Abstract BACKGROUND: D-dimer levels increase with age, and research has suggested that using an age-adjusted D-dimer threshold may improve diagnostic efficiency without compromising safety. The ...objective of this study was to assess the safety of using an age-adjusted D-dimer threshold in the workup of patients with suspected pulmonary embolism (PE). METHODS: We report the outcomes of 923 patients aged > 50 years presenting to our ED with suspected PE, a calculated Revised Geneva Score (RGS), and a D-dimer test. All patients underwent CT pulmonary angiography (CTPA). We compared the false-negative rate for PE of a conventional D-dimer threshold with an age-adjusted D-dimer threshold and report the proportion of patients for whom an age-adjusted D-dimer threshold would obviate the need for CTPA. RESULTS: Among 104 patients with a negative conventional D-dimer test result and an RGS ≤ 10, no PE was observed within 90 days (false-negative rate, 0%; 95% CI, 0%-2.8%). Among 273 patients with a negative age-adjusted D-dimer result and an RGS ≤ 10, four PEs were observed within 90 days (false-negative rate, 1.5%; 95% CI, 0.4%-3.7%). We observed an 18.3% (95% CI, 15.9%-21.0%) absolute reduction in the proportion of patients aged > 50 years who would merit CTPA by using an age-adjusted D-dimer threshold compared with a conventional D-dimer threshold. CONCLUSIONS: Use of an age-adjusted D-dimer threshold reduces imaging among patients aged > 50 years with an RGS ≤ 10. Although the adoption of an age-adjusted D-dimer threshold is probably safe, the CIs surrounding the additional 1.5% of PEs missed necessitate prospective study before this practice can be adopted into routine clinical care.
Abstract
The nova rate in the Milky Way remains largely uncertain, despite its vital importance in constraining models of Galactic chemical evolution as well as understanding progenitor channels for ...Type Ia supernovae. The rate has been previously estimated to be in the range of ≈10–300 yr
−1
, either based on extrapolations from a handful of very bright optical novae or the nova rates in nearby galaxies; both methods are subject to debatable assumptions. The total discovery rate of optical novae remains much smaller (≈5–10 yr
−1
) than these estimates, even with the advent of all-sky optical time-domain surveys. Here, we present a systematic sample of 12 spectroscopically confirmed Galactic novae detected in the first 17 months of Palomar Gattini-IR (PGIR), a wide-field near-infrared time-domain survey. Operating in the
J
band (≈1.2
μ
m), which is significantly less affected by dust extinction compared to optical bands, the extinction distribution of the PGIR sample is highly skewed to a large extinction values (>50% of events obscured by
A
V
≳ 5 mag). Using recent estimates for the distribution of Galactic mass and dust, we show that the extinction distribution of the PGIR sample is commensurate with dust models. The PGIR extinction distribution is inconsistent with that reported in previous optical searches (null-hypothesis probability <0.01%), suggesting that a large population of highly obscured novae have been systematically missed in previous optical searches. We perform the first quantitative simulation of a 3
π
time-domain survey to estimate the Galactic nova rate using PGIR, and derive a rate of
≈
43.7
−
8.7
+
19.5
yr
−1
. Our results suggest that all-sky near-infrared time-domain surveys are well poised to uncover the Galactic nova population.
Administrative discretion can range from benign to troubling, and law enforcement officers possess the power to use physical violence in the discharge of their duties. Body‐worn cameras (BWCs) are a ...workplace surveillance technology intended to monitor officer behavior in the field, but officers exercise discretion over whether or not to activate their cameras. So, what drives officers to activate BWCs? Combining unique survey and administrative data, three competing explanations of BWC activation are compared in one department: Officer demographics, job function, and attitudes. Job function covariates offer robust predictive power of BWC activation frequency. Demographics do not predict BWC activations except rank, which negatively correlates with activation. Though the bulk of attitudinal measures do not predict BWC activations, negative relationships are noted with how officers perceive BWCs to impact their professional discretion, and their belief that cameras expose officers to public outrage and disapproval.
A hallmark of prostate cancer progression is dysregulation of lipid metabolism via overexpression of fatty acid synthase (FASN), a key enzyme in de novo fatty acid synthesis. Metastatic ...castration-resistant prostate cancer (mCRPC) develops resistance to inhibitors of androgen receptor (AR) signaling through a variety of mechanisms, including the emergence of the constitutively active AR variant V7 (AR-V7). Here, we developed an FASN inhibitor (IPI-9119) and demonstrated that selective FASN inhibition antagonizes CRPC growth through metabolic reprogramming and results in reduced protein expression and transcriptional activity of both full-length AR (AR-FL) and AR-V7. Activation of the reticulum endoplasmic stress response resulting in reduced protein synthesis was involved in IPI-9119–mediated inhibition of the AR pathway. In vivo, IPI-9119 reduced growth of AR-V7–driven CRPC xenografts and human mCRPC-derived organoids and enhanced the efficacy of enzalutamide in CRPC cells. In human mCRPC, both FASN and AR-FL were detected in 87% of metastases. AR-V7 was found in 39% of bone metastases and consistently coexpressed with FASN. In patients treated with enzalutamide and/or abiraterone FASN/AR-V7 double-positive metastases were found in 77% of cases. These findings provide a compelling rationale for the use of FASN inhibitors in mCRPCs, including those overexpressing AR-V7.
Abstract
Animal movements reflect temporal and spatial availability of resources as well as when, where, and how individuals access such resources. To test these relationships for a predatory ...reptile, we quantified the effects of prey abundance on the spatial ecology of invasive brown treesnakes (
Boiga irregularis
) on Guam. Five months after toxicant-mediated suppression of a brown treesnake population, we simultaneously used visual encounter surveys to generate relative rodent abundance and radiotelemetry of snakes to document movements of surviving snakes. After snake suppression, encounter rates for small mammals increased 22-fold and brown treesnakes had smaller mean daily movement distances (24 ± 13 m/day,
$$\overline{x }$$
x
¯
± SD) and activity areas (5.47 ± 5 ha) than all previous observations. Additionally, snakes frequenting forest edges, where our small mammal encounters were the highest, had smaller mean daily movement distances and three-dimensional activity volumes compared to those within the forest interior. Collectively, these results suggest that reduced movements by snakes were in part a response to increased prey availability. The impact of prey availability on snake movement may be a management consideration when attempting to control cryptic invasive species using tools that rely on movement of the target species to be effective.
Exercise can alter the skeletal muscle DNA methylome, yet little is known about the role of the DNA methylation machinery in exercise capacity. Here, we show that DNMT3A expression in oxidative red ...muscle increases greatly following a bout of endurance exercise. Muscle‐specific Dnmt3a knockout mice have reduced tolerance to endurance exercise, accompanied by reduction in oxidative capacity and mitochondrial respiration. Moreover, Dnmt3a‐deficient muscle overproduces reactive oxygen species (ROS), the major contributors to muscle dysfunction. Mechanistically, we show that DNMT3A suppresses the Aldh1l1 transcription by binding to its promoter region, altering its epigenetic profile. Forced expression of ALDH1L1 elevates NADPH levels, which results in overproduction of ROS by the action of NADPH oxidase complex, ultimately resulting in mitochondrial defects in myotubes. Thus, inhibition of ALDH1L1 pathway can rescue oxidative stress and mitochondrial dysfunction from Dnmt3a deficiency in myotubes. Finally, we show that in vivo knockdown of Aldh1l1 largely rescues exercise intolerance in Dnmt3a‐deficient mice. Together, we establish that DNMT3A in skeletal muscle plays a pivotal role in endurance exercise by controlling intracellular oxidative stress.
SYNOPSIS
Exercise significantly alters the DNA methylation profile of skeletal muscle, yet little is known about the underlying function of the DNA methylation machinery during exercise performance. Skeletal muscle DNA methyltransferase 3 (DNMT3) is necessary to maintain mitochondrial function and oxidative capacity, and support endurance exercise by suppressing Aldh1l1 transcription.
DNMT3A expression is increased in the oxidative soleus muscle during exercise.
Muscle‐specific Dnmt3a knockout mice display a reduced tolerance to endurance exercise.
Dnmt3a knockout soleus muscle overproduces ROS and exhibits mitochondrial dysfunction.
Aldh1l1 is a direct target gene of DNMT3A mediating mitochondrial dysfunction in red oxidative muscle.
Aldh1l1 knockdown partially restores exercise intolerance of Dnmt3a knockout mice.
Skeletal muscle‐expressed DNA methyltransferase 3 maintains mitochondrial function and oxidative capacity by suppressing Aldh1l1 transcription.
Skeletal muscle atrophy is a highly-prevalent and debilitating condition that remains poorly understood at the molecular level. Previous work found that aging, fasting, and immobilization promote ...skeletal muscle atrophy via expression of activating transcription factor 4 (ATF4) in skeletal muscle fibers. However, the direct biochemical mechanism by which ATF4 promotes muscle atrophy is unknown. ATF4 is a member of the basic leucine zipper transcription factor (bZIP) superfamily. Because bZIP transcription factors are obligate dimers, and because ATF4 is unable to form highly-stable homodimers, we hypothesized that ATF4 may promote muscle atrophy by forming a heterodimer with another bZIP family member. To test this hypothesis, we biochemically isolated skeletal muscle proteins that associate with the dimerization- and DNA-binding domain of ATF4 (the bZIP domain) in mouse skeletal muscle fibers in vivo. Interestingly, we found that ATF4 forms at least five distinct heterodimeric bZIP transcription factors in skeletal muscle fibers. Furthermore, one of these heterodimers, composed of ATF4 and CCAAT enhancer-binding protein β (C/EBPβ), mediates muscle atrophy. Within skeletal muscle fibers, the ATF4–C/EBPβ heterodimer interacts with a previously unrecognized and evolutionarily conserved ATF–C/EBP composite site in exon 4 of the Gadd45a gene. This three-way interaction between ATF4, C/EBPβ, and the ATF–C/EBP composite site activates the Gadd45a gene, which encodes a critical mediator of muscle atrophy. Together, these results identify a biochemical mechanism by which ATF4 induces skeletal muscle atrophy, providing molecular-level insights into the etiology of skeletal muscle atrophy.
Tumour resistance to radiotherapy remains a barrier to improving cancer patient outcomes. To overcome radioresistance, certain drugs have been found to sensitize cells to ionizing radiation (IR). In ...theory, more potent radiosensitizing drugs should increase tumour kill and improve patient outcomes. In practice, clinical utility of potent radiosensitizing drugs is curtailed by off-target side effects. Here we report potent anti-tubulin drugs conjugated to anti-ErbB antibodies selectively radiosensitize to tumours based on surface receptor expression. While two classes of potent anti-tubulins, auristatins and maytansinoids, indiscriminately radiosensitize tumour cells, conjugating these potent anti-tubulins to anti-ErbB antibodies restrict their radiosensitizing capacity. Of translational significance, we report that a clinically used maytansinoid ADC, ado-trastuzumab emtansine (T-DM1), with IR prolongs tumour control in target expressing HER2+ tumours but not target negative tumours. In contrast to ErbB signal inhibition, our findings establish an alternative therapeutic paradigm for ErbB-based radiosensitization using antibodies to restrict radiosensitizer delivery.
Incidental pulmonary nodules that require follow-up are often noted on chest CT. Evidence-based guidelines regarding appropriate follow-up have been published, but the rate of adherence to guideline ...recommendations is unknown. Furthermore, it is unknown whether the radiology report affects the nodule follow-up rate.
A review of 1,000 CT pulmonary angiographic studies ordered in the emergency department was performed to determine the presence of an incidental pulmonary nodule. Fleischner Society guidelines were applied to ascertain if follow-up was recommended. Radiology reports were classified on the basis of whether nodules were listed in the findings section only, were noted in the impression section, or had explicit recommendations for follow-up. Whether the rate of nodule follow-up was affected by the radiology report was determined according to these 3 groups.
Incidental pulmonary nodules that required follow-up were noted on 9.9% (95% confidence interval, 8%-12%) of CT pulmonary angiographic studies. Follow-up for nodules was poor overall (29% 28 of 96; 95% confidence interval, 20%-38%) and decreased significantly when the nodules were mentioned in the findings section only (0% 0 of 12). Specific instructions to follow up nodules in radiology reports still resulted in a low follow-up rate of 29% (19 of 65; 95% confidence interval, 18%-40%).
Incidental pulmonary nodules detected on CT pulmonary angiography are common and are frequently not followed up appropriately. Although the inclusion of a pulmonary nodule in the impression section of a radiology report is helpful, it does not ensure follow-up. Better systems for appropriate identification and follow-up of incidental findings are needed.
Metaplastic breast cancer (MpBC) is a rare aggressive subtype that responds poorly to cytotoxics. Median survival is approximately 8 months for metastatic disease. We report results for advanced MpBC ...treated with ipilimumab + nivolumab, a cohort of S1609 for rare cancers (DART: NCT02834013).
Prospective, open-label, multicenter phase II (two-stage) trial of ipilimumab (1 mg/kg i.v. every 6 weeks) plus nivolumab (240 mg i.v. every 2 weeks) for advanced MpBC. Primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity.
Overall, 17 evaluable patients enrolled. Median age was 60 years (26-85); median number of prior therapy lines was 2 (0-5). ORR was 18%; 3 of 17 patients achieved objective responses (1 complete, 2 partial responses; 2 spindle cell, 1 chondromyxoid histology), which are ongoing at 28+, 33+, and 34+ months, respectively. Median PFS and OS were 2 and 12 months, respectively. Altogether, 11 patients (65%) experienced adverse events (AE), including one grade 5 AE. Eight patients (47%) developed an immune-related AE (irAE), with adrenal insufficiency observed in all 3 responders. Responses occurred in tumors with low tumor mutational burden, low PD-L1, and absent tumor-infiltrating lymphocytes.
The ipilimumab and nivolumab combination showed no new safety signals and met its primary endpoint with 18% ORR in advanced, chemotherapy-refractory MpBC. All responses are ongoing at >2 to almost 3 years later. The effect of ipilimumab and nivolumab was associated with exceptional responses in a subset of patients versus no activity. This combination warrants further investigation in MpBC, with special attention to understanding mechanism of action, and carefully designed to weigh against the significant risks of irAEs.
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