ABSTRACT Introduction Interindividual variability in drug response remains a significant clinical challenge, leading to therapeutic failure and toxicity. Much of this variability is unexplained by classical host-centric pharmacokinetic (PK) models, highlighting a critical gap in understanding of drug disposition. This review addresses this gap by establishing the gut microbiome as an important determinant of drug fate. Areas covered This narrative review with scoping approach examines how microbial enzymes affect therapeutics through comprehensive analysis of mechanistic and clinical studies. Key examples discussed include irinotecan, digoxin, and sulfasalazine. We highlight specific situations where the influence of gut bacteria is particularly significant, such as with low-bioavailability drugs and in patients with an ileocolonic anastomosis, where gut bacteria directly impact drug absorption and metabolism. Additionally, we address the limitations of current PK models and explore the potential of new integrated approaches. Expert opinion We propose that the gut microbiome should be recognized as a ‘fifth pillar’ of PKs. This shift in perspective is crucial for advancing personalized medicine. In this new model, a ‘PK profile card’ integrating microbial, genomic, and clinical data will help guide dosing. We anticipate microbiome analysis to become a standard clinical tool to optimize drug efficacy and safety.

Abstract Introduction Emergent intracranial stenting (EIS) is increasingly employed in the context of the acute ischaemic stroke treatment, but requires intraprocedural antiplatelet therapy (APT), which may raise haemorrhagic risk. This study aimed to evaluate the safety and effectiveness of different APT regimens during EIS. Patients and methods This is a subanalysis of the RESISTANT registry, which is a multicenter retrospective registry of patients with acute ischaemic stroke treated with intracranial EIS between 2016 and 2023. Patients receiving intraprocedural antithrombotics were included. Primary efficacy outcomes were stent patency (intraprocedural and within 24 hours) and 3-month mRS. Secondary outcome was successful reperfusion (modified thrombolysis in cerebral infarction ≥ 2b), and the safety outcome was sICH. Multivariable and propensity score-matched analyses were performed. Results Among 827 patients, 4 APT strategies were identified: single APT (n = 102), oral dual antiplatelet therapy (dAPT) (Aspirin + Clopidogrel or Ticagrelor; n = 83), Cangrelor (n = 92) and GP IIb/IIIa inhibitors (GPi) (n = 550). Intravenous agents (Cangrelor/GPi) showed a trend towards lower risk of intraprocedural stent occlusion compared to oral dAPT (adjusted odds ratio [aOR] 0.30, [95% CI, 0.09–1.01], P = .053), though this did not reach statistical significance. GP IIb/IIIa inhibitors continued to demonstrate a protective trend at 24 hours (aOR 0.25, [95% CI, 0.06–0.99], P = .047), without a significant increase in sICH. Both intravenous agents were independently associated with higher odds of successful final reperfusion (odds ratio [OR] 4.35, [95% CI, 1.57–12.09], P = .001). No significant differences emerged between GPi and Cangrelor in matched analysis. No significant difference was observed on good functional outcome between APT strategies. Conclusion In the setting of EIS, intravenous APT agents (Cangrelor or GPi) were associated with improved stent patency and higher rates of successful reperfusion, without a significant increase in symptomatic haemorrhage.

Abstract Rationale Intra-arterial fibrinolytics may be used for distal remaining vessel occlusions after incomplete mechanical thrombectomy (MT). However, their efficacy in improving reperfusion in this specific clinical scenario is unclear. While better reperfusion may lead to improved clinical outcomes, additional fibrinolytics could also increase the risk of hemorrhagic complications. Aim To assess the safety and reperfusion efficacy of intra-arterial tenecteplase (TNK) compared to no further interventional treatment in patients with incomplete reperfusion and mechanically non-amendable residual occlusions after MT. Methods and design This is an international, multicenter, randomized (1:1) controlled, two-arm, open, assessor-blinded, surrogate endpoint trial. The interventional arm receives 3 mg (not weight-adjusted) intra-arterial TNK, administered as close as possible to the residual occlusion. The control arm receives no further interventional treatment. Sample size TECNO will randomize 156 participants 1:1 to 3 mg intra-arterial tenecteplase or no further interventional treatment. This sample size is based on anticipated absolute improvements in early and late reperfusion with intra-arterial TNK of 25% and 30%, respectively. Outcomes The two co-primary imaging outcomes are early and late reperfusion. Early reperfusion is defined as an extended Thrombolysis in Cerebral Infarction (eTICI) score ⩾ 2a for residual occlusions on angiography 25 min after randomization. Late reperfusion is defined as the absence of a wedge-shaped perfusion delay on delay-sensitive perfusion maps assessed on 24 h ± 6 h perfusion imaging. Standard secondary clinical outcomes will be assessed at 24 h and 90 ± 15 days. Discussion The TECNO trial will provide evidence on the safety and reperfusion efficacy of locally administered intra-arterial TNK in patients with residual occlusions following MT.

Abstract Background The no-reflow phenomenon, characterized by impaired microvascular reperfusion despite successful macrovascular recanalization, has been identified as a potential contributor to poor outcomes in acute ischemic stroke (AIS) treated with endovascular therapy (EVT). This systematic review and meta-analysis aimed to assess the prevalence and clinical impact of no-reflow phenomenon in AIS patients undergoing EVT. Methods We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) and observational studies reporting the no-reflow phenomenon after EVT. Databases searched included PubMed, Embase, and CENTRAL (inception to February 9, 2025). Outcomes included no-reflow prevalence, functional outcomes (mRS), early neurological recovery, infarct volume, hemorrhagic complications, and 90-day mortality. Pooled risk ratios (RR) or mean differences (MD) were calculated using random-effects meta-analysis, and heterogeneity was assessed with I2. Results Eight studies (n = 1483 patients) were included. The pooled prevalence of no-reflow was 20.5% (95% CI 6.2%–49.9%; I2 = 96.9%). Compared with controls, patients with no-reflow had reduced early neurological recovery (RR 0.76; 95% CI 0.64–0.90) and increased risk of hemorrhagic transformation (RR 1.82; 95% CI 1.18–2.79) and symptomatic intracranial hemorrhage (RR 1.88; 95% CI 1.00–3.56). Differences in functional independence (mRS 0–2) and mortality were not statistically significant. Subgroup analyses based on study design revealed divergent patterns, particularly for infarct volume, which was significantly greater in no-reflow patients in post-hoc RCTs but not in the overall analysis. Conclusion No-reflow affects one in five EVT-treated patients and is associated with adverse neurological and hemorrhagic outcomes. Findings highlight the need for standardized definitions and prospective trials to clarify its clinical impact.

Abstract Introduction Covert brain infarctions (CBIs) are associated with cardiovascular risk factors (cvRFs). We aimed to evaluate the presence and therapeutic implications of modifiable cvRFs in patients with incidentally discovered CBI on routine neuroimaging. Patients and methods The SILENT cohort (NCT05685069) is a prospective, multicentred European cohort recruiting patients with incidentally detected focal CBIs on routine MRI, without prior clinical stroke. Modifiable cvRFs and their control were assessed using applicable international guidelines during a dedicated outpatient visit, including a clinical examination and laboratory work-up. Associations between cvRF profiles and the number of CBIs were analysed using linear regression. Results We included 231 patients (mean age 65 years, n = 130 [56%] male) with a total of 445 CBI lesions. Most CBIs were of lacunar type (n = 226; 51%) and the most common location was the cerebellum (n = 220; 50%). One hundred and fifty (65%) patients had at least 1, 112 (49%) at least 2 and 56 (24%) at least 3 known modifiable cvRFs. Among hypertensive patients, 69 (53%) had uncontrolled hypertension; 22 (65%) of diabetics were insufficiently controlled and 74 (58%) patients with dyslipidaemia had poorly controlled low-density lipoprotein cholesterol. Therapeutic measures were made for 144 patients (62%), including antiplatelet initiation in 107 (46%) and a statin in 69 (30%). The number of cvRFs per patient was significantly associated with the number of CBIs, rate ratio 1.08 (95% Confidence Interval (CI), 1.04−1.13). Conclusion In patients with incidentally discovered CBI, we found a high burden of poorly controlled cvRFs. Our findings highlight the importance and yield of a dedicated clinical and laboratory assessment of cvRFs in patients with CBIs.

Background/Objectives: Forensic DNA phenotyping (FDP) enables the prediction of externally visible characteristics (EVCs) such as eye, hair, and skin color, ancestry, and age from biological traces. However, low template DNA (LT-DNA), often derived from degraded or trace samples, poses significant challenges due to allelic dropout, contamination, and incomplete profiles. This review evaluates recent advances in FDP from LT-DNA, focusing on the integration of machine learning (ML) models to improve predictive accuracy and operational readiness, while addressing ethical and population-related considerations. Methods: A comprehensive literature review was conducted on FDP and ML applications in forensic genomics. Key areas examined include SNP-based trait modeling, genotype imputation, epigenetic age estimation, and probabilistic inference. Comparative performance of ML algorithms (Random Forests, Support Vector Machines, Gradient Boosting, and deep learning) was assessed using datasets such as the 1000 Genomes Project, UK Biobank, and forensic casework samples. Ethical frameworks and validation standards were also analyzed. Results: ML approaches significantly enhance phenotype prediction from LT-DNA, achieving AUC > 0.9 for eye color and improving SNP recovery by up to 15% through imputation. Tools like HIrisPlex-S and VISAGE panels remain robust for eye and hair color, with moderate accuracy for skin tone and emerging capabilities for age and facial morphology. Limitations persist in admixed populations and traits with polygenic complexity. Interpretability and bias mitigation remain critical for forensic admissibility. Conclusions: L integration strengthens FDP from LT-DNA, offering valuable investigative leads in challenging scenarios. Future directions include multi-omics integration, portable sequencing platforms, inclusive reference datasets, and explainable AI to ensure accuracy, transparency, and ethical compliance in forensic applications.

Objectives The COVID-19-associated hyperinflammatory syndrome (cHIS) score has been proposed as a tool for identifying patients at risk of clinical deterioration. This study evaluated the predictive accuracy of the admission cHIS score for invasive mechanical ventilation and ICU mortality in critically ill COVID-19 patients. Methods We conducted a single-center retrospective observational study including 85 adults with laboratory-confirmed COVID-19 who were admitted to the ICU. The cHIS score was calculated on admission, and patients were stratified into two groups (<3 and ≥3). Associations with mechanical ventilation and ICU mortality were examined using ROC curve analysis and multivariable logistic regression, adjusted for age and comorbidity burden. Results An admission cHIS score ≥3 demonstrated moderate discrimination for ICU mortality (AUROC = 0.70; sensitivity = 0.76; specificity = 0.66) and mechanical ventilation (AUROC = 0.71; sensitivity = 0.73; specificity = 0.65). Higher cHIS scores were significantly associated with both outcomes in unadjusted analyses. After adjustment, the associations were attenuated and became borderline for mortality and mechanical ventilation, suggesting potential confounding by age and underlying comorbidities. Key inflammatory markers within the cHIS score—CRP, LDH, and D-dimer—showed the strongest individual associations with adverse outcomes. Kaplan–Meier analysis demonstrated significantly reduced survival probabilities in patients with cHIS ≥3. Conclusion The admission cHIS score reflects the degree of systemic hyperinflammation and is associated with greater illness severity, ICU mortality, and the need for mechanical ventilation. Although its predictive value diminishes after adjusting for age and comorbidities, the score remains a useful adjunct for early risk stratification in critically ill COVID-19 patients. Larger multicenter studies are needed to determine its independent prognostic utility.

Background and Objectives: Diabetes mellitus (DM) is a major risk factor for cardiovascular diseases (CVD), including acute myocardial infarction (MI), and is frequently associated with cardiac autonomic neuropathy (CAN). Post-MI autonomic dysfunction contributes to adverse outcomes, but data on prognostic markers in diabetic patients remain limited. This study aimed to (1) compare autonomic nervous system (ANS) function between patients with MI and DM (MI/DM), MI without DM, and DM without MI; (2) assess differences in MI/DM patients based on survival status; and (3) identify prognostic factors for all-cause mortality in diabetic patients following MI. Materials and Methods: This retrospective–prospective study included 375 patients: 93 MI/DM, 229 MI, and 53 DM. MI patients were treated with fibrinolytic or conservative therapy. All participants underwent cardiovascular reflex tests (CARTs) and 24 h Holter ECG with heart rate variability (HRV) analysis; DM patients without MI were tested in an outpatient setting. The primary endpoint was all-cause mortality during a median follow-up of 38 months. Univariable and multivariable Cox regression analyses were performed to determine mortality predictors. Results: Autonomic dysfunction was prevalent in all groups, with MI/DM patients showing the most pronounced impairment, particularly in parasympathetic function. MI/DM patients had significantly lower SDNN values and higher prevalence of definite parasympathetic dysfunction than other groups. In the MI/DM group, abnormal Valsalva maneuver (VM) was more frequent among non-survivors. Multivariable analysis identified abnormal VM and NSTEMI as predictors of overall mortality. Conclusions: Diabetic patients after MI exhibit the most severe autonomic impairment, predominantly parasympathetic, which may contribute to their increased cardiovascular risk. In this high-risk group, abnormal VM and NSTEMI presentations independently predict long-term mortality. Assessment of autonomic function, particularly VM, may provide valuable prognostic information and aid in risk stratification.

AIM The aim of this study was to evaluate the impact of hospital antibiotic consumption on the rate of antimicrobial resistance (AMR) of gram-negative bacteria, specifically the Enterobacteriaceae family and the genus Acinetobacter, in the University Clinical Center (UCC) Tuzla, Bosnia and Herzegovina. METHODS A five-year retrospective, observational, pharmacoepidemiological study was conducted (2014 to 2018). Antibiotic consumption was calculated using the WHO Anatomical Therapeutic Chemical/defined daily dose (ATC/DDD) methodology and expressed as DDD per 100 bed-days (BD). Microbiological data were obtained for Klebsiella pneumoniae, Escherichia coli, Proteus mirabilis, and Acinetobacter species. The temporal associations between consumption and resistance were analyzed using linear regression and autoregressive integrated moving average (ARIMA) models. RESULTS The total antibiotic consumption at UCC Tuzla significantly increased from 61.35 to 73.51 DDD/100 BD (p=0.003). Consumption in intensive care units (ICUs) was significantly higher than the hospital-wide average (p<0.001), reaching up to 178.53 DDD/100 BD. ARIMA modeling confirmed significant positive correlations between the use of fluoroquinolones (J01MA) and resistance in Acinetobacter baumannii (beta = 7.678, p=0.006) and K. pneumoniae (beta = 18.368, p<0.001)9. A similar correlation was found for carbapenems (J01DD) and E. coli resistance (beta = 14.066, p=0.004). CONCLUSION The study demonstrates a significant temporal association between the volume of broad-spectrum antibiotic consumption and the escalation of AMR. The high selective pressure in ICUs identifies these units as primary reservoirs for multidrug-resistant pathogens. These findings highlight the importance of multidisciplinary antimicrobial stewardship programs and restricted use of reserve antibiotics to preserve therapeutic efficacy.

The 3ω technique is a prominent thermal conductivity measurement methodology for thin films, substrates, nanowires, and thermal boundary conductance. The extraction of the thermal conductivity typically relies on measuring the thermal response across a wide range of frequencies and determining the slope within acceptable limiting conditions, which can be a time-consuming process prone to error from the amplification of noise when taking the derivative of discrete temperature data to determine thermal conductivity. Here, we develop and demonstrate a frequency-modulated 3ω method (FM-3ω) with which we directly measure the derivative of the 3ω signal by varying the center frequency ω, eliminating the need to postprocess the data, thereby reducing the time to take such measurements from hours to minutes. Our modulation approach is a frequency modulation method in which the frequency ω of the excitation current is sinusoidally varied over time. We show that our new method produces results with similar accuracy to the traditional method on bulk sapphire and borofloat 33 samples, and we further explore the limitations of modulation depth and center frequency on the results. We find that thermal conductivity measurements from the FM-3ω method agree well with thermal conductivities extracted through linear fits to temperature data over similar frequency windows of the traditional method. Our method provides a new strategy using frequency modulation and tandem demodulation to directly measure the derivative of temperature, thus contributing to the advancement of thermal transport sciences by increasing the ease and pace of measuring the thermal conductivity of thin films and multilayer structures.

Perfluorohexyloctane (F6H8) is a semifluorinated alkane recently approved for ophthalmic treatment of dry eye disease. Although considered locally safe for topical use, its structural similarity to persistent per- and polyfluoroalkyl substances (PFAS) raises concerns about systemic accumulation and long-term toxicity. To investigate potential hepatic effects, we examined the metabolic impact of F6H8 exposure in human HepaRG hepatocytes across a broad concentration range representing short- and long-term exposure scenarios. Combined targeted and untargeted metabolic profiling by ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-QTOFMS) was performed on intracellular extracts and extracellular media. F6H8 induced pronounced, concentration-dependent metabolic alterations, many of which exhibited non-monotonic responses. Low concentrations primarily affected amino acid, fatty acid, and lipid metabolism, while central carbon metabolism was disrupted only at the highest exposures. Notably, a putative biotransformation product, perfluorohexyloctanoic acid, was detected, suggesting metabolic persistence and conversion to a PFAS-like structure. This metabolite showed strong associations with cellular metabolic profiles and elicited metabolic changes that only partially overlapped with those induced by the parent compound, indicating distinct biological activity following biotransformation. These findings indicate that F6H8 elicits broad metabolic reprogramming and may not be metabolically inert as previously assumed. Given its clinical use and structural similarity to persistent fluorochemicals, the results highlight the need for comprehensive, long-term safety assessment of F6H8 and related semifluorinated alkanes.

Summary Background Data on cancer incidence and associated risk factors among women with HIV are limited. We investigated cancer burden among women with HIV. Methods We included all women ≥18 years from the two large multicentre observational cohort collaborations (D:A:D and RESPOND). The primary outcomes were incidence of all cancers, HPV-related and common individual cancers including breast cancer, lung cancer, and non-Hodgkin lymphoma (NHL) from 2006 to 2021. Baseline was defined as the latest date of entry into local cohort enrolment and 1st January 2006 for D:A:D and 1st January 2012 for RESPOND. Participants were followed from baseline until the date of first cancer, final follow-up or administrative censoring—whichever occurred first. We assessed risk factors using multivariable Poisson regression by applying robust standard errors and determined a population attributable fraction (PAF) for key risk factors for cancers. Findings Among 17,512 women included, median age at baseline was 39.5 years (interquartile range, IQR 32.5–46.0). Over 141,404 person-years (PYS) and a median 9.2 (5.5–10.1) years of follow-up, 832 women were diagnosed with any cancer; incidence rate 5.9 (95% CI 5.5–6.4)/1000 PYS, 163 HPV-related cancers (1.1 [1.0–1.3]/1000 PYS), 150 breast cancers (1.1 [0.9–1.2]/1000 PYS), 94 lung cancers (0.7 [0.5–0.8]/1000 PYS) and 72 NHL (0.5 [0.4–0.6]/1000 PYS). Older age (≥45 vs. <45 years), Southern Europe (vs. Western Europe) and smoking were associated with an increased risk of overall cancers. Lower pre-ART nadir CD4, time-updated CD4, and a prior AIDS diagnosis were associated with lung- and HPV-related cancer. In PAF analysis, smoking and HIV-related factors such as lower current CD4, nadir CD4 and HIV viremia significantly contributed to cancer risk. Interpretation Our findings suggest that women with HIV older than 45 years, past or current immunosuppressed or current smokers could be candidates for intensified cancer screening and prevention. Funding The Highly Active Antiretroviral Therapy Oversight Committee, The CHU St Pierre Brussels HIV Cohort, The Austrian HIV Cohort Study, The Australian HIV Observational Database, The AIDS Therapy Evaluation in the Netherlands national observational HIV cohort, The Brighton HIV Cohort, The National Croatian HIV Cohort, The EuroSIDA cohort, The Frankfurt HIV Cohort Study, The Georgian National AIDS Health Information System, The Nice HIV Cohort, The 10.13039/100025411Isabel Foundation, The Modena HIV Cohort, The PISCIS Cohort Study, The Swiss HIV Cohort Study, The Swedish InfCare HIV Cohort, The Royal Free HIV Cohort Study, The San Raffaele Scientific Institute, The University Hospital Bonn HIV Cohort, The University of Cologne HIV Cohort, Merck Life Sciences, 10.13039/100010877ViiV Healthcare, and Gilead Sciences.