Citations

Due to extensive pathophysiological changes in critically ill patients, standard dosing of antibiotics may lead to inadequate drug exposure. This is concerning, as insufficient plasma drug concentrations may lead to treatment failure, whereas excessive drug exposure may increase the risk of toxic adverse events. The role of inflammation as a factor influencing the pharmacokinetics (PK) and pharmacodynamics (PD) of antibiotics remains largely unknown. PK/PD target attainment of antibiotics can be improved through therapeutic drug monitoring, i.e., measurement of drug concentrations in the blood with subsequent dosage adjustment to reach a certain target. Besides, population PK models may be used to predict drug exposure and tailor dosing in an individual patient (model‐informed precision dosing). Inflammatory biomarkers have been proposed to measure inflammation levels and guide antibiotic treatment. However, their potential to guide antibiotic dosing is unclear. This narrative review describes associations between inflammation and PK/PD of antibiotics in critically ill patients, and the role of biomarkers, therapeutic drug monitoring and model‐informed precision dosing in improving antibiotic dosing. A focus of future research should be on the interplay between inflammation and PK/PD of antibiotics by including inflammatory biomarkers in PK/PD models and using big data to predict antibiotic exposure in critically ill patients.

Abstract INTRODUCTION We investigated associations of plasma proteins with blood‐based amyloid/tau/neurodegeneration/inflammation (A/T/N/I) biomarkers for Alzheimer's disease (AD). METHODS Plasma proteomics and clinical data from the Indiana AD Research Center ( N = 498) were used. Association analysis of plasma proteins with blood A/T/N/I biomarkers as well as diagnosis was performed, followed by replication in an independent cohort ( N = 323), network analysis, pathway enrichment, and machine learning classification to identify proteins and pathways related to AD risk. RESULTS We identified 35 proteins associated with AD, 20 of which were replicated in the independent cohort. We identified 150, 448, and 219 proteins associated with T/N/I biomarkers, respectively, revealing biomarker‐specific pathways. Network analysis identified two modules associated with T/N/I biomarkers, preserved in cerebrospinal fluid (CSF), and their enriched pathways. The classification model of proteins effectively differentiated AD (area under the curve [AUC] = 0.930). CONCLUSION Our findings suggest dysregulated plasma proteins and pathways in AD, enhancing our understanding of molecular mechanisms and diagnostic strategies for AD. Highlights Plasma proteins were identified as being associated with Alzheimer's disease (AD) and plasma biomarkers. The identified proteins were replicated in both plasma and cerebrospinal fluid (CSF) proteomics. The identified proteins were associated with AD biomarker‐specific pathways. The identified proteins improved the performance of the AD classification. Protein network analysis identified network modules and their enriched pathways.

ABSTRACT Objective Despite the availability of approved treatments, a substantial proportion of patients with bipolar disorder experience treatment‐resistant bipolar depression (TRBD), characterized by persistent depressive symptoms unresponsive to standard therapies. However, a universally accepted definition of TRBD is lacking. This consensus document, developed by the International Society for Bipolar Disorders (ISBD) Task Force on TRBD, aims to provide a standardized definition of TRBD to facilitate clinical trials, research, and treatment strategies. Methods The Task Force employed a literature review, clinical trials analysis, and expert consensus meetings to define TRBD. Results TRBD was defined as the failure to achieve a significant and sustained clinical response after at least two approved and adequately dosed pharmacological treatments, administered for a sufficient duration with treatment adherence. For bipolar I (BD‐I) depression, approved treatments included quetiapine (300–600 mg/day for ≥ 8 weeks), lurasidone (20–120 mg/day for ≥ 6 weeks), the combination of olanzapine (6–12 mg/day) and fluoxetine (25–75 mg/day for ≥ 8 weeks), cariprazine (1.5–3 mg/day for ≥ 6 weeks), and lumateperone (42 mg/day for ≥ 6 weeks). For bipolar II (BD‐II) depression, approved treatments included quetiapine (300–600 mg/day for ≥ 8 weeks) and lumateperone (42 mg/day for ≥ 6 weeks). Conclusion This consensus definition aims to provide clarity for clinical trials, improve consistency in research, and guide treatment approaches and inform regulatory pathways. It represents a foundational step in addressing the unmet needs in TRBD and promoting the development of innovative therapeutic strategies. Future efforts will focus on adapting the definition to better align with real‐world clinical challenges and optimize patient care.

Abstract Background: With over 1 billion individuals affected globally, obesity and obesity related diseases is now a leading cause of death. Metabolic and bariatric surgery (MBS) has emerged as a cornerstone intervention for severe obesity and its associated comorbidities. Despite its efficacy, postoperative care and follow-up after MBS remains highly variable worldwide. Objective: The PARTNER study aimed to evaluate global clinical practices in the postoperative management following MBS by surveying multidisciplinary healthcare professionals . Methods: This study was an international online survey conducted between October 2024 and January 2025. A multidisciplinary team developed the questionnaire based on existing literature and international guidelines. The survey assessed five domains: follow-up care, postoperative treatment, dietary management, patient support, and measurement of surgical outcomes. Responses were analysed descriptively. Results: A total of 262 responses were received from 62 countries. Most respondents were bariatric surgeons (72.1%) working in public healthcare systems (73.3%). While 78.7% reported conducting three-month postoperative reviews, only 23.7% offered indefinite follow-up. Hybrid models of care (virtual and in-person) were common (56.9%). VTE prophylaxis and postoperative PPI use were recommended by 64.1% and 84.3% respectively. Nearly all respondents (98.1%) provided dietary advice, with protein and micronutrient supplementation widely endorsed. Only 56.1% routinely referred patients for psychological follow-up. Definitions of surgical success and failure varied widely, with inconsistent objective outcome measures. Conclusion: The PARTNER study reveals significant international variation in postoperative management practices following MBS. These findings underscore the need for more standardized, evidence-based guidelines to improve long-term outcomes and equity of care worldwide.

Acquired angioedema due to C1-inhibitor deficiency (AAE-C1INH) is a rare condition characterized by the localized swelling of the deeper skin layers and mucous membranes, especially the face, lips, tongue, throat, and gastrointestinal tract. AAE-C1INH is strongly associated with lymphoproliferative disorders, although it can also be linked to autoimmune conditions, solid tumors, infections, or even occur without an identifiable cause. We present the case of a 45-year-old female patient with complaints of recurrent abdominal pain, bloating, and joint swelling. Laboratory testing showed decreased C1q and C4 complement levels, and C1 esterase inhibitor levels, indicative of AAE-C1INH. Further work up confirmed a diagnosis of extranodal marginal zone lymphoma with involvement of the bone marrow and spleen. Treatment with rituximab led to resolution of angioedema symptoms and almost complete remission of underlying lymphoma. This case underscores the importance of evaluating an underlying lymphoproliferative disorder in AAE-C1INH. Therefore, the early participation of a multidisciplinary team including specialists in immunology, hematology, and oncology is necessary for appropriate management.

Neuromotor control of the diaphragm muscle (DIAm) after C 2 spinal hemisection (C 2 SH) is impacted differentially between ipsilateral and contralateral sides. We show neural drive to ipsilateral phrenic motor neurons decreases after C 2 SH, leading to a reduction in the number of DIAm motor units (MUs) recruited. Contralateral neural drive increases after C 2 SH, leading to an increase in the number of MU recruited. These results provide novel information about the impact of C 2 SH on DIAm neuromotor control.

Abstract The roles of nucleoplasm-residing nucleoporins (NUP) in solid tumors, including prostate cancer, remain unknown. In this study, we reveal the clinical significance and mechanistic role of the off-pore NUP, soluble POM121 (sPOM121), as a crucial transcriptional regulator that enhances the aggressiveness of metastatic prostate cancer. Using orthogonal methodologies in human samples, sPOM121 was identified as the predominantly expressed nucleoplasmic NUP in prostate cancer. Unbiased proteomic and epigenomic studies demonstrate that sPOM121, through its C-terminus, interacts with the chromatin remodeler SMARCA5 at gene promoter sites and localizes at nuclear condensates, reprogramming gene expression. Indeed, sPOM121 regulates a distinct oncogenic gene network, including β-catenin, leading to prostate cancer progression and immune evasion. Importantly, targeting the sPOM121/β-catenin axis in patient-derived preclinical and syngeneic mouse models halts prostate cancer aggressiveness and enhances antitumor immunity. Taken together, these findings reveal previously unknown actionable reprogramming functions of off-pore NUPs in solid tumors. Significance: This study uncovers how oncogenic signaling programs are transcriptionally heightened by the NUP sPOM121 in metastatic prostate cancer. Localization of sPOM121 at active transcriptional nuclear condensates propels disease progression and immune evasion, offering novel anticancer therapeutic opportunities.

Abstract Background and Aims Invasive coronary function testing (CFT) identifies coronary vasomotor disorders in up to 90% of patients with angina with non-obstructive coronary arteries (ANOCA). The ILIAS ANOCA trial hypothesized that routine ad hoc CFT would be feasible, safe, and effective in providing an early, comprehensive diagnosis. Additionally, it was anticipated that combining CFT with a disease-specific treatment protocol would significantly improve quality of life in ANOCA patients compared with standard care. Methods After excluding patients with obstructive coronary artery disease (CAD) during clinically indicated invasive coronary angiography (ICA), eligible patients underwent CFT and were randomized to either the standard care group, where CFT results remained blinded, or the intervention group, where CFT results were disclosed along with a tailored medical therapy protocol. The primary outcome was the mean difference in the within-subject change in Seattle Angina Questionnaire summary score (SAQSS) between groups from baseline to a follow-up of 6 months. The trial is registered with the International Clinical Trials Registry Platform (NL-OMON20739). Results A total of 255 patients consented, of whom 153 patients (60%) without CAD underwent CFT and were randomized 1:1 to the standard care (n = 76) or intervention group (n = 77). All CFT procedures were successful without adverse events. A vasomotor disorder was identified in 120 patients (78%). At 6-month follow-up, the SAQSS improved significantly in the intervention group compared with the control group, with an intervention effect of 9.4 units (95% confidence interval 3.9–14.9, P = .001). There were no major adverse cardiac events at the 6-month follow-up. Conclusions Routine CFT during the initial ICA was feasible, safe, and had high diagnostic yield. Implementing a pragmatic CFT protocol combined with a disease-specific treatment protocol significantly improved disease-related quality of life in patients with ANOCA compared with standard care.