bluuebunny/crossref_metadata_2025_split huggingface dataset:
TOR and paradigm change: cell growth is controlled
Authors: Hall Michael N. 
Published: September 2016

This year marks the 25th anniversary of the discovery of target of rapamycin (TOR), a highly conserved kinase and central controller of cell growth. In this Retrospective, I briefly describe the discovery of TOR and the subsequent elucidation of its cellular role. I place particular emphasis on an article by Barbet et al. from 1996, the first suggesting that TOR controls cell growth in response to nutrients.
Increased Dietary Salt Changes Baroreceptor Sensitivity and Intrarenal Renin–Angiotensin System in Goldblatt Hypertension
Authors: Shimoura Caroline G. , Lincevicius Gisele S. , Nishi Erika E. , Girardi Adriana C. C. , Simon Karin A. , Bergamaschi Cassia T. , Campos Ruy R. 
Published: September 2016

Abstract

BACKGROUND
Renovascular hypertension (2-kidney 1-clip model (2K1C)) is characterized by renin–angiotensin system (RAS) activation. Increased Angiotensin II (AngII) leads to sympathoexcitation, oxidative stress, and alterations in sodium and water balance.

AIM
The aim of this study was to evaluate whether a discrete increase in sodium chloride intake in 2K1C rats leads to changes in cardiovascular and autonomic function, oxidative stress, and renin angiotensin aldosterone system.

METHODS
After 4 weeks of induction of hypertension, rats were fed a normal sodium diet (0.4% NaCl) or a high-sodium diet (2% NaCl) for 2 consecutive weeks. Experiments were carried out for 6 weeks after clipping. Mean arterial pressure (MAP), renal sympathetic nerve activity (rSNA), arterial baroreflex control of rSNA, and heart rate (HR) were assessed. Thiobarbituric acid reactive substances and glutathione were measured as indicators of systemic oxidative stress. Angiostensin-converting enzyme (ACE), ACE2, and angiotensinogen were evaluated in clipped and unclipped kidneys as also urinary angiotensinogen and plasma renin activity. Angiotensinogen, plasma renin activity (PRA) and angiotensin-converting enzyme (ACE) and ACE2 in clipped and unclipped kidneys were evaluated.

RESULTS
High-sodium diet did not change systemic oxidative stress, and basal values of MAP, HR, or rSNA; however, increased renal (−0.7±0.2 vs. −1.5±0.1 spikes/s/mm Hg) and cardiac (−0.9±0.14 vs. −1.5±0.14 bpm/mm Hg) baroreceptor reflex sensitivity in 2K1C rats. Although there was no alteration in PRA, a high-salt diet significantly decreased urinary angiotensinogen, ACE, and ACE2 expressions in the clipped and unclipped kidneys.

CONCLUSIONS
Increased arterial baroreceptor control associated with a suppression of the intrarenal RAS in the 2K1C rats on high-salt diet provide a salt-resistant effect on hypertension and sympathoexcitation in renovascular hypertensive rats.
Human Albumin Use in Adults in U.S. Academic Medical Centers
Authors: Suarez Jose I. , Martin Renee H. , Hohmann Samuel F. , Calvillo Eusebia , Bershad Eric M. , Venkatasubba Rao Chethan P. , Georgiadis Alexandros , Flower Oliver , Zygun David , Finfer Simon 
Published: September 2016

Objective:
To determine rates and predictors of albumin administration, and estimated costs in hospitalized adults in the United States.

Design:
Cohort study of adult patients from the University HealthSystem Consortium database from 2009 to 2013.

Setting:
One hundred twenty academic medical centers and 299 affiliated hospitals.

Patients:
A total of 12,366,264 hospitalization records.

Interventions:
Analysis of rates and predictors of albumin administration, and estimated costs.

Measurements and Main Results:
Overall the proportion of admissions during which albumin was administered increased from 6.2% in 2009 to 7.5% in 2013; absolute difference 1.3% (95% CI, 1.30–1.40%; p < 0.0001). The increase was greater in surgical patients from 11.7% in 2009 to 15.1% in 2013; absolute difference 3.4% (95% CI, 3.26–3.46%; p < 0.0001). Albumin use varied geographically being lowest with no increase in hospitals in the North Eastern United States (4.9% in 2009 and 5.3% in 2013) and was more common in bigger (> 750 beds; 5.2% in 2009 and 7.3% in 2013) compared to smaller hospitals (< 250 beds; 4.4% in 2009 to 6.2% in 2013). Factors independently associated with albumin use were appropriate indication for albumin use (odds ratio, 65.220; 95% CI, 62.459–68.103); surgical admission (odds ratio, 7.942; 95% CI, 7.889–7.995); and high severity of illness (odds ratio, 8.933; 95% CI, 8.825–9.042). Total estimated albumin cost significantly increased from $325 million in 2009 to $468 million in 2013; (absolute increase of $233 million), p value less than 0.0001.

Conclusions:
The proportion of hospitalized adults in the United States receiving albumin has increased, with marked, and currently unexplained, geographic variability and variability by hospital size.
Human Sepsis Eicosanoid and Proresolving Lipid Mediator Temporal Profiles: Correlations With Survival and Clinical Outcomes
Authors: Dalli Jesmond , Colas Romain A. , Quintana Carolina , Barragan-Bradford Diana , Hurwitz Shelley , Levy Bruce D. , Choi Augustine M. , Serhan Charles N. , Baron Rebecca M. 
Published: September 2016

Objective:
To identify and measure recently described chemical mediators, termed specialized pro-resolving mediators that actively regulate the resolution of acute-inflammation, and correlate measurements with clinical outcomes.

Design:
Herein, deidentified plasma was collected from sepsis patients (n = 22 subjects) within 48 hours of admission to the ICU and on days 3 and 7 thereafter and subjected to lipid mediator profiling.

Setting:
Brigham and Women’s Hospital Medical Intensive Care Unit.

Subjects:
Patients in the medical ICU with sepsis.

Measurements and Main Results:
In all patients, we identified more than 30 bioactive mediators and pathway markers in peripheral blood using established criteria for arachidonic acid, eicosapentaenoic acid, and docosahexaenoic acid metabolomes. These included inflammation initiating mediators leukotriene B4 and prostaglandin E2 and pro-resolving mediators resolvin D1, resolvin D2, and protectin D1. In sepsis nonsurvivors, we found significantly higher inflammation-initiating mediators including prostaglandin F2α and leukotriene B4 and pro-resolving mediators, including resolvin E1, resolvin D5, and 17R-protectin D1 than was observed in surviving sepsis subjects. This signature was present at ICU admission and persisted for 7 days. Further analysis revealed increased respiratory failure in nonsurvivors. Higher inflammation-initiating mediators (including prostaglandin F2α) and select proresolving pathways were associated with the development of acute respiratory distress syndrome, whereas other traditional clinical indices were not predictive of acute respiratory distress syndrome development.

Conclusions:
These results provide peripheral blood lipid mediator profiles in sepsis that correlate with survival and acute respiratory distress syndrome development, thus suggesting plausible novel biomarkers and biologic targets for critical illness.
Cytokine Release Syndrome After Chimeric Antigen Receptor T Cell Therapy for Acute Lymphoblastic Leukemia
Authors: Fitzgerald Julie C. , Weiss Scott L. , Maude Shannon L. , Barrett David M. , Lacey Simon F. , Melenhorst J. Joseph , Shaw Pamela , Berg Robert A. , June Carl H. , Porter David L. , Frey Noelle V. , Grupp Stephan A. , Teachey David T. 
Published: September 2016

Objective:
Initial success with chimeric antigen receptor–modified T cell therapy for relapsed/refractory acute lymphoblastic leukemia is leading to expanded use through multicenter trials. Cytokine release syndrome, the most severe toxicity, presents a novel critical illness syndrome with limited data regarding diagnosis, prognosis, and therapy. We sought to characterize the timing, severity, and intensive care management of cytokine release syndrome after chimeric antigen receptor–modified T cell therapy.

Design:
Retrospective cohort study.

Setting:
Academic children’s hospital.

Patients:
Thirty-nine subjects with relapsed/refractory acute lymphoblastic leukemia treated with chimeric antigen receptor–modified T cell therapy on a phase I/IIa clinical trial (ClinicalTrials.gov number NCT01626495).

Interventions:
All subjects received chimeric antigen receptor–modified T cell therapy. Thirteen subjects with cardiovascular dysfunction were treated with the interleukin-6 receptor antibody tocilizumab.

Measurements and Main Results:
Eighteen subjects (46%) developed grade 3–4 cytokine release syndrome, with prolonged fever (median, 6.5 d), hyperferritinemia (median peak ferritin, 60,214 ng/mL), and organ dysfunction. Fourteen (36%) developed cardiovascular dysfunction treated with vasoactive infusions a median of 5 days after T cell therapy. Six (15%) developed acute respiratory failure treated with invasive mechanical ventilation a median of 6 days after T cell therapy; five met criteria for acute respiratory distress syndrome. Encephalopathy, hepatic, and renal dysfunction manifested later than cardiovascular and respiratory dysfunction. Subjects had a median of 15 organ dysfunction days (interquartile range, 8–20). Treatment with tocilizumab in 13 subjects resulted in rapid defervescence (median, 4 hr) and clinical improvement.

Conclusions:
Grade 3–4 cytokine release syndrome occurred in 46% of patients following T cell therapy for relapsed/refractory acute lymphoblastic leukemia. Clinicians should be aware of expanding use of this breakthrough therapy and implications for critical care units in cancer centers.
Sepsis Pathophysiology, Chronic Critical Illness, and Persistent Inflammation-Immunosuppression and Catabolism Syndrome
Authors: Mira Juan C. , Gentile Lori F. , Mathias Brittany J. , Efron Philip A. , Brakenridge Scott C. , Mohr Alicia M. , Moore Frederick A. , Moldawer Lyle L. 
Published: September 2016

Objectives:
To provide an appraisal of the evolving paradigms in the pathophysiology of sepsis and propose the evolution of a new phenotype of critically ill patients, its potential underlying mechanism, and its implications for the future of sepsis management and research.

Design:
Literature search using PubMed, MEDLINE, EMBASE, and Google Scholar.

Measurements and Main Results:
Sepsis remains one of the most debilitating and expensive illnesses, and its prevalence is not declining. What is changing is our definition(s), its clinical course, and how we manage the septic patient. Once thought to be predominantly a syndrome of over exuberant inflammation, sepsis is now recognized as a syndrome of aberrant host protective immunity. Earlier recognition and compliance with treatment bundles has fortunately led to a decline in multiple organ failure and in-hospital mortality. Unfortunately, more and more sepsis patients, especially the aged, are suffering chronic critical illness, rarely fully recover, and often experience an indolent death. Patients with chronic critical illness often exhibit “a persistent inflammation-immunosuppression and catabolism syndrome,” and it is proposed here that this state of persisting inflammation, immunosuppression and catabolism contributes to many of these adverse clinical outcomes. The underlying cause of inflammation-immunosuppression and catabolism syndrome is currently unknown, but there is increasing evidence that altered myelopoiesis, reduced effector T-cell function, and expansion of immature myeloid-derived suppressor cells are all contributory.

Conclusions:
Although newer therapeutic interventions are targeting the inflammatory, the immunosuppressive, and the protein catabolic responses individually, successful treatment of the septic patient with chronic critical illness and persistent inflammation-immunosuppression and catabolism syndrome may require a more complementary approach.
Evaluation of RBC Transfusion Practice in Adult ICUs and the Effect of Restrictive Transfusion Protocols on Routine Care
Authors: Seitz Kevin P. , Sevransky Jonathan E. , Martin Greg S. , Roback John D. , Murphy David J. 
Published: September 2016

Objective:Research supports the efficacy and safety of restrictive transfusion protocols to reduce avoidable RBC transfusions, but evidence of their effectiveness in practice is limited. This study assessed whether admission to an ICU with an restrictive transfusion protocol reduces the likelihood of transfusion for adult patients.Design:Observational study using data from the multicenter, cohort Critical Illness Outcomes Study. Patient-level analyses were conducted with RBC transfusion on day of enrollment as the outcome and admission to an ICU with a restrictive transfusion protocol as the exposure of interest. Covariates included demographics, hospital course (e.g., lowest hematocrit, blood loss), severity of illness (e.g., Sequential Organ Failure Assessment score), interventions (e.g., sedation/analgesia), and ICU characteristics (e.g., size). Multivariable logistic regression modeling assessed the independent effects of restrictive transfusion protocols on transfusions.Setting:Fifty-nine U.S. ICUs.Patients:A total of 6,027 adult ICU patients.Interventions:None.Measurements and Main Results:Of the 59 study ICUs, 24 had an restrictive transfusion protocol; 2,510 patients (41.6%) were in an ICU with an restrictive transfusion protocol. The frequency of RBC transfusion among patients with severe (hematocrit, < 21%), moderate (hematocrit, 21–30%), and mild (hematocrit, > 30%) anemia in restrictive transfusion protocol ICUs was 67%, 19%, and 4%, respectively, compared with 60%, 14%, and 2% for those in ICUs without an restrictive transfusion protocol. Only 27% of transfusions were associated with a hematocrit less than 21%. Adjusting for confounding factors, restrictive transfusion protocols independently reduced the odds of transfusion in moderate anemia with an odds ratio of 0.59 (95% CI, 0.36–0.96) while demonstrating no effect in mild (p= 0.93) or severe (p= 0.52) anemia.Conclusions:In this sample of ICU patients, transfusions often occurred outside evidence-based guidelines, but admission to an ICU with an restrictive transfusion protocol did reduce the risk of transfusion in moderately anemic patients controlling for patient and ICU factors. This study supports the effectiveness of restrictive transfusion protocols for influencing transfusions in clinical practice.
Opening the Door: The Experience of Chronic Critical Illness in a Long-Term Acute Care Hospital
Authors: Lamas Daniela J. , Owens Robert L. , Nace R. Nicholas , Massaro Anthony F. , Pertsch Nathan J. , Gass Jonathon , Bernacki Rachelle E. , Block Susan D. 
Published: September 2016

Objective:
Chronically critically ill patients have recurrent infections, organ dysfunction, and at least half die within 1 year. They are frequently cared for in long-term acute care hospitals, yet little is known about their experience in this setting. Our objective was to explore the understanding and expectations and goals of these patients and surrogates.

Design:
We conducted semi-structured interviews with chronically critically ill long-term acute care hospital patients or surrogates. Conversations were recorded, transcribed, and analyzed.

Setting:
One long-term acute care hospital.

Subjects:
Chronically critically ill patients, defined by tracheotomy for prolonged mechanical ventilation, or surrogates.

Intervention:
Semi-structured conversation about quality of life, expectations, and planning for setbacks.

Measurements and Main Results:
A total of 50 subjects (30 patients and 20 surrogates) were enrolled. Thematic analyses demonstrated: 1) poor quality of life for patients; 2) surrogate stress and anxiety; 3) optimistic health expectations; 4) poor planning for medical setbacks; and 5) disruptive care transitions. Nearly 80% of patient and their surrogate decision makers identified going home as a goal; 38% were at home at 1 year.

Conclusions:
Our study describes the experience of chronically critically ill patients and surrogates in an long-term acute care hospital and the feasibility of patient-focused research in this setting. Our findings indicate overly optimistic expectations about return home and unmet palliative care needs, suggesting the need for integration of palliative care within the long-term acute care hospital. Further research is also needed to more fully understand the challenges of this growing population of ICU survivors.
Single Session Treatment of Rolling Acne Scars Using Tumescent Anesthesia, 20% Trichloracetic Acid Extensive Subcision, and Fractional CO2 Laser
Authors: Taylor Mark B. , Zaleski-Larsen Lisa , McGraw Timothy A. 
Published: September 2016

BACKGROUNDSuccessful treatment of acne scars is challenging. Many modalities have been used with marginal success.OBJECTIVEThe authors describe a combination of a superficial chemical peel, subcision, and fractional carbon dioxide (CO2) laser resurfacing in a single-treatment session as a novel treatment approach for rolling acne scars.METHODSA total of 114 patients (75 women and 39 men) with predominantly rolling acne scars were treated with a 20% trichloracetic acid chemical peel, subcision with a novel dissecting instrument, and the CO2laser under tumescent anesthesia. This was a retrospective, uncontrolled, unblinded study.RESULTSThe mean improvement after a single treatment was 2.9 on a scale of 1 to 4 with few complications. Ninety percent of the patients were satisfied with their final result and desired no additional treatment.CONCLUSIONThe combination of a trichloracetic acid 20% chemical peel, subcision, and fractional CO2laser resurfacing combined with tumescent anesthesia is both safe and effective in the treatment of rolling acne scars.
Variable Linezolid Exposure in Intensive Care Unit Patients—Possible Role of Drug–Drug Interactions
Authors: Töpper Christoph , Steinbach Cathérine L. , Dorn Christoph , Kratzer Alexander , Wicha Sebastian G. , Schleibinger Michael , Liebchen Uwe , Kees Frieder , Salzberger Bernd , Kees Martin G. 
Published: September 2016

Background:
Standard doses of linezolid may not be suitable for all patient groups. Intensive care unit (ICU) patients in particular may be at risk of inadequate concentrations. This study investigated variability of drug exposure and its potential sources in this population.

Methods:
Plasma concentrations of linezolid were determined by high-performance liquid chromatography in a convenience sample of 20 ICU patients treated with intravenous linezolid 600 mg twice daily. Ultrafiltration applying physiological conditions (pH 7.4/37°C) was used to determine the unbound fraction. Individual pharmacokinetic (PK) parameters were estimated by population PK modeling. As measures of exposure to linezolid, area under the concentration–time curve (AUC) and trough concentrations (Cmin) were calculated and compared with published therapeutic ranges (AUC 200–400 mg*h/L, Cmin 2–10 mg/L). Coadministered inhibitors or inducers of cytochrome P450 and/or P-glycoprotein were noted.

Results:
Data from 18 patients were included into the PK evaluation. Drug exposure was highly variable (median, range: AUC 185, 48–618 mg*h/L, calculated Cmin 2.92, 0.0062–18.9 mg/L), and only a minority of patients had values within the target ranges (6 and 7, respectively). AUC and Cmin were linearly correlated (R = 0.98), and classification of patients (underexposed/within therapeutic range/overexposed) according to AUC or Cmin was concordant in 15 cases. Coadministration of inhibitors was associated with a trend to higher drug exposure, whereas 3 patients treated with levothyroxine showed exceedingly low drug exposure (AUC ∼60 mg*h/L, Cmin <0.4 mg/L). The median unbound fraction in all 20 patients was 90.9%.

Conclusions:
Drug exposure after standard doses of linezolid is highly variable and difficult to predict in ICU patients, and therapeutic drug monitoring seems advisable. PK drug–drug interactions might partly be responsible and should be further investigated; protein binding appears to be stable and irrelevant.
A RESCUE THERAPY FOR PERSISTENT OPTIC DISK PIT MACULOPATHY IN PREVIOUSLY VITRECTOMIZED EYES
Authors: Figueroa Marta S. , Nadal Jeroni , Contreras Inés 
Published: September 2016

Purpose:
To report the results of vitrectomy with platelet-rich plasma (PRP) application and gas tamponade as a rescue therapy in previously vitrectomized eyes with optic disk pit (ODP) maculopathy.

Methods:
Three patients with visual loss due to persistent or recurrent ODP maculopathy who had undergone previous vitrectomy were offered application of PRP. Platelet-rich plasma was obtained by centrifugation of a blood sample from each patient. Surgery consisted of vitrectomy and internal limiting membrane peeling if the membrane had not been already removed (in two eyes). After fluid/air exchange, three drops of PRP were applied on the ODP followed by 8% C3F8 tamponade. Immediately after surgery, the patient remained supine for 30 minutes and then kept a face-down position for 2 weeks.

Results:
Optic disk pit maculopathy improved as soon as two weeks after surgery and resolved in all eyes between six and eight months after PRP application. Patients were followed up for three years, with no recurrences. Visual acuity remained stable in one eye and improved in two eyes.

Conclusion:
Vitrectomy with PRP application may be useful as a rescue therapy in patients with refractory ODP maculopathy. Platelet-rich plasma may act by promoting the closure of the communication between the vitreous and the intraretinal/subretinal space at the pit. This treatment may avoid potentially harmful maneuvers that have been used to treat ODP maculopathy.
OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY OF A29 BIRDSHOT CHORIORETINOPATHY COMPLICATED BY RETINAL NEOVASCULARIZATION
Authors: Phasukkijwatana Nopasak , Iafe Nicholas , Sarraf David 
Published: September 2016

Purpose:
To describe the quantitative optical coherence tomography angiography analysis of the superficial and deep retinal capillary plexus in a case of A29 birdshot chorioretinopathy (BCR) complicated by retinal neovascularization.

Methods:
Multimodal retinal imaging, including optical coherence tomography angiography with quantitated vessel density analysis of the superficial and deep retinal capillary plexus, was performed in a case of A29 BCR. Capillary density (mm−1) was defined as the total vessel length (mm) per area (mm2).

Results:
A 39-year-old healthy white man presented with vitreous hemorrhage and retinal neovascularization at baseline. Clinical presentation was consistent with BCR and human leukocyte antigen testing confirmed A29 positivity. Optical coherence tomography angiography was performed 6 years after the diagnosis and revealed capillary density reduction in the superficial and especially in the deep retinal capillary plexus. Quantitative vessel density analysis was compared with the mean capillary density of 11 age-matched normal eyes and demonstrated 6% and 18% reduction of the superficial plexus in the right and left eyes of our patient, respectively. For the deep plexus, a reduction of 25% and 32% was found in the right and left eyes, respectively.

Conclusion:
In this patient with BCR, capillary density reduction was most marked at the deep retinal capillary plexus level and may explain the development of retinal neovascularization in this case. Quantitative optical coherence tomography angiography may be a useful tool to study and to monitor retinal microvascular changes in patients with BCR and should be further explored as a biomarker of therapeutic response.