Citations

Abstract DNMT3A and TET2 are epigenetic regulator genes commonly mutated in age-related clonal hematopoiesis (CH). Despite having opposed epigenetic functions, these mutations are associated with increased all-cause mortality and a low risk for progression to hematologic neoplasms. Although individual impacts on the epigenome have been described using different model systems, the phenotypic complexity in humans remains to be elucidated. Here, we make use of a natural inflammatory response occurring during coronavirus disease 2019 (COVID-19), to understand the association of these mutations with inflammatory morbidity (acute respiratory distress syndrome [ARDS]) and mortality. We demonstrate the age-independent, negative impact of DNMT3A mutant (DNMT3Amt) CH on COVID-19–related ARDS and mortality. Using single-cell proteogenomics we show that DNMT3A mutations involve myeloid and lymphoid lineage cells. Using single-cell multiomics sequencing, we identify cell-specific gene expression changes associated with DNMT3A mutations, along with significant epigenomic deregulation affecting enhancer accessibility, resulting in overexpression of interleukin-32 (IL-32), a proinflammatory cytokine that can result in inflammasome activation in monocytes and macrophages. Finally, we show with single-cell resolution that the loss of function of DNMT3A is directly associated with increased chromatin accessibility in mutant cells. Hence, we demonstrate the negative prognostic impact of DNMT3Amt CH on COVID-19–related ARDS and mortality. DNMT3Amt CH in the context of COVID-19, was associated with inflammatory transcriptional priming, resulting in overexpression of IL32. This overexpression was secondary to increased chromatic accessibility, specific to DNMT3Amt CH cells. DNMT3Amt CH can thus serve as a potential biomarker for adverse outcomes in COVID-19.

This article presents a summary of the third American Association for Dental, Oral, and Craniofacial Research Meeting within a Meeting, which was held during the 2024 annual meeting in New Orleans, Louisiana. Speakers were challenged to reflect on how women are differentially affected by health and societal issues by factors that go beyond biology. The goal was to promote current research on women’s issues that are relevant to dental, oral, and craniofacial scientists.

Objective Dermoid cyst (DC) is a congenital cyst with the potential to have intracranial extension (ICE). This study aims to evaluate the imaging yield and surgical outcomes of nasal, medial brow, forehead, and scalp DCs. Design Retrospective review of craniofacial DCs treated at our institution between 1992 and 2024. Results A total of 117 patients (57 females) were included. The median age at cyst detection and removal were 4.8 months (IQR 3.6-9.6) and 1.8 years (IQR 0.9-5.3), respectively. In 42 patients, parents have noticed the presence of the cyst immediately after birth. Cyst wall rupture during surgical removal was reported in 15.4%. The median follow-up time was 1.3 months (IQR 0.5-12.2). Three patients experienced recurrence. No postoperative complication was reported. The regions with the highest prevalence of ICE were the forehead, frontotemporal scalp, and nasal region. The lateral frontal/temporal scalp had a 33.3% rate of ICE. Midline forehead/scalp lesions demonstrated a higher risk of ICE compared to their lateral equivalents (54.5% vs 17.5%, P = .03). The sensitivity and specificity of magnetic resonance imaging (MRI) were 100% and 95.7%, while for computed tomography (CT scans) were 72.7% and 96.5%. The Area Under the Curve for MRI was 0.978, and for CT was 0.846. The sensitivity and specificity of ultrasound were 50% and 100%. Conclusions Midline forehead/scalp DCs are more prone to extend intracranially than lateral DCs. MRI had a higher sensitivity and specificity than CT scans in detecting ICE. Routine screening imaging should be considered in midline forehead/scalp, lateral frontal/temporal, and nasal DCs.

Exchanges in medical practice are necessary for training. The use of movies for promoting medical practice was introduced in the late 19th century. The authors analyzed an unidentified movie titled Trepanation for Rolandic Zone Tumor (Trépanation pour tumeur de la zone rolandique) stored at the Établissement de Communication et de Production Audiovisuelle de la Défense of the French Ministry of Armed Forces. This silent black-and-white movie, lasting 15 minutes and depicting the removal of a meningioma, did not contain information or a legend. The surgical tools used were those developed by Thierry de Martel. The furniture and interior design shown in the film corresponded with the Vercingétorix Clinic that this surgeon had acquired in Paris. A publication from 1922 contained 14 pictures taken from the movie presented in this paper and referred to a movie directed in 1911 by Thierry de Martel. This is strong circumstantial evidence that the film was directed and the surgery was performed by Thierry de Martel at the Vercingétorix Clinic in Paris, France, in 1911 while using the technology of the Gaumont company. This is a contemporary testimony to what surgical practice was over a century ago, and it illustrates how movies were, and remain, a unique way to learn and teach medicine.

Importance Since 2018, a movement has emerged to define Alzheimer disease (AD) as a purely biological entity based on biomarker findings. The recent revision of the Alzheimer’s Association (AA) criteria for AD furthers this direction. However, concerns about a purely biological definition of AD being applied clinically, the understanding of AD by society at large, and the translation of blood-based biomarkers into clinical practice prompt these International Working Group (IWG) updated recommendations. Objective To consider the revised AA criteria and to offer an alternative definitional view of AD as a clinical-biological construct for clinical use. The recommendations of the 2021 IWG diagnostic criteria are updated for further elaborating at-risk and presymptomatic states. Evidence Review PubMed was searched for articles published between July 1, 2020, and March 1, 2024, using the terms “biomarker” OR “amyloid” OR “tau” OR “neurodegeneration” OR “preclinical” OR “CSF” OR “PET” OR “plasma” AND “Alzheimer’s disease.” The references of relevant articles were also searched. Findings In the new AA diagnostic criteria, AD can be defined clinically as encompassing cognitively normal people having a core 1 AD biomarker. However, recent literature shows that the majority of biomarker-positive cognitively normal individuals will not become symptomatic along a proximate timeline. In the clinical setting, disclosing a diagnosis of AD to cognitively normal people with only core 1 AD biomarkers represents the most problematic implication of a purely biological definition of the disease. Conclusions and Relevance The ultimate aim of the field was to foster effective AD treatments, including preventing symptoms and dementia. The approach of diagnosing AD without a clinical and biological construct would be unwarranted and potentially concerning without a clear knowledge of when or whether symptoms will ever develop. It is recommended that those who are amyloid-positive only and, more generally, most biomarker-positive cognitively normal individuals, should not be labeled as having AD. Rather, they should be considered as being at risk for AD. The expansion of presymptomatic AD is viewed as a better diagnostic construct for those with a specific pattern of biomarkers, indicating that they are proximate to the expression of symptoms in the near future.

Background Acute ischemic stroke arising from medium vessel occlusions (MeVO) poses substantial challenges in treatment and management. This study aims to elucidate the outcomes and factors contributing to achieving excellent recanalization (modified Thrombolysis in Cerebral Infarction [mTICI] 2c–3) versus successful recanalization (mTICI 2b) in patients with MeVO stroke undergoing mechanical thrombectomy (MT). Methods We conducted a multinational study analyzing data from the MAD‐MT (Multicenter Analysis of Distal Medium Vessel Occlusions: Effect of Mechanical Thrombectomy) registry, encompassing 37 centers across North America, Asia, and Europe, collected between September 2017 and July 2023. The study included acute ischemic stroke patients with MeVO treated with MT, with or without intravenous thrombolysis, who achieved mTICI 2b–3 post‐MT. Results Among 1463 patients with successful recanalization (mTICI 2b–3), 523 achieved mTICI 2b recanalization, and 940 achieved mTICI 2c–3. Distal occlusions exhibited higher odds of excellent recanalization compared with proximal MeVO vessel occlusions (odds ratio, 1.58; 95% CI, 1.17–2.15; P = 0.003). Cardioembolic stroke pathogenesis was associated with a higher likelihood of excellent recanalization (1.67; 95% CI, 1.07–2.59; P = 0.018). Patients achieving mTICI 2c–3 recanalization demonstrated lower initial National Institutes of Health Stroke Scale scores, significant improvements in postprocedural National Institutes of Health Stroke Scale shift, and a higher percentage of favorable 90‐day outcomes compared with those with mTICI 2b. However, no significant difference in 90‐day mortality rates was observed. Conclusion This study underscores that among patients with MeVO stroke with successful recanalization (mTICI 2b–3) there is higher likelihood of achieving excellent recanalization (mTICI 2c–3) in distal occlusions and cardioembolic pathogenesis. mTICI 2c–3 scores post‐MT correlate with improved clinical outcomes compared with mTICI 2b, affirming the superiority of excellent recanalization over successful recanalization in patients with MeVO stroke. Further prospective studies and randomized controlled trials are warranted for validation.

Abstract Background: Despite the proven effectiveness of endovascular therapy (EVT) in acute ischemic strokes (AIS) involving anterior circulation large vessel occlusions, isolated posterior cerebral artery (PCA) occlusions (iPCAo) remain underexplored in clinical trials. This study investigates the comparative effectiveness and safety of EVT against medical management (MM) in patients with iPCAo. Methods: This multinational, multicenter propensity score-weighted study analyzed data from the Multicenter Analysis of primary Distal medium vessel occlusions: effect of Mechanical Thrombectomy (MAD-MT) registry, involving 37 centers across North America, Asia, and Europe. We included iPCAo patients treated with either EVT or MM. The primary outcome was the modified Rankin Scale (mRS) at 90 days, with secondary outcomes including functional independence, mortality, and safety profiles such as hemorrhagic complications. Results: A total of 177 patients were analyzed (88 MM and 89 EVT). EVT showed a statistically significant improvement in 90-day mRS scores (OR = 0.55, 95% CI = 0.30–1.00, p = 0.048), functional independence (OR = 2.52, 95% CI = 1.02–6.20, p = 0.045), and a reduction in 90-day mortality (OR = 0.12, 95% CI = 0.03–0.54, p = 0.006) compared to MM. Hemorrhagic complications were not significantly different between the groups. Conclusion: EVT for iPCAo is associated with better neurological outcomes and lower mortality compared to MM, without an increased risk of hemorrhagic complications. Nevertheless, these results should be interpreted with caution due to the study’s observational design. The findings are hypothesis-generating and highlight the need for future randomized controlled trials to confirm these observations and establish definitive treatment guidelines for this patient population.

Abstract Purpose: Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating toxicity of many drugs used in cancer treatment. There are numerous available strategies for preventing or treating CIPN, but few are guideline-recommended, due to limited evidence of their effectiveness. The primary objective of this survey was to understand what strategies patients used to prevent or treat CIPN, and to understand their perceptions around CIPN prevention and treatment. Methods: The Multinational Association of Supportive Care in Cancer (MASCC) Neurological Complications Study Group created a cross-sectional online survey to recruit individuals who are currently or had previously received neurotoxic chemotherapy treatment and self-reported peripheral neuropathy. Descriptive statistics were reported. Results: Most of the 447 survey participants did not use any CIPN prevention strategy (71%), though given options of any strategy the plurality preferred a prescribed medication or supplement (30%). The most common treatment strategy used was exercise (47%), with some patients trying prescription medications including non-guideline recommended gabapentin (33%) or guideline-recommended duloxetine (8%) options. Nearly half of participants (49%) used at least one non-prescribed medication for treating CIPN. Patient’s often followed suggestions of their medical oncology clinical team, but sometimes relied on the internet or other patients to recommend non-prescription strategies. Conclusion: In the absence of many guideline-recommended strategies for CIPN prevention and treatment, some patients use options with minimal evidence of effectiveness. Additional research is needed to determine which strategies are effective for prevention and treatment so these can be implemented in practice to improve treatment outcomes in patients with cancer.