Citations

Abstract The Physician-Scientist Trainee Diversity Summit, hosted by the American Physician Scientists Association and the Burroughs Wellcome Fund, was conceived in 2019 with the mission of developing strategic plans to diversify the physician-scientist community using human-centered design thinking. In June 2024, the second iteration of this conference was held in Raleigh, North Carolina, and brought together a network of scientific and medical organizations to discuss issues of justice, equity, diversity, and inclusion facing physician-scientist trainees. This article summarizes the progress made from the first meeting, the proceedings of the 2024 Summit, and a thematic analysis of the recent meeting, offering tangible solutions to the physician-scientist community for supporting diversity and accessibility.

AbstractThis study compares delays in otolaryngologic care between patients in Mekelle, Ethiopia and Harare, Zimbabwe using the Three Delays model. Patient surveys conducted among 46 patients in Zimbabwe during October 2022 and 105 patients in Ethiopia during June 2023 revealed a significantly higher prevalence of delays in seeking and reaching care in Ethiopia. This was in the aftermath of the Tigray War, which damaged the region's health care infrastructure and diminished the trust of patients. In Zimbabwe, there was poor awareness among patients and nonotolaryngologist providers of otolaryngology disease and care capacity leading to delays in seeking and reaching care. Patients in both countries faced delays in receiving appropriate care due to resource limitations, with Ethiopia's constraints worsened by the recent war and Zimbabwe's by consistent health care underfunding. The longest delays were observed in head and neck oncology care. These findings provide a foundation for understanding otolaryngologic care delays in these low‐ and middle‐income countries.

Background Brain arteriovenous malformations (AVMs) are abnormal connections between feeding arteries and draining veins, associated with significant risks of haemorrhage, seizures and other neurological deficits. Preoperative embolization is commonly used as an adjunct to microsurgical resection, with the aim of reducing intraoperative complications and improving outcomes. However, the efficacy and safety of this approach remain controversial. Methods This study is a subanalysis of the Multicenter International Study for Treatment of Brain AVMs consortium. We retrospectively analysed 486 patients with brain AVMs treated with microsurgical resection between January 2010 and December 2023. Patients were divided into two groups: those who underwent microsurgery alone (n=245) and those who received preoperative embolization, followed by microsurgery (n=241). Propensity score matching was employed, resulting in 288 matched patients (144 in each group). The primary outcomes were rates of complete AVM obliteration and functional outcomes (measured by the modified Rankin Scale (mRS)). Secondary outcomes included complication rates, mortality, hospital length of stay and postsurgical rupture. Results After matching, the complete obliteration rate was 97% with no significant difference between the microsurgery-only group and the preoperative embolization group (p=0.12). The proportion of patients with an mRS score of 0–2 at the last follow-up was similar in both groups (83% vs 84%; p=0.67). The median hospital stay was significantly longer for the embolisation group (9 days vs 7 days; p=0.017). Complication rates (24% vs 22%; p=0.57) and mortality rates (4.9% vs 2.1%; p=0.20) were comparable between the two groups. No significant differences were observed in postsurgical rupture, recurrence or retreatment rates. Conclusions In this large multicentre study, preoperative embolization did not significantly improve AVM obliteration rates, functional outcomes or reduce complications compared with microsurgery alone.

ABSTRACT Genes involved in the regulation of chromatin structure are frequently disrupted in cancer, contributing to an aberrant transcriptome and phenotypic plasticity. Yet, therapeutics targeting mutant forms of chromatin-modifying enzymes have yielded only modest clinical utility, underscoring the difficulty of targeting the epigenomic underpinnings of aberrant gene regulatory networks. Here, we sought to identify novel epigenetic vulnerabilities in diffuse large B-cell lymphoma (DLBCL). Through phenotypic screens and biochemical analysis, we demonstrated that inhibition of the H3K9 demethylases KDM4A and KDM4C elicits potent, subtype-agnostic cytotoxicity by antagonizing transcriptional networks associated with B-cell identity and epigenetically rewiring heterochromatin. KDM4 demethylases associated with the KRAB zinc finger ZNF587, and their enzymatic inhibition led to DNA replication stress and DNA damage-induced cGAS-STING activation. Broad surveys of transcriptional data from patients also revealed KDM4 family dysregulation in several other cancer types. To explore this potential therapeutic avenue, we performed high-throughput small molecule screens with H3K9me3 nucleosome substrates and identified novel KDM4 demethylase inhibitors. AI-guided protein-ligand binding predictions suggested diverse modes of action for various small molecule hits. Our findings underscore the relevance of targeting fundamental transcriptional and epigenetic mechanisms for anti-cancer therapy. HIGHLIGHTS Phenotypic screens identified JIB-04 as a potent anti-cancer agent for multiple subtypes of diffuse large B-cell lymphoma JIB-04 binds and inhibits KDM4 demethylases resulting in epigenomic rewiring of heterochromatin KDM4 demethylases cooperate with KRAB zinc fingers to limit DNA replication stress, and KDM4 inhibition instigates DNA-damage and cGAS-STING activation in several human cancers High-throughput small molecule screens with semi-synthetic nucleosome substrates and AI-guided molecular docking simulations identify novel KDM4 inhibitors

Abstract Cardiac implantable electronic device infections (CIEDIs) present substantial challenges for infectious diseases specialists, encompassing diagnosis, management, and complex decision making involving patients, families, and multidisciplinary teams. This review, guided by a common clinical case presentation encountered in daily practice, navigates through the diagnostic process, management strategies in unique scenarios, long-term follow-up, and critical discussions required for CIEDIs.