Proton beam radiotherapy versus transarterial chemoembolization for hepatocellular carcinoma: Results of a randomized clinical trial.

BACKGROUND: This study compares survival rates, recurrence patterns, toxicity, and treatment cost in patients with hepatocellular carcinoma (HCC) treated with either transarterial chemoembolization (TACE) or proton beam radiotherapy (PBT). METHODS: Subjects with untreated HCC meeting Milan or San Francisco transplant criteria were recruited. Subjects were randomized to receive PBT (n = 36) or TACE (n = 40). Proton therapy was administered in 15 fractions over 3 weeks to a total dose of 70.2 Gy. TACE was repeated until complete or maximal response. The primary outcome measure was overall survival (OS). Secondary end points were progression-free survival (PFS), local control (LC), toxicity, and cost. RESULTS: Of the 76 randomized patients, 74 were assessed for outcome measures. The 2-year OS for PBT versus TACE was similar at 68%, 95% confidence interval (CI), 0.54-0.86, and 65%, 95% CI, 0.52-0.83 (p = .80), however, median PFS was improved for PBT versus TACE (not reached vs. 12 months, p = .002). LC was improved with PBT versus TACE (hazard ratio, 5.64; 95% CI, 1.78-17.9, p = .003). Days of posttreatment hospitalization were 24 for PBT and 166 for TACE (p < .001). Total mean cost per patient for treatment and posttreatment care revealed a 28% cost savings for PBT. CONCLUSIONS: PBT and TACE yielded similar OS for treatment of HCC, but PFS and LC were improved with PBT compared to TACE. Patients treated with PBT required fewer courses of treatment, fewer posttreatment hospitalization days, and reduced cost of treatment compared to TACE. These data support the use of PBT as a viable treatment alternative to TACE for patients with HCC within transplant criteria.

Association of Radiotherapy Duration With Clinical Outcomes in Patients With Esophageal Cancer Treated in NRG Oncology Trials: A Secondary Analysis of NRG Oncology Randomized Clinical Trials.

Importance: For many types of epithelial malignant neoplasms that are treated with definitive radiotherapy (RT), treatment prolongation and interruptions have an adverse effect on outcomes. Objective: To analyze the association between RT duration and outcomes in patients with esophageal cancer who were treated with definitive chemoradiotherapy (CRT). Design, Setting, and Participants: This study was an unplanned, post hoc secondary analysis of 3 prospective, multi-institutional phase 3 randomized clinical trials (Radiation Therapy Oncology Group [RTOG] 8501, RTOG 9405, and RTOG 0436) of the National Cancer Institute-sponsored NRG Oncology (formerly the National Surgical Adjuvant Breast and Bowel Project, RTOG, and Gynecologic Oncology Group). Enrolled patients with nonmetastatic esophageal cancer underwent definitive CRT in the trials between 1986 and 2013, with follow-up occurring through 2014. Data analyses were conducted between March 2022 to February 2023. Exposures: Treatment groups in the trials used standard-dose RT (50 Gy) and concurrent chemotherapy. Main Outcomes and Measures: The outcomes were local-regional failure (LRF), distant failure, disease-free survival (DFS), and overall survival (OS). Multivariable models were used to examine the associations between these outcomes and both RT duration and interruptions. Radiotherapy duration was analyzed as a dichotomized variable using an X-Tile software to choose a cut point and its median value as a cut point, as well as a continuous variable. Results: The analysis included 509 patients (median [IQR] age, 64 [57-70] years; 418 males [82%]; and 376 White individuals [74%]). The median (IQR) follow-up was 4.01 (2.93-4.92) years for surviving patients. The median cut point of RT duration was 39 days or less in 271 patients (53%) vs more than 39 days in 238 patients (47%), and the X-Tile software cut point was 45 days or less in 446 patients (88%) vs more than 45 days in 63 patients (12%). Radiotherapy interruptions occurred in 207 patients (41%). Female (vs male) sex and other (vs White) race and ethnicity were associated with longer RT duration and RT interruptions. In the multivariable models, RT duration longer than 45 days was associated with inferior DFS (hazard ratio [HR], 1.34; 95% CI, 1.01-1.77; P = .04). The HR for OS was 1.33, but the results were not statistically significant (95% CI, 0.99-1.77; P = .05). Radiotherapy duration longer than 39 days (vs ≤39 days) was associated with a higher risk of LRF (HR, 1.32; 95% CI, 1.06-1.65; P = .01). As a continuous variable, RT duration (per 1 week increase) was associated with DFS failure (HR, 1.14; 95% CI, 1.01-1.28; P = .03). The HR for LRF 1.13, but the result was not statistically significant (95% CI, 0.99-1.28; P = .07). Conclusions and Relevance: Results of this study indicated that in patients with esophageal cancer receiving definitive CRT, prolonged RT duration was associated with inferior outcomes; female patients and those with other (vs White) race and ethnicity were more likely to have longer RT duration and experience RT interruptions. Radiotherapy interruptions should be minimized to optimize outcomes.

Glycopeptide characterization of Sf9-derived SARS-CoV-2 spike protein recombinant vaccine candidates expedited by the use of glycopeptide libraries.

RATIONALE: We report the N-glycosylation pattern of Sf9 insect cell-derived recombinant spike proteins being developed as candidate vaccine antigens for SARS-CoV-2 (COVID-19) (Sanofi). The method has been optimised to produce peptides with single, isolated glycosylation sites using multiple protease digests. The development and use of glycopeptide libraries from previous developmental phases allowed for faster analysis than processing datasets from individual batches from first principles. METHODS: Purified spike proteins were reduced, alkylated, and digested with proteolytic enzymes. Three different protease digests were utilised to generate peptides with isolated glycosylation sites. The glycopeptides were then analysed using a Waters Q-TOF while using a data-dependent acquisition mass spectrometry experiment. Glycopeptide mapping data processing and glycan classification were performed using Genedata Expressionist via a specialised workflow that used libraries of previously detected glycopeptides to greatly reduce processing time. RESULTS: Two different spike proteins from six manufacturers were analysed. There was a strong similarity at each site across batches and manufacturers. The majority of the glycans present were of the truncated class, although at sites N61, N234, and N717/714 high mannose structures were dominant and at N1173/1170 aglycosylation was dominant for both variant proteins. A comparison was performed on a commercially available spike protein and our results were found to be similar to those of earlier reports. CONCLUSIONS: Our data clearly show that the overall glycosylation pattern of both spike protein variants was highly similar from batch to batch, and between materials produced at different manufacturing facilities. The use of our glycopeptide libraries greatly expedited the generation of site-specific glycan occupancy data for a large glycoprotein. We compared our method with previously obtained data from a commercially available insect cell-derived spike protein and the results were comparable to published findings.

High-density genetic linkage mapping reveals low stability of QTLs across environments for economic traits in Eucalyptus.

Introduction: Eucalyptus urophylla, E. tereticornis and their hybrids are the most important commercial forest tree species in South China where they are grown for pulpwood and solid wood production. Construction of a fine-scale genetic linkage map and detecting quantitative trait loci (QTL) for economically important traits linked to these end-uses will facilitate identification of the main candidate genes and elucidate the regulatory mechanisms. Method: A high-density consensus map (a total of 2754 SNPs with 1359.18 cM) was constructed using genotyping by sequencing (GBS) on clonal progenies of E. urophylla × tereticornis hybrids. QTL mapping of growth and wood property traits were conducted in three common garden experiments, resulting in a total of 108 QTLs. A total of 1052 candidate genes were screened by the efficient combination of QTL mapping and transcriptome analysis. Results: Only ten QTLs were found to be stable across two environments, and only one (qSG10Stable mapped on chromosome 10, and associated with lignin syringyl-to-guaiacyl ratio) was stable across all three environments. Compared to other QTLs, qSG10Stable explained a very high level of phenotypic variation (18.4-23.6%), perhaps suggesting that QTLs with strong effects may be more stably inherited across multiple environments. Screened candidate genes were associated with some transcription factor families, such as TALE, which play an important role in the secondary growth of plant cell walls and the regulation of wood formation. Discussion: While QTLs such as qSG10Stable, found to be stable across three sites, appear to be comparatively uncommon, their identification is likely to be a key to practical QTL-based breeding. Further research involving clonally-replicated populations, deployed across multiple target planting sites, will be required to further elucidate QTL-by-environment interactions.

Advancing Structure Characterization of PS-80 by Charge-Reduced Mass Spectrometry and Software-Assisted Composition Analysis.

The commercially available Polysorbate 80 (PS-80) is a highly heterogeneous product. It is a complex and structurally diverse mixture consisting of polymeric species containing polyoxyethylenes (POEs), fatty acid esters, with/or without a carbohydrate core. The core is primarily sorbitan, with some isosorbide and sorbitol. Depending on the sources of fatty acids and the degrees of esterification, multiple combinations of fatty acid esters are commonly observed. A number of POE intermediates, such as polyoxyethylene glycols, POE-sorbitans, POE-isosorbides, and an array of fatty acid esters from these intermediates remain in the raw material as well. The complex composition of PS-80 is difficult to control and poses a significant characterization challenge for its use in the pharmaceutical industry. Here, we present a novel solution for PS-80 characterization using ultra high-performance liquid chromatography coupled with charge-reduction high resolution mass spectrometry. Post column co-infusion of triethylamine focused the signal into mainly singly charged molecular ions and reduced the extent of in-source fragmentation, resulting in a simpler ion map and enhanced measurement of PS-80 species. The data processing workflow is designed to programmatically identify PS-80 component classes and reduce the burden of manually analyzing complex MS data. The 2-dimensional graphical representation of the data helps visualize these features. Together, these innovative methodologies enabled us to analyze components in PS-80 with unprecedented detail and shall be a useful tool to study formulation and stability of pharmaceutical preparations. The power of this approach was demonstrated by comparing the composition of PS-80 obtained from different vendors.

Implications of the 2019-2020 megafires for the biogeography and conservation of Australian vegetation.

Australia's 2019-2020 'Black Summer' bushfires burnt more than 8 million hectares of vegetation across the south-east of the continent, an event unprecedented in the last 200 years. Here we report the impacts of these fires on vascular plant species and communities. Using a map of the fires generated from remotely sensed hotspot data we show that, across 11 Australian bioregions, 17 major native vegetation groups were severely burnt, and up to 67-83% of globally significant rainforests and eucalypt forests and woodlands. Based on geocoded species occurrence data we estimate that >50% of known populations or ranges of 816 native vascular plant species were burnt during the fires, including more than 100 species with geographic ranges more than 500 km across. Habitat and fire response data show that most affected species are resilient to fire. However, the massive biogeographic, demographic and taxonomic breadth of impacts of the 2019-2020 fires may leave some ecosystems, particularly relictual Gondwanan rainforests, susceptible to regeneration failure and landscape-scale decline.

Genomic Predictions Using Low-Density SNP Markers, Pedigree and GWAS Information: A Case Study with the Non-Model Species Eucalyptus cladocalyx.

High-throughput genotyping techniques have enabled large-scale genomic analysis to precisely predict complex traits in many plant species. However, not all species can be well represented in commercial SNP (single nucleotide polymorphism) arrays. In this study, a high-density SNP array (60 K) developed for commercial Eucalyptus was used to genotype a breeding population of Eucalyptus cladocalyx, yielding only ~3.9 K informative SNPs. Traditional Bayesian genomic models were investigated to predict flowering, stem quality and growth traits by considering the following effects: (i) polygenic background and all informative markers (GS model) and (ii) polygenic background, QTL-genotype effects (determined by GWAS) and SNP markers that were not associated with any trait (GSq model). The estimates of pedigree-based heritability and genomic heritability varied from 0.08 to 0.34 and 0.002 to 0.5, respectively, whereas the predictive ability varied from 0.19 (GS) and 0.45 (GSq). The GSq approach outperformed GS models in terms of predictive ability when the proportion of the variance explained by the significant marker-trait associations was higher than those explained by the polygenic background and non-significant markers. This approach can be particularly useful for plant/tree species poorly represented in the high-density SNP arrays, developed for economically important species, or when high-density marker panels are not available.

Hypofractionated Proton Therapy in Early Prostate Cancer: Results of a Phase I/II Trial at Loma Linda University.

PURPOSE: To determine whether a hypofractionated proton therapy regimen will control early-stage disease and maintain low rates of side effects similar to results obtained using standard-fraction proton therapy at our institution. MATERIALS AND METHODS: A cohort of 146 patients with low-risk prostate cancer according to National Comprehensive Cancer Network guidelines (Gleason score <7, prostate-specific antigen [PSA] <10, tumor stage of T1-T2a) received 60 Gy (cobalt Gy equivalent) of proton therapy (20 fractions of 3.0 Gy per fraction) in 4 weeks, a dose biologically equivalent to standard fractionation (44-45 fractions of 1.8 Gy to a total of 79.2 to 81 Gy in 0 weeks). Patients were evaluated at least weekly during treatment, at which time documentation of treatment tolerance and acute reactions was obtained. Follow-up visits were conducted every 3 months for the first 1 years, every 6 months for the next 3 years, then annually. Follow-up visits consisted of history and physical examination, PSA measurements, and evaluation of toxicity. RESULTS: The median follow-up time was 42 months (range, 3-96 months). Acute grade 2 urinary toxicity occurred in 16% (20/120) of the patients; acute grade 2 or higher gastrointestinal toxicity was seen in 1.7% (2/120). At 9 months, 1 patient had late grade 3 urinary toxicity, which resolved by 12 months; no grade 3 gastrointestinal toxicities occurred. The 3-year biochemical survival rate was 99.3% (144/145). The median time to PSA nadir was 30 months. CONCLUSION: Hypofractionated proton therapy of 60 Gy in 20 fractions was safe and effective for patients with low-risk prostate cancer.

The role of Frankia inoculation in casuarina plantations in China.

Casuarina trees are planted along the coast from Hainan province in South China to the Zhoushan Islands of Zhejiang province in Southeastern China. Three key species, Casuarina equisetifolia, Casuarina cunninghamiana and Casuarina glauca, are used as windbreaks, in agroforestry systems, and for the production of timber and fuel wood. Frankia have been studied in China since 1984. Today, Frankia research fields are very wide, and cover morphology, physiology and genetic diversity, and the application of inocula for specific purposes on poor quality sites. In this paper, we review the role of Frankia inoculations in nurseries and casuarina plantations in China and discuss the benefits of inoculation.

Improved long-term patient-reported health and well-being outcomes of early-stage breast cancer treated with partial breast proton therapy.

BACKGROUND: Because early-stage breast cancer can be treated successfully by a variety of breast-conservation approaches, long-term quality of life (QoL) is an important consideration in assessing treatment outcomes for these patients. This study compares patient-reported QoL outcomes among women with stage 0-2 disease treated via lumpectomy followed by whole breast irradiation (WBI) or partial breast proton irradiation (PBPT). METHODS: In this cross-sectional study, 129 participants evaluated QoL several years post-treatment by responding to subjective instruments, including established scalar questionnaires and self-report measures. Responses were averaged between the two groups. RESULTS: At 6.5 years (median) postdiagnosis, participants' demographic, and clinical characteristics were similar. Patient-reported outcomes were reported as mean scale scores for the two groups, all displaying significant differences favoring PBPT, including: cosmetic breast cancer treatment outcome scale (BCTOS) (PBPT mean 1.45, WBI mean 1.88, P < 0.001); breast pain (PBPT mean 1.30, WBI mean 1.67, P < 0.05); breast texture (BPT mean 1.44, WBI mean 1.91, P < 0.001); clothing fit (PBPT mean 1.06, WBI 1.46, P < 0.001); fatigue (PBPT mean 2.24, WBI mean 3.77, P < 0.002); impact of daily life fatigue on personal relations (OBPT mean 0.83, WBI mean 2.15, P < 0.001); and self-consciousness (appearance dissatisfaction) (PBPT mean 1.38, WBI mean 1.77, P < 0.004). CONCLUSION: Patients' responses suggest that PBPT is associated with improved overall QoL compared to standard whole breast treatment. These self-perceptions are reported by patients who are 5-10 years post-treatment, and that PBPT may enhance QoL in a multitude of interrelated ways.

Correction to: Applicability and accuracy of pretest probability calculations implemented in the NICE clinical guideline for decision making about imaging in patients with chest pain of recent onset.

The original version of this article, published on 19 March 2018, unfortunately contained a mistake. The following correction has therefore been made in the original: The names of the authors Philipp A. Kaufmann, Ronny Ralf Buechel and Bernhard A. Herzog were presented incorrectly.

Complementary middle-down and intact monoclonal antibody proteoform characterization by capillary zone electrophoresis - mass spectrometry.

High-resolution capillary zone electrophoresis - mass spectrometry (CZE-MS) has been of increasing interest for the analysis of biopharmaceuticals. In this work, a combination of middle-down and intact CZE-MS analyses has been implemented for the characterization of a biotherapeutic monoclonal antibody (mAb) with a variety of post-translational modifications (PTMs) and glycosylation structures. Middle-down and intact CZE separations were performed in an acidified methanol-water background electrolyte on a capillary with a positively charged coating (M7C4I) coupled to an Orbitrap mass spectrometer using a commercial sheathless interface (CESI). Middle-down analysis of the IdeS-digested mAb provided characterization of PTMs of digestion fragments. High resolution CZE enabled separation of charge variants corresponding to 2X-deamidated, 1X-deamidated, and non-deamidated forms at baseline resolution. In the course of the middle-down CZE-MS analysis, separation of glycoforms of the FC /2 fragment was accomplished due to hydrodynamic volume differences. Several identified PTMs were confirmed by CZE-MS2 . Incorporation of TCEP-HCl reducing agent in the sample solvent resulted in successful analysis of reduced forms without the need for alkylation. CZE-MS studies on the intact mAb under denaturing conditions enabled baseline separation of the 2X-glycosylated, 1X-glycosylated, and aglycosylated populations as a result of hydrodynamic volume differences. The presence of a trace quantity of dissociated light chain was also detected in the intact protein analysis. Characterization of the mAb under native conditions verified identifications achieved via intact analysis and allowed for quantitative confirmation of proteoforms. Analysis of mAbs using CZE-MS represents a complementary approach to the more conventional liquid-chromatography - mass spectrometry-based approaches.

Applicability and accuracy of pretest probability calculations implemented in the NICE clinical guideline for decision making about imaging in patients with chest pain of recent onset.

OBJECTIVES: To analyse the implementation, applicability and accuracy of the pretest probability calculation provided by NICE clinical guideline 95 for decision making about imaging in patients with chest pain of recent onset. METHODS: The definitions for pretest probability calculation in the original Duke clinical score and the NICE guideline were compared. We also calculated the agreement and disagreement in pretest probability and the resulting imaging and management groups based on individual patient data from the Collaborative Meta-Analysis of Cardiac CT (CoMe-CCT). RESULTS: 4,673 individual patient data from the CoMe-CCT Consortium were analysed. Major differences in definitions in the Duke clinical score and NICE guideline were found for the predictors age and number of risk factors. Pretest probability calculation using guideline criteria was only possible for 30.8 % (1,439/4,673) of patients despite availability of all required data due to ambiguity in guideline definitions for risk factors and age groups. Agreement regarding patient management groups was found in only 70 % (366/523) of patients in whom pretest probability calculation was possible according to both models. CONCLUSIONS: Our results suggest that pretest probability calculation for clinical decision making about cardiac imaging as implemented in the NICE clinical guideline for patients has relevant limitations. KEY POINTS: • Duke clinical score is not implemented correctly in NICE guideline 95. • Pretest probability assessment in NICE guideline 95 is impossible for most patients. • Improved clinical decision making requires accurate pretest probability calculation. • These refinements are essential for appropriate use of cardiac CT.

Impact and cost-effectiveness of formal gastroenterology outpatient referral Clinical Assessment Service.

OBJECTIVE: The aim was to assess the financial and operational impact of our new gastroenterology referral pathway model on our services. DESIGN: An electronic 'Clinical Assessment Service' (CAS) proforma and an information platform were developed, and all data were analysed retrospectively. SETTING: Royal Wolverhampton NHS Trust. PATIENTS: 14 245 general practitioner (GP) referrals were received during January 2014-December 2016 with 9773 of them being triaged via our CAS. MAIN OUTCOME MEASURES: We looked into patients' clinical outcome along with departmental performance and finances. RESULTS: A new outpatient appointment was offered to 60.1% (n=5873) of the CAS referred patients. Endoscopic or radiological investigations were requested for 29.2% (n=2854) of patients prior to deciding on further management plan. Out of those, 27% (n=765) went on to receive another gastroenterology (GI) clinic appointment. The remaining 21.3% (n=2089) of the CAS patients were discharged back to their GP following initial investigations. 5.5% (n=538) were discharged back to primary care with a letter of advice, whereas 5.2% (n=509) were deemed inappropriate for GI clinic and were redirected to other specialists. Overall, 32% (n=3127) of patients were managed without a face to face consultation in the GI clinic. This corresponds to 3136 less outpatient appointments with estimated reduced expenditure by the Clinical Commissioning Group (CCG) of £481K. The 18-week performance and waiting times remained stable despite the increasing referral population. The DNA rate dropped from 14% pre to 8.5%. CONCLUSIONS: Our clinical assessment model has, in addition to the clinical benefits, a considerable positive financial impact to the health economy.

Fractionated Proton Beam Therapy for Acoustic Neuromas: Tumor Control and Hearing Preservation.

PURPOSE: This prospective cohort evaluated patients with acoustic neuroma treated with proton irradiation at Loma Linda University Medical Center. A dose of 50.4 Gy in 28 fractions was given to improve hearing preservation while maintaining tumor control. PATIENTS AND METHODS: Ninety-five patients were treated from March 1991 to March 2008. Fractionated proton radiotherapy at daily doses of 1.8 Gy was employed. Patients were treated to 1 of 3 total doses: 59.4 Gy, used initially for patients without serviceable hearing; 54 Gy, used for patients with serviceable hearing through October 2000; and 50.4 Gy used since 2001 for patients with serviceable hearing. Survival and local control were calculated using the Kaplan-Meier method. Logistic regression analysis was preformed comparing dose, tumor size, and tumor location with hearing preservation. RESULTS: Ninety-four patients were assessable; the median follow-up was 64 months. Five-year local control rates for the 59.4 Gy, 54 Gy, and 50.4 Gy groups were 95%, 97%, and 92%, respectively (P = .80); the overall 10-year actuarial control rate was 90%. Cranial nerve injuries occurred in <5% in all groups. Four-year actuarial rates of hearing preservation were maintained in 44% of patients treated with 54 Gy and 64% treated with 50.4 Gy (P = .284). On multivariate analysis, initial tumor diameter (≤1.5 cm) was found to be a prognostic factor for maintaining serviceable hearing in both groups (P = .011). CONCLUSIONS: Fractionated proton therapy of 50.4 Gy offers excellent local control and minimal cranial nerve toxicities. Improved rates of hearing preservation that are comparable with radiosurgery were seen with 50.4 Gy compared with higher doses, although this did not reach significance. Maintaining hearing was found to be associated with smaller initial tumor size.

Effects of vertebral-body-sparing proton craniospinal irradiation on the spine of young pediatric patients with medulloblastoma.

PURPOSE: To investigate the long-term effects of vertebral-body-sparing proton craniospinal irradiation (CSI) on the spine of young patients with medulloblastoma. METHODS AND MATERIALS: Six children between the ages of 3 and 5 years with medulloblastoma were treated with vertebral-body-sparing proton CSI after maximal safe resection. Radiation therapy was delivered in the supine position with posterior beams targeting the craniospinal axis, and the proton beam was stopped anterior to the thecal sac. Patients were treated with a dose of either 23.4 Gy or 36 Gy to the craniospinal axis followed by a boost to the posterior fossa and any metastatic lesions. Chemotherapy varied by protocol. Radiographic effects on the spine were evaluated with serial imaging, either with magnetic resonance imaging scans or plain film using Cobb angle calculations, the presence of thoracic lordosis, lumbar vertebral body-to-disc height ratios, and anterior-posterior height ratios. Clinical outcomes were evaluated by patient/family interview and medical chart review. RESULTS: Overall survival and disease free survival were 83% (5/6) at follow-up. Median clinical and radiographic follow-up were 13.6 years and 12.3 years, respectively. Two patients were clinically diagnosed with scoliosis and treated conservatively. At the time of follow-up, no patients had experienced chronic back pain or required spine surgery. No patients were identified to have thoracic lordosis. Diminished growth of the posterior portions of vertebral bodies was identified in all patients, with an average posterior to anterior ratio of 0.88, which was accompanied by compensatory hypertrophy of the posterior intervertebral discs. CONCLUSION: Vertebral-body-sparing CSI with proton beam did not appear to cause increased severe spinal abnormalities in patients treated at our institution. This approach could be considered in future clinical trials in an effort to reduce toxicity and the risk of secondary malignancy and to improve adult height.

End-of-Life Care Patterns at a Community Hospital: The Rest of the Story.

We undertook a retrospective review of a subset of expired patients at our community hospital to evaluate end-of-life care patterns and the use of advanced care planning tools among patients who died in the hospital. These 162 expired patients fell into 1 of the 3 diagnosis-related groups of cardiac, respiratory, or infectious disease. Seventy-nine percent of patients arrived to the hospital with no requested limitations in the extent of resuscitative efforts, even though 98% of all patients had major or extreme severity of illness and risk of mortality scores. The presence of an advance directive requesting a limitation of resuscitative efforts modestly impacted resources and procedures, even though utilization in this group was high. Among the 21% of patients with preexisting limits, 21% requested more aggressive support during their course. Critical care unit utilization was seen in 69% of patients for a median of 48 hours. A request for palliative care consultation was received in 44% of patients but only occurred in 30% of all patients due to the short period between the consultation request and patient death (median 37 hours). Among this group of dying patients, engagement of the palliative care team came too late in the course of many patients, suggesting that automated tools embedded in the electronic medical record might be helpful in the identification of appropriate patients earlier.

ß-Adrenergic Receptors Regulate the Acquisition and Consolidation Phases of Aversive Memory Formation Through Distinct, Temporally Regulated Signaling Pathways.

Memory formation requires the temporal coordination of molecular events and cellular processes following a learned event. During Pavlovian threat (fear) conditioning (PTC), sensory and neuromodulatory inputs converge on post-synaptic neurons within the lateral nucleus of the amygdala (LA). By activating an intracellular cascade of signaling molecules, these G-protein-coupled neuromodulatory receptors are capable of recruiting a diverse profile of plasticity-related proteins. Here we report that norepinephrine, through its actions on ß-adrenergic receptors (ßARs), modulates aversive memory formation following PTC through two molecularly and temporally distinct signaling mechanisms. Specifically, using behavioral pharmacology and biochemistry in adult rats, we determined that ßAR activity during, but not after PTC training initiates the activation of two plasticity-related targets: AMPA receptors (AMPARs) for memory acquisition and short-term memory and extracellular regulated kinase (ERK) for consolidating the learned association into a long-term memory. These findings reveal that ßAR activity during, but not following PTC sets in motion cascading molecular events for the acquisition (AMPARs) and subsequent consolidation (ERK) of learned associations.