BLM helicase protein negatively regulates stress granule formation through unwinding RNA G-quadruplex structures.

Bloom's syndrome (BLM) protein is a known nuclear helicase that is able to unwind DNA secondary structures such as G-quadruplexes (G4s). However, its role in the regulation of cytoplasmic processes that involve RNA G-quadruplexes (rG4s) has not been previously studied. Here, we demonstrate that BLM is recruited to stress granules (SGs), which are cytoplasmic biomolecular condensates composed of RNAs and RNA-binding proteins. BLM is enriched in SGs upon different stress conditions and in an rG4-dependent manner. Also, we show that BLM unwinds rG4s and acts as a negative regulator of SG formation. Altogether, our data expand the cellular activity of BLM and shed light on the function that helicases play in the dynamics of biomolecular condensates.

TP53 missense mutations in PDAC are associated with enhanced fibrosis and an immunosuppressive microenvironment.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer, which is refractory to all currently available treatments and bears dismal prognosis. About 70% of all PDAC cases harbor mutations in the TP53 tumor suppressor gene. Many of those are missense mutations, resulting in abundant production of mutant p53 (mutp53) protein in the cancer cells. Analysis of human PDAC patient data from The Cancer Genome Atlas (TCGA) revealed a negative association between the presence of missense mutp53 and infiltration of CD8+ T cells into the tumor. Moreover, CD8+ T cell infiltration was negatively correlated with the expression of fibrosis-associated genes. Importantly, silencing of endogenous mutp53 in KPC cells, derived from mouse PDAC tumors driven by mutant Kras and mutp53, down-regulated fibrosis and elevated CD8+ T cell infiltration in the tumors arising upon orthotopic injection of these cells into the pancreas of syngeneic mice. Moreover, the tumors generated by mutp53-silenced KPC cells were markedly smaller than those elicited by mutp53-proficient control KPC cells. Altogether, our findings suggest that missense p53 mutations may contribute to worse PDAC prognosis by promoting a more vigorous fibrotic tumor microenvironment and impeding the ability of the immune system to eliminate the cancer cells.

Satisfaction, Salaries, and Sustainability: Results of a National Survey of Pediatric Program Directors.

OBJECTIVE: Describe the career and work environment of pediatric program directors (PDs) and associated factors, including salary disparities and long-term career plans. METHODS: A national, anonymous, electronic survey was sent to all categorical residency PD members of the Association of Pediatric Program Directors. Surveys assessed PD demographics, characteristics of the residency program and PD positions (including salary), and measures of satisfaction. Chi-square and Fisher's exact tests were used to analyze results. RESULTS: A total of 149 PDs (74%) responded. Significantly more men earned $250,000 or more annually (26.9% vs 6.1% of women), and gender remained a significant independent predictor of salary after controlling for age, academic rank, and subspecialty. Satisfaction was high for most measures, although 20% or more reported low satisfaction with pay (38.9%), administrative workload (32.1%), managing accreditation and expectations of the Accreditation Council for Graduate Medical Education (31.9%), resources (27.9%), work/life balance (24.1%), and being valued by administration (20.0%). Only 34.3% saw the PD position as an end goal, and 29.5% stated they would be in their current position in 5 years. Satisfaction with the PD career, with faculty relationships, with resident performance, and with administrative workload was associated with plans to remain. CONCLUSIONS: Most pediatric program directors did not view the position of PD as their long-term career goal, and many identified administrative duties and work/life balance as contributing to significant dissatisfaction. Without changes to address these issues, PD turnover may be high, with potential negative implications for the success of training programs.

Peer-Debriefing After Distressing Patient Care Events: A Workshop for Pediatric Residents.

Introduction: When confronted with a distressing patient care event, physicians experience feelings of failure, inadequacy, and self-doubt that negatively impact emotional well-being and have been linked to burnout and premature exit from the medical profession. A need exists within the medical community for improved emotional processing of distressing patient care events, particularly for resident physicians at the beginning of their careers. Methods: To encourage physicians to communicate as a means of initiating emotional processing after a distressing patient care event, a workshop was developed for pediatric residents providing training on a peer-debriefing model taken from the bereavement counseling literature. The workshop is designed to take 60 minutes, including dedicated opportunities to observe and conduct debriefing sessions based on the residents' own distressing patient care experiences. Included are the workshop facilitation guide, the adapted peer-debriefing model, hypothetical patient care scenarios, and pre- and postsession survey evaluation forms. Results: Pre- and posttraining survey metrics revealed statistically significant and meaningful increases in pediatric residents' self-reported comfort with and likelihood of leading a peer-debriefing session in an appropriate clinical setting. Discussion: This workshop is a well-received, effective intervention that provides pediatric residents with a tool to aid in the timely emotional processing of distressing patient care events. It has been adopted into the standard educational curriculum of our home institution's pediatric residency program. This workshop may be extended throughout the field, helping physicians at all levels of practice process the inevitable distress inherent in caring for the sick.

Linking actin networks and cell membrane via a reaction-diffusion-elastic description of nonlinear filopodia initiation.

Reaction-diffusion models have been used to describe pattern formation on the cellular scale, and traditionally do not include feedback between cellular shape changes and biochemical reactions. We introduce here a distinct reaction-diffusion-elasticity approach: The reaction-diffusion part describes bistability between two actin orientations, coupled to the elastic energy of the cell membrane deformations. This coupling supports spatially localized patterns, even when such solutions do not exist in the uncoupled self-inhibited reaction-diffusion system. We apply this concept to describe the nonlinear (threshold driven) initiation mechanism of actin-based cellular protrusions and provide support by several experimental observations.

Assessing the utility of procedural training for pediatrics residents in general pediatric practice.

BACKGROUND: The Accreditation Council for Graduate Medical Education (ACGME) recommends that residents gain broad procedural competence in pediatrics training. There is little recent information regarding practice patterns after graduation. OBJECTIVE: We analyzed reported procedures performed in actual practice by graduates of a general pediatrics residency program. METHODS: We conducted an online survey from April 2007 to April 2011 of graduates of a single pediatrics program from a large children's hospital. Eligible participants completed general pediatrics residency training between 1992 and 2006. Graduates were asked about the adequacy of their training for each procedure, as well as the frequency of commonly performed procedures in their practice. As the primary analysis, procedures were divided into emergent and urgent procedures. RESULTS: Our response rate was 54% (209 of 387). General pediatricians rarely performed emergent procedures, such as endotracheal intubation, intraosseous line placement, thoracostomy, and thoracentesis. Instead, they more commonly performed urgent procedures, such as laceration repair, fracture or dislocation care, bladder catheterization, foreign body removal, and incision and drainage of simple abscesses. Statistically significant differences existed between emergent and urgent procedures (P < .001). CONCLUSIONS: In a single, large, urban, pediatrics residency, 15 years of graduates who practiced general pediatrics after graduation reported they rarely performed emergent procedures, such as endotracheal intubation, but more often performed urgent procedures, such as laceration repair. These results may have implications for ACGME recommendations regarding the amount and type of procedural training required for general pediatrics residents.

Effective temperature of red-blood-cell membrane fluctuations.

Biologically driven nonequilibrium fluctuations are often characterized by their non-Gaussianity or by an "effective temperature", which is frequency dependent and higher than the ambient temperature. We address these two measures theoretically by examining a randomly kicked particle, with a variable number of kicking motors, and show how these two indicators of nonequilibrium behavior can contradict. Our results are compared with new experiments on shape fluctuations of red-blood cell membranes, and demonstrate how the physical nature of the motors in this system can be revealed using these global measures of nonequilibrium.

National profile of nonemergent pediatric emergency department visits.

OBJECTIVE: Emergency department (ED) crowding prevents the efficient and effective use of health services and compromises quality. Patients who use the ED for nonemergent health concerns may unnecessarily crowd ED services. In this article we describe characteristics of pediatric patients in the United States who use EDs for nonemergent visits. METHODS: We analyzed data from the 2002-2005 Medical Expenditure Panel Survey. The Medical Expenditure Panel Survey is conducted by the Agency for Healthcare Research and Quality and consists of a nationally representative sample of the civilian noninstitutionalized population of the United States. Our study sample consisted of 5512 person-years of observation. We included only ED visits for children from birth to 17 years of age with a specified International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis code. The main dependent variable for our multivariate logistic model was nonemergent ED use, which was constructed by using the New York University ED-classification algorithm. Independent variables were derived from Andersen's Behavioral Model of Health Services Utilization. RESULTS: We found that from 2002 to 2005, a nationally representative sample of US children from birth to 17 years of age used EDs for various nonemergent or primary care-treatable diagnoses. Overall, children from higher-income families had higher ED expenditures than children from lower-income families. Children with private insurance had higher total ED expenditures than publicly insured or uninsured children, but uninsured children had the highest out-of-pocket expenditures. We found that children from birth to 2 years of age were less likely to use the ED for nonemergent diagnoses (odds ratio [OR]: 0.13; P < .01) compared with older children. Non-Hispanic black children were also less likely to use the ED for nonemergent diagnoses (OR: 0.40; P = .03) than were non-Hispanic white children. CONCLUSION: Children's sociodemographic characteristics were predictors of nonemergent use of ED services.