bluuebunny/crossref_metadata_2025_split huggingface dataset:
Probody Therapeutics: An Emerging Class of Therapies Designed to Enhance On-Target Effects with Reduced Off-Tumor Toxicity for Use in Immuno-Oncology
Authors: Autio Karen A. , Boni Valentina , Humphrey Rachel W. , Naing Aung 
Published: October 2019

AbstractThe deep and durable antitumor effects of antibody-based immunotherapies such as immune checkpoint inhibitors (ICIs) have revolutionized oncology and transformed the therapeutic landscape for many cancers. Several anti–programmed death receptor 1 and anti–programmed death receptor ligand 1 antibodies have been approved for use in advanced solid tumors, including melanoma, non–small cell lung cancer, bladder cancer, and other cancers. ICIs are under development across many tumor types and preliminary results are compelling. However, ICIs have been associated with severe immune-related adverse events (irAEs), including rash, diarrhea, colitis, hypophysitis, hepatotoxicity, and hypothyroidism, which in some cases lead to high morbidity, are potentially life-threatening, and limit the duration of treatment. The incidence of severe irAEs increases further when programmed cell death-1 and programmed cell death ligand-1 inhibitors are combined with anti–CTLA-4 and/or other multidrug regimens. Probody therapeutics, a new class of recombinant, proteolytically activated antibody prodrugs are in early development and are designed to exploit the hallmark of dysregulation of tumor protease activity to deliver their therapeutic effects within the tumor microenvironment (TME) rather than peripheral tissue. TME targeting, rather than systemic targeting, may reduce irAEs in tissues distant from the tumor. Probody therapeutic technology has been applied to multiple antibody formats, including immunotherapies, Probody drug conjugates, and T-cell–redirecting bispecific Probody therapeutics. In preclinical models, Probody therapeutics have consistently maintained anticancer activity with improved safety in animals compared with the non-Probody parent antibody. In the clinical setting, Probody therapeutics may expand or create therapeutic windows for anticancer therapies.
Circulating Tumor Cells Exhibit Metastatic Tropism and Reveal Brain Metastasis Drivers
Authors: Klotz Remi , Thomas Amal , Teng Teng , Han Sung Min , Iriondo Oihana , Li Lin , Restrepo-Vassalli Sara , Wang Alan , Izadian Negeen , MacKay Matthew , Moon Byoung-San , Liu Kevin J. , Ganesan Sathish Kumar , Lee Grace , Kang Diane S. , Walmsley Charlotte S. , Pinto Christopher , Press Michael F. , Lu Wange , Lu Janice , Juric Dejan , Bardia Aditya , Hicks James , Salhia Bodour , Attenello Frank , Smith Andrew D. , Yu Min 
Published: October 2019

Abstract

Hematogenous metastasis is initiated by a subset of circulating tumor cells (CTC) shed from primary or metastatic tumors into the blood circulation. Thus, CTCs provide a unique patient biopsy resource to decipher the cellular subpopulations that initiate metastasis and their molecular properties. However, one crucial question is whether CTCs derived and expanded ex vivo from patients recapitulate human metastatic disease in an animal model. Here, we show that CTC lines established from patients with breast cancer are capable of generating metastases in mice with a pattern recapitulating most major organs from corresponding patients. Genome-wide sequencing analyses of metastatic variants identified semaphorin 4D as a regulator of tumor cell transmigration through the blood–brain barrier and MYC as a crucial regulator for the adaptation of disseminated tumor cells to the activated brain microenvironment. These data provide the direct experimental evidence of the promising role of CTCs as a prognostic factor for site-specific metastasis.

Significance:
Interests abound in gaining new knowledge of the physiopathology of brain metastasis. In a direct metastatic tropism analysis, we demonstrated that ex vivo–cultured CTCs from 4 patients with breast cancer showed organotropism, revealing molecular features that allow a subset of CTCs to enter and grow in the brain.
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Activation During Sinus Rhythm in Ventricles With Healed Infarction
Authors: Rottmann Markus , Kleber Andre G. , Barkagan Michael , Sroubek Jakub , Leshem Eran , Shapira-Daniels Ayelet , Buxton Alfred E. , Anter Elad 
Published: October 2019

Background:
In infarct-related ventricular tachycardia (VT), the circuit often corresponds to a location characterized by activation slowing during sinus rhythm (SR). However, the relationship between activation slowing during SR and vulnerability for reentry and correlation to components of the VT circuit are unknown. This study examined the relationship between activation slowing during SR and vulnerability for reentry and correlated these areas with components of the circuit.

Methods:
In a porcine model of healed infarction, the spatial distribution of endocardial activation velocity was compared between SR and VT. Isthmus sites were defined using activation and entrainment mapping as areas exhibiting diastolic activity within the circuit while bystanders were defined as areas displaying diastolic activity outside the circuit.

Results:

Of 15 swine, 9 had inducible VT (5.2±3.0 per animal) while in 6 swine VT could not be induced despite stimulation from 4 RV and LV sites at 2 drive trains with 6 extra-stimuli down to refractoriness. Infarcts with VT had a greater magnitude of activation slowing during SR. A minimal endocardial activation velocity cutoff ≤0.1 m/s differentiated inducible from noninducible infarctions (
P
=0.015). Regions of maximal endocardial slowing during SR corresponded to the VT isthmus (area under curve=0.84 95% CI, 0.78–0.90) while bystander sites exhibited near-normal activation during SR. VT circuits were complex with 41.7% exhibiting discontinuous propagation with intramural bridges of slow conduction and delayed quasi-simultaneous endocardial activation. Regions forming the VT isthmus borders had faster activation during SR while regions forming the inner isthmus were activated faster during VT.

Conclusions:
Endocardial activation slowing during SR may differentiate infarctions vulnerable for VT from those less vulnerable for VT. Sites of slow activation during SR correspond to sites forming the VT isthmus but not to bystander sites.
Causal Effect of Lp(a) [Lipoprotein(a)] Level on Ischemic Stroke and Alzheimer Disease
Authors: Pan Yuesong , Li Hao , Wang Yilong , Meng Xia , Wang Yongjun 
Published: October 2019

Background and Purpose—
Stroke and Alzheimer disease are 2 major causes of neurological disability in aged people and shared overlapping predictors. In recent prospective studies, high Lp(a) [lipoprotein(a)] level is associated with high risk of stroke but low risk of Alzheimer disease. Whether this reflects a causal association remains to be established. The aim of this study is to examine the causal associations of Lp(a) concentrations on ischemic stroke, ischemic stroke subtypes, and Alzheimer disease.

Methods—
We used 9 single-nucleotide polymorphisms associated with Lp(a) concentrations as instrumental variables. Summary-level data on ischemic stroke and its subtypes were obtained from the Multiancestry Genome-Wide Association Study of Stroke consortium with European individuals ≤446 696 individuals. Summary-level data on Alzheimer disease were obtained from the International Genomics of Alzheimer Project With European individuals ≤54 162 individuals. Two-sample Mendelian randomization (MR) estimates were calculated with inverse-variance weighted, penalized inverse-variance weighted, simple median, weighted median, and MR Pleiotropy Residual Sum and Outlier approaches, and MR-Egger regression was used to explore pleiotropy.

Results—

Genetically predicted 1-SD log-transformed increase in Lp(a) concentrations was associated with a substantial increase in risk of large artery stroke (odds ratio, 1.20; 95% CI, 1.11–1.30;
P
<0.001) and a reduce in risk of small vessel stroke (odds ratio, 0.92; 95% CI, 0.88–0.97;
P
=0.001) and Alzheimer disease (odds ratio, 0.94; 95% CI, 0.91–0.97;
P
<0.001) using inverse-variance weighted method. No significant association was observed for total ischemic stroke or cardioembolic stroke. MR-Egger indicated no evidence of pleiotropic bias. Results were broadly consistent in sensitivity analyses using penalized inverse-variance weighted, simple median, weighted median, and MR Pleiotropy Residual Sum and Outlier approaches accounting for potential genetic pleiotropy or outliers.

Conclusions—
This study provides evidence to support that high Lp(a) concentrations was causally associated with an increased risk of large artery stroke but a decreased risk of small vessel stroke and Alzheimer disease. The mechanism underlying the double-edged sword effect of Lp(a) concentrations on neurological system requires further investigation.
Mechanisms Reducing ENSO Amplitude and Asymmetry via an Enhanced Seasonal Cycle in the Mid-Holocene
Authors: Iwakiri Tomoki , Watanabe Masahiro 
Published: October 2019

Abstract
Paleo proxy records have suggested that El Niño–Southern Oscillation (ENSO) variability during the mid-Holocene [8200 to 4200 years ago (8.2–4.2 ka)] was weaker than during the instrumental periods, but the mechanisms remain unclear. We examined processes of ENSO suppression using a coupled general circulation model (CGCM) that simulates ENSO amplitude and skewness under the present climate reasonably well. Two long simulations were performed: one using the preindustrial condition (CTRL) and the other using the 8-ka insolation having a greater seasonal cycle (MH8K). Consistent with proxy records and previous modeling studies, the ENSO amplitude weakened by 20% in MH8K compared to CTRL, mainly because of reduced thermocline feedback during the mature and decay phases. The weak thermocline feedback, likely a result of the loose equatorial thermocline in the mid-Holocene, suppresses the occurrence of extreme El Niño events and consequently explains the reduction in both ENSO amplitude and asymmetry. In MH8K, strengthened trade winds over the western-central Pacific Ocean act to cool the surface via evaporation while warmer water in the southern subtropical Pacific is transported beneath the equatorial thermocline, both contributing to diffuse the thermocline. Multimodel simulations for the mid-Holocene showed mean state changes and ENSO weakening similar to MH8K, but most models did not show reduced ENSO skewness, probably because of the failure in reproducing extreme El Niño events under the present climate.
Cytomegalic Inclusion Disease of the Developing Fetus: A Potentially Preventable Cause of Congenital Mental Defect
Authors: Elliott G. B. , Elliott K. A. 
Published: October 2019

Infection after infancy by salivary gland virus produces an apparently harmless salivary cytomegaly, Huge inclusion bodies develop which equal nuclei in size. Specific antibodies appear in the serum. The infection is a serious risk to the fetus when transmitted during early pregnancy, despite lack of clinical illness shown by the mother. Actively growing fetal tissues, especially those of brain and liver, show necrosis without reaction which progresses silently for up to six months before birth. Shortly after bjrth, a characteristic clinical picture may supervene which imitates “erythroblastosis fetalis” or “neonatal hepatitis.” The concurrent brain injury has a highly characteristic periventricular location. Full cerebral development is blocked, leading to mental defect, spasticity, micro or obstructive-hydrocephaly, sometimes recognizable at birth.
Headache due to spontaneous spinal cerebrospinal fluid leak secondary to cerebrospinal fluid-venous fistula: Case series
Authors: Duvall Jaclyn R , Robertson Carrie E , Cutsforth-Gregory Jeremy K , Carr Carrie M , Atkinson John LD , Garza Ivan 
Published: October 2019

Objective Cerebrospinal fluid-venous fistula is an uncommon cause of spontaneous spinal cerebrospinal fluid leak (SSCSFL). We aim to describe the clinical presentation, imaging evaluation, treatment and outcome of SSCSFL secondary to cerebrospinal fluid-venous fistula. Methods A retrospective review was undertaken of SSCSFL cases secondary to cerebrospinal fluid-venous fistula confirmed radiologically or intraoperatively, seen at our institution from January 1994 to March 2019. Cases with undetermined SSCSFL etiology, alternative etiology or unconfirmed fistula were excluded. Results Forty-four of 156 patients met the inclusion criteria (31 women, 13 men). Mean age of symptom onset was 52.6 years (SD 8.7, range 33–71 years). Headache was the presenting symptom in almost all, typically daily (69%), and most often in occipital/suboccipital regions. Headache character was most commonly pressure (38%), followed by throbbing/pulsing (21.4%). Orthostatic headache worsening occurred in 69% and an even greater percentage of patients (88%) reported Valsalva-induced headache exacerbation or precipitation. Headache occurred in isolation to Valsalva maneuvers in 12%. Of 37 patients with documented cerebrospinal fluid opening pressure, 13% were <6 cmH2O; 84%, 7–20 cmH2O; and one, 25 cmH2O. Fistulas were almost exclusively thoracic (95.5%). Only one patient responded definitively to epidural blood patch (EBP). Forty-two patients underwent surgery. Most improved following surgery; 48.7% were completely headache free and 26.8% had at least 50% improvement. Conclusion In our series, cerebrospinal fluid-venous fistula was associated with a greater occurrence of Valsalva-induced headache exacerbation or precipitation than orthostatic headache and did not respond to EBP. Surgery provided significant improvement. Cerebrospinal fluid-venous fistula should be considered early in the differential diagnosis of Valsalva-induced (“cough”) headache.
Congenital Cardiothoracic Surgeons and Palliative Care: A National Survey Study
Authors: Morell Emily , Thompson Jess , Rajagopal Satish , Blume Elizabeth D. , May Rachna 
Published: October 2019

Background: The majority of children with advanced heart disease in the inpatient setting die in an intensive care unit under 1 year of age following multiple interventions. While pediatric cardiology and palliative care provider attitudes have been described, little is known about pediatric cardiothoracic surgeon attitudes toward palliative care in children with advanced heart disease. Objective: To describe perspectives of pediatric cardiothoracic surgeons regarding palliative care in pediatric heart disease. Design: Cross-sectional web-based national survey. Results: Of the 220 surgeons who were e-mailed the survey, 36 opened the survey and 5 did not meet inclusion criteria (n = 31). Median years of practice was 23.5 (range: 12-41 years), and 87.1% were male. Almost all (90%) reported that they had experience consulting palliative care. While 68% felt palliative care consultation was initiated at the appropriate time, 29% felt it occurred too late. When asked the appropriate timing for palliative care consultation in hypoplastic left heart syndrome, 45% selected “at time of prenatal diagnosis” and 30% selected “when surgical and transcatheter options have been exhausted.” Common barriers to palliative care involvement included the perception of “giving up” (40%) and concern for undermining parental hope (36%). Conclusions: While a majority of pediatric cardiothoracic surgeons are familiar with palliative care, there is variation in perception of appropriate timing of consultation. Significant barriers to consultation still exist, including concern that parents will think they are “giving” up, undermining parental hope, and influence of palliative care on the medical care team’s approach.
Ultrasonographic Assessment of Deltoid Ligament Integrity in Ankle Fractures
Authors: Rosa Isabel , Rodeia Joaquim , Fernandes Pedro Xavier , Teixeira Raquel , Saldanha Tiago , Consciência José Guimarães 
Published: October 2019

Background: Regardless of fibular status, the presence of a superficial deltoid ligament disruption or a combination of deep and superficial deltoid ligament disruption is central to the decision-making process in treating ankle fractures. The aims of the present study were to test whether ultrasonography can assess deltoid ligament integrity and to determine its validity and reliability by comparing it with gravity stress radiography. Methods: A consecutive series of 81 eligible patients with a nondisplaced or minimally displaced fibula fracture identified on a standard radiograph were prospectively enrolled. All patients underwent gravity stress radiography and ultrasonography. Image analysis included the layer type, integrity, and tear site of the deltoid ligament. Ultrasound validity and intra- and interobserver reliability were assessed by the interpretations of the first author and an independent observer who were blinded to the results. Results: Of all patients, 64 (79.0%) had a deltoid ligament disruption; most of the tears were of both the superficial and deep layers, partial and proximal attachment tears, and only 8 (12.5%) were complete tears. Patients with an intact deltoid ligament had a mean medial clear space (MCS) value of 2.7 ± 0.5 mm, and those with deltoid ligament tears had a mean MCS value of 5.9 ± 3.4 mm ( P < .001). In a comparison between ultrasonography and gravity radiography, we found a sensitivity of 100% versus 97%, a specificity of 90% versus 100%, a positive predictive value of 97% versus 100%, and a negative predictive value of 100% versus 90%, respectively. The intra- and interobserver reliability was evaluated as almost perfect in all conditions. In a comparison between ultrasonography and gravity radiography, we found a sensitivity of 100% versus 97%, a specificity of 90% versus 100%, a positive predictive value of 97% versus 100%, and a negative predictive value of 100% versus 90%, respectively. Conclusion: Ultrasonography proved to be an accurate tool, allowing the identification of deltoid ligament disruption and the involved components in a more dynamic fashion. Its relative ease of use and lack of ionizing radiation make it a useful and confident technique that can be performed by an orthopedist. Level of Evidence: Level II, prospective comparative study.
Measurement of mobility and physical function in hospitalised trauma patients: A systematic review of instruments and their measurement properties
Authors: Calthorpe Sara , Kimmel Lara A , Webb Melissa J , Gabbe Belinda J , Holland Anne E 
Published: October 2019

Introduction It is well recognised that organised trauma systems reduce trauma patient mortality. As established systems mature, there is an increasing need to better understand the patient recovery trajectory. Mobility and physical function are key aspects of recovery, but the optimal instruments for measurement in the acute hospital setting remain unclear. Methods A systematic review was undertaken to identify and describe mobility and physical function instruments scored by direct patient assessment, in adult trauma patients in an acute hospital setting. Databases were searched with no date restrictions. Instruments that were specific to subgroups or related to individual conditions, diseases or joints were excluded. The consensus-based standards for the selection of health measurement instruments checklist was used to assess risk of bias where relevant. Clinimetric properties were reported where possible, including reliability, validity and responsiveness. Results Fourteen thousand one hundred and fourteen articles were identified with 37 eligible for final review, including six instruments. None had been specifically designed for use in a heterogeneous range of trauma patients. The Functional Independence Measure was the most commonly cited (n = 10 studies), with evidence of construct validity, responsiveness and minimal floor/ceiling effects (<3%). The Acute Care Index of Function (n = 1 study) was found to be valid and responsive whilst the modified Iowa Level of Assistance (n = 2 studies) was reliable and responsive, but ceiling effects ranged from 26% to 37%. Little clinimetric data were available for other measures. Conclusion Evidence from a few studies show promise for the use of the Functional Independence Measure, Acute Care Index of Function and modified Iowa Level of Assistance to measure mobility and physical function in trauma patients, however comprehensive clinimetric data are lacking. Future research should test these scores in specifically designed clinimetric property studies in defined trauma patient populations. This would enable the identification of a gold standard measure for evaluating treatment effectiveness, enabling benchmarking between centres, allow prediction of recovery pathways and optimise trauma patient outcomes.
A Vascular Malformation in the Carotid Sheath at the Carotid Bifurcation Mimicking Carotid Body Tumor
Authors: Gao Xixiang , Li Yang , Meng Liang , Tong Zhu , Guo Lianrui , Zhang Jian , Gu Yongquan 
Published: October 2019

Background: The carotid sheath contains clinically important and vital anatomical neurogenic, vascular, and lymphatic structures that allow for a great variety of lesions. Vascular anomalies found in the carotid sheath are rarely reported and may be easily misdiagnosed as arterial aneurysms, neurogenic tumors, paragangliomas, or lymphatic masses. Method: We present a 60-year-old woman with a vascular malformation arising within the carotid sheath at the right carotid bifurcation, which mimics carotid body tumor. Result: The mass was excised successfully with an uneventful postoperative course, and histological analysis suggested a vascular malformation with thin-walled blood vessels, lined by endothelial cells and separated by fibrous tissue. The patient was in good clinical condition without signs of relapse of the mass at 6-month follow-up. Conclusion: Vascular malformation is a rare but existing possibility of pathology in the carotid sheath, which can be effectively removed by meticulous surgery.
Health care provider’s experiences, practices, and recommendations for interventions and screening of cystic fibrosis patients with disordered eating: A qualitative analysis
Authors: Quick Virginia , Chang Grace 
Published: October 2019

Objectives To investigate health care providers’ perspectives on their experiences and practices with cystic fibrosis patients exhibiting disordered eating behaviors and their recommendations for interventions and screening of this population. Methods Experienced health care providers (N = 17) were recruited from the Cystic Fibrosis Foundation listserv to participate in a semi-structured interview via phone. Two trained qualitative researchers independently coded audio-recorded interview scripts. Major themes were generated from questions inquiring health care providers’ perspectives on their experiences and practices with cystic fibrosis patients exhibiting disordered eating behaviors and their recommendations for better interventions and screening of disordered eating. Results The most prominent disordered eating behaviors observed by health care providers in cystic fibrosis patients were misusing pancreatic enzyme medication (53%), food restriction behaviors (47%), binge eating (29%), and skipping meals (29%). Over half (53%) of health care providers reported not having policies or procedures for disordered eating of cystic fibrosis patients. All health care providers thought it would be beneficial to have a cystic fibrosis-specific disordered eating screening tool. Recommendations by health care providers included developing a national standard protocol for cystic fibrosis disordered eating and educational training for health care providers. Discussion Ongoing development of evidence-based guidelines for screening and treating disordered eating among cystic fibrosis patients is warranted including development of a cystic fibrosis-specific disordered eating screening tool.