bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Effect of Adjuvant Pelvic Radiotherapy on Distant Metastasis for Uterine Carcinosarcoma
Authors: Eng Nina L. , Rana Shushan R. , Hall Kevin L. , Eng Tony Y. 
Published: January 2021

Background:
Uterine carcinosarcomas (UCS) are rare tumors that carry a poor prognosis and high recurrence rate. Standard treatment consists of surgical resection and chemotherapy, though the benefit of adjuvant radiotherapy (RT) has yet to be determined. This study assessed survival rates between patients with UCS who underwent surgical resection alone and patients who underwent combinations of surgery, chemotherapy, and RT.

Materials and Methods:
We conducted a retrospective review of all patients who underwent surgical resection for UCS between 1993 and 2011 at a single institution. We assessed 3-year disease-free survival, locoregional recurrence-free survival, distant metastases-free survival (DMFS), and overall survival rates and utilized Kaplan-Meier modeling to analyze differences between UCS treatment modalities.

Results:
Twenty-four patients underwent UCS surgical resection between 1993 and 2011. The mean age was 61 (range: 39 to 75 y). Of these patients, 100% (n=24) underwent surgical resection, 25% (n=6) underwent surgery and adjuvant chemotherapy, 29% (n=7) underwent surgery and adjuvant RT, and 33% (n=8) underwent surgery and adjuvant chemotherapy and RT. At 3 years median follow, there was no significant difference in overall survival between treatment modalities. The addition of radiation therapy conferred increased DMFS in patients undergoing surgery irrespective of adjuvant chemotherapy (44% vs. 83%, P=0.0211).
In patients receiving adjuvant chemotherapy, the significant increase in DMFS persisted with the addition of RT (P=0.0310). Lymph node involvement (n=8) was associated with a lower locoregional recurrence-free survival (38% vs. 92%, P=0.0029).

Conclusions:
RT may offer a potential benefit in reducing the rate of distant metastases, though there were no statistically significant improvements in survival metrics.
Pituitary adenylate cyclase-activating polypeptide/vasoactive intestinal peptide (Part 2): biology and clinical importance in central nervous system and inflammatory disorders
Authors: Moody Terry W. , Jensen Robert T. 
Published: January 2021

Purpose of review
To discuss recent advances of vasoactive intestinal peptide/pituitary adenylate cyclase-activating polypeptide (VIP/PACAP) receptors in the selected central nervous system (CNS) and inflammatory disorders.

Recent findings
Recent studies provide evidence that PACAP plays an important role in a number of CNS disorders, particularly the pathogenesis of headaches (migraine, etc.) as well as posttraumatic stress disorder and drug/alcohol/smoking addiction. VIP has important therapeutic effects in a number of autoimmune/inflammatory disorder such as rheumatoid arthritis. In some cases, these insights have advanced to therapeutic trials.

Summary
Recent insights from studies of VIP/PACAP and their receptors in both CNS disorders (migraine, posttraumatic stress disorder, addiction [drugs, alcohol, smoking]) and inflammatory disorders [such as rheumatoid arthritis] are suggesting new treatment approaches. The elucidation of the importance of VIP/PACAP system in these disorders combined recent development of specific drugs acting on this system (i.e., monoclonal VIP/PACAP antibodies) will likely lead to importance novel treatment approaches in these diseases.
Radiologic and clinicopathologic characteristics of thyroid nodules with focal 68Ga-DOTATATE PET activity
Authors: Kohlenberg Jacob D. , Panda Ananya , Johnson Geoffrey B. , Castro M. Regina 
Published: January 2021

Objective
Our aim was to determine the radiologic and clinicopathologic characteristics of thyroid nodules with focal 68Ga-DOTATATE activity.

Methods
In this retrospective study of 1927 consecutive 68Ga-DOTATATE PET scans, 85 patients with incidental and nonincidental focal 68Ga-DOTATATE avid thyroid nodules were identified, of which 31 patients with 33 thyroid nodules underwent fine-needle aspiration (FNA) or surgery. These 33 nodules were reviewed for Krenning score and SUVmax of the thyroid nodule, contralateral thyroid lobe and left atrium.

Results
Cytology/histopathology included 58% (19/33) with benign findings, 18% (6/33) medullary thyroid carcinoma (MTC), 9% (3/33) atypia or follicular lesion of undetermined significance (AUS/FLUS), 9% (3/33) suspicious for follicular neoplasm and Hurthle cell adenoma (SFN/HCA) and 6% (2/33) nondiagnostic cytology. Median serum calcitonin was 1156 pg/mL (range, 460–1828) in MTC and was <5.0 pg/mL (<5.0–12.5) in patients with benign nodules. Nodules had Krenning score of 1, 2 and 3 in 46% (15/33), 27% (9/33) and 27% (9/33). The majority of MTC and AUS/FLUS nodules had a Krenning score of 3, and there was substantial intragroup variation in Krenning score among the benign nodules. The mean SUVmax for the entire cohort was 5.5 ± 2.9 (mean ± SD), and the range was 2.0–13.0. There was overlap in the nodule/contralateral thyroid SUVmax ratios between groups. The MTC and AUS/FLUS nodules tended to have a higher nodule/blood pool SUVmax ratio than the other pathologic groups.

Conclusion
There was considerable variation in radiologic characteristics among benign thyroid nodules. The ratio of thyroid nodule SUVmax/blood pool SUVmax may be useful to differentiate pathologic groups, but larger studies are needed to investigate this further. Given the potential for malignancy in thyroid nodules with focal 68Ga-DOTATATE activity, further evaluation with serum calcitonin and FNA may be considered.
Video Abstract: http://links.lww.com/NMC/A186
Timing of Intravenous Epinephrine Administration During Out-of-Hospital Cardiac Arrest
Authors: Fukuda Tatsuma , Ohashi-Fukuda Naoko , Inokuchi Ryota , Kondo Yutaka , Taira Takayuki , Kukita Ichiro 
Published: January 2021

ABSTRACT

Background:
Current guidelines for cardiopulmonary resuscitation recommend that standard dose of epinephrine be administered every 3 to 5 min during cardiac arrest. However, there is controversy about the association between timing of epinephrine administration and outcomes after out-of-hospital cardiac arrest (OHCA). This study aimed to determine whether the timing of intravenous epinephrine administration is associated with outcomes after OHCA.

Methods:
We analyzed Japanese government-led nationwide population-based registry data for OHCA. Adult OHCA patients who received intravenous epinephrine by emergency medical service personnel in the prehospital setting from 2011 to 2017 were included. Multivariable logistic regression models were used to assess the associations between time to first epinephrine administration and outcomes after OHCA. Subsequently, associations between early (≤20 min) versus delayed (>20 min) epinephrine administration and outcomes after OHCA were examined using propensity score-matched analyses. The primary outcome was 1-month neurologically favorable survival.

Results:
A total of 119,946 patients (mean [SD] age, 75.2 [14.8] years; 61.4% male) were included. The median time to epinephrine was 23 min (interquartile range, 19–29). Longer time to epinephrine was significantly associated with a decreased chance of 1-month neurologically favorable survival (multivariable adjusted OR per minute delay, 0.91 [95% CI, 0.90–0.92]). In the propensity score-matched cohort, when compared with early (≤20 min) epinephrine, delayed (>20 min) epinephrine was associated with a decreased chance of 1-month neurologically favorable survival (959/42,804 [2.2%] vs. 330/42,804 [0.8%]; RR, 0.34; 95% CI, 0.30–0.39; NNT, 69).

Conclusions:
Delay in epinephrine administration was associated with a decreased chance of 1-month neurologically favorable survival among patients with OHCA.
Long-term Persistence of Allosensitization After Islet Allograft Failure
Authors: Rios Paola , Baidal David , Lemos Joana , Camhi Stephanie S. , Infante Marco , Padilla Nathalia , Alvarez Gil Ana M. , Fuenmayor Virginia , Ambut Jonathan , Qasmi Fatima A. , Mantero Alejandro M. , Cayetano Shari Messinger , Ruiz Phillip , Ricordi Camillo , Alejandro Rodolfo 
Published: January 2021

Background.
Allosensitization has been reported after discontinuation of immunosuppression following graft failure in islet transplantation (ITx) recipients, though duration of its persistence is unknown.

Methods.
We evaluated 35 patients with type 1 diabetes who received ITx, including 17 who developed graft failure (ITx alone, n = 13; ITx plus bone marrow-derived hematopoietic stem cells, n = 4) and 18 with persistent graft function. Panel-reactive antibody (PRA) was measured yearly for the duration of graft function within 1 y after graft failure at enrollment and yearly thereafter.

Results.
In ITx alone graft failure patients, 61% (8/13) were PRA-positive at 6 y postgraft failure, and 46% (6/13) developed donor-specific anti-HLA antibodies (DSA to 2 ± 1 donors) during follow-up. The degree of sensitization was variable (cPRA ranging between 22% and 100% after graft failure). Allosensitization persisted for 7–15 y. Three subjects (3/13) were not allosensitized. In ITx plus bone marrow-derived hematopoietic stem cell recipients, cPRA-positivity (88%–98%) and DSA positivity persisted for 15 y in 75% (3/4) of subjects.

Conclusions.
Allosensitization was minimal while subjects remained on immunosuppression, but after discontinuation of immunosuppressive therapy, the majority of subjects (77%) became allosensitized with persistence of PRA positivity for up to 15 y. Persistence of allosensitization in this patient population is of clinical importance as it may result in longer transplant waiting list times for identification of a suitable donor in the case of requiring a subsequent transplant.
Modeling hepatitis C virus kinetics during liver transplantation highlights the role of the liver in virus clearance
Authors: Shekhtman Louis , Navasa Miquel , Sansone Natasha , Crespo Gonzalo , Subramanya Gitanjali , Chung Tje Lin , Pérez-del-Pulgar Sofía , Perelson Alan S. , Cotler Scott J. , Uprichard Susan L. , Dahari Harel , Forns Xavier 
Published: January 2021

AbstractWhile the liver, specifically hepatocytes, are widely accepted as the main source for hepatitis C virus (HCV) production, the role of the liver/hepatocytes in the clearance of circulating HCV remains largely unknown. Here we evaluated the function of the liver/hepatocytes in clearing virus from the circulation by investigating viral clearance during liver transplantation and from culture medium in vitro. Frequent HCV kinetic data during liver transplantation were recorded from 5 individuals throughout the anhepatic (AH) phase and for 4 hours after reperfusion (RP), along with recordings of fluid balances. Using mathematical modeling, the serum viral clearance rate, c, was estimated. Analogously, we monitored the clearance rate of HCV at 37°C from culture medium in vitro in the absence and presence of chronically infected Huh7 human hepatoma cells. During the AH phase, in 3 transplant cases viral levels remained at pre-AH levels, while in the other 2 cases HCV declined (half-life, t1/2~1h). Immediately post-RP, virus declined in a biphasic manner in Cases 1-4 consisting of an extremely rapid (median t1/2=5min) decline followed by a slower decline (HCV t1/2=67min). In Case 5, HCV remained at the same level post-RP as at the end of AH. Declines in virus level were not explained by adjusting for dilution from IV fluid and blood products. Consistent with what was observed in the majority of patients in the anhepatic phase, the t1/2 of HCV in cell culture was much longer in the absence of chronically HCV-infected Huh7 cells. Therefore, kinetic and modeling results from both in vivo liver transplantation cases and in vitro cell culture studies suggest that the liver plays a major role in clearing HCV from the circulation.
A Whole-Brain Functional Connectivity Model of Alzheimer’s Disease Pathology
Authors: Prakash Ruchika S. , McKenna Michael R. , Gbadeyan Oyetunde , Shankar Anita R. , Andridge Rebecca , Scharre Douglas W. 
Published: January 2021

AbstractEarly detection of Alzheimer’s disease (AD) is a necessity as prognosis is poor upon symptom onset. Although previous work diagnosing AD from protein-based biomarkers has been encouraging, cerebrospinal (CSF) biomarker measurement of AD proteins requires invasive lumbar puncture, whereas assessment of direct accumulation requires radioactive substance exposure in positron emission tomography (PET) imaging. Functional magnetic resonance imaging (fMRI)-based neuromarkers, offers an alternative, especially those built by capitalizing on variance distributed across the entire human connectome. In this study, we employed connectome-based predictive modeling (CPM) to build a model of functional connections that would predict CSF p-tau/Aβ42 (PATH-fc model) in individuals diagnosed with Mild Cognitive Impairment (MCI) and AD dementia. fMRI, CSF-based biomarker data, and longitudinal data from neuropsychological testing from the Alzheimer’s Disease NeuroImaging Initiative (ADNI) were utilized to build the PATH-fc model. Our results provide support for successful in-sample fit of the PATH-fc model in predicting AD pathology in MCI and AD dementia individuals. The PATH-fc model, distributed across all ten canonical networks, additionally predicted cognitive decline on composite measures of global cognition and executive functioning. Our highly distributed pathology-based model of functional connectivity disruptions had a striking overlap with the spatial affinities of amyloid and tau pathology, and included the default mode network as the hub of such network-based disruptions in AD. Future work validating this model in other external datasets, and to midlife adults and older adults with no known diagnosis, will critically extend this neuromarker development work using fMRI.Significance StatementAlzheimer’s disease (AD) is clinical-pathological syndrome with multi-domain amnestic symptoms considered the hallmark feature of the disease. However, accumulating evidence from autopsy studies evince support for the onset of pathophysiological processes well before the onset of symptoms. Although CSF- and PET-based biomarkers provide indirect and direct estimates of AD pathology, both methodologies are invasive. In here, we implemented a supervised machine learning algorithm – connectome-based predictive modeling – on fMRI data and found support for a whole-brain model of functional connectivity to predict AD pathology and decline in cognitive functioning over a two-year period. Our study provides support for AD pathology dependent functional connectivity disturbances in large-scale functional networks to influence the trajectory of key cognitive domains in MCI and AD patients.
Using numerical modeling and simulation to assess the ethical burden in clinical trials and how it relates to the proportion of responders in a trial sample
Authors: Boissel Jean-Pierre , Pérol David , Décousus Hervé , Klingmann Ingrid , Hommel Marc 
Published: January 2021

ABSTRACTIn order to propose a more precise definition and explore how to reduce ethical losses in randomized controlled clinical trials (RCTs), we set out to identify trial participants who do not contribute to demonstrating that the treatment in the experimental arm is superior to that in the control arm. RCTs emerged mid-last century as the gold standard for assessing efficacy, becoming the cornerstone of the value of new therapies, yet their ethical grounds are a matter of debate. We introduce the concept of unnecessary participants in RCTs, the sum of non-informative participants and non-responders. The non-informative participants are considered not informative with respect to the efficacy measured in the trial in contrast to responders who carry all the information required to conclude on the treatment’s efficacy. The non-responders present the event whether or not they are treated with the experimental treatment. The unnecessary participants carry the burden of having to participate in a clinical trial without benefiting from it, which might include experiencing side effects. Thus, these unnecessary participants carry the ethical loss that is inherent to the RCT methodology. On the contrary, responders to the experimental treatment bear its entire efficacy in the RCT. Starting from the proportions observed in a real placebo-controlled trial from the literature, we carried out simulations of RCTs progressively increasing the proportion of responders up to 100%. We show that the number of unnecessary participants decreases steadily until the RCT’s ethical loss reaches a minimum. In parallel, the trial sample size decreases (presumably its cost as well), although the trial’s statistical power increases as shown by the increase of the chi-square comparing the event rates between the two arms. Thus, we expect that increasing the proportion of responders in RCTs would contribute to making them more ethically acceptable, with less false negative outcomes.
External Validations of Cardiovascular Clinical Prediction Models: A Large-scale Review of the Literature
Authors: Wessler Benjamin S. , Nelson Jason , Park Jinny G. , McGinnes Hannah , Gulati Gaurav , Brazil Riley , Van Calster Ben , van Klaveren D. , Venema Esmee , Steyerberg Ewout , Paulus Jessica K. , Kent David M. 
Published: January 2021

AbstractBackgroundThere are many clinical prediction models (CPMs) available to inform treatment decisions for patients with cardiovascular disease. However, the extent to which they have been externally tested and how well they generally perform has not been broadly evaluated.MethodsA SCOPUS citation search was run on March 22, 2017 to identify external validations of cardiovascular CPMs in the Tufts PACE CPM Registry. We assessed the extent of external validation, performance heterogeneity across databases, and explored factors associated with model performance, including a global assessment of the clinical relatedness between the derivation and validation data.Results2030 external validations of 1382 CPMs were identified. 807 (58%) of the CPMs in the Registry have never been externally validated. On average there were 1.5 validations per CPM (range 0-94). The median external validation AUC was 0.73 (25th−75thpercentile [IQR] 0.66, 0.79), representing a median percent decrease in discrimination of −11.1% (IQR −32.4%, +2.7%) compared to performance on derivation data. 81% (n = 1333) of validations reporting AUC showed discrimination below that reported in the derivation dataset. 53% (n = 983) of the validations report some measure of CPM calibration. For CPMs evaluated more than once, there was typically a large range of performance. Of 1702 validations classified by relatedness, the percent change in discrimination was −3.7% (IQR −13.2, 3.1) for ‘closely related’ validations (n=123), −9.0 (IQR −27.6, 3.9) for ‘related validations’ (n=862) and −17.2% (IQR −42.3, 0) for ‘distantly related’ validations (n=717) (p<0.001).ConclusionMany published cardiovascular CPMs have never been externally validated and for those that have, apparent performance during development is often overly optimistic. A single external validation appears insufficient to broadly understand the performance heterogeneity across different settings.
Pre-stimulus alpha activities predict the confidence in subjective judgment by modulating post-stimulus theta oscillation
Authors: Qian Haoyue , Lu Yang , Liu Zhiyuan , Weng Xue , Guo Xiuyan , Li Lin , Zheng Li , Xu Min , Cai Xiaohan , Men Weiwei , Gao Jiahong , Gao Xiangping 
Published: January 2021

AbstractEven when making arbitrary decisions, people tend to feel varying levels of confidence, which is associated with the pre-stimulus neural oscillation of the brain. We investigated varying confidence in a pure subjective judgment task, and how this confidence was predicted by pre-stimulus alpha oscillations. Participants made pure subjective judgments where their prior experience seems to be helpful but actually useless, and their fluctuating confidence was related to the choice boundary process rather than the evidence accumulation process, suggesting participants underwent varying confidence resulting from the internal signals. With EEG and MEG analyses, we not only revealed the linkage between confidence and pre-stimulus alpha activities, but also successfully located this linkage onto decision-making relevant brain areas, i.e. MCC/PCC and SMA. Moreover, we unveiled a specific pathway underlying such linkage, that is, the influence of pre-stimulus alpha activities on decision confidence was fulfilled through modulating post-stimulus theta activities of SMA.
How the Easter Egg Weevils Got Their Spots: Phylogenomics reveals Müllerian Mimicry inPachyrhynchus(Coleoptera, Curculionidae)
Authors: Van Dam Matthew H. , Cabras Analyn Anzano , Lam Athena W. 
Published: January 2021

ABSTRACTThe evolutionary origins of mimicry in the Easter Egg weevil,Pachyrhynchus,have fascinated researchers since first noted more than a century ago by Alfred Russel Wallace. Müllerian mimicry, or mimicry in which two or more distasteful species look similar, is widespread throughout the animal kingdom. Given the varied but discrete color patterns inPachyrhynchus,this genus presents one of the best opportunities to study the evolution of both perfect and imperfect mimicry. We analyzed more than 10,000 UCE loci using a novel partitioning strategy to resolve the relationships of closely related species in the genus. Our results indicate that many of the mimetic color patterns observed in sympatric species are due to convergent evolution. We suggest that this convergence is driven by frequency-dependent selection.
Mathematical modeling of theCandida albicansyeast to hyphal transition reveals novel control strategies
Authors: Wooten David J. , Zañudo Jorge Gómez Tejeda , Murrugarra David , Perry Austin M. , Dongari-Bagtzoglou Anna , Laubenbacher Reinhard , Nobile Clarissa J. , Albert Réka 
Published: January 2021

AbstractCandida albicans, an opportunistic fungal pathogen, is a significant cause of human infections, particularly in immunocompromised individuals. Phenotypic plasticity between two morphological phenotypes, yeast and hyphae, is a key mechanism by whichC. albicanscan thrive in many microenvironments and cause disease in the host. Understanding the decision points and key driver genes controlling this important transition, and how these genes respond to different environmental signals is critical to understanding howC. albicanscauses infections in the host. Here we build and analyze a Boolean dynamical model of theC. albicansyeast to hyphal transition, integrating multiple environmental factors and regulatory mechanisms. We validate the model by a systematic comparison to prior experiments, which led to agreement in 18 out of 22 cases. The discrepancies motivate alternative hypotheses that are testable by follow-up experiments. Analysis of this model revealed two time-constrained windows of opportunity that must be met for the complete transition from the yeast to hyphal phenotype, as well as control strategies that can robustly prevent this transition. We experimentally validate two of these control predictions inC. albicansstrains lacking the transcription factorUME6and the histone deacetylaseHDA1, respectively. This model will serve as a strong base from which to develop a systems biology understanding ofC. albicansmorphogenesis.