Unveiling the molecular landscape of cognitive aging: insights from polygenic risk scores, DNA methylation, and gene expression.

BACKGROUND: Aging represents a significant risk factor for the occurrence of cerebral small vessel disease, associated with white matter (WM) lesions, and to age-related cognitive alterations, though the precise mechanisms remain largely unknown. This study aimed to investigate the impact of polygenic risk scores (PRS) for WM integrity, together with age-related DNA methylation, and gene expression alterations, on cognitive aging in a cross-sectional healthy aging cohort. The PRSs were calculated using genome-wide association study (GWAS) summary statistics for magnetic resonance imaging (MRI) markers of WM integrity, including WM hyperintensities, fractional anisotropy (FA), and mean diffusivity (MD). These scores were utilized to predict age-related cognitive changes and evaluate their correlation with structural brain changes, which distinguish individuals with higher and lower cognitive scores. To reduce the dimensionality of the data and identify age-related DNA methylation and transcriptomic alterations, Sparse Partial Least Squares-Discriminant Analysis (sPLS-DA) was used. Subsequently, a canonical correlation algorithm was used to integrate the three types of omics data (PRS, DNA methylation, and gene expression data) and identify an individual "omics" signature that distinguishes subjects with varying cognitive profiles. RESULTS: We found a positive association between MD-PRS and long-term memory, as well as a correlation between MD-PRS and structural brain changes, effectively discriminating between individuals with lower and higher memory scores. Furthermore, we observed an enrichment of polygenic signals in genes related to both vascular and non-vascular factors. Age-related alterations in DNA methylation and gene expression indicated dysregulation of critical molecular features and signaling pathways involved in aging and lifespan regulation. The integration of multi-omics data underscored the involvement of synaptic dysfunction, axonal degeneration, microtubule organization, and glycosylation in the process of cognitive aging. CONCLUSIONS: These findings provide valuable insights into the biological mechanisms underlying the association between WM coherence and cognitive aging. Additionally, they highlight how age-associated DNA methylation and gene expression changes contribute to cognitive aging.

Candida: The Ruthless Opportunist.

Spondylodiscitis is a pathology with a devastating potential for functional limitation in patients, which may involve immobilization for months due to the risk of compression or even spinal cord section. It is a rare type of infection occurring in the vertebrae and discs of the spine, and most are bacterial. Fungal cases are rare. We present the clinical case of a 52-year-old female patient with a past medical history of vesicular lithiasis and degenerative disc disease of the cervical spine and no home medication. The patient was hospitalized in the surgery service for about 3.5 months due to necro-hemorrhagic lithiasic pancreatitis that evolved into septic shock and needed organ support in intensive care for 2.5 weeks. Several cycles of antibiotics and endoscopic retrograde cholangiopancreatography (ERCP) with stent placement were performed. She was readmitted for urgent care to the hospital of residence with fever, sweating, and low back pain with sciatica five days after discharge. Lumbar CT and MRI evidence showed the destruction of about two-thirds of the vertebral bodies L3-L4, L5-S1, and adjacent discs, pointing to the diagnosis of infectious spondylodiscitis. Candida albicans was found in blood cultures and lumbar biopsies. The patient was treated with oral fluconazole 400 mg/day for eight months, and the control MRIs showed slow but favorable bone sclerosis over time. She spent a total of 13.5 months in the hospital, including five months in bedbound status. The patient left the hospital walking without any assistance, with an upright mood and disposition. The most likely main fungal infectious factors were the manipulation of the bile ducts, immunosuppression associated with corticosteroid therapy, and multiorgan septic failure. The authors highlight this clinical case for its rarity, complications leading to candidemia, diagnostic and therapeutic delay, complexity, and risk of irreversible injuries to which the patient was subjected. The total recuperation of the patient after such a long physical and emotional struggle was very gratifying.

Translation and Cross-Cultural Adaptation of Quality of Life Scale in Patients with Onychomycosis.

(1) Background: Onychomycosis (OM) is a fungal nail infection, considered a risk factor for diabetic foot ulcers. It is associated with changes in quality of life, in terms of pain, self-confidence and self-esteem. The aim was to translate and adapt the OM quality of life questionnaire "OnyCOE-tTM-Quality Of Life Questionnaire Onychomycosis (Nail Fungal Condition)". (2) Methods: This study followed the guidelines proposed by Beaton et al. (2000), where two English to Portuguese translations were performed and, after an expert consensus, a common version was obtained. This was followed by two back-translations. The expert committee achieved semantic equivalence, idioms and concepts. The pre-test was applied to 49 people. The final version and processed data were sent to the authors. (3) Results: We adapted terms semantically, modified statements syntactically, altering items from interrogative to affirmative. (4) Conclusions: The translated version of the "Quality of life-Onychomycosis" questionnaire suggested that it can be used for further studies to test validity and reliability in this population.

Quality of life and therapeutic regimen management in onychomycosis patients and in vitro study of antiseptic solutions.

Onychomycosis or tinea unguium (EE12.1) and Onychomycosis due to non-dermatophyte moulds (1F2D.5) (OM) is a fungal infection of the nail plates with a high prevalence that often affects vulnerable people with co-existing health problems. Gold standard pharmacological treatments for onychomycosis have been associated with low success rates and increasing antifungal resistance, suggesting that treatment outcome is dependent on multiple variables. Here, the prevalence of OM and quality of life were characterized in two vulnerable populations-Hospital patients and Homeless people. Comparing both groups, the most prevalent fungal species were identified in Hospital patients. Then, the in vitro fungicidal properties of the antiseptics povidone-iodine, polyhexamethylene biguanide-betaine, octenidine dihydrochloride, and a super-oxidized solution against two ATCC strains (Candida albicans and Aspergillus niger) and three clinical fungal isolates from Hospital patients (Candida parapsilosis, Trichophyton interdigitale, and Trichophyton rubrum) were tested. OM prevalence was high in both patient groups studied, who also reported a reduction in quality of life and concerns about the state of their feet. In addition, Hospital patients had a non-negligent therapeutic regimen management style. Antiseptics tested in vitro revealed antifungal properties. As antiseptics are low-cost and easy to apply and have few iatrogenic effects, the demonstration of fungicidal properties of these solutions suggests that they may constitute potential supportive therapeutics for OM.

NT-pro-BNP correlates with disease severity and predicts outcome in cerebral haemorrhage patients: Cohort study.

BACKGROUND: Intracerebral haemorrhage (ICH) is a devastating condition, with more than half of patients dying or becoming dependent after such an event. Natriuretic peptides, frequently used in the management of heart failure, have been shown to correlate with disease severity and prognosis in brain disorders. The aim of this study was to test the hypothesis that NT-pro-BNP correlates with disease severity and is an independent prognostic marker for non-traumatic ICH patients. METHODS: A consecutive sample of 201 non-traumatic ICH patients, who were non-comatose on admission and medically treated in a stroke unit, were evaluated for in-hospital mortality and three-month functional dependency (modified Rankin Scale >2). NT-pro-BNP measurement was performed after admission. Independent predictors of the outcomes in study were assessed using logistic regression and the incremental value of NT-pro-BNP on three previously validated severity scores was evaluated using the variation in C-statistic (Δc). Values of p < .05 were considered significant. RESULTS: In-hospital mortality rate was 8.0%, and 40.3% of patients achieved good functional outcome. NT-pro-BNP correlated with hematoma volume (r = 0.186) and amount of intraventricular blood (r = 0.240). Higher levels of NT-pro-BNP were independently associated with death (Expß = 1.650) and functional dependency (Expß = 1.449). NT-pro-BNP increased the discrimination of the ICH-GS for mortality prediction (Δc = 0.043) and of FUNC and ICH scores for functional outcome prediction (Δc = 0.060 and 0.055 respectively). Admission NT-pro-BNP levels were independently associated with hematoma size. CONCLUSIONS: NT-pro-BNP is an independent prognostic factor for low-risk non-traumatic ICH patients and a valid marker of disease severity in this patient population.

Distinctive CD8+ T cell and MHC class I signatures in polycythemia vera patients.

Polycythemia vera (PV) is a myeloproliferative neoplasm characterized by overproduction of red blood cells. We have performed a comprehensive characterization of blood immune cells for expression of naïve and memory receptors as well as ß2m-associated and ß2m-free MHC class I heavy chains, also known as closed and open conformers, respectively, in PV patients and age-matched controls (CTR). We show that the peripheral CD3+CD8+ T cell pool in PV patients is clearly divided into two discrete populations, a more granular CD3+CD8high T cell population enriched in effector-memory CD45RA+ T cells (CD8+ TEMRA) when compared to CTR (P < 0.001), and a less granular CD3+CD8int T cell population that is completely absent in the CTR group (78 vs. 0%, P < 0.001) and is a mixture of naïve (CD8+ TN) and CD8+ TEMRA cells expressing intermediate levels of CD28, i.e., CD3+CD8intCD28int. While the percentage of CD3+CD8int TN cells correlated positively with the number of erythrocytes, the percentage of CD3+CD8int TEMRA correlated negatively with the number of platelets. Finally, we report that PV patients' lymphocytes and monocytes display lower levels of closed (W6/32+) MHC-I conformers at the cell surface while exhibiting increased amounts of open (HC-10+) MHC-I conformers. The implications of this distinctive immune signature are discussed.

A rocky planet transiting a nearby low-mass star.

M-dwarf stars--hydrogen-burning stars that are smaller than 60 per cent of the size of the Sun--are the most common class of star in our Galaxy and outnumber Sun-like stars by a ratio of 12:1. Recent results have shown that M dwarfs host Earth-sized planets in great numbers: the average number of M-dwarf planets that are between 0.5 to 1.5 times the size of Earth is at least 1.4 per star. The nearest such planets known to transit their star are 39 parsecs away, too distant for detailed follow-up observations to measure the planetary masses or to study their atmospheres. Here we report observations of GJ 1132b, a planet with a size of 1.2 Earth radii that is transiting a small star 12 parsecs away. Our Doppler mass measurement of GJ 1132b yields a density consistent with an Earth-like bulk composition, similar to the compositions of the six known exoplanets with masses less than six times that of the Earth and precisely measured densities. Receiving 19 times more stellar radiation than the Earth, the planet is too hot to be habitable but is cool enough to support a substantial atmosphere, one that has probably been considerably depleted of hydrogen. Because the host star is nearby and only 21 per cent the radius of the Sun, existing and upcoming telescopes will be able to observe the composition and dynamics of the planetary atmosphere.