Chemotherapy disrupts learning, neurogenesis and theta activity in the adult brain.

Chemotherapy, especially if prolonged, disrupts attention, working memory and speed of processing in humans. Most cancer drugs that cross the blood-brain barrier also decrease adult neurogenesis. Because new neurons are generated in the hippocampus, this decrease may contribute to the deficits in working memory and related thought processes. The neurophysiological mechanisms that underlie these deficits are generally unknown. A possible mediator is hippocampal oscillatory activity within the theta range (3-12 Hz). Theta activity predicts and promotes efficient learning in healthy animals and humans. Here, we hypothesised that chemotherapy disrupts learning via decreases in hippocampal adult neurogenesis and theta activity. Temozolomide was administered to adult male Sprague-Dawley rats in a cyclic manner for several weeks. Treatment was followed by training with different types of eyeblink classical conditioning, a form of associative learning. Chemotherapy reduced both neurogenesis and endogenous theta activity, as well as disrupted learning and related theta-band responses to the conditioned stimulus. The detrimental effects of temozolomide only occurred after several weeks of treatment, and only on a task that requires the association of events across a temporal gap and not during training with temporally overlapping stimuli. Chemotherapy did not disrupt the memory for previously learned associations, a memory independent of (new neurons in) the hippocampus. In conclusion, prolonged systemic chemotherapy is associated with a decrease in hippocampal adult neurogenesis and theta activity that may explain the selective deficits in processes of learning that describe the 'chemobrain'.

High-Dose Frameless Stereotactic Radiosurgery for Trigeminal Neuralgia: A Single-Institution Experience and Systematic Review.

OBJECTIVE: Stereotactic radiosurgery is an effective treatment option for trigeminal neuralgia (TN), with frameless stereotactic radiosurgery (fSRS) allowing for a less invasive experience. A single-institutional series and systematic review of the literature were performed for cases of TN treated with fSRS. METHODS: Patients at our institution with TN that were treated with fSRS from the years 2012-2021 were included. Similarly, multiple databases were searched for studies regarding TN treated with fSRS where patient-level data was included from 2004-2020. Pain levels, via the Barrow Neurological Institute (BNI) scale, before and after treatment were analyzed. Pooled analysis was performed to compare treatment outcomes between studies using CyberKnife and LINAC modalities. RESULTS: Twenty-three patients at our institution were treated with LINAC fSRS (median treatment dose: 85 Gy). Most patients had TN refractory to previous procedural treatments. Eight (35%) patients had an excellent posttreatment response (BNI I-II), while 11 (48%) patients had a good result (BNI IIIa/b). Eight patients had recurrence of pain. A total of 30 articles were included in the systematic review, encompassing 1705 patients. At last follow-up, 63.1% (774/1227) of patients endorsed an excellent response, while 16.1% (197/1227) had a good response, and 22.5% (215/957) of patients had recurrence. Pain response, facial numbness rates, and pain recurrence rates were not significantly different between CyberKnife and LINAC modalities. CONCLUSIONS: Frameless SRS for TN appears to be an efficacious noninvasive option for patients with substantial comorbidities, who have failed other treatment methods, although it can be limited by higher recurrence rates.

Associative learning increases adult neurogenesis during a critical period.

Learning increases the number of immature neurons that survive and mature in the adult hippocampus. One-week-old cells are more likely to survive in response to learning than cells in animals that are exposed to training but do not learn. Because neurogenesis is an ongoing and overlapping process, it is possible that learning differentially affects new cells as a function of their maturity. To address this issue, we examined the effects of associative learning on the survival of cells at different stages of development. Training did not alter the number of cells that were produced during the training experience. Cells that were 1-2 weeks of age at the time of training survived after learning but cells that were younger or older did not. In contrast, cells that were produced during training were less likely to survive than cells in untrained animals. Additionally, the number of cells that were generated after learning in trained animals was not different from the number in untrained animals. Finally, survival was not increased if the memory was expressed when the cells were about 1-week-old. Together, these results indicate that new neurons are rescued from death by initial acquisition, not the expression or reacquisition, of an associative memory and only during a critical period. Overall, these results suggest the presence of a feedback system, which controls how many new neurons become incorporated into the adult brain in response to learning.

Changing the rate and hippocampal dependence of trace eyeblink conditioning: slow learning enhances survival of new neurons.

Trace eyeblink conditioning in which a conditioned stimulus and unconditioned stimulus are separated by a gap, is hippocampal dependent and can rescue new neurons in the adult dentate gyrus from death (e.g., Beylin et al., 2001; Gould et al., 1999). Tasks requiring more training trials for reliable expression of the conditioned response are most effective in enhancing survival of neurons (Waddell & Shors, 2008). To dissociate hippocampal dependence from acquisition rate, we facilitated hippocampal-dependent trace eyeblink conditioning in two ways: a shorter trace interval and signaling the intertrial interval with a post-US cue. Trace conditioning with a shorter trace interval (250ms) requires an intact hippocampus, and acquisition is faster relative to rats trained with a 500ms trace interval (e.g., Weiss et al., 1999). Using excitotoxic hippocampal lesions, we confirmed that eyeblink conditioning with the 250 or 500ms trace interval is hippocampal dependent. However, training with the post-US cue was not hippocampal dependent. The majority of lesion rats in this condition reached criterion of conditioned responding. To determine whether hippocampal dependence is sufficient to rescue adult-generated neurons in the dentate gyrus, rats were injected with BrdU and trained in one of the three trace eyeblink arrangements one week later. Of these training procedures, only the 500ms trace interval enhanced survival of new cells; acquisition of this task proceeded slowly relative to the 250ms and post-US cue conditions. These data demonstrate that rate of acquisition and not hippocampal dependence determines the impact of learning on adult neurogenesis.

Prospective Validation and Comparative Analysis of Coronary Risk Stratification Strategies Among Emergency Department Patients With Chest Pain.

Background Coronary risk stratification is recommended for emergency department patients with chest pain. Many protocols are designed as "rule-out" binary classification strategies, while others use graded-risk stratification. The comparative performance of competing approaches at varying levels of risk tolerance has not been widely reported. Methods and Results This is a prospective cohort study of adult patients with chest pain presenting between January 2018 and December 2019 to 13 medical center emergency departments within an integrated healthcare delivery system. Using an electronic clinical decision support interface, we externally validated and assessed the net benefit (at varying risk thresholds) of several coronary risk scores (History, ECG, Age, Risk Factors, and Troponin [HEART] score, HEART pathway, Emergency Department Assessment of Chest Pain Score Accelerated Diagnostic Protocol), troponin-only strategies (fourth-generation assay), unstructured physician gestalt, and a novel risk algorithm (RISTRA-ACS). The primary outcome was 60-day major adverse cardiac event defined as myocardial infarction, cardiac arrest, cardiogenic shock, coronary revascularization, or all-cause mortality. There were 13 192 patient encounters included with a 60-day major adverse cardiac event incidence of 3.7%. RISTRA-ACS and HEART pathway had the lowest negative likelihood ratios (0.06, 95% CI, 0.03-0.10 and 0.07, 95% CI, 0.04-0.11, respectively) and the greatest net benefit across a range of low-risk thresholds. RISTRA-ACS demonstrated the highest discrimination for 60-day major adverse cardiac event (area under the receiver operating characteristic curve 0.92, 95% CI, 0.91-0.94, P<0.0001). Conclusions RISTRA-ACS and HEART pathway were the optimal rule-out approaches, while RISTRA-ACS was the best-performing graded-risk approach. RISTRA-ACS offers promise as a versatile single approach to emergency department coronary risk stratification. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03286179.

Graded Coronary Risk Stratification for Emergency Department Patients With Chest Pain: A Controlled Cohort Study.

Background Resource utilization among emergency department (ED) patients with possible coronary chest pain is highly variable. Methods and Results Controlled cohort study amongst 21 EDs of an integrated healthcare system examining the implementation of a graded coronary risk stratification algorithm (RISTRA-ACS [risk stratification for acute coronary syndrome]). Thirteen EDs had access to RISTRA-ACS within the electronic health record (RISTRA sites) beginning in month 24 of a 48-month study period (January 2016 to December 2019); the remaining 8 EDs served as contemporaneous controls. Study participants had a chief complaint of chest pain and serum troponin measurement in the ED. The primary outcome was index visit resource utilization (observation unit or hospital admission, or 7-day objective cardiac testing). Secondary outcomes were 30-day objective cardiac testing, 60-day major adverse cardiac events (MACE), and 60-day MACE-CR (MACE excluding coronary revascularization). Difference-in-differences analyses controlled for secular trends with stratification by estimated risk and adjustment for risk factors, ED physician and facility. A total of 154 914 encounters were included. Relative to control sites, 30-day objective cardiac testing decreased at RISTRA sites among patients with low (≤2%) estimated 60-day MACE risk (-2.5%, 95% CI -3.7 to -1.2%, P<0.001) and increased among patients with non-low (>2%) estimated risk (+2.8%, 95% CI +0.6 to +4.9%, P=0.014), without significant overall change (-1.0%, 95% CI -2.1 to 0.1%, P=0.079). There were no statistically significant differences in index visit resource utilization, 60-day MACE or 60-day MACE-CR. Conclusions Implementation of RISTRA-ACS was associated with better allocation of 30-day objective cardiac testing and no change in index visit resource utilization or 60-day MACE. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03286179.

Crosstalk between nonclassical monocytes and alveolar macrophages mediates transplant ischemia-reperfusion injury through classical monocyte recruitment.

Primary graft dysfunction (PGD) is the predominant cause of early graft loss following lung transplantation. We recently demonstrated that donor pulmonary intravascular nonclassical monocytes (NCM) initiate neutrophil recruitment. Simultaneously, host-origin classical monocytes (CM) permeabilize the vascular endothelium to allow neutrophil extravasation necessary for PGD. Here, we show that a CCL2-CCR2 axis is necessary for CM recruitment. Surprisingly, although intravital imaging and multichannel flow cytometry revealed that depletion of donor NCM abrogated CM recruitment, single cell RNA sequencing identified donor alveolar macrophages (AM) as predominant CCL2 secretors. Unbiased transcriptomic analysis of murine tissues combined with murine KOs and chimeras indicated that IL-1ß production by donor NCM was responsible for the early activation of AM and CCL2 release. IL-1ß production by NCM was NLRP3 inflammasome dependent and inhibited by treatment with a clinically approved sulphonylurea. Production of CCL2 in the donor AM occurred through IL-1R-dependent activation of the PKC and NF-κB pathway. Accordingly, we show that IL-1ß-dependent paracrine interaction between donor NCM and AM leads to recruitment of recipient CM necessary for PGD. Since depletion of donor NCM, IL-1ß, or IL-1R antagonism and inflammasome inhibition abrogated recruitment of CM and PGD and are feasible using FDA-approved compounds, our findings may have potential for clinical translation.

Automated Retrospective Calculation of the EDACS and HEART Scores in a Multicenter Prospective Cohort of Emergency Department Chest Pain Patients.

OBJECTIVES: Coronary risk scores are commonly applied to emergency department patients with undifferentiated chest pain. Two prominent risk score-based protocols are the Emergency Department Assessment of Chest pain Score Accelerated Diagnostic Protocol (EDACS-ADP) and the History, ECG, Age, Risk factors, and Troponin (HEART) pathway. Since prospective documentation of these risk determinations can be challenging to obtain, quality improvement projects could benefit from automated retrospective risk score classification methodologies. METHODS: EDACS-ADP and HEART pathway data elements were prospectively collected using a Web-based electronic clinical decision support (eCDS) tool over a 24-month period (2018-2019) among patients presenting with chest pain to 13 EDs within an integrated health system. Data elements were also extracted and processed electronically (retrospectively) from the electronic health record (EHR) for the same patients. The primary outcome was agreement between the prospective/eCDS and retrospective/EHR data sets on dichotomous risk protocol classification, as assessed by kappa statistics (ĸ). RESULTS: There were 12,110 eligible eCDS uses during the study period, of which 66 and 47% were low-risk encounters by EDACS-ADP and HEART pathway, respectively. Agreement on low-risk status was acceptable for EDACS-ADP (ĸ = 0.73, 95% confidence interval [CI] = 0.72 to 0.75) and HEART pathway (ĸ = 0.69, 95% CI = 0.68 to 0.70) and for the continuous scores (interclass correlation coefficients = 0.87 and 0.84 for EDACS and HEART, respectively). CONCLUSIONS: Automated retrospective determination of low risk status by either the EDACS-ADP or the HEART pathway provides acceptable agreement compared to prospective score calculations, providing a feasible risk adjustment option for use in large data set analyses.

Performance of Coronary Risk Scores Among Patients With Chest Pain in the Emergency Department.

BACKGROUND: Both the modified History, Electrocardiogram, Age, Risk factors and Troponin (HEART) score and the Emergency Department Assessment of Chest pain Score (EDACS) can identify patients with possible acute coronary syndrome (ACS) at low risk (<1%) for major adverse cardiac events (MACE). OBJECTIVES: The authors sought to assess the comparative accuracy of the EDACS (original and simplified) and modified HEART risk scores when using cardiac troponin I (cTnI) cutoffs below the 99th percentile, and obtain precise MACE risk estimates. METHODS: The authors conducted a retrospective study of adult emergency department (ED) patients evaluated for possible ACS in an integrated health care system between 2013 and 2015. Negative predictive values for MACE (composite of myocardial infarction, cardiogenic shock, cardiac arrest, and all-cause mortality) were determined at 60 days. Reclassification analyses were used to assess the comparative accuracy of risk scores and lower cTnI cutoffs. RESULTS: A total of 118,822 patients with possible ACS were included. The 3 risk scores' accuracies were optimized using the lower limit of cTnI quantitation (<0.02 ng/ml) to define low risk for 60-day MACE, with reclassification yields ranging between 3.4% and 3.9%, while maintaining similar negative predictive values (range 99.49% to 99.55%; p = 0.27). The original EDACS identified the largest proportion of patients as low risk (60.6%; p < 0.0001). CONCLUSIONS: Among ED patients with possible ACS, the modified HEART score, original EDACS, and simplified EDACS all predicted a low risk of 60-day MACE with improved accuracy using a cTnI cutoff below the 99th percentile. The original EDACS identified the most low-risk patients, and thus may be the preferred risk score.

Impact of relative contraindications to home management in emergency department patients with low-risk pulmonary embolism.

RATIONALE: Studies of adults presenting to the emergency department (ED) with acute pulmonary embolism (PE) suggest that those who are low risk on the PE Severity Index (classes I and II) can be managed safely without hospitalization. However, the impact of relative contraindications to home management on outcomes has not been described. OBJECTIVES: To compare 5-day and 30-day adverse event rates among low-risk ED patients with acute PE without and with outpatient ineligibility criteria. METHODS: We conducted a retrospective multicenter cohort study of adults presenting to the ED with acute low-risk PE between 2010 and 2012. We evaluated the association between outpatient treatment eligibility criteria based on a comprehensive list of relative contraindications and 5-day adverse events and 30-day outcomes, including major hemorrhage, recurrent venous thromboembolism, and all-cause mortality. MEASUREMENTS AND MAIN RESULTS: Of 423 adults with acute low-risk PE, 271 (64.1%) had no relative contraindications to outpatient treatment (outpatient eligible), whereas 152 (35.9%) had at least one contraindication (outpatient ineligible). Relative contraindications were categorized as PE-related factors (n = 112; 26.5%), comorbid illness (n = 42; 9.9%), and psychosocial barriers (n = 19; 4.5%). There were no 5-day events in the outpatient-eligible group (95% upper confidence limit, 1.7%) and two events (1.3%; 95% confidence interval [CI], 0.1-5.0%) in the outpatient-ineligible group (P = 0.13). At 30 days, there were five events (two recurrent venous thromboemboli and three major bleeding events) in the outpatient-eligible group (1.8%; 95% CI, 0.7-4.4%) compared with nine in the ineligible group (5.9%; 95% CI, 2.7-10.9%; P < 0.05). This difference remained significant when controlling for PE severity class. CONCLUSIONS: Nearly two-thirds of adults presenting to the ED with low-risk PE were potentially eligible for outpatient therapy. Relative contraindications to outpatient management were associated with an increased frequency of adverse events at 30 days among adults with low-risk PE.

Training vs. body image: does training improve subjective appearance ratings?

The purpose of this study was to determine if a short-term exercise program (6 weeks) could improve subjective physical appearance ratings. Twenty-five previously sedentary adult men (aged 18-40 years) were randomly assigned to one of 3 training groups: cardiovascular, strength, or control. Subjects participating in an exercise group trained for an average of 34 minutes, 3 times per week. All subjects were pre- and posttested to determine body composition, strength, and cardiovascular fitness. Subjects were also digitally photographed from 4 angles. The photographs were rated by the subjects and by a panel of 6 judges using an analog scale. There was no significant difference in the groups by trials interaction effect for pre- and post-Vo(2)max, percent fat, total lean tissue, percent limb fat, percent trunk fat, lean trunk tissue, or lean limb tissue. The subjects rated themselves higher than the panel, with average scores of 4.74 vs. 3.46, 4.26 vs. 3.10, and 4.61 vs. 3.49 for the cardiovascular, strength, and control groups, respectively (p < 0.05). The men of the panel rated the subjects significantly higher than did the women, with average scores of 4.61 vs. 2.31, 4.13 vs. 2.06, and 4.53 vs. 2.18 for the cardiovascular, resistance, and control groups, respectively (p < 0.05). This study showed that a 6-week training program did not change self-rated or panel-rated appearance scores.