Citations

Glioblastoma (GBM) is a devastating cancer with a dismal prognosis. Current treatment includes temozolomide (TMZ), which is more effective in about 50% of GBMs that have O 6 - methylguanine DNA methyltransferase ( MGMT ) promoter methylation. MGMT is a DNA repair protein that reverses TMZ-induced DNA damage. EGFR is a prime oncogene in GBM. Here, we report that EGFR inhibition induced the down-regulation of MGMT in GBM cells, revealing a previously unidentified link between EGFR signaling and response to TMZ. EGFR inhibition led to activation of two transcription factors, activator protein-1 (AP-1), which repressed MGMT transcription, and nuclear factor κB (NF-κB), which up-regulated MGMT transcription. EGFR inhibition also induced AP-1–mediated transcription of miR-616. miR-616 inhibited both MGMT translation and NF-κB activation. Thus, the overall effect of EGFR inhibition was down-regulation of MGMT expression. In addition, we provided an explanation for the prior failure of clinical trials that used concomitant EGFR tyrosine kinase inhibitors (TKIs) and TMZ. TMZ up-regulated MGMT, and concomitant treatment with EGFR TKIs and TMZ failed to down-regulate MGMT. However, pretreatment with EGFR TKIs followed by TMZ efficiently down-regulated MGMT and enhanced TMZ sensitivity in experimental models. Posttreatment tumor tissues from two clinical trials were used to validate these findings. We demonstrated that EGFR inhibitors induced down-regulation of MGMT in posttreatment resected tumor tissues from patients with GBM and the failure of EGFR inhibition to down-regulate MGMT if TMZ was used concomitantly. These data support using EGFR TKIs before TMZ treatment as a therapeutic approach in MGMT unmethylated GBM.

Abstract Unvetted scientific claims about vaccines can spread rapidly and undermine decades of progress in immunization and public trust. A recent non-peer-reviewed analysis, promoted at political hearings, in the documentary “An Inconvenient Study,” and on social media, has been used to suggest that vaccinated children experience higher rates of chronic illness than unvaccinated peers. Despite standard regression models, critical flaws - uncontrolled confounding, exposure misclassification, unequal follow-up, and outcome multiplicity, invalidate causal inference. An independent group of international experts critically appraises this analysis and contrast its claims with the consistent evidence confirming vaccine safety and effectiveness. We also show how poorly designed studies can distort public discourse, amplify misinformation, and fuel vaccine hesitancy. We outline actions to strengthen research integrity, such as transparent data sharing, labeling of non-peer-reviewed content, and evidence-based communication. Safeguarding public health demands that vaccine evidence be methodologically sound, reviewed, and interpreted by qualified experts.

Abstract Background Acute hypoxemic and hypercapnic respiratory failure are among the most common reasons for ICU admission and need for invasive mechanical ventilation. Noninvasive respiratory support (NIRS) strategies—including high-flow nasal cannula (HFNC), noninvasive ventilation (NIV), and continuous positive airway pressure (CPAP)—may prevent intubation, improve outcomes, and reduce ICU utilization. However, there is uncertainty regarding optimal patient and modality selection, resulting in variable implementation. There are no clinical practice guidelines comprehensively addressing the use of the different noninvasive respiratory support strategies across the spectrum of acute respiratory failure. Objective To update and develop new evidence-based clinical practice recommendations informing noninvasive respiratory support use, including HFNC, NIV and CPAP, in adults with acute respiratory failure. Methods A multidisciplinary panel used the GRADE approach to address four PICO questions related to the use of NIRS for hypoxemic and hypercapnic respiratory failure, preoxygenation for intubation, and post-extubation respiratory support. Recommendations were informed by several systematic reviews and network meta-analyses. Results The panel made a strong recommendation for HFNC and a conditional recommendation for NIV or CPAP for adults with acute hypoxemic respiratory failure with close monitoring for the need for escalation of respiratory support, based primarily on effects on need for intubation. For acute hypercapnic respiratory failure, the panel made a strong recommendation for NIV to reduce mortality and need for invasive mechanical ventilation, and a conditional recommendation for HFNC only in patients with less severe hypercapnia and with mild acidemia (eg, pH > 7.25), provided that close monitoring and prompt escalation to NIV are available. The panel made a strong recommendation for HFNC or NIV for preoxygenation prior to endotracheal intubation to prevent peri-intubation hypoxemia. The panel also issued a risk-based recommendation, suggesting HFNC for low-risk patients and NIV for high-risk patients to reduce the need for re-intubation following extubation after critical illness. Conclusions Noninvasive respiratory support strategies are effective in improving outcomes in a range of clinical scenarios. We provide evidence-based recommendations, which can be further informed by patient risk, institutional capacity, and interface tolerance.

Abstract Aims Transcatheter mitral valve replacement (TMVR) with the Tendyne Mitral Valve System is a treatment option for patients with severe symptomatic mitral regurgitation (MR) unsuitable for conventional mitral valve surgery or transcatheter edge-to-edge repair (TEER). This study sought to evaluate the safety and effectiveness of TMVR through 5-year follow-up. Methods and Results The Tendyne Expanded Clinical Study is a prospective, single-arm, multicentre study that enrolled patients between November 2014 and June 2020. The study enrolled 191 patients (mean age 74.1 ± 8.0 years, 62.8% male, 70.2% New York Heart Association Class (NYHA) class III/IV, 88.5% secondary MR), of whom 186 (97.4%) underwent TMVR with Tendyne. MR grade decreased from ≥3+ in 99.5% patients at baseline to grade ≤1+ in 95.3% at 5 years. In those patients surviving to 5 years (n = 49), durable symptomatic improvement was evidenced by 73.5% patients being in NYHA class I/II at 5 years. The Kansas City Cardiomyopathy Questionnaire overall summary score increased from 48.5 ± 22.5 points at baseline to 67.6 ± 21.5 points at 5 years. Serious adverse events that occurred through 5 years included life-threatening bleeding (11.5%), fatal bleeding (2.6%), renal insufficiency/failure (28.8%), endocarditis (7.3%), device thrombosis (5.8%), and new onset atrial fibrillation (13.1%). No structural device degeneration or device embolism occurred through 5 years. Conclusions The Tendyne TMVR was effective at achieving immediate and sustainable elimination of MR, which was associated with symptomatic improvement and absence of structural valve degeneration in a high-risk cohort over 5 years. These findings support TMVR with the Tendyne System as an alternative for patients with appropriate mitral valve anatomy and symptomatic secondary MR unsuitable for mitral surgery or TEER.

Background/Objectives: Cardiovascular disease (CVD) burden decreased in the North Africa and Middle East (NAME) region between 1990 and 2019. This study used Global Burden of Disease (GBD) 2023 data to examine whether trends in mortality, disability-adjusted life years (DALYs), incidence, and prevalence continued through 2023 across all 21 NAME countries. Methods: We analysed age-standardised CVD mortality, incidence, prevalence, and DALY rates from 1990 to 2023. Joinpoint regression identified changes in temporal trends and calculated the annual percent change (APC) and average annual percent change (AAPC) with 95% confidence intervals (CIs). Results: Age-standardised CVD mortality decreased from 579.6 per 100,000 in 1990 to 358.2 in 2023 (AAPC: −1.42%; 95% CI: −1.48 to −1.35). However, no significant reduction occurred between 2019 and 2023 (APC: −0.33%; 95% CI: −1.37 to 1.75). DALY, incidence, and prevalence rates followed similar patterns, with no significant decline in the final years of this study. Egypt was the only country with a long-term increase in CVD mortality, which accelerated after 2020 (APC: +5.20%; 95% CI: 1.20 to 12.87). High systolic blood pressure, dietary risks, lead exposure, and air pollution were the leading modifiable risk factors. Conclusions: The earlier decline in CVD burden in the NAME region did not clearly continue after 2019. The region is currently off track to meet Sustainable Development Goal 3.4 by 2030. Future progress may depend on improved blood pressure control, lipid management, dietary habits, and environmental risk reduction.

Purpose: To evaluate the diagnostic performance and limitations of a general-purpose multimodal large language model (GPT-5.4) in detecting early keratoconus (KC) using corneal tomography images. Methods: This retrospective study included 66 eyes: 15 with subclinical KC, 18 with forme fruste keratoconus (ffKC), and 33 normal controls. Control eyes were obtained from refractive surgery candidates with normal corneas. For each eye, a standardized four-map Pentacam tomography image was analyzed using GPT-5.4 (OpenAI) with a predefined prompt. Only images were provided, without clinical or demographic data. Diagnostic performance for detecting early KC was assessed using sensitivity, specificity, predictive values, accuracy, and receiver operating characteristic (ROC) analysis. Results: GPT-5.4 demonstrated low sensitivity (30.3%) and high specificity (100%) for detecting early KC, with an overall accuracy of 65.2% and an area under the ROC curve of 0.65. The model showed a strong tendency to classify eyes as normal, resulting in a high rate of false-negative classifications. Multiclass analysis revealed a stage-dependent performance pattern, with excellent classification of normal corneas (100%), moderate detection of subclinical KC (53.3%), and poor detection of ffKC (11.1%), with most ffKC cases misclassified as normal. Conclusions: GPT-5.4 demonstrates high specificity but limited sensitivity for detecting early KC using image-only input and is not a reliable diagnostic or screening tool in its current form.

Background: Prior research has revealed gender disparities in the financial relationships between industry and orthopaedic surgeons. Despite attempts to level the playing field, it remains unclear whether these efforts have reduced or eliminated gender disparities in financial relationships between industry and orthopaedic surgeons. Methods: The Centers for Medicare and Medicaid Services (CMS) Open Payments database was queried from January 1, 2024, to December 31, 2024 for orthopaedic surgeons receiving “consulting fee” or “royalty or license” payments of $1,000 or more. Surgeon characteristics were recorded from the CMS database and public sources. Total payment amounts and number of payments were calculated. Characteristics were compared by gender between those receiving any industry payment, consulting payment, and royalty payment. Multivariable linear regression analyses were used to identify factors associated with payment amount and number of payments. Results were compared with a study using similar data from 2016 to 2017. Results: A total of 3,714 surgeons received industry payments, with 3,514 (95%) being men. Of those receiving royalty payments (n = 1,374), 1.5% (n = 21) were women. Of those receiving consulting payments (n = 3,122), 6.2% (n = 194) were women. Men (β = 1.57 [95% confidence interval [CI]: 0.41-2.73, p = 0.008), years of experience (β = 0.09 [95% CI: 0.07-0.12], p < 0.001), and adult reconstruction (β = 1.77 [95% CI: 0.76-2.79], p = 0.001) were associated with a greater total number of payments. Hand surgery (β = −2.57 [95% CI: 3.97 to −1.17], p < 0.001), pediatrics (β = −2.62 [95% CI: 4.60 to −0.64], p = 0.01), and sports (β = −1.12 [95% CI: 2.08 to −0.16], p = 0.02) were associated with the fewer total number of payments. Men (β = 0.34 [95% CI: 0.10-0.57], p = 0.004), years of experience (β = 0.051 [95% CI: 0.046-0.056], p < 0.001), and adult reconstruction (β = 0.47 [95% CI: 0.27-0.68], p < 0.001) were associated with greater payment amounts, while hand (β = −0.96 [95% CI: 1.24 to −0.68], p < 0.001) and pediatrics (β = −0.79 [95% CI: 1.18 to −0.39], p < 0.001) were associated with lower payment amounts. When examining trends over time, men received 1.57 (2024) vs. 5.17 (2016-2017) additional payments and 40% (2024) vs. 197% (2016-2017) larger payments compared with women. Conclusions: Gender disparities in financial relationships (i.e., number of payments and payment amounts) between industry and orthopaedic surgeons persist, though are improved compared with prior research from about a decade ago.