bluuebunny/crossref_metadata_2025_split huggingface dataset:
LRRC8A is essential for swelling‐activated chloride current and for regulatory volume decrease in astrocytes
Authors: Formaggio Francesco , Saracino Emanuela , Mola Maria Grazia , Rao Shreyas Balachandra , Amiry-Moghaddam Mahmood , Muccini Michele , Zamboni Roberto , Nicchia Grazia Paola , Caprini Marco , Benfenati Valentina 
Published: June 2018

ABSTRACTConsolidated evidence indicates that astroglial cells are critical in the homeostatic regulation of cellular volume by means of ion channels and aquaporin‐4. Volume‐regulated anion channel (VRAC) is the chloride channel that is activated upon cell swelling and critically contributes to cell volume regulation in astrocytes. The molecular identity of VRAC has been recently defined, revealing that it belongs to the leucine‐rich repeat‐containing 8 (LRRC8) protein family. However, there is a lack of evidence demonstrating that LRRC8A underpins VRAC currents in astrocyte. Nonetheless, direct evidence of the role of LRRC8A in astrocytic regulatory volume decrease remains to be proved. Here, we aim to bridge this gap in knowledge by combining RNA interference specific for LRRC8A with patch‐clamp analyses and a water‐permeability assay. We demonstrated that LRRC8A molecular expression is essential for swelling‐activated chloride current via VRAC in primary‐cultured cortical astrocytes. The knockdown of LRRC8A with a specific short interference RNA abolished the recovery of the cell volume after swelling induced by hypotonic challenge. In addition, immunoblotting, immunofluorescence, confocal imaging, and immunogold electron microscopy demonstrated that LRRC8A is expressed in the plasma membrane of primary cortical astrocytes and in situ in astrocytes at the perivascular interface with endothelial cells. Collectively, our results suggest that LRRC8A is an essential subunit of VRAC and a key factor for astroglial volume homeostasis.—Formaggio, F., Saracino, E., Mola, M. G., Rao, S. B., Amiry‐Moghaddam, M., Muccini, M., Zamboni, R., Nicchia, G. P., Caprini, M., Benfenati, V. LRRC8A is essential for swelling‐activated chloride current and for regulatory volume decrease in astrocytes. FASEB J. 33, 101–113 (2019). www.fasebj.org
Chemotherapy‐generated cell debris stimulates colon carcinoma tumor growth via osteopontin
Authors: Chang Jaimie , Bhasin Swati S. , Bielenberg Diane R. , Sukhatme Vikas P. , Bhasin Manoj , Huang Sui , Kieran Mark W. , Panigrahy Dipak 
Published: June 2018

ABSTRACTColon cancer recurrence after therapy, such as 5‐fluorouracil (5‐FU), remains a challenge in the clinical setting. Chemotherapy reduces tumor burden by inducing cell death; however, the resulting dead tumor cells, or debris, may paradoxically stimulate angiogenesis, inflammation, and tumor growth. Here, we demonstrate that 5‐FU‐generated colon carcinoma debris stimulates the growth of a subthreshold inoculum of living tumor cells in subcutaneous and orthotopic models. Debris triggered the release of osteopontin (OPN) by tumor cells and host macrophages. Both coinjection of debris and systemic treatment with 5‐FU increased plasma OPN levels in tumor‐bearing mice. RNA expression levels of secreted phosphoprotein 1, the gene that encodes OPN, correlate with poor prognosis in patients with colorectal cancer and are elevated in chemotherapy‐treated patients who experience tumor recurrence vs. no recurrence. Pharmacologic and genetic ablation of OPN inhibited debris‐stimulated tumor growth. Systemic treatment with a combination of a neutralizing OPN antibody and 5‐FU dramatically inhibited tumor growth. These results demonstrate a novel mechanism of tumor progression mediated by OPN released in response to chemotherapy‐generated tumor cell debris. Neutralization of debris‐stimulated OPN represents a potential therapeutic strategy to overcome the inherent limitation of cytotoxic therapies as a result of the generation of cell debris.—Chang, J., Bhasin,S. S., Bielenberg,D. R., Sukhatme,V. P., Bhasin,M., Huang,S., Kieran,M. W., Panigrahy,D.Chemotherapy‐generated cell debris stimulates colon carcinoma tumor growth via osteopontin. FASEB J. 33,114–125 (2019). www.fasebj.org
Novel noncanonical regulation of soluble VEGF/VEGFR2 signaling by mechanosensitive ion channel TRPV4
Authors: Kanugula Anantha K. , Adapala Ravi K. , Midha Priya , Cappelli Holly C. , Meszaros J. Gary , Paruchuri Sailaja , Chilian William M. , Thodeti Charles K. 
Published: June 2018

ABSTRACTVEGF signaling via VEGF receptor‐2 (VEGFR2) is a major regulator of endothelial cell (EC) functions, including angiogenesis. Although most studies of angiogenesis focus on soluble VEGF signaling, mechanical signaling also plays a critical role. Here, we examined the consequence of disruption of mechanical signaling on soluble signaling pathways. Specifically, we observed that small interfering RNA (siRNA) knockdown of a mechanosensitive ion channel, transient receptor potential vanilloid 4 (TRPV4), significantly reduced perinuclear (Golgi) VEGFR2 in human ECs with a concomitant increase in phosphorylation at Y1175 and membrane translocation. TRPV4 knockout (KO) ECs exhibited increased plasma membrane localization of phospho‐VEGFR2 compared with normal ECs. The knockdown also increased phospho‐VEGFR2 in whole cell lysates and membrane fractions compared with control siRNA‐treated cells. siRNA knockdown of TRPV4 enhanced nuclear localization of mechanosensitive transcription factors, yes‐associated protein/transcriptional coactivator with PDZ‐binding motif via rho kinase, which were shown to increase VEGFR2 trafficking to the plasma membrane. Furthermore, TRPV4 deletion/knockdown enhanced VEGF‐mediated migration in vitro and increased expression of VEGFR2 in vivo in the vasculature of TRPV4 KO tumors compared with wild‐type tumors. Our results thus show that TRPV4 channels regulate VEGFR2 trafficking and activation to identify novel cross‐talk between mechanical (TRPV4) and soluble (VEGF) signaling that controls EC migration and angiogenesis.—Kanugula, A. K., Adapala, R. K., Midha, P., Cappelli, H. C., Meszaros, J. G., Paruchuri, S., Chilian, W. M., Thodeti, C. K., Novel noncanonical regulation of soluble VEGF/VEGFR2 signaling by mechanosensitive ion channel TRPV4. FASEB J. 33, 195–203 (2019). www.fasebj.org
Compliance With the National SEP-1 Quality Measure and Association With Sepsis Outcomes: A Multicenter Retrospective Cohort Study*
Authors: Rhee Chanu , Filbin Michael R. , Massaro Anthony F. , Bulger Amy L. , McEachern Donna , Tobin Kathleen A. , Kitch Barrett T. , Thurlo-Walsh Bert , Kadar Aran , Koffman Alexandra , Pande Anupam , Hamad Yasir , Warren David K. , Jones Travis M. , O’Brien Cara , Anderson Deverick J. , Wang Rui , Klompas Michael 
Published: June 2018

Objectives:
Many septic patients receive care that fails the Centers for Medicare and Medicaid Services’ SEP-1 measure, but it is unclear whether this reflects meaningful lapses in care, differences in clinical characteristics, or excessive rigidity of the “all-or-nothing” measure. We compared outcomes in cases that passed versus failed SEP-1 during the first 2 years after the measure was implemented.

Design:
Retrospective cohort study.

Setting:
Seven U.S. hospitals.

Patients:
Adult patients included in SEP-1 reporting between October 2015 and September 2017.

Interventions:
None.

Measurements and Main Results:
Of 851 sepsis cases in the cohort, 281 (33%) passed SEP-1 and 570 (67%) failed. SEP-1 failures had higher rates of septic shock (20% vs 9%; p < 0.001), hospital-onset sepsis (11% vs 4%; p = 0.001), and vague presenting symptoms (46% vs 30%; p < 0.001). The most common reasons for failure were omission of 3- and 6-hour lactate measurements (228/570 failures, 40%). Only 86 of 570 failures (15.1%) had greater than 3-hour delays until broad-spectrum antibiotics. Cases that failed SEP-1 had higher in-hospital mortality rates (18.4% vs 11.0%; odds ratio, 1.82; 95% CI, 1.19–2.80; p = 0.006), but this association was no longer significant after adjusting for differences in clinical characteristics and severity of illness (adjusted odds ratio, 1.36; 95% CI, 0.85–2.18; p = 0.205). Delays of greater than 3 hours until antibiotics were significantly associated with death (adjusted odds ratio, 1.94; 95% CI, 1.04–3.62; p = 0.038), whereas failing SEP-1 for any other reason was not (adjusted odds ratio, 1.10; 95% CI, 0.70–1.72; p = 0.674).

Conclusions:
Crude mortality rates were higher in sepsis cases that failed versus passed SEP-1, but there was no difference after adjusting for clinical characteristics and severity of illness. Delays in antibiotic administration were associated with higher mortality but only accounted for a small fraction of SEP-1 failures. SEP-1 may not clearly differentiate between high- and low-quality care, and detailed risk adjustment is necessary to properly interpret associations between SEP-1 compliance and mortality.
A Case for Change in Adult Critical Care Training for Physicians in the United States: A White Paper Developed by the Critical Care as a Specialty Task Force of the Society of Critical Care Medicine*
Authors: Tisherman Samuel A. , Spevetz Antoinette , Blosser Sandralee A. , Brown Daniel , Chang Cherylee , Efron Philip A. , O’Connor Michael , Sevransky Jonathan E. , Wessman Brian T. 
Published: June 2018

Objectives:
In the United States, physician training in Critical Care Medicine has developed as a subspecialty of different primary boards, despite significant commonality in knowledge and skills. The Society of Critical Care Medicine appointed a multidisciplinary Task Force to examine alternative approaches for future training.

Design:
The Task Force reviewed the literature and conducted informal discussions with key stakeholders. Specific topics reviewed included the history of critical care training, commonalities among subspecialties, developments since a similar review in 2004, international experience, quality patient care, and financial and workforce issues.

Main Results:
The Task Force believes that options for future training include establishment of a 1) primary specialty of critical care; 2) unified fellowship and certification process; or 3) unified certification process with separate fellowship programs within the current specialties versus 4) maintaining multiple specialty-based fellowship programs and certification processes.

Conclusions:
1) Changing the current Critical Care Medicine training paradigms may benefit trainees and patient care. 2) Multiple pathways into critical care training for all interested trainees are desirable for meeting future intensivist workforce demands. 3) The current subspecialties within separate boards are not “distinct and well-defined field[s] of medical practice” per the American Board of Medical Specialties. Recommendations for first steps are as follows: 1) as the society representing multidisciplinary critical care, the Society of Critical Care Medicine has an opportunity to organize a meeting of all stakeholders to discuss the issues regarding Critical Care Medicine training and consider cooperative approaches for the future. 2) A common Critical Care Medicine examination, possibly with a small percentage of base-specialty–specific questions, should be considered. 3) Institutions with multiple Critical Care Medicine fellowship programs should consider developing joint, multidisciplinary training curricula. 4) The boards that offer Critical Care Medicine examinations, along with national critical care societies, should consider ways to shorten training time.
Reproductive Coercion
Authors: Kovar Cheryl L. 
Published: June 2018

Abstract
Background and Purpose: Reproductive coercion involves behavior that interferes with the individual's unique ability to make decisions about their reproductive health. The concept was first recognized in 2010. Reproductive coercion is intended to maintain power and control in a relationship by someone past, present, or future wishing to be involved in an intimate or dating relationship with an adult or adolescent. Three forms of coercion have been identified: contraceptive sabotage, pregnancy pressure, and control of pregnancy outcomes. Methods: A search for scientific literature was conducted examining studies involving reproductive coercion as well as evidence-based interventions that could be used by nurses in the clinic setting. Conclusions: Prevalence of reproductive coercion is estimated to range from 8% to 16%. There is a high association between intimate partner violence (IPV), sexually transmitted infections (STIs), and unintended pregnancy. Adolescents are at greater risk for reproductive coercion than older women. Implications for Practice: There are interventions we can incorporate into our clinical practices to screen and assess women for reproductive coercion. Women experiencing reproductive coercion are at risk for unintended pregnancy, STIs, IPV, and forced pregnancy outcomes.
Maternity Nurses' Knowledge and Practice of Breastfeeding in Mississippi
Authors: Alakaam Amir , Lemacks Jennifer , Yadrick Kathleen , Connell Carol , Choi Hwanseok Winston , Newman Ray G. 
Published: June 2018

ABSTRACT

Background:
Mississippi has the lowest rates of breastfeeding of all states at 6 months and at 1 year. Registered nurses working in the maternity setting can be influential in mothers' decision to breastfeed.

Purpose:
The purpose of this study was to examine registered nurses' knowledge and practice related to breastfeeding; and to identify facilitators and barriers to implementing the Ten Steps to Successful Breastfeeding in Mississippi hospitals.

Methods:
302 Registered nurses working in hospital maternity/birthing settings in Mississippi completed a questionnaire. Breastfeeding knowledge and practices overall scores were categorized into: poor and good. Chi-square analysis and Spearman correlations were used to determine correlations among the variables.

Results:
Overall breastfeeding knowledge and practices of respondents was good. Only 4% earned a perfect score. Most believed they were effective (77%) in meeting the needs of new mothers. Significant positive associations were noted among knowledge and effectiveness, and other variables. Resistance to change and staffing shortages were the main barriers to implementing the Ten Steps; raising awareness about the importance of the Ten Steps and providing a lactation consultant were the main facilitators.

Conclusion:
More research is needed to understand reasons behind low breastfeeding rates in Mississippi.
Is There a Relationship Between Gestational Diabetes and Perinatal Depression?
Authors: Clevesy Marcia A. , Gatlin Tricia K. , Strebel Kord T. 
Published: June 2018

Abstract
Perinatal depression (PND) is one of the leading complications associated with childbirth. Early detection and treatment of depression, particularly during the perinatal period, is essential for the promotion of positive maternal–child outcomes. Gestational diabetes mellitus (GDM) has been suggested as a confounding factor associated with PND. Concerns associated with PND include interference with maternal–newborn bonding and long-term effects of neurobehavioral consequences. An exemplar case describing one woman's experience with GDM and her subsequent complications associated with PND is presented to discuss maternal depression and its plausible association with GDM. Recommendations include universal screening with the validated Edinburgh Postnatal Depression Scale screening tool during the early perinatal period to reduce incidence of maternal–newborn complications associated with PND and promote underpinnings for best practice.
Human Immunodeficiency Virus Infection Increases the Risk of Incident Uveitis Among People Living With HIV/AIDS
Authors: Yen Yung-Feng , Feng Jia-Yih , Yi-Fong Su Vincent , Chuang Pei-Hung , Ko Ming-Chung , Chen Chu-Chieh , Li Yi-Jie , Pan Sheng-Wei , Su Wei-Juin 
Published: June 2018

Background:
Case reports indicated that HIV itself may be a direct cause of uveitis. However, the association of HIV with incident uveitis has not been extensively studied. This nationwide cohort study determined the association of HIV with incident uveitis.

Methods:
Since January 1, 2003, we identified adult people living with HIV/AIDS (PLWHA) from Taiwan Centers for Disease Control HIV Surveillance Database. A control cohort without HIV infection, matched for age and sex, was selected for comparison from the Taiwan National Health Insurance Research Database. The time-dependent Cox proportional hazards model was used to determine the associations of HIV and highly active antiretroviral therapy (HAART) with incident uveitis, while considering death as a competing risk event.

Results:
Of the total 120,430 patients (24,086 PLWHA and 96,344 matched controls), 609 (0.51%) had incident uveitis, including 334 (1.39%) PLWHA and 265 (0.28%) controls. After adjusting for age, sex, and comorbidities, HIV infection was found to be an independent risk factor for incident uveitis [adjusted hazard ratio (AHR), 5.55; 95% confidence interval (CI): 4.67 to 6.59]. Within PLWHA, the risk of incident uveitis was significantly higher in those who received HAART (AHR, 2.46; 95% CI: 1.71 to 3.54). In addition, considering the short- and long-term effects of HAART on incident uveitis, HAART was found to associate with a higher risk of uveitis development within 1 year of treatment (AHR, 3.36; 95% CI: 2.41 to 4.69), but not after 1 year of HAART initiation (AHR, 1.14; 95% CI: 0.76 to 1.72).

Conclusions:
HIV infection is an independent risk factor for incident uveitis.
Brief Report: Antimalarial Benefit of HIV Antiretroviral Therapy in Areas of Low to Moderate Malaria Transmission Intensity
Authors: Greenhalgh Scott , Hobbs Charlotte V. , Parikh Sunil 
Published: June 2018

Background:
We previously used mathematical modeling to predict reduced malaria incidence in children with protease inhibitor (PI)-, compared with nonnucleoside reverse transcriptase inhibitor–, based highly active antiretroviral therapy (HAART), in moderate to high malaria transmission areas. These effects were accounted for, in part, by pharmacokinetic (PK) interactions between PIs and artemether–lumefantrine (AL).

Objective:
Because of potentially reduced malaria transmission reservoirs in HIV-infected children due to PI/AL PK interactions impacting non–HIV-infected children, we estimate the antimalarial benefit of PI-based HAART in all children, and in HIV-infected children only residing in low to moderate malaria transmission areas.

Design:
A dynamic model of malaria transmission was developed to evaluate the PK interaction of PI-based HAART with the antimalarial, AL for preventing malaria.

Methods:
To evaluate the benefit of HIV PI-based HAART on malaria incidence, a malaria transmission model with varying degrees of HIV newborn prevalence was developed using recent pediatric clinical trial data in Lilongwe, Malawi.

Results:
Comparing situations of low to high HIV newborn prevalence, and low to moderate malaria transmission intensities, our model predicts the combination of PI-based HAART with AL-treated malaria prevents 0.04–24.8 and 0.05–34.5 annual incidences of malaria overall per 1000 children, and saves 0.003–1.66 and 0.003–2.30 disability-adjusted life years per 1000 children, respectively. When incorporating seasonality, 0.01–7.3 and 0.01–5.9 annual incidences of malaria overall per 1000 children, and 0.0–0.5 and 0.001–0.41 disability-adjusted life years per 100 children, are prevented, respectively.

Conclusions:
In low to moderate malaria transmission intensity areas, PI-based HAART may reduce malaria events in children when AL is used.
Integrated Treatment for Smoking Cessation, Anxiety, and Depressed Mood in People Living With HIV: A Randomized Controlled Trial
Authors: O'Cleirigh Conall , Zvolensky Michael J. , Smits Jasper A. J. , Labbe Allison K. , Coleman Jessica N. , Wilner Julianne G. , Stanton Amelia M. , Gonzalez Adam , Garey Lorra , Regenauer Kristen S. , Rosenfield David 
Published: June 2018

Objective:
Among people living with HIV, cigarette smoking rates are higher than among the general population, and anxiety, depression, and their disorders are common and associated with smoking and poorer outcomes during cessation. This study evaluated the efficacy of an integrated smoking cessation intervention, developed to target anxiety, depression, and smoking cessation concurrently among people living with HIV.

Method:
Smokers living with HIV who reported at least moderate motivation to quit smoking were randomized into a novel 9-week integrated intervention (QUIT), consisting of 1 psychoeducation (prerandomization) session and 9 weekly 1-hour sessions of cognitive behavioral therapy for smoking cessation and anxiety/depression plus nicotine replacement therapy, or a 9-week enhanced standard smoking intervention (ETAU), consisting of 1 psychoeducation session (prerandomization) and 4 brief weekly check-in sessions plus nicotine replacement therapy. All were instructed to make a quit attempt at week 6.

Results:
Seventy-two participants were enrolled, and 53 were randomized. 41/53 participants completed the active treatment phase of the study. 7-day point-prevalence abstinence, verified with expired carbon monoxide, was significantly higher among those in the integrated intervention than those in the enhanced standard intervention both end-of-treatment {[MQUIT = 59%, METAU = 9%; b = 5.60, 95% confidence interval: (2.64 to 8.56), t(332) = 3.72, P < 0.001]} and 6-months post-quit date {[MQUIT = 46%, METAU = 5%; b = 7.69, 95% confidence interval: (4.60 to 10.78), t(332) = 4.90, P < 0.001]}. Consideration of patterns of missingness did not alter the significance of these findings.

Conclusions:
The integrated intervention was associated with substantially higher short-term and long-term abstinence rates than the enhanced standard intervention. These data provide promising initial evidence supporting the benefits of an integrated anxiety–depression/smoking cessation program specifically tailored for people living with HIV.
A Roadmap for Aspiring Surgeon-Scientists in Today's Healthcare Environment
Authors: Goldstein Allan M. , Blair Alex B. , Keswani Sundeep G. , Gosain Ankush , Morowitz Michael , Kuo John S. , Levine Matthew , Ahuja Nita , Hackam David J. 
Published: June 2018

Objective:
Surgeon-scientists are an essential component of the field of academic surgery, contributing to the fundamental understanding of disease and the discovery of innovative therapies. Despite this recognized value, the current landscape of academic medicine presents significant barriers to establishing and maintaining a successful career as a surgeon performing basic/translational research. Our objective is to define these barriers to academic success for surgeons, and to provide a consensus strategy for optimizing the chances of success.

Summary Background Data:
There is a significant decline in the proportion of academic surgeons who are pursuing basic science/translational research, which represents a potential threat to the very identify of the translational surgeon-scientist.

Methods:
Based on published literature and expert opinion, the Basic Science Committee of the Society of University of Surgeons prepared this roadmap to encourage and guide the next generation of surgeon-scientists as they embark on their academic careers.

Results:
This roadmap highlights key elements to consider in choosing an initial job and the importance of identifying a team of committed mentors. Expectations and guidelines for the first several years in practice are offered.

Conclusions:
With guidance and mentorship, aspiring surgeonscientists can overcome the challenges inherent in choosing this career path and sustain the important legacy of those before them.