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Although rare, gastrointestinal vaso-occlusive crisis in sickle cell disease results in potentially life-threatening ischemia and death. Here we present a case of a 34-year-old patient with sickle cell disease who developed an acute pain crisis complicated by hypovolemia, hypoxia, and hypotension. The patient was treated with supportive measures. Diagnosis can be challenging and difficult to differentiate from usual pain crisis.

Although implicated in adhesion, only a few studies address how the actin assembly factors guide cell positioning in multicellular tissues. The formin, Dia1, localizes to the proliferative basal layer of the epidermis. In organotypic cultures, Dia1 depletion reduced basal cell density and resulted in stratified tissues with disorganized differentiation and proliferative markers. Since crowding induces differentiation in epidermal tissues, we hypothesized that Dia1 is essential to reach densities amenable to differentiation before or during stratification. Consistent with this, forced crowding of Dia1-deficient cells rescued transcriptional abnormalities. We find Dia1 promotes rapid growth of lateral cell–cell adhesions, necessary for the construction of a highly crowded monolayer. In aggregation assays, cells sorted into distinct layers based on Dia1 expression status. These results suggest that as basal cells proliferate, reintegration and packing of Dia1-positive daughter cells is favored, whereas Dia1-negative cells tend to delaminate to a suprabasal compartment. This work elucidates the role of formin expression patterns in constructing distinct cellular domains within stratified epithelia.

Pathological and genomic profiling have transformed breast cancer care by matching patients to targeted treatments. However, tumors evolve and evade therapeutic interventions often through the acquisition of genomic mutations. Here we examine patients profiled with tissue (TBx) and liquid biopsy (LBx) as part of routine clinical care, to characterize the tumor evolutionary landscape and identify potential vulnerabilities in the relapsed setting. Real-world evidence demonstrates that LBx is utilized later in care and identifies associations with intervening therapy. While driver events are frequently shared, acquired LBx alterations are detected in a majority of patients, with the highest frequency in ER+ disease and in patients with longer biopsy intervals. Acquired mutations are often polyclonal and present at lower allelic fractions, suggesting multi-clonal convergent evolution. In addition to well-characterized resistance mutations (e.g., ESR1, NF1, RB1, ERBB2), we observe a diversity of rarer but potentially targetable mutations (e.g., PIK3CA, HRAS/NRAS/KRAS, FGFR1/2/3, BRAF) and fusions (e.g., FGFR1/2, ERBB2, RET), as well as BRCA1/2 reversions through a variety of mechanisms, including splice alterations and structural deletions. This study provides insights on treatment and selection-driven tumor evolution and identifies potential combinatorial treatment options in advanced breast cancer.

Tissue morphogenesis arises from the culmination of changes in cell-cell junction length. Mechanochemical signaling in the form of RhoA underlies these ratcheted contractions, which occur asymmetrically. The underlying mechanisms of asymmetry remain unknown. We use optogenetically controlled RhoA in model epithelia together with biophysical modeling to uncover the mechanism lending to asymmetric vertex motion. Using optogenetic and pharmacological approaches, we find that both local and global RhoA activation can drive asymmetric junction contraction in the absence of tissue-scale patterning. We find that standard vertex models with homogeneous junction properties are insufficient to recapitulate the observed junction dynamics. Furthermore, these experiments reveal a local coupling of RhoA activation with E-cadherin accumulation. This motivates a coupling of RhoA-mediated increases in tension and E-cadherin-mediated adhesion strengthening. We then demonstrate that incorporating this force-sensitive adhesion strengthening into a continuum model is successful in capturing the observed junction dynamics. Thus, we find that a force-dependent intercellular "clutch" at tricellular vertices stabilizes vertex motion under increasing tension and is sufficient to generate asymmetries in junction contraction.

Purpose Examine the factors improving performance on national medical licensing board examinations. Rationale Accreditation Council for Graduate Medical Education (ACGME) accredited residency programs report the United States Medical Licensing Examination (USMLE) Step 1 and Comprehensive Osteopathic Licensing Examination-USA (COMLEX-USA) Level 1 scores as the most important criteria in selecting candidates to interview. Hypotheses (1) Certain resources are superior for exam preparation. (2) Certain practice tests better assess exam preparedness. (3) USMLE performance will correlate with the COMLEX-USA. Methods One-hundred and two (102) medical students were surveyed regarding preparation for and performance on COMLEX-USA Level 1 and USMLE Step 1. Results USMLE-specific question banks were positively correlated with performance on COMLEX-USA Level 1 and USMLE Step 1 while COMLEX-specific question banks showed no correlation. National Board of Medical Examiners (NBME) Comprehensive Basic Science Self Assessment (CBSSA) and National Board of Osteopathic Medical Examiners (NBOME) Comprehensive Osteopathic Medical Self-Assessment Examination (COMSAE) practice examinations were positively correlated with performance on the USMLE Step 1 and the COMLEX-USA Level 1. Scores on USMLE Step 1 and COMLEX-USA Level 1 were highly correlated. Students who took USMLE Step 1 performed better on COMLEX-USA Level 1 than those who did not. Conclusion COMLEX-specific resources may not adequately prepare students for COMLEX-USA Level 1. Students studying for COMLEX-USA Level 1 may benefit by preparing for USMLE Step 1.

The effects of processing parameters on the in-flight particle behavior, phase composition, and properties of air plasma sprayed ytterbium disilicate (Yb2Si2O7) coatings were investigated in this study. With the increase in plasma enthalpy, in-flight particle temperature increases. Higher particle temperature caused an increase in silica (SiO2) evaporation from the Yb2Si2O7 particles and, as a result, additional Yb2SiO5 phase appears in the Yb2Si2O7 coating. Thermal expansion tests showed the coating containing a higher volume of Yb2SiO5 phase has a larger coefficient of thermal expansion (CTE). Thermal cycling tests in a steam environment indicated that the Yb2SiO5 phase content in the APS Yb2Si2O7 coatings has a significant effect on the EBC's durability. Thermal cycling lives decrease with the increase of Yb2SiO5 phase content in APS Yb2Si2O7 coatings. Analysis of the failed coatings indicated that the predominant EBC failure mechanisms are due to growth of the thermally growth oxides (TGO) as well as the stresses induced by CTE mismatch. Furthermore, Calcium–magnesium–alumina-silicate (CMAS) corrosion tests showed that the recession rate decreases with the increase of Yb2SiO5 phase content in APS Yb2Si2O7 coatings.

Several health plants and other organizations are collaborating with the Centers for Disease Control and Prevention to develop a syndromic surveillance system with national coverage that includes more than 20 million people. A principal design feature of this system is reliance on daily reporting of counts of individuals with syndromes of interest in specified geographic regions rather than reporting of individual encounter-level information. On request from public health agencies, health plans and telephone triage services provide additional information regarding individuals who are part of apparent clusters of illness. This reporting framework has several advantages, including less sharing of protected health information, less risk that confidential information will be distributed inappropriately, the prospect of better public acceptance, greater acceptance by health plans, and less effort and cost for both health plans and public health agencies. If successful, this system will allow any organization with appropriate data to contribute vital information to public health syndromic surveillance systems while preserving individuals’ privacy to the greatest extent possible.

This paper utilizes a technology road-mapping approach to demonstrate how a traditional technology management process can be applied to improve planning practices for technology-driven service innovations. With location based services (LBS) as the focus, the paper explores business, market, product and services drivers in developing the technology roadmap. Thus, the study demonstrates that technology management theory and processes from the product domain may be usefully applied to the management of technology-driven service innovations. The case study analysis identified service drivers including security, privacy and mobility as important factors for LBS success. Potentially disruptive service innovations resulting from the convergence of the computer and wireless industries are explored.

BackgroundSurveillance for influenza and influenza-like illness (ILI) is important for guiding public health prevention programs to mitigate the morbidity and mortality caused by influenza, including pandemic influenza. Nontraditional sources of data for influenza and ILI surveillance are of interest to public health authorities if their validity can be established.Methods/principal findingsNational telephone triage call data were collected through automated means for purposes of syndromic surveillance. For the 17 states with at least 500,000 inhabitants eligible to use the telephone triage services, call volume for respiratory syndrome was compared to CDC weekly number of influenza isolates and percentage of visits to sentinel providers for ILI. The degree to which the call data were correlated with either CDC viral isolates or sentinel provider percentage ILI data was highly variable among states.ConclusionsTelephone triage data in the U.S. are patchy in coverage and therefore not a reliable source of ILI surveillance data on a national scale. However, in states displaying a higher correlation between the call data and the CDC data, call data may be useful as an adjunct to state-level surveillance data, for example at times when sentinel surveillance is not in operation or in areas where sentinel provider coverage is considered insufficient. Sufficient population coverage, a specific ILI syndrome definition, and the use of a threshold of percentage of calls that are for ILI would likely improve the utility of such data for ILI surveillance purposes.

Directed cell migration plays an important role in wound healing and many other cellular processes. To move directionally, a cell must become asymmetric and establish a dominant protrusion in which localized actin polymerization is a hallmark. We demonstrate that Arp2/3 protein complex, an actin polymerization nucleator consisting of seven protein subunits, is localized to the leading protrusions of cells in culture and in rat healing wounds. The localization of the Arp2/3 protein complex is consistent with its function to promote protrusion and migration. However, the mechanism that restricts the localization of this complex in migrating cells remains unknown. We demonstrate that messenger RNAs (mRNAs) for all the seven subunits of the Arp2/3 complex are localized at the leading protrusions of cells in culture and in wounds. This is the first evidence that mRNAs encoding a protein complex are co-localized to a common site of function. Interestingly, mRNA for Dia-I, a formin protein and another actin nucleator for actin bundles (such as stress fibers), is not localized. Such differential localization of mRNAs for the two actin nucleators suggests that these two functions are sequestered by mRNA sorting. We also demonstrate that the Arp2/3 mRNA localization is dependent on both the actin and microtubule cytoskeletons because disrupting either system abolishes Arp2/3 mRNA localization. The expression and localization of Arp2/3 mRNAs are dependent on serum, indicating Arp2/3 mRNA expression and sorting are consequences of a cellular response to the extracellular environment. Current work focuses on identification of the localization signal sequences and the physiological significance of Arp2/3 mRNA sorting in directed fibroblasts migration.

Albino rats (N = 12) were tested with free trials in an E-Maze to determine their preference for removal by the E or by a mechanical handling box. None of the Ss were deprived of food or water and the only apparent reinforcement was removal from the maze. Half of the Ss had a history of handling by E whereas the other six had not been handled before their first removal from the goal box. The results suggested that the prehandled rats preferred removal by E whereas untamed Ss preferred mechanical removal.

A student-community planned clinic was begun in an inner-city high-rise housing development; continuous evening operation has been maintained for two years. The problems encountered included apathy of public officials and medical professionals, wariness of people in the community, lack of money and complications in medical staffing. In spite of these difficulties, an apparently stable community-student-physician relation has developed. During the first year of operation 1426 patients were seen, almost exclusively for minor illness. However, 53 per cent of patients in whom secondary diagnoses were made (9.5 per cent of all patients) had serious medical problems underlying the minor illnesses that led them to seek medical care. Almost 17 per cent of all patients were referred to municipal hospitals or other medical centers in the city. The clinic therefore appeared to provide an effective portal of entry for patients into the existing health-care system of the city.

We wish to comment on the editorial by Silverman (A hospice setting for humane neonatal death, Pediatrics 69:239, 1982), which we find both insightful and timely. We feel we must take issue with some of Silverman's statements. Over the last 3½ years we have actively incorporated hospice concepts into our neonatal program at Denver Children's Hospital, creating a so-called Neonatal Hospice Program. 1. We agree that health care professionals involved in neonatal intensive care tend to be oriented to "rescue" care; however, in our own experience we have found that with adequate training not only are the staff members open, but often they are very willing to switch from a rescue to palliative mode of treatment in the appropriate circumstances.