Beyond the Do-not-resuscitate Order: An Expanded Approach to Decision-making Regarding Cardiopulmonary Resuscitation in Older Surgical Patients.

American Society of Anesthesiologists guidelines recommend that anesthesiologists revisit do-not-resuscitate orders preoperatively and revise them if necessary based on patient preferences. In patients without do-not-resuscitate orders or other directives limiting treatment however, "full code" is the default option irrespective of clinical circumstances and patient preferences. It is time to revisit this approach based on (1) increasing understanding of the power of default options in healthcare settings, (2) changing demographics and growing evidence suggesting that an expanding subset of patients is vulnerable to poor outcomes after perioperative cardiopulmonary resuscitation (CPR), and (3) recommendations from multiple societies promoting risk assessment and goal-concordant care in older surgical patients. The authors reconsider current guidelines in the context of these developments and advocate for an expanded approach to decision-making regarding CPR, which involves identifying high-risk elderly patients and eliciting their preferences regarding CPR irrespective of existing or presumed code status.

A polarity pathway for exocyst-dependent intracellular tube extension.

Lumen extension in intracellular tubes can occur when vesicles fuse with an invading apical membrane. Within the Caenorhabditis elegans excretory cell, which forms an intracellular tube, the exocyst vesicle-tethering complex is enriched at the lumenal membrane and is required for its outgrowth, suggesting that exocyst-targeted vesicles extend the lumen. Here, we identify a pathway that promotes intracellular tube extension by enriching the exocyst at the lumenal membrane. We show that PAR-6 and PKC-3/aPKC concentrate at the lumenal membrane and promote lumen extension. Using acute protein depletion, we find that PAR-6 is required for exocyst membrane recruitment, whereas PAR-3, which can recruit the exocyst in mammals, appears dispensable for exocyst localization and lumen extension. Finally, we show that CDC-42 and RhoGEF EXC-5/FGD regulate lumen extension by recruiting PAR-6 and PKC-3 to the lumenal membrane. Our findings reveal a pathway that connects CDC-42, PAR proteins, and the exocyst to extend intracellular tubes.

Influenza spread on context-specific networks lifted from interaction-based diary data.

Studying the spread of infections is an important tool in limiting or preventing future outbreaks. A first step in understanding disease dynamics is constructing networks that reproduce features of real-world interactions. In this paper, we generate networks that maintain some features of the partial interaction networks that were recorded in an existing diary-based survey at the University of Warwick. To preserve realistic structure in our artificial networks, we use a context-specific approach. In particular, we propose different algorithms for producing larger home, work and social networks. Our networks are able to maintain much of the interaction structure in the original diary-based survey and provide a means of accounting for the interactions of survey participants with non-participants. Simulating a discrete susceptible-infected-recovered model on the full network produces epidemic behaviour which shares characteristics with previous influenza seasons. Our approach allows us to explore how disease transmission and dynamic responses to infection differ depending on interaction context. We find that, while social interactions may be the first to be reduced after influenza infection, limiting work and school encounters may be significantly more effective in controlling the overall severity of the epidemic.

Cdc42 regulates junctional actin but not cell polarization in the Caenorhabditis elegans epidermis.

During morphogenesis, adherens junctions (AJs) remodel to allow changes in cell shape and position while preserving adhesion. Here, we examine the function of Rho guanosine triphosphatase CDC-42 in AJ formation and regulation during Caenorhabditis elegans embryo elongation, a process driven by asymmetric epidermal cell shape changes. cdc-42 mutant embryos arrest during elongation with epidermal ruptures. Unexpectedly, we find using time-lapse fluorescence imaging that cdc-42 is not required for epidermal cell polarization or junction assembly, but rather is needed for proper junctional actin regulation during elongation. We show that the RhoGAP PAC-1/ARHGAP21 inhibits CDC-42 activity at AJs, and loss of PAC-1 or the interacting linker protein PICC-1/CCDC85A-C blocks elongation in embryos with compromised AJ function. pac-1 embryos exhibit dynamic accumulations of junctional F-actin and an increase in AJ protein levels. Our findings identify a previously unrecognized molecular mechanism for inhibiting junctional CDC-42 to control actin organization and AJ protein levels during epithelial morphogenesis.

The Role of a Hospital Ethics Consultation Service in Decision-Making for Unrepresented Patients.

Despite increased calls for hospital ethics committees to serve as default decision-makers about life-sustaining treatment (LST) for unrepresented patients who lack decision-making capacity or a surrogate decision-maker and whose wishes regarding medical care are not known, little is known about how committees currently function in these cases. This was a retrospective cohort study of all ethics committee consultations involving decision-making about LST for unrepresented patients at a large academic hospital from 2007 to 2013. There were 310 ethics committee consultations, twenty-five (8.1 per cent) of which involved unrepresented patients. In thirteen (52.0 per cent) cases, the ethics consultants evaluated a possible substitute decision-maker identified by social workers and/or case managers. In the remaining cases, the ethics consultants worked with the medical team to contact previous healthcare professionals to provide substituted judgement, found prior advance care planning documents, or identified the patient's best interest as the decision-making standard. In the majority of cases, the final decision was to limit or withdraw LST (72 per cent) or to change code status to Do Not Resuscitate/Do Not Intubate (12 per cent). Substitute decision-makers who had been evaluated through the ethics consultation process and who made the final decision alone were more likely to continue LST than cases in which physicians made the final decision (50 per cent vs 6.3 per cent, p = 0.04). In our centre, the primary role of ethics consultants in decision-making for unrepresented patients is to identify appropriate decision-making standards. In the absence of other data suggesting that ethics committees, as currently constituted, are ready to serve as substitute decision-makers for unrepresented patients, caution is necessary before designating these committees as default decision-makers.

Graded effects of unregulated smooth muscle myosin on intestinal architecture, intestinal motility and vascular function in zebrafish.

Smooth muscle contraction is controlled by the regulated activity of the myosin heavy chain ATPase (Myh11). Myh11 mutations have diverse effects in the cardiovascular, digestive and genitourinary systems in humans and animal models. We previously reported a recessive missense mutation, meltdown (mlt), which converts a highly conserved tryptophan to arginine (W512R) in the rigid relay loop of zebrafish Myh11. The mlt mutation disrupts myosin regulation and non-autonomously induces invasive expansion of the intestinal epithelium. Here, we report two newly identified missense mutations in the switch-1 (S237Y) and coil-coiled (L1287M) domains of Myh11 that fail to complement mlt Cell invasion was not detected in either homozygous mutant but could be induced by oxidative stress and activation of oncogenic signaling pathways. The smooth muscle defect imparted by the mlt and S237Y mutations also delayed intestinal transit, and altered vascular function, as measured by blood flow in the dorsal aorta. The cell-invasion phenotype induced by the three myh11 mutants correlated with the degree of myosin deregulation. These findings suggest that the vertebrate intestinal epithelium is tuned to the physical state of the surrounding stroma, which, in turn, governs its response to physiologic and pathologic stimuli. Genetic variants that alter the regulation of smooth muscle myosin might be risk factors for diseases affecting the intestine, vasculature, and other tissues that contain smooth muscle or contractile cells that express smooth muscle proteins, particularly in the setting of redox stress.

Treatment of facet cysts associated with neurogenic intermittent claudication with x-stop.

BACKGROUND: Facet degeneration often leads to the formation of synovial facet cysts. As facet cysts invade the spinal canal, they become a contributing factor to spinal stenosis. Previous studies have demonstrated successful treatment of neurogenic intermittent claudication (NIC), a major symptom of spinal stenosis, with an interspinous process device. PURPOSE: To compare clinical outcomes of patients with and without synovial facet cysts treated with an interspinous process device. STUDY DESIGN: Retrospective review of prospective data of consecutive patients undergoing the X-Stop procedure at an institution. OUTCOME MEASURES: Visual Analog Scale; Oswestry Disability Index; sitting, standing, and walking tolerances; and satisfaction survey. METHODS: Review of all patients from 2006 to 2010 undergoing X-Stop procedure at an institution. Imaging studies were used to identify the presence and measure the size of the facet cysts in 285 patients with a minimum of 6-month follow-up. Comparative clinical outcomes determined if X-Stop is a successful treatment option for patients with NIC in conjunction with synovial facet cysts (<3 mm, ≥3 mm). RESULTS: Fifty-eight of 285 patients (20.4%) were determined to have a synovial cyst as a contributing component of spinal stenosis. Twelve of 58 patients were noted to have a cyst ≥3 mm. The mean follow-up time for patients with and without a facet cyst was 21 months (6-55±12 mo) and 22 months (6-61±12 mo), respectively. The age of the patient at the time of the operation with and without facet cysts was 73 (±10 y). Patients without synovial cysts, with synovial cysts, and cysts ≥3 mm had an average change in Oswestry Disability Index of 15.6, 15.8, and 16.2, respectively. Visual Analog Scale scores were 2.3, 1.8, and 2.3, respectively. In addition, on satisfaction surveys 72.4%, 82.0%, and 77.8% were either very or somewhat satisfied, respectively. Overall complications included 4 spinous process fracture, 4 hematomas, 1 wound infection, and 1 implant migration. CONCLUSIONS: No statistical difference was noted in any of the outcome measures among patients with small facet cysts, large facet cysts, or without facet cysts when treated with an interspinous process device. We can thus conclude that X-Stop is an appropriate treatment consideration for NIC with or without the presence of synovial facet cysts.

Smooth muscle tension induces invasive remodeling of the zebrafish intestine.

The signals that initiate cell invasion are not well understood, but there is increasing evidence that extracellular physical signals play an important role. Here we show that epithelial cell invasion in the intestine of zebrafish meltdown (mlt) mutants arises in response to unregulated contractile tone in the surrounding smooth muscle cell layer. Physical signaling in mlt drives formation of membrane protrusions within the epithelium that resemble invadopodia, matrix-degrading protrusions present in invasive cancer cells. Knockdown of Tks5, a Src substrate that is required for invadopodia formation in mammalian cells blocked formation of the protrusions and rescued invasion in mlt. Activation of Src-signaling induced invadopodia-like protrusions in wild type epithelial cells, however the cells did not migrate into the tissue stroma, thus indicating that the protrusions were required but not sufficient for invasion in this in vivo model. Transcriptional profiling experiments showed that genes responsive to reactive oxygen species (ROS) were upregulated in mlt larvae. ROS generators induced invadopodia-like protrusions and invasion in heterozygous mlt larvae but had no effect in wild type larvae. Co-activation of oncogenic Ras and Wnt signaling enhanced the responsiveness of mlt heterozygotes to the ROS generators. These findings present the first direct evidence that invadopodia play a role in tissue cell invasion in vivo. In addition, they identify an inducible physical signaling pathway sensitive to redox and oncogenic signaling that can drive this process.

Arachnoid ossificans containing metaplastic hematopoietic marrow resulting in diffuse thoracic intrathecal cysts and severe myelopathy.

OBJECTIVE: To present a rare case of multiple compressive thoracic intradural cysts with pathologic arachnoid ossification, review the literature and present the surgical options. Few reports have identified the existence of arachnoid calcifications and intrathecal cysts causing progressive myelopathy. The literature regarding each of these pathologies is limited to case reports. Their clinical significance is not well studied, although known to cause neurologic sequelae. METHODS: An 81-year-old female clinically presents with rapidly progressive myelopathy. Pre-operative magnetic resonance imaging identified multiple compressive thoracic intrathecal cysts. Surgical exploration and decompression of these cysts identified calcified plaques within the arachnoid. Histopathologic examination revealed fibrocalcific tissue undergoing ossification with bone marrow elements. RESULTS: Due to progressive myelopathy, the thoracic cysts were decompressed and calcified plaques were excised, once identified intra-operatively. CONCLUSIONS: On last examination, the patient's neurologic status had not improved, but had stabilized. The rate of neurologic improvement from excision and decompression is variable, but it may still be warranted in the face of progressive neurologic deficits.

Complications of the lateral transpsoas approach for lumbar interbody arthrodesis: a case series and literature review.

BACKGROUND: The lateral transpsoas approach to the lumbar spine was developed to eliminate the need for an anterior-approach surgeon and retraction of the great vessels and has the potential for shorter operative times. However, the reported complications associated with this approach vary. QUESTIONS/PURPOSES: We identified the incidence of complications associated with the lateral transpsoas approach to the lumbar spine. PATIENTS AND METHODS: We retrospectively reviewed 45 patients who underwent a lateral transpsoas approach to the spine for various diagnoses between January 1, 2006, and October 31, 2010. The patients' average age was 63.3 years. Sixteen (35.6%) patients had prior lumbar spinal surgery. Twenty-one patients (46.7%) underwent supplemental posterior instrumentation. Minimum followup was 0 months (mean, 11 months; range, 0-34 months). RESULTS: Eighteen of the 45 patients (40%) had complications: 10 (22.2%) developed postoperative iliopsoas weakness, three had quadriceps weakness, and one experienced foot drop. Eight patients (17.8%) developed anterior thigh hypoesthesia, which did not fully resolve in seven of the eight patients at an average of 9 months' followup. Three patients had postoperative radiculopathies, one a durotomy, and one died postoperatively from a pulmonary embolism. CONCLUSIONS: We found a 40% incidence of complications and a nontrivial frequency and severity of postoperative weakness, numbness, and radicular pain in patients who underwent a lateral transpsoas approach to the spine. Given the expanding use of the approach, a thorough understanding of the risks associated with it is essential for patient education, medical decision making, and identifying methods of reducing such complications. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.

Documentation of decision-making capacity, informed consent, and health care proxies: a study of surrogate consent.

BACKGROUND: Patients in the general hospital are routinely asked to make decisions about their medical care. However, some of them are unable to express a choice, understand the information provided, weigh the options, or make a decision for themselves; when this occurs, the task of making an appropriate medical decision is left to another-a substitute decision-maker (SDM). OBJECTIVE: We sought to understand the practice patterns surrounding surrogate consent. We hypothesized that SDMs would be used frequently for patients with an altered mental status (AMS) but that there would be insufficient documentation of health care proxies (HCP) and of clinician assessment of a patient's decision-making capacity. METHODS: A retrospective chart review was conducted on inpatients who underwent a lumbar puncture. The review assessed whether patients had a HCP in the record, if the patient's mental status was evaluated prior to obtaining informed consent, if the patient's capacity was addressed in this assessment, and whether a SDM was asked to provide the informed consent. RESULTS: Consistent with our hypotheses, we found that the majority of patients did not have documentation of a HCP in the record. We found that the mental status of all patients was assessed prior to the procedure, but that documentation regarding assessment of decision-making capacity was lacking. CONCLUSIONS: Our pilot investigation suggests that there is need for improvement in our evaluation and documentation of altered mental status and a patient's ability to make informed decisions. To this end, several quality-improvement suggestions are discussed.

mll ortholog containing functional domains of human MLL is expressed throughout the zebrafish lifespan and in haematopoietic tissues.

Infant leukaemia is an embryonal disease in which the underlying MLL translocations initiate in utero. Zebrafish offer unique potential to understand how MLL impacts haematopoiesis from the earliest embryonic timepoints and how translocations cause leukaemia as an embryonal process. In this study, a zebrafish mll cDNA syntenic to human MLL spanning the 5' to 3' UTRs, was cloned from embryos, and mll expression was characterized over the zebrafish lifespan. The protein encoded by the 35-exon ORF exhibited 46·4% overall identity to human MLL and 68-100% conservation in functional domains (AT-hooks, SNL, CXXC, PHD, bromodomain, FYRN, taspase1 sites, FYRC, SET). Maternally supplied transcripts were detected at 0-2 hpf. Strong ubiquitous early zygotic expression progressed to a cephalo-caudal gradient during later embryogenesis. mll was expressed in the intermediate cell mass (ICM) where primitive erythrocytes are produced and in the kidney where definitive haematopoiesis occurs in adults. mll exhibits high cross species conservation, is developmentally regulated in haematopoietic and other tissues and is expressed from the earliest embryonic timepoints throughout the zebrafish lifespan. Haematopoietic tissue expression validates using zebrafish for MLL haematopoiesis and leukaemia models.

Characterization of zebrafish intestinal smooth muscle development using a novel sm22α-b promoter.

Smooth muscle cells provide structural support for many tissues and control essential physiological processes, such as blood pressure and gastrointestinal motility. Relatively little is known about the early stages of intestinal smooth muscle development and its relationship to the development of the enteric nervous system, which regulates intestinal motility. Here, we report an evolutionarily conserved 523 base pair regulatory element within the promoter of the zebrafish sm22α-b (transgelin1) gene that directs transgene expression in smooth muscle cells of the intestine and other tissues. Comparative genomic analysis identified a conserved motif within this element consisting of two Serum Response Factor binding sites that is also present in the promoters of many mammalian smooth muscle genes. We established a stable line expressing GFP in smooth muscle cell and used this line to describe lineage relationships among cells within different intestinal smooth muscle layers and their co-development with the enteric nervous system (ENS).

Chemical modulation of receptor signaling inhibits regenerative angiogenesis in adult zebrafish.

We examined the role of angiogenesis and the need for receptor signaling using chemical inhibition of the vascular endothelial growth factor receptor in the adult zebrafish tail fin. Using a small-molecule inhibitor, we were able to exert precise control over blood vessel regeneration. An angiogenic limit to tissue regeneration was determined, as avascular tissue containing skin, pigment, neuronal axons and bone precursors could regenerate up to about 1 mm. This indicates that tissues can regenerate without direct interaction with endothelial cells and at a distance from blood supply. We also investigated whether the effects of chemical inhibition could be enhanced in zebrafish vascular mutants. We found that adult zebrafish, heterozygous for a mutation in the critical receptor effector phospholipase Cgamma1, show a greater sensitivity to chemical inhibition. This study illustrates the utility of the adult zebrafish as a new model system for receptor signaling and chemical biology.