Shift Happens: Emergency Physician Perspectives on Fatigue and Shift Work.

Research has shown that shiftworkers experience poor sleep and high levels of fatigue. Although considerable research has been performed on fatigue within many shift-work occupations, very little has been done with emergency physicians (EPs). This qualitative study was conducted with the goal of gaining insight into EPs' perceptions of fatigue at work. Twenty EPs from an academic medical center participated in virtual interviews, with nine open-ended questions asked in a semi-structured interview format. Twelve common topics with four main themes emerged from the interviews. Three of these common themes included sources of fatigue (including both work- and home-related sources), consequences of fatigue (including impacts on individuals and performance), and prevention and mitigation strategies to cope with fatigue. The fourth main theme was the belief in the inevitability of fatigue due to high cognitive load, emotionally taxing work experiences, work unpredictability, and the 24/7 shift-work nature of emergency medicine. EPs' experiences with fatigue are consistent with but extend those of other types of shiftworkers. Our findings suggest that EPs tend to incorporate the inevitability of fatigue at work into their identity as EPs and experience a sense of learned helplessness as a result, suggesting areas for future interventions.

Association Between Laboratory Values and Adverse Events in Adults Post-Hematopoietic Stem Cell Transplant During and After Rehabilitation.

OBJECTIVE: The objective of this study was to examine the relationship between adverse events (AEs) and critical events (CEs) during and after rehabilitation in cancer patients post-hemopoietic stem cell transplant (HSCT) or bone marrow transplant (BMT) and to identify whether particular laboratory values are associated with increased risk of AEs or CEs. DESIGN: A retrospective chart review (2012-2017) of hospitalized patients ages 18-75 years who received a diagnosis of cancer and BMT or HSCT receiving rehabilitation services SETTING: Urban Midwest tertiary, research and academic hospital. PARTICIPANTS: In total, 99 hospitalized adults with HSCT or BMT participated in 300 rehabilitation sessions. INTERVENTIONS: Physical or occupational therapy using a symptom-based approach in which patient symptoms were monitored and therapy was adjusted in real time MAIN OUTCOME MEASURES: Incidence of AEs or CEs occurring during or within 48 hours of rehabilitation. RESULTS: A total of 300 rehabilitation sessions were carried out where 99.7% had 1 or more laboratory values outside reference range. In only 3.3% of therapy sessions an AE occurred during or within 2 hours of rehabilitation. Within 48 hours postrehabilitation, AEs occurred in 22.3% and CEs in 4%. No laboratory value was significantly associated with increased risk of AEs or CEs during rehabilitation. A hemoglobin <8.0 g/dL conferred an increased risk of AEs (odds ratio [OR], 2.85-6.89) depending on timeframe analyzed and overall risk of CE (OR, 3.75). Lower hemoglobin levels (<7.5 g/dL and <7.0 g/dL) did not increase this risk. Low platelets (<25 k/µL) increased the risk of AEs on day 1, 2 and overall (OR, 2.5-2.72) and overall risk of CEs (OR, 6.62). CONCLUSIONS: Our research demonstrates a low rate of AEs and CEs during or within 2 hours of rehabilitation but supports the need to monitor patients when hemoglobin is <8 g/dL or platelets are <25 k/µL due to the increased risk of events.

Identification and Characterization of Oral Injury in Suspected Child Abuse Cases: One Health System's Experience.

OBJECTIVES: Accurately differentiating inflicted from accidental injury in infants and toddlers is critical. Many studies have documented characteristics of inflicted bruises, fractures, and head injuries facilitating the development of clinical tools. There are few studies characterizing inflicted oral injuries, and no clinical tools exist. This study identified characteristics that differentiated inflicted from accidental oral injuries in children younger than 24 months. METHODS: Retrospective review using International Classification of Diseases, Ninth Revision billing codes and an internal clinical database tool identified children younger than 24 months between 2004 and 2014. Two groups were created according to the presence or absence of a child abuse diagnosis resulting in an accidental injury and suspected child abuse (SCA) group. Statistical analyses were performed on patient demographics, history of trauma, oral injury characterization, bruises, and fractures. RESULTS: Billing codes were applied differently between the accidental injury and SCA groups, even when the same injury was described. Patients with SCA were younger and less mobile when compared with those with accidental injuries (P < 0.0001). Tongue injuries (P < 0.0001) and oropharynx bruising (P = 0.0018) were observed more and lacerations were observed less (P < 0.0001) in the SCA group. The SCA group was less likely to have a trauma history than those with accidental injury (P < 0.0001). CONCLUSIONS: Several differences in patient characteristics, trauma history, injury type, and location were identified between the accidental versus SCA groups. A future clinical tool that incorporates age, history of trauma on presentation, tongue injury, and oropharynx bruising may assist medical providers in placing child physical abuse in the differential diagnosis.

Radiologic Assessment of Skull Fracture Healing in Young Children.

BACKGROUND: Skull fractures are commonly seen after both accidental and nonaccidental head injuries in young children. A history of recent trauma may be lacking in either an accidental or nonaccidental head injury event. Furthermore, skull fractures do not offer an indication of the stage of healing on radiologic studies because they do not heal with callus formation as seen with long bone fractures. Thus, a better understanding on the timing of skull fracture resolution may provide guidance on the medical evaluation for accidental or nonaccidental head injury. OBJECTIVE: The aim of the study was to determine the time required for radiographic skull fracture resolution in children younger than 24 months. METHODS: This was a retrospective observational analysis of children younger than 24 months referred with skull fractures between January 2008 and December 2012. Analysis included children with accidental head injuries with a known time interval since injury and a negative skeletal survey who underwent serial radiographic studies. Complete healing of a skull fracture was defined as resolution of fracture lucency by radiograph. RESULTS: Of the 26 children who met inclusion criteria, 11 (42.3%) demonstrated resolution of skull fracture(s) on follow-up imaging. Fracture resolution on radiologic studies ranged from 2 to 18 weeks. Twelve fractures in 10 children demonstrated fracture resolution at 10 or more weeks after injury. CONCLUSIONS: Healing or resolution of a skull fracture can take months in children younger than 24 months. With the high variability in skull fracture presentation and large window to fracture resolution, unexplained or multiple skull fractures in children younger than 24 months may be the result of a single or multiple events of head trauma.

The Alzheimer's disease transcriptome mimics the neuroprotective signature of IGF-1 receptor-deficient neurons.

Seminal studies using post-mortem brains of patients with Alzheimer's disease evidenced aberrant insulin-like growth factor 1 receptor (IGF1R) signalling. Addressing causality, work in animal models recently demonstrated that long-term suppression of IGF1R signalling alleviates Alzheimer's disease progression and promotes neuroprotection. However, the underlying mechanisms remain largely elusive. Here, we showed that genetically ablating IGF1R in neurons of the ageing brain efficiently protects from neuroinflammation, anxiety and memory impairments induced by intracerebroventricular injection of amyloid-ß oligomers. In our mutant mice, the suppression of IGF1R signalling also invariably led to small neuronal soma size, indicative of profound changes in cellular homeodynamics. To gain insight into transcriptional signatures leading to Alzheimer's disease-relevant neuronal defence, we performed genome-wide microarray analysis on laser-dissected hippocampal CA1 after neuronal IGF1R knockout, in the presence or absence of APP/PS1 transgenes. Functional analysis comparing neurons in early-stage Alzheimer's disease with IGF1R knockout neurons revealed strongly convergent transcriptomic signatures, notably involving neurite growth, cytoskeleton organization, cellular stress response and neurotransmission. Moreover, in Alzheimer's disease neurons, a high proportion of genes responding to Alzheimer's disease showed a reversed differential expression when IGF1R was deleted. One of the genes consistently highlighted in genome-wide comparison was the neurofilament medium polypeptide Nefm. We found that NEFM accumulated in hippocampus in the presence of amyloid pathology, and decreased to control levels under IGF1R deletion, suggesting that reorganized cytoskeleton likely plays a role in neuroprotection. These findings demonstrated that significant resistance of the brain to amyloid-ß can be achieved lifelong by suppressing neuronal IGF1R and identified IGF-dependent molecular pathways that coordinate an intrinsic program for neuroprotection against proteotoxicity. Our data also indicate that neuronal defences against Alzheimer's disease rely on an endogenous gene expression profile similar to the neuroprotective response activated by genetic disruption of IGF1R signalling. This study highlights neuronal IGF1R signalling as a relevant target for developing Alzheimer's disease prevention strategies.

Hypothalamic neurogenesis persists in the aging brain and is controlled by energy-sensing IGF-I pathway.

Hypothalamic tanycytes are specialized glial cells lining the third ventricle. They are recently identified as adult stem and/or progenitor cells, able to self-renew and give rise to new neurons postnatally. However, the long-term neurogenic potential of tanycytes and the pathways regulating lifelong cell replacement in the adult hypothalamus are largely unexplored. Using inducible nestin-CreER(T2) for conditional mutagenesis, we performed lineage tracing of adult hypothalamic stem and/or progenitor cells (HySC) and demonstrated that new neurons continue to be born throughout adult life. This neurogenesis was targeted to numerous hypothalamic nuclei and produced different types of neurons in the dorsal periventricular regions. Some adult-born neurons integrated the median eminence and arcuate nucleus during aging and produced growth hormone releasing hormone. We showed that adult hypothalamic neurogenesis was tightly controlled by insulin-like growth factors (IGF). Knockout of IGF-1 receptor from hypothalamic stem and/or progenitor cells increased neuronal production and enhanced α-tanycyte self-renewal, preserving this stem cell-like population from age-related attrition. Our data indicate that adult hypothalamus retains the capacity of cell renewal, and thus, a substantial degree of structural plasticity throughout lifespan.

Blocking IGF Signaling in Adult Neurons Alleviates Alzheimer's Disease Pathology through Amyloid-ß Clearance.

Alzheimer's disease (AD) is a frequent and irreversible age-related neurodegeneration without efficient treatment. Experimental AD in mice responds positively to decreased insulin-like growth factor I (IGF-I) signaling, a pathway also implicated in aging. Here we aimed to protect the aging brain from devastating amyloid pathology by making specifically adult neurons resistant to IGF signaling. To achieve that, we knocked out neuronal IGF-1R during adulthood in APP/PS1 mice. We found that mutants exhibited improved spatial memory and reduced anxiety. Mutant brains displayed fewer amyloid plaques, less amyloid-ß (Aß), and diminished neuroinflammation. Surprisingly, adult neurons undergoing IGF-1R knock-out reduced their apical soma and developed leaner dendrites, indicative of remarkable structural plasticity entailing condensed forebrain neuroarchitecture. Neurons lacking IGF-1R in AD showed less accumulation of Aß-containing autophagic vacuoles. At the same time, plasma Aß levels were increased. Our data indicate that neuronal IGF-1R ablation, via preserved autophagic compartment and enhanced systemic elimination, offers lifelong protection from AD pathology by clearing toxic Aß. Neuronal IGF-1R, and possibly other cell size-controlling pathways are promising targets for AD treatment. SIGNIFICANCE STATEMENT: We found compelling evidence in vivo that Alzheimer's disease (AD) progression is significantly delayed when insulin-like growth factor (IGF) signaling is blocked in adult neurons. To show that, we built a novel mouse model, combining inducible neuron-specific IGF-1R knock-out with AD transgenics. Analysis of the experimental AD phenotype revealed less abundant amyloid-ß (Aß) peptides, fewer plaques, and diminished neuroinflammation in mutants with inactivated IGF signaling, together with clearly preserved behavioral and memory performances. We present for the first time evidence that IGF signaling has profound effects on neuronal proteostasis and maintenance of cell morphology in vivo. Our results indicate in a model highly pertinent to translational research that neuronal IGF resistance may represent a pathophysiologically relevant mechanism of the brain for preventing Aß accumulation.

Maternal surfactant protein A influences the immunoprotective properties of milk in a murine model.

BACKGROUND: Maternal surfactant protein A (SP-A), a collectin with innate immune system function, is critical to newborn mouse survival preventing bacterial peritonitis associated with a nonhygienic environmental exposure. We hypothesized that SP-A improves newborn survival by optimizing milk immunoprotection. METHODS: Regional (lung) and systemic (milk and serum) immunologic responses to a novel antigen, 2,4-dintirophenyl keyhole limpet hemocyanin (DNP-KLH), and to a nonhygienic environment were evaluated in wild-type (WT) and SP-A null murine dams. Cross-fostering pups assessed the impact of milk on newborn survival. RESULTS: Maternal SP-A optimized antigen-specific milk secretory IgA (sIgA) production following the DNP-KLH exposure. Milk total and environment-specific sIgA production was not dependent on maternal SP-A in the nonhygienic exposure. At baseline, SP-A null milk contained physiologically meaningful increases in two proinflammatory cytokines compared with WT milk. The lack of SP-A plus the nonhygienic environmental exposure synergistically increased the number of proinflammatory cytokines contained in milk. Finally, the SP-A null genotype decreased pup survival during a nonhygienic environmental exposure. CONCLUSION: Maternal SP-A impacts milk sIgA and cytokine content, and is associated with improved newborn health.

Long-term use of ventricular assist device as a bridge to recovery in acute fulminant myocarditis.

We report the successful long-term use of a left ventricular assist device (Berlin EXCOR) as a bridge to recovery in a patient with fulminant parvovirus B19 myocarditis. The use of this device allowed time for myocardial recovery, avoiding the need for cardiac transplantation.

Endotoxin inhalation alters lung development in neonatal mice.

BACKGROUND: Childhood asthma is a significant public health problem. Epidemiologic evidence suggests an association between childhood asthma exacerbations and early life exposure to environmental endotoxin. Although the pathogenesis of endotoxin-induced adult asthma is well studied, questions remain about the impact of environmental endotoxin on pulmonary responsiveness in early life. METHODS: We developed a murine model of neonatal/juvenile endotoxin exposures approximating those in young children and evaluated the lungs inflammatory and remodeling responses. RESULTS: Persistent lung inflammation induced by the inhalation of endotoxin in early life was demonstrated by the influx of inflammatory cells and pro-inflammatory mediators to the airways and resulted in abnormal alveolarization. CONCLUSIONS: Results of this study advance the understanding of the impact early life endotoxin inhalation has on the lower airways, and demonstrates the importance of an experimental design that approximates environmental exposures as they occur in young children.

Active surveillance of small renal masses offers short-term oncological efficacy equivalent to radical and partial nephrectomy.

UNLABELLED: Study Type - Therapy (case series) Level of Evidence 4. What's known on the subject? and What does the study add? Active surveillance of small renal masses has traditionally been reserved for elderly patients deemed unfit for surgery or ablation. There is increasing evidence showing the safety of active surveillance in the management of small renal masses. In this retrospective study we compared outcomes for patients with small renal masses managed with active surveillance, radical nephrectomy and partial nephrectomy. We showed that active surveillance was safe and appeared as effective as immediate surgery in the management of small renal tumours. OBJECTIVE: • To compare the oncological outcomes of active surveillance (AS), radical nephrectomy (RN) and partial nephrectomy (PN) in the management of T1a small renal masses (SRMs). PATIENTS AND METHODS: • At present AS is used in the treatment of SRMs in elderly patients with multiple co-morbidities or in those who decline surgery. • We identified all patients with T1a SRMs managed with RN, PN or AS. • Retrospective data were collected from patient case records with survival data and cause of death cross-referenced with the Oxford Cancer Intelligence Unit. RESULTS: • A total of 202 patients with 234 T1a SRMs (solid or Bosniak IV) were identified; 71 patients were managed with AS, 41 with an RN and 90 by PN. • Over a median follow-up of 34 months the mean growth rate on AS was 0.21 cm/year with 53% of SRMs managed with AS showing negative or zero growth. • No statistically significant difference was observed in overall (OS) and cancer-specific (CSS) survival for AS, RN and PN (AS-CSS 98.6%, AS-OS 83%; RN-CSS 92.6%, RN-OS 80.4%; PN-CSS 96.6%, PN-OS 90.0%). CONCLUSIONS: • Active surveillance of SRMs offers oncological efficacy equivalent to surgery in the short/intermediate term. • The results of this study support a multicentre prospective randomized controlled trial designed to compare the oncological efficacy of AS and surgery.

Surfactant-associated protein A provides critical immunoprotection in neonatal mice.

The collectins surfactant-associated protein A (SP-A) and SP-D are components of innate immunity that are present before birth. Both proteins bind pathogens and assist in clearing infection. The significance of SP-A and SP-D as components of the neonatal immune system has not been investigated. To determine the role of SP-A and SP-D in neonatal immunity, wild-type, SP-A null, and SP-D null mice were bred in a bacterium-laden environment (corn dust bedding) or in a semisterile environment (cellulose fiber bedding). When reared in the corn dust bedding, SP-A null pups had significant mortality (P < 0.001) compared to both wild-type and SP-D null pups exposed to the same environment. The mortality of the SP-A null pups was associated with significant gastrointestinal tract pathology but little lung pathology. Moribund SP-A null newborn mice exhibited Bacillus sp. and Enterococcus sp. peritonitis. When the mother or newborn produced SP-A, newborn survival was significantly improved (P < 0.05) compared to the results when there was a complete absence of SP-A in both the mother and the pup. Significant sources of SP-A likely to protect a newborn include the neonatal lung and gastrointestinal tract but not the lactating mammary tissue of the mother. Furthermore, exogenous SP-A delivered by mouth to newborn SP-A null pups with SP-A null mothers improved newborn survival in the corn dust environment. Therefore, a lack of SP-D did not affect newborn survival, while SP-A produced by either the mother or the pup or oral exogenous SP-A significantly reduced newborn mortality associated with environmentally induced infection in SP-A null newborns.

Galectin-1 in secondary alveolar septae of neonatal mouse lung.

In mice, alveolarization occurs during postnatal days 4 through 12, when secondary alveolar septae create thin-walled alveoli in the distal lung. We hypothesized that genes predominantly expressed in newly forming secondary alveolar septae influence the process of alveolarization. To address this hypothesis, tips of secondary alveolar septae were isolated from sections of postnatal day 6 mouse lung tissue using laser capture microdissection. Total RNA was isolated and amplified from the dissected alveolar septal tips and from intact postnatal day 6 lung tissue. Gene expression in the samples was characterized using Affymetrix mouse U74AN2 GeneChips. Galectin-1 was an abundantly expressed transcript that was enriched in the alveolar septal tips compared with levels in the whole lung tissue. Galectins are beta-galactoside-binding proteins involved in the regulation of cell proliferation, differentiation, and apoptosis in fibroblasts, muscle cells and endothelial cells, cell types that are present in the alveolar wall. Immunostaining in postnatal day 6 lung tissue confirmed that galectin-1 protein is concentrated in the tips of secondary alveolar septae, predominantly in myofibroblasts. Fibroblasts isolated from day 6 neonatal mouse lung tissue contained galectin-1 protein. Real-time PCR demonstrated that galectin-1 mRNA levels in mouse lung tissue peak at postnatal day 6. Immunoblot analysis confirmed that peak levels of lung galectin-1 protein are found at postnatal days 6 to 12. The increased expression of galectin-1 at the site and time of ongoing alveolarization in the newborn mouse is suggestive that galectin-1 may play an important role in this critical aspect of lung development.

Early exposure to a nonhygienic environment alters pulmonary immunity and allergic responses.

The hygiene hypothesis suggests that early life exposure to a nonhygienic environment that contains endotoxin reduces the risk of developing allergic diseases. The mechanisms underlying the hygiene hypothesis are unclear and may involve subtle immune system interactions that occur during maturation. Experimental objectives of this study were to use a novel animal model to test the hygiene hypothesis and to characterize early life immune system responses to a nonhygienic environment. Mice were reared in corn dust, a grain-processing byproduct with a high-endotoxin content and microbial products or in a low-endotoxin environment. The influence of early or later life exposure to corn dust on a subsequent allergen stimulus (ovalbumin) was assessed by bronchoalveolar lavage (BAL) cell analysis, lung histology, serum IgE, and BAL cytokine measurements. The influence of the corn dust environment on the developing pulmonary immune system was assessed by BAL cell analysis and immunostaining of lung tissue. The corn dust environment contained significantly more endotoxin (P < 0.001), and the dust exposures attenuated the cellular inflammatory response to ovalbumin in the adult mouse (P < 0.01) but did not reduce serum IgE levels or alter baseline BAL fluid proinflammatory cytokine levels. The corn dust environment did not induce significant neutrophilia in lavage fluid but significantly increased the number of antigen-presenting cells in alveolar walls early in life by approximately 37%. In conclusion, exposure to a nonhygienic environment did not induce significant airway neutrophilia, yet altered the population of immunologically active cells in the lung and reduced subsequent allergic inflammation.