Mycobacterium avium subspecies paratuberculosis (MAP) infection, and its impact on gut microbiome of individuals with multiple sclerosis.

The microbial ecology of Mycobacterium avium subspecies paratuberculosis infections (MAP) within the context of Multiple Sclerosis (MS) is largely an unexplored topic in the literature. Thus, we have characterized the compositional and predicted functional differences of the gut microbiome between MS patients with MAP (MAP+) and without (MAP-) infection. This was done in the context of exposome differences (through self-reported filled questionnaires), principally in anthropometric and sociodemographic patterns to gain an understanding of the gut microbiome dynamics. 16S rRNA microbiome profiling of faecal samples (n = 69) was performed for four groups, which differed by disease and MAP infection: healthy cohort (HC) MAP-; HC MAP+ ; MS MAP-; and MS MAP+ . Using a dynamic strategy, with MAP infection and time of sampling as occupancy models, we have recovered the core microbiome for both HC and MS individuals. Additional application of neutral modeling suggests key genera that are under selection pressure by the hosts. These include members of the phyla Actinobacteriota, Bacteroidota, and Firmicutes. As several subjects provided multiple samples, a Quasi Conditional Association Test that incorporates paired-nature of samples found major differences in Archaea. To consolidate treatment groups, confounders, microbiome, and the disease outcome parameters, a mediation analysis is performed for MS cohort. This highlighted certain genera i.e., Sutterella, Akkermansia, Bacteriodes, Gastranaerophilales, Alistipes, Balutia, Faecalibacterium, Lachnospiraceae, Anaerostipes, Ruminococcaceae, Eggerthellaceae and Clostridia-UCG-014 having mediatory effect using disease duration as an outcome and MAP infection as a treatment group. Our analyses indicate that the gut microbiome may be an important target for dietary and lifestyle intervention in MS patients with and without MAP infection.

Microplastics and nanoplastics in cardiovascular disease-a narrative review with worrying links.

With the widespread use of plastic products and the increase in waste, microplastics and nanoplastics (MNPs) have become an important issue in global environmental pollution. In recent years, an increasing number of studies have shown that MNPs may have negative impacts on human health. This review aimed to explore the association between MNPs and cardiovascular disease and provide an outlook for future research. Research has shown that there may be a link between MNPs exposure and cardiovascular disease. Laboratory studies have shown that animals exposed to MNPs often exhibit abnormalities in the cardiovascular system, such as increased blood pressure, vascular inflammation, and myocardial damage. Epidemiological surveys have also revealed that people exposed to MNPs are more likely to suffer from cardiovascular diseases, such as hypertension and myocardial infarction. Although the specific impact mechanism is not fully understood, there are several possible pathways of action, including the effects of toxic substances on MNPs and interference with the endocrine system. In summary, MNPs exposure may have a negative impact on cardiovascular health, but further research is needed to confirm its specific mechanism and extent of impact to guide relevant public health and environmental policies.

Mycobacterium paratuberculosis: A HERV Turn-On for Autoimmunity, Neurodegeneration, and Cancer?

Human endogenous retroviruses (HERVs) are remnants of ancient retroviral infections that, over millions of years, became integrated into the human genome. While normally inactive, environmental stimuli such as infections have contributed to the transcriptional reactivation of HERV-promoting pathological conditions, including the development of autoimmunity, neurodegenerative disease and cancer. What infections trigger HERV activation? Mycobacterium avium subspecies paratuberculosis (MAP) is a pluripotent driver of human disease. Aside from granulomatous diseases, Crohn's disease, sarcoidosis and Blau syndrome, MAP is associated with autoimmune disease: type one diabetes (T1D), multiple sclerosis (MS), rheumatoid arthritis (RA) and autoimmune thyroiditis. MAP is also associated with Alzheimer's disease (AD) and Parkinson's disease (PD). Autoimmune diabetes, MS and RA are the diseases with the strongest MAP/HERV association. There are several other diseases associated with HERV activation, including diseases whose epidemiology and/or pathology would prompt speculation for a causal role of MAP. These include non-solar uveal melanoma, colon cancer, glioblastoma and amyotrophic lateral sclerosis (ALS). This article further points to MAP infection as a contributor to autoimmunity, neurodegenerative disease and cancer via the un-silencing of HERV. We examine the link between the ever-increasing number of MAP-associated diseases and the MAP/HERV intersection with these diverse medical conditions, and propose treatment opportunities based upon this association.

Lifestyle interventions in cardiometabolic HFpEF: dietary and exercise modalities.

Heart failure with preserved ejection fraction (HFpEF) is rapidly growing as the most common form of heart failure. Among HFpEF phenotypes, the cardiometabolic/obese HFpEF - HFpEF driven by cardiometabolic alterations - emerges as one of the most prevalent forms of this syndrome and the one on which recent therapeutic success have been made. Indeed, pharmacological approaches with sodium-glucose cotransporter type 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) have proved to be effective due to metabolic protective effects. Similarly, lifestyle changes, including diet and exercise are crucial in HFpEF management. Increasing evidence supports the important role of diet and physical activity in the pathogenesis, prognosis, and potential reversal of HFpEF. Metabolic derangements and systemic inflammation are key features of HFpEF and represent the main targets of lifestyle interventions. However, the underlying mechanisms of the beneficial effects of these interventions in HFpEF are incompletely understood. Hence, there is an unmet need of tailored lifestyle intervention modalities for patients with HFpEF. Here we present the current available evidence on lifestyle interventions in HFpEF management and therapeutics, discussing their modalities and potential mechanisms.

The Humoral Immune Response against Human Endogenous Retroviruses in Celiac Disease: A Case-Control Study.

BACKGROUND: Celiac disease (CD) is an immune-mediated disease characterized by disruptions of the small intestine. Factors such as viral and bacterial infections can trigger CD. Recently, the reactivation of Human Endogenous Retroviruses (HERVs) has also been implicated, but little is known about their specific role in patients with celiac disease. METHODS: The purpose of this study is to explore the humoral immune response mounted against epitopes derived from the envelope portion of three families of HERVs (HERV-K, HERV-H, and HERV-W) in CD patients. Reactivity against the HERV-K, HERV-H, and HERV-W env-su peptides was tested by indirect ELISAs in plasma of 40 patients with celiac disease and 41 age-matched healthy subjects (HCs). RESULTS: HERV-K, HERV-H, and HERV-W env-su peptides triggered different antibody responses in CD patients compared to HCs, with a stronger reactivity (p = 0.0001). CONCLUSIONS: Present results show, for the first time, that epitopes of HERV-K, HERV-H, and HERV-W are more recognized in patients with CD. Taking into consideration their proinflammatory and autoimmune features, this might suggest that HERVs may contribute to the development of CD or its exacerbation in genetically predisposed subjects. Finally, to elucidate the interplay between gut inflammation and HERVs during the inflammatory process, further studies are required. Those investigations should focus on the expression levels of HERVs and their relationship with the immune response, specifically examining anti-transglutaminase 2 (TG2) antibody levels under both gluten-free and gluten-containing dietary conditions.

Network analysis of gut microbial communities reveal key genera for a multiple sclerosis cohort with Mycobacterium avium subspecies paratuberculosis infection.

BACKGROUND: In gut ecosystems, there is a complex interplay of biotic and abiotic interactions that decide the overall fitness of an individual. Divulging the microbe-microbe and microbe-host interactions may lead to better strategies in disease management, as microbes rarely act in isolation. Network inference for microbial communities is often a challenging task limited by both analytical assumptions as well as experimental approaches. Even after the network topologies are obtained, identification of important nodes within the context of underlying disease aetiology remains a convoluted task. We therefore present a network perspective on complex interactions in gut microbial profiles of individuals who have multiple sclerosis with and without Mycobacterium avium subspecies paratuberculosis (MAP) infection. Our exposé is guided by recent advancements in network-wide statistical measures that identify the keystone nodes. We have utilised several centrality measures, including a recently published metric, Integrated View of Influence (IVI), that is robust against biases. RESULTS: The ecological networks were generated on microbial abundance data (n = 69 samples) utilising 16 S rRNA amplification. Using SPIEC-EASI, a sparse inverse covariance estimation approach, we have obtained networks separately for MAP positive (+), MAP negative (-) and healthy controls (as a baseline). Using IVI metric, we identified top 20 keystone nodes and regressed them against covariates of interest using a generalised linear latent variable model. Our analyses suggest Eisenbergiella to be of pivotal importance in MS irrespective of MAP infection. For MAP + cohort, Pyarmidobacter, and Peptoclostridium were predominately the most influential genera, also hinting at an infection model similar to those observed in Inflammatory Bowel Diseases (IBDs). In MAP- cohort, on the other hand, Coprostanoligenes group was the most influential genera that reduces cholesterol and supports the intestinal barrier. CONCLUSIONS: The identification of keystone nodes, their co-occurrences, and associations with the exposome (meta data) advances our understanding of biological interactions through which MAP infection shapes the microbiome in MS individuals, suggesting the link to the inflammatory process of IBDs. The associations presented in this study may lead to development of improved diagnostics and effective vaccines for the management of the disease.

Daytime plasma cortisol and cortisol response to dexamethasone suppression are associated with a prothrombotic state in hypertension.

Background and aims: A prothrombotic state was demonstrated in patients with Cushing's syndrome and is involved in the development and progression of cardiovascular and renal damage in hypertensive patients. This study was designed to examine the relationships between cortisol secretion and the hemostatic and fibrinolytic systems in hypertension. Methods: In 149 middle-aged, nondiabetic, essential hypertensive patients free of cardiovascular and renal complications, we measured hemostatic markers that express the spontaneous activation of the coagulation and fibrinolytic systems and assessed daily cortisol levels (8 AM, 3 PM, 12 AM; area under the curve, AUC-cortisol) together with the cortisol response to dexamethasone overnight suppression (DST-cortisol). Results: Plasma levels of D-dimer (D-dim), prothrombin fragment 1 + 2 (F1 + 2), and von Willebrand factor (vWF) were progressively and significantly higher across tertiles of AUC-cortisol and DST-cortisol, whereas no differences were observed in fibrinogen, tissue plasminogen activator, plasminogen activator inhibitor-1, antithrombin III, protein C, and protein S. D-dim, F1 + 2, and vWF were significantly and directly correlated with age and both AUC-cortisol and DST-cortisol. Multivariate regression analysis showed that both AUC-cortisol and DST-cortisol were related to plasma D-dim, F1 + 2, and vWF independently of age, body mass index, blood pressure, and renal function. Conclusion: Greater daily cortisol profile and cortisol response to overnight suppression are independently associated with a prothrombotic state in hypertensive patients and might contribute to the development of organ damage and higher risk of cardiovascular complications.

Exploring the Association between Cathepsin B and Parkinson's Disease.

OBJECTIVE: The aim of this study is to investigate the association between Cathepsin B and Parkinson's Disease (PD), with a particular focus on determining the role of N-acetylaspartate as a potential mediator. METHODS: We used summary-level data from Genome-Wide Association Studies (GWAS) for a two-sample Mendelian randomization (MR) analysis, exploring the association between Cathepsin B (3301 cases) and PD (4681 cases). A sequential two-step MR approach was applied (8148 cases) to study the role of N-acetylaspartate. RESULTS: The MR analysis yielded that genetically predicted elevated Cathepsin B levels correlated with a reduced risk of developing PD (p = 0.0133, OR: 0.9171, 95% CI: 0.8563-0.9821). On the other hand, the analysis provided insufficient evidence to determine that PD affected Cathepsin B levels (p = 0.8567, OR: 1.0035, 95% CI: 0.9666-1.0418). The estimated effect of N-acetylaspartate in this process was 7.52% (95% CI = -3.65% to 18.69%). CONCLUSIONS: This study suggested that elevated Cathepsin B levels decreased the risk of developing PD, with the mediation effect of N-acetylaspartate. Further research is needed to better understand this relationship.

Comprehensive Echographic Evaluation of Insulinoma, From Bedside to Endoscopic Ultrasonography: A Case Report and Brief Review of the Literature.

Insulinoma is a neuroendocrine tumor of the pancreas, and its identification with bedside ultrasonography (US) is extremely rare. With the aim of providing a comprehensive description of the main US characteristics of this rare form of neuroendocrine neoplasm, we are here describing an interesting case of a young woman with insulinoma, identified by using both bedside and endoscopic ultrasounds.

Semaglutide Treatment in Adult-Onset Autoimmune Diabetes: A Case Study With Long-Term Follow-Up and Periodic Evaluation of Beta-Cell Function.

Latent autoimmune diabetes of adults (LADA) is a form of autoimmune diabetes that typically occurs in adulthood and has intermediate characteristics between type 1 and type 2 diabetes. To optimize the diagnostic and therapeutic approach, recently, a subclassification of LADA has been proposed based on some clinical features, antibodies, and beta cellular function at onset. In this paper, we expose an interesting case showing the effectiveness of early treatment with a glucagon-like peptide receptor agonist (semaglutide) in maintaining long-term good glycemic control and associated with the preservation of beta-cell function over a five-year observation period in a young woman with LADA.

Cortisol secretion and abnormalities of glucose metabolism in nondiabetic patients with hypertension.

OBJECTIVE: Glycometabolic changes are associated with hypercortisolism in Cushing's syndrome. Because impaired glucose tolerance (IGT) and insulin resistance are frequently detected in patients with essential hypertension, we hypothesized that in these patients, early glycometabolic abnormalities might be related to differences in regulation of cortisol secretion. METHODS: In a cross-sectional study, we included 155 nondiabetic, essential hypertensive patients who were free of organ complications. The homeostasis model assessment (HOMA) index and the area under the curve of plasma glucose (AUC-glucose) and insulin (AUC-insulin) concentration following an oral glucose tolerance test were measured, together with daily plasma cortisol (8 a.m., 3 p.m. and 12 a.m.; AUC-cortisol) and 8 a.m. cortisol after 1 mg overnight dexamethasone suppression test (DST). RESULTS: IGT was present in 27% of patients who were older and had higher BMI, plasma triglycerides and uric acid, AUC-cortisol and DST-cortisol, and lower HDL-cholesterol. Frequency of IGT increased progressively across tertiles of DST-cortisol, together with levels of glycated hemoglobin, fasting insulin and C-peptide, HOMA-index, AUC-glucose, and AUC-insulin. AUC-cortisol and DST-cortisol were directly correlated with insulin, C-peptide, HOMA-index, AUC-glucose, and AUC-insulin. Multivariate regression analysis showed that DST-cortisol was directly and independently correlated with HOMA index, AUC-glucose, and AUC-insulin. In a logistic regression model, both AUC-cortisol and DST-cortisol independently predicted IGT. CONCLUSION: Daily cortisol and cortisol response to DST are independent determinants of IGT and insulin resistance in nondiabetic patients with hypertension, suggesting that even subtle differences in regulation of cortisol secretion might increase the risk of these patients to develop diabetes.

Correlation between antibodies against the pathogenic pHERV-W envelope protein and the inflammatory phase of multiple sclerosis.

The role of retroviral envelope proteins belonging to the Human Endogenous Retroviral family 'W' (HERV-W), specifically syncytin-1 and pathogenic HERV-W (pHERV-W), as potential risk factors in multiple sclerosis (MS) has been established. This study aimed to investigate the humoral response to syncytin-1 and pHERV-W-derived peptides in a group of relapsing remitting MS patients categorized as having acute or stable disease. Furthermore, an inhibition assay was conducted to assess the extent of cross-reactivity between the two epitopes. The findings revealed that MS patients in the acute phase exhibited a higher specific antibody response to the pHERV-W env epitope compared to syncytin-1. This suggests a potential pathogenic role for pHERV-W env during the inflammatory stages of central nervous system involvement, and these antibody responses could serve as useful biomarkers for monitoring the progression of the disease.

Fecal Microbiota Transplantation in Irritable Bowel Syndrome: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Irritable bowel syndrome (IBS) poses a significant challenge due to its poorly understood pathogenesis, substantial morbidity, and often inadequate treatment outcomes. The role of fecal microbiota transplantation (FMT) in managing IBS symptoms remains inconclusive. This systematic review and meta-analysis aimed to ascertain the effectiveness of FMT in relieving symptoms in IBS patients. A thorough search was executed on PubMed/Medline and Embase databases until 14 June 2023, including all studies on FMT use in IBS patients. We examined the efficiency of FMT in reducing patients' symptoms overall and in particular subgroups, classified by placebo preparation, FMT preparation, frequency, and route of administration. Among 1015 identified studies, seven met the inclusion criteria for the meta-analysis. The overall symptomatology of FMT-treated IBS patients did not significantly differ from the control group (Odds Ratio (OR) = 0.99, 95% Confidence Interval (CI) 0.39-2.5). Multiple doses of FMT compared with non-FMT placebo, or single-donor FMT therapy compared with autologous FMT placebo also showed no significant benefit (OR = 0.32, 95%CI (0.07-1.32), p = 0.11, and OR = 1.67, 95%CI (0.59-4.67), p = 0.32, respectively). However, a single dose of multiple-donor FMT administered via colonoscopy (lower gastrointestinal (GI) administration) significantly improved patient symptoms compared with autologous FMT placebo (OR = 2.54, 95%CI (1.20-5.37), p = 0.01, and OR = 2.2, 95%CI (1.20-4.03), p = 0.01, respectively). The studies included in the analysis showed a low risk of bias and no publication bias. In conclusion, lower GI administration of a single dose of multiple-donor FMT significantly alleviates patient complaints compared with the autologous FMT used as a placebo. The underlying mechanisms need to be better understood, and further experimental studies are desired to fill the current gaps.

Endogenous retrovirus group FRD member 1 is a potential biomarker for prognosis and immunotherapy for kidney renal clear cell carcinoma.

Introduction: The activation of endogenous retroviral (ERV) genes in kidney renal clear cell carcinoma (KIRC) suggests the necessity for further research on their functions. Methods: In this study, KIRC and healthy cohorts were obtained from TGGA and GEO datasets. Subsequently, differential analysis and functional annotation were conducted using GO, KEGG, and GSEA. Clinical outcomes were then observed and utilized in the development of a nomogram. Results: We observed the general low expression of ERVFRD-1 in KIRC tumors compared to normal tissue (P < 0.001) across multiple cohorts. Differential analysis and functional annotation using GO, KEGG, GSEA analysis revealed significant involvement of ERVFRD-1 in tumor immunoregulation: a close relation to the infiltration levels of mast cells and Treg cell (P < 0.001) and occurrence with a variety of immune markers. Methylation status was then applied to uncover potential mechanisms of ERVFRD-1 in KIRC. Notably, higher expression levels of ERVFRD-1 were associated with extended overall survival, disease-specific survival, and progression-free survival. Finally, based on Cox regression analysis, we constructed a nomogram incorporating ERVFRD-1, pathologic T, and age, which exhibited promising predictive power in assessing the survival outcomes of KIRC patients. Discussion: To sum up, our study suggests that ERVFRD-1 plays a role in regulating immunological activity within the tumor microenvironment and is associated with overall survival in KIRC patients. ERVFRD-1 may therefore be a sensitive biomarker for diagnosis, immunotherapy, and prognosis assessment of KIRC.

Lipoprotein(a): Just an Innocent Bystander in Arterial Hypertension?

Elevated plasma lipoprotein(a) [Lp(a)] is a relatively common and highly heritable trait conferring individuals time-dependent risk of developing atherosclerotic cardiovascular disease (CVD). Following its first description, Lp(a) triggered enormous scientific interest in the late 1980s, subsequently dampened in the mid-1990s by controversial findings of some prospective studies. It was only in the last decade that a large body of evidence has provided strong arguments for a causal and independent association between elevated Lp(a) levels and CVD, causing renewed interest in this lipoprotein as an emerging risk factor with a likely contribution to cardiovascular residual risk. Accordingly, the 2022 consensus statement of the European Atherosclerosis Society has suggested inclusion of Lp(a) measurement in global risk estimation. The development of highly effective Lp(a)-lowering drugs (e.g., antisense oligonucleotides and small interfering RNA, both blocking LPA gene expression) which are still under assessment in phase 3 trials, will provide a unique opportunity to reduce "residual cardiovascular risk" in high-risk populations, including patients with arterial hypertension. The current evidence in support of a specific role of Lp(a) in hypertension is somehow controversial and this narrative review aims to overview the general mechanisms relating Lp(a) to blood pressure regulation and hypertension-related cardiovascular and renal damage.

Mycobacterium avium subsp. paratuberculosis Antigens Elicit a Strong IgG4 Response in Patients with Multiple Sclerosis and Exacerbate Experimental Autoimmune Encephalomyelitis.

Neuroinflammation can be triggered by microbial products disrupting immune regulation. In this study, we investigated the levels of IgG1, IgG2, IgG3, and IgG4 subclasses against the heat shock protein (HSP)70533-545 peptide and lipopentapeptide (MAP_Lp5) derived from Mycobacterium avium subsp. paratuberculosis (MAP) in the blood samples of Japanese and Italian individuals with relapsing remitting multiple sclerosis (MS). Additionally, we examined the impact of this peptide on MOG-induced experimental autoimmune encephalomyelitis (EAE). A total of 130 Japanese and 130 Italian subjects were retrospectively analyzed using the indirect ELISA method. Furthermore, a group of C57BL/6J mice received immunization with the MAP_HSP70533-545 peptide two weeks prior to the active induction of MOG35-55 EAE. The results revealed a significantly robust antibody response against MAP_HSP70533-545 in serum of both Japanese and Italian MS patients compared to their respective control groups. Moreover, heightened levels of serum IgG4 antibodies specific to MAP antigens were correlated with the severity of the disease. Additionally, EAE mice that were immunized with MAP_HSP70533-545 peptide exhibited more severe disease symptoms and increased reactivity of MOG35-55-specific T-cell compared to untreated mice. These findings provide evidence suggesting a potential link between MAP and the development or exacerbation of MS, particularly in a subgroup of MS patients with elevated serum IgG4 levels.

Omega-3 Fatty Acids in Arterial Hypertension: Is There Any Good News?

Omega-3 polyunsaturated fatty acids (ω-3 PUFAs), including alpha-linolenic acid (ALA) and its derivatives eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are "essential" fatty acids mainly obtained from diet sources comprising plant oils, marine blue fish, and commercially available fish oil supplements. Many epidemiological and retrospective studies suggested that ω-3 PUFA consumption decreases the risk of cardiovascular disease, but results of early intervention trials have not consistently confirmed this effect. In recent years, some large-scale randomized controlled trials have shed new light on the potential role of ω-3 PUFAs, particularly high-dose EPA-only formulations, in cardiovascular prevention, making them an attractive tool for the treatment of "residual" cardiovascular risk. ω-3 PUFAs' beneficial effects on cardiovascular outcomes go far beyond the reduction in triglyceride levels and are thought to be mediated by their broadly documented "pleiotropic" actions, most of which are directed to vascular protection. A considerable number of clinical studies and meta-analyses suggest the beneficial effects of ω-3 PUFAs in the regulation of blood pressure in hypertensive and normotensive subjects. These effects occur mostly through regulation of the vascular tone that could be mediated by both endothelium-dependent and independent mechanisms. In this narrative review, we summarize the results of both experimental and clinical studies that evaluated the effect of ω-3 PUFAs on blood pressure, highlighting the mechanisms of their action on the vascular system and their possible impact on hypertension, hypertension-related vascular damage, and, ultimately, cardiovascular outcomes.

Effects of Monacolin K in Nondiabetic Patients with NAFLD: A Pilot Study.

Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver condition with significant risk of progression to steatohepatitis and cirrhosis. Therapeutic strategies in NAFLD include lifestyle changes mainly related to dietary interventions and use of drugs or nutritional components that could improve plasma lipid profiles and insulin sensitivity and decrease the local inflammatory response. In this study, we tested the effects of monacolin K, an inhibitor of HMCoA reductase. In a prospective, uncontrolled, open study, we treated 24 patients with NAFLD and mild hypercholesterolemia with 10 mg/day of monacolin K. At baseline and after 26 weeks, we measured in plasma liver tests, lipids, malondialdehyde, and oxidized glutathione, and assessed biochemical steatosis scores, liver elastography, and body composition with bioimpedance analysis. Monacolin K significantly reduced plasma alanine aminotransferase, cholesterol, triglycerides and the homeostatic model assessment (HOMA) index that indicated improved insulin sensitivity. No significant changes were found in body fat mass and visceral fat, nor in liver elastography, while the fatty liver index (FLI) was significantly decreased. Plasma levels of both malondialdehyde and oxidized glutathione were markedly reduced by monacolin K treatment, suggesting a reduction in oxidative stress and lipid peroxidation. In summary, this pilot study suggests possible benefits of monacolin K use in NAFLD patients that could be linked to a reduction in oxidative stress. This hypothesis should be further investigated in future studies.

BCG Vaccination and the Risk of Type 1 Diabetes Mellitus: A Systematic Review and Meta-Analysis.

(1) Background: Type 1 diabetes mellitus (T1D) is an autoimmune disease characterized by progressive and irreversible autoimmune destruction of pancreatic beta cell islets, resulting in absolute insulin deficiency. To date, several epidemiologic and observational studies have evaluated the possible impact of BCG vaccination on T1D development, but the results are controversial. To elucidate this issue, we aimed to conduct a systematic review and meta-analysis of published cohort studies in this field. (2) Methods: A systematic search was performed for relevant studies published up to 20 September 2022 using Pubmed/Medline, Embase, and Scopus. Cohort studies, containing original information about the association between T1D and BCG vaccination, were included for further analysis. Pooled estimates and 95% confidence intervals (CI) for the risk ratio of T1D in BCG-vaccinated individuals compared to unvaccinated ones were assessed using the fixed effect model. (3) Results: Out of 630 potentially relevant articles, five cohort studies met the inclusion criteria. The total population of all included studies was 864,582. The overall pooled risk ratio of T1D development in BCG vaccinated and unvaccinated individuals was found to be 1.018 (95% CI 0.908-1.141, I2: 0%). (4) Conclusions: Our study revealed no protective or facilitative effect of prior BCG vaccination in T1D development.

A Multigene-Panel Study Identifies Single Nucleotide Polymorphisms Associated with Prostate Cancer Risk.

The immune system plays a critical role in modulating cancer development and progression. Polymorphisms in key genes involved in immune responses are known to affect susceptibility to cancer. Here, we analyzed 35 genes to evaluate the association between variants of genes involved in immune responses and prostate cancer risk. Thirty-five genes were analyzed in 47 patients with prostate cancer and 43 healthy controls using next-generation sequencing. Allelic and genotype frequencies were calculated in both cohorts, and a generalized linear mixed model was applied to test the relationship between prostate cancer risk and nucleotide substitution. Odds ratios were calculated to describe the association between each single nucleotide polymorphism (SNP) and prostate cancer risk. Significant changes in allelic and genotypic distributions were observed for IL4R, IL12RB1, IL12RB2, IL6, TMPRSS2, and ACE2. Furthermore, a generalized linear mixed model identified statistically significant associations between prostate cancer risk and SNPs in IL12RB2, IL13, IL17A, IL4R, MAPT, and TFNRS1B. Finally, a statistically significant association was observed between IL2RA and TNFRSF1B and Gleason scores, and between SLC11A1, TNFRSF1B and PSA values. We identified SNPs in inflammation and two prostate cancer-associated genes. Our results provide new insights into the immunogenetic landscape of prostate cancer and the impact that SNPs on immune genes may have on affecting the susceptibility to prostate cancer.