Fumarate induces vesicular release of mtDNA to drive innate immunity.

Mutations in fumarate hydratase (FH) cause hereditary leiomyomatosis and renal cell carcinoma1. Loss of FH in the kidney elicits several oncogenic signalling cascades through the accumulation of the oncometabolite fumarate2. However, although the long-term consequences of FH loss have been described, the acute response has not so far been investigated. Here we generated an inducible mouse model to study the chronology of FH loss in the kidney. We show that loss of FH leads to early alterations of mitochondrial morphology and the release of mitochondrial DNA (mtDNA) into the cytosol, where it triggers the activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)-TANK-binding kinase 1 (TBK1) pathway and stimulates an inflammatory response that is also partially dependent on retinoic-acid-inducible gene I (RIG-I). Mechanistically, we show that this phenotype is mediated by fumarate and occurs selectively through mitochondrial-derived vesicles in a manner that depends on sorting nexin 9 (SNX9). These results reveal that increased levels of intracellular fumarate induce a remodelling of the mitochondrial network and the generation of mitochondrial-derived vesicles, which allows the release of mtDNAin the cytosol and subsequent activation of the innate immune response.

Microbiome modulates immunotherapy response in cutaneous squamous cell carcinoma.

The gut microbiome is increasingly recognized to alter cancer risk, progression and response to treatments such as immunotherapy, especially in cutaneous melanoma. However, whether the microbiome influences immune checkpoint inhibitor (ICI) immunotherapy response to non-melanoma skin cancer has not yet been defined. As squamous cell carcinomas (SCC) are in closest proximity to the skin microbiome, we hypothesized that the skin microbiome, which regulates cutaneous immunity, might affect SCC-associated anti-PD1 immunotherapy treatment response. We used ultraviolet radiation to induce SCC in SKH1 hairless mice. We then treated the mice with broad-band antibiotics to deplete the microbiome, followed by colonisation by candidate skin and gut bacteria or persistent antibiotic treatment, all in parallel with ICI treatment. We longitudinally monitored skin and gut microbiome dynamics by 16S rRNA gene sequencing and tumour burden by periodic tumour measurements and histologic assessment. Our study revealed that antibiotics-induced abrogation of the microbiome reduced the tumour burden, suggesting a functional role of the microbiome in non-melanoma skin cancer therapy response.

The "Syringe Hickey": An Alternative Skin Marking Method for Lumbar Puncture.

BACKGROUND: Lumbar puncture is a procedure that is commonly performed in emergency departments. Despite their absence from procedure kits, emergency physicians often use skin markers to delineate landmarks for a lumbar puncture. We prefer to create a temporary indentation in the skin using the suction of a syringe. This "syringe hickey" eliminates the need for a skin marker. DISCUSSION: We created a photo demonstration comparing the syringe hickey to a skin marker for site marking. The syringe hickey was created using a 10-mL syringe aspirated to 5 mL on the forearm for 1 min. The syringe hickey lasted over 30 min on a range of skin tones across the Fitzpatrick Scale. The skin marker faded but the syringe hickey maintained its definition after application of ultrasound gel and sterilization with either chlorhexidine or betadine. CONCLUSIONS: The syringe hickey is a simple skin marking technique that is resistant to antiseptic agents and ultrasound gel. The syringe hickey may be useful for other procedures that require puncture site marking.

Arterial Line Placement Pitfalls Can Be Demonstrated and Visualized With an Inexpensive, Wearable Trainer.

BACKGROUND: Radial arterial line placement is commonly performed in various clinical settings, including the emergency department. However, learners are successful on the first attempt only half of the time. Simulation can provide learners with procedure practice opportunities outside of clinical practice to increase confidence and chances of success. OBJECTIVES: We set out to build an arterial line trainer that would be inexpensive and reusable, wearable, anatomically realistic, and echogenic to allow for ultrasound use. We also hoped to devise a clear option that would allow for demonstration of procedure pitfalls. DISCUSSION: The arterial line trainer requires 4 hours of assembly time and costs $160. This includes enough material to make 48 tissue pads. The ballistics gel pad is echogenic; it can be customized with clear gel for direct anatomic visualization or dyed gel for more realism. The trainer also has a pulsatile artery for practice using anatomic landmarks. Visualization of the following important arterial line placement pitfalls is possible: suboptimal angle of approach, inadequate advancement of the catheter, and through-and-through vessel puncture. CONCLUSIONS: Our inexpensive trainer can help physicians and physicians in training conceptualize, practice, and troubleshoot the pitfalls of arterial line placement. Training programs looking to help learners understand the mechanics of arterial line placement may find it a useful tool.

Clinical Presentation of Toddlers With New Intracranial Space-Occupying Lesions: A Case Series.

OBJECTIVE: Intracranial space occupying lesions (ICSOLs) like tumors and abscesses can be life-threatening conditions. It can be especially difficult to diagnose these conditions in toddlers. We aimed to describe symptoms and signs present in a sample of toddlers with ICSOLs. METHODS: We performed a retrospective chart review of 15 toddlers with intracranial tumors, abscesses, or infected cysts. We collected data on the presence of various signs and symptoms on presentation to the emergency department. RESULTS: Eight toddlers (53%) presented with vomiting. A change in behavior was the second most common symptom (6, 40%). Seven children (47%) had motor weakness, and 5 (33%) had ataxia. Eleven of the 12 children with tumors (92%) had documented abnormal neurologic signs on initial physical examination. CONCLUSIONS: Vomiting, a change in behavior, and an abnormal neurologic examination were common signs and symptoms in our sample of toddlers with ICSOLs. An accurate history and appropriate neurologic examination can help physicians make this challenging diagnosis in this age group.

Development of a Programme Theory for Early Intervention Vocational Rehabilitation: A Realist Literature Review.

Purpose Little is currently known about how early intervention vocational rehabilitation (EIVR) works for people with newly acquired neurological conditions such as traumatic brain injury, acquired brain injury and spinal cord injury. This study aims, from a realist framework, to identify relevant literature and develop an initial programme theory to understand how EIVR might work for people experiencing acquired neurological disability. Realist reviews are ideally placed to address the identified knowledge gap as they assist in gaining a deeper understanding of how the intervention works, for whom it works best, and the contexts that promote the activation of desired outcomes. Methods We used a seven-step iterative process to synthesise literature using a realist approach. The steps included: development of initial programme theory, literature search, article selection, extracting and data organising, synthesis of evidence and programme theory refinement. We performed a literature search using the following databases: Cinahl, Embase, EMcare, Medline, PsychInfo and Scopus. Articles were selected if they contributed to the knowledge describing what is EIVR and how it works in newly acquired neurological conditions. Data were extracted and synthesised to develop a programme theory for EIVR. Results Following screening of 448 references, 37 documents were eligible for data extraction. We developed a refined programme theory of EIVR consisting of three contexts (prioritisation of exploring work options, return to work discussed as an option, and workplace support), nine mechanisms (ensuring rehabilitation teams' culture, fostering hope, exploring options, optimising self-efficacy, maintaining worker identity, staying connected, setting goals, engaging employer, and flexing roles) and three outcomes (confidence in ability to work, psychological adjustment, and engagement in solution focussed options). Conclusions This appears to be the first paper to explore how EIVR works, for whom and in what situations. We have produced a programme theory that may provide an initial understanding of EIVR following acquired neurological conditions.

Emergency Department Thoracotomy: A Cost-Effective Model for Simulation Training.

BACKGROUND: Simulation provides a safe learning environment where high-stakes, low-frequency procedures can be practiced without the fear of being unsuccessful or causing harm. Emergency department thoracotomy (EDT) is one such procedure. Realistic thoracotomy models are expensive and not readily available. OBJECTIVE: Our objective is to describe a cost-effective, realistic, reproducible, and reusable thoracotomy model for simulation training. METHODS: We modified a commercially available clothes mannequin torso to expose the chest and abdominal cavity. A plastic skeleton composed of a spinal cord and ribs was placed inside the torso. Tubing was used to simulate the aorta and esophagus; both tubes were secured to the distal spine with zip ties. Commercially available lungs and heart were placed inside the chest cavity. A small rubber ball simulated the left lung to be able to maneuver the lung. The heart was covered with plastic wrap to simulate the pericardium. Thick tape was used to simulate the pleural cavity. Yoga mats were used to simulate the intercostal muscles, subcutaneous tissue, and skin. RESULTS: This model was tested with Emergency Medicine (EM) residents during a simulation session. A voluntary survey was available for residents to provide feedback. Survey results confirmed that the model provided valuable education, with overall positive feedback. CONCLUSION: This EDT model provides a valuable teaching opportunity to EM residents who otherwise might not have the opportunity to perform this procedure. Residents agreed that the model improved their confidence and is an effective method in providing the opportunity to practice this low-frequency, high-stakes procedure.

The Effect of Medical Marijuana Laws on Body Weight.

This study is the first to examine the effects of medical marijuana laws (MMLs) on body weight, physical wellness, and exercise. Using data from the 1990 to 2012 Behavioral Risk Factor Surveillance System and a difference-in-difference approach, we find that the enforcement of MMLs is associated with a 2% to 6% decline in the probability of obesity. We find some evidence of age-specific heterogeneity in mechanisms. For older individuals, MML-induced increases in physical mobility may be a relatively important channel, while for younger individuals, a reduction in consumption of alcohol, a substitute for marijuana, appears more important. These findings are consistent with the hypothesis that MMLs may be more likely to induce marijuana use for health-related reasons among older individuals, and cause substitution toward lower-calorie recreational 'highs' among younger individuals. Our estimates suggest that MMLs induce a $58 to $115 per-person annual reduction in obesity-related medical costs. Copyright © 2015 John Wiley & Sons, Ltd.

An Inexpensive Esophageal Balloon Tamponade Trainer.

BACKGROUND: Emergency medicine practitioners must be able to perform rare, life-saving procedures. One such example is esophageal balloon tamponade, which is complex, fraught with complications, and difficult to demonstrate and practice. DISCUSSION: We constructed a simple, inexpensive model esophagus and stomach that we attached to a mannequin, allowing emergency medicine residents to visualize and practice esophageal balloon tamponade device placement. CONCLUSION: Our esophageal balloon tamponade model was easy to construct and allowed demonstration, conceptual visualization, and simulated performance of the procedure.

Effect of Educational Debt on Emergency Medicine Residents: A Qualitative Study Using Individual Interviews.

STUDY OBJECTIVE: In 2001, less than 20% of emergency medicine residents had more than $150,000 of educational debt. Our emergency medicine residents anecdotally reported much larger debt loads. Surveys have reported that debt affects career and life choices. Qualitative approaches are well suited to explore how and why such complex phenomena occur. We aim to gain a better understanding of how our emergency medicine residents experience debt. METHODS: We conducted individual semistructured interviews with emergency medicine residents. We collected self-reported data related to educational debt and asked open-ended questions about debt influence on career choices, personal life, future plans, and financial decisions. We undertook a structured thematic analysis using a qualitative approach based in the grounded theory method. RESULTS: Median educational debt was $212,000. Six themes emerged from our analysis: (1) debt influenced career and life decisions by altering priorities; (2) residents experienced debt as a persistent source of background stress and felt powerless to change it; (3) residents made use of various techniques to negotiate debt in order to focus on day-to-day work; (4) personal debt philosophy, based on individual values and obtained from family, shaped how debt affected each individual; (5) debt had a normative effect and was acculturated in residency; and (6) residents reported a wide range of financial knowledge, but recognized its importance to career success. CONCLUSION: Our emergency medicine residents' debt experience is complex and involves multiple dimensions. Given our current understanding, simple solutions are unlikely to be effective in adequately addressing this issue.

Pediatric acute osteomyelitis in the postvaccine, methicillin-resistant Staphylococcus aureus era.

OBJECTIVE: We sought to describe the causative organisms, bones involved, and complications in cases of pediatric osteomyelitis in the postvaccine age and in the era of increasing infection with community-associated methicillin-resistant Staphylococcus aureus (MRSA). METHODS: We reviewed the medical records of children 12 years and younger presenting to our pediatric emergency department between January 1, 2003, and December 31, 2012, with the diagnosis of osteomyelitis. We reviewed operative cultures, blood cultures, and imaging studies. We identified causative organisms, bone(s) involved, time to therapeutic antibiotic treatment, and local and hematogenous complications. RESULTS: The most common organism identified was methicillin-sensitive S aureus (26/55), followed by MRSA (21/55). Seventy-three bone areas were affected in 67 subjects. The most common bone area was the femur (24/73). Forty-six subjects had 75 local complications. The most common organism in cases with local complications was MRSA (49%). Three subjects had hematogenous complications of deep venous thrombosis, septic pulmonary embolus, and endophthalmitis. Subjects with complications had shorter time to therapeutic antibiotic treatment. When an operative culture was done after therapeutic antibiotics were given, an organism was identified from the operative culture in 84% of cases. CONCLUSION: Treatment of pediatric osteomyelitis should include antibiotic coverage for MRSA. Most cases of pediatric osteomyelitis occur in the long bones. Hematogenous complications may include deep venous thrombosis and may be related to treatment with a central venous catheter. Operative culture yield when antibiotics have already been given is high, and antibiotic treatment should not be delayed until operative cultures are obtained.

Ten-m2 is required for the generation of binocular visual circuits.

Functional binocular vision requires that inputs arising from the two retinae are integrated and precisely organized within central visual areas. Previous studies have demonstrated an important role for one member of the Ten-m/Odz/teneurin family, Ten-m3, in the mapping of ipsilateral retinal projections. Here, we have identified a distinct role for another closely related family member, Ten-m2, in the formation of the ipsilateral projection in the mouse visual system. Ten-m2 expression was observed in the retina, dorsal lateral geniculate nucleus (dLGN), superior colliculus (SC), and primary visual cortex (V1) of the developing mouse. Anterograde and retrograde tracing experiments in Ten-m2 knock-out (KO) mice revealed a specific decrease in ipsilateral retinal ganglion cells projecting to dLGN and SC. This reduction was most prominent in regions corresponding to ventral retina. No change in the topography of ipsilateral or contralateral projections was observed. While expression of a critical ipsilateral fate determinant, Zic2, appeared unaltered, a notable reduction in one of its downstream targets, EphB1, was observed in ventral retina, suggesting that Ten-m2 may interact with this molecular pathway. Immunohistochemistry for c-fos, a neural activity marker, revealed that the area of V1 driven by ipsilateral inputs was reduced in KOs, while the ratio of ipsilateral-to-contralateral responses contributing to binocular activation during visually evoked potential recordings was also diminished. Finally, a novel two-alternative swim task revealed specific deficits associated with dorsal visual field. These data demonstrate a requirement for Ten-m2 in the establishment of ipsilateral projections, and thus the generation of binocular circuits, critical for mammalian visual function.

Finger counting: an alternative method for estimating pediatric weights.

OBJECTIVES: We compared the accuracy of a conceptually simple pediatric weight estimation technique, the finger counting method, with other commonly used methods. METHODS: We prospectively collected cross-sectional data on a convenience sample of 207 children aged 1 to 9 presenting to our pediatric emergency department. Bland-Altman plots were constructed to compare the finger counting method to the Broselow tape method, parental estimate, the Luscombe formula, and the advanced pediatric life support (APLS) formula. Proportions within 10% and 20% of measured weight were compared. RESULTS: Mean difference and range of agreement in kilograms for Bland-Altman plots were as follows: -1.8 (95% confidence interval [CI], -2.3 to -1.3) and 15.4 (95% CI, 13.6-17.2) for the finger counting method; -1.4 (95% CI, -2.0 to -0.9) and 15.8 (95% CI, 13.9-17.6) for the Broselow method; -0.02 (95% CI, -0.53 to 0.49) and 14.8 (95% CI, 13-16.6) for parental estimate; 0.2 (95% CI, -0.33 to 0.72) and 15.3 (95% CI, 13.5-17.2) for the Luscombe formula; and -3.8 (95% CI, -4.4 to -3.2) and 17.2 (95% CI, 15.2-19.2) for the APLS formula. The finger counting method estimated weights within 10% in 59% of children (95% CI, 52%-65%) and within 20% in 87% of children (95% CI, 81%-91%). Proportions within 10% were similar for all methods, except the APLS method, which was lower. CONCLUSIONS: The finger counting method is an acceptable alternative to the Broselow method for weight estimation in children aged 1 to 9 years. It outperforms the traditional APLS method but underestimates weights compared with parental estimate and the Luscombe formula.

Pediatric procedural sedation with propofol using a higher initial bolus dose.

OBJECTIVES: We sought to describe the doses of propofol used for sedation in our pediatric emergency department, along with the range of procedures performed under propofol sedation. We also planned to describe clinically important physiologic changes seen and physician satisfaction with propofol at the doses observed. METHODS: This was a prospective observational case series. Physicians completed a data collection form after the propofol sedation. The physicians were asked to report physiologic changes that occurred during sedation and rate their satisfaction with propofol as a sedation agent on a 100-mm visual analog scale. RESULTS: Eight hundred eighty-six sedation events were reported. The median initial dose of propofol given was 2.0 mg/kg and the median total dose was 3.6 mg/kg. Propofol was used for a wide range of procedures. The most common physiologic change was desaturation/hypoxia (desaturation to <90% in 7.2%). No deaths, unplanned intubations, or surgical airway placements were reported. Treating physicians reported a median satisfaction score of 97 mm. CONCLUSIONS: A 2-mg/kg initial bolus dose of propofol for pediatric sedation was well tolerated and useful for a wide range of procedures. Physicians should expect to find a high level of satisfaction with this dose.

Caring for the caregiver in dementia.

Caregiver stress is higher for dementia caregiving than other types. By focusing on the family, FPs can help to ease the burden.