Association of Anticoagulant Use With Hemorrhage Location and Etiology in Incident Spontaneous Intracerebral Hemorrhage.

BACKGROUND: It is unknown whether hypertensive microangiopathy or cerebral amyloid angiopathy (CAA) predisposes more to anticoagulant-associated intracerebral hemorrhage (AA-ICH). The purpose of our study was to determine whether AA-ICH is associated with lobar location and probable CAA. METHODS: This was a cross-sectional analysis of patients with first-ever spontaneous ICH admitted to a tertiary hospital in Boston, between 2008 and 2023. Univariable and multivariable logistic regression were used to investigate the association between anticoagulation use and both lobar hemorrhage location and probable CAA on magnetic resonance imaging (MRI) by Boston Criteria 2.0 or computed tomography by Simplified Edinburgh Criteria. RESULTS: A total of 1104 patients (mean [SD] age, 73 [12]; 499 females [45.0%]) were included. Of the 1104 patients, 268 (24.3%) had AA-ICH: 148 (55.2%) with vitamin K antagonists and 107 (39.9%) with direct oral anticoagulants. Brain MRI was performed in 695 (63.0%) patients. The proportion of patients with lobar hemorrhage was not different between those with and without AA-ICH (121/268 [45.1%] versus 424/836 [50.7%]; odds ratio [OR], 0.80 [95% CI, 0.61-1.05]; P=0.113). Patients with AA-ICH were less likely to have probable CAA on MRI (17/146 [11.6%] versus 127/549 [23.1%]; OR, 0.44 [95% CI, 0.25-0.75]; P=0.002) and probable CAA on MRI or computed tomography if MRI not performed (27/268 [10.0%] versus 200/836 [23.9%]; OR, 0.36 [95% CI, 0.23-0.55]; P<0.001). Among patients with AA-ICH, there were no differences in the proportion with lobar hemorrhage (63/148 [42.6%] versus 46/107 [43.0%]; OR, 1.02 [95% CI, 0.62-1.68]; P=0.946) or probable CAA on MRI (10/72 [13.9%] versus 7/69 [10.1%]; OR, 0.70 [95% CI, 0.25-1.96]; P=0.495) between vitamin K antagonists and direct oral anticoagulant users. CONCLUSIONS: AA-ICH was not associated with lobar hemorrhage location but was associated with reduced odds of probable CAA. These results suggest that hypertensive microangiopathy may predispose more toward incident AA-ICH than CAA and emphasize the importance of blood pressure control among anticoagulant users. These findings require replication in additional cohorts.

Pain catastrophizing and risk of progression to widespread pain among patients with chronic low back pain: A retrospective cohort study.

BACKGROUND: Chronic low back pain often progresses to widespread pain. Although many factors are associated with progression, their roles in contributing to chronic widespread pain (CWP) are often unclear. OBJECTIVE: To determine if pain catastrophizing is an independent risk factor for CWP. DESIGN: Retrospective cohort study within a national pain research registry from April 2016 through August 2022. METHODS: A total of 1111 participants with chronic low back pain, but without CWP, were included. Participants were followed at quarterly intervals for up to 48 months to measure CWP risk. Survival analyses involved Kaplan-Meier plots and the Cox proportional hazards model to measure CWP risk according to pain catastrophizing and subscale scores for rumination, magnification, and helplessness. RESULTS: Crude CWP risks for moderate pain catastrophizing (HR, 2.13; 95% CI, 1.54-2.95; P < 0.001) and high pain catastrophizing (HR, 3.98; 95% CI, 2.95-5.35; P < 0.001) were each elevated in comparison with low pain catastrophizing. Adjusted CWP risks for moderate pain catastrophizing (HR, 1.80; 95% CI, 1.27-2.53; P < 0.001) and high pain catastrophizing (HR, 2.82; 95% CI, 1.98-4.02; P < 0.001) remained elevated in analyses that controlled for potential confounders. Corresponding results were observed in the survival analyses involving rumination, magnification, and helplessness. CONCLUSIONS: Pain catastrophizing appears to be an independent risk factor for progression to CWP among patients with chronic low back pain. These findings provide a rationale for interventions aimed at reducing pain catastrophizing, including rumination, magnification, and helplessness, among patients with chronic low back pain.

Anaplasmosis-induced hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening inflammatory syndrome of severe immune system activation. It is a diagnostic challenge with high morbidity and mortality. We present a case of HLH due to anaplasmosis infection. A 54-year-old man with chronic obstructive pulmonary disease presented with fever, nausea, vomiting, dyspnea, and arthralgias for 6 days. He had a rapidly progressive clinical decline requiring intubation for acute respiratory failure and dialysis for acute renal failure. He tested positive for anaplasmosis. His workup met criteria for HLH. He was treated with doxycycline and a steroid taper with clinical improvement allowing for extubation and renal recovery. Patients with persistent fevers, hepatosplenomegaly, cytopenias, and hyperferritinemia should be worked up for HLH.

Muscle-specific 4E-BP1 signaling activation improves metabolic parameters during aging and obesity.

Eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) is a key downstream effector of mTOR complex 1 (mTORC1) that represses cap-dependent mRNA translation initiation by sequestering the translation initiation factor eIF4E. Reduced mTORC1 signaling is associated with life span extension and improved metabolic homeostasis, yet the downstream targets that mediate these benefits are unclear. Here, we demonstrated that enhanced 4E-BP1 activity in mouse skeletal muscle protects against age- and diet-induced insulin resistance and metabolic rate decline. Transgenic animals displayed increased energy expenditure; altered adipose tissue distribution, including reduced white adipose accumulation and preserved brown adipose mass; and were protected from hepatic steatosis. Skeletal muscle-specific 4E-BP1 mediated metabolic protection directly through increased translation of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and enhanced respiratory function. Non-cell autonomous protection was through preservation of brown adipose tissue metabolism, which was increased in 4E-BP1 transgenic animals during normal aging and in a response to diet-induced type 2 diabetes. Adipose phenotypes may derive from enhanced skeletal muscle expression and secretion of the known myokine FGF21. Unlike skeletal muscle, enhanced adipose-specific 4E-BP1 activity was not protective but instead was deleterious in response to the same challenges. These findings indicate that regulation of 4E-BP1 in skeletal muscle may serve as an important conduit through which mTORC1 controls metabolism.

TEN1 is essential for CDC13-mediated telomere capping.

Telomere binding proteins protect chromosome ends from degradation and mask chromosome termini from checkpoint surveillance. In Saccharomyces cerevisiae, Cdc13 binds single-stranded G-rich telomere repeats, maintaining telomere integrity and length. Two additional proteins, Ten1 and Stn1, interact with Cdc13 but their contributions to telomere integrity are not well defined. Ten1 is known to prevent accumulation of aberrant single-stranded telomere DNA; whether this results from defective end protection or defective telomere replication is unclear. Here we report our analysis of a new group of ten1 temperature-sensitive (ts) mutants. At permissive temperatures, ten1-ts strains display greatly elongated telomeres. After shift to nonpermissive conditions, however, ten1-ts mutants accumulate extensive telomeric single-stranded DNA. Cdk1 activity is required to generate these single-stranded regions, and deleting the EXO1 nuclease partially suppresses ten1-ts growth defects. This is similar to cdc13-1 mutants, suggesting ten1-ts strains are defective for end protection. Moreover, like Cdc13, our analysis reveals Ten1 promotes de novo telomere addition. Interestingly, in ten1-ts strains at high temperatures, telomeric single-stranded DNA and Rad52-YFP repair foci are strongly induced despite Cdc13 remaining associated with telomeres, revealing Cdc13 telomere binding is not sufficient for end protection. Finally, unlike cdc13-1 mutants, ten1-ts strains display strong synthetic interactions with mutations in the POLalpha complex. These results emphasize that Cdc13 relies on Ten1 to execute its essential function, but leave open the possibility that Ten1 has a Cdc13-independent role in DNA replication.