Federal University of Health Sciences of Porto Alegre

Despite invasive methods are the gold standard for intracranial pressure (ICP) measurement, several non-invasive techniques (nICP) have been proposed as surrogate, although their use remains insufficiently recognized in clinical practice. These include transcranial Doppler blood flow velocity assessment (arterial or venous), optic nerve sheath diameter (ONSD), automated pupillometry, measurement of skull expansion and compliance, brain imaging, double-depth ophthalmic artery blood flow velocity, and ultrasound time-of-flight. The main limitations of all indirect methods are calibration and zeroing, which constrain the absolute accuracy of non-invasive ICP monitoring. For transcranial Doppler-based methods, the 95

Cocaine remains one of the most widely consumed illicit drugs globally, representing a significant public health challenge. While its acute reinforcing effects are mediated by the facilitation of dopaminergic and serotonergic neurotransmission, chronic exposure leads to pervasive neurobiological adaptations and systemic toxicity. Beyond its psychoactive properties, cocaine exerts multifaceted cytotoxic effects across several organ systems, including the brain, heart, and liver, primarily through the induction of oxidative stress, mitochondrial dysfunction, and the activation of apoptotic pathways. This review provides a comprehensive analysis of these cellular and molecular mechanisms and introduces novel evidence regarding the toxicological impact of seized cocaine. Original in vitro data demonstrate that the association of cocaine with common adulterants, levamisole, phenacetin, and caffeine, markedly exacerbates cytotoxicity through synergistic interactions. Furthermore, this review examines the pivotal role of the sigma-1 receptor (σ1R) in cocaine-induced toxicity, supported by molecular docking analyses that characterize specific interactions between the cocaine, adulterants, and conserved receptor residues. This receptor-mediated framework suggests a central mechanism contributing to the drug’s combined toxic and reinforcing properties. Collectively, these findings integrate experimental, computational, and literature-based evidence to offer a broader mechanistic understanding of cocaine-induced toxicity and its modulation by adulterants, providing compelling evidence for the role of σ1R in these cytotoxic processes.

Breast cancer (BC) remains a leading cause of morbidity and mortality worldwide, and while cytotoxic chemotherapy is essential for disease control, it is frequently accompanied by systemic toxicities that may compromise patient quality of life and long-term outcomes. In this study, we investigated the interplay between metabolic, redox, and inflammatory biomarkers in BC patients undergoing anthracycline- and taxane-based chemotherapy. Our findings revealed a constellation of alterations, including a pro-atherogenic lipid profile with elevated total cholesterol, triglycerides, and LDL-c alongside reduced HDL-c; evidence of oxidative stress characterized by increased malondialdehyde (MDA) and nitric oxide (NO) levels with concomitant depletion of glutathione (GSH) and partial compensatory catalase activity; and a chronic low-grade inflammatory state marked by elevated IL-6 and TNF-α. Anthropometric measures further supported this profile, as patients presented higher rates of overweight, obesity, and central adiposity, which may contribute to metabolic and inflammatory imbalance. Together, these findings suggest the presence of a cardiometabolic vulnerability profile in breast cancer patients undergoing chemotherapy, reflecting the combined influence of treatment-related and baseline metabolic factors. From a translational perspective, the integration of routinely available biomarkers—lipid fractions, oxidative stress indicators, and inflammatory cytokines may provide a practical framework to characterize this vulnerability. However, given the cross-sectional design and limited sample size, these findings should be interpreted as exploratory and hypothesis-generating. Further prospective studies with larger cohorts and inclusion of cardiovascular endpoints are required to determine the clinical utility of these biomarkers in potential risk assessment and patient management.

BACKGROUND AND AIMS:The burden of metabolic dysfunction-associated steatohepatitis (MASH) cirrhosis is rapidly rising globally. There are several therapeutic agents under clinical development for the treatment of cirrhosis due to MASH; however, their relative efficacy has not been systematically assessed. This systematic review and network meta-analysis was performed to compare the histological efficacy of available therapeutic agents for compensated MASH cirrhosis. METHODS:PubMed and Cochrane Library databases were searched from inception to May 25, 2025, for randomised controlled trials (RCTs) evaluating pharmacological treatments in patients with biopsy-proven compensated MASH cirrhosis (F4c). The primary endpoint was fibrosis regression of at least one stage without MASH worsening, and the secondary endpoint was MASH resolution. Treatment comparisons were conducted via network meta-analysis, and ranking probabilities were estimated using the surface under the cumulative ranking (SUCRA) curve analysis. RESULTS:Nine RCTs with 3266 participants met the eligibility criteria. Efruxifermin was the only intervention significantly superior to placebo for ≥ 1-stage fibrosis improvement without worsening of MASH. The highest-ranked interventions for fibrosis improvement were efruxifermin (SUCRA: 77.44), cilofexor + firsocostat (SUCRA: 72.38) and aldafermin (SUCRA: 71.27). For MASH resolution, efruxifermin, semaglutide + cilofexor + firsocostat and semaglutide were significantly superior to placebo. Efruxifermin (SUCRA: 81.38), semaglutide + cilofexor + firsocostat (SUCRA: 74.07) and semaglutide (SUCRA: 63.88) had the highest probability of ranking best for MASH resolution. CONCLUSION:This network meta-analysis provides relative rank-order estimates of the histological efficacy of available pharmacological therapies for compensated MASH cirrhosis. These data may have implications for the design of future clinical trials.

AIM:To evaluate the effects of tirzepatide on physical function in adults with overweight or obesity. METHODS:We searched PubMed, Embase, and the Cochrane Library up to July 20, 2025 for randomized controlled trials (RCTs) comparing once-weekly tirzepatide 10 or 15 mg with placebo and reporting validated physical function outcomes. Primary endpoints were changes from baseline in the 36-Item Short Form Health Survey (SF-36) physical function domain and in the Impact of Weight on Quality of Life-Lite Clinical Trials (IWQOL-Lite-CT) physical function subscale. Random-effects models were used to calculate pooled mean differences (MD) with 95% confidence intervals (CI). Heterogeneity was assessed with I2 statistics. RESULTS:Six RCTs comprising 4531 participants, of whom 2802 underwent tirzepatide treatment were included. Tirzepatide significantly improved physical function compared with placebo, both in SF-36 physical function (MD 2.26 points; 95% CI, 1.76-2.76; I2 = 99.8%; p < 0.001) and IWQOL-Lite-CT physical function (MD 10.10 points; 95% CI, 8.61-11.60; I2 = 99.8%; p < 0.001). Subgroup analyses by dose demonstrated consistent benefits for both 10 and 15 mg groups. The overall certainty of evidence, rated by GRADE, was moderate due to risk of bias and inconsistency across studies. CONCLUSIONS:Tirzepatide 10 and 15 mg once weekly significantly improve patient-reported physical function in adults with overweight or obesity. These findings suggest tirzepatide enhances perceived physical capacity and quality of life, although the extremely high between-study heterogeneity limits the interpretability of pooled estimates and warrants cautious interpretation.