacking of RBPs and charting a course towards novel therapeutic interventions that promise to reshape the landscape of antiviral therapy.\Ultimately, it beckons the scientific community to embark on a voyage of discovery, unraveling the secrets of viral hijacking of RBPs and paving the way for transformative advances in antiviral therapeutics. The stage is set for a new chapter in the battle against viral infections, where knowledge becomes the sword and innovation the shield against the pernicious machinations of viral pathogens.

Malawi has developed an excellent, nation-wide system for monitoring people infected with HIV and keeping track of key epidemic markers. Their success lies in two things: the focus on simplicity and the use of data collection not only to track the epidemic and identify problems but also to give regular feedback and support to every clinic in the country. This achievement is the more remarkable given that Malawi is one of the poorest countries in the world, ranking 190 out of 194 countries by GDP, but has one of the most severe epidemics of HIV in the world, ranking 9th out of 168 countries by HIV prevalence. We first discuss the current state and likely future epidemic trends in Malawi: unless we know where we are and where we are going we cannot decide what to do or how to do it to in order to achieve a better outcome. We then discuss the history and development of Malawi’s patient monitoring system, as reported in their Integrated HIV Program Reports,ix which have been published quarterly since the beginning of 2004. We consider the current state of patient monitoring and support as reflected in the most recent report for the third quarter (Q3) of 2016 and comment on some of the questions that this raises. Finally, we consider ways in which the current system could be improved by strengthening Malawi’s analytical capacity and making better use of this unique data set. The focus here is on HIV in adultsv because if ART is initiated early in all adults living with HIV this should include testing all pregnant women for HIV and starting them on treatment immediately. However, PMTCT is especially important and care must be given to reducing MTCT and identifying the long-term child survivors of mother-to-child transmission and this demands a complementary assessment. There is an ongoing debate about the relative merits of treatment and prevention in reducing transmission and it should be made clear that the primary reason for starting people on treatment early is that it is in the best interest of the individual patient to start treatment as soon as possible after becoming infected. Allowing a person’s immune system to deteriorate to any degree is not consistent with the clinician’s commitment to ‘first do no harm’ and even those with the highest CD4⁺ cell count are at a substantially increased risk of death. What matters, therefore, is to get as many people as possible onto ART, ensure that they remain virally suppressed, and consider prevention in this context.

Follicular helper CD4+ T cells (TFH) are a major cellular pool for the maintenance of HIV reservoir. Therefore, the delineation of the follicular (F)/germinal center (GC) immune landscape will significantly advance our understanding of HIV pathogenesis. We have applied multiplex confocal imaging, in combination with relevant computational tools, to investigate, F/GC in situ immune dynamics in viremic (vir-HIV), antiretroviral treated (cART HIV) People Living With HIV (PLWH) and compare them to reactive, non-infected controls. Lymph nodes (LNs) from viremic and cART PLWH could be further grouped based on their TFH cell densities in high-TFH and low-TFH subgroups. These subgroups were also characterized by different in situ distribution of PD1hi TFH cells. The significantly accumulated follicular, compared to extrafollicular, FOXP3hi CD4+ T cells found in the low-TFH cART-HIV group were characterized by a less scattered in situ distribution and strongly correlated with the cell density of CD8+ T cells in this group. An inverse correlation between plasma viral load and LN GrzBhiCD8+ T and CD16hiCD15lo cells was found. Our data reveal the complex GC immune landscaping in HIV infection and suggest that follicular FOXP3hi CD4+ T cells could be negative regulators of TFH cell prevalence in cART-HIV.

Thoracic aortic aneurysm (TAA) has a prevalence of 0.16%-0.34% and an incidence of 7.6 per 100,000 person-years, accounting for 1%-2% of all deaths in Western countries. Currently, no effective pharmacological therapies have been identified to slow TAA development and prevent TAA rupture. Large TAAs are treated with open surgical repair and less invasive thoracic endovascular aortic repair, both of which have high perioperative mortality risk. Therefore, there is an urgent medical need to identify the cellular and molecular mechanisms underlying TAA development and rupture to develop new therapies. In this review, we summarize animal TAA models including recent developments in porcine and zebrafish models: porcine models can assess new therapeutic devices or intervention strategies in a large mammal and zebrafish models can employ large-scale small-molecule suppressor screening in microwells. The second part of the review covers current views of TAA pathogenesis, with a focus on the roles of the transforming growth factor-beta (TGFβ) pathway and the vascular smooth muscle cell (VSMC)-elastin-contractile unit. The last part discusses TAA treatment options as they emerge from recent preclinical studies.

The article describes how atherosclerosis and coronavirus disease 19 (COVID-19) may affect each other. The features of this comorbid pathogenesis at various levels (vascular, cellular and molecular) are considered. A bidirectional influence of these conditions is described: the presence of cardiovascular diseases affects different individual susceptibility to viral infection. In turn, SARS-CoV-2 can have a negative effect on the endothelium and cardiomyocytes, causing blood clotting, secretion of pro-inflammatory cytokines, and thus exacerbating the development of atherosclerosis. In addition to the established entry into cells via ACE2 принимая во внимание его влияние на, other mechanisms of SARS-CoV-2 entry are currently under investigation, for example, through CD147. Pathogenesis of comorbidity can be determined by the influence of the virus on various links which are meaningful for atherogenesis: generation of oxidized forms of LDL, launch of a cytokine storm, damage to the endothelial glycocalyx, and mitochondrial injury. The transformation of a stable plaque into an unstable one plays an important role in the pathogenesis of atherosclerosis complications and can be triggered by COVID-19. The impact of SARS-CoV-2 on large vessels such as aorta is more complex than previously thought considering its impact on vasa vasorum. Current information on the mutual influence of the medicines used in the treatment of atherosclerosis and acute COVID-19 is briefly summarized

Hearing loss in infancy leads to preventable speech, language, and cognitive developmental delay [1, 2]. Sensorineural hearing loss (SNHL) is caused by damages, problems, or issues related to the inner ear such as the cochlea with or without the auditory nerve; cranial nerve VIII, involvement. There are three anatomic areas which include the outer ear: composed of the auricle and external auditory canal and the middle ear: which includes the tympanic membrane, ossicles, and the middle ear space, the inner ear: composed of the cochlea, semi-circular canals, and internal auditory canals. The unique anatomical shape of the auricle catches the incoming sound waves to send them down the external auditory canal. Hearing risk assessment should be part of all health visits while regular hearing screening checks are done for all children from 4 to 21 years [1, 2]. Assessment of hearing loss includes history, physical examination and specific hearing assessment tests.

Biofilms are usually defined as surface-associated microbial communities, surrounded by an extracellular polymeric substance matrix. There are three major steps that are observed in biofilm formation: initial attachment events, microcolony formation and construction of mushroom-like structure with secretion of extracelluar polymeric substances. These substances can be considered a mechanism to protect the bacterial community from external insults.Biofilms, significantly increase the ability of the pathogen to evade both host defenses and antibiotics and they are being implicated in the pathogenesis and also clinical manifestation of several infections. They cause a variety of persistent infections, such as native valve endocarditis, osteomyelitis, dental caries, middle ear infections, ocular implant infections, urinary tract infections and cystic fibrosis. Established biofilms can tolerate antimicrobial agents at concentrations of 10–1000-times that needed to kill genetically equivalent planktonic bacteria, and are also resistant to phagocytosis, making biofilms extremely difficult to eradicate from living hosts. Consequently, biofilm-related infections that appear to respond to a therapeutic course of antibiotics may relapse weeks or even months later, making surgical removal and replacement of the infected tissue or medical device a frequent and unfortunate necessity.Several pathogens associated with chronic infections, including Pseudomonas aeruginosa in cystic fibrosis pneumonia, Haemophilus influenzae and Streptococcus pneumoniae in chronic otitis media and Enteropathogenic Escherichia coli in recurrent urinary tract infections, are linked to biofilm formation.

Spondyloarthritis comprises of a group of inflammatory diseases of the joints and spine with various clinical manifestations. The group includes ankylosing spondylitis, reactive arthritis, psoriatic arthritis, arthritis associated with inflammatory bowel disease, and undifferentiated spondyloarthritis. The exact etiology and pathogenesis of spondyloarthritis are still unknown, but five hypotheses explaining the pathogenesis exist. These hypotheses suggest that spondyloarthritis is caused by arthritogenic peptides, an unfolded protein response, HLA-B27 homodimer formation, malfunctioning endoplasmic reticulum aminopeptidases, and, last but not least, gut inflammation and dysbiosis. Here we discuss the five hypotheses and the evidence supporting each. In all of these hypotheses, HLA-B27 plays a central role. It is likely that a combination of these hypotheses, with HLA-B27 taking center stage, will eventually explain the development of spondyloarthritis in predisposed individuals.

Microbiota plays a key role in various body’s functions, physiological, metabolic and immunological processes, through different mechanisms such as the regulation of the development and/or functions of different types of immune cells in the intestines. Several evidences indicate that alteration in the gut microbiota can influence infectious and non-infectious diseases. Bacteria that resides on the mucosal surface or within the mucus layer participate in interactions with the host immune system, and a healthy gut microbiota is essential for the development of mucosal immunity. The immunomodulatory activity of probiotics has been proposed in several bowel disorders or in aging-related dysfunctions. In HIV infected patients, the intestinal immune system is affected and inflammation persists during ART therapy too. Several studies are in progress to investigate the ability of probiotics to modulate epithelial barrier functions, microbiota composition and microbial translocation in HIV infection. This mini-review aims to suggest how the use of probiotics is beneficial not only in maintaining a healthy status but also to improve conditions in HIV subjects.

Background: The coexistence of HIV infection and latent tuberculosis infection (LTBI) presents a significant public health concern due to the increased risk of tuberculosis (TB) reactivation and progression to active disease. The multicenter observational cohort study, TUBHIVIT, conducted in Italy from 2017 to 2023, aimed to assess the prevalence of LTBI among people living with HIV (PLHIV) and their outcomes following LTBI screening and therapy initiation. Methods: We performed a prospective study in 5 referral centers for HIV care in Italy. PLHIV who consented to participate underwent QuantiFERON-TB Gold Plus and clinical, microbiological, and radiological assessments to exclude subclinical tuberculosis, as opportune. PLHIV diagnosed with LTBI that started chemoprophylaxis were followed until the ending of therapy. Results: A total of 1105 PLHIV were screened for LTBI using the QuantiFERON-TB Gold Plus test, revealing a prevalence of 3.4% of positive results (38/1105). Non-Italy-born individuals exhibited a significantly higher likelihood of testing positive. Thirty-one were diagnosed with LTBI, 1 showed active subclinical TB, 6 were lost to follow-up before discriminating between latent and active TB. Among PLHIV diagnosed with LTBI, 83.9% (26/31) started chemoprophylaxis. Most individuals received 6-9 months of isoniazid-based therapy. Of the 26 PLHIV commencing chemoprophylaxis, 18 (69.2%) completed the therapy, while 3 discontinued it and 5 were still on treatment at the time of the analysis. Adverse events were observed in two cases, while in one case the patient refused to continue the treatment.

Two decades after the antiretroviral therapy (ART) introduction, several challenges still prevail in maintaining people living with HIV (PLHIV), even with "Test and Treat" and/or "Rapid Start of ART" initiatives, as well as the scale-up of ART worldwide to promote access and adherence to treatment. This review examined articles on ART adherence in Africa between 2016 and 2023, published in English and indexed in PubMed. A total of 16 articles out of 2415 were eligible and included for analyses. Overall, ART adherence rates in SSA regions ranged from 43% to 84%. Rates in the centre of the SSA region ranged from 58% to 80%, in the north from 50% to 83%, in the south from 77% to 84%, in the west from 43% to 60% and in the east from 69% to 73%. Most African countries use the self-report to assess treatment adherence, although unreliable. The main factors with negative influence on ART adherence were comorbidities, lack of motivation, socioeconomic difficulties or side effects. Conclusion: Adherence to ART is a good indicator for controlling the spread of HIV. It is important to overcome the barriers that make it difficult to comply with ART and reinforce the factors that facilitate the accession of medication.

Retroviruses perpetuate their survival by incorporating a copy of their genome into the host cell, a critical step catalyzed by the virally encoded integrase. The viral capsid plays an important role during the viral life-cycle, including nuclear importation in case of lentiviruses and integration targeting events, hence, targeting the integrase and the viral capsid is a favorable therapeutic strategy. While integrase strand transfer inhibitors (INSTIs) are recommended as first-line regimens given their high efficacy and tolerability, lenacapavir is the first capsid inhibitor and the newest addition to the HIV treatment arsenal. These inhibitors are however designed for treatment of HIV-1 infection, and their efficacy against HIV-2 remains widely understudied and inconclusive, supported only by few limited phenotypic susceptibility studies. We therefore carried out inhibition profiling of a panel of second-generation INSTIs and lenacapavir against HIV-2 in cell culture, utilizing pseudovirion inhibition profiling assays. Our results show that the tested INSTIs and lenacapavir exerted excellent efficacy against ROD-based HIV-2 integrase, and interestingly, raltegravir also showed modest antiviral activity against the SARS-CoV-2 Omicron variant in antiviral assays carried out in Vero E6 cells.

This review provides information on acne transcriptomics allowing deeper insights into acne pathogenesis and isotretinoin´s mode of action. Puberty-induced insulin-like growth factor 1 (IGF-1), insulin and androgen signaling activate the kinase AKT and mechanistic target of rapamycin complex 1 (mTORC1). Western diet (hyperglycemic carbohydrates, milk/dairy products) as well co-stimulate AKT/mTORC1 signaling. AKT-mediated phosphorylation of nuclear FoxO1 and FoxO3 results in their extrusion into the cytoplasm, a critical switch, which enhances the transactivation of lipogenic and proinflammatory transcription factors including androgen receptor (AR), sterol regulatory element-binding transcription factor 1 (SREBF1), peroxisome proliferator-activated receptor γ (PPARγ), and signal transducer and activator of transcription 3 (STAT3) but reduces FoxO1-dependent expression of GATA binding protein 6 (GATA6), the key transcription factor of infundibular keratinocyte homeostasis. AKT-mediated phosphorylation of the p53-binding protein MDM2 promotes the degradation of p53. In contrast, isotretinoin enhances the expression of p53, FoxO1 and FoxO3 in sebaceous glands of acne patients. Overexpression of these proapoptotic transcription factors explains isotretinoin´s desired sebum-suppressive effect via induction of sebocyte apoptosis but also its adverse effects including teratogenicity (neural crest cell apoptosis), reduced ovarian reserve (granulosa cell apoptosis), risk of depression (apoptosis of hypothalamic neurons), VLDL hyperlipidemia, intracranial hypertension and dry skin.

Abstract: The glucocorticoid receptor (GR), including both alternative spliced isoforms (GRa and GRb), has been implicated in the development of primary open-angle glaucoma (POAG) and iatrogenic glucocorticoid-induced glaucoma (GIG). POAG is the most common form of glaucoma, which is the leading cause of irreversible vision loss and blindness in the world. Glucocorticoids (GCs) are commonly used therapeutically for ocular and numerous other diseases/conditions. One serious side effect of prolonged GC therapy is the development of iatrogenic secondary ocular hypertension (OHT) and OAG (i.e. GC-induced glaucoma (GIG)) that clinically and pathologically mimics POAG. GC-induced OHT is caused by pathogenic damage to the trabecular meshwork (TM), a tissue involved in regulating aqueous humor outflow and intraocular pressure. TM cells derived from POAG eyes (GTM cells) have lower expression of GRb, a dominant negative regulator of GC activity, compared to TM cells from age-matched control eyes. Therefore, GTM cells have a greater pathogenic response to GCs. Almost all POAG patients develop GC-OHT when treated with GCs, in contrast to a GC responder rate of 40% in the normal population. Increased expression of GRb can block GC-induced pathogenic changes in TM cells and reverse GC-OHT in mice. Endogenous expression of GRb in the TM may relate to differences in the development of GC-OHT among the normal population. A number of studies have suggested increased levels of endogenous cortisol in POAG patients as well as differences in cortisol metabolism, suggesting that GCs may be involved in the development of POAG. Additional studies are warranted to better understand the molecular mechanisms involved in POAG and GIG in order to develop new disease modifying therapies to better treat these two sight threatening forms of glaucoma.

The recent pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread so rapidly and severely affected the people of almost every country in the world. The highly contagious nature of this virus makes it difficult to take control of the present pandemic situation. With no specific treatment available, the coronavirus disease 2019 (COVID-19) presents a threat to people of all ages including the elderly people and people with other medical complications as a vulnerable group to this disease. Better understanding of viral pathogenesis, appropriate preventive measures, early diagnosis and supportive treatments of the infected patients are now the general solutions to fight against this viral transmission. But, as an emerging disease, most about it remains still poorly understood. This article holds an overview on the origin and structure, pathogenesis, diagnosis and possible therapeutic options for the causative agent, SARS-CoV-2 and disease, COVID-19. However, few therapeutic options, laboratory experiments and other strategies proposed here need to be further clinically tested.

Summary— Introduction: HIV (human immunodeficiency virus) is a virus that attacks and destroys one type of white blood cell, in particular, the CD4 lymphocytes, which are responsible for the body's immune response. This weakens the immune system to such an extent that it can no longer fight other viruses, bacteria, protozoa, fungi, and tumors. Methods: We investigated the potential biological role of the natural compound Polydatin (or piceid) using SwissDock, a web service to predict the molecular interactions that can occur between a target protein and a small molecule. Discussion: For the first time, we have investigated the role of polydatin against HIV-1 protease and HIV-2 protease through a computational approach by comparing their estimated ΔG values (kcal/mol) and the nature of the interactions between the residues in the catalytic center of the HIV proteases.Conclusion: From these simulations, Polydatin has excellent physical properties and an excellent estimated ΔG value (kcal/mol) of about -9.9 kcal/mol against HIV-2 protease and ΔG value (kcal/mol) of about -9.5 kcal/mol against HIV-1 protease. In addition, Polydatin was able to bind to two key amino acids of the catalytic triad sequence common to asparagine proteases (Asp25 and Gly27)

Summary— Introduction: HIV (human immunodeficiency virus) is a virus that attacks and destroys one type of white blood cell in particular, the CD4 lymphocytes, which are responsible for the body's immune response. This weakens the immune system to such an extent that it can no longer fight other viruses, bacteria, protozoa, fungi and tumours. Methods: We investigated the potential biological role of the natural compound Polydatin (or piceid) using SwissDock, a web service to predict the molecular interactions that can occur between a target protein and a small molecule. Discussion: For the first time, we have investigated the role of polydatin against HIV-1 protease and HIV-2 protease through a computational approach by comparing their estimated ΔG values (kcal/mol) and the nature of the interactions between the residues in the catalytic centre of the HIV proteases.Conclusion: From these simulations, Polydatin has excellent physical properties and an excellent estimated ΔG value (kcal/mol) of about -9.9 kcal/mol against HIV-2 protease and ΔG value (kcal/mol) of about -9.5 kcal/mol against HIV-1 protease. In addition, Polydatin was able to bind to two key amino acids of the catalytic triad sequence common to asparagine proteases (Asp25 and Gly27)

Background: Pharmacists need up-to-date knowledge and decision-making support in HIV care. We aim to develop MARVIN-Pharma, an adapted artificial intelligence-based chatbot initially for people with HIV, to assist pharmacists, considering evidence-based needs. Methods: From Dec 2022 to Dec 2023, an online needs-assessment survey evaluated Québec pharmacists' knowledge, attitudes, involvement, and barriers relative to HIV care, alongside perceptions relevant to the usability of MARVIN-Pharma. Recruitment involved convenience and snowball sampling, targeting National HIV and Hepatitis Mentoring Program affiliates. Results: Forty-one pharmacists (28 community, 13 hospital-based) across 15 Québec municipalities participated. Participants perceived their HIV knowledge as moderate (M=3.74/6). They held largely favorable attitudes towards providing HIV care (M=4.02/6). They reported a “little” involvement in the delivery of HIV care services (M=2.08/5), most often ART adherence counseling, refilling, and monitoring. The most common barriers reported to HIV care delivery were a lack of time, staff resources, clinical tools, and HIV information/training, with pharmacists at least somewhat agreeing that they experienced each (M≥4.00/6). On average, MARVIN-Pharma's acceptability and compatibility were in the ‘undecided’ range (M=4.34, M=4.13/7, respectively), while pharmacists agreed to their self-efficacy to use online health services (M=5.6/7). Conclusion: MARVIN-Pharma might help address pharmacists' knowledge gaps and barriers to HIV treatment and care, but pharmacist engagement in the chatbot’s development seems vital for its future uptake and usability.

Infection with human immunodeficiency virus (HIV) and induced acquired immune deficiency syndrome (AIDS) represent one of the greatest health burdens worldwide. The complex pathophysiological pathways that link highly active antiretroviral therapy (HAART) and HIV infection per se with dyslipidemia make the management of lipid disorders and the subsequent increase in cardiovascular risk essential for the treatment of people living with HIV (PLHIV). Amongst the HAART regimens, darunavir and atazanavir in terms of protease inhibitors, tenofovir disoproxil fumarate, nevirapine or rilpivirine in terms of nucleoside reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors respectively, and especially integrase inhibitors, have demonstrated the most favorable lipid profile emerging as sustainable options in HAART substitution. To this day, statins remain the cornerstone pharmacotherapy for dyslipidemia in PLHIV, although important drug-drug interactions with different HAART agents should be taken into account upon treatment initiation. For those intolerant or not meeting therapeutic goals, the addition of ezetimibe, PCSK9, bempedoic acid, fibrates or fish oils should also be considered. This review summarizes the current literature on the multifactorial etiology and intricate pathophysiology of hyperlipidemia in PLHIV, with an emphasis on the role of different HAART agents, while also providing valuable insights into potential switching strategies and therapeutic options.

There is a significant overlap between HIV infection and substance use disorders. Dopamine (DA) is the most abundantly upregulated neurotransmitter in Methamphetamine abuse, with receptors (DRD1-5) that are expressed by neurons as well as by a large diversity of cell types, including innate immune cells that are targets of HIV infection, making them responsive to the hyperdopaminergic environment that is characteristic of stimulant drugs. Therefore, the presence of high levels of dopamine may affect the pathogenesis of HIV, particularly in the brain. The stimulation of HIV-latently infected U1 promonocytes with DA significantly increased viral p24 levels in the supernatant at 24 hrs, suggesting effects on activation and replication. Using selective agonists to different DRDs, we found that DRD1 played a major role in activating viral transcription, followed by DRD4, which increased p24 with a slower kinetic. Transcriptome and systems biology analyses led to the identification of a cluster of genes responsive to DA, where S100A8 and S100A9 were most significantly correlated with the early increase of p24 levels following DA stimulation. Conversely, DA increased the expression of these genes’ transcripts at the protein level, respectively MRP8 and MRP14, which form a complex also known as Calprotectin. Interestingly, MRP8/14 was able to stimulate HIV transcription in latent U1 cells, and this occurred via binding to the receptor for advanced glycosylation end-product (RAGE). Using selective agonists, both DRD1 and DRD4 increased MRP8/14 on the surface and in the cytoplasm, as well as secreted in the supernatants. On the other hand, while DRD1/5 did not affect the expression of RAGE, DRD4 stimulation caused its downregulation, offering a mechanistic for the delayed effect via DRD4 on p24 increase. To cross-validate MRP8/14 as a DA signature with biomarker value, we tested its expression in HIV+ Meth users’ brains and peripheral cells. MRP8/14+ cells were more frequently identified in mesolimbic areas such as basal ganglia of HIV+ Meth+ cases compared to HIV+ non-Meth users or to controls. Likewise, MRP8/14+ CD11b+ monocytes were more frequent in HIV+ Meth users, particularly in participants with detectable viral load in the CSF. Overall, our results suggest that the MRP8 and MRP14 complex may serve as a signature to distinguish subjects using addictive substances in the context of HIV, and that this may play a role in aggravating HIV pathology by promoting viral replication in people with HIV who use Meth.

Stroke represents one of the neurological diseases most responsible for death and permanent disability in the world. Different factors, such as thrombus, emboli and atherosclerosis, take part in the intricate pathophysiology of stroke. Comprehending the molecular processes involved in this mechanism is crucial to developing new, specific and efficient treatments. Some common mechanisms are excitotoxicity and calcium overload, oxidative stress, and neuroinflammation. Furthermore, non-coding RNAs (ncRNAs) are critical in pathophysiology and recovery after cerebral ischaemia. ncRNAs, particularly microRNAs, and the long non-coding RNAs (lncRNAs) are essential for angiogenesis and neuroprotection, and they have been suggested to be therapeutic, diagnostic and prognostic tools in cerebrovascular diseases, including stroke. This review summarizes the intricate molecular mechanisms underlying ischemic and hemorrhagic stroke and delves into the function of miRNAs in the development of brain damage. Furthermore, we will analyze new perspectives on treatment based on molecular mechanisms in addition to traditional stroke therapies.

C. albicans Dfg5 and Dcw1 are homologous cell wall alpha-1,6-mannosidases with important functions. Our past studies have shown that Dfg5 and Dcw1 function in cell wall biogenesis via cross-linking of glycoproteins into the cell wall, thus playing a key role in cell wall integrity. Additionally, Dfg5 and Dcw1 are required for hyphal morphogenesis. However, the exact functions of Dfg5 and Dcw1 in cell wall integrity, hyphal morphogenesis, and pathogenesis were not known. In this study, we determined the relation of Dfg5 and Dcw1 with Hog1 MAPK, that plays a key role in cell wall integrity via regulation of chitin synthesis in C. albicans. Additionally, we also determined the effect of dfg5 and dcw1 mutations on gene expression of transcriptional regulators of hyphal morphogenesis. Furthermore, we determined the effects of dfg5 and dcw1 mutations on pathogenesis in a mouse model of oral candidiasis. Our results demonstrate that dfg5 and dcw1 mutations, as well as hog1 knock-out mutation result in dysregulation of chitin synthesis resulting in a cell separation defect. The heterozygous and conditional mutations of dfg5 and dcw1 result in decreased levels of Cst20, a positive regulator of hyphal morphogenesis. However, mutations of dfg5 and dcw1 mutations resulted in increased levels of all the five negative regulators of hyphal morphogenesis – Tup1, Nrg1, Mig1, Rbf1 and Rfg1. However, Tup1 levels were significantly higher than other negative regulators indicating that Dfg5 and Dcw1 function in hyphal morphogenesis by repression of Tup1. Finally, dfg5 and dcw1 mutations affected the ability of C. albicans to cause oral candidiasis in mice. Thus, cell wall glycosidases, Dfg5 and Dcw1, are required for virulence and pathogenesis and represent novel drug targets.

Leukemia cutis (LC) is defined as leukemic infiltration of the epidermis, the dermis, and the subcutaneous tissue. Leukemia cutis may follow or occur simultaneously with the diagnosis of systemic leukemia. However, cutaneous lesions are occasionally diagnosed as the primary manifestation of leukemia. Leukemic skin infiltrations demonstrate considerable variation regarding number of changes, distribution, and morphology. The highest incidence of LC is observed in chronic lymphocytic leukemia, monocytic and myelomonocytic acute myeloid leukemia, and in T-cell lineage leukemia. Although the pathogenic mechanism of the invasion of leukemic cells into the skin is not well understood, chemokine receptors and adhesion molecules as well as genetic characteristics of leukemia are thought to play a role. Leukemic skin lesions may be localized or disseminated and may occur alone or in combination on any site of the skin, most frequently in the trunk and extremities. The most common clinical presentations of leukemia cutis are papules, nodules, macules, plaques, and ulcers. In most patients, complete or partial resolution of cutaneous infiltrations occurs simultaneously with hematologic remission. However, in patients with resistant disease or recurrent skin infiltration, local radiotherapy can be used. This review presents recent data on the pathogenesis, diagnosis and treatment of leukemic skin involvement in different types of leukemia

Barrett’s esophagus (BE) is a premalignant lesion for esophageal adenocarcinoma (EAC). Development of Barrett’s esophagus is caused by biliary reflux that provokes intensive mutagenesis in stem cells of epithelium in distal esophagus and gastro-esophageal junction. Other possible cell origins of Barrett’s esophagus include stem cells of mucosal esophageal glands and their ducts, of stomach, residual embryonic cells and circulating bone marrow stem cells. Classic conception of healing of caustic lesion was replaced by idea of cytokine storm that forms inflammatory microenvironment for phenotypic shift toward intestinal metaplasia of distal esophagus. The review summarizes contemporary concepts of BE and EAC pathogenesis.

According to global data, there is a male reproductive potential decrease. Pathogenesis of male infertility often is associated with autoimmunity towards sperm antigens essential for fertilization. Antisperm autoantibodies (ASAs) have immobilizing and cytotoxic properties, impairing spermatogenesis, causing sperm agglutination, altering spermatozoa motility and acrosomal reaction, thus preventing ovum fertilization. Infertility diagnosis requires mandatory check for the ASAs. The concept of blood-testis barrier currently is re-formulated with emphasis of informational paracrine and juxtacrine effects, rather than simple anatomical separation. Aetiology of male infertility includes both autoimmune and non-autoimmune diseases, but equally develops through autoimmune links of pathogenesis. Varicocele commonly leads to infertility due to testicular ischemic damage, venous stasis, local hyperthermia, and hypoandrogenism. However, varicocelectomy can alter blood-testis barrier facilitating ASAs production as well. There are contradictory data on the role of ASAs in pathogenesis of varicocele-related infertility. Infection and inflammation both promote ASAs production due to “danger concept” mechanisms and because of antigen mimicry. Systemic pro-autoimmune influences like hyperprolactinemia, hypoandrogenism and hypothyroidism also facilitate ASAs production. Diagnostic value of various ASAs was not yet clearly attributed, and their cut-levels not agreed neither in sera nor in ejaculate. The assessment of the autoimmunity role in pathogenesis of male infertility is ambiguous.

The biogeography of inflammation in ulcerative colitis (UC) suggests a proximal to distal concentration gradient of a toxin. Hydrogen sulfide (H2S) has long been considered one such toxin candidate, and dietary sulfur along with the abundance of sulfate reducing bacteria (SRB) were considered the primary determinants of H2S production and clinical course of UC. The metabolic milieu in the lumen of the colon, however, is the result of a multitude of factors beyond dietary sulfur intake and SRB abundance. Here we present an updated formulation of the H2S toxin hypothesis for UC pathogenesis, which strives to incorporate the interdependency of diet composition and the metabolic activity of the entire colon microbial community. Specifically, we suggest that the increasing severity of inflammation along the proximal-to-distal axis in UC is due to dilution of beneficial factors, concentration of toxic factors, and changing detoxification capacity of the host, all of which are intimately linked to the nutrient flow from the diet.

HIV infection is a nowadays pathology that affect persons from all of the world. Pathogenesis of the HIV-infection and cancer is a great problem, with a complexity directions in research. More important in HIV infection to patients, is also to take into consideration others things, such as prevention, diagnosis, monitoring, treatment, including control measures. This previously mentioned, should be supported by statistical studies that report on restricted or extended geographical areas, to the level of social class and age. In our written text we try to describe from our opinion, strategies in HIV, infection, status knowing as a social and as a healthcare problem.

The RV144 trial represents the only vaccine trial to demonstrate any protective effect against HIV-1 infection. While the reason(s) for this protection are still being evaluated, it serves as justification for widespread efforts aimed at developing new, more effective HIV-1 vaccines. Advances in our knowledge of HIV-1 immunogens and host antibody responses to these immunogens are crucial to informing vaccine design. While the envelope (Env) protein is the only viral protein present on the surface of virions, it exists in a complex trimeric conformation and is decorated with an array of variable N-linked glycans, making it an important but difficult target for vaccine design. Thus far, efforts to elicit a protective humoral immune response using structural mimics of native Env trimers have been unsuccessful. Notably, the aforementioned N-linked glycans serve as a component of many of the epitopes crucial for the induction of potentially protective broadly neutralizing antibodies (bnAbs). Thus, a greater understanding of Env structural determinants, most critically Env glycosylation, will no doubt be of importance in generating effective immunogens. Recent studies have identified the HIV-1 Env signal peptide (SP) as an important contributor to Env glycosylation. Further investigation into the mechanisms by which the SP directs glycosylation will be important, both in the context of understanding HIV-1 biology and in order to inform HIV-1 vaccine design.

Seven human coronaviruses (hCoVs) are known to infect humans. The most recent one, SARS-CoV-2, was isolated and identified in January 2020 from a patient presenting with severe respiratory illness in Wuhan, China. Even though viral coinfections have the potential to influence the resultant disease pattern in the host, very few studies have looked at the disease outcomes in patients infected with both HIV and hCoVs. Groups are now reporting that even though HIV-positive patients can be infected with hCoVs, the likelihood of developing severe CoV-related diseases in these patients is often similar to what is seen in the general population. This review aimed to summarize the current knowledge of coinfections reported for HIV and hCoVs. Moreover, based on the available data, this review aimed to theorize why HIV-positive patients do not frequently develop severe CoV-related diseases.

The information about the BCoV receptors, co/receptors that might be involved in the BCoV entry to the host cells is inconceivable. In addition to that, the roles of other host cell proteases, such as Furin and TMPRSS2, have not yet been well studied during BCoV replication. The current study’s main objectives are to identify some novel BCoV receptors and host cell proteases that might fine-tune the BCoV replication, tissue tropism, and molecular pathogenesis. We used a combination of some in silico prediction, molecular docking, and gene expression profile tools to predict some new BCoV receptors out of some known other coronavirus receptors and some host cell enzymes that are potentially involved in BCoV replication. To achieve these goals, we applied the in-silico prediction tools to check the potential interactions between eh BCoV/S glycoprotein and some known coronaviruses receptors (ACE2, APN1, NPR1, CECAM-1, AXL, and DPP4). We also established some potential models for the interaction between the BCoV/S and some common host cell proteases proved to play important roles in other coronavirus replication cycle (Furin, TMPRRS2, and Cathepsin-L). To confirm our prediction models, we assessed the gene expression profiles of these potential receptors and proteases in some bovine cell lines infected with BCoV using the next generation sequencing and the qRT-PCR assay. Our results show that the NPR1, AXL1 and the ACE2 have the strongest and firm binding affinities to the BCoV-S protein. Our prediction models and gene expression profiles show the potential bindings of the Furin and TMPRSS2 to the BCoV-S polybasic cleavage site (RRSRR|A). Notably, high expression of the host cell Furin was observed in response to both BCoV/Ent and BCoV/Resp infection, whereas TMPRSS2 expression was upregulated in the case of the BCoV/Ent infection, positioning Furin as a common receptor for different BCoV isolates. Further research is needed to study the roles of these top-ranked receptors and host cell proteases in molecular pathogenesis, and tissue tropism.

Acquired immunodeficiency syndrome (AIDS) is an enormous global health threat stemming from human immunodeficiency virus (HIV-1) infection. Up to now, the tremendous advances in combination antiretroviral therapy (cART) have shifted HIV-1 infection from a fatal illness into a manageable chronic disorder. However, the presence of latent reservoirs, multifaceted nature of HIV-1, drug resistance, severe off-target effects, poor adherence, and high cost restrict the efficacy of current cART targeting the distinct stages of the virus life cycle. Therefore, there is an unmet need for discovery of new therapeutics that not only bypass the limitations of the current therapy but also protect the body health at the same time. The main goal for complete HIV-1 eradication is purging latently infected cells from the patients’ bodies. A potential strategy called “lock-in apoptosis” targeting the budding phase of life cycle of virus leading to susceptibility to apoptosis of HIV-1 infected cells for elimination of HIV-1 reservoirs and ultimately for a complete eradication. The current work intends to present the main advantages and disadvantages of United States Food and Drug Administration (FDA) approved anti-HIV-1 drugs as well as plausible strategies for the design and development of more anti-HIV-1 compounds with better potency, favorable pharmacokinetic profiles, and improved safety issues.

Background: Histoplasmosis is a systemic mycosis, present globally. We aimed to describe cases of histoplasmosis (Hc) and to establish a risk profile associated to Hc in HIV-infected patients (HIV+). Methods: This was a retrospective study of patients with a clinical-. laboratorial diagnosis of Hc. Data was fed into REDCap and statistical analysis was done with R . Results: We included 99 records, 65 HIV+ and 34 HIV-. Average age was 39 years. Median time from onset to diagnosis was 8 weeks in HIV- and 22 weeks in HIV+. Disseminated histoplasmosis occurred in 79.4% HIV+, vs 36.4% HIV-. Median CD4 count was 70. Co-infection with tuberculosis was present in 20% of HIV+. Blood cultures were positive in 32.3% of HIV+ vs 11.8% of HIV- (p=0.025); bone marrow culture was positive in 36.9% vs 8.8%(p=0.003). Most HIV+ patients (71.4%) were hospitalized. On univariate analysis, anemia, leukopenia, intensive care, use of vasopressors and mechanical ventilation were associated with death in HIV+. Conclusions: Most of our patients with histoplasmosis were HIV+, presenting advanced AIDS. Diagnosis was late in HIV+ patients, and they frequently presented disseminated Hc, required hospitalization, and died. Early screening for Hc in HIV+ and drug induced immunosuppressed patients is crucial.

Antiretroviral therapy has effectively suppressed HIV infection and replication and prolonged the lifespan of HIV-infected individuals. In the meantime, various complications including type 2 diabetes associated with long-term antiviral therapy have shown steady increases. Metformin has been the front-line anti-hyperglycemic drug of choice and the most widely prescribed medication for the treatment of type 2 diabetes. However, little is known about the effects of Metformin on HIV infection and replication. In this study, we showed that Metformin treatment enhanced HIV gene expression and transcription in HIV-transfected 293T and HIV-infected Jurkat and human PBMC. Moreover, we demonstrated that Metformin treatment resulted in increased CREB expression and phosphorylation, and TBP expression. Furthermore, we showed that Metformin treatment increased the recruitment of phosphorylated CREB and TBP to the HIV LTR promoter. Lastly, we showed that inhibition of CREB activation significantly abrogated Metformin-enhanced HIV gene expression. Taken together, these results demonstrated that Metformin treatment increased HIV transcription, gene expression, and production though increased CREB phosphorylation and recruitment to the HIV LTR promoter. These findings may help design the clinical management plan and HIV cure strategy of using metformin to treat type 2 diabetes, a comorbidity with an increasing prevalence, in people living with HIV.

Autoimmune bullous diseases (AIBDs) are a group of conditions marked by the formation of blisters and erosions on the skin and mucous membranes. Knowing that, most of the AIBDs are severe and resistant to treatment, we decided to look upon the nutritional aspect as a light for the future for both - patients and clinicians. In this review, we would like to summarize the evidence of the role of nutrition in pathogenesis and treatment of the following AIBDs: i) pemphigus, ii) bullous pemphigoid and mucous membrane pemphigoid, iii) dermatitis herpetiformis, and iv) epidermolysis bullosa aqusita.

Treatment of neurological disease is hampered by the lack of validated specific and sensitive biomarkers, resulting in delayed diagnosis and nonspecific disease modifying therapies. For example, in ALS the lack of a sensitive and specific biomarker impedes the ability to administer a treatment prior to or at the onset of motor neuron dysfunction. Although viral or other infectious etiologies have been proposed as a contributing factor to neurodegeneration, it can be argued that these are casual and not causal associations. In the case of ALS, evidence for direct causality would require in vivo validation of specific nucleotide sequences of microbial origin which are known to be neuroinvasive with tropism for motor neurons, such as polio and non-polio. Several viral enteropathogens recapitulate the pathological events in sporadic ALS, including the ability to cleave TDP-43 resulting in accumulation of misfolded proteins in the cytoplasm. This review provides supporting evidence that motor neuron disease is causally related to specific enteroviruses and argues that prospective validation is imperative for effective prevention and treatment.

AbstractBackground: Empowering Communities, Combating HIV/AIDS: The Indispensable Role of Community-Based Strategies in Awareness and PreventionObjective: Highlight the significance of community-based approaches in addressing the ongoing HIV/AIDS pandemic through enhanced awareness, reduced stigma, and effective prevention measures.Method: This article provides a theoretical analysis of community-based HIV/AIDS interventions, drawing upon key strategies and successful examples from diverse settings.Results: Community-based initiatives emerge as critical factors in empowering individuals and communities to take ownership of their health. Through culturally-sensitive education, accessible testing, and comprehensive support services, these initiatives effectively diminish the social stigma surrounding HIV/AIDS and promote preventative behaviors. Examples of successful programs illustrate the potential of community-driven approaches to achieve measurable reductions in transmission rates and improved health outcomes.Conclusion: The fight against HIV/AIDS necessitates robust community engagement. Community-based interventions, grounded in local knowledge and addressing specific needs, offer a promising pathway towards fostering health equity, reducing stigma, and ultimately curtailing the spread of the virus. Further research and investment in these initiatives are crucial to ensuring their scalability and sustained impact on global HIV/AIDS prevention efforts.

Cerebrospinal fluid (CSF) viral escape has been poorly described among people with HIV-associated cryptococcal meningitis. We determined the prevalence of CSF viral escape and HIV-1 viral load (VL) trajectories in individuals treated for HIV-associated cryptococcal meningitis. A retrospective longitudinal study was performed using paired CSF and plasma collected prior to and during the antifungal treatment of 83 participants recruited at the Botswana site of the phase-3 AMBITION-cm trial (2018-2021). HIV-1 RNA levels were quantified then CSF viral escape (CSF HIV-1 RNA ≥ 0.5 log10 higher than plasma) and HIV-1 VL trajectories were assessed. CSF viral escape occurred in 20/62 (32.3%; 95% confidence interval [CI]: 21.9%-44.6%), 13/52 (25.0%; 95% CI: 15.2%-38.2%) and 1/33 (3.0%; 95% CI: 0.16%-15.3%) participants at days 1, 7 and 14 respectively. CSF viral escape was significantly lower on day 14 compared to days 1 and 7, p=0.003 and p=0.02, respectively. HIV-1 VL de-creased significantly from day 1 to day 14 post antifungal therapy in the CSF but not in the plasma (OR, 0.56; 95% CI: 0.41-0.77; p<0.001). CSF viral escape is high among individuals presenting with HIV-associated cryptococcal meningitis; however, antifungal therapy may reverse this, highlighting the importance of rapid initiation of antifungal therapy in these patients.

Human papillomavirus (HPV) is a well-known cause of cervical cancer, with HIV infection exacerbating the prevalence of high-risk HPV (HR-HPV) and cervical intraepithelial neoplasia (CIN). ART has been shown to reduce the likelihood of developing squamous intraepithelial lesions (SILs) and HR-HPV prevalence, although its impact on invasive cervical cancer remains inconclusive. In a study in Accra, 250 sexually active HIV-positive women exhibited a high HPV prevalence, emphasising the need for regular screening. HPV testing, visual inspection with acetic acid (VIA), and cytology-based tests are primary screening methods, each with specific advantages and limitations. Cervical cancer rates in sub-Saharan Africa are alarmingly high, necessitating targeted vaccination and prevention strategies.

Methylation is a biochemical process involving the addition of a methyl group (-CH3) to various chemical compounds. It plays a crucial role in maintaining the homeostasis of the endothelium, which lines the interior surface of blood vessels and has been linked, among other conditions, to coronary artery disease (CAD). Despite significant progress in CAD diagnosis and treatment, intensive research continues into genotypic and phenotypic CAD biomarkers. This review explores the significance of the methylation pathway and folate metabolism in CAD pathogenesis, with a focus on endothelial dysfunction resulting from deficiency in the active form of folate (5-MTHF). We discuss emerging areas of research into CAD biomarkers and factors influencing the methylation process. By highlighting genetically determined methylation disorders, particularly the MTHFR polymorphism, we propose the potential use of the active form of folic acid (5-MTHF) as a novel CAD biomarker and personalized pharmaceutical for selected patient groups. Our aim is to improve the identification of individuals at high risk of CAD and enhance their prognosis.

The etiology of autism spectrum disorder (ASD) has not yet been completely elucidated. Through time, multiple attempts have been made to uncover the causes of ASD. Different theories have been proposed, such as that it is caused by “Gods Wrath,” alterations in the gut–brain axis with an emphasis on gut dysbiosis, post vaccine complications, and genetic or even autoimmune causes. In this review we present data covering over 170 000 participants at age ranging from 2 to 14 years focusing on human cell changes rather than using animal models found in previous studies. The male/female ratio was 4:1. Data collection occurred in many countries covering ethnically diversified subjects. Moreover, we aimed to show how the progress in genetic techniques influences the explanation of medical White Papers in ASD area.

PG9, PG16, PGT121, and PGT145 antibodies were identified from culture media of activated memory B-cells of an infected donor and shown to neutralize many HIV-1 strains. Since HIV-1 spreads via both free virions and cell-cell fusion, we examined the effect of the antibodies on HIV-1 Env-mediated cell-cell fusion. Clone69TRevEnv cells that express Env in the absence of tetracycline were labeled with Calcein-AM Green, and incubated with CD4+ SupT1 cells labeled with CellTrace™ Calcein Red-Orange, with or without antibodies. Monoclonal antibodies PG9, PG16, 2G12, PGT121, and PGT145 (at up to 50 µg/mL) had little or no inhibitory effect on fusion between HIV-Env and SupT1 cells. By contrast, Hippeastrum hybrid agglutinin completely inhibited fusion. Our results indicate that transmission of the virus or viral genetic material would not be inhibited by these broadly neutralizing antibodies. Thus, antibodies generated by HIV-1 vaccines should be screened for their inhibitory effect on Env-mediated cell-cell fusion.

Helicobacter pylori (H. pylori) is a Gram-negative bacterium that colonizes the gastric mucosa and is associated with various gastrointestinal disorders. H. pylori is a pervasive pathogen, infecting nearly 50% of the world's population, and presents a substantial concern due to its link with gastric cancer, ranking as the third most common cause of global cancer-related mortality. This review article provides an updated and comprehensive overview of the current understanding of H. pylori infection, focusing on its pathogenesis, diagnosis, and treatment strategies. The intricate mechanisms underlying its pathogenesis, including virulence factors and host interactions, are discussed in detail. Diagnostic methods, ranging from traditional techniques to advanced molecular approaches, are explored, highlighting their strengths and limitations. The evolving landscape of treatment strategies, including antibiotic regimens and emerging therapeutic approaches, is thoroughly examined. Through a critical synthesis of recent research findings, this article offers valuable insights into the contemporary knowledge of Helicobacter pylori infection, guiding both clinicians and researchers toward effective management and future directions in combating this global health challenge.

Psoriatic arthritis (PsA) is a persistent, inflammatory disease that affects individuals with psoriasis, arthritis, and enthesitis. Research has demonstrated that inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-23 (IL-23), and interleukin-17 (IL-17) play a pivotal role in both the onset and progression of PsA. These cytokines are generated by activated immune cells and stimulate the attraction of inflammatory cells to the synovium and joint tissues, resulting in the deterioration of cartilage and bone. The blocking of these cytokines has become a successful treatment strategy for PsA, as biological drugs that inhibit TNF-α, IL-23, and IL-17 have demonstrated notable clinical benefits. The association between PsA and other types of inflammatory cytokines or chemokines, excluding TNF-α, IL-23, and IL-17, has been extensively investigated in numerous studies. These findings may provide a chance for the discovery of novel therapeutic agents targeting other molecules, distinct from the currently approved biologics and targeted synthetic disease-modifying antirheumatic drugs. In this review, we discuss the current understanding of the role of inflammatory cytokines in PsA pathogenesis and clinical implications of targeting these cytokines for PsA treatment.

Peyronie's disease (PD) is a benign condition caused by plaque formation on the tunica albuginea of the penis. It is associated with penile pain, curvature, and shortening, and contributes to erectile dysfunction, which worsens patient quality of life. In recent years, understanding of the detailed mechanisms and risk factors involved in development of PD has been increasing. In this review, the pathological mechanisms and several closely related signaling pathways, including TGF-β, WNT/β-catenin, Hedgehog, YAP/TAZ, MAPK, ROCK, and PI3K/AKT, are described. Findings regarding cross-talk among these pathways are then discussed to elucidate the complicated cascade behind tunica albuginea fibrosis. Finally, various risk factors including genetic involved in the development of PD are presented and their association with the disease summarized. The purpose of this review is to provide better understanding regarding involvement of risk factors in the molecular mechanisms associated with PD pathogenesis, as well as provide insight into disease prevention and novel therapeutic interventions.

Traumatic spinal cord injury (SCI) elicits an acute inflammatory response which comprises numerous cell populations. It is driven by the immediate response of macro-phages and reactive M1 microglia, which triggers activation of genes responsible for the dysregulated microenvironment within the lesion site and in the spinal cord parenchyma immediately adjacent to the lesion. Recently published data indicate that microglia induces astrocyte activation and determines the fate of astrocytes. Conversely, astrocytes have the potency to trigger microglial activation and control their cellular functions. Here we review current information about the release of diverse signaling molecules (pro-inflammatory vs anti-inflammatory) in individual cell phenotypes (microglia, astrocytes, blood inflammatory cells) in acute and subacute SCI stages, and how they contribute to delayed neuronal death in a the surrounding spinal cord tissue which is spared and functional but reactive. In addition, temporal correlation in progressive degeneration of neurons and astrocytes and their functional interactions after SCI are discussed. Finally, the review highlight the time-dependent transformation of reactive mi-croglia (M1) and astrocytes (A1) into their neuroprotective phenotypes (M2a, M2c and A2) which are crucial for spontaneous post-SCI locomotor recovery. We also provide sug-gestions on how to increase functional outcome after SCI and discuss key therapeutic approaches.

With the emergence of the novel corona virus SARS-CoV-2 since December 2019, more than 43 million cases have been reported worldwide. This virus has shown high infectivity and severe symptoms in some cases leading to over 1 million deaths globally. Despite the collaborative and concerted research efforts that has been made, no effective treatment for COVID-19 (corona virus disease-2019) is currently available. SARS-CoV-2 uses the angiotensin converting enzyme 2 (ACE2) as an initial mediator for viral attachment and host cell invasion. ACE2 is widely distributed in human tissues including the cell surface of lung cells which represent the primary site of the infection. Inhibiting or reducing cell surface availability of ACE2 represents a promising therapy for tackling COVID-19. In this context, most ACE2–based therapeutic strategies have aimed to achieve this through the use of angiotensin converting enzyme (ACE) inhibitors or neutralizing the virus by exogenous administration of ACE2. However, through this review, we present another perspective focusing on the subcellular localization and trafficking of ACE2. Membrane targeting of ACE2, shedding and its cellular trafficking pathways including internalization are not well elucidated. Therefore, hereby we present an overview on the fate of newly synthesized ACE2, its post translational modifications, what is known of its trafficking pathways. In addition, we highlight the possibility that some of the identified ACE2 missense variants might affect its trafficking efficiency and localization and hence may explain some of the observed variable severity of SARS-CoV-2 infections. Extensive understanding of these processes is necessary to evaluate the potential use of ACE2 as a credible therapeutic target.

As a medical student (Granada University Medical School, Spain), interested in Pediatrics, expended countless hours at the hospital pediatric facilities and got to know many of the children and their medical problems. A particular case, still vivid on my mind, awaken my scientific curiosity. One day, walking and talking with a seven years old child he unexpectedly felt down unconscious with multiple, incontrollable and erratic muscular contractions involving face, body and extremities and salivating. I was overwhelmed thinking it was the child’ last hour. At the time, my knowledge of epilepsy was nil. Following the seizures, the child was up, talking and walking with me as if nothing has happened and without any knowledge of the event. What could have caused the brain motor cortex to suddenly discharge that amount of altered activity causing generalized and erratic muscular contractions remains inexplicable. I migrated to USA, become a Pediatric (Developmental) Pathologist and Director of the Pediatrics Autopsy Service (1962-1999) at the Dartmouth-Hitchcock Medical Center, New Hampshire. I carried out countless postmortem studied of children brains, normal (unaltered) as well as those altered by hemorrhagic, hypoxic-ischemic and/or traumatic damage. With an NIH Fellowship, I spend one year (1967-68) at the Cajal Institute (Madrid, Spain) studying Cajal’ old Golgi preparations and learning about the method. Some of my Golgi studies of children’ brains have been published: The Human Brain. Prenatal Development and Structure, Springer, Heidelberg, Germany, 2012. The present monograph explores the developmental neuropathology of selected perinatal cortical injuries through their acute, subacute and chronic stages. Including: a) how an altered neuronal activity evolves in a damaged cortical region; b) how it moves through the cortex (epileptic auras); and c) how it reaches the motor cortex to be discharged as erratic and incontrollable muscular contractions. Understanding these processes should provide insights into the pathogenesis of epilepsy secondary to perinatal brain damage.

Hepatocellular carcinoma (HCC) is currently the third leading cause of malignancy-related mortalities worldwide. Natural killer (NK) cells are involved in the critical role of first line immunological defense against cancer development. Defects in NK cell functions are recognized as important mechanisms for immune evasion of tumor cells. NK cell function appears to be attenuated in HCC, and many previous reports suggested that NK cells play a critical role in controlling HCC, suggesting that boosting the activity of dysfunctional NK cells can enhance tumor cell killing. However, the detailed mechanisms of NK cell dysfunction in tumor microenvironment of HCC remain largely unknown. A better understanding of the mechanisms of NK cell dysfunction in HCC will help in the NK cell-mediated eradication of cancer cells and prolong patient survival. In this review, we describe the various mechanisms underlying NK cell dysfunction in HCC. Further, we summarize current advances in the approaches to enhance endogenous NK cell function and in adoptive NK cell therapies, to cure this difficult-to-treat cancer.

Understanding the clinical conditions and outcomes of Covid-19 infected patients with immunodeficiency like HIV will be an information for improving management and treatment modalities. It was reported a patient of HIV plus clinical confirmed Covid-19 in this presentation.

Distal Sensory Peripheral Neuropathy (DSP) is a common complication in HIV-infected individ-uals, leading to chronic pain and reduced quality of life. Despite antiretroviral therapy (ART), DSP persists, often prompting the use of opioid analgesics, which can paradoxically worsen symptoms through opioid-induced microbial dysbiosis. This study employs the HIV Tg26 mouse model to investigate HIV-DSP development and assess gut microbiome changes in response to chronic morphine treatment and ART using 16s rRNA sequencing. Our results reveal that chronic morphine and ART exacerbate HIV-DSP in Tg26 mice, primarily through mechanical pain path-ways. As the gut microbiome may be involved in chronic pain persistence, microbiome analysis indicated distinct bacterial community changes between WT and Tg26 mice as well as morphine and ART-induced microbial changes in the Tg26 mice. This study reveals the Tg26 mice model to be a relevant system that can help elucidate the pathogenic mechanisms of opioid and ART-induced exacerbation of HIV-associated pain. Our results shed light on the intricate inter-play between HIV infection, ART, opioid use, and the gut microbiome in chronic pain development. They hold implications for understanding the mechanisms underlying HIV-associated pain and microbial dysbiosis, with potential for future research focused on prevention and treatment strategies.

The advent of immunotherapy and specifically of immune checkpoint inhibitors (ICIs) for the treatment of solid tumors has deeply transformed therapeutic algorithms in medical oncology. Approximately one third of patients treated with ICIs may develop immune-related adverse events, being the gastrointestinal tract often affected with different grades of mucosal inflammation. Checkpoint inhibitors colitis (CIC) presents with watery or bloody diarrhoea and in case of severe activity requires ICIs discontinuation. The pathogenesis of CIC is multifactorial and still partially unknow: anti-tumor activity that collaterally effects the colonic tissue and the upregulation of specific systemic inflammatory pathways (i.e., CD8+ cytotoxic and CD4+ T lymphocytes) are mainly involved. Many open issues remain on treatment timing and options, and biological treatment, above all with anti-TNF alpha, can be offered to these patients aiming to rapidly resume the oncological therapies. This review aims to summarize the pathogenetic mechanisms underlying CIC and to discuss evidenced-based management including the role of biological therapy.

Alcohol effects on hepatic lipid metabolism through various mechanisms, leading synergistically to an accumulation of fatty acids (FA) and triglycerides. Obesity, as well as, the dietary fat [saturated fatty acids (FA) versus poly-unsaturated fatty acids (PUFA)] may modulate the hepatic fat. Alcohol inhibits adenosine monophosphate activated kinase (AMPK). AMPK activates peroxisome proliferators activated receptor a (PPARα) and leads to a decreased activation of sterol regulatory element binding protein 1c (SRABP1c). The inhibition of AMPK, and thus of PPARα results in an inhibition of FAs oxidation. This ß-oxidation is further reduced due to mitochondrial damage induced through cytochrome P4502E1 (CYP2E1) driven oxidative stress. Furthermore, the synthesis of FAs is stimulated through an activation of SHREP1. In addition, alcohol consumption leads to a reduced production of adiponectin in adipocytes due to oxidative stress and to an increased mobilization of FAs from adipose tissue and from the gut as chylomicrons. On the other side, the secretion of FAs via very low density lipoproteins (VLDL) from the liver is inhibited by alcohol. Alcohol also affects signal pathways such as early growth response 1 (Egr-1) associated with the expression of tumour necrosis factor  (TNF), and the mammalian target of rapamycin (mTOR) a key regulator of autophagy. Both have influence the pathogenesis of alcoholic fatty liver. Alcohol-induced gut dysbiosis is contributing to the severity of ALD by increasing metabolism of ethanol in the gut and promoting intestinal dysfunction. Moreover, pathogen associated molecular paterns (PAMPS) via specific Toll-like receptors (TLR) bacterial overgrowth is leading to the translocation of bacteria. Endotoxins, and toxic ethanol metabolites enter the enterohepatic circulation reaching the liver, inducing the activation of the nuclear factor kappa-B (NFB) pathway. Pro-inflammatory cytokines released in the process contribute to inflammation and fibrosis. In addition, cellular apoptosis is inhibited in the favor of necrosis.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic systemic inflammation causing progressive joint damage that can lead to lifelong disability. The pathogenesis of RA involves a complex network of various cytokines and cells that trigger synovial cell proliferation and cause damage to both cartilage and bone. Involvement of the cytokines TNF- and IL-6 is central to the pathogenesis of RA, but recent research has revealed that other cytokines such as IL-17, IL-23, GM-CSF, IL-33, and IL-2 also play a role. Clarification of RA pathology has led to the development of therapeutic agents such as biological disease-modifying anti-rheumatic drugs (DMARDs) and Janus kinase (JAK) inhibitors, and further details of the immunological background to RA are emerging. This review covers existing knowledge regarding the roles of cytokines, related immune cells and the immune system in RA, manipulation of which may offer the potential for even safer and more effective treatments in the future.

Pigment nephropathy is an acute decline in renal function following the deposition of endogenous haem-containing proteins in the kidneys. Haem pigments such as myoglobin and haemoglobin are filtered by glomeruli and absorbed by the proximal tubules. They cause renal vasoconstriction, tubular obstruction, increased oxidative stress and inflammation. Haem is associated with inflammation in sterile and infectious conditions, contributing to the pathogenesis of many disorders such as rhabdomyolysis and haemolytic diseases. In fact, haem appears to be a signaling molecule that is able to activate the inflammasome pathway. Recent studies highlight a pathogenic function for haem in triggering inflammatory responses through the activation of the nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome. Among the inflammasome multiprotein complexes, the NLRP3 inflammasome has been the most widely characterized as a trigger of inflammatory caspases and the maturation of interleukin-18 and -1β. In the present review, we discuss the latest evidence on the importance of inflammasome-mediated inflammation in pigment nephropathy. Finally, we highlight the potential role of inflammasome inhibitors in the prophylaxis and treatment of pigment nephropathy.

Rosacea is a chronic inflammatory skin disease characterized by recurrent erythema, flushing, telangiectasia, papules, pustules, and phymatous changes in the central area of the face. Patients with this condition often experience a significant negative impact on their quality of life, self-esteem, and overall well-being. Despite its prevalence, the pathogenesis of rosacea is not yet fully understood. Recent research advances are reshaping our understanding of the underlying mechanisms of rosacea, and treatment options based on the pathophysiological perspective hold promise to improve patient outcomes and reduce incidence. In this comprehensive review, we investigate the pathogenesis of rosacea in-depth, with a focus on emerging and novel mechanisms, and provide an up-to-date overview of therapeutic strategies that target the diverse pathogenic mechanisms of rosacea. Lastly, we discuss potential future research directions aimed at enhancing our understanding of the condition and developing effective treatments.

Treatment of HIV-associated lymphoma (HIV-Ly) with autologous stem cell transplantation (ASCT) has shown a surprisingly low relapse rate in several series. The aim of this study was to compare the clinical outcomes of HIV-Ly and lymphomas of the general population receiving ASCT. We compared two series of consecutive HIV-positive and HIV-negative patients, based on a 1:1 propensity score analysis, matching for age, sex, histology, disease status and prior therapies. We identified 44 patients in both groups. All HIV-positive patients received combination antiretroviral therapy (cART). With a median follow-up of 51 months, PFS was significantly higher in HIV-positive patients (4-years PFS 81% and 51%, in HIV-positive and HIV-negative patients, respectively, p=0.027). Four-year OS was 81% for HIV-positive and 67% in HIV-negative patients (p=0.15). The relapse rate was significantly higher in HIV-negative patients (36% vs 23%) (p=0.04). Our results clearly show that ASCT is an effective curative option for HIV-Ly, with better PFS and lower relapse rate compared to uninfected patients. A favourable effect of ASCT on HIV infection and immune system recovery, potential off-target effects of cART or other yet unknown factors may account for this observation.

The ribonuclease H (RNase H) active site of HIV-1 reverse transcriptase (RT) is the only viral enzyme not targeted by approved antiretroviral drugs. Using a fluorescence-based in vitro assay, we screened 65,239 compounds at a final concentration of 10 µM to identify inhibitors of RT RNase H activity. We identified 41 compounds that exhibited 50% inhibitory concentration (i.e., IC50) values &lt; 1.0 µM. Two of these compounds, 2-(4-methyl-3-(piperidin-1-ylsulfonyl)phenyl)benzo[d]isothiazol-3(2H)-one (1) and ethyl 2-(2-(3-oxobenzo[d]isothiazol-2(3H)-yl)thiazol-4-yl)acetate (2), which both share the same benzisothiazolone pharmacophore, demonstrate robust antiviral activity (50% effective concentrations of 1.68 ± 0.94 µM and 2.68 ± 0.54, respectively) in the absence of cellular toxicity. A limited structure-activity relationship analysis identified two additional benzisothiazolone analogs, 2-methylbenzo[d]isothiazol-3(2H)-one (3) and N,N-diethyl-3-(3-oxobenzo[d]isothiazol-2(3H)-yl)benzenesulfonamide (4), which also resulted in inhibition of RT RNase H activity and virus replication. Compounds 1, 2 and 4, but not 3, inhibited the DNA polymerase activity of RT (IC50 values ~ 1 to 6 µM). In conclusion, benzisothiazolone derivatives represent a new class of multifunctional RT inhibitors that warrants further assessment for the treatment of HIV-1 infection.

Respiratory syncytial virus (RSV) is a common respiratory virus that can cause mild to severe illness in people of all ages. The most common symptoms of an RSV infection are cough, runny nose, and fever. However, RSV can also cause more serious complications, such as tracheobronchitis, bronchiolitis, pneumonia, and apnea. RSV is especially dangerous for infants, young children, and older adults. RSV is a seasonal virus, with peak incidence in the winter months. The virus spreads through respiratory droplets produced when an infected person coughs or sneezes. The virus can also be spread through contact with contaminated surfaces. Treatment is aimed at relieving symptoms and preventing complications. This review will provide an overview of the medical significance, virology, pathogenesis, immunity, epidemiology, symptoms, risk factors, and complications associated with RSV, and the diagnosis and management of RSV infections.

Inflammatory bowel disease (IBD), including Crohn’s Disease (CD) and Ulcerative Colitis (UC) are chronic multifactorial disorders which affect the gastrointestinal tract with variable extent. Despite extensive research, their etiology and exact pathogenesis are still unknown. Cell-free DNAs (cfDNAs) are defined as any DNA fragments which are free from origin cell and able to circulate into bloodstream with or without microvescicles. CfDNAs are now being increasingly studied in different human diseases, like cancer or inflammatory diseases. However, to date it is unclear how IBD etiology is linked to cfDNAs in plasma. Extrachromosomal circular DNA (eccDNA) are non-plasmidic, nuclear, circular and closed DNA molecules found in all eukaryotes tested. CfDNAs appear to play an important role in autoimmune diseases, inflammatory processes, and cancer; recently, interest has also grown in IBD, and their role in the pathogenesis of IBD has been suggested. We now suggest that eccDNAs also plays a role in IBD. In this review we have comprehensively collected available knowledge in literature regarding cfDNA, eccDNA, and structures involving them such as neutrophil extracellular traps and exosomes, and their role in IBD. Finally, we focused on old and novel potential molecular therapies and drug delivery systems, such as nanoparticles, for IBD treatment.

Breast cancer pathogenesis, treatment, and patient outcomes are shaped by tumor-intrinsic genomic alterations that divide breast tumors into molecular subtypes. These molecular subtypes often dictate viable therapeutic interventions, and ultimately, patient outcomes. However, heterogeneity of therapeutic response may be a result of underlying epigenetic features that may further stratify breast cancer patient outcomes. In this review we examine non-genetic mechanisms that drive functional changes to chromatin in breast cancer to contribute to cell and tumor fitness, and highlight how epigenetic activity may inform therapeutic response. We conclude by providing perspectives on the future of therapeutic targeting of epigenetic enzymes, an approach which holds untapped potential to improve breast cancer patient outcomes.

Coronavirus disease (COVID-19) is an infectious disease caused by a new virus which causes respiratory illness. Older adults and people who have previous chronic medical conditions are at higher risk for more serious complications from COVID-19.Hypovitaminosis D is attributed to the increased risk of lung injury and acute respiratory distress syndrome (ARDS) as well as diabetes, Cardiovascular event and associated comorbidities, which are the main causes of severe clinical problem in COVID-19 patients. Considering the protective role of vitamin D through modulating the innate and adaptive immune system as well as inhibition of Renin Angiotensin System (RAS), vitamin D supplementation might boost the immune system of COVID-19 patients and reduce severity of the disease in vitamin D deficient individuals.

Positive-sense single-stranded RNA (+ssRNA) viruses comprise many (re-)emerging human pathogens that pose a public health problem. Our innate immune system and in particular the interferon response form the important first line of defense against these viruses. Given their genetic flexibility, these viruses have therefore developed multiple strategies to evade the innate immune response in order to optimize their replication capacity. Already many molecular mechanisms of innate immune evasion by +ssRNA viruses have been identified. However, research addressing the effect of host innate immune evasion on the pathology caused by the viral infection is less prevalent in literature, though very relevant and interesting. Since interferons have been implicated in inflammatory diseases and immunopathology in addition to their protective role in infection, the influence of antagonizing the immune response may have an ambiguous effect on the clinical outcome of the viral disease. Therefore, this review discusses what is currently known about the role of interferons and host immune evasion in the pathogenesis of emerging viruses belonging to the coronaviruses, alphaviruses and flaviviruses.

The presence of anti SARS-CoV2-RBD antibody (Anti-RBD) prevents severe COVID-19. We aimed to determine the accuracy of a point-of-care Anti-RBD test implemented in person living with HIV (PLWH), systemic lupus erythematosus (SLE), and chronic kidney disease (CKD). We enrolled 182 non-comorbid subjects and 335 persons with comorbid (PLWH, SLE, CKD) to test anti-RBD assay compared to surrogate viral neutralization (SVNT) as the reference test. We performed linear correlation analysis between anti-RBD vs SVNT and a ROC analyses to ascertain anti-RBD cut-off at 30%, 60%, and 90% inhibition of SVNT to calculate accuracy. Correlations of anti-RBD to SVNT among all groups were excellent with R= 0.7903, R=0.7843, R=0.8153 among non-comorbid, SLE and CKD groups, respectively, with significantly higher correlation among the PLWH group (R=0.8877; p-value=0.0072) compared to non-comorbid group. The accuracy of the anti-RBD test among PLWH and CKD group was similar with the non-comorbid but showed lower sensitivity in the SLE group (p=0.000014). The specificity of the test remained high in all groups. In conclusion, the Anti-RBD test had excellent correlation to SVNT. The persistently high specificity in all groups suggests that this test can be reliably utilized to detect presence of low neutralization capacity, prompting additional vaccination.

Microbicides, topical antiseptic agents, and a revolutionary advance in HIV prevention aim to prevent the entry of infectious agents into the human body, thus stopping the sexual transmission of HIV and other sexually transmitted diseases. Microbicides represent the promise of a new age in preventive measures against one of the world's most pressing health challenges. In addition to their direct antiviral effects during HIV transmission, microbicides also influence vaginal mucosal immunity. This article reviews microbicides by presenting different drug classifications and highlighting significant representatives from each group. It also explains their mechanisms of action and presents information about vaginal mucosal immune responses, emphasizing the critical role they play in responding to HIV during sexual transmission. For each chemical compound, the article provides a brief overview of relevant preclinical and clinical research, emphasizing their potential as microbicides.The article offers insights into the multifaceted impact of microbicides, which signify a pivotal step forward in the pursuit of effective and accessible pre-exposure prophylaxis (PrEP).

Human Immunodeficiency Virus (HIV) infection and its latent recurrent infection make vaccine development a significant challenge for traditional vaccines; however, the mRNA delivery of multiepitope antigens capable of creating antibodies against the surface proteins of HIV-1 and HIV-2 along with their respective Nef proteins, responsible for the latent infection can bring a most effective, as well as affordable solution to the unresolved epidemics of HIV. In this paper, we present the complete design of a multiepitope vaccine to prevent acute infections and inactivate Nef proteins that block the MHC-1 and MHC-2 pathways to hide the virus for later reinfection.

HIV/AIDS infection increases vulnerability to ill-health states and has a major impact on the general health status. This study aims to describe Angolan adolescents and adults’ comprehensive knowledge of HIV/AIDS and its associated factors based on the 2016 demographic and health survey (DHS). Data from 19,785 individuals between the ages of 15 and 49 years old, who re-sponded to all the DHS questions between October 2015 and March 2016 were included in this study. Multivariable analysis using logistic regression was used to compute the adjusted odds ratio and respective 95% confidence intervals. In Angola, 47.7% of the respondents had general com-prehensive knowledge of HIV/AIDS. The odds of having comprehensive knowledge about HIV/AIDS were higher among individuals who watch television (aOR: 2.40; 95% CI: 2.11, 2.72) or read journals and magazines (aOR: 1.99; 95% CI: 1.72, 2.30) more than once a week and, people with primary or higher-level education (aOR: 1.83; 95% CI: 1.67, 2.00). Similarly, for people living in urban areas (aOR: 1.51; 95% CI: 1.34, 1.71). These results may reflect important inequities and can assist decision-makers in advocating to continue to invest in health literacy for HIV but also in the development of tailored interventions in this area.

South Africa is afflicted with the worst epidemic of HIV in the world a legacy of the system of oscillating migrant labour in the region and the consequent social disruption that was the legacy of Apartheid. The initial response from the national government was slow and ineffective but once the magnitude of the epidemic became apparent the government began to respond. The investment in HIV- and TB-related activities in 2013 was R22 Bn or (US$2.5; 2013 exchange rate) of which the South Africa government contributed 80% and the Presidents Emergency Plan for AIDS Relief (PEPFAR) 17%. South Africa now has the more people on anti-retroviral therapy than any other country and treatment is being started much sooner after infection. Much of the best biomedical, virological, immunological, mathematical and social science around the treatment and prevention of HIV and AIDS and the associated epidemic of TB has been done by South African’s and their international collaborators. If the efforts to control the epidemic are maintained South Africa is on track to meet the UNAIDS 90-90-90target by 2020 and to End AIDS by 2030 in spite of the magnitude of the problem. While individual, patient level data are increasingly available, especially in the Western Cape, much greater efforts need to be made to ensure that the information collected in this way is used to give feedback and support to clinic staff, to ensure that health clinics are providing the best possible service, and to individual patients and people living with HIV to ensure that they are receiving the best possible care and support. South Africa needs to make better use of the rich and detailed data that are being collected from individual clinics and their patients to identify problems or difficulties at the clinic level and to ensure that individual patients are retained on treatment, are virally suppressed and receive the best possible care and support.

Introduction: Inflammation is a significant contributor to cardiovascular disease (CVD) in people with HIV (PWH), who face twice the risk of CVD compared to the general population. The presence of co-existing rheumatic disease (RD) may further exacerbate inflammation and increase the incidence of CVD events in this population. Methods: We conducted a retrospective study using electronic health record (EHR) data from the Veterans Affairs Medical Center in Atlanta, covering the period from 2000 to 2019. The study included 3,930 veterans with HIV, and assessed the impact of rheumatic disease therapies (RDT) on CVD outcomes. The primary outcome was the first occurrence of a CVD event. Results: Rheumatic disease was significantly associated with an increased risk of CVD events (OR = 2.67; p < 0.001). Additionally, exposure to multiple RDTs (aHR = 2.121, p = 0.047), NSAIDs (aHR = 1.694, p = 0.003), glucocorticoids (aHR = 2.332, p < 0.0001), and hypouricemic agents and colchicine (aHR = 3.445, p < 0.0001) were all significantly associated with increased CVD events. Conclusion: The co-existence of HIV infection and rheumatic disease, along with the use of RDTs, may amplify the risk of CVD events in PWH. These findings underscore the need for further investigation into the relationship between RD, RDTs, and CVD risk in larger, controlled studies, given the potential implications for treatment decisions in this patient population.

M184V is a single-base mutation in the YMDD domain of reverse transcriptase (RT). The M184V resistance-associated mutation is related to virological unresponsiveness to lamivudine (3TC) and emtricitabine (FTC) and induces high-level resistance to these two antiretroviral agents. M184V is rapidly selected in the setting of non-suppressive antiretroviral therapy (ART) and accumulates in the HIV reservoir. There were continuous efforts to evaluate the impact of M184V mutation on the treatment outcomes in people with HIV (PWH). Since lamivudine remains an extensively used part of recommended antiretroviral combinations, M184V is commonly detected in patients with virological failure. ART guidelines do not recommend the use of drugs impacted by resistance-associated mutations as they have been confirmed to comprise a risk factor for virological failure. However, previous authors suggest that 3TC/FTC can remain active even in the presence of M184V. Obtaining the viral resistance profile for each individual both treated or ART-naïve is a key challenge for lifelong treatment management.Given the potential benefits of lamivudine in the ART combinations, the investigation of M184V remains of high interest for clinicians and researchers. This is a review of literature for the challenges in treating both naïve and experienced individuals carrying the M184V resistance mutation, including virological failure, virological suppression, and resistance to ART.