Factors influencing prophylactic surgical intervention in women with genetic predisposition for breast cancer.

INTRODUCTION: In the United States, 5%-10% of breast cancer cases are due to genetic predisposition. Among this population, prophylactic mastectomy is viable risk-reducing option. OBJECTIVE: The objective of this study is to understand the timing to prophylactic mastectomy in patients with genetic predisposition to breast cancer and uncover factors influencing this decision. METHODS: This study is a retrospective review of patients diagnosed with genetic predisposition for breast cancer from 2010 to 2020. RESULTS: In a cohort of 506 patients with genetic predisposition for breast cancer, 154 (30.4%) underwent prophylactic mastectomy, the remainder opted for surveillance alone. The median time from diagnosis to mastectomy was 1.1 years (IQR, 0.5-3.1 years). During the surveillance period, 118 patients (33.5%) underwent breast biopsy. Of the patients with benign or atypical findings, 35 (36.8%) pursued prophylactic mastectomy, a median of 0.5 years (IQR, 0.2-1.6 years) after their gene diagnosis. The most common factor impacting the decision to undergo prophylactic mastectomy was having a family member with cancer (54.7%) followed by a personal diagnosis of other cancer(s) (27.5%). CONCLUSION: Understanding the factors influencing the decision to undergo prophylactic surgery will allow for more effective shared decision-making for primary care providers, breast surgeons, and reconstructive surgeons.

Risk assessment with gene expression markers in sepsis development.

Infection is a commonplace, usually self-limiting, condition but can lead to sepsis, a severe life-threatening dysregulated host response. We investigate the individual phenotypic predisposition to developing uncomplicated infection or sepsis in a large cohort of non-infected patients undergoing major elective surgery. Whole-blood RNA sequencing analysis was performed on preoperative samples from 267 patients. These patients developed postoperative infection with (n = 77) or without (n = 49) sepsis, developed non-infectious systemic inflammatory response (n = 31), or had an uncomplicated postoperative course (n = 110). Machine learning classification models built on preoperative transcriptomic signatures predict postoperative outcomes including sepsis with an area under the curve of up to 0.910 (mean 0.855) and sensitivity/specificity up to 0.767/0.804 (mean 0.746/0.769). Our models, confirmed by quantitative reverse-transcription PCR (RT-qPCR), potentially offer a risk prediction tool for the development of postoperative sepsis with implications for patient management. They identify an individual predisposition to developing sepsis that warrants further exploration to better understand the underlying pathophysiology.

Glioma oncogenesis in the Constitutional mismatch repair deficiency (CMMRD) syndrome.

Background: Constitutional mismatch repair deficiency (CMMRD) is a cancer predisposition due to biallelic mutations in one of the mismatch repair (MMR) genes associated with early onset of cancers, especially high-grade gliomas. Our aim was to decipher the molecular specificities of these gliomas. Methods: Clinical, histopathological, and whole exome sequencing data were analyzed in 12 children with genetically proven CMMRD and a high-grade glioma. Results: PDL1 expression was present in immunohistochemistry in 50% of the samples. In 9 patients, the glioma harbored an ultra-hypermutated phenotype (104-635 coding single nucleotide variants (SNV) per Mb, median 204). Driver mutations in POLE and POLD1 exonuclease domains were described for 8 and 1 patients respectively and were always present in the mutation burst with the highest variant allele frequency (VAF). The mutational signatures were dominated by MMR-related ones and similar in the different mutation bursts of a same patient without subsequent enrichment of the mutation signatures with POL-driven ones. Median number of coding SNV with VAF above one of the driving polymerase mutation per Mb was 57 (17-191). Our findings suggest that somatic polymerase alterations does not entirely explain the ultra-hypermutant phenotype. SETD2, TP53, NF1, EPHB2, PRKDC, and DICER1 genes were frequently mutated with higher VAF than the deleterious somatic polymerase mutation. Conclusions: CMMRD-associated gliomas have a specific oncogenesis that does not involve usual pathways and mutations seen in sporadic pediatric or adult glioblastomas. Frequent alterations in other pathways such as MAPK may suggest the use of other targeted therapies along with PD1 inhibitors.

Genetic markers of late radiation toxicity in the era of image-guided radiotherapy: lower toxicity rates reduce the predictive value of γ-H2AX foci decay ratio in patients undergoing pelvic radiotherapy.

BACKGROUND: A predictive assay for late radiation toxicity would allow more personalized treatment planning, reducing the burden of toxicity for the more sensitive minority, and improving the therapeutic index for the majority. In a previous study in prostate cancer patients, the γ-H2AX foci decay ratio (γ-FDR) was the strongest predictor of late radiation toxicity. The current study aimed to validate this finding in a more varied group of patients with pelvic cancer. Additionally, the potential correlation between the γ-FDR and patient-reported outcomes was investigated. METHODS: Prostate and gynecological cancer patients with ≥ 24 months of follow-up were included in the current analysis. Toxicity was evaluated by physician (CTCAE version 4) and patient (EORTC questionnaires). γ-FDRs were determined in ex vivo irradiated lymphocytes. Correlation between γ-FDR and toxicity was assessed using both linear and logistic regression analyses. The highest toxicity grade recorded during follow-up was used. The association between global quality of life and γ-FDR was tested by comparing the change in quality of life over time in patients with γ-FDR < or ≥ 3.41, a previously established threshold. RESULTS: Eighty-eight patients were included. Physician-assessed and patient-reported cumulative grade ≥ 2 toxicity was 25% and 29%, respectively; which is much lower than in the previous cohort (i.e., 51% CTCAE grade ≥ 2). Patients with toxicity exhibited less favorable dose-volume parameters. In men, these parameters showed significant improvement compared to the previous cohort. The proportion of patients with a low γ-FDR increased with severity of toxicity, but this trend was not statistically significant. In addition, a γ-FDR < 3.41 was not correlated with the development of moderate to severe toxicity. Post-treatment decline in global quality of life was minimal, and similar for patients with γ-FDR < or ≥ 3.41. CONCLUSIONS: In the present study, the γ-H2AX foci decay ratio could not be validated as a predictor of late radiation toxicity in patients with pelvic cancer. Improved radiotherapy techniques with smaller irradiated bladder and bowel volumes have probably resulted in less toxicities. Future studies on genetic markers of toxicity should be powered on these lower incidences. We further recommend taking persistency, next to severity, into consideration.

Phenotypic spectrum and tumor risk in Simpson-Golabi-Behmel syndrome: Case series and comprehensive literature review.

Simpson-Golabi-Behmel syndrome (SGBS) is a rare congenital overgrowth condition characterized by macrosomia, macroglossia, coarse facial features, and development delays. It is caused by pathogenic variants in the GPC3 gene on chromosome Xq26.2. Here, we performed a comprehensive literature review and phenotyping of known patients with molecularly confirmed SGBS and reviewed a novel cohort of 22 patients. Using these data, we characterized the tumor risk for Wilms tumor and hepatoblastoma to suggest appropriate screening for this patient population. In addition, we discuss the phenotypic overlap between SGBS and Beckwith-Wiedemann Spectrum.

Cowden Syndrome: A Rare Cause of Intestinal Polyposis.

Cowden syndrome (CS) is a rare autosomal dominant genodermatosis disorder. This disease is characterized by the development of several hamartomata lesions in a variety of tissues from all three embryonic layers. The most well-known hamartomata are those of the gastrointestinal system, which represent one of the major criteria for the diagnosis of CS. Yet, the most frequent initial presenting symptom of the disease is thought to be mucocutaneous symptoms such as trichilemmomas, acral keratosis, and oral papilloma. Early diagnosis and management are essential to improving the quality of life for patients with CS as this disorder predisposes them to cancers such as thyroid, breast, gastrointestinal, and endometrial cancers. This report presents a rare case of CS in a Bahraini child who presented with macrocephaly and had numerous intestinal polyposis. Genetic testing using whole exome sequencing confirmed the diagnosis, identifying a pathogenic de novo phosphatase and tensin homolog gene (PTEN) variant (Chr10 NM_000314.8: c.17_18del p.(Lys6Argfs*4)) in a heterozygous state. This variant has been confirmed by Sanger sequencing.

Case report: Germline POT1 mutation in a patient with GIST and lung adenocarcinoma.

The gene protection of telomere 1 (POT1) is involved in telomere maintenance and stability and plays a crucial role in the preservation of genomic stability. POT1 is considered a high-penetrance melanoma susceptibility gene; however, the number of cancer types associated with the pathogenic germline variants of POT1 is gradually increasing, including chronic lymphocytic leukemia (CLL), angiosarcomas, and gliomas, even though many associations are still elusive. Here, we reported a case of a 60-year-old man who showed early-onset multiple neoplasms, including multiple melanomas, gastrointestinal stromal tumor (GIST), and lung adenocarcinoma. Next-generation sequencing (NGS) analyses revealed a germline heterozygous pathogenic variant in the POT1 gene. Notably, GIST and lung adenocarcinoma were not previously reported in association with the POT1 germline variant. Lung cancer susceptibility syndrome is very rare and the actual knowledge is limited to a few genes although major genetic factors are unidentified. Recently, genome-wide association studies (GWAS) have pointed out an association between POT1 variants and lung cancer. This case report highlights the clinical relevance of POT1 alterations, particularly their potential involvement in lung cancer. It also suggests that POT1 testing may be warranted in patients with familial cancer syndrome, particularly those with a history of melanoma and other solid tumors.

Pancreatic beta cell function and insulin resistance profiles in first-degree relatives of patients with prediabetes and type 2 diabetes.

AIMS: To evaluate insulin secretion and insulin resistance profiles in individuals with family history of prediabetes and type 2 diabetes. METHODS: This was a cross-sectional study to evaluate clinical and metabolic profiles between individuals with type 2 diabetes, prediabetes and their relatives. There were 911 subjects divided into five groups: (i) normoglycemic (NG), (ii) type 2 diabetes, (iii) prediabetes, (iv) first-degree relatives of patients with type 2 diabetes (famT2D), and (v) first-degree relatives of patients with prediabetes (famPD); anthropometrical, biochemical and nutritional evaluation, as well as insulin resistance and pancreatic beta cell function measurement was performed by oral glucose tolerance to compare between groups. RESULTS: The most prevalent type 2 diabetes risk factors were dyslipidemia (81%), family history of type 2 diabetes (76%), central obesity (73%), male sex (63%), and sedentary lifestyle (60%), and most of them were progressively associated to prediabetes and type 2 diabetes groups. Insulin sensitivity was lower in famT2D groups in comparison to NG group (p < 0.0001). FamPD and famT2D had a 10% lower pancreatic beta cell function (DI) than the NG group (NG group 2.78 ± 1.0, famPD 2.5 ± 0.85, famT2D 2.4 ± 0.75, p˂0.001). CONCLUSIONS: FamPD and famT2D patients had lower pancreatic beta cell function than NG patients, highlighting that defects in insulin secretion and insulin sensitivity appear long time before the development of hyperglycemia in patients genetically predisposed.

SEC16A Variants Predispose to Chronic Pancreatitis by Impairing ER-to-Golgi Transport and Inducing ER Stress.

Chronic pancreatitis (CP) is a complex disease with genetic and environmental factors at play. Through trio exome sequencing, a de novo SEC16A frameshift variant in a Chinese teenage CP patient is identified. Subsequent targeted next-generation sequencing of the SEC16A gene in 1,061 Chinese CP patients and 1,196 controls reveals a higher allele frequency of rare nonsynonymous SEC16A variants in patients (4.90% vs 2.93%; odds ratio [OR], 1.71; 95% confidence interval [CI], 1.26-2.33). Similar enrichments are noted in a French cohort (OR, 2.74; 95% CI, 1.67-4.50) and in a biobank meta-analysis (OR, 1.16; 95% CI, 1.04-1.31). Notably, Chinese CP patients with SEC16A variants exhibit a median onset age 5 years earlier than those without (40.0 vs 45.0; p = 0.012). Functional studies using three CRISPR/Cas9-edited HEK293T cell lines show that loss-of-function SEC16A variants disrupt coat protein complex II (COPII) formation, impede secretory protein vesicles trafficking, and induce endoplasmic reticulum (ER) stress due to protein overload. Sec16a+/- mice, which demonstrate impaired zymogen secretion and exacerbated ER stress compared to Sec16a+/+, are further generated. In cerulein-stimulated pancreatitis models, Sec16a+/- mice display heightened pancreatic inflammation and fibrosis compared to wild-type mice. These findings implicate a novel pathogenic mechanism predisposing to CP.

Hereditary Colorectal Cancer and Polyposis Syndromes Caused by Variants in Uncommon Genes.

A substantial number of hereditary colorectal cancer (CRC) and colonic polyposis cannot be explained by alteration in confirmed predisposition genes, such as mismatch repair (MMR) genes, APC and MUTYH. Recently, a certain number of potential predisposition genes have been suggested, involving each a small number of cases reported so far. Here, we describe the detection of rare variants in the NTLH1, AXIN2, RNF43, BUB1, and TP53 genes in nine unrelated patients who were suspected for inherited CRC and/or colonic polyposis. Seven of them were classified as pathogenic or likely pathogenic variants (PV/LPV). Clinical manifestations of carriers were largely consistent with reported cases with, nevertheless, distinct characteristics. PV/LPV in these uncommon gene can be responsible for up to 2.7% of inherited CRC or colonic polyposis syndromes. Our findings provide supporting evidence for the role of these genes in cancer predisposition, and contribute to the determination of related cancer spectrum and cancer risk for carriers, allowing for the establishment of appropriate screening strategy and genetic counseling in affected families.

Primary CNS Burkitt Lymphoma Presenting as Sudden Bilateral Blindness in a Patient With Underlying Kabuki Syndrome: A Case Report.

Burkitt lymphoma is an aggressive B-cell non-Hodgkin lymphoma (NHL). Primary CNS lymphoma (PCNSL) is a rare disease, and the subtype of Burkitt lymphoma presenting as a sole CNS lesion is an even rarer diagnosis. Acute sudden blindness is a rare presenting symptom of PCNSL or NHL in general. We present an interesting case of a four-year-old boy with dysmorphic features whose visual examination showed a sudden bilateral loss of vision. There was bilateral eye proptosis and complete ptosis. Extraocular muscles were fixed straight. The pupils were fixed and mid dilated bilaterally and there was grade 3/4 papilledema in both eyes. Neuroimaging showed a mass in the base of the skull, extending to orbits and sinuses. A cervical biopsy of the enlarged lymph nodes was taken and a histopathological diagnosis of Burkitt lymphoma was made. Genetic analysis showed a GNB1 mutation, and the patient was diagnosed with Kabuki syndrome by a pediatrician, based on characteristic dysmorphic features. Treatment with steroids and chemotherapy was initiated.

Familial Spontaneous Keloids: Examining Thoracic Manifestations in Two Brothers.

Keloids are complex fibroproliferative disorders with diverse clinical presentations. Spontaneous keloids (SKs) represent a rare subtype that emerges without any known preceding traumatic event. This report presents a case of familial spontaneous keloids appearing on the thoracic region in two brothers with no prior history of trauma or keloid occurrence in other family members. The lesions exhibited progressive growth over several years but responded to cycles of triamcinolone treatment. This case underscores an unusual spontaneous occurrence of keloids in the thoracic region of two siblings, highlighting the potential genetic predisposition in the aetiology of these lesions. Additionally, this instance reinforces the concept that keloids can develop spontaneously without any apparent trauma in the affected area.

Identification of Novel Potential Predisposing Variants in Familial Acute Myeloid Leukemia.

BACKGROUND: Myeloid neoplasms, including acute myeloid leukemia, have been traditionally among the less investigated cancer types concerning germline predisposition. Indeed, myeloid neoplasms with germline predisposition are challenging to identify because often display similar clinical and morphological characteristics of sporadic cases and have similar age at diagnosis. However, a misidentifications of familiarity in myeloid neoplasms have a critical impact on clinical management both for the carriers and their relatives. AIMS: We conducted a family segregation study, in order to identify novel cancer predisposing genes in myeloid neoplasms and classify novel identified variants. METHODS AND RESULTS: We performed a thorough genomic analysis using a large custom gene panel (256 genes), the Myelo-Panel, targeted on cancer predisposing genes. In particular, we assessed both germline and somatic variants in four families, each with two siblings, who developed hematological neoplasms: seven acute myeloid leukemia and one Philadelphia-positive chronic myeloid leukemia. In each family, we identified at least one novel potentially predisposing variant, affecting also genes not included in the current European LeukemiaNet guidelines for AML management. Moreover, we suggest reclassification of two germline variants as pathogenic: likely pathogenic p.S21Tfs*139 in CEPBA and VUS p.K392Afs*66 in DDX41. CONCLUSION: We believe that predisposition to hematological neoplasms is still underestimated and particularly difficult to diagnosed. Considering that misidentification of familiarity in myeloid neoplasms have a critical impact on the clinical management both for the carriers and their relatives, our study highlights the importance of revision, in this clinical context, of clinical practices that should include thorough reconstruction of family history and in-depth genetic testing.

Impact of Consanguinity and Familial Aggregation on Vitiligo Epidemiology in Saudi Arabia: A Case-Control Study.

Background Vitiligo, characterized by depigmented patches due to melanocyte loss, involves genetic, autoimmune, and environmental factors. Recent studies suggest a link between family history, consanguinity, and vitiligo prevalence, particularly in regions with prevalent consanguineous marriages. This study explored the relationship between consanguinity and familial vitiligo prevalence in Saudi Arabia. Methods A case-control study enrolled 792 participants from Saudi dermatology clinics (382 vitiligo cases, 408 controls). Family histories and consanguinity levels were assessed. Logistic regression analysis, adjusting for relevant variables, evaluated associations. Results Significant associations were found between vitiligo and both parental consanguinity and family history. Cases had higher consanguinity rates, with 246 out of 382 (64.4%), compared to controls, with 161 out of 408 (39.5%). A positive family history of vitiligo was more common in cases, with 184 out of 382 (48.2%) than in controls, with 90 out of 408 (22.1%). Logistic regression identified parental consanguinity and positive family history as significant risk factors for vitiligo, with adjusted odds ratios (aOR) of 2.39 and 2.92, respectively. Their synergistic effect notably amplified the risk (aOR = 7.58), indicating a complex genetic and familial influence on vitiligo in Saudi Arabia. Conclusions Consanguinity showed a significant association with vitiligo prevalence, highlighting genetic factors' role. Further genetic research is needed to identify specific mutations in vitiligo among consanguineous populations. Genetic counseling and awareness programs are crucial in regions with high consanguinity rates to mitigate vitiligo and other genetic disorders' risks.

Daytime Napping, Incident Atrial Fibrillation, and Dynamic Transitions With Dementia.

Background: Associations between napping and incident atrial fibrillation (AF) remain unknown, and few studies have accounted for dynamic transitions between AF and dementia. Objectives: The purpose of this study was to evaluate associations between napping with incident AF and the dynamic transitions of AF and dementia, as well as the mediation pathway of left ventricular (LV) size and function. Methods: A total of 476,588 participants from UK Biobank were included. Napping frequency and other sleep behaviors were evaluated. Incident AF, dementia, and mortality were ascertained via linkage to external registry databases. LV size and function indices were obtained from cardiovascular magnetic resonance imaging phenotypes. A multistate survival analysis was conducted to examine daytime napping in relation to dynamic transitions. Weighed AF genetic risk score was calculated. Results: Frequent daytime napping, compared to never/rarely napping, was associated with a 1.17-fold AF risk (HR: 1.17; 95% CI: 1.12-1.22), which persisted after controlling for other sleep behaviors. Genetic predisposition significantly modified associations between napping and AF (P for interaction <0.001), with stronger associations observed in those of low and moderate genetic risk. LV ejection fraction significantly mediated 26.2% (95% CI: 4.2%-74.1%) of associations between napping and AF. Frequent napping was also associated with a 1.27-fold risk of transition from AF to comorbidity of AF and dementia. Conclusions: Our findings highlight the potential importance of screening for napping in view of the association with incident AF and dementia. Routine evaluations of the LV ejection fraction could be warranted to timely identify early indications of AF onset among habitual nappers.

Adenomas from individuals with pathogenic biallelic variants in the MUTYH and NTHL1 genes demonstrate base excision repair tumour mutational signature profiles similar to colorectal cancers, expanding potential diagnostic and variant classification applications.

Background: Colorectal cancers (CRCs) from people with biallelic germline likely pathogenic/pathogenic variants in MUTYH or NTHL1 exhibit specific single base substitution (SBS) mutational signatures, namely combined SBS18 and SBS36 (SBS18+SBS36), and SBS30, respectively. The aim was to determine if adenomas from biallelic cases demonstrated these mutational signatures at diagnostic levels. Methods: Whole-exome sequencing of FFPE tissue and matched blood-derived DNA was performed on 9 adenomas and 15 CRCs from 13 biallelic MUTYH cases, on 7 adenomas and 2 CRCs from 5 biallelic NTHL1 cases and on 27 adenomas and 26 CRCs from 46 non-hereditary (sporadic) participants. All samples were assessed for COSMIC v3.2 SBS mutational signatures. Results: In biallelic MUTYH cases, SBS18+SBS36 signature proportions in adenomas (mean±standard deviation, 65.6%±29.6%) were not significantly different to those observed in CRCs (76.2%±20.5%, p-value=0.37), but were significantly higher compared with non-hereditary adenomas (7.6%±7.0%, p-value=3.4×10-4). Similarly, in biallelic NTHL1 cases, SBS30 signature proportions in adenomas (74.5%±9.4%) were similar to those in CRCs (78.8%±2.4%) but significantly higher compared with non-hereditary adenomas (2.8%±3.6%, p-value=5.1×10-7). Additionally, a compound heterozygote with the c.1187G>A p.(Gly396Asp) pathogenic variant and the c.533G>C p.(Gly178Ala) variant of unknown significance (VUS) in MUTYH demonstrated high levels of SBS18+SBS36 in four adenomas and one CRC, providing evidence for reclassification of the VUS to pathogenic. Conclusions: SBS18+SBS36 and SBS30 were enriched in adenomas at comparable proportions observed in CRCs from biallelic MUTYH and biallelic NTHL1 cases, respectively. Therefore, testing adenomas may improve the identification of biallelic cases and facilitate variant classification, ultimately enabling opportunities for CRC prevention.

Inherited genetic predisposition and imaging concordance in degenerative lumbar scoliosis patients and their descendants.

BACKGROUND: Offspring consistently exhibit similar imaging features as their parents in cases of degenerative lumbar scoliosis (DLS). Nevertheless, the role of genetic factors in the pathogenesis of DLS remains uncertain. METHODS: A prospective analysis was conducted on 35 patients with DLS and their 36 offspring. Genomic DNA was extracted from 71 blood samples for gene mutation analysis using whole exome sequencin. Various demographic and imaging parameters were compared. RESULTS: In 11 pedigrees of the 35 family members with DLS, 13 suspected pathogenic genes were identified. Among the 35 DLS patients, 11/35(31.5%) exhibited susceptibility gene mutations (mutant group), while 24/35(68.5%) had no pathogenic gene mutations (non-mutant group). AVR was more severe in mutant group than that in no-mutant group (p < 0.05). Among the 36 offspring, 11/36(30.6%) cohorts presented susceptibility genes (mutant group), 25/36(69.4%) cohorts presented no pathogenic genes (no-mutant group). More cohorts in the mutant group presented vertebral rotation (72.8%) and scoliosis (45.5%) than those (24%), (12%) in the no-mutant group, respectively (p < 0.05). Among the 36 offspring, 8/36(22.2%) presented scoliosis (study group), they all presented the same scoliosis orientation and apex vertebrae/disc location to their parents, the other 28/36(77.8%) cohorts without scoliosis were enrolled as control group, the mutation rate (62.5%) was higher in study group than that (21.4%) in control group. CONCLUSIONS: Genetic influences are significant in the onset of DLS, with affected families showing similar scoliosis patterns and identical apex vertebrae. Moreover, individuals with genetic mutations tend to have more pronounced vertebral rotation and at a higher risk of developing scoliosis.

Leisure Sedentary Behavior, Physical Activities, and Cardiovascular Disease Among Individuals With Metabolic Dysfunction-Associated Fatty Liver Disease.

BACKGROUND: Metabolic dysfunction-associated fatty liver disease is a significant risk factor for cardiovascular disease (CVD). This study assesses the association between leisure-time physical activity, sedentary behavior, and CVD risk among patients with metabolic dysfunction-associated fatty liver disease, considering genetic predisposition to CVD. METHODS: This cohort study included 157 794 participants with metabolic dysfunction-associated fatty liver disease from the UK Biobank who were free of CVD at baseline. The study measured leisure-time sedentary behaviors (watching TV, using a computer, and driving) and physical activities (walking for pleasure, light and heavy do-it-yourself activities, strenuous sports, and other exercises) in terms of frequency and duration over the 4 weeks before assessment. Both a Cox proportional hazard model and an isotemporal substitution model were utilized in the study to assess the association between leisure sedentary behavior, physical activities, and CVD risk. RESULTS: During a median 12.5 years of follow-up, 26 355 CVD cases were reported, including 19 746 coronary heart disease, 4836 stroke, and 7398 heart failure cases. High physical activity levels were linked to a significantly lower risk of CVD (21%), coronary heart disease (20%), stroke (15%), and heart failure (31%). In contrast, individuals with >6.5 h/d of sedentary behavior faced a 16% to 21% higher risk of these conditions compared with those with ≤3.5 h/d. Notably, replacing 30 minutes of inactivity with physical activity reduced CVD risks by 3% to 16%, particularly with strenuous sports. A significant interaction was observed between physical activity, sedentary behavior, and genetic predisposition in relation to stroke risk. CONCLUSIONS: Among patients with metabolic dysfunction-associated fatty liver disease, higher leisure-time physical activity levels correlate with reduced CVD risks, while increased sedentary behavior is linked to higher CVD risks. Replacing sedentary time with physical activity consistently shows benefits in reducing CVD outcomes, irrespective of genetic predisposition.

Tuberculous Meningitis Genetic predisposition: Understanding cellular interactions, molecular mechanisms and genetic dimensions.

Tuberculous meningitis, a severe form of tuberculosis caused by Mycobacterium tuberculosis (BK), remains a major public health challenge worldwide. In addition to the complex mechanisms of the innate and adaptive immune response against Mycobacterium tuberculosis, there is a crucial genetic dimension to consider. Individuals with specific genetic variations may have altered immune responses that make them more susceptible to this form of tuberculosis. Genetic mutations in genes encoding surface receptors, adaptor proteins, kinases, transcription factors, nucleic receptors and other molecules involved in cellular interactions and molecular mechanisms have been associated with susceptibility to TB. Understanding the molecular mechanisms of immune interactions in host response to Mycobacterium tuberculosis is crucial to understanding the genetic dimension in susceptibility to tuberculosis, particularly its dreaded form of tuberculous meningitis. The aim of this update is to explore in details the key interactions between the main players in innate and adaptive immunity during infection with Mycobacterium tuberculosis, with particular emphasis on the genetic factors associated with susceptibility to tuberculosis, especially its dreaded form of tuberculous meningitis.