bluuebunny/crossref_metadata_2025 huggingface dataset:
Segmental Gracilis Muscle Transplantation for Midfacial Animation in Möbius Syndrome: A 29-Year Experience
Authors: Roy Mélissa , Klar Erin , Ho Emily S. , Zuker Ronald M. , Borschel Gregory H.
Published: February 2019

Background:

Möbius syndrome is a complex congenital disorder of unclear cause involving multiple cranial nerves and typically presenting with bilateral facial and abducens nerves palsies. At The Hospital for Sick Children, Toronto, Ontario, Canada, microneurovascular transfer of free-muscle transplant is the procedure of choice for midfacial animation. The primary aim of this study was to investigate surgical outcomes of the procedure in terms of complications, secondary revisions, and smile excursion gains.

Methods:

A retrospective 29-year review was performed using patient records from a single tertiary care center. The authors included children with Möbius syndrome who had undergone facial animation surgery with a free segmental gracilis muscle transfer and microneurovascular repair between January 1, 1985, and August 31, 2014. Smile excursion measures were obtained using the Facial Assessment by Computer Evaluation–Gram on a subset of the included patients.

Results:

A total of 107 patients undergoing 197 reconstructive procedures met inclusion criteria. Most reconstructions relied on the motor nerve branch to the masseter for innervation [n = 174 (88 percent)]. Thirteen complications were reported, of which six required surgical interventions. Three revision procedures were performed: scar revision, muscle repositioning, and removal of infected permanent suture material. The use of the motor nerve branch to the masseter resulted in good commissure excursion gains (average, 4.61 mm for bilateral cases and 9.34 mm for unilateral reconstructions).

Conclusion:

Midfacial animation with segmental gracilis muscle transfer for patients with Möbius syndrome provides gains in the amplitude and symmetry of oral commissure excursion and carries a reasonably low complication rate.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, IV.
The Role of Muscle Stem Cells in Regeneration and Recovery after Denervation: A Review
Authors: Wong Alvin , Pomerantz Jason H.
Published: February 2019

Background:

Skeletal muscle denervation is a complex clinical problem that still lacks a comprehensive solution. Previous studies have suggested that prolonged periods of denervation lead to a decline in the muscle stem cell population, negatively affecting the ability of muscle to regenerate following reinnervation. Recent advances in the understanding of muscle stem cell biology, along with new techniques that increase the ability to identify and manipulate these cells, provide an opportunity to definitively address the impact of muscle stem cells in recovery from denervation and their potential role in treatment.

Methods:

A comprehensive review of the literature on the biology of muscle denervation, and the effect of denervation injury on muscle stem cell behavior, was performed.

Results:

In this review, the authors discuss the current understanding of muscle stem cell biology in the setting of denervation atrophy, review barriers to successful reinnervation, and review options available to patients following denervation injury. The authors also discuss potential use of muscle stem cells in future therapies.

Conclusions:

Although the clinical treatment of prolonged denervation injury has improved in recent years, regeneration of native muscle remains elusive. Muscle stem cells have been demonstrated to be of central importance in muscle regeneration following injury, and may be a powerful tool that provides effective new options for future treatments. Additional work clarifying the effect of denervation injury on satellite cells is needed to determine whether they are a limiting factor in recovery and to demonstrate whether their clinical use as a cell-based therapy in denervation injury can be efficacious.
The Urogenital Epithelium and Corporal Tissues Are the Primary Targets of Rejection in Penile Vascularized Composite Allotransplantation: A New Real-Time Tissue-Based Monitoring System
Authors: Lough Denver M. , Sopko Nikolai A. , Matsui Hotaka , Miller Devin , Swanson Edward W. , Bluebond-Langner Rachel , Brandacher Gerald , Burnett Arthur L. , Bivalacqua Trinity J. , Redett Richard J.
Published: February 2019

Background:

Although significant surgical advances have been made in the form of microvascular surgery and autologous free tissue transfer, penile reconstruction still poses several difficult challenges. Although interest in penile vascularized composite allotransplantation has grown since the first attempted transplant in 2006, little is known regarding the kinetics of rejection and subsequent function of penile allografts. The penis contains multiple tissue types that are not qualified by the Banff 2007 vascularized composite allotransplantation classification system, including urogenital mucosal epithelium and erectile tissues. In this study, the authors investigate the propagation of rejection and the resultant function following rejection in rat and human penile tissues.

Methods:

Rejected human and rat penile tissues were examined using an ex vivo real-time tissue-based derivative of the classic mixed lymphocyte reaction assay to determine the interactions occurring between en bloc penile tissues and peripheral blood mononuclear cells (autologous and allogeneic). Correlative in vivo heterotopic rat penile vascularized composite allotransplantation was used to correlate ex vivo findings.

Results:

In both human and rat ex vivo systems and in vivo rat vascularized composite allotransplantation, the urethral mucosa was the first to undergo rejection-associated apoptosis. The urethral mucosa was the most immunogenic and led to the highest level of peripheral blood mononuclear cell proliferative generations in all systems, whereas the neural tissues of the penis remained immune privileged.

Conclusion:

These findings are the first to describe the kinetics of rejection in both human and rat penile vascularized composite allotransplantation and that the urethral mucosa is the most antigenic, suffering the highest level of rejection-associated apoptosis and peripheral blood mononuclear cell proliferative aggregation.
Pioneers of Breast Implant–Associated Anaplastic Large Cell Lymphoma: History from Case Report to Global Recognition
Authors: Miranda Roberto N. , Medeiros L. Jeffrey , Ferrufino-Schmidt Maria C. , Keech John A. , Brody Garry S. , de Jong Daphne , Dogan Ahmet , Clemens Mark W.
Published: February 2019

The first case of breast implant–associated anaplastic large cell lymphoma (breast implant ALCL) was described by John Keech and the late Brevator Creech in 1997. In the following 2 decades, much research has led to acceptance of breast implant ALCL as a specific clinicopathologic entity, a process that we bring up to life through the memories of 6 persons who were involved in this progress, although we acknowledge that many others also have contributed to the current state of the art of this disease. Dr. Keech recalls the events that led him and Creech to first report the disease. Ahmet Dogan and colleagues at the Mayo Clinic described a series of 4 patients with breast implant ALCL, and led to increased awareness of breast implant ALCL in the pathology community. Daphne de Jong and colleagues in the Netherlands were the first to provide epidemiologic evidence to support the association between breast implants and ALCL. Garry Brody was one of the first investigators to collect a large number of patients with the disease, present the spectrum of clinical findings, and alert the community of plastic surgeons. Roberto Miranda and L. Jeffrey Medeiros and colleagues studied the pathologic findings of a large number of cases of breast implant ALCL, and published the findings in 2 impactful studies in the medical oncology literature. The recognition and acceptance of this disease by surgeons, epidemiologists, and medical oncologists, working together, has led to subsequent studies on the pathogenesis and optimal therapy of this disease.
Molecular Drivers of Breast Implant–Associated Anaplastic Large Cell Lymphoma
Authors: Blombery Piers , Thompson Ella R. , Prince H. Miles
Published: February 2019

Breast implant–associated anaplastic large cell lymphoma (BIA-ALCL) is a rare T-cell lymphoproliferative disorder occurring in patients with breast implants. Genomic characterization performed in BIA-ALCL to date has demonstrated qualitatively similar molecular abnormalities to those seen in its more common counterpart [ALK-negative systemic anaplastic large cell lymphoma (sALCL)] including JAK/STAT activation and MYC/TP53 dysregulation. Despite these observed similarities at the molecular level, the outcomes of sALCL and BIA-ALCL are markedly different with sALCL typically associated with an aggressive course and inferior outcomes compared with BIA-ALCL. This review describes the findings of high-throughput sequencing and other genomic characterization to date in BIA-ALCL and the insights these studies have given into the molecular drivers of this rare lymphoma subtype.
Expectations of Racism and Carotid Intima-Media Thickness in African American Women
Authors: Lewis Tené T. , Lampert Rachel , Charles Domonique , Katz Stuart
Published: February 2019

Objective

Several researchers have argued that racism-related stressors play an important role in adverse cardiovascular outcomes among African American women. However, studies have primarily focused on experiences of racism; thus, the role of expectations of racism is insufficiently understood. The current proof-of-concept study was designed to examine associations among expectations of racism, self-reported experiences of racism, and carotid intima-media thickness (IMT), a marker of cardiovascular risk, in African American women.

Methods

Participants were 52 healthy African American women, aged 30 to 50 years (M (SD) = 40.8 (4.3)). Expectations of racism were assessed with a modified version of the Race-Based Rejection Sensitivity Questionnaire, experiences of racism were assessed with the Schedule of Racist Events, and carotid IMT was measured using B-mode ultrasound.

Results

In linear regression analyses adjusted for age, expectations of racism were associated with higher levels of carotid IMT (b = .04, SE = .014, p = .013), after adjusting for experiences of racism. Findings remained significant after additional adjustments for cardiovascular risk factors (b = .03, SE = .014, p = .032). Associations were not confounded by additional stressors, hostility, or negative affect (depressive symptoms).

Conclusions

Independent of actual reports of racism, “expectations” of racism may be associated with increased cardiovascular risk in African American women. In addition, although experiences of discrimination were associated with depressive symptoms, expectations of racism were not, suggesting that other negative emotions likely play a role. Future studies are needed to replicate these results in larger samples and to explore the psychological and physiological pathways through which expectations of racism might affect cardiovascular disease risk across a range of populations.
Prenatal Maternal Depression and Neonatal Immune Responses
Authors: Hahn Jill , Gold Diane R. , Coull Brent A. , McCormick Marie C. , Finn Patricia W. , Perkins David L. , Rich-Edwards Janet W. , Rifas Shiman Sheryl L. , Oken Emily , Kubzansky Laura D.
Published: February 2019

Objective

The aim of the study was to examine the association of lifetime maternal depression with regulation of immune responses in the infant, measured by cytokine levels and lymphocyte proliferation (LP) in cord blood mononuclear cells collected at delivery.

Methods

We studied women recruited in early pregnancy into the Project Viva longitudinal cohort who had cord blood assayed after delivery (N = 463). Women reported about depressive symptoms in midpregnancy (Edinburgh Postnatal Depression Scale) and depression history by questionnaire. Immune responses were assayed by an index of LP, and concentrations of five cytokines (interleukin [IL]-6, IL-10, IL-13, tumor necrosis tumor necrosis factor factor α, and interferon γ) after incubation of cord blood mononuclear cells either in medium alone or stimulated with phytohemagglutinin (PHA), cockroach extract, or house dust mite extract. We examined associations of maternal depression with these sets of cytokine measures using multivariable linear or tobit regression analyses.

Results

After adjustment for confounders (mother's age, race/ethnicity, education, household income, season of birth, and child sex), levels of IL-10 after stimulation with cockroach or dust mite allergen were lower in cord blood from ever versus never depressed women, and a similar trend was evident in IL-10 stimulated with PHA (percentage difference: cockroach extract = −41.4, p = .027; house dust mite extract = 1–36.0, p = .071; PHA = −24.2, p = .333). No significant differences were seen in levels of other cytokines or LP.

Conclusions

Maternal depression is associated with offspring immune responses at birth, which may have implications for later life atopic risk or immune function.
Imaging of Usual and Unusual Complication of Rotator Cuff Repair
Authors: Albano Domenico , Chianca Vito , Zappia Marcello , Russo Raffaele , Romano Stefania , Sconfienza Luca Maria , Di Pietto Francesco
Published: February 2019

Several complications may be encountered after rotator cuff (RC) repair. A thorough knowledge of surgical interventions, normal postoperative findings, and postoperative complications is crucial to provide a timely diagnosis, improving the clinical outcome of patients. Postoperative complications may involve RC, implanted device, osteochondral tissue, surgical-site infection, peripheral nerves, soft tissues, and vascular structures. In this review, we discuss the usual and unusual complications detectable after RC repair.
Volume Computed Tomography Perfusion Imaging: Evaluation of the Significance in Oncologic Follow-up of Metastasizing Renal Cell Carcinoma in the Early Period of Targeted Therapy — Preliminary Results
Authors: Vehabovic-Delic Aida , Balic Marija , Rossmann Christopher , Bauernhofer Thomas , Deutschmann Hannes A. , Schoellnast Helmut
Published: February 2019

Introduction

The aim of this study was to assess the significance of volume computed tomography perfusion imaging of metastasizing renal cell carcinoma (mRCC) in the early period after the initiation of targeted therapy.

Methods

Blood flow (BF), blood volume, and clearance (CL) were calculated in 10 patients with histologically verified mRCC before and 1 month after initiation of targeted therapy using compartmental analysis algorithms. In addition, the longest diameter of tumor was measured for both time points and compared. Correlation test was performed between perfusion parameters and size changes with time to progression (TTP).

Results

Blood flow and CL were significantly lower after therapy initiation, whereas blood volume and the long diameter remained unchanged. Median values before and after 4 weeks of therapy were 144.2 versus 99.4 mL/min/100 mL for BF (P = 0.009) and 115.5 versus 46.8 mL/min/100 mL for CL (P = 0.007). Changes in BF and CL showed very strong negative correlation with TTP (r = −0.838, P = 0.009 and r = −0.826, P = 0.011, respectively).

Conclusions

Our preliminary study results indicate that volume computed tomography perfusion may assess targeted therapy response of mRCC earlier than the currently used Response Evaluation Criteria in Solid Tumors. In addition, changes in BF and CL may be a promising parameter for prediction of TTP.
Bosniak IIF and III Renal Cysts: Can Apparent Diffusion Coefficient–Derived Texture Features Discriminate Between Malignant and Benign IIF and III Cysts?
Authors: Gillingham Nicolas , Chandarana Hersh , Kamath Amita , Shaish Hiram , Hindman Nicole
Published: February 2019

Objective

The aim of this study was to determine which apparent diffusion coefficient–derived texture features are associated with malignancy in Bosniak IIF and III renal cystic lesions.

Methods

Twenty benign and 7 malignant Bosniak IIF (22) or III (5) renal cysts, as evaluated with magnetic resonance imaging, were assessed for progression to pathology-confirmed malignancy. Whole-cyst volumes of interest were manually segmented from apparent diffusion coefficient maps. Texture features were extracted from each volume of interest, including first-order histogram-based features and higher-order features, and data were analyzed with the Mann-Whitney U test to predict malignant progression.

Results

Eleven of 17 first-order features were significantly greater in benign compared with malignant cysts. Eight higher-order gray-level co-occurrence matrix (GLCM) texture features were significantly different between groups, 5 of which were greater in the benign population.

Conclusions

Apparent diffusion coefficient–derived texture measures may help differentiate between benign and malignant Bosniak IIF and III cysts.
Hsp70 Gene Polymorphisms Are Associated With Disease Susceptibility and HRQOL Improvement in Chinese Han Population With Systemic Lupus Erythematosus
Authors: Xie Qiao-Mei , Lou Qiu-Yue , Huang Shun-Wei , Hu Hua-Qing , Li Su-Su , Zhang Man , Sun Xiu-Xiu , Xu Jian-Hua , Jiang Shan-Qun , Liu Sheng-Xiu , Xu Sheng-Qian , Cai Jing , Liu Shuang , Pan Fa-Ming , Tao Jin-Hui , Qian Long , Wang Chun-Huai , Liang Chun-Mei , Huang Hai-Liang , Pan Hai-Feng , Su Hong , Zou Yan-Feng
Published: February 2019

Objectives

The aim of this study is to investigate whether heat shock protein 70 (Hsp70) gene polymorphisms are implicated in systemic lupus erythematous (SLE) susceptibility, the efficacy of glucocorticoids (GCs) treatment, and improvement of health-related quality of life.

Methods

A total of 499 SLE patients and 499 controls were included in a case-control study, and 468 SLE patients treated with GCs for 12 weeks were involved in a follow-up study. Patients who completed the 12-week follow-up were divided into GCs-sensitive and GCs-insensitive group by using the SLE disease activity index. The SF-36 was used to evaluate the health-related quality of life of SLE patients, and genotyping was performed by improved multiplex ligation detection reaction.

Results

rs2075800 was associated with SLE susceptibility (adjusted odds ratio [ORadj], 1.437; 95% confidence interval [CI], 1.113–1.855;Padj= 0.005;PBH= 0.020 by dominant model; ORadj, 1.602; 95% CI, 1.072–2.395;Padj= 0.022;PBH= 0.029 by TT vs CC model; ORadj= 1.396; 95% CI = 1.067–1.826;Padj= 0.015;PBH= 0.029 by TC vs CC model). In the follow-up study, rs2075799 was associated with the improvement in mental health (p= 0.004,PBH= 0.044), but we failed to find any association between the efficacy of GCs and Hsp70 gene polymorphisms.

Conclusions

Hsp70 gene polymorphisms may be associated with susceptibility to SLE and improvement of mental health in Chinese Han population.
Renal Sympathetic Denervation
Authors: Schmidt Martin , Roessner Florian , Berger Manuel , Tesche Christian , Rieber Johannes , Bauner Kerstin , Huber Armin , Rummeny Ernst , Hoffmann Ellen , Ebersberger Ullrich
Published: February 2019

Objectives:

Left ventricular (LV) hypertrophy in resistant hypertensive patients is associated with a reduced intramyocardial perfusion. Renal sympathetic denervation (RDN) has been shown to reduce blood pressure (BP) and sympathetic tone. We aimed to prospectively investigate the effect of RDN on functional myocardial parameters and myocardial perfusion reserve (MPR) using cardiac magnetic resonance imaging (cMRI) in patients with resistant hypertension.

Methods:

A total of 15 resistant hypertensive patients (11 male individuals, mean age 62±13 y) were included. Adenosine stress-induced cMRI was performed at baseline, 3, 6, and 12 months after RDN. RDN was performed using a single soft-tip radiofrequency catheter (Symplicity). cMRI semiquantitative perfusion analysis was performed using the upslope of myocardial signal enhancement to derive the myocardial perfusion reserve index.

Results:

Both systolic-BP and diastolic-BP significantly decreased from 148±14 to 133±14 mm Hg and 87±14 to 80±10 mm Hg, respectively (P<0.05). LV septal wall thickness was significantly reduced (P<0.001). LV ejection fraction and MPR lacked significant trends 12 months after RDN.

Conclusions:

In this pilot study, RDN significantly reduced LV mass and LV septal wall thickness, as diagnosed by cMRI, with no significant changes in MPR. cMRI may help in diagnosing clinically relevant changes of functional myocardial parameters after interventional therapy in resistant hypertensive patients.
Comparisons of Stress Physiology of Providers in Real-Life Resuscitations and Virtual Reality–Simulated Resuscitations
Authors: Chang Todd P. , Beshay Youssef , Hollinger Trevor , Sherman Joshua M.
Published: February 2019

Background

Virtual reality (VR) is a promising simulation medium for high-stakes, low-frequency events such as pediatric resuscitation. The psychological fidelity of VR compared with a real resuscitation in an emergency department (ED) is relatively unknown. The objective was to determine whether stress physiology changes were equivalent between ED and VR resuscitations.

Methods

This was a single-site pilot equivalence study evaluating head-mounted VR resuscitation scenarios using board-certified/eligible pediatric ED physicians. Subjects had heart rates (HRs) and salivary cortisol levels recorded throughout 8-hour evening ED shifts and during one 1-hour VR session. Additional samples and subjective workload perception (NASA Task Load Index) were collected for critical resuscitations. A delta HR and delta cortisol level described the difference in mean HR and mean cortisol level between shifts with and shifts without resuscitations. Another delta calculation was performed from pre-VR to post-VR. Nonparametric univariate statistics was examined for significant differences in delta HR or cortisol levels between the ED setting and VR.

Results

Sixteen subjects had 69 shifts monitored with 31 resuscitations. In the ED, delta HR was +13.9 bpm (P < 0.001) and delta cortisol was +0.10 μg/dL (P = 0.006). In VR, delta HR was +6.5 bpm (P < 0.001) but minimal delta cortisol (−0.02 μg/dL, P = 0.05). Emergency department resuscitations both HR and cortisol levels were more than VR resuscitations (P < 0.03). NASA Task Load Index scores were higher in VR resuscitations with +26 score difference (P = 0.01).

Conclusions

Virtual reality resuscitations increase HR but show less stress physiology changes than ED resuscitations within an actual 8-hour shift. Further inquiry into stress physiology and optimal VR simulation is warranted.
Not all deep vein thrombosis is created equal: Incidence of preexisting chronic deep vein thrombosis among high-risk traumatized patients
Authors: Tefft Amy , Moss Tovah , Stanley Andrew , Malhotra Ajai K.
Published: February 2019

BACKGROUND

Traumatized patients are at risk of developing deep vein thrombosis (DVT) and DVT prophylaxis is the standard of care. The Centers for Medicare and Medicaid Services classifies DVT as a hospital-acquired condition and can deny payment for treatment of DVT and, in addition, place financial penalties on hospitals with higher than acceptable rates of DVT, unless the DVT was preexisting. We sought to determine the rate of preexisting chronic DVT among symptomatic traumatized inpatients at our ACS-verified Level 1 trauma center.

METHODS

Retrospective review of all traumatized patients admitted for >48 hours over a 7-year study period ending December 2016. Patients who had undergone lower extremity duplex ultrasound (LEDUS) were reviewed further to evaluate the results of these tests. Patients were classified as having either no DVT, acute DVT, or chronic (preexisting) DVT based on sonographic characteristics. Incidence, patient demographics, injury severity and outcomes were compared for patients with and without DVT and also for patients with acute and chronic DVT.

RESULTS

Five thousand five hundred forty-three patients met inclusion criteria. Of those, 391 (7.0%) had undergone at least one LEDUS for suspicion of DVT. Deep vein thrombosis was diagnosed in 64 (16%) of the patients undergoing LEDUS and thus 1.1% of the entire population had symptomatic DVT diagnosed during admission. Of the 64 patients with DVT, sonographic characteristics classified 56 (87.5%) as “acute.” 6 (9%) as “chronic” (preexisting) and 2 (3.5%) as “indeterminate.” Among the six patients found to have a preexisting DVT only three (50%) acknowledged a history of DVT.

CONCLUSION

In the absence of routine DVT surveillance almost 10% of traumatized patients diagnosed with DVT likely have chronic preexisting DVT that is unknown to the patient in 50% of cases. This has significant financial implications for hospitals.

LEVEL OF EVIDENCE

Epidemiologic/Prognostic, level III.
Molecular Patterns Discriminate Accommodation and Subclinical Antibody-mediated Rejection in Kidney Transplantation
Authors: Hruba Petra , Krejcik Zdenek , Stranecky Viktor , Maluskova Jana , Slatinska Janka , Gueler Faikah , Gwinner Wilfried , Bräsen Jan Hinrich , Wohlfahrtova Mariana , Parikova Alena , Osickova Klara , Fronek Jiri , Seda Ondrej , Prefertusova Lucie , Honsova Eva , Viklicky Ondrej
Published: February 2019

Background.

Accommodation in ABO-incompatible (ABOi) transplantation and subclinical antibody-mediated rejection in HLA-incompatible (HLAi) transplantation share several morphological similarities. Because the clinical long-term outcomes differ, we hypothesized different molecular processes involved in ABOi transplantation and subclinical antibody-mediated rejection.

Methods.

Using Illumina Human HT-12 v4 Expression BeadChips, the whole transcriptome was evaluated based on 3-month protocol C4d+ biopsies in otherwise stable ABOi and HLAi kidney grafts, as well as in C4d-negative HLA-compatible grafts exhibiting normal histological findings. Top differently regulated genes were further validated using real-time quantitative polymerase chain reaction in another patient cohort and complement regulatory proteins by immunohistochemistry.

Results.

In the case of genes involved in immune response–related biological processes, ABOi and HLAi cohorts had similar transcriptomic profiles to C4d-negative controls. The majority of deregulated genes in the ABOi and HLAi groups consisted of metallothioneins and epithelial transporter genes. Increased expression of epithelial transporters (SLC4A1, SLC4A9, SLC17A3, SLC12A3, and SLC30A2) and class 1 metallothioneins (MT1F, MT1G, and MT1X) in HLAi transplantation was validated by real-time quantitative polymerase chain reaction. In comparison to controls, both incompatible cohorts were characterized by the upregulation of intrarenal complement regulatory genes. CD46 and CD59 transcripts were increased in the ABOi cohort, whereas CD46 solely in HLAi group, and CD59 protein expression was similar in both incompatible groups.

Conclusions.

Several epithelial transporters and metallothioneins discriminate subclinical antibody-mediated rejection in HLAi transplantation from accommodation in ABOi transplantation, which suggest different involved downstream mechanisms and increased risk of injury in HLAi settings. Metallothioneins with their antioxidative properties may help to attenuate the inflammation response induced by donor-specific anti-HLA antibody binding.
Patterns and Predictors of Mortality After Waitlist Dropout of Patients With Hepatocellular Carcinoma Awaiting Liver Transplantation
Authors: Gorgen Andre , Rosales Roizar , Sadler Erin , Beecroft Robert , Knox Jennifer , Dawson Laura A. , Ghanekar Anand , Grant David , Greig Paul D. , Sapisochin Gonzalo
Published: February 2019

Background.

There is a lack of information about survival after dropout from the liver transplant waiting list. Therefore, we aimed to assess the overall survival, and risk factors for death, after waiting list dropout due to hepatocellular carcinoma (HCC) progression.

Methods.

We assessed patients who dropped out of the liver transplant waiting list between 2000 and 2016 in a single, large academic North American center. Patients were divided into 3 groups according to the types of HCC progression: locally advanced disease (LAD), extrahepatic disease (EHD), and macrovascular invasion (MVI). The primary outcome was overall survival. Survival was assessed by the Kaplan-Meier method. Predictors of death after dropout were assessed by multivariable Cox regression.

Results.

During the study period, 172 patients dropped out due to HCC progression. Of those, 37 (21.5%), 74 (43%), and 61 (35.5%) dropped out due to LAD, EHD, and MVI, respectively. Median survival according to cause of dropout (LAD, EHD, or MVI) was 1.0, 4.4, or 3.3 months, respectively (P = 0.01). Model for End-stage Liver Disease (MELD) score (hazard ratio [HR], 1.04; 95% confidence interval [CI], 1.01-1.08), alcoholic liver disease (HR, 1.66; 95% CI, 1.02-2.71), and α-fetoprotein >1000 ng/mL (HR, 1.86; 95% CI, 1.22-2.84) were predictors of mortality after dropout. Dropout due to EHD (HR, 0.61; 95% CI, 0.38-0.98) and undergoing treatment after dropout were protective factors (HR, 0.32; 95% CI, 0.21-0.48) for death.

Conclusions.

Patient prognosis after dropout is dismal. However, a subgroup of patients may have longer survival. The present study identifies the patterns of waitlist dropout in patients with HCC and provides evidence for the effectiveness of treatment strategies offered to HCC patients after dropout.
Cyclosporine A as a Cardioprotective Agent During Donor Heart Retrieval, Storage, or Transportation: Benefits and Limitations
Authors: Gao Ling , Hicks Mark , Villanueva Jeanette E. , Doyle Aoife , Chew Hong C. , Qui Min Ru , Jabbour Andrew , Dhital Kumud K. , Macdonald Peter S.
Published: February 2019

Background.

Storage of donor hearts in cardioplegic solutions supplemented with conditioning agents activating endogenous mitochondrial protective signaling enhanced their postreperfusion recovery. The present study investigates the role of timing and duration of cardiac exposure to cyclosporine A (CsA), another putative mitochondrial protectant, on cardiac functional recovery and potential mechanisms of CsA action in an isolated working rat heart model of donor heart retrieval and storage.

Methods.

After measurement of baseline function, hearts were arrested and stored for 6 hours at 4°C in either Celsior alone or Celsior + CsA (0.2 µM), then reperfused for 45 minutes in Krebs solution, when functional recovery was assessed. Two additional groups of Celsior-alone stored hearts were exposed to 0.2 µM CsA for the initial 15 minutes (nonworking period) or the full 45-minute period of reperfusion. Coronary effluent was collected pre- and poststorage for assessment of lactate dehydrogenase release. Tissue samples were collected at the end of each study for immunoblotting and histological studies.

Results.

CsA supplementation during cold storage or the first 15-minute reperfusion significantly improved functional recovery and significantly increased phospho-AMPKαThr172 and phospho-ULK-1Ser757. Hearts exposed to CsA for 45 minutes at reperfusion recovered poorly with no phospho–AMP-activated protein kinase α activation, decreased phospho-eNOSSer633, and decreased mitochondrial cytochrome c content with increased lactate dehydrogenase release.

Conclusions.

Inclusion of CsA during cold storage is cardioprotective. Effects of CsA addition to the perfusate during reperfusion were time dependent, with benefits at 15 minutes but not 45 minutes of reperfusion. The toxic effect with the presence of CsA for the full 45-minute reperfusion is associated with impaired mitochondrial integrity and decreased eNOS phosphorylation.
Hospitalization Trends for Acute Kidney Injury in Kidney Transplant Recipients in the United States, 2004–2014
Authors: Garg Neetika , Kumar Nilay , Singh Tripti , Parajuli Sandesh , Astor Brad C. , Mandelbrot Didier , Djamali Arjang
Published: February 2019

Background.

The incidence of acute kidney injury (AKI) and AKI requiring dialysis (AKI-D) in the general population is increasing. However, there is limited information on the epidemiology of AKI-related hospitalizations in the prevalent US kidney transplant population.

Methods.

We analyzed trends in the incidence of hospitalizations with primary diagnosis of AKI and secondary diagnosis of AKI and AKI-D using data from the National Inpatient Sample 2004–2014. Co-primary endpoints were in-hospital mortality, length of stay (LOS), and cost. Survey analysis techniques were used to compute national estimates. Linear trends in outcomes were evaluated using linear regression.

Results.

There were a total of 37 562 hospitalizations for primary AKI, 136 628 for secondary AKI, and 10 731 for AKI-D during the study period. We found an increase in hospitalizations for all 3 diagnoses over time (13.7–24.7 per thousand kidney transplant recipients [KTRs] for primary AKI, 37.4–108.0 per thousand KTRs for secondary AKI, and 4.2–6.0 per thousand KTRs for AKI-D; all P trend < 0.01). This was accompanied by significant improvements in in-hospital mortality (3.2%–0.5% for primary and 6.1%–4.4% for secondary AKI; both P trend < 0.01), average LOS (5.3–4.6 days for primary and 8.4–7.2 days for secondary AKI; both P trend < 0.001), and cost ($11 635–$8234 for primary and $21 373–$17 470 for secondary AKI; P trend < 0.001 for both).

Conclusions.

The incidence of hospitalizations for AKI and AKI-D among KTRs is rapidly rising. This has been accompanied by significant improvements in in-hospital mortality, LOS, and cost.
Twenty-year Follow-up of Histocompatibility Leukocyte Antigen-matched Kidney and Bone Marrow Cotransplantation for Multiple Myeloma With End-stage Renal Disease: Lessons Learned
Authors: Spitzer Thomas R. , Tolkoff-Rubin Nina , Cosimi A. Benedict , McAfee Steven , Dey Bimalangshu R. , Chen Yi-Bin , Delmonico Francis , Sykes Megan , Sachs David H. , Kawai Tatsuo
Published: February 2019

Background.

Specific immune tolerance of transplanted organs in association with either transient or sustained lymphohematopoietic chimerism has been demonstrated in several preclinical animal models and clinically in patients who are full donor chimeras after hematopoietic stem cell transplantation and subsequently received kidney transplants from the same donor. Most recently, tolerance induction has been extended to patients in whom chimerism was intentionally induced at the time of kidney transplantation.

Methods.

Twenty years ago, we reported the first successful histocompatibility leukocyte antigen-matched sibling donor bone marrow and kidney transplant following nonmyeloablative conditioning in a patient with multiple myeloma and end-stage renal disease (ESRD). After 2 decades, she has normal renal function in the absence of ongoing systemic immunosuppressive therapy. Nine patients have subsequently undergone similar treatment for multiple myeloma with ESRD.

Results.

In the initial patient, hematopoietic chimerism was detectable for only 105 days after the transplant. In subsequent patients, chimerism detection ranged from 49 days to >14 years. Nevertheless, a long remission of the myeloma and long-term immunosuppression-free survival of the kidney allograft were achieved in 7 of the 10 patients, 5 of whom currently survive.

Conclusions.

This initial patient demonstrated the feasibility of performing combined histocompatibility leukocyte antigen-matched, sibling donor bone marrow and kidney transplantation for ESRD due to multiple myeloma. This experience paved the way for extending the initial trial to 9 additional patients with multiple myeloma and ESRD and, more recently, to tolerance induction strategies involving combined bone marrow and kidney transplantation for patients with and without an underlying malignancy.
The Association of 25-Hydroxyvitamin D Levels with Late Cytomegalovirus Infection in Kidney Transplant Recipients: the Wisconsin Allograft Recipient Database
Authors: Astor Brad C. , Djamali Arjang , Mandelbrot Didier A. , Parajuli Sandesh , Melamed Michal L.
Published: February 2019

Background.

Cytomegalovirus (CMV) infection is a major cause of morbidity and mortality in kidney transplant recipients. Vitamin D has an integral role in proper immune function, and deficiency is common among kidney transplant recipients. It remains unclear whether 25-hydroxyvitamin D [25(OH)D] level is associated with CMV infection in kidney transplant recipients.

Methods.

We examined the relationship between 25(OH)D levels, measured at least 6 months posttransplant, and subsequent CMV infection in 1976 recipients free of prior CMV infection.

Results.

Of 1976 recipients, 251 (12.7%) were vitamin D deficient [25(OH)D <20 ng/mL] and 548 (27.7%) were insufficient (20–29 ng/mL) at the time of the first 25(OH)D measurement. A total of 107 recipients had a CMV infection within 1 year of a 25(OH)D measurement. Vitamin D deficiency was associated with a 1.81-fold higher risk (relative hazard = 1.81; 95% confidence interval [CI], 1.06-3.09) than vitamin D sufficiency after adjustment for baseline characteristics and concurrent graft function and blood calcineurin inhibitor concentration. Each 1 ng/mL lower 25(OH)D was associated with a 2% higher risk of infection (95% CI, 0%-4%) in continuous analyses after adjustment.

Conclusions.

Low 25(OH)D is common in kidney transplant recipients and associated with late CMV infection. These results highlight the need for interventional trials to assess the potential for vitamin D supplementation to reduce infectious complications in kidney transplant recipients.
A Recipient Risk Prediction Tool for Short-term Mortality After Pediatric Heart Transplantation
Authors: Choudhry Swati , Wang Yunfei , Denfield Susan W. , Cabrera Antonio G. , Price Jack F. , Tunuguntla Hari P. , Dharnidharka Vikas R. , Canter Charles E. , Dreyer William J.
Published: February 2019

Background.

The first year after heart transplantation (HT) has the highest risk of mortality. We aim to derive and validate a recipient risk prediction tool for early mortality after pediatric HT.

Methods.

The International Society for Heart and Lung Transplantation (ISHLT) registry was used to identify patients (≤18 y) who underwent primary HT during January 2000–December 2014. Independent predictors of 1-year mortality were identified based on recipient characteristics at HT. Risk scores were assigned based on the magnitude of relative odds of 1-year mortality. The predictive capability of the ISHLT registry derived recipient risk score was externally validated using the Scientific Registry of Transplant Recipients registry data from 2015 to 2017 to ensure a cohort of patients completely exclusive from the derivation cohort.

Results.

A total of 5045 eligible patients were included in the analysis. The 20-point risk scoring system incorporated 8 recipient variables, including age at HT, diagnosis, pre-HT ventilator use, extracorporeal membrane oxygenation, inhaled nitric oxide use, infection, estimated glomerular filtration rate, and serum bilirubin. Compared with low-risk score group, high-risk group had 7-fold increased risk of 1-year mortality (hazard ratio 7.4; 95% CI [5.2-9.1]; P < 0.001). The C-statistics (0.77) and Hosmer-Lemeshow goodness of fit (0.9) for recipient risk score using derivation cohort from ISHLT registry performed well and was similar to the internal and external validation cohort (C-statistics 0.75, 0.78 and Hosmer-Lemeshow goodness of fit P = 0.4, 0.3, respectively).

Conclusions.

This study derived and externally validated a simple risk predictive model based on recipient characteristics at HT that has good prediction characteristics for 1-year post-HT mortality. This model may help clinicians identify candidates who are at a higher risk for post-HT mortality and may optimize organ sharing.
Global & Temporal Patterns of Submicroscopic Plasmodium falciparum Malaria Infection
Authors: Whittaker Charles , Slater Hannah , Bousema Teun , Drakeley Chris , Ghani Azra , Okell Lucy
Published: February 2019

Molecular detection of Plasmodium falciparum infection has revealed large numbers of individuals with low-density (yet transmissible) infections undetectable by microscopy. Here we present an updated systematic review of cross-sectional malaria surveys to explore the prevalence and drivers of these submicroscopic infections and define where they are likely to be relevant to malaria control efforts. Our results show that submicroscopic infections predominate in low transmission settings, but also reveal marked geographical variation in their prevalence, being highest in South American surveys and lowest in West African studies. Whilst current transmission levels partly explain these results, we find that historical transmission intensity also represents a crucial determinant of the size of the submicroscopic reservoir. Submicroscopic infection was more likely in adults than children, although we did not observe a statistically significant influence of seasonality. Our results suggest that the contribution of submicroscopic infections to transmission likely varies substantially across settings, potentially warranting different approaches to their targeting in the approach to elimination.
Density-dependent natural selection mediates harvest-induced trait changes
Authors: Bouffet-Halle Alix , Mériguet Jacques , Carmignac David , Agostini Simon , Millot Alexis , Perret Samuel , Motard Eric , Decenciere Beatriz , Edeline Eric
Published: February 2019

Rapid life-history changes caused by size-selective harvesting are often interpreted as a response to direct harvest selection against a large body size. However, similar trait changes may result from a harvest-induced relaxation of natural selection for a large body size via density-dependent selection. Here, we show evidence of such density-dependent selection favouring large-bodied individuals at high population densities, in replicated pond populations of medaka fish. Harvesting, in contrast, selected medaka directly against large-bodied medaka and, in parallel, decreased medaka population densities. Five years of harvesting were enough for harvested and unharvested medaka populations to inherit the classically-predicted trait differences, whereby harvested medaka grew slower and matured earlier than unharvested medaka. We demonstrate that this life-history divergence was not driven by direct harvest selection for a smaller body size in harvested populations, but by density-dependent natural selection for a larger body size in unharvested populations.
Human CST suppresses origin licensing and promotes AND-1/Ctf4 chromatin association
Authors: Wang Yilin , Brady Kathryn S. , Caiello Benjamin , Ackerson Stephanie M. , Stewart Jason A.
Published: February 2019

Human CTC1-STN1-TEN1 (CST) is an RPA-like single-stranded DNA binding protein that interacts with DNA polymerase α-primase (pol α) and functions in telomere replication. Previous studies suggest that CST also promotes replication restart following fork stalling. However, the precise role of CST in genome-wide replication remains unclear. In this study, we sought to understand whether CST alters origin licensing and activation. Replication origins are licensed by loading of the minichromosome maintenance 2-7 (MCM) complex in G1 followed by replisome assembly and origin firing in S-phase. We find that CST directly interacts with the MCM complex and disrupts binding of CDT1 to MCM, leading to decreased origin licensing. We also show that CST enhances replisome assembly by promoting AND-1/pol α chromatin association. Moreover, these interactions are not dependent on exogenous replication stress, suggesting that CST acts as a specialized replication factor during normal replication. Overall, our findings implicate CST as a novel regulator of origin licensing and replisome assembly/fork progression through interactions with MCM, AND-1 and pol α.
An ambiguous N-terminus drives the dual targeting of an antioxidant protein Thioredoxin peroxidase (TgTPx1/2) to endosymbiotic organelles inToxoplasma gondii
Authors: Mastud Pragati , Patankar Swati
Published: February 2019

Toxoplasma gondiiharbors two endosymbiotic organelles: a relict plastid, the apicoplast and a mitochondrion. The parasite expresses an antioxidant protein, thioredoxin peroxidase 1/2 (TgTPx1/2), that is dually targeted to these organelles. Nuclear-encoded proteins such as TgTPx1/2 are trafficked to the apicoplast via a secretory route through the endoplasmic reticulum (ER) and to the mitochondrion via a non-secretory pathway comprising of translocon uptake. Given the two distinct trafficking pathways for localization to the two organelles, the signals in TgTPx1/2 for this dual targeting are open areas of investigation. Here we show that the signals for apicoplast and mitochondrial trafficking lie in the N-terminal 50 amino acids of the protein and are overlapping. Interestingly, mutational analysis of the overlapping stretch shows that despite this overlap, the signals for individual organellar uptake can be easily separated. Further, deletions in the N-terminus also reveal a 10 amino acid stretch that is responsible for targeting the protein from punctate structures surrounding the apicoplast into the organelle itself. Collectively, results presented in this report suggest that an ambiguous signal sequence for organellar uptake combined with a hierarchy of recognition by the protein trafficking machinery drives the dual targeting of TgTPx1/2.
The Hsp70/Hsp90 Co-Chaperone Hop/Stip1 Shifts the Proteostatic Balance from Folding Towards Degradation
Authors: Bhattacharya Kaushik , Weidenauer Lorenz , Morán Luengo Tania , Echeverría Pablo C. , Bernasconi Lilia , Wider Diana , Villemin Matthieu , Bauer Christoph , Rüdiger Stefan G. D. , Quadroni Manfredo , Picard Didier
Published: February 2019

Hop/Stip1/Sti1 is thought to be essential as a co-chaperone to facilitate substrate transfer between the Hsp70 and Hsp90 molecular chaperones. Despite this proposed key function for protein folding and maturation, it is not essential in a number of eukaryotes and bacteria lack an ortholog. We set out to identify and to characterize its eukaryote-specific function. Human cell lines and the budding yeast with deletions of the Hop/Sti1 gene display reduced proteasome activity due to inefficient capping of the core particle with regulatory particles. Unexpectedly, knock-out cells are more proficient at preventing protein aggregation and at promoting protein refolding. Without the restraint by Hop, a more efficient folding activity of the prokaryote-like Hsp70/Hsp90 complex, which can also be demonstrated in vitro, compensates for the proteasomal defect and ensures an alternate proteostatic equilibrium. Thus, cells may act on Hop to shift the proteostatic balance between folding and degradation.