bluuebunny/crossref_metadata_2025 huggingface dataset:
Multicenter Validation of Histopathologic Tumor Regression Grade After Neoadjuvant Chemotherapy in Muscle-invasive Bladder Carcinoma
Authors: Voskuilen Charlotte S. , Oo Htoo Zarni , Genitsch Vera , Smit Laura A. , Vidal Alvaro , Meneses Manuel , Necchi Andrea , Colecchia Maurizio , Xylinas Evanguelos , Fontugne Jacqueline , Sibony Mathilde , Rouprêt Morgan , Lenfant Louis , Côté Jean-François , Buser Lorenz , Saba Karim , Furrer Marc A. , van der Heijden Michiel S. , Daugaard Mads , Black Peter C. , van Rhijn Bas W.G. , Hendricksen Kees , Poyet Cédric , Seiler Roland
Published: September 2019

Response classification after neoadjuvant chemotherapy in muscle-invasive bladder carcinoma is based on the TNM stage at radical cystectomy. We recently showed that histopathologic tumor regression grades (TRGs) add prognostic information to TNM. Our aim was to validate the prognostic significance of TRG in muscle-invasive bladder cancer in a multicenter setting. We enrolled 389 patients who underwent cisplatin-based chemotherapy before radical cystectomy in 8 centers between 2010 and 2016. Median follow-up was 2.2 years. TRG was determined in radical cystectomy specimens by local pathologists. Central pathology review was conducted in 20% of cases, which were randomly selected. The major response was defined as ≤pT1N0. The remaining patients were grouped into partial responders (≥ypT2N0-3 and TRG 2) and nonresponders (≥ypT2N0-3 and TRG 3). TRG was successfully determined in all cases, and interobserver agreement in central pathology review was high (κ=0.83). After combining TRG and TNM, 47%, 15%, and 38% of patients were major, partial, and nonresponders, respectively. Combination of TRG and TNM showed significant prognostic discrimination of overall survival (major responder: reference; partial responder: hazard ratio 3.5 [95% confidence interval: 1.8-6.8]; nonresponder: hazard ratio 6.1 [95% confidence interval: 3.6-10.3]). This discrimination was superior compared with TNM staging alone, supported by 2 goodness-of-fit criteria (P=0.041). TRG is a simple, reproducible histopathologic measurement of response to neoadjuvant chemotherapy in muscle-invasive bladder cancer. Integrating TRG with TNM staging resulted in significantly better prognostic stratification than TNM staging alone.
Active Seizures in Children Are Often Subtle and Unrecognized by Prehospital Providers
Authors: Rose Emily , Abramson Tiffany M. , Kearl Yvette L. , Loza-Gomez Angelica
Published: September 2019

Early recognition and treatment of seizures is essential for optimal patient outcomes. Seizure activity, particularly in young children, can be subtle and often go unrecognized by providers. This case series retrospectively identified 7 cases of pediatric patients (14 years and younger) who presented to the emergency department with active seizure activity that was unrecognized by the prehospital care providers. The presentation of these patients, their clinical signs of seizure, and emergency department disposition are highlighted in this series.
Facial Artery Pseudoaneurysm in a Child Diagnosed With Point-of-Care Ultrasound
Authors: Abulfaraj Maher M. , Deanehan J. Kate
Published: September 2019

This case describes a 3-year-old boy who was brought to the pediatric emergency department for evaluation of facial swelling. The patient's history was remarkable for a deep facial laceration 5 days prior that required surgical repair in the operating room. On the day of presentation, he was noted to have mild swelling and tenderness to palpation of the left jaw below the mandible, in the same location as his recent laceration repair. Point-of-care ultrasound (POCUS) revealed a pseudoaneurysm with an arterial feeding vessel. This was confirmed by radiology-performed ultrasound, and the patient underwent a coil embolization procedure. To our knowledge, this is the first reported case of a pseudoaneurysm being diagnosed by POCUS in a pediatric patient. This case demonstrates the utility of POCUS in facilitating the timely recognition of vascular mass lesions and guiding management in the emergency department to avoid complications.
The Value of Serum Amyloid A Levels in Familial Mediterranean Fever to Identify Occult Inflammation During Asymptomatic Periods
Authors: Çakan Mustafa , Karadağ Şerife Gül , Tanatar Ayşe , Sönmez Hafize Emine , Ayaz Nuray Aktay
Published: September 2019

Objective

The aim of this observational study was to evaluate whether there was any correlation between the acute phase reactants in children with familial Mediterranean fever (FMF) during attack and attack-free periods.

Methods

The study was conducted between June 2016 and January 2018. Clinical features and laboratory parameters of children with FMF during attack and attack-free periods were recorded longitudinally.

Results

The cohort consisted of 168 children with FMF (84 boys, 84 girls). Median values of acute phase reactants during FMF attacks were 433.5 mg/L (34.0–1780.0 mg/L) for serum amyloid A (SAA), 56.7 mg/L (7.6–379.0 mg/L) for C-reactive protein (CRP), and 37.5 mm/h (5–100 mm/h) for erythrocyte sedimentation rate (ESR). Median values for the same tests in attack-free periods were 3.2 mg/L (0.1–25.0 mg/L), 1.7 mg/L (0.1–12.7 mg/L), and 8 mm/h (1–30 mm/h), respectively. Correlation analyses showed that SAA and CRP were highly correlated in FMF attack (r = 0.67, p < 0.01), but no correlation was found between SAA and ESR levels. C-reactive protein was elevated in 13.6%, ESR in 20.8%, and SAA in 28.5% of the patients during attack-free period. Age at onset, sex of the patients, and characteristics of attacks were found to be not associated with elevated SAA in attack-free period. On the other hand, having homozygous exon 10 mutation and having elevated CRP were found to be associated with high SAA in attack-free period.

Conclusions

C-reactive protein and SAA correlate well with FMF attacks. Therefore, checking for SAA during a FMF attack is not required. However, SAA seems to be the most sensitive method for demonstrating subclinical inflammation in attack-free period. Thus, checking SAA levels might be a valuable tool in selected FMF patients.
The Relationship Between Autonomic Dysfunction of the Gastrointestinal Tract and Emotional Distress in Patients With Systemic Sclerosis
Authors: DiRenzo Dana , Russell James , Bingham Clifton O. , McMahan Zsuzsanna
Published: September 2019

Background/Objectives

We hypothesized that emotional distress in systemic sclerosis (SSc) patients with moderate to severe gastrointestinal (GI) dysfunction is associated with dysautonomia. We sought to determine (1) the clinical characteristics associated with emotional distress in SSc, (2) the odds of having dysautonomia in those with emotional distress, and (3) whether GI dysautonomia, as measured by the Survey of Autonomic Symptoms (SAS), correlates with GI dysautonomia on the Composite Autonomic Symptom Score-31 (COMPASS-31).

Methods

Clinical and demographic features from our prospective cohort study were compared among SSc patients with and without GI-associated emotional distress (University of California at Los Angeles Scleroderma Clinical Trial Consortium Gastrointestinal Tract 2.0 well-being subscale >0.5 or ≤0.5) in cross-sectional analysis. Covariates/confounders independently associated with emotional distress were used to construct multivariable logistic regression models. The COMPASS-31 and SAS GI subdomains were compared with Spearman correlation.

Results

Forty-six patients with SSc were enrolled in the study. In univariate analyses, age (odds ratio [OR], 1.06; p = 0.026), severity of GI dysautonomia (COMPASS-31: OR, 1.41; p = 0.003), anti–centromere (A/B) antibodies (OR, 3.60; p = 0.044), and anti–PM-Scl (75/100) antibodies (OR, 0.15; p = 0.035) were associated with emotional distress. In the adjusted model, those with more severe GI dysautonomia remained more likely to have emotional distress (OR, 1.85; p = 0.026); those with anti–PM-Scl (75/100) antibodies were less likely to have emotional distress (OR, 0.03; p = 0.031). The SAS and COMPASS-31 GI subdomains moderately correlated (ρ = 0.68, p < 0.001).

Conclusions

In SSc, increased symptom burden related to GI dysautonomia is associated with emotional distress. Multidisciplinary approaches addressing both the physical and emotional needs of the SSc patient may be warranted to optimize patient care.
Spectral Photon-Counting Computed Tomography for Coronary Stent Imaging
Authors: Bratke Grischa , Hickethier Tilman , Bar-Ness Daniel , Bunck Alexander Christian , Maintz David , Pahn Gregor , Coulon Philippe , Si-Mohamed Salim , Douek Philippe , Sigovan Monica
Published: September 2019

Objectives

In-stent restenosis (ISR) is one of the main long-term complications after coronary stent placement, and the ability to evaluate ISR noninvasively using coronary computed tomography (CT) angiography remains challenging. For this application, spectral photon-counting CT (SPCCT) has the potential to increase image quality and reduce artifacts due to its advanced detector technology.

Our study aimed to verify the technical and clinical potential of a novel SPCCT prototype using an ISR phantom setup.

Materials and Methods

Soft plaque-like restenosis (45 HU; approximately 50% of the stent lumen) were inserted into 10 different coronary stents (3 mm diameter), which were placed in a vessel phantom and filled with a contrast agent (400 HU). A research prototype SPCCT and a clinical dual-layer CT (DLCT; IQon; Philips) with comparable acquisition and reconstruction parameters were used to scan the phantoms. Conventional polyenergetic (PolyE) and monoenergetic (MonoE) images with 4 different energy levels (40, 60, 90, 120 keV) were reconstructed. Qualitative (delineation of the stenosis and adjacent residual lumen using a 5-point Likert scale) and quantitative (image noise, visible lumen diameter, lumen diameter adjacent to the stenosis, contrast-to-noise ratio of the restenosis) parameters were evaluated for both systems.

Results

The qualitative results averaged over all reconstructions were significantly superior for SPCCT compared with DLCT (eg, subjective rating of the best reconstruction of each scanner: DLCT PolyE: 2.80 ± 0.42 vs SPCCT MonoE 40 keV: 4.25 ± 1.03). Stenosis could be clearly detected in 9 and suspected in 10 of the 10 stents with both SPCCT and DLCT. The residual lumen next to the stenosis was clearly delineable in 7 of 10 stents (0.64 ± 0.11 mm or 34.97% of the measured stent lumen) with SPCCT, while it was not possible to delineate the residual lumen for all stents using DLCT. The measured diameter of the lumen within the stent was significantly higher for SPCCT compared with DLCT in all reconstructions with the best results for the MonoE 40 keV images (SPCCT: 1.80 ± 0.17 mm; DLCT: 1.50 ± 0.31 mm). The image noise and the contrast-to-noise ratio were better for DLCT than for SPCCT (contrast-to-noise ratio: DLCT MonoE 40: 31.58 ± 12.54; SPCCT MonoE 40: 4.64 ± 1.30).

Conclusions

Spectral photon-counting CT allowed for the noninvasive evaluation of ISR with reliable results regarding the residual lumen for most tested stents and the clear identification or suspicion of stenosis for all stents. In contrast, the residual lumen could not be detected for a single stent using DLCT.
Risk of Hypersensitivity Reactions to Iopromide After Intra-Arterial Versus Intravenous Administration
Authors: Endrikat Jan , Michel Alexander , Kölbach Ralf , Lengsfeld Philipp , Vogtländer Kai
Published: September 2019

Objective

The aim of this study was to compare the risk of hypersensitivity reactions to iopromide after intra-arterial (IA) administration and intravenous (IV) administration.

Materials and Methods

Four observational studies were pooled. Almost half of the study population (48.1%) was from Europe, and one quarter each from China (27.6%) and other Asia countries (24.1%). All patients received iopromide either intra-arterially or intravenously for angiographic procedures (mostly cardio-angiography) or contrast-enhanced computed tomography. A nested case-control analysis, including a multivariable logistic regression model, was performed. Cases were defined by patients with a typical and unequivocal hypersensitivity (assumed non–IgE-mediated) reaction; controls were patients without any recorded reaction. The primary target variable is the odds ratio of having a hypersensitivity reaction after IA versus IV administration.

Results

A total of 133,331 patients met the inclusion criteria, 105,460 and 27,871 patients received iopromide IV or IA, respectively. Hypersensitivity reactions were recorded for 822 patients, and 132,509 patients served as controls.

Major risk factors for hypersensitivity reactions were method of injection (IV vs IA), age (18 to <50 years vs ≥65 years), history of allergy or previous contrast media reaction (all P < 0.001), and asthma (P = 0.005).

A total of 766 patients (0.7%) and 56 patients (0.2%) were recorded with hypersensitivity reactions after IV or IA administration, respectively (P < 0.0001).

Adjusted odds ratio (IA vs IV) was 0.23 (95% confidence interval, 0.16–0.32) for all countries together: for China only, 0.22 (0.11–0.44); for all countries without China, 0.36 (0.25–0.53).

Most frequent reactions were erythema/urticaria/rash, pruritus, and cough/sneezing.

Conclusions

Hypersensitivity reactions to iopromide were significantly less frequently recorded after IA administrations. This could be related to the delayed and diluted arrival of iopromide to the lungs.
68Ga-DOTATATE
Authors: Delbeke Dominique , Newman Grace , Deppen Steve , Shah Chirayu , Ndolo Josephine , Shi Chanjuan , Bailey Christina E. , Jessop Aaron C. , Sandler Martin P.
Published: September 2019

Purpose

To measure the SUVs in the tail of the pancreas compared with normal liver parenchyma and somatostatin receptor–positive lesions.

Materials and Methods

68Ga-DOTATATE PET/low mAs CT of 35 patients were reviewed.

Results

There was no significant difference (P = 0.59) between the SUVaverage of normal liver and the SUVpeak of normal tail. Five patients had uptake in the tail slightly above that of normal liver that were interpreted equivocally. In one of these patients with 68Ga-DOTATATE uptake in a peripancreatic lymph node, proven neuroendocrine tumor underwent a distal pancreatectomy and pathologic examination revealed islet cell hyperplasia.

Conclusions

68Ga-DOTATATE uptake in the tail of the pancreas above that of normal liver indicates a somatostatin receptor–avid lesion. Uptake in the tail of the pancreas equal to the liver can be normal. Patients with uptake equivalent to the liver should undergo further anatomical imaging before procedural intervention.
68Ga-PSMA PET/CT in Giant Retroperitoneal Liposarcoma
Authors: Inanir Sabahat , Kesim Selin , Ergelen Rabia , Tınay İlker , Türköz Hüseyin Kemal
Published: September 2019

Primary retroperitoneal liposarcoma is an extremely rare malignant tumor. Herein, we report a case with an incidentally detected giant retroperitoneal liposarcoma on 68Ga-PSMA PET/CT during primary staging for prostate cancer.
Selective Internal Radiation Therapy for Liver Metastasis of Papillary Thyroid Carcinoma
Authors: Kesim Selin , Ones Tunc , Ozguven Salih , Dulundu Ender , Baltacioglu Feyyaz
Published: September 2019

Papillary carcinoma of thyroid (PTC) is the most common neoplasm of the thyroid gland that usually invades lymphatics rather than blood vessels. Hematogenous metastasis of PTC is rare, and distant metastasis to the liver is even rarer. Selective internal radiation therapy with 90Y microspheres is a well-recognized technique in the treatment of liver metastases. Herein, we present a case of PTC with radioactive iodine-negative hepatic metastasis detected by 18F-FDG PET/CT and treated with selective internal radiation therapy.
68Ga-PSMA-HBED-CC PET/CT and 18F-FDG PET/CT in Ewing Sarcoma
Authors: Parihar Ashwin Singh , Sood Apurva , Mittal Bhagwant Rai , Kumar Rajender , Singh Harmandeep , Dhatt Sarvdeep Singh
Published: September 2019

We present a case of a 19-year-old woman with Ewing sarcoma of the iliac bone in whom 68Ga-PSMA-HBED-CC PET/CT showed high radiotracer activity in the primary tumor. The present case documents the in vivo expression of PSMA in Ewing sarcoma family of tumors and adds on to the list of nonprostatic malignancies showing PSMA expression.
68Ga-DOTATATE PET/CT of Ectopic Cushing Syndrome Due to Appendicular Carcinoid
Authors: Diwaker Chakra , Shah Ravi Kumar , Patil Virendra , Jadhav Swati , Lila Anurag , Bandgar Tushar , Shah Nalini
Published: September 2019

Approximately 5% to 15% cases of endogenous Cushing syndrome are due to ectopic adrenocorticotrophic hormone (ACTH)–producing neuroendocrine tumors, which are commonly located in bronchopulmonary system, thymus, and gastrointestinal tract including pancreas. Although carcinoid tumors of the appendix are revealed in 0.3% of patients undergoing routine appendectomy, ACTH-secreting appendicular carcinoid is a rare entity. We present a case of a 22-year-old woman with ectopic ACTH-dependent Cushing syndrome due to an appendicular carcinoid, which was localized with the help of 68Ga-DOTATATE PET/CT scan.
Salvage of Exposed Cardiac Implants Using Fasciocutaneous Rotation Flaps
Authors: Dağdelen Dağhan , Aksoy Alper
Published: September 2019

Introduction

Implantation rates of cardiac implantable electrophysiological devices (CIEDs) are rising, mainly because of the expansion of implantable cardioverter-defibrillators indications for primary prevention. As the CIED usage increases, CIED-related complications are also in rise. Transvenous approach and laser utilization techniques are replacing the open heart surgeries, for removal of CIED systems that are suspected to be infected. In this study, we aimed to share our new method of fasciocutaneous flap coverage results of patients with exposed CIED systems who were not eligible for the CIED replacement surgery for various reasons.

Patients and Methods

Patients operated with rotational fasciocutaneous flaps with addition of pectoralis fascia, owing to their exposed CIEDs between June 2016 and January 2019, were enlisted. Patients with signs of infection whether systemic or limited to the CIED pocket with or without positive blood cultures were referred to infectious diseases department and not included in this study. Patients included in the study were evaluated retrospectively in terms of demographic data, implanted CIED type, time elapsed from implantation to exposure, from referral to flap coverage operation, total follow-up time, survival ratios during follow-up, and complications related to flap coverage operation. In addition, indications for CIED implantation, patient comorbidities, and culture results obtained from the capsule encompassing the CIED battery unit were included to the evaluation.

Results

A total of 13 patients with exposed CIEDs have undergone total capsulectomy and CIED system coverage with rotational fasciocutaneous flaps. The mean patient age ± SD was 60.2 ± 13.4 years. The average time elapsed from CIED implantation to exposure was 27.3 ± 15.4 months. The average time spanned from initial referral to operation was 6 ± 1.6 days. The most prevalent comorbidity was diabetes mellitus. The average time elapsed during operation for pectoral fascia incorporated rotation flaps was 90 ± 10.6 minutes. Coagulase negative staphylococci were the dominant species (46.5%) obtained from capsule cultures. Apart from 1 case of hematoma, no early or late operation–related complication was encountered.

Conclusions

A more precise definition of contamination and infection has to be made in guidelines, which may lead the first group to be treated without extraction. Surgical method defined in this study can be used for the treatment of patients in contaminated CIED subgroup, conserving individuals from risks of device extraction.
Comparing the Health Burden of Living With Nasal Deformity in Actual Patients and Healthy Individuals
Authors: Aldihan Khalid , Alnasyan Abdulmalik , Albassam Abdullah , Alghonaim Yazeed , Aldekhayel Salah
Published: September 2019

Background

Rhinoplasty is a one of the most commonly performed facial surgery aiming at restoring facial aesthetics and improving quality of life. Utility outcome scores are modern, and emerging tools are used to evaluate the burden of a health state on individuals. The study aims to evaluate the impact of living with nasal deformity among real patients and healthy individuals using utility outcome scores.

Methods

A cross-sectional study was conducted at Otolaryngology and Plastic Surgery clinics in a tertiary center. Healthy individuals were recruited from public facilities. A case scenario was developed to reflect an imaginary patient (Nora) with a functional and aesthetic nasal deformity and distributed to participants. Three utility outcomes scores were used: visual analog scale (VAS), time trade-off (TTO), and standard gambling (SG).

Results

A total of 407 adult participants were included. Most participants were female (52%). Healthy individuals comprised 71%, and actual patients comprised 29%. Mean VAS score was 0.77 (ie, participants scored Nora's health state as 77%), TTO score was 0.87 (ie, participants were willing to sacrifice 4 years to have Nora's condition corrected), and SD score was 0.91 (ie, participants were willing to take a 9% risk of death to have Nora's condition corrected). Scores differed among actual patients and healthy individuals (P < 0.0001 for VAS and TTO, P = 0.02 for SG).

Conclusion

Living with a nasal deformity has a significant impact on quality of life. Both patients and healthy individuals are willing to trade a significant number of years to get the condition corrected.
Prehospital plasma in injured patients is associated with survival principally in blunt injury: Results from two randomized prehospital plasma trials
Authors: Reitz Katherine M. , Moore Hunter B. , Guyette Frank X. , Sauaia Angela , Pusateri Anthony E. , Moore Ernest E. , Hassoune Adnan , Chapman Michael P. , Daley Brian J. , Miller Richard S. , Harbrecht Brian G. , Claridge Jeffrey A. , Phelan Herb A. , Brown Joshua B. , Zuckerbraun Brian S. , Neal Matthew D. , Yazer Mark H. , Sperry Jason L.
Published: September 2019

Introduction

Recent evidence demonstrated that prehospital plasma in patients at risk of hemorrhagic shock was safe for ground transport and resulted in a 28-day survival benefit for air medical transport patients. Whether any beneficial effect of prehospital plasma varies across injury mechanism remains unknown.

Methods

We performed a secondary analysis using a harmonized data set derived from two recent prehospital plasma randomized trials. Identical inclusion/exclusion criteria and primary/secondary outcomes were used for the trials. Prehospital time, arrival shock parameters, and 24-hour transfusion requirements were compared across plasma and control groups stratified by mechanism of injury. Stratified survival analysis and Cox hazard regression were performed to determine the independent survival benefits of plasma across blunt and penetrating injury.

Results

Blunt patients had higher injury severity, were older, and had a lower Glasgow Coma Scale. Arrival indices of shock and coagulation parameters were similar across blunt and penetrating injury. The percentage of patients with a prehospital time less than 20 minutes was significantly higher for penetrating patients relative to blunt injured patients (28.0% vs. 11.6%, p < 0.01). Stratified Kaplan-Meier curves demonstrated a significant separation for blunt injured patients (n = 465, p = 0.01) with no separation demonstrated for penetrating injured patients (n = 161, p = 0.60) Stratified Cox hazard regression verified, after controlling for all important confounders, that prehospital plasma was associated with a 32% lower independent hazard for 28-day mortality in blunt injured patients (hazard ratio, 0.68; 95% confidence interval, 0.47–0.96; p = 0.03) with no independent survival benefit found in penetrating patients (hazard ratio, 1.16; 95% confidence interval, 0.4–3.1; p = 0.78).

Conclusion

A survival benefit associated with prehospital plasma at 24 hours and 28 days exists primarily in blunt injured patients with no benefit shown in penetrating trauma patients. No detrimental effects attributable to plasma are demonstrated in penetrating injury. These results have important relevance to military and civilian trauma systems.

LEVEL OF EVIDENCE

Therapeutic, I.
Lifting the burden: State Medicaid expansion reduces financial risk for the injured
Authors: Scott John W. , Shrime Mark G. , Stewart Barclay T. , Arbabi Saman , Bulger Eileen M. , Cuschieri Joseph , Maier Ronald V. , Robinson Bryce R. H.
Published: September 2019

BACKGROUND

Injuries are unanticipated and can be expensive to treat. Patients without sufficient health insurance are at risk for financial strain because of high out-of-pocket (OOP) health care costs relative to their income. We hypothesized that the 2014 Medicaid expansion (ME) in Washington (WA) state, which extended coverage to more than 600,000 WA residents, was associated with a reduction in financial risk among trauma patients.

METHODS

We analyzed all trauma patients aged 18 to 64 years admitted to the sole level 1 trauma center in WA from 2012 to 2017. We defined 2012 to 2013 as the prepolicy period and 2014 to 2017 as the postpolicy period. We used a multivariable linear regression model to evaluate for changes in length of stay, inpatient mortality, and discharge disposition. To evaluate for financial strain, we used WA state and US census data to estimate postsubsistence income and OOP expenses for our sample and then applied these two estimates to determine catastrophic health expenditure (CHE) risk as defined by the World Health Organization (OOP health expenses ≥40% of estimated household postsubsistence income).

RESULTS

A total of 16,801 trauma patients were included. After ME, the Medicaid coverage rate increased from 20.4% to 41.0%, and the uninsured rate decreased from 19.2% to 3.7% (p < 0.001 for both). There was no significant change in private insurance coverage. Medicaid expansion was not associated with significant changes in clinical outcomes or discharge disposition. Estimated CHE risk by payer was 81.4% for the uninsured, 25.9% for private insurance, and less than 0.1% for Medicaid. After ME, the risk of CHE for the policy-eligible sample fell from 26.4% to 14.0% (p < 0.01).

CONCLUSION

State ME led to an 80% reduction in the uninsured rate among patients admitted for injury, with an associated large reduction in the risk of CHE. However, privately insured patients were not fully protected from CHE. Additional research is needed to evaluate the impact of these policies on the financial viability of trauma centers.

LEVEL OF EVIDENCE

Economic analysis, level II.
Arteritic Orbital Ischemia Producing Afferent and Efferent Pupillary Defects
Authors: Hussain Mariam , Kini Ashwini , Al Othman Bayan , Ponce Claudia Prospero , Li Helen , Lee Andrew G.
Published: September 2019

A 67-year-old woman presented with acute loss of vision to no light perception (NLP), a right afferent pupillary defect, and anisocoria with a nonreactive and dilated pupil in the right eye. Fundus examination showed pallid optic disc edema and a central retinal artery occlusion (CRAO) in the right eye. A temporal artery biopsy showed giant cell arteritis (GCA). Orbital involvement in GCA has been reported previously. However the combination of an afferent and efferent pupillary defect, NLP vision, pallid disc edema, and a CRAO in an elderly patient is likely a unique clinical combination that should strongly suggest GCA. Clinicians should be aware of the myriad presentations of GCA, including orbital ischemia.
Lack of apolipoprotein A1 impairs optimal regulatory T cell homeostasis at steady state due to impaired IL-2 signaling
Authors: Gaddis Dalia E. , Wu Runpei , Parks John S. , Sorci-Thomas Mary G. , Hedrick Catherine C.
Published: September 2019

Apolipoprotein A1 (ApoA1), the major constituent of the high-density lipoprotein (HDL) molecule, exhibits anti-inflammatory properties. Our laboratory has previously shown that ApoA1 protects against switching of regulatory T (Treg) cells to atherogenic T follicular helper cells in Western diet-fed mice. However, the role of ApoA1 in modulating Treg cell homeostasis in the absence of atherosclerosis remains uncharacterized. Here, we show that ApoA1 is required for normal Treg cell homeostasis and functioning at steady state. Specifically, lack of ApoA1 decreased the numbers of both natural and induced Treg cells and also lowered Treg cell-based homeostatic proliferation and suppressive functions. Importantly, these changes occurred without affecting other T cell populations. Finally, we determined that the observed phenotypes were caused by changes to cholesterol content and reduced interleukin-2 (IL-2) receptor signaling in ApoA1-deficient Treg cells. Overall, our results show that ApoA1-HDL is necessary for Treg cell homeostasis and functioning.
Updated functional annotation of the Mycobacterium bovis AF2122/97 reference genome
Authors: Farrell Damien , Crispell Joseph , Gordon Stephen V.
Published: September 2019

Mycobacterium bovis AF2122/97 is the reference strain for the bovine tuberculosis bacillus. We here report an update to the M. bovis AF2122/97 genome annotation to reflect 616 new protein identifications which replace many of the old hypothetical coding sequences and proteins of unknown function in the genome. These changes integrate information from functional assignments of orthologous coding sequences in the Mycobacterium tuberculosis H37Rv genome. We have also added 69 additional new gene names.
Glymphatic Optimal Mass Transport with Lagrangian Workflow Reveals Advective and Diffusion Driven Solute Transport
Authors: Koundal Sunil , Elkin Rena , Nadeem Saad , Xue Yuechuan , Constantinou Stefan , Sanggaard Simon , Liu Xiaodan , Monte Brittany , Xu Feng , Van Nostrand William , Nedergaard Maiken , Lee Hedok , Wardlaw Joanna , Benveniste Helene , Tannenbaum Allen
Published: September 2019

The presence of advection in neuropil is contested and solute transport is claimed to occur by diffusion only. To address this controversy, we implemented a regularized version of the optimal mass transport (rOMT) problem, wherein the advection/diffusion equation is the only a priori assumption required. rOMT analysis with a Lagrangian perspective of glymphatic system (GS) transport revealed that solute speed was faster in cerebrospinal fluid (CSF) compared to grey and white matter. rOMT analysis also demonstrated 2-fold differences in regional particle speed within the brain parenchyma. Collectively, these results imply that advective transport dominates in CSF while diffusion and advection both contribute to transport in parenchyma. In rats with chronic hypertension, solute transport in perivascular spaces (PVS) and PVS-to-tissue transfer was slower compared to normotension. Thus, the analytical framework of rOMT provides novel insights in local variation and dynamics of GS transport that may have implications for neurodegenerative diseases.
Shared regulatory pathways reveal novel genetic correlations between grip strength and neuromuscular disorders
Authors: Gokuladhas Sreemol , Schierding William , Cameron-Smith David , Wake Melissa , Scotter Emma L. , O’Sullivan Justin
Published: September 2019

Background

Muscle weakness and muscle wasting can be a consequence of aging (sarcopenia) and neuromuscular disorders (NMD). Genome-wide association (GWA) studies have identified genetic variants associated with grip strength (GS, an inverse measure of muscle weakness) and NMD (multiple sclerosis (MS), myasthenia gravis (MG) and amyotrophic lateral sclerosis (ALS)). However, how these variants contribute to the muscle weakness caused by aging or NMD remains obscure.

Methods

We have integrated GS and NMD associated SNPs in a multimorbid analysis that leverages high-throughput chromatin interaction (Hi-C) data and expression quantitative trait loci (eQTL) data to identify allele-specific gene regulation (i.e. eGenes). Pathways and shared drug targets that are enriched by colocalised eGenes were then identified using pathway and drug enrichment analysis.

Results

We identified gene regulatory mechanisms (eQTL-eGene effects) associated with GS, MG, MS and ALS. The eQTLs associated with GS regulate a subset of eGenes that are also regulated by the eQTLs of MS, MG and ALS. Yet, we did not find any eGenes commonly regulated by all four phenotypes associated eQTLs. By contrast, we identified three pathways (mTOR signaling, axon guidance, and alcoholism) that are commonly affected by the gene regulatory mechanisms associated with all four phenotypes. 13% of the eGenes we identified were known drug targets, and GS shares at least one druggable eGene and pathway with each of the NMD phenotypes.

Conclusions

Collectively, these findings identify significant biological overlaps between GS and NMD, demonstrating the potential for spatial genetic analysis to identify mechanisms underlying muscle weakness due to aging and NMD.
A novel function of M. tuberculosis chaperonin paralog GroEL1 in copper homeostasis
Authors: Ansari Mohammed Yousuf , Batra Sakshi D. , Ojha Hina , Ashish  , Tyagi Jaya S. , Mande Shekhar C.
Published: September 2019

Mycobacterial GroELs namely GroEL1 and GroEL2 belong to the family of molecular chaperones, chaperonins. Chaperonins in Escherichia coli are termed as GroEL and GroES which are encoded by essential genes and are involved in cellular protein folding. GroEL1 has a characteristic Histidine-rich C-terminus contrary to its essential paralog GroEL2 and E. coli GroEL which have hydrophobic (GGM) repeats. Since Histidine richness is likely to be involved in metal binding, in this study we have attempted to decipher the role of GroEL1 protein in chelating metals and the consequent role on M. tuberculosis physiology. Using isothermal titration calorimetry (ITC), we found that GroEL1 binds copper, nickel and cobalt, with the highest binding affinity to copper. Since copper is known to be toxic at higher concentration, we cultured Wild Type M. tuberculosis H37Rv, groEL1 knock-out and groEL1-complemented strain with increasing concentrations of copper. We found that M. tuberculosis groEL1 knock out strain is more sensitive to copper than the wild type. Further hypothesizing that the probable mode of action of copper is by induction of oxidative stress, we attempted to understand the role of GroEL1 in redox silencing and hydroxyl radical mediated DNA damage. We interestingly found through our in vitro studies that GroEL1 is helpful in protection from copper stress through maintaining redox balance and free radical mediated DNA damage. Thus, these results indicate that the duplication of chaperonin genes in M. tuberculosis might have led to their evolutionary divergence and resulted in a functional divergence of chaperonins.
Establishing RPTE-derived cell lines expressing hTERT for studying BK polyomavirus
Authors: Zhao Linbo , Imperiale Michael J.
Published: September 2019

We previously established an infection model for BKPyV in primary human renal proximal tubule epithelial (RPTE) cells. Use of these cells is limited by their inability to be passaged extensively. We describe RPTE cells immortalized with hTERT, which can serve as a model system for acute or persistent BKPyV infection.
An improved de novo assembly and annotation of the tomato reference genome using single-molecule sequencing, Hi-C proximity ligation and optical maps
Authors: Hosmani Prashant S. , Flores-Gonzalez Mirella , van de Geest Henri , Maumus Florian , Bakker Linda V. , Schijlen Elio , van Haarst Jan , Cordewener Jan , Sanchez-Perez Gabino , Peters Sander , Fei Zhangjun , Giovannoni James J. , Mueller Lukas A. , Saha Surya
Published: September 2019

The original Heinz 1706 reference genome was produced by a large team of scientists from across the globe from a variety of input sources that included 454 sequences in addition to full-length BACs, BAC and fosmid ends sequenced with Sanger technology. We present here the latest tomato reference genome (SL4.0) assembledde novofrom PacBio long reads and scaffolded using Hi-C contact maps. The assembly was validated using Bionano optical maps and 10X linked-read sequences. This assembly is highly contiguous with fewer gaps compared to previous genome builds and almost all scaffolds have been anchored and oriented to the 12 tomato chromosomes. We have found more repeats compared to the previous versions and one of the largest repeat classes identified are the LTR retrotransposons. We also describe updates to the reference genome and annotation since the last publication. The corresponding ITAG4.0 annotation has 4,794 novel genes along with 29,281 genes preserved from ITAG2.4. Most of the updated genes have extensions in the 5’ and 3’ UTRs resulting in doubling of annotated UTRs per gene. The genome and annotation can be accessed using SGN through BLAST database, Pathway database (SolCyc), Apollo, JBrowse genome browser and FTP available athttps://solgenomics.net.
Making the MOSTest of imaging genetics
Authors: van der Meer Dennis , Frei Oleksandr , Kaufmann Tobias , Shadrin Alexey A. , Devor Anna , Smeland Olav B. , Thompson Wes , Fan Chun Chieh , Holland Dominic , Westlye Lars T. , Andreassen Ole A. , Dale Anders M.
Published: September 2019

Regional brain morphology has a complex genetic architecture, consisting of many common polymorphisms with small individual effects, which has proven challenging for genome-wide association studies to date, despite its high heritability1,2. Given the distributed nature of the genetic signal across brain regions, joint analysis of regional morphology measures in a multivariate statistical framework provides a way to enhance discovery of genetic variants with current sample sizes. While several multivariate approaches to GWAS have been put forward over the past years3–5, none are optimally suited for complex, large-scale data. Here, we applied the Multivariate Omnibus Statistical Test (MOSTest), with an efficient computational design enabling rapid and reliable permutation-based inference, to 171 subcortical and cortical brain morphology measures from 26,502 participants of the UK Biobank (mean age 55.5 years, 52.0% female). At the conventional genome-wide significance threshold of α=5×10−8, MOSTest identifies 347 genetic loci associated with regional brain morphology, more than any previous study, improving upon the discovery of established GWAS approaches more than threefold. Our findings implicate more than 5% of all protein-coding genes and provide evidence for gene sets involved in neuron development and differentiation. As such, MOSTest, which we have made publicly available, enhances our understanding of the genetic determinants of regional brain morphology.
3D Exploration of the Brainstem in 50-micron Resolution MRI
Authors: Makris N , Rushmore RJ , Wilson-Braun P , Papadimitriou G , Ng I , Rathi Y N , Zhang F , O’Donnell LJ , Kubicki M , Yeterian E , Lemaire JJ , Calabrese E , Johnson GA , Kikinis R
Published: September 2019

The brainstem, a structure of vital importance in the mammals, is currently becoming a principal focus in cognitive, affective and clinical neuroscience. Midbrain, pontine and medullar structures are the epicenter of conduit, cranial nerve and such integrative functions as consciousness, emotional processing, pain and motivation. In this study, we parcellated the nuclear masses and the principal fiber pathways that were visible in a high resolution T2-weighted MRI dataset of 50-micron isotropic voxels of a postmortem human brainstem. Based on this analysis, we generated a detailed map of the human brainstem. To assess the validity of our maps, we compared our observations with histological maps of traditional human brainstem atlases. Moreover, we reconstructed the motor, sensory and integrative neural systems of the brainstem and rendered them in 3D representations. We anticipate the utilization of these maps by the neuroimaging community at large for applications in basic neuroscience as well as in neurology, psychiatry and neurosurgery, due to their versatile computational nature in 2D and 3D representations in a publicly available capacity.
DNA repair by Rad52 liquid droplets
Authors: Oshidari Roxanne , Huang Richard , Medghalchi Maryam , Tse Elizabeth Y.W. , Ashgriz Nasser , Lee Hyun O. , Wyatt Haley , Mekhail Karim
Published: September 2019

Cellular processes are influenced by liquid phase separation, but its role in DNA repair is unclear. Here, we show that in Saccharomyces cerevisiae, Rad52 DNA repair proteins at different DNA damage sites assemble liquid droplets that fuse into a repair centre droplet. This larger droplet concentrates tubulin and projects short aster-like microtubule filaments, which tether the droplet to longer microtubule filaments mediating the mobilization of damaged DNA to the nuclear periphery for repair.
Anxious and obsessive-compulsive traits are independently associated with valuation of non-instrumental information
Authors: Bennett Daniel , Sutcliffe Kiran , Tan Nicholas Poh-Jie , Smillie Luke D.
Published: September 2019

Aversion to uncertainty about the future has been proposed as a transdiagnostic trait underlying psychiatric diagnoses including obsessive-compulsive disorder and generalised anxiety. This association might explain the frequency of pathological information-seeking behaviours such as compulsive checking and reassurance-seeking in these disorders. Here we tested the behavioural predictions of this model using a non-instrumental information-seeking task that measured preferences for unusable information about future outcomes in different payout domains (gain, loss, and mixed gain/loss). We administered this task, along with a targeted battery of self-report questionnaires, to a general-population sample of 146 adult participants. Using computational cognitive modelling of choices to test competing theories of information valuation, we found evidence for a model in which preferences for costless and costly information about future outcomes were independent, and in which information preference was modulated by both outcome mean and outcome variance. Critically, we also found positive associations between a model parameter controlling preference for costly information and individual differences in latent traits of both anxiety and obsessive-compulsion. These associations were invariant across different payout domains, providing evidence that individuals high in obsessive-compulsive and anxious traits show a generalised increase in willingness-to-pay for unusable information about uncertain future outcomes, even though this behaviour reduces their expected future reward.
Delta-1 functionalized hydrogel promotes hESC-cardiomyocyte graft proliferation and maintains heart function post-injury
Authors: Gerbin Kaytlyn A , Mitzelfelt Katie A , Guan Xuan , Martinson Amy M , Murry Charles E
Published: September 2019

Current cell transplantation techniques are hindered by small graft size, requiring high cell doses to achieve therapeutic cardiac remuscularization. Enhancing the proliferation of transplanted human stem cell-derived cardiomyocytes (hESC-CMs) could address this, allowing an otherwise subtherapeutic cell dose to prevent disease progression after myocardial infarction. Here, we designed a hydrogel that activates Notch signaling through 3D presentation of the Notch ligand Delta-1 to use as an injectate for transplanting hESC-CMs into the infarcted rat myocardium. After four weeks, hESC-CM proliferation increased 2-fold and resulted in a 3-fold increase in graft size with the Delta-1 hydrogel compared to controls. To stringently test the effect of Notch-mediated graft expansion on long-term heart function, a normally subtherapeutic dose of hESC-CMs was implanted into the infarcted myocardium and cardiac function was evaluated by echocardiography. Transplantation of the Delta-1 hydrogel + hESC-CMs augmented heart function and was significantly higher at three months compared to controls. Graft size and hESC-CM proliferation were also increased at three months post-implantation. Collectively, these results demonstrate the therapeutic approach of a Delta-1 functionalized hydrogel to reduce the cell dose required to achieve functional benefit after myocardial infarction by enhancing hESC-CM graft size and proliferation.
A dynamic interaction between CD19 and the tetraspanin CD81 controls B cell co-receptor trafficking
Authors: Susa Katherine J. , Seegar Tom C. M. , Blacklow Stephen C. , Kruse Andrew C.
Published: September 2019

CD81 and its binding partner CD19 are core subunits of the B cell co-receptor complex. While CD19 is a single-pass transmembrane protein belonging to the extensively studied Ig superfamily, CD81 belongs to a conserved but poorly understood family of four-pass transmembrane proteins called tetraspanins. These functionally diverse proteins play important roles in a wide variety of different organ systems by controlling protein trafficking and other cellular processes. Here, we show that CD81 relies on its ectodomain to control trafficking of CD19 to the cell surface. Moreover, the anti-CD81 antibody 5A6, which binds selectively to activated B cells, recognizes a conformational epitope on CD81 that is masked when CD81 is in complex with CD19. Mutations of CD81 in this contact interface suppress its CD19 surface-export activity. Taken together, these data indicate that the CD81 - CD19 interaction is dynamically regulated upon B cell activation, suggesting that this dynamism can be exploited to regulate B cell function. These results are not only important for understanding B cell biology, but also have important implications for understanding tetraspanin function more generally.
TRAF6 controls spinogenesis instructing synapse density and neuronal activity through binding neuroplastin
Authors: Vemula Sampath Kumar , Malci Ayse , Junge Lennart , Lehmann Anne-Christin , Rama Ramya , Hradsky Johannes , Matute Ricardo A. , Weber André , Prigge Matthias , Naumann Michael , Kreutz Michael R. , Seidenbecher Constanze I. , Gundelfinger Eckart D. , Herrera-Molina Rodrigo
Published: September 2019

Synaptogenic mechanisms and their relevance to achieve a correct synapse density and activity in mature neurons are poorly understood. Here, we show that the tumor necrosis factor receptor-associated factor 6 (TRAF6) controls early spinogenesis by binding the cell adhesion molecule neuroplastin which is has been related to synapse formation in vivo. TRAF6-neuroplastin co-precipitations from brain samples and co-transfected HEK cells is explained by direct interaction of the proteins based on three-dimensional modelling and biochemical identification of intracellular amino acids of neuroplastin binding the TRAF-C domain of TRAF6 with micromolar affinity. TRAF6 was not only required for normal spinogenesis but also was strictly necessary to restore failed spinogenesis in neuroplastin-deficient neurons. Independently from neuroplastin’s extracellular adhesive properties or interaction with another known partner i.e. the plasma membrane Ca2+ ATPases, TRAF6 mediated formation of new postsynapses by neuroplastin overexpression in rat hippocampal neurons. Furthermore, TRAF6-controlled spinogenesis was required for the establishment of a correct synapse density as well as proper synaptic activity and intrinsic neuronal activity as demonstrated with intracellular and extracellular electrophysiological recordings. These findings provide a novel mechanism for early synapse formation that shapes connectivity and functioning of hippocampal neurons.