Polygenic risk prediction models for colorectal cancer: a systematic review

Background Risk prediction models incorporating single nucleotide polymorphisms (SNPs) could lead to individualized prevention of colorectal cancer (CRC). However, the added value of incorporating SNPs into models with only traditional risk factors is still not clear. Hence, our primary aim was to summarize literature on risk prediction models including genetic variants for CRC, while our secondary aim was to evaluate the improvement of discriminatory accuracy when adding SNPs to a prediction model with only traditional risk factors. Methods We conducted a systematic review on prediction models incorporating multiple SNPs for CRC risk prediction. We tested whether a significant trend in the increase of Area Under Curve (AUC) according to the number of SNPs could be observed, and estimated the correlation between AUC improvement and number of SNPs. We estimated pooled AUC improvement for SNP-enhanced models compared with non-SNP-enhanced models using random effects meta-analysis, and conducted meta-regression to investigate the association of specific factors with AUC improvement. Results We included 33 studies, 78.79% using genetic risk scores to combine genetic data. We found no significant trend in AUC improvement according to the number of SNPs (p for trend = 0.774), and no correlation between the number of SNPs and AUC improvement (p = 0.695). Pooled AUC improvement was 0.040 (95% CI: 0.035, 0.045), and the number of cases in the study and the AUC of the starting model were inversely associated with AUC improvement obtained when adding SNPs to a prediction model. In addition, models constructed in Asian individuals achieved better AUC improvement with the incorporation of SNPs compared with those developed among individuals of European ancestry. Conclusions Though not conclusive, our results provide insights on factors influencing discriminatory accuracy of SNP-enhanced models. Genetic variants might be useful to inform stratified CRC screening in the future, but further research is needed.

Inflammatory Burden and Immunomodulative Therapeutics of Cardiovascular Diseases

Phenotyping cardiovascular illness and recognising heterogeneities within are pivotal in the contemporary era. Besides traditional risk factors, accumulated evidence suggested that a high inflammatory burden has emerged as a key characteristic modulating both the pathogenesis and progression of cardiovascular diseases, inclusive of atherosclerosis and myocardial infarction. To mechanistically elucidate the correlation, signalling pathways downstream to Toll-like receptors, nucleotide oligomerisation domain-like receptors, interleukins, tumour necrosis factor, and corresponding cytokines were raised as central mechanisms exerting the effect of inflammation. Other remarkable adjuvant factors include oxidative stress and secondary ferroptosis. These molecular discoveries have propelled pharmaceutical advancements. Statin was suggested to confer cardiovascular benefits not only by lowering cholesterol levels but also by attenuating inflammation. Colchicine was repurposed as an immunomodulator co-administered with coronary intervention. Novel interleukin-1β and −6 antagonists exhibited promising cardiac benefits in the recent trials as well. Moreover, manipulation of gut microbiota and associated metabolites was addressed to antagonise inflammation-related cardiovascular pathophysiology. The gut-cardio-renal axis was therein established to explain the mutual interrelationship. As for future perspectives, artificial intelligence in conjunction with machine learning could better elucidate the sequencing of the microbiome and data mining. Comprehensively understanding the interplay between the gut microbiome and its cardiovascular impact will help identify future therapeutic targets, affording holistic care for patients with cardiovascular diseases.

È possibile una gestione “ideale” della pandemia da malattia renale cronica?

Chronic Kidney Disease (CKD) is recognized as one of the major categories of noncommunicable epidemic diseases and in the last decades it has been largely growing in incidence and prevalence all over the world. Ideal management of CKD pandemic should be comprehensive of measures of tertiary, secondary, primary and primordial prevention. So, it should include prompt diagnosis and treatment of traditional and non-traditional risk factors for CKD, optimal conservative treatment for non-dialysis dependent CKD patients and appropriated dialysis therapy or renal transplantation for patients with end-stage renal disease. However, these goals are not easy to obtain on a global scale. It would be possible only by a broad and holistic approach, ranging from good governance to achievement of the sustainable development goals (SDGs).

Evaluation of the long-term prognostic ability of triglyceride-glucose index for elderly acute coronary syndrome patients: a cohort study

Background With the advancement of the world population aging, more attention should be paid to the prognosis of elderly patients with acute coronary syndrome (ACS). Triglyceride-glucose (TyG) index is a reliable indicator of insulin resistance (IR) and is closely related to traditional risk factors of cardiovascular disease (CVD). However, the effect of TyG index on the prognosis of long-term adverse events in elderly ACS patients has not been reported. This study evaluated the prognostic power of TyG index in predicting adverse events in elderly ACS patients. Methods In this study, 662 ACS patients > 80 years old who were hospitalized from January 2006 to December 2012 were enrolled consecutively and the general clinical data and baseline blood biochemical indicators were collected. The follow-up time after discharge was 40–120 months (median, 63 months; interquartile range, 51‒74 months). In addition, the following formula was used to calculate the TyG index: Ln [fasting TG (mg/dL) × FBG (mg/dL)/2], and patients were divided into three groups according to the tertile of the TyG index. Results The mean age of the subjects was 81.87 ± 2.14 years, the proportion of females was 28.10%, and the mean TyG index was 8.76 ± 0.72. The TyG index was closely associated with the traditional risk factors of CVD. In the fully-adjusted Cox regression model, the Hazard ratio (95% CI) of all-cause mortality (in tertile 3) was 1.64 (1.06, 2.54) and major adverse cardiac event (MACE) (in tertile 3) was 1.36 (1.05, 1.95) for each SD increase in the TyG index. The subgroup analyses also confirmed the significant association of the TyG index and long-term prognosis. Conclusion The TyG index is an independent predictor of long-term all-cause mortality and MACE in elderly ACS patients.

A malignus daganatok és az ischaemiás stroke kapcsolata.

Összefoglaló. A malignus daganat és a stroke egy-egy betegnél gyakran kombinálódik, sokszor egyidejűleg diagnosztizálják, vagy rövid idő telik el a két kórkép felismerése között. Az együttes megjelenés hátterében elsősorban a hasonló tradicionális rizikófaktorok állhatnak: az idősebb életkor, a magas vérnyomás, a hyperlipidaemia, a cukorbetegség, az elhízás és a dohányzás. Az átfedő kockázati tényezőkön túl a daganat által okozott hiperkoaguláció artériás és vénás thrombosis kialakulásához vezethet. A hiperkoaguláció hátterének kutatása főként a thrombocyták és a szöveti faktor aktiválására és a heparanáz fokozott expressziójára fókuszált, és felvetődött a neutrophil extracelluláris csapdák szerepe is. A daganat által okozott hiperkoagulációhoz társuló cryptogen (tradicionális rizikófaktor nélküli) stroke-ban sokszor található magasabb D-dimer-szint, és a CT/MRI-képeken gyakrabban látszanak multifokális, több ér ellátási területében megjelenő ischaemiás laesiók, melyek ritkábban fordulnak elő a tradicionális rizikófaktorokkal magyarázható stroke-okban. Az előzőkön kívül a daganatok kezelésére alkalmazott kemoterápia és sugárterápia is emeli a stroke kockázatát. A malignus daganatokhoz társuló stroke-ok megelőzése érdekében további vizsgálatok szükségesek a daganat által okozott hiperkoaguláció és vascularis változások pontosabb megértéséhez. Orv Hetil. 2022; 163(1): 3–11. Summary. Cancer and stroke have long been studied individually, but their detrimental forces together have also been a strong point of focus. The occurrence of both cancer and stroke in a patient is often a reflection of their similar risk factors (hypertension, hyperlipidemia, diabetes, obesity, and smoking), however, a subgroup of the cancer stroke population is believed to occur due to cancer-associated hypercoagulability. A deeper look into the cancer-associated hypercoagulable environment has indicated that thrombosis may be explained by cancer’s role in several factors, including activation of platelets and tissue factor, elevated expression of heparanase and influence on neutrophilic extracellular traps. When a cryptogenic stroke (stroke lacking the aforementioned risk factors) occurs due to the cancer-induced hypercoagulation state, patient serum D-dimer levels have been found elevated, and CT/MRI images of the brain have shown multivascular infarctions compared to stroke patients with traditional risk factors. Additionally, cancer treatment – chemotherapy and radiation – have also been found to increase the occurrence of cerebral vascular thrombosis. Further investigations are required to better understand cancer-associated vascular pathophysiologic changes and how to discern their unique strokes compared to strokes from other etiologies. With these insights, the prevalence of strokes in the cancer population could be decreased. Orv Hetil. 2022; 163(1): 3–11.

Missed opportunities to identify cryptococcosis in COVID-19 patients: a case report and literature review

SARS-CoV-2 may activate both innate and adaptive immune responses ultimately leading to a dysregulated immune response prompting the use of immunomodulatory therapy. Although viral pneumonia increases the risk of invasive fungal infections, it remains unclear whether SARS-CoV-2 infection, immunomodulatory therapy, or a combination of both are responsible for the increased recognition of opportunistic infections in COVID-19 patients. Cases of cryptococcosis have previously been reported following treatment with corticosteroids, interleukin (IL)-6 inhibitors, and Janus kinase (JAK) inhibitors, for patients with autoimmune diseases, but their effect on the immunologic response in patients with COVID-19 remains unknown. Herein, we present the case of a patient with COVID-19 who received high-dose corticosteroids and was later found to have cryptococcosis despite no traditional risk factors. As our case and previous cases of cryptococcosis in patients with COVID-19 demonstrate, clinicians must be suspicious of cryptococcosis in COVID-19 patients who clinically deteriorate following treatment with immunomodulatory therapies.

Characterization of the LPS and 3OHFA Contents in the Lipoprotein Fractions and Lipoprotein Particles of Healthy Men

Atherosclerosis is a chronic inflammatory disease that is caused by the accumulation of LDL particles in the intima, causing the activation of immune cells and triggering an inflammatory response. LPS is a potent activator of the innate immune response and it can be transported by lipoproteins. Since humans are much more sensitive to LPS than other mammals, and very low amounts of LPS can elicit an immune response, the aim of this study is to characterize the distribution of LPS and its immunogenic portion (3OHFAs) among lipoprotein types of healthy men. We separated lipoprotein fractions by ultracentrifugation and the amount of each 3OHFA was measured by MS in each lipoprotein fraction to calculate LPS concentration. Lipoprotein particle concentration was measured by NMR. LDL and HDL fractions transported the highest concentration of LPS (35.7% and 31.5%, respectively), but VLDL particles carried more LPS molecules per particle (0.55 molecules/particle) than LDL or HDL (p < 0.01). The distribution of LPS and all 3OHFAs among lipoprotein fractions showed high interindividual variability, suggesting that they may be studied as a potential biomarker. This may help understand the role of LPS in atherosclerosis in those cases where the disease cannot be explained by traditional risk factors.