Citations

As a major reason for irreversible vision loss, glaucoma is a significant public health concern. Its multifactorial nature demands a nuanced understanding of its pathophysiology, risk factors, and management. An understanding, and continuous refinement, of diagnostic and therapeutic modalities, including pharmacological interventions, novel methods of drug delivery, and surgical techniques (including minimally invasive glaucoma surgeries) are critical. The advent of personalized medicine, genetic profiling, and innovative biomarkers for identifying susceptible individuals and tailoring treatment strategies may help prevent blindness and improve patient outcomes. Evaluation of the impact of lifestyle modifications and holistic approaches and integration of telemedicine and artificial intelligence in glaucoma management may revolutionize current glaucoma practice. In addressing the global challenge of glaucoma blindness, this narrative review highlights ongoing initiatives, public health policies, and community-based interventions. This includes raising awareness, enhancing early detection programs, and access to care, particularly in underserved populations.

Abstract Aims This study aims to describe the prevalence of discordant mild/moderate aortic stenosis (AS) in a population-based study and to identify the mechanisms that lead to reduced stroke volume (SV) and discordant moderate AS. Methods and results Discordant high-gradient (HG)-mild AS, defined as AVA > 1.5 cm2 and mean pressure gradient (MG) of 20–40 mmHg, and discordant low-gradient (LG) moderate AS, defined as AVA 1.0–1.5 cm2 and MG < 20 mmHg, were assessed in 883 individuals from the DANCAVAS screening study with aortic valve calcification and 257 individuals form the PROGRESSA study excluding those with left ventricular (LV) ejection fraction < 50%. In the DANCAVAS cohort, 150 men had mild/moderate AS of which 34% had discordance between MG and AVA, representing 66% with moderate AS. Among 262 patients in the combined cohort, 39% had discordant LG-moderate AS and 6% discordant HG-mild AS. Compared with concordant mild and moderate AS, individuals with discordant LG-moderate AS were more likely to present with LV concentric remodelling geometry (26 vs. 33 vs. 45%, P < 0.001), increased valvulo-arterial impedance (3.3 ± 0.7 vs. 3.6 ± 0.5 vs. 4.1 ± 0.7 mmHg/mL/m2, P < 0.001), and reduced systemic arterial compliance (SAC) (0.74 ± 0.22 vs. 0.81 ± 0.22 vs. 0.64 ± 0.18 mL/m2/mmHg, P < 0.001). Factors associated with SV index were relative wall thickness, LV end-diastolic diameter index, SAC, and LV remodelling pattern. Conclusion Discordant moderate AS is common, accounting for two-thirds of patients with moderate AS in the general male population. Patients with discordant LG-moderate AS have predominantly a concentric remodelling pattern with reduced SV. Reduced SV index was associated with signs of reduced vascular compliance, suggesting that altered vascular properties drive differences in remodelling patterns and discordant moderate AS.

Abstract Increasing evidence suggests that Alzheimer’s disease (AD) pathogenesis strongly correlates with neuroinflammation. Peripheral monocytes are crucial components of the human immune system that may play a role in neuroinflammation, but their contribution to AD pathogenesis is largely understudied partially due to the lack of appropriate human models. Here, we present human cortical organoid microphysiological systems (hCO-MPSs) for modeling dynamic AD neuroinflammation mediated by monocytes. By incorporating 3D printed devices into an existing cortical organoid protocol, 96 hCO-MPSs can be established with significantly reduced necrosis and hypoxia as well as enhanced viability within a commonly used 96 well plate, and each hCO-MPS consists of a doughnut-shaped hCO and a 3D printed device per well. Using this approach, monocytes from AD patients exhibit higher infiltration, decreased amyloid-beta (Aβ) clearance, and stronger inflammatory responses compared to monocytes from age-matched control donors. Moreover, pro-inflammatory effects such as elevated astrocyte activation and neuronal apoptosis were observed to be induced by AD monocytes. Furthermore, the significant increase in the expression of IL1B and CCL3, both at the transcriptional and protein levels, indicated the pivotal role of these cytokine and chemokine in monocyte-mediated AD neuroinflammation. Our findings provide insight for understanding monocytes’ role in AD pathogenesis, and the user-friendly MPS models we present are compatible with existing laboratory settings, highlighting their potential for modeling neuroinflammation and developing new therapeutics for various neuroinflammatory diseases.

ABSTRACTBackgroundCommercial biomarkers and multiparametric MRI (mpMRI) have been utilized to triage men with elevated prostate specific antigen (PSA) and determine patients most likely to harbor clinically‐significant prostate cancer (csPCa). We studied combinations of mpMRI, PSA‐based and novel extracellular vesicle (EV)‐based biomarkers to determine the optimal pre‐biopsy testing to predict csPCa at biopsy.MethodsMen presenting with elevated PSA (≥ 2 ng/mL) were prospectively enrolled and all men underwent clinically indicated mpMRI and blinded study blood draws to determine PSA, prostate health index (PHI) scoring, and EV serum levels. MRI‐fusion transperineal prostate biopsy was performed in all patients. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated, and receiver operator characteristic (ROC) curves were constructed. Bootstrapping analysis was performed to provide more accurate assessment of predictive abilities.ResultsUltimately, 175 consecutive men were prospectively enrolled. Median age in the study population was 65 years. Combinations of biomarkers and MRI demonstrated better predictive ability for csPCa on biopsy than individual modalities. Predictive ability was greatest for PHI density (PHID)‐mpMRI with an AUC of 0.86 (95% CI: 0.80–0.92) while combinations of PSA density ‐mpMRI (AUC: 0.81; 95% CI: 0.73–0.89) and STEAP1‐mpMRI (AUC: 0.77; 95% CI: 0.70–0.86) demonstrated similar ability to predict csPCa. The study is limited by small, predominantly white patient cohort and requires external validation.ConclusionsInclusion of prostate density with biomarkers increases prognostic ability for detecting csPCa. EV density can refine prediction of csPCa and in combination with PHID‐mpMRI leads to superior specificity, thereby decreasing unnecessary biopsies.

Migraine is one of the most prevalent and disabling neurological diseases, significantly affecting quality of life and productivity, as well as contributing to substantial societal costs. Recent innovations, including calcitonin gene-related peptide (CGRP) pathway inhibitors and onabotulinumtoxinA, have transformed migraine prevention by offering high efficacy and excellent tolerability, thus improving adherence. Clinical trials and real-world studies show that significant reductions in migraine frequency and, in some cases, complete migraine freedom is achievable. In this Position Statement, we advocate for raising the standards of migraine prevention by setting ambitious treatment goals aimed at optimal outcomes, such as migraine freedom or very low number of days with migraine or moderate/severe headache. We emphasize the importance of addressing residual migraine burden, highlighting that achieving a ≥50% reduction in monthly migraine days, although often considered a successful response, may not fully restore quality of life. Relying solely on percentage-based improvements can obscure the persisting impact of residual burden. This Position Statement does not want to change the standards for clinical trials but aims primarily at real-world clinical practice and proposes a shift from percentage-based measures of success to absolute goals while on treatment. We outline a framework that categorizes outcomes into four tiers: migraine freedom (no days with migraine or moderate-to-severe headache), optimal control (less than four days with migraine or moderate-to-severe headache), modest control (four to six days with migraine or moderate-to-severe headache) and insufficient control (more than days with migraine or moderate-to-severe headache). Focusing on residual burden while on treatment aims to further improve patient quality of life and drive innovation in preventive therapies and non-pharmacological approaches. By advocating for higher standards, this Position Statement, is not aimed primarily to drive reimbursement policies for migraine preventive treatments, but seeks to inspire clinicians, researchers and policymakers to prioritize ambitious goals in migraine prevention, ultimately enhancing patient outcomes and reducing the broader societal and economic impact of this debilitating condition.

Background Traumatic brain injury (TBI) commonly elicits acute (APTH) and/or persistent (PPTH) post-traumatic headache. Calcitonin gene related peptide (CGRP) has been implicated as a contributor to PTH pathophysiology. We explored the possibility of sexual dimorphism in the effects of CGRP receptor (CGRP-R) blockade in a preclinical model of PTH induced by a mild TBI (mTBI) in male or female mice. Methods Mice were lightly anesthetized and placed on a tissue paper stage prior to receiving a sham procedure or mTBI resulting from a closed-head weight drop injury. Behavioral responses to periorbital and hindpaw tactile (von Frey filaments) or thermal (hot plate) stimuli over the first 14 days post-mTBI were evaluated as measures of APTH. The PPTH phase was studied following the resolution of mTBI-induced APTH at days 14 and 28. PPTH was precipitated by exposure to bright lights (i.e., bright light stress, BLS). Olcegepant was delivered subcutaneously either repeatedly beginning 2 h after mTBI to produce a sustained block of CGRP-R signaling across the APTH phase, or as a single administration on days 14 or 28 post-mTBI to evaluate possible effects during the PPTH phase. Results mTBI, but not sham-procedure, produced periorbital and hindpaw tactile allodynia, as well as thermal hypersensitivity in mice of both sexes. APTH-related hypersensitivity was transient and resolved by day 14 post-injury. No sex differences were observed in the magnitude or duration of APTH-related pain behaviors. Sustained CGRP-R blockade was, however, significantly more effective in female than male mice in inhibiting pain behaviors in the APTH phase and in preventing the emergence of BLS-induced PPTH. CGRP-R blockade following the resolution of mTBI-induced APTH pain behaviors, on either day 14 or 28, minimally altered BLS-induced PPTH in either sex. Conclusions Sustained CGRP-R blockade starting soon after mTBI significantly inhibited APTH and prevented the expression of PPTH with greater analgesic effects in females compared to males. Delayed CGRP-R blockade beginning after resolution of APTH phase was minimally effective in preventing expression of PPTH in either sex. These data are consistent with previous observations that CGRP induces pain behaviors preferentially in females. Early and continuous CGRP blockade following mTBI may represent a viable treatment option for PTH treatment and the prevention of PTH persistence, especially in females.

The rising incidence of cancer among young women highlights the importance of understanding treatment‐related gonadotoxicity, which can lead to infertility and long‐term health complications from premature estrogen decline. Although anti‐Müllerian hormone is considered the most reliable indicator of ovarian reserve, its interpretation among oncology patients is complex because it is dependent on the treatment modality, necessitating further research to fully understand the impact of specific treatments on anti‐Müllerian hormone and to identify alternative markers to reliably assess the ovarian toxicity of newer cancer therapies.