bluuebunny/crossref_metadata_2025_split huggingface dataset:
Heterogeneous delivery across the blood-brain barrier limits the efficacy of an EGFR-targeting antibody drug conjugate in glioblastoma
Authors: Marin Bianca-Maria , Porath Kendra A , Jain Sonia , Kim Minjee , Conage-Pough Jason E , Oh Ju-Hee , Miller Caitlyn L , Talele Surabhi , Kitange Gaspar J , Tian Shulan , Burgenske Danielle M , Mladek Ann C , Gupta Shiv K , Decker Paul A , McMinn Madison H , Stopka Sylwia A , Regan Michael S , He Lihong , Carlson Brett L , Bakken Katrina , Burns Terence C , Parney Ian F , Giannini Caterina , Agar Nathalie Y R , Eckel-Passow Jeanette E , Cochran Jennifer R , Elmquist William F , Vaubel Rachael A , White Forest M , Sarkaria Jann N 
Published: May 2021

Abstract

Background
Antibody drug conjugates (ADCs) targeting the epidermal growth factor receptor (EGFR), such as depatuxizumab mafodotin (Depatux-M), is a promising therapeutic strategy for glioblastoma (GBM) but recent clinical trials did not demonstrate a survival benefit. Understanding the mechanisms of failure for this promising strategy is critically important.

Methods
PDX models were employed to study efficacy of systemic vs intracranial delivery of Depatux-M. Immunofluorescence and MALDI-MSI were performed to detect drug levels in the brain. EGFR levels and compensatory pathways were studied using quantitative flow cytometry, Western blots, RNAseq, FISH, and phosphoproteomics.

Results
Systemic delivery of Depatux-M was highly effective in nine of 10 EGFR-amplified heterotopic PDXs with survival extending beyond one year in eight PDXs. Acquired resistance in two PDXs (GBM12 and GBM46) was driven by suppression of EGFR expression or emergence of a novel short-variant of EGFR lacking the epitope for the Depatux-M antibody. In contrast to the profound benefit observed in heterotopic tumors, only two of seven intrinsically sensitive PDXs were responsive to Depatux-M as intracranial tumors. Poor efficacy in orthotopic PDXs was associated with limited and heterogeneous distribution of Depatux-M into tumor tissues, and artificial disruption of the BBB or bypass of the BBB by direct intracranial injection of Depatux-M into orthotopic tumors markedly enhanced the efficacy of drug treatment.

Conclusions
Despite profound intrinsic sensitivity to Depatux-M, limited drug delivery into brain tumor may have been a key contributor to lack of efficacy in recently failed clinical trials.
A photosynthesis operon in the chloroplast genome drives speciation in evening primroses
Authors: Zupok Arkadiusz , Kozul Danijela , Schöttler Mark Aurel , Niehörster Julia , Garbsch Frauke , Liere Karsten , Fischer Axel , Zoschke Reimo , Malinova Irina , Bock Ralph , Greiner Stephan 
Published: May 2021

AbstractGenetic incompatibility between the cytoplasm and the nucleus is thought to be a major factor in species formation, but mechanistic understanding of this process is poor. In evening primroses (Oenothera spp.), a model plant for organelle genetics and population biology, hybrid offspring regularly display chloroplast–nuclear incompatibility. This usually manifests in bleached plants, more rarely in hybrid sterility or embryonic lethality. Hence, most of these incompatibilities affect photosynthetic capability, a trait that is under selection in changing environments. Here we show that light-dependent misregulation of the plastid psbB operon, which encodes core subunits of photosystem II and the cytochrome b6f complex, can lead to hybrid incompatibility, and this ultimately drives speciation. This misregulation causes an impaired light acclimation response in incompatible plants. Moreover, as a result of their different chloroplast genotypes, the parental lines differ in photosynthesis performance upon exposure to different light conditions. Significantly, the incompatible chloroplast genome is naturally found in xeric habitats with high light intensities, whereas the compatible one is limited to mesic habitats. Consequently, our data raise the possibility that the hybridization barrier evolved as a result of adaptation to specific climatic conditions.
Factors Negatively Influencing Postoperative Improvement After Laminoplasty in Degenerative Cervical Myelopathy
Authors: Inose Hiroyuki , Yoshii Toshitaka , Kimura Atsushi , Takeshita Katsushi , Inoue Hirokazu , Maekawa Asato , Endo Kenji , Furuya Takeo , Nakamura Akira , Mori Kanji , Kanbara Shunsuke , Imagama Shiro , Seki Shoji , Matsunaga Shunji , Okawa Atsushi 
Published: May 2021

Study Design:
This was a retrospective study of prospectively collected data.

Objective:
In this study, we aimed to characterize a population of patients with degenerative cervical myelopathy (DCM) and a history of poor postoperative neurological recovery and to identify risk factors associated with poor neurological recovery after laminoplasty.

Summary of Background Data:
Kyphotic cervical alignment has been considered a relative contraindication to laminoplasty in recent years; hence, laminoplasty has been decreasingly performed for the treatment of DCM in patients with cervical kyphosis. However, the effect of global spinal alignment on postoperative outcomes has not been extensively investigated.

Materials and Methods:
We prospectively enrolled patients who were scheduled for laminoplasty for DCM. Outcome (at enrollment and 1 y after surgery) and risk factor analyses were performed by comparing the good recovery and poor recovery groups. The Spearman correlation coefficient was used to evaluate the relationships between the recovery rate and the preoperative radiographic factors.

Results:
In total, 101 patients completed the 1-year follow-up. Regarding clinical outcomes, the Japanese Orthopedic Association score for the assessment of cervical myelopathy, European Quality of Life-5 Dimensions, and Neck Disability Index scores improved postoperatively. The recovery rate was significantly correlated with the preoperative sagittal vertical axis (SVA). The patients in the poor recovery group were older than those in the good recovery group. Univariate analyses showed that the SVA and T1 pelvic angle were significantly higher in the poor recovery group. Lastly, stepwise logistic regression analysis showed that a higher SVA was an independent predictor of poor recovery after laminoplasty.

Conclusions:
The SVA and T1 pelvic angle were significantly higher in the poor recovery group. A high preoperative SVA is an independent predictor for poor recovery after laminoplasty. Therefore, indications for laminoplasty in elderly DCM patients with a high preoperative SVA should be carefully considered.

Level of Evidence:
Level III.
Flow-through Anterolateral Thigh Flaps: Report of 3 Consecutive Cases and Review of its Utility
Authors: Saad Noah H. , Rosso Kelly , Wang Howard , Cromack Douglas , Karamanos Efstathios 
Published: May 2021

Summary
In the field of plastic and reconstructive surgery, soft tissue reconstruction of Gustilo 3B with peripheral vascular disease or 3C fractures is a complex treatment algorithm. The concomitant issue of soft tissue coverage with vascular reconstruction is the main challenge when opting for free tissue transfer. The flow-through flap offers the surgeon the ability to treat a vascular injury or high-grade stenosis to maintain distal perfusion, while also providing soft tissue coverage. In this study, we present a case series of 3 patients who underwent flow-through anterolateral thigh free flap for lower extremity soft tissue coverage. Each patient had a history of trauma and either single vessel runoff or a dominant branch with diminutive secondary blood flow to the foot. All patients successfully underwent free flap reconstruction of lower extremity wounds while concomitantly reconstructing diseased arterial supply. Only 1 patient suffered partial flap loss postoperatively that was treated with debridement and split thickness skin grafting. Flow-through free tissue transfer is a valuable treatment option not only in Gustilo 3C fractures requiring soft tissue coverage, but also in patients with Gustilo 3B fractures with peripheral vascular disease.
Pathophysiology of cardiogenic shock
Authors: Bertini Pietro , Guarracino Fabio 
Published: May 2021

Purpose of review
We describe the pathophysiology of cardiogenic shock (CS), from the main pathways to the inflammatory mechanisms and the proteomic features.

Recent findings
Although the classical pathophysiological pathways underlying CS, namely reduced organ perfusion due to inadequate cardiac output and peripheral vasoconstriction, have been well-established for a long time, the role of macro-and micro-hemodynamics in the magnitude of the disease and its prognosis has been investigated extensively only over the last few years. Moreover, to complete the complex picture of CS pathophysiology, the study of cytokine cascade, inflammation, and proteomic analysis has been addressed recently.

Summary
Understanding the pathophysiology of CS is important to treat it optimally.
Limits of the Glasgow Coma Scale When Assessing for Sepsis in Allogeneic Hematopoietic Cell Transplant Recipients
Authors: Lind Margaret L. , Rosas Mirta Maravilla , McFarland Lindsay , Taylor Lenise , Olson Sandra , Pergam Steven A. 
Published: May 2021

Background
The well-documented association between acute mental status changes and sepsis development and progression makes acute mental status an attractive factor for sepsis screening tools. However, the usefulness of acute mental status within these criteria is limited to the frequency and accuracy of its capture. The Glasgow Coma Scale (GCS) score—the acute mental status indicator in many clinical sepsis criteria—is infrequently captured among allogeneic hematopoietic cell transplant recipients with suspected infections, and its ability to serve as an indicator of acute mental status among this high-risk population is unknown.

Objective
We evaluated the GCS score as an indicator of acute mental status during the 24 hours after suspected infection onset among allogeneic hematopoietic cell transplant recipients.

Methods
Using data from the first 100 days posttransplant for patients transplanted at a single center between September 2010 and July 2017, we evaluated the GCS score as an indicator of documented acute mental status during the 24 hours after suspected infection onset. From all inpatients with suspected infections, we randomly selected a cohort based on previously published estimates of GCS score frequency among hematopoietic cell transplant recipients with suspected infections and performed chart review to ascertain documentation of clinical acute mental status within the 24 hours after suspected infection onset.

Results
A total of 773 patients had ≥1 suspected infections and experienced 1,655 suspected infections during follow-up—625 of which had an accompanying GCS score. Among the randomly selected cohort of 100 persons with suspected infection, 28 were accompanied with documented acute mental status, including 18 without a recorded GCS. In relation to documented acute mental status, the GCS had moderate to high sensitivity and high specificity.

Discussion
These data indicate that, among allogeneic hematopoietic cell transplant recipients with suspected infections, the GCS scores are infrequently collected and have a moderate sensitivity. If sepsis screening tools inclusive of acute mental status changes are to be used, nursing teams need to increase measurement of GCS scores among high sepsis risk patients or identify a standard alternative indicator.
Case Report: Unilateral Cranial Nerve IV Palsy Secondary to Trochlear Schwannoma
Authors: Gebran Jason Jihad , Quan Amy Jill 
Published: May 2021

SIGNIFICANCE
Cranial nerve IV palsy is the most common cranial nerve affected in both pediatric and adult patients with vertical and/or torsional diplopia. The condition has multiple known etiologies, including schwannoma, which is rarely reported in the literature. Schwannoma should be considered when the most common etiologies have been ruled out.

PURPOSE
This report documents a rare case of cranial nerve IV palsy secondary to a trochlear schwannoma. Treatment and management considerations will be discussed.

CASE REPORT
A 57-year-old man presented to the clinic for evaluation of his recent-onset vertical diplopia. He was diagnosed with left cranial nerve IV palsy. MRI of the brain and orbits revealed the presence of a schwannoma along the course of his left fourth cranial nerve. It did not compress any other cranial nerves or the brainstem. The patient was referred to the neuro-ophthalmology clinic for further evaluation. He was managed conservatively with prismatic spectacle correction to relieve his diplopia. Repeat MRI of the brain and orbits was recommended every 6 months.

CONCLUSIONS
Although rare, schwannoma of the fourth cranial nerve should be considered in cases of cranial nerve IV palsies without an obvious etiology. Neuroimaging of the brain and orbits is warranted in cases where more common etiologies have been ruled out or when other cranial nerves and/or the brainstem are involved.
Effect of Hygiene Procedures on Lens Case Contamination with Povidone-Iodine or Multipurpose Disinfecting Solutions
Authors: Nakagawa Masahiro , Nakagawa Ritsue , Willcox Mark D. P. , Vijay Ajay Kumar 
Published: May 2021

SIGNIFICANCE
A multipurpose disinfecting solution (MPDS), which contains povidone-iodine (PI) as a disinfectant, has high disinfecting efficacy not only on planktonic bacterium but also on the case biofilms. The addition of case hygiene practice removed more bacteria from cases than MPDS alone.

PURPOSE
This study compared the ability of two MPDSs, one containing PI and another containing polyaminopropyl biguanide and polyquaternium, to reduce bacterial numbers in solution or adhered to the cases following case hygiene procedures.

METHODS
Bacterial strains (Delftia acidovorans, Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Serratia marcescens, Staphylococcus aureus, and Staphylococcus epidermidis) were exposed to the MPDSs for the recommended disinfection times, and the viable number evaluated according to ISO 14729. Cases were inoculated with bacterial strains and incubated for 24 hours to allow for biofilm formation. Cases were disinfected with both disinfecting solutions for 4 hours and rinsed, followed by recapping or air-drying, or tissue-wiping and air-drying for 18 hours. The number of survivors was counted using standard culture techniques.

RESULTS
Both products exceeded the recommended 3-log reduction against planktonic bacteria. Regarding biofilm, after rinsing and recapping wet, the numbers of D. acidovorans (mean difference [95% confidence interval] log10 colony-forming units per case, −2.9 [0.8 to −4.6], P < .01), P. aeruginosa (−2.0 [0.5 to −3.1], P < .01), S. marcescens (−1.7 [0.8 to −3.5], P < .05), and S. epidermidis (−2.1 [0.6 to −3.5], P < .05) in PI cases were significantly lower than in the dual-disinfectant MPDS storage cases. After air-drying, the PI storage cases had significantly lower numbers of S. maltophilia (−2.6 [0.6 to −4.0], P < .01), D. acidovorans (−1.6 [0.7 to −3.3], P < .05), and S. aureus (−1.6 [0.7 to −3.1], P < .05). The addition of tissue-wiping reduced the bacterial numbers in the MPDS storage cases to levels in the PI storage cases.

CONCLUSIONS
Contact lens users should be recommended to tissue-wipe and air-dry their lens storage cases after disinfection with regular MPDS.
Practice Guideline: Use of Quantitative EEG for the Diagnosis of Mild Traumatic Brain Injury: Report of the Guideline Committee of the American Clinical Neurophysiology Society
Authors: Tenney Jeffrey R. , Gloss David , Arya Ravindra , Kaplan Peter W. , Lesser Ronald , Sexton Vicki , Nuwer Marc 
Published: May 2021

Summary:
Despite many decades of research, controversy regarding the utility of quantitative EEG (qEEG) for the accurate diagnosis of mild traumatic brain injury (mTBI) remains. This guideline is meant to assist clinicians by providing an expert review of the clinical usefulness of qEEG techniques for the diagnosis of mTBI. This guideline addresses the following primary aim: For patients with or without posttraumatic symptoms (abnormal cognition or behavior), does qEEG either at the time of injury or remote from the injury, as compared with current clinical diagnostic criteria, accurately identify those patients with mTBI (i.e., concussion)? Secondary aims included differentiating between mTBI and other diagnoses, detecting mTBI in the presence of central nervous system medications, and pertinence of statistical methods for measurements of qEEG components. It was found that for patients with or without symptoms of abnormal cognition or behavior, current evidence does not support the clinical use of qEEG either at the time of the injury or remote from the injury to diagnose mTBI (level U). In addition, the evidence does not support the use of qEEG to differentiate mTBI from other diagnoses or detect mTBI in the presence of central nervous system medications, and suitable statistical methods do not exist when using qEEG to identify patients with mTBI. Based upon the current literature review, qEEG remains an investigational tool for mTBI diagnosis (class III evidence).
Serum antibodies to surface proteins ofChlamydia trachomatisas candidate biomarkers of disease: Results from the Baltimore Chlamydia Adolescent/Young Adult Reproductive Management (CHARM) cohort
Authors: Marques Patricia X. , Wand Handan , Nandy Melissa , Tan Chun , Shou Huizhong , Terplan Mishka , Mark Katrina , Brotman Rebecca M. , Wilson David P. , Ravel Jacques , Hsia Ru-ching , M. Bavoil Patrik 
Published: May 2021

AbstractBackgroundWe previously observed that the nine-member family of autotransported polymorphic membrane proteins (Pmps) ofChlamydia trachomatisis variably expressed in cell culture. Additionally,C. trachomatis-infected patients display variable Pmp-specific serum antibody profiles indirectly suggesting expression of unique Pmp profiles is an adaptive response to host-specific stimuli during infection. Here, we propose that the host response to Pmps and other outer surface proteins may correlate with disease severity.MethodsThis study tests this hypothesis using an ELISA that measures serum IgG antibodies specific for the nineC. trachomatisPmp subtypes and four immunodominant antigens (MOMP, OmcB, GroEL, ClpP) in 265 participants of theChlamydiaAdolescent/Young Adult Reproductive Management (CHARM) cohort.ResultsMoreC. trachomatis-infected females displayed high Pmp-specific antibody levels (cut-off Indexes) than males (35.9-40.7% of femalesvs. 24.2-30.0% of males), with statistical significance for PmpC, F and H (P<0.05). Differences in Pmp-specific antibody profiles were not observed betweenC. trachomatis-infected females with a clinical diagnosis of pelvic inflammatory disease (PID) and those without. However, a statistically significant association between high levels of OmcB-specific antibody and a PID diagnosis (P<0.05) was observed.ConclusionsUsing antibody levels as an indirect measure of antigen expression, our results suggest that gender- and/or site-specific (cervix in femalesvs. urethra in males) stimuli controlpmpexpression in infected patients. They also support the possible existence of immune biomarkers of chlamydial infection associated with disease and underline the need for high resolution screening in human serum.
Deep learning-based risk stratification for HER2-negative breast cancer patients
Authors: Jaber Mustafa I. , Beziaeva Liudmila , Szeto Christopher W. , Benz Stephen C. 
Published: May 2021

ABSTRACTIn this paper, we present our analysis of the tumor microenvironment in digital pathology images to stratify risk in HER2-negative breast cancer patients using clinicopathological, spatial image, and cell-based features in a Cox’s proportional hazard model. We start the analysis by processing a set of 304 training pathology images using our in-house pan-cancer trained tumor, stroma, and lymphocyte region identification convolutional neural networks. The next step is computation of spatial regions of interest, namely: lymphocytes within (and adjacent to) tumor, lymphocytes within (and adjacent to) stroma, and stroma within (and adjacent to) tumor areas. Various cell-level information in these regions are then summarized, augmented to clinicopathological data, and linked to patient’s survival to train a Cox’s proportional hazards model. The proposed model outperformed a baseline model based on clinicopathological features only in analysis of an untouched test set of 202 whole slide images with p 8.49E-08 (HR = 0.4273).
Molecular basis and evolutionary cost of a novel phenotype of macrolides/lincosamides resistance in Staphylococcus haemolyticus
Authors: Xu Ruilin , Song Tianqiang , Du Hong , Wang Qiang , Zhang Haifang 
Published: May 2021

ABSTRACTStaphylococcus haemolyticus (S. haemolyticus) is a coagulase-negative Staphylococcus and has become one of the primary pathogens of nosocomial infections. After a long period using the antibiotics against the infections caused by S. haemolyticus, S. haemolyticus developed several resistance phenotypes of macrolides and lincosamides. Here, we acquired four S. haemolyticus clinical isolates, of which three isolates demonstrated antibiotic resistance as reported previously, while one was resistant to both erythromycin and clindamycin without erythromycin induction. Such novel phenotype, known as constitutive Macrolides-Lincosamides-Streptogramins (MLS) resistance, was reported in other bacteria, but it was found for the first time in S. haemolyticus. To further investigate such behavior, we confirmed that the deletion of the methyltransferase ErmC upstream leader peptide was critical to cause constitutive MLS resistance based on the analysis of potential antibiotic resistance genes via whole-genome sequencing and experimental verification. In addition, we discovered that the continuous expression of ErmC may inhibit the growth of S. haemolyticus, which turned out to be the cost with no MLS pressure. Taken together, this study firstly reported the constitutive MLS resistance in S. haemolyticus, and provided new ideas for using macrolides and lincosamides in clinical treatment.
BL-02: a versatile X-ray scattering and diffraction beamline for engineering applications at Indus-2 synchrotron source
Authors: Gupta Pooja , Rao P. N. , Swami M. K. , Bhakar A. , Lal Sohan , Garg S. R. , Garg C. K. , Gauttam P. K. , Kane S. R. , Raghuwanshi V. K. , Rai S. K. 
Published: May 2021

A hard X-ray engineering applications beamline (BL-02) was commissioned recently and started operation in March 2019 at the Indian synchrotron source, Indus-2. This bending-magnet-based beamline is capable of operating in various beam modes, viz. white, pink and monochromatic beam. The beamline utilizes the X-ray diffraction technique in energy-dispersive and angle-dispersive modes to carry out experiments mainly focused on engineering problems, viz. stress measurement, texture measurement and determination of elastic constants in a variety of bulk as well as thin-film samples. An open-cradle six-circle diffractometer with ∼12 kg load capacity allows accommodation of a wide variety of engineering samples and qualifies the beamline as a unique facility at Indus-2. The high-resolution mode of this beamline is suitably designed so as to carry out line profile analysis for characterization of micro- and nano-structures. In the present article the beamline is described starting from the beamline design, layout, optics involved, various operational modes and experimental stations. Experiments executed to validate the beamline design parameters and to demonstrate the capabilities of the beamline are also described. The future facilities to be incorporated to enhance the capabilities of the beamline are also discussed.