Citations

To examine the association between post-stroke depression (PSD) and macrostructural and microstructural brain measures, and to explore whether changes in accelerometer-measured physical activity (PA) are associated with PSD, we conducted an exploratory study in UK Biobank with dementia-free participants diagnosed with at least one prior stroke. Eligible participants (n = 1186) completed an MRI scan. Depression was classified based on positive depression screening scores (PHQ-2 ≥ 3). Multivariate linear regression models assessed the relationships between depression and structural and diffusion measures generated from brain MRI scans. Logistic regression models were used to examine the relationship between accelerometer-measured daily PA and future depression (n = 367). Depression was positively associated with total white matter hyperintensities (WMHs) volume (standardized β [95% CI]—0.1339 [0.012, 0.256]; FDR-adjusted p-value—0.039), periventricular WMHs volume (standardized β [95% CI]—0.1351 [0.020, 0.250]; FDR-adjusted p-value—0.027), and reduced MD for commissural fibers (standardized β [95% CI]—−0.139 [−0.255, −0.024]; adjusted p-value—0.045). The odds of depression decreased by 0.3% for each daily minute spent in objectively measured light PA, while each minute spent in sleep from midnight to 6:00 AM was associated with a 0.9% decrease in the odds of depression. This early-stage analysis using a population cohort offers a scientific rationale for researchers using multimodal data sources to investigate the heterogenous nature of PSD and, potentially, identify stroke patients at risk of poor outcomes.

Background/Objectives: Stereotactic body radiation therapy (SBRT) for skull base reirradiation is particularly challenging, as patients have already received substantial radiation doses to the region, and nearby normal organs may have approached their tolerance limit from prior treatments. In this study, we reviewed the characteristics and capabilities of four advanced external beam radiation delivery systems and four modern treatment planning systems and evaluated the treatment plan quality of each technique using skull base reirradiation patient cases. Methods: SBRT plans were generated for sixteen skull base reirradiation patients using four modalities: the GK plan for the Elekta Leksell Gamma Knife Perfexion/ICON, the CyberKnife (CK) plan for the Accuray CyberKnife, the intensity-modulated proton therapy (IMPT) plan for the Hitachi ProBeat-FR proton therapy machine, and the volumetric-modulated arc therapy (VMAT) plan for the Varian TrueBeam STx. These plans were evaluated and compared using two novel gradient indices in addition to traditional dosimetry metrics for targets and organs at risk (OARs). The steepest border gradient quantified the percent prescription dose fall-off per millimeter at the boundary between the target and adjacent critical structures. This gradient index highlighted the system’s ability to spare nearby critical OARs. The volume gradient assessed the extent of dose spread outside the target toward the patient’s body. Results: All plans achieved comparable target coverage and conformity, while IMPT and VMAT demonstrated significantly better uniformity. The GK plans exhibited the highest border gradient, up to 20.9%/mm, followed by small-spot-size IMPT plans and CK plans. Additionally, IMPT plans showed the benefit of reduced dose spread in low-dose regions and the lowest maximum and mean doses to the brainstem and carotid artery. Conclusions: The advanced external beam radiotherapy modalities evaluated in this study are well-suited for SBRT in skull base reirradiation, which demands precise targeting of tumors with highly conformal doses and steep dose gradients to protect nearby normal structures.

Background: Variability in recanalization success during endovascular treatment for acute ischemic stroke (AIS) has led to increased interests in thrombus composition and associated cellular materials. While evidence suggests that bacteria may influence thrombus characteristics, limited data exist on microbiological profiles of thrombi in stroke patients. Objectives: Characterization of bacterial communities present in thrombi of AIS patients undergoing mechanical thrombectomy, providing insights into microbial contributions to stroke pathogenesis and treatment outcomes. Methods: Thrombi were collected from 20 AIS patients. After extracting metagenome, 16S rDNA sequencing was performed. Bioinformatic analysis included taxonomy and diversity assessments. The presence of bacterial DNA and viable bacteria in thrombi was validated using polymerase chain reaction (PCR) and bacterial culturing followed by matrix-assisted laser desorption ionization–time of flight (MALDI-TOF) analysis, respectively. Results: 16S rDNA was amplified in 19/20 thrombi (95%). Analysis identified a diverse microbial community, with Corynebacterium spp. as the most prevalent genus, followed by Staphylococcus spp., Bifidobacterium spp., Methylobacterium spp., and Anaerococcus spp. Alpha diversity analyses (Shannon index: 4.0–6.0 and Simpson index: 0.8–1.0) revealed moderate to high microbial diversity across samples; beta diversity demonstrated distinct clustering, indicating inter-patient variability in microbial profiles. PCR confirmed the presence of DNA specific to dominant bacterial taxa identified through sequencing. Culturing showed the presence of Staphylococcus epidermidis and Enterococcus faecalis in some clots as identified through MALDI analysis. Conclusions: This study shows bacterial communities present in AIS patients’ thrombi, suggesting a potential link between microbial signatures and thrombus characteristics.

Background: Previous reports have emphasized disparities in the utilization of invasive respiratory support for bacterial pneumonia among various racial and ethnic minority groups with bacterial pneumonia. However, there is a shortage of detailed epidemiological data on this, particularly after the onset of the COVID-19 pandemic. Methods: We used the National In-patient Sample to conduct a retrospective cohort analysis from 2017 to 2021. We included patients hospitalized across the United States with a primary diagnosis of bacterial pneumonia. Statistical methods used included Pearson chi-square and multivariable regression analyses. Examining racial and ethnic differences in hospitalized subjects’ usage of invasive mechanical ventilation for bacterial pneumonia was the primary outcome of the study. Secondary outcomes included mortality, use of noninvasive ventilation, and hospital stay. Results: The study found significant differences among racial and ethnic groups in pneumonia-related outcomes and the need for advanced respiratory ventilator assistance. Black and Asian American and Pacific Islander (AAPI) subjects had the highest rates of invasive mechanical ventilation compared with other racial groups, with adjusted odds ratios (ORs) indicating a higher likelihood of requiring this intervention for Black (OR 1.15) and AAPI (OR 1.31) subjects. For secondary outcomes, Black and AAPI subjects experienced longer hospital stays than other racial and ethnic groups. Noninvasive ventilation rates were comparable across groups. Mortality rates were the highest among Black subjects, but were elevated for all racial and ethnic minority subjects compared with white subjects. The pandemic exacerbated these disparities, leading to increased rates of both invasive and noninvasive ventilation and higher mortality, with particularly pronounced effects seen in AAPI patients, thereby worsening existing health inequities. Conclusions: The study suggests potential racial–ethnic disparities in invasive mechanical ventilation use among Black and AAPI subjects, but further investigation is needed to confirm these findings and explore underlying causes.

Objective(s): To quantify and compare pre-procedure worry versus the experience of pain, gagging, and dyspnea during in-office laryngoscopy procedures in patients who did or did not receive pre-procedure anxiolytics, and to explore patient perception of intra-procedure interventions. Methods: Patients undergoing awake laryngology procedures at a quaternary care center were enrolled. The State-Trait Anxiety Inventory (STAI) Y1 and Y2 questionnaires were administered to establish baseline levels of state anxiety and trait anxiety, respectively. Pre-procedure and post-procedure surveys assessed patient perception of select interventions. Results: 34 patients were enrolled (35.3% female, 91.2% white, mean age 60 years). Pre-procedure, 51.5% of patients reported some degree of worry about pain, 61.8% about gagging, 52.9% about dyspnea, and 55.9% about having something in their nose/throat. Post-procedure, 54.5% reported experiencing pain to some degree, 63.6% had gagging, 39.4% had dyspnea, and 78.7% were bothered by having something in their nose/throat. Patients who received a pre-procedure anxiolytic were significantly more likely to report more pain compared to those who did not. The highest rated interventions were pre-procedural education (97.0% “Very helpful”), verbal reassurance (96.9%), provider communicating steps of the procedure (96.9%), and reminders to breathe (87.5%). Conclusion: For patients undergoing awake laryngology procedures, the anticipation of gagging, pain, trouble breathing, and scope-related discomfort are worrisome factors. Of these, scope-related discomfort and gagging are the most often-reported sources of intraprocedural discomfort. The interventions patients found most helpful were based on preprocedural education and clear intraprocedural communication, which suggests that purposeful communication has a role in relieving anxiety. Level of evidence: Level 4

A man in his 80s presented with 3 weeks of lower back pain, generalised weakness, poor appetite and intermittent melena, without genitourinary symptoms or recent trauma. CT showed an old L1 compression fracture and new sclerotic lesions in the L3 and L4 vertebrae, as well as mildly enlarged abdominal lymph nodes. 3 days later, he returned to the emergency department with worsening symptoms, including new left hemiparesis. A head CT revealed a right subdural haematoma (SDH) with a midline shift. Despite treatment for disseminated intravascular coagulation, the patient’s condition deteriorated, leading to a suspicion of spontaneous intracranial hypotension. An autopsy revealed disseminated metastatic adenocarcinoma with dura and leptomeningeal metastases, ultimately causing spontaneous SDH and subsequent transtentorial herniation. This case highlights the impact of anchoring bias in clinical decision-making and the importance of early recognition of underlying malignancy as the aetiology of spontaneous SDH in patients presenting with signs and symptoms of metastatic cancer.

Background and Objectives: Physician scheduling affects job satisfaction and retention. This study explores how family medicine residency inpatient staffing relates to core faculty retention and program director (PD) perception of faculty satisfaction with work-life integration. Methods: A total of 280 family medicine residency PDs responded to the 2023 Council of Academic Family Medicine Education Research Alliance survey. We used the ꭓ2 test to explore associations among program demographics, inpatient staffing characteristics, faculty retention, and PD-reported faculty satisfaction with work-life integration. We measured associations among pairs of ordinal variables with Spearman’s correlation. Results: In two-thirds (66%) of programs, faculty cover the inpatient service at least every 8 weeks, with 40% of programs reporting averages of 70 or more hours per inpatient week; nevertheless, most programs’ faculty were perceived to be satisfied with less than 10% turnover. The number of hours per week was inversely associated with PD-reported faculty satisfaction (r=-0.21, P=.001). Faculty turnover was directly associated with community size (r=0.17, P=.01). Faculty turnover was more likely to be greater than 10% if the number of hours per inpatient week was more than 89 (odds ratio 12.4, P=.02). Faculty turnover, PD-reported faculty dissatisfaction, and plans to change inpatient staffing were all correlated (r>0.28, P<.0001). Conclusions: Most family medicine residencies have core faculty cover the inpatient service at least once every 8 weeks, during which they work at least 60 hours per week. Longer hours are associated with lower perceived faculty satisfaction of work-life integration, with a threshold effect on faculty turnover. Family medicine residency programs must carefully balance the needs of residents, the community served, and faculty themselves.

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