Transcriptomics, regional cerebral blood flow (rCBF), and a spatial motor virtual reality task were integrated using mediation analysis in a novel demonstration of "imaging omics". Data collected in ...NCAA Division I football athletes cleared for play before in-season training showed significant relationships in a) elevated levels of miR-30d and miR-92a to elevated putamen rCBF, (b) elevated putamen rCBF to compromised balance scores, and (c) compromised balance scores to elevated miRNA levels. rCBF acted as a mediator variable (minimum 70% mediation, significant Sobel's test) between abnormal miRNA levels and compromised balance scores. Given the involvement of these miRNAs in inflammation and immune function, and that vascular perfusion is a component of the inflammatory response, these findings support a chronic inflammatory model of repetitive head acceleration events (HAEs). rCBF, a systems biology measure, was necessary for miRNA to affect behavior. These results suggest miRNA as a potential diagnostic biomarker for repetitive HAEs.
Somatic mutations in spliceosome genes are detectable in ∼50% of patients with myelodysplastic syndromes (MDS). We hypothesize that cells harbouring spliceosome gene mutations have increased ...sensitivity to pharmacological perturbation of the spliceosome. We focus on mutant U2AF1 and utilize sudemycin compounds that modulate pre-mRNA splicing. We find that haematopoietic cells expressing mutant U2AF1(S34F), including primary patient cells, have an increased sensitivity to in vitro sudemycin treatment relative to controls. In vivo sudemycin treatment of U2AF1(S34F) transgenic mice alters splicing and reverts haematopoietic progenitor cell expansion induced by mutant U2AF1 expression. The splicing effects of sudemycin and U2AF1(S34F) can be cumulative in cells exposed to both perturbations-drug and mutation-compared with cells exposed to either alone. These cumulative effects may result in downstream phenotypic consequences in sudemycin-treated mutant cells. Taken together, these data suggest a potential for treating haematological cancers harbouring U2AF1 mutations with pre-mRNA splicing modulators like sudemycins.
There have been over 769 million cases of COVID-19, and up to 50% of infected individuals are asymptomatic. The purpose of this study aimed to assess the use of a clinical-grade physiological ...wearable monitoring system, ANNE One, to develop an artificial intelligence algorithm for (1) cough detection and (2) early detection of COVID-19, through the retrospective analysis of prospectively collected physiological data from longitudinal wear of ANNE sensors in a multicenter single arm study of subjects at high risk for COVID-19 due to occupational or home exposures. The study employed a two-fold approach: cough detection algorithm development and COVID-19 detection algorithm development. For cough detection, healthy individuals wore an ANNE One chest sensor during scripted activity. The final performance of the algorithm achieved an F-1 score of 83.3% in twenty-seven healthy subjects during biomarker validation. In the COVID-19 detection algorithm, individuals at high-risk for developing COVID-19 because of recent exposures received ANNE One sensors and completed daily symptom surveys. An algorithm analyzing vital parameters (heart rate, respiratory rate, cough count, etc.) for early COVID-19 detection was developed. The COVID-19 detection algorithm exhibited a sensitivity of 0.47 and specificity of 0.72 for detecting COVID-19 in 325 individuals with recent exposures. Participants demonstrated high adherence (≥ 4 days of wear per week). ANNE One shows promise for detection of COVID-19. Inclusion of respiratory biomarkers (e.g., cough count) enhanced the algorithm's predictive ability. These findings highlight the potential value of wearable devices in early disease detection and monitoring.
Abstract
BACKGROUND
Laser interstitial thermal therapy (LITT) is a promising approach for cytoreduction of deep-seated gliomas. However, parameters contributing to treatment success remain unclear.
...OBJECTIVE
To identify extent of ablation (EOA) and time to chemotherapy (TTC) as predictors of improved overall and progression-free survival (OS, PFS) and suggest laser parameters to achieve optimal EOA.
METHODS
Demographic, clinical, and survival data were collected retrospectively from 20 patients undergoing LITT for newly diagnosed glioblastoma (nGBM). EOA was calculated through magnetic resonance imaging-based volumetric analysis. Kaplan-Meier and multivariate Cox regression were used to examine the relationship between EOA with OS and PFS accounting for covariates (age, isocitrate dehydrogenase-1 (IDH1) mutation, O6-methylguanine-DNA methyltransferase hypermethylation). The effect of laser thermodynamic parameters (power, energy, time) on EOA was identified through linear regression.
RESULTS
Median OS and PFS for the entire cohort were 36.2 and 3.5 mo respectively. Patient's with >70% EOA had significantly improved PFS compared to ≤70% EOA (5.2 vs 2.3 mo, P = .01) and trended toward improved OS (36.2 vs 11 mo, P = .07) on univariate and multivariate analysis. Total laser power was a significant predictor for increased EOA when accounting for preoperative lesion volume (P = .001). Chemotherapy within 16 d of surgery significantly predicted improved PFS compared to delaying chemotherapy (9.4 vs 3.1 mo, P = .009).
CONCLUSION
Increased EOA was a predictor of improved PFS with evidence of a trend toward improved OS in LITT treatment of nGBM. A strategy favoring higher laser power during tumor ablation may achieve optimal EOA. Early transition to chemotherapy after LITT improves PFS.
Mucopolysaccharidosis type I (MPS I) is a progressive, multi-systemic, inherited metabolic disease caused by deficiency of α-L-iduronidase (IDUA). Current treatments for this disease are ineffective ...in treating central nervous system (CNS) disease due to the inability of lysosomal enzymes to traverse the blood-brain barrier. A noninvasive and effective approach was taken in the treatment of CNS disease by intranasal administration of an IDUA-encoding adeno-associated virus serotype 9 (AAV9) vector. Adult IDUA-deficient mice aged 3 months were instilled intranasally with AAV9-IDUA vector. Animals sacrificed 5 months post instillation exhibited IDUA enzyme activity levels that were up to 50-fold that of wild-type mice in the olfactory bulb, with wild-type levels of enzyme restored in all other parts of the brain. Intranasal treatment with AAV9-IDUA also resulted in the reduction of tissue glycosaminoglycan storage materials in the brain. There was strong IDUA immunofluorescence staining of tissue sections observed in the nasal epithelium and olfactory bulb, but there was no evidence of the presence of transduced cells in other portions of the brain. This indicates that reduction of storage materials most likely occurred as a result of enzyme diffusion from the olfactory bulb and the nasal epithelium into deeper areas of the brain. At 8 months of age, neurocognitive testing using the Barnes maze to assess spatial navigation demonstrated that treated IDUA-deficient mice were no different from normal control animals, while untreated IDUA-deficient mice exhibited significant learning and navigation deficits. This novel, noninvasive strategy for intranasal AAV9-IDUA instillation could potentially be used to treat CNS manifestations of human MPS I.
OBJECTIVE:Cardiac surgery is frequently followed by postoperative delirium, which is associated with increased 1-year mortality, late cognitive deficits, and higher costs. Currently, there are no ...recommendations for pharmacologic prevention of postoperative delirium. Impaired cholinergic transmission is believed to play an important role in the development of delirium. We tested the hypothesis that prophylactic short-term administration of oral rivastigmine, a cholinesterase inhibitor, reduces the incidence of delirium in elderly patients during the first 6 days after elective cardiac surgery.
DESIGN:Double-blind, randomized, placebo-controlled trial.
SETTING:One Swiss University Hospital.
PATIENTS:One hundred twenty patients aged 65 or older undergoing elective cardiac surgery with cardiopulmonary bypass.
INTERVENTION:Patients were randomly assigned to receive either placebo or 3 doses of 1.5 mg of oral rivastigmine per day starting the evening before surgery and continuing until the evening of the sixth postoperative day.
MEASUREMENTS AND MAIN RESULTS:The primary predefined outcome was delirium diagnosed with the Confusion Assessment Method within 6 days postoperatively. Secondary outcome measures were the results of daily Mini-Mental State Examinations and clock drawing tests, and the use of a rescue treatment consisting of haloperidol and/or lorazepam in patients with delirium. Delirium developed in 17 of 57 (30%) and 18 of 56 (32%) patients in the placebo and rivastigmine groups, respectively (p = 0.8). There was no treatment effect on the time course of Mini-Mental State Examinations and clock drawing tests (p = 0.4 and p = 0.8, respectively). There was no significant difference in the number of patients receiving haloperidol (18 of 57 and 17 of 56, p = 0.9) or lorazepam (38 of 57 and 35 of 56, p = 0.6) in the placebo and rivastigmine groups, respectively.
CONCLUSION:This negative or, because of methodologic issues, possibly failed trial does not support short-term prophylactic administration of oral rivastigmine to prevent postoperative delirium in elderly patients undergoing elective cardiac surgery with cardiopulmonary bypass.
Somatic mutations and copy number variation in the ERBB family are frequent in urothelial carcinoma (UC) and may represent viable therapeutic targets. We studied whether afatinib (an oral, ...irreversible inhibitor of the ErbB family) has activity in UC and if specific ERBB molecular alterations are associated with clinical response.
In this phase II trial, patients with metastatic platinum-refractory UC received afatinib 40 mg/day continuously until progression or intolerance. The primary end point was 3-month progression-free survival (PFS3). Prespecified tumor analysis for alterations in EGFR, HER2, ERBB3, and ERBB4 was conducted.
The first-stage enrollment goal of 23 patients was met. Patient demographic data included: 78% male, median age 67 years (range, 36 to 82 years), hemoglobin < 10 g/dL in 17%, liver metastases in 30%, median time from prior chemotherapy of 3.6 months, and Eastern Cooperative Oncology Group performance status ≤ 1 in 100%. No unexpected toxicities were observed; two patients required dose reduction for grade 3 fatigue and rash. Overall, five of 23 patients (21.7%) met PFS3 (two partial response, three stable disease). Notably, among the 21 tumors analyzed, five of six patients (83.3%) with HER2 and/or ERBB3 alterations achieved PFS3 (PFS = 10.3, 7.0, 6.9, 6.3, and 5.0 months, respectively) versus none of 15 patients without alterations (P < .001). Three of four patients with HER2 amplification and three of three patients with ERBB3 somatic mutations (G284R, V104M, and R103G) met PFS3. One patient with both HER2 amplification and ERBB3 mutation never progressed on therapy, but treatment was discontinued after 10.3 months as a result of depressed ejection fraction. The median time to progression/discontinuation was 6.6 months in patients with HER2/ERBB3 alterations versus 1.4 months in patients without alterations (P < .001).
Afatinib demonstrated significant activity in patients with platinum-refractory UC with HER2 or ERBB3 alterations. The potential contribution of ERBB3 to afatinib sensitivity is novel. Afatinib deserves further investigation in molecularly selected UC.
Pregnant trauma patients (PTPs) undergo observation and fetal monitoring following trauma due to possible fetal delivery (FD) or adverse outcome. There is a paucity of data on PTP outcomes, ...especially related to risk factors for FD. We aimed to identify predictors of posttraumatic FD in potentially viable pregnancies.
All PTPs (≥18 years) with ≥24-weeks gestational age were included in this multicenter retrospective study at 12 Level-I and II trauma centers between 2016 and 2021. Pregnant trauma patients who underwent FD ((+) FD) were compared to those who did not deliver ((-) FD) during the index hospitalization. Univariate analyses and multivariable logistic regression were performed to identify predictors of FD.
Of 591 PTPs, 63 (10.7%) underwent FD, with 4 (6.3%) maternal deaths. The (+) FD group was similar in maternal age (27 vs. 28 years, p = 0.310) but had older gestational age (37 vs. 30 weeks, p < 0.001) and higher mean injury severity score (7.0 vs. 1.5, p < 0.001) compared with the (-) FD group. The (+) FD group had higher rates of vaginal bleeding (6.3% vs. 1.1%, p = 0.002), uterine contractions (46% vs. 23.5%, p < 0.001), and abnormal fetal heart tracing (54.7% vs. 14.6%, p < 0.001). On multivariate analysis, independent predictors for (+) FD included abdominal injury (odds ratio OR, 4.07; confidence interval CI, 1.11-15.02; p = 0.035), gestational age (OR, 1.68 per week ≥24 weeks; CI, 1.44-1.95; p < 0.001), abnormal FHT (OR, 12.72; CI, 5.19-31.17; p < 0.001), and premature rupture of membranes (OR, 35.97; CI, 7.28-177.74; p < 0.001).
The FD rate was approximately 10% for PTPs with viable fetal gestational age. Independent risk factors for (+) FD included maternal and fetal factors, many of which are available on initial trauma bay evaluation. These risk factors may help predict FD in the trauma setting and shape future guidelines regarding the recommended observation of PTPs.
Therapeutic/Care Management; Level III.
Pediatric pedestrian injuries (PPI) are a major public health concern. This study utilized geospatial analysis to characterize the risk and injury severity of PPI.
A retrospective chart review of PPI ...patients (age < 18) from a level 1 trauma center was performed (2013–2020). A geographic information system geocoded injury location to home and other public landmarks. Incidents were aggregated to zip codes and the Local Indicators of Spatial Association statistic tested for spatial clustering of injury rates per 10,000 children. Predictors for increased injury severity were assessed by logistic regression.
PPI encompassed 6% (n = 188) of pediatric traumas. Most patients were black (54%), male (58%), >13 years (56%), and with Medicaid insurance (68%). Nine zip codes comprised a statistically significant cluster of PPI. Nearly half (40%) occurred within a quarter mile of home; 7% occurred at home. Most (65%) PPI occurred within 1 mile of a school, and 45% occurred within a quarter mile of a park. Nearly all (99%) PPI occurred within a quarter mile of a major intersection and/or roadway. Using admission to ICU as a marker for injury severity, farther distance from home (OR 1.060, 95% CI 1.001–1.121, p = 0.045) and age <13 years (3.662, 95% CI 1.854–7.231, p < 0.001) were independent predictors of injury severity.
There are significant sociodemographic disparities in PPI. Most injuries occur near patients’ homes and other public landmarks. Multidisciplinary injury prevention collaboration can help inform policymakers, direct local safety programs, and provide a model for PPI prevention at the national level.
Level IV.
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