bluuebunny/crossref_metadata_2025 huggingface dataset:
Gray Matter Nucleus Hyperintensity After Monthly Triple-Dose Gadopentetate Dimeglumine With Long-term Magnetic Resonance Imaging
Authors: DeBevits John J. , Munbodh Reshma , Bageac Devin , Wu Rong , DiCamillo Paul A. , Hu Chaoran , Wang Lihong , Naismith Robert T. , Karimeddini David , Dhib-Jalbut Suhayl , Redko Sviatoslav , Cook Stuart D. , Cadavid Diego , Wolansky Leo
Published: August 2020

Objectives

Gadolinium deposition is widely believed to occur, but questions regarding accumulation pattern and permanence remain. We conducted a retrospective study of intracranial signal changes on monthly triple-dose contrast-enhanced magnetic resonance imaging (MRI) examinations from the previously published Betaseron vs. Copaxone in Multiple Sclerosis With Triple-Dose Gadolinium and 3-Tesla MRI Endpoints Trial (N = 67) to characterize the dynamics of gadolinium deposition in several deep brain nuclei and track persistence versus washout of gadolinium deposition on long-term follow-up (LTFU) examinations (N = 28) obtained approximately 10 years after enrollment in the Betaseron vs. Copaxone in Multiple Sclerosis With Triple-Dose Gadolinium and 3-Tesla MRI Endpoints Trial.

Materials and Methods

Using T2 and proton density images and using image analysis software (ITK-SNAP), manual regions of interest were created ascribing boundaries of the caudate nucleus, dentate nucleus, globus pallidus, pulvinar, putamen, white matter, and air. Intensity analysis was conducted on T1-weighted fat-saturated (fat-sat) images using the FSL package. A linear rigid-body transform was calculated from the fat-sat image at each target time point to the region of interest segmentation reference time point fat-sat image. Serial MRI signal was analyzed using linear mixed regression modeling with random intercept. Annual MRI signal changes including LTFU scans were assessed with t test.

Results

During monthly scanning, all gray matter structures demonstrated a significant (P < 0.0001) increase in contrast-to-noise ratio. Yearly changes in deposition showed distinctive patterns for the specific nucleus: globus pallidus showed complete retention, pulvinar showed partial washout, while dentate, caudate, and putamen returned to baseline (ie, complete washout).

Conclusions

Monthly increased contrast-to-noise ratio in gray matter nuclei is consistent with gadolinium deposition over time. The study also suggests that some deep gray matter nuclei permanently retain gadolinium, whereas others demonstrate washout of soluble gadolinium.
A Solution for Homogeneous Liver Enhancement in Computed Tomography
Authors: Martens Bibi , Wildberger Joachim E. , Hendriks Babs M.F. , Van Kuijk Sander M.J. , Nijssen Estelle C. , Peters Nicky H.G.M. , De Vos-Geelen Judith , Mihl Casper
Published: August 2020

Objectives

The aim of the study was to reach homogeneous enhancement of the liver, irrespective of total body weight (TBW) or tube voltage. An easy-to-use rule of thumb, the 10-to-10 rule, which pairs a 10 kV reduction in tube voltage with a 10% decrease in contrast media (CM) dose, was evaluated.

Materials and Methods

A total of 256 patients scheduled for an abdominal CT in portal venous phase were randomly allocated to 1 of 4 groups. In group 1 (n = 64), a tube voltage of 120 kV and a TBW-adapted CM injection protocol was used: 0.521 g I/kg. In group 2 (n = 63), tube voltage was 90 kV and the TBW-adapted CM dosing factor remained 0.521 g I/kg. In group 3 (n = 63), tube voltage was reduced by 20 kV and CM dosing factor by 20% compared with group 1, in line with the 10-to-10 rule (100 kV; 0.417 g I/kg). In group 4 (n = 66), tube voltage was decreased by 30 kV paired with a 30% decrease in CM dosing factor compared with group 1, in line with the 10-to-10 rule (90 kV; 0.365 g I/kg). Objective image quality was evaluated by measuring attenuation in Hounsfield units (HU), signal-to-noise ratio, and contrast-to-noise ratio in the liver. Overall subjective image quality was assessed by 2 experienced readers by using a 5-point Likert scale. Two-sided P values below 0.05 were considered significant.

Results

Mean attenuation values in groups 1, 3, and 4 were comparable (118.2 ± 10.0, 117.6 ± 13.9, 117.3 ± 21.6 HU, respectively), whereas attenuation in group 2 (141.0 ± 18.2 HU) was significantly higher than all other groups (P < 0.01). No significant difference in attenuation was found between weight categories 80 kg or less and greater than 80 kg within the 4 groups (P ≥ 0.371). No significant differences in subjective image quality were found (P = 0.180).

Conclusions

The proposed 10-to-10 rule is an easily reproducible method resulting in similar enhancement in portal venous CT of the liver throughout the patient population, irrespective of TBW or tube voltage.
Magnetization Transfer Imaging Predicts Porcine Kidney Recovery After Revascularization of Renal Artery Stenosis
Authors: Afarideh Mohsen , Jiang Kai , Ferguson Christopher M. , Woollard John R. , Glockner James F. , Lerman Lilach O.
Published: August 2020

Objectives

Magnetization transfer imaging is a novel noninvasive tool for the detection of kidney fibrosis, but its association with kidney function and hemodynamics is unclear. Renovascular disease (RVD) associated with metabolic derangements elicits renal fibrosis and is often unresponsive to percutaneous transluminal angioplasty (PTRA), but tools to predict therapeutic success are unavailable. We hypothesized that magnetization transfer imaging predicts kidney recovery after PTRA in swine with unilateral RVD.

Materials and Methods

Stenotic kidney (STK) and contralateral kidney magnetization transfer ratios (MTRs; M
t/M
0) were measured at 3.0-T magnetic resonance imaging, at offset frequencies of 600 and 1000 Hz, before and 1 month post-PTRA in 7 RVD pigs. Stenotic kidney MTR was correlated to renal perfusion, renal blood flow (RBF), and glomerular filtration rate (GFR), determined using multidetector computed tomography and with ex vivo renal fibrosis (trichrome staining). Untreated RVD (n = 6) and normal pigs (n = 7) served as controls.

Results

Renovascular disease induced hypertension and renal dysfunction. Blood pressure and renal perfusion were unchanged post-PTRA, but GFR and RBF increased. Baseline cortical STK-MTR predicted post-PTRA renal perfusion and RBF, and MTR changes associated inversely with changes in perfusion and normalized GFR. Stenotic kidney MTR at 600 Hz showed closer association with renal parameters, but both frequencies predicted post-PTRA cortical fibrosis.

Conclusions

Renal STK-MTR, particularly at 600 Hz offset, is sensitive to hemodynamic changes after PTRA in swine RVD and capable of noninvasively predicting post-PTRA kidney perfusion, RBF, and fibrosis. Therefore, STK-MTR may be a valuable tool to predict renal hemodynamic and functional recovery, as well as residual kidney fibrosis after revascularization in RVD.
Measured Multipoint Ultra-High b-Value Diffusion MRI in the Assessment of MRI-Detected Prostate Lesions
Authors: Tavakoli Anoshirwan Andrej , Kuder Tristan Anselm , Tichy Diana , Radtke Jan Philipp , Görtz Magdalena , Schütz Viktoria , Stenzinger Albrecht , Hohenfellner Markus , Schlemmer Heinz-Peter , Bonekamp David
Published: August 2020

Objectives

The aim of this study was to assess quantitative ultra-high b-value (UHB) diffusion magnetic resonance imaging (MRI)–derived parameters in comparison to standard clinical apparent diffusion coefficient (SD-ADC-2b-1000, SD-ADC-2b-1500) for the prediction of clinically significant prostate cancer, defined as Gleason Grade Group greater than or equal to 2.

Materials and Methods

Seventy-three patients who underwent 3-T prostate MRI with diffusion-weighted imaging acquired at b = 50/500/1000/1500s/mm2 and b = 100/500/1000/1500/2250/3000/4000 s/mm2 were included. Magnetic resonance lesions were segmented manually on individual sequences, then matched to targeted transrectal ultrasonography/MRI fusion biopsies. Monoexponential 2-point and multipoint fits of standard diffusion and of UHB diffusion were calculated with incremental b-values. Furthermore, a kurtosis fit with parameters D
app and K
app with incremental b-values was obtained. Each parameter was examined for prediction of clinically significant prostate cancer using bootstrapped receiver operating characteristics and decision curve analysis. Parameter models were compared using Vuong test.

Results

Fifty of 73 men (age, 66 years [interquartile range, 61–72]; prostate-specific antigen, 6.6 ng/mL [interquartile range, 5–9.7]) had 64 MRI-detected lesions. The performance of SD-ADC-2b-1000 (area under the curve, 0.82) and SD-ADC-2b-1500 (area under the curve, 0.82) was not statistically different (P = 0.99), with SD-ADC-2b-1500 selected as reference. Compared with the reference model, none of the 19 tested logistic regression parameter models including multipoint and 2-point UHB-ADC, D
app, and K
app with incremental b-values of up to 4000 s/mm2 outperformed SD-ADC-2b-1500 (all P's > 0.05). Decision curve analysis confirmed these results indicating no higher net benefit for UHB parameters in comparison to SD-ADC-2b-1500 in the clinically important range from 3% to 20% of cancer threshold probability. Net reduction analysis showed no reduction of MR lesions requiring biopsy.

Conclusions

Despite evaluation of a large b-value range and inclusion of 2-point, multipoint, and kurtosis models, none of the parameters provided better predictive performance than standard 2-point ADC measurements using b-values 50/1000 or 50/1500. Our results suggest that most of the diagnostic benefits available in diffusion MRI are already represented in an ADC composed of one low and one 1000 to 1500 s/mm2 b-value.
Added Value of CT Arterial Subtraction Images in Liver Imaging Reporting and Data System Treatment Response Categorization for Transcatheter Arterial Chemoembolization-Treated Hepatocellular Carcinoma
Authors: Huh Jimi , Kim Bohyun , Lee Jei Hee , Won Je Hwan , Kim Jinoo , Kwon Yohan , Kim Jai Keun
Published: August 2020

Objectives

The aim of this study was to assess the benefit of adding arterial subtraction images from computed tomography (CT) to the Liver Imaging Reporting and Data System (LI-RADS) v2018 treatment response (LR-TR) categorization in patients treated with transcatheter arterial chemoembolization (TACE) for hepatocellular carcinoma (HCC).

Materials and Methods

This retrospective study included 115 patients with 151 HCCs treated by TACE using an emulsion of doxorubicin and iodized oil who underwent multiphasic CT protocol that additionally generated arterial subtraction images based on nonrigid anatomic correction algorithm. Of 151 HCCs, 67 (44.4%) were viable and 84 (55.6%) were nonviable. Two independent readers assessed the per-lesion LR-TR categories in set 1 of multiphasic CT images alone and set 2 including both set 1 and CT arterial subtraction images, besides diagnostic confidence, and the quality of subtraction images. The sensitivity and specificity of LR-TR viable category between the sets were compared using the generalized estimating equation. Interobserver agreements of LR-TR categorization in each set and the quality of subtraction images were assessed by Cohen κ.

Results

The quality of subtraction images was mostly good to perfect (98.7%) with good interobserver agreement (κ = 0.71), and none were nondiagnostic. For detecting viable HCC, LR-TR viable category showed sensitivity of 53.7% to 56.7% and specificity of 96.4% to 98.8% in set 1. In comparison, set 2 showed significantly higher sensitivity of 88.1% to 89.6% (P < 0.002) and equivalent specificity of 94% to 95.2% (P > 0.13) for the same category. In sets 1 and 2, 31.3% to 34.3% and 9% to 10.4% of viable HCC were miscategorized as LR-TR nonviable, respectively. LR-TR equivocal category was less assigned in set 2 (1.3%) than in set 1 (6.6%–7.9%). Set 2 showed slightly higher level of confidence for LR-TR categorization compared with set 1 (3.4 ± 0.8 vs 3.8 ± 0.5). Interobserver agreement was excellent in both sets (κ = 0.85 in set 1 and 0.97 in set 2).

Conclusions

The LR-TR viable category is highly specific but inadequately sensitive for detecting viable tumor in TACE-treated HCC on conventional multiphasic CT. Adding arterial subtraction images to the conventional CT images significantly increases sensitivity without compromising the specificity and improves the diagnostic confidence of LR-TR viable category.
Association Between Intravenous Fluid Resuscitation and Hospital Mortality in Post Cardiac Arrest Patients: A Retrospective Study
Authors: Gul Fahad , Peterson Eric , Dejoy Robert , Albano Jeri , Chaudhary Siddique , Valestra Paul , Azmaiparashvili Zurab , Lo Kevin Bryan , Rangaswami Janani , Patarroyo-Aponte Gabriel
Published: August 2020

Objective:

To assess the role for intravenous fluid (IVF) resuscitation in the postarrest state. Primary outcome was survival to hospital discharge and 30-day mortality. Secondary outcomes were associations with amount of vasopressor use and mechanical ventilation days.

Design:

Retrospective study design.

Setting:

Single-center tertiary hospital in Philadelphia, Pennsylvania.

Patients:

All patients admitted to the intensive care unit between 2018 and 2019.

Interventions:

Patients were divided into two groups based on amount of IVF received within 24 h <30 mL/kg (restricted) and over 30 mL/kg (liberal).

Measurements and Main Results:

A total of 264 patients were included in the study, with 200 included in the restrictive (<30 mL/kg) group and 64 included in the liberal (>30 mg/kg) group. There was no difference in 30-day mortality between the two groups with 146 (73%) deaths in the restrictive groups and 44 (69%) deaths in the liberal group (P = 0.53). There was also no significant difference between those who survived to hospital discharge in the liberal and restrictive groups on Kaplan–Meier analysis (Log-rank = 1.476 P = 0.224). However, there was a significant difference between restrictive and liberal groups with the duration of mechanical ventilation (4 ± 6 days vs. 6 ± 9 days; P = 0.03) and in the rates of two or more vasopressor use (38% vs. 59%; P = 0.002). End-stage renal disease (ESRD) (OR = 2.39; P = 0.03) and volume of fluids in mL/kg/24 h (OR = 1.025; P < 0.0001) were independently associated with higher vasopressor need. Volume of fluid in mL/kg/24 h (P = 0.01), ESRD (P = 0.015), and chronic obstructive pulmonary disease (P = 0.04) were significantly associated with duration of mechanical ventilation, even after adjusting for demographic factors, comorbidities, and mortality.

Conclusions:

A liberal strategy of IVF used in resuscitation after cardiac arrest is not associated with higher mortality. However, it predicts higher vasopressor use and duration of mechanical ventilation.
The Septic Neutrophil—Friend or Foe
Authors: Wei Yibing , Kim Jiyoun , Ernits Harri , Remick Daniel
Published: August 2020

Neutrophils play a critical role in the eradication of pathogenic organisms, particularly bacteria. However, in the septic patient the prolonged activation and accumulation of neutrophils may augment tissue and organ injury. This review discusses the different activation states and chemotaxis of neutrophils in septic patients. Neutrophil killing of bacteria and the formation of neutrophil extracellular traps represent important components of the innate immune response and they become dysregulated during sepsis, possibly through changes in their metabolism. Delayed neutrophil apoptosis may contribute to organ injury, or allow better clearance of pathogens. Neutrophils provide a friendly immune response to clear infections, but excessive activation and recruitment has the potential to turn them into potent foes.
Shock Index and Postpartum Hemorrhage in Vaginal Deliveries: A Multicenter Retrospective Study
Authors: Ushida Takafumi , Kotani Tomomi , Imai Kenji , Nakano-Kobayashi Tomoko , Nakamura Noriyuki , Moriyama Yoshinori , Yoshida Shigeru , Yamashita Mamoru , Kajiyama Hiroaki , Kikkawa Fumitaka
Published: August 2020

Introduction:

Shock index (SI), calculated by dividing heart rate by systolic blood pressure, is used to detect hemodynamic instability and hypovolemia. In obstetric practice, limited evidence is available regarding its usefulness in detecting postpartum hemorrhage (PPH). We aimed to evaluate the usefulness of SI in detecting PPH in vaginal deliveries using clinical data from 12 primary maternity care units in Japan.

Material and methods:

In this multicenter retrospective study, a total of 30,820 women who delivered vaginally at term at 12 primary maternity care units from January 2012 to December 2018 were included. Systolic and diastolic blood pressures and heart rate were measured at five different time points from admission to postpartum 2 h, and postpartum blood loss was measured. We evaluated the trend of average SI and the performance of each vital sign for detection of PPH.

Results:

The trend of average SI during labor and the immediate postpartum period was approximately 0.7 in women with blood loss of <500 mL. SI from the time of delivery of the placenta increased with an increase in blood loss. SI had the highest area under the receiver operating characteristic curve of 0.699 [95% confidence interval (CI), 0.682–0.716] and 0.758 (95% CI, 0.729–0.788) for PPH of ≥1,000 and ≥1,500 mL, respectively. However, both sensitivity of SI (1.0) for PPH (≥1,000 mL; 29.9%, and ≥1,500 mL; 40.5%, respectively) and correlation between maximum SI and blood loss (coefficient of correlation, 0.263) were low.

Conclusions:

SI is a better parameter for PPH detection in vaginal deliveries than other vital signs. However, clinical judgment must incorporate other vital signs and symptoms associated with hypovolemic shock due to the low sensitivity of SI.
Efficacy and Safety of Everolimus With Reduced Tacrolimus in Liver Transplant Recipients: 24-month Results From the Pooled Analysis of 2 Randomized Controlled Trials
Authors: Lee Sung-Gyu , Jeng Long-Bin , Saliba Faouzi , Singh Soin Arvinder , Lee Wei-Chen , De Simone Paolo , Nevens Frederik , Suh Kyung-Suk , Fischer Lutz , Jin Joo Dong , Fung John , Joh Jae-Won , Kaido Toshimi , Grant David , Meier Matthias , Rauer Barbara , Sips Carole , Kaneko Shuhei , Levy Gary
Published: August 2020

Background and Methods.

Data from 2 randomized liver transplant trials (N = 772; H2304 [deceased donor, n = 488], H2307 [living donor, n = 284]) were pooled to further evaluate the efficacy and safety of everolimus with reduced tacrolimus (EVR + rTAC) versus standard tacrolimus (sTAC) regimen at month 24.

Results.

EVR + rTAC was comparable to sTAC for composite efficacy failure of treated biopsy-proven acute rejection, graft loss, or death (9.8% versus 10.8%; difference, −1.0%; 95% confidence interval, −5.4 to 3.4; P = 0.641) at month 24. EVR + rTAC was superior to sTAC for the mean change in estimated glomerular filtration rate (eGFR) from randomization to month 24 (−8.37 versus −13.40 mL/min/1.73 m2; P = 0.001). A subanalysis of renal function by chronic kidney disease (CKD) stage at randomization showed significantly lower decline in eGFR from randomization to month 24 for patients with CKD stage 1/2 (eGFR ≥ 60 mL/min/1.73 m2) in EVR + rTAC group versus sTAC (−12.82 versus −17.67 mL/min/1.73 m2, P = 0.009). In patients transplanted for hepatocellular carcinoma (HCC) beyond Milan criteria, HCC recurrence was numerically lower although not statistically significant with EVR + rTAC versus sTAC group (5.9% [1 of 17] versus 23.1% [6 of 26], P = 0.215), while comparable in patients within Milan criteria (2.9% [3 of 102] versus 2.1% [2 of 96], P = 1.000), irrespective of pretransplant alpha-fetoprotein levels.

Conclusions.

EVR + rTAC versus sTAC showed comparable efficacy and safety with significantly better renal function, particularly in patients with normal/mildly decreased renal function (CKD stage 1/2) at randomization and a trend toward lower HCC recurrence in patients transplanted with HCC beyond Milan at month 24. Further long-term data would be required to confirm these results.
The Impact of Intraoperative Donor Blood on Packed Red Blood Cell Transfusion During Deceased Donor Liver Transplantation: A Retrospective Cohort Study
Authors: Shaylor Ruth , Desmond Fiona , Lee Dong-Kyu , Koshy Anoop Ninan , Hui Victor , Tang Gia Toan , Fink Michael , Weinberg Laurence
Published: August 2020

Background.

Blood from deceased organ donors, also known as donor blood (DB), has the potential to reduce the need for packed red blood cells (PRBCs) during liver transplantation (LT). We hypothesized that DB removed during organ procurement is a viable resource that could reduce the need for PRBCs during LT.

Methods.

We retrospectively examined data on LT recipients aged over 18 y who underwent a deceased donor LT. The primary aim was to compare the incidence of PRBC transfusion in LT patients who received intraoperative DB (the DB group) to those who did not (the nondonor blood [NDB] group).

Results.

After a propensity score matching process, 175 patients received DB and 175 did not. The median (first–third quartile) volume of DB transfused was 690.0 mL (500.0–900.0), equivalent to a median of 3.1 units (2.3–4.1). More patients in the NDB group received an intraoperative PRBC transfusion than in the DB group: 74.3% (95% confidence intervals, 67.8-80.8) compared with 60% (95% confidence intervals, 52.7-67.3); P = 0.004. The median number of PRBCs transfused intraoperatively was higher in the NDB group compared with the DB group: 3 units (0–6) compared with 2 units (0–4); P = 0.004. There were no significant differences observed in the secondary outcomes.

Conclusions.

Use of DB removed during organ procurement and reinfused to the recipient is a viable resource for reducing the requirements for PRBCs during LT. Use of DB minimizes the exposure of the recipient to multiple donor sources.
Perfusate Analysis During Dual Hypothermic Oxygenated Machine Perfusion of Liver Grafts: Correlations With Donor Factors and Early Outcomes
Authors: Patrono Damiano , Catalano Giorgia , Rizza Giorgia , Lavorato Nicola , Berchialla Paola , Gambella Alessandro , Caropreso Paola , Mengozzi Giulio , Romagnoli Renato
Published: August 2020

Background.

Liver graft viability assessment has long been considered a limit of hypothermic oxygenated machine perfusion (HOPE). Aim of this study was assessing correlations of easily available perfusate parameters (PP) (aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, glucose, lactate, and pH) with graft features and outcome.

Methods.

In the period October 2018–February 2020, perfusate samples were obtained every 30 minutes during 50 dual-HOPE (D-HOPE) procedures. Correlations of PP with graft factors, 90-day graft loss, early allograft dysfunction (EAD), L-GrAFT score, acute kidney injury, and comprehensive complication index were analyzed using Pearson coefficient, receiver-operating characteristics analysis and by univariable and multivariable regression.

Results.

Median D-HOPE time was 122 minutes. All parameters were normalized to liver weight. Only macrovesicular steatosis (MaS) significantly impacted PP levels and slope. Grafts with ≥30% MaS exhibited significantly different PP values and slope. Graft loss and EAD rate were 2% (n = 1) and 26% (n = 13). All PP except lactate correlated with EAD, 90-minute alanine aminotransferase showing the highest area under the receiver-operating characteristics curve (0.84). However, at multivariable analysis, the only factor independently associated with EAD was MaS (odds ratio, 5.44; confidence interval, 1.05-28.21; P = 0.04). Ninety minutes lactate dehydrogenase had the strongest correlation with L-GrAFT (R = 0.70; P < 0.001). PP correlated poorly with comprehensive complication index and grades 2–3 acute kidney injury rate.

Conclusions.

PP were predictive of graft function after transplant, but their association with graft survival and clinical outcomes requires further evaluation. MaS influenced levels of PP and was the only independent predictor of EAD.
Mechanism of Transplanted Islet Engraftment in Visceral White Adipose Tissue
Authors: Sakata Naoaki , Yoshimatsu Gumpei , Tanaka Tomoko , Yamada Teppei , Kawakami Ryo , Kodama Shohta
Published: August 2020

Background.

White adipose tissue (WAT) is a candidate transplantation site for islets. However, the mechanism of islet engraftment in WAT has not been fully investigated. In this study, we attempted to clarify the therapeutic effect and mechanism of islet transplantation into visceral WAT.

Methods.

Two hundred mouse islets were transplanted into epididymal WAT of syngeneic diabetic mice by wrapping islets with the tissue (fat-covered group). Mice that received intraperitoneal and renal subcapsular islet transplantations were used as negative and positive control groups, respectively.

Results.

The transplant efficacy, including improvements in blood glucose and plasma insulin levels and in glucose tolerance tests, of the fat-covered group was superior to the negative control group and almost equal to the positive control group. Vessel density of engrafted islets in the fat-covered group was higher than that in the positive control group. It was speculated that the mechanism of islet engraftment in WAT might consist of trapping islets in WAT, adhesion of islets via a combination of adhesion factors (fibronectin and integrin β1), and promotion of angiogenesis in islets by expression of angiogenic factors induced by adiponectin.

Conclusions.

Visceral WAT is an important candidate for islet transplantation. Adhesion factors and adiponectin might contribute to islet engraftment into WAT. Further studies to elucidate the detailed mechanism are necessary.
Impact of Morbid Obesity on Liver Transplant Candidacy and Outcomes: National and Regional Trends
Authors: Kaur Navpreet , Emamaullee Juliet , Lian Tiffany , Lo Mary , Ender Philip , Kahn Jeffrey , Sher Linda
Published: August 2020

Background.

Body mass index (BMI) limits for liver transplant (LT) candidacy are controversial. In this study, we evaluate waitlist and post-LT outcomes, and prognostic factors and examine regional patterns of LT waitlist registration in patients with BMI ≥40 versus BMI 18–39.

Methods.

United Network for Organ Sharing (UNOS) data were analyzed to assess waitlist dropout, post-LT survival, and prognostic factors for patient survival. The distribution of waitlisted patients with BMI ≥40 was compared with the Centers for Disease Control Behavioral Risk Factors Surveillance System data to explore the rates of morbid obesity in the general population of each UNOS region.

Results.

Post-LT outcomes demonstrate a small but significantly lower 1- and 3-y overall survival for patients with BMI ≥45. Risk factors for post-LT mortality for patients with BMI ≥40 included age >60 y, prior surgery, and diabetes on multivariable analysis. Model for End-Stage Liver Disease >30 was significant on univariable analysis only, likely due to the limited number of patients with BMI ≥40; however, median Model for End-Stage Liver Disease scores in this BMI group were higher than those in patients with lower BMI across all UNOS regions. Patients with BMI ≥40 had a higher waitlist dropout in 4 regions. Comparison with BRFSS data illustrated that the proportion of waitlisted patients with BMI ≥40 was significantly lower than the observed rates of morbid obesity in the general population in 3 regions.

Conclusions.

While BMI ≥45 is associated with modestly lower patient survival, careful selection may equalize these numbers.
Live Confocal Imaging as a Novel Tool to Assess Liver Quality: Insights From a Murine Model
Authors: Cardini Benno , Fodor Margot , Hermann Martin , Wieser Verena , Hautz Theresa , Mellitzer Vanessa , Schwelberger Hubert , Resch Thomas , Weißenbacher Annemarie , Margreiter Christian , Zelger Bettina , Tilg Herbert , Öfner Dietmar , Schneeberger Stefan , Troppmair Jakob , Maglione Manuel , Oberhuber Rupert
Published: August 2020

Background.

In an experimental murine liver clamping model, we aimed to investigate the efficacy of real-time confocal microscopy (RCM) in assessing viability of steatotic livers in comparison to standard assessment tools, including histopathological evaluation.

Methods.

C57Bl/6 mice were subjected to a methionine-choline-deficient diet causing nonalcoholic fatty liver disease or to Lieber DeCarli diet causing ethanol-induced liver injury. Untreated animals served as controls. Liver biopsies were analyzed following challenge with 45 min of warm ischemia time and either 4 h of reperfusion or 24 h of cold storage. Organ quality assessment was performed at defined time points by RCM, histological staining, measurement of serum alanine aminotransferase activity, and expression analyses of proinflammatory cytokines. Additionally, survival analysis was performed.

Results.

Cold as well as warm ischemia time resulted in a significant decrease in cell viability when compared with naive livers as well as nonischemic-challenged steatotic livers (P < 0.05) as assessed by RCM. Furthermore, RCM revealed the actual cellular damage at early time points, while established methods including H&E-staining and serum transaminase profile failed.

Conclusions.

In a translational attempt, we demonstrate that RCM is a suitable diagnostic tool to obtain information about functional damage of the liver apart from standard approaches.
Evaluating the Impact of Pulmonary Artery Obstruction After Lung Transplant Surgery: A Systematic Review and Meta-analysis
Authors: Kumar Nicolas , Hussain Nasir , Kumar Julia , Essandoh Michael K. , Bhatt Amar M. , Awad Hamdy , Perez William J. , Whitson Bryan A. , Ganapathi Asvin M. , Mokadam Nahush A. , Gorelik Leonid , Turner Katja , Iyer Manoj H.
Published: August 2020

Background.

Pulmonary artery obstruction is an uncommon but significant complication after lung transplantation. Although numerous reports have documented its occurrence, the hemodynamic parameters associated with its presentation and diagnostic considerations remain ill-defined. This systematic review summarizes evidence in the literature surrounding pulmonary artery obstruction after lung transplantation surgery.

Methods.

Databases were searched for all articles and abstracts reporting on pulmonary artery obstruction. Data collected included the number of patients studied, patient characteristics, incidences of pulmonary artery obstruction, and timing and imaging modality used for diagnosis.

Results.

Thirty-four full-text citations were included in this review. The point prevalence of pulmonary artery obstruction was 3.66%. The peak pulmonary artery velocity associated with obstruction was found to be 2.60 ± 0.58 m/s. The diameter of the obstructed pulmonary artery predictive of poor outcomes was noted to be 0.78 ± 0.40 cm. The majority of diagnoses were made in the late postoperative period using pulmonary angiogram and transesophageal echocardiography. Overall, 76% of patients (47 of 62) required emergent procedural reintervention, and 23% of patients (14 of 62) diagnosed with pulmonary artery obstruction died during their hospital stay.

Conclusions.

This systematic review underscores the importance of identifying pulmonary artery obstruction immediately after lung transplant surgery. The clinical implications of these results warrant the development of identification and management strategies for early detection of irregularities in pulmonary artery anastomosis in lung transplant patients.
Generation of tonsil organoids as anex vivomodel for SARS-CoV-2 infection
Authors: Kim Han Kyung , Kim Hyeryeon , Lee Myoung Kyu , Choi Woo Hee , Jang Yejin , Shin Jin Soo , Park Jun-Yeol , Hyun Seong-In , Kim Kang Hyun , Han Hyun Wook , Kim Meehyein , Lim Young Chang , Yoo Jongman
Published: August 2020

Palatine tonsil (hereinafter referred to as “tonsil”) plays role in the immune system’s first line of defense against foreign pathogens. Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a worldwide pandemic since the infection was first reported in China in December 2019. The aim of this study was to establish tonsil epithelial cell-derived organoids and to examine their feasibility as anex vivomodel for SARS-CoV-2 infection. Using an optimized protocol, we achieved 3D tonsil organoid culture from human tonsil tissue that reflects the distinctive characteristics of the tonsil epithelium, such as its cellular composition, histologic properties, and molecular biological features. Notably, we verified that SARS-CoV-2 can infect tonsil organoids with a robust replication efficiency. Furthermore, treatment with remdesivir, an antiviral agent, effectively protected them from viral infection. Therefore, tonsil organoids could be available for investigation of SARS-CoV-2 infection-mediated pathology and for preclinical screening of novel antiviral drug candidates.

One-sentence Summary

This study established tonsil epithelial cell-derived organoids and demonstrated their feasibility as anex vivomodel for SARS-CoV-2 infection.
Evaluating geographic variation within molecular operational taxonomic units (OTUs) using network analyses in Scandinavian lakes
Authors: Forster Dominik , Lentendu Guillaume , Wilson Monica , Mahé Frédéric , Leese Florian , Andersen Tom , Khomich Maryia , Dunthorn Micah
Published: August 2020

Operational taxonomic units (OTUs) are usually treated as if they are internally uniform in environmental metabarcoding studies of microbial and macrobial eukaryotes, even when the OTUs are being used to infer biogeographic patterns. The OTUs constructed by the program Swarm have underlying network topologies in which nodes represent amplicons and edges represent 1 nucleotide differences between nodes. Such networks can be exploited to search for biogeographic patterns within each OTU. To do this, here we used an available protistan metabarcoding dataset consisting of the hypervariable V4 region of the 18S rRNA locus amplified from 77 lakes collected across Norway and Sweden. The 82 most abundant and wide-spread OTUs constructed by Swarm were evaluated using shortest path, assortativity, and geographical analyses. We found that while pairs of amplicons from the same lake were usually connected directly to each other within the OTUs, these pairs of amplicons from the same lake did not form assortative clusters within the OTUs, and amplicons were not more connected with other amplicons occurring in neighboring lakes than expected by chance. This new approach to looking at within-OTU is applicable to other metabarcoding datasets and we provide code to perform these analyses.
Bacterial symbionts in animal development: arginine biosynthesis complementation enables larval settlement in a marine sponge
Authors: Song Hao , Hewitt Olivia H , Degnan Sandie M
Published: August 2020

Larval settlement and metamorphosis are regulated by nitric oxide (NO) signalling in a wide diversity of marine invertebrates (1-10). It is surprising, then, that in most invertebrates, the substrate for NO synthesis – arginine – cannot be biosynthesized but instead must be exogenously sourced (11). In the sponge Amphimedon queenslandica, vertically-inherited proteobacterial symbionts in the larva are able to biosynthesize arginine (12,13). Here we test the hypothesis that symbionts might provide arginine to the sponge host so that nitric oxide synthase expressed in the larva can produce NO, which induces metamorphosis (8), and the byproduct citrulline (Fig. 1). First, we find support for an arginine-citrulline biosynthetic loop in this sponge larval holobiont using stable isotope tracing. In symbionts, incorporated 13C-citrulline decreases as 13C-arginine increases, consistent with the use of exogenous citrulline for arginine synthesis. In contrast, 13C-citrulline accumulates in larvae as 13C-arginine decreases, demonstrating the uptake of exogenous arginine and its conversion to NO and citrulline. Second, we show that while Amphimedon larvae can derive arginine directly from seawater, normal settlement and metamorphosis can occur in artificial sea water lacking arginine. Together, these results support holobiont complementation of the arginine-citrulline loop and NO biosynthesis in Amphimedon larvae, suggesting a critical role for bacterial symbionts in the development of this marine sponge. Given that NO regulates settlement and metamorphosis in diverse animal phyla (1-10) and arginine is procured externally in most animals (11), we propose that symbionts may play a equally critical regulatory role in this essential life cycle transition in other metazoans.
DNA-based nanocarriers to enhance the optoacoustic contrast of tumorsin vivo
Authors: Joseph James , Baumann Kevin N. , Postigo Alejandro , Bollepalli Laura , Bohndiek Sarah E. , Hernández-Ainsa Silvia
Published: August 2020

Optoacoustic tomography (OT) enables non-invasive deep tissue imaging of optical contrast at high spatio-temporal resolution. The applications of OT in cancer imaging often rely on the use of molecular imaging contrast agents based on near infrared dyes to enhance contrast at the tumor site. While these agents afford excellent biocompatibility and minimal toxicity, they present limited optoacoustic signal generation capability and rapid renal clearance, which can impede their tumor imaging efficacy. In this work, a synthetic strategy to overcome these limitations utilizing biodegradable DNA-based nanocarrier (DNA-NC) platforms is introduced. DNA-NCs enable the incorporation of near infrared dyes (in this case, IRDye 800CW) at precise positions to enable fluorescence quenching and maximize optoacoustic signal generation. Furthermore, these DNA-NCs show a prolonged blood circulation compared to the native fluorophores, facilitating tumor accumulation by the Enhanced Permeability and Retention (EPR) effect.In vivoimaging of tumor xenografts in mice following intravenous administration of DNA-NCs revealed enhanced OT signals at 24h when compared to free fluorophores, indicating promise for this method to enhance the optoacoustic signal generation capability and tumor uptake of clinically relevant near infrared dyes.
Human muscle stem cells are refractory to aging
Authors: Novak James S. , Mázala Davi A.G. , Nearing Marie , Habib Nayab F. , Dickson Tessa , Ioffe Olga B. , Harris Brent T. , Fidelia-Lambert Marie N. , Rossi Christopher T. , Hill D. Ashely , Wagner Kathryn R. , Hoffman Eric P. , Partridge Terence A.
Published: August 2020

Age-related loss of muscle mass and strength is widely attributed to limitation in the capacity of muscle resident satellite cells to perform their myogenic function. This idea contains two notions that have not been comprehensively evaluated by experiment. First, it entails the idea that we damage and lose substantial amounts of muscle in the course of our normal daily activities. Second, it suggests that mechanisms of muscle repair are in some way exhausted, thus limiting muscle regeneration. A third option is that the aged environment becomes inimical to the conduct of muscle regeneration. In the present study we used our established model of human muscle xenografting to test whether muscle samples taken from cadavers, of a range of ages, maintained their myogenic potential after being transplanted into immunodeficient mice. We find no measurable difference in regeneration across the range of ages investigated up to 78 years of age. Moreover, we report that satellite cells maintained their myogenic capacity even when muscles were grafted 11 days postmortem in our model. We conclude that the loss of muscle mass with increasing age is not attributable to any intrinsic loss of myogenicity and is most likely a reflection of progressive and detrimental changes in the muscle micro-environment such as to disfavor the myogenic function of these cells.
Genetic signatures of human brain structure: A comparison between GWAS and relatedness-based regression
Authors: Lyu Bingjiang , Tsvetanov Kamen A. , Tyler Lorraine K. , Clarke Alex ,   Cam-CAN, Amos William
Published: August 2020

Identifying the genetic variations impacting human brain structure and their further effects on cognitive functions, is important for our understanding of the fundamental bases of cognition. In this study, we take two different approaches to this issue: classical genome-wide association analysis (GWAS) and a relatedness-based regression approach (REL) to search for associations between genotype and brain structural measures of gray matter and white matter. Instead of searching genetic variants by testing the association between a phenotype trait and the genotype of each single-nucleotide polymorphism (SNP) as in GWAS, REL takes advantage of multiple SNPs within a genomic window as a single measure, which potentially find associations wherever the functional SNP is in linkage disequilibrium (LD) with SNPs that have been sampled. We also conducted a simulation analysis to systemically compare GWAS and REL with respect to different levels of LD. Both methods succeed in identifying genetic variations associated with regional and global brain structural measures and tend to give complementary results due to the different aspects of genetic properties used. Simulation results suggest that GWAS outperforms REL when the signal is relatively weak. However, the collective effects due to local LD boost the performance of REL with increasing signal strength, resulting in better performance than GWAS. Our study suggests that the optimal approach may vary across the genome and that pre-testing for LD could allow GWAS to be preferred where LD is high and REL to be used where LD is low, or the local pattern of LD is complex.
Targeted Transcriptome Analysis using Synthetic Long Read Sequencing Uncovers Isoform Reprograming in the Progression of Colon Cancer
Authors: Liu Silvia , Wu Indira , Yu Yan-Ping , Balamotis Michael , Ren Baoguo , Yehezkel Tuval Ben , Luo Jian-Hua
Published: August 2020

Diversity in human gene expression stems, to a large extent, from splicing exons into multiple mRNA isoforms. Characterization of isoforms requires accurate long-read sequencing. However, read lengths, high error rates, low throughput and large input requirements are some of the challenges that remain to be addressed in sequencing technologies.

In this study, we used a barcoding-based synthetic long read (SLR) isoform sequencing approach, LoopSeq, to generate sequencing reads sufficiently long and accurate to identify isoforms using standard short read Illumina sequencers. The method identifies isoforms from control RNA samples with 99.4% accuracy and a 0.01% per-base error rate, exceeding the accuracy reported for other long-read sequencing technologies.

Applied to targeted transcriptome sequencing of over 10,000 genes from colon cancers and their metastatic counterparts, LoopSeq revealed large scale isoform redistributions from benign colon mucosa to primary colon cancer and metastatic cancer and identified several novel gene fusion isoforms in the colon cancer samples. Strikingly, our data showed that most single nucleotide variants (SNV’s) occurred dominantly in specific isoforms and that some SNVs underwent isoform switching in cancer progression.

The ability to use short read sequencers to generate accurate long-read isoform information as the raw unit of transcriptional information holds promise as a new and widely accessible approach in RNA isoform analyses.
BrumiR: A toolkit forde novodiscovery of microRNAs from sRNA-seq data
Authors: Moraga Carol , Sanchez Evelyn , Ferrarini Mariana Galvão , Gutierrez Rodrigo A. , Vidal Elena A. , Sagot Marie-France
Published: August 2020

MicroRNAs (miRNAs) are small non-coding RNAs that are key players in the regulation of gene expression. In the last decade, with the increasing accessibility of high-throughput sequencing technologies, different methods have been developed to identify miRNAs, most of which rely on pre-existing reference genomes. However, when a reference genome is absent or is not of high quality, such identification becomes more difficult. In this context, we developed BrumiR, an algorithm that is able to discover miRNAs directly and exclusively from sRNA-seq data. We benchmarked BrumiR with datasets encompassing animal and plant species using real and simulated sRNA-seq experiments. The results demonstrate that BrumiR reaches the highest recall for miRNA discovery, while at the same time being much faster and more efficient than the state-of-the-art tools evaluated. The latter allows BrumiR to analyze a large number of sRNA-seq experiments, from plants or animals species. Moreover, BrumiR detects additional information regarding other expressed sequences (sRNAs, isomiRs, etc.), thus maximizing the biological insight gained from sRNA-seq experiments. Finally, when a reference genome is available, BrumiR provides a new mapping tool (BrumiR2ref) that performs ana posterioriexhaustive search to identify the precursor sequences. The code of BrumiR is freely available athttps://github.com/camoragaq/BrumiR.
Epigenetic change induced byin uterodietary challenge provokes phenotypic variability across multiple generations of mice
Authors: Van de Pette Mathew , Galvao Antonio , Millership Steven J. , To Wilson , Dimond Andrew , Prodani Chiara , McNamara Grainne , Bruno Ludovica , Sardini Alessandro , Webster Zoe , McGinty James , French Paul , Uren Anthony G. , Castillo-Fernandez Juan , John Rosalind M. , Ferguson-Smith Anne C. , Merkenschlager Matthias , Kelsey Gavin , Fisher Amanda G.
Published: August 2020

Transmission of epigenetic information between generations occurs in nematodes, flies and plants, mediated by specialised small RNA pathways, histone H3K9me3, H3K27me3, H4K16ac and DNA methylation1-3. In higher vertebrates, epidemiological and experimental evidence supports similar trans-generational effects4,5although the mechanisms that underpin these are incompletely understood6-9. We generated a luciferase reporter knock-in mouse for the imprintedDlk1locus, to visualise and track epigenetic fidelity across generations. We showed that exposure to high-fat diet (HFD) in pregnancy provokes sustained re-expression of the normally silent maternalDlk1allele in offspring, coincident with increased DNA methylation at theDlk1 sDMR. Interestingly, maternalDlk1mis-expression was also evident in the next generation (F2), exclusively in animals derived from F1-exposed females. Oocytes from these females showed altered microRNA and gene expression, without any major changes in underlying DNA methylation, and correctly imprintedDlk1expression resumed in subsequent generations (F3 onwards). Our results reveal how canonical and non-canonical imprinting mechanisms enable the foetal epigenome to adapt toin uterochallenge to modulate the properties of two successive generations of offspring.