Design and microfabrication of a high-aspect-ratio PDMS microbeam array for parallel nanonewton force measurement and protein printing

Journal of Micromechanics and Microengineering, 17(3): pp. 623-632.Cell and protein mechanics has applications ranging from cellular development to tissue engineering. Techniques such as magnetic tweezers, optic tweezers, and atomic force microscopy have been used to measure cell deformation forces on the order of piconewtons to nanonewtons. In this study, an array of polymeric polydimethylsiloxane (PDMS) microbeams with diameters of 10-40μm and lengths of 118μm was fabricated from Sylgard® with curing agent concentrations ranging from 5% to 20%. Resulting spring constants were 100-300nN/μm. The elastic modulus of PDMS was determined experimentally at different curing agent concentrations and found to be 346kPa to 704kPa in a millimeter-scale array and ~1MPa in a microbeam array. Additionally, the microbeam array was used to print laminin for the purpose of cell adhesion. Linear and non-linear finite element analyses are presented and compared to the closed-from solution. Conclusion: The highly compliant, transparent, biocompatible PDMS may offer a method for more rapid throughput in cell and protein mechanics force measurement experiments with sensitivities necessary for highly compliant structures such as axons

Observational Research Using Propensity Scores

In most observational studies, treatments or other "exposures" (in an epidemiologic sense) do not occur at random. Instead, treatments or other such interventions depend on several patient-related and patient-independent characteristics. Such factors, associated with the receipt vs nonreceipt of treatment, may also be-independently-associated with outcomes. Thus, confounding exists making it difficult to ascertain the true association between treatments and outcomes. Propensity scores (PS) represent an intuitive set of approaches to reduce the influence of such "confounding" factors. PS is a computed probability of treatment, a value that is estimated for each patient in an observational study and then applied (in a variety of ways such as matching, stratification, weighting, etc.) to reduce distortion in the true nature of the association between treatment (or any similar exposure) and outcomes. Despite several advantages, PS-based methods cannot account for unmeasured confounding, ie, for factors that are not being included in the computation of PS

Cost-Comparison of Two Trabecular Micro-Bypass Stents Versus Selective Laser Trabeculoplasty or Medications Only for Intraocular Pressure Control for Patients with Open-Angle Glaucoma

Aim: Patients with open-angle glaucoma (OAG) whose intraocular pressure is not adequately controlled by one medication have several treatment options in the US. This analysis evaluated direct costs of unilateral eye treatment with two trabecular micro-bypass stents (two iStents) compared to selective laser trabeculoplasty (SLT) or medications only. Materials and methods: A population-based, annual state-transition, probabilistic, cost-of-care model was used to assess OAG-related costs over 5 years. Patients were modeled to initiate treatment in year zero with two iStents, SLT, or medications only. In years 1–5, patients could remain on initial treatment or move to another treatment option(s), or filtration surgery. Treatment strategy change probabilities were identified by a clinician panel. Direct costs were included for drugs, procedures, and complications. Results: The projected average cumulative cost at 5 years was lower in the two-stent treatment arm ($4,420) compared to the SLT arm ($4,730) or medications-only arm ($6,217). Initial year-zero costs were higher with two iStents ($2,810) than with SLT ($842) or medications only ($996). Average marginal annual costs in years 1–5 were $322 for two iStents,$777 for SLT, and $1,044 for medications only. The cumulative cost differences between two iStents vs SLT or medications only decreased over time, with breakeven by 5 or 3 years post-initiation, respectively. By year 5, cumulative savings with two iStents over SLT or medications only was$309 or $1,797, respectively. Limitations: This analysis relies on clinical expert panel opinion and would benefit from real-world evidence on use of multiple procedures and treatment switching after two-stent treatment, SLT, or polypharmaceutical initial approaches. Conclusions: Despite higher costs in year zero, annual costs thereafter were lowest in the two-stent treatment arm. Two-stent treatment may reduce OAG-related health resource use, leading to direct savings, especially over medications only or at longer time horizons

Sodium Phosphate Does Not Increase Risk for Acute Kidney Injury After Routine Colonoscopy, Compared With Polyethylene Glycol

Oral sodium phosphate (OSP) is a common bowel purgative administered before colonoscopy; the Food and Drug Administration has warned against its use because of concerns about acute kidney injury (AKI) from the absorbed phosphate and dystrophic calcification. However, it is not clear if OSP is associated with AKI in the general population or in high-risk subgroups undergoing colonoscopy. We estimated the risk of AKI among patients undergoing a screening colonoscopy using OSP vs polyethylene glycol (PEG) for bowel cleansing in a large, US-based claims database

The Drivers of Pathology in Zoonotic Avian Influenza: The Interplay Between Host and Pathogen

The emergence of zoonotic strains of avian influenza (AI) that cause high rates of mortality in people has caused significant global concern, with a looming threat that one of these strains may develop sustained human-to-human transmission and cause a pandemic outbreak. Most notable of these viral strains are the H5N1 highly pathogenic AI and the H7N9 low pathogenicity AI viruses, both of which have mortality rates above 30%. Understanding of their mechanisms of infection and pathobiology is key to our preparation for these and future viral strains of high consequence. AI viruses typically circulate in wild bird populations, commonly infecting waterfowl and also regularly entering commercial poultry flocks. Live poultry markets provide an ideal environment for the spread AI and potentially the selection of mutants with a greater propensity for infecting humans because of the potential for spill over from birds to humans. Pathology from these AI virus infections is associated with a dysregulated immune response, which is characterized by systemic spread of the virus, lymphopenia, and hypercytokinemia. It has been well documented that host/pathogen interactions, particularly molecules of the immune system, play a significant role in both disease susceptibility as well as disease outcome. Here, we review the immune/virus interactions in both avian and mammalian species, and provide an overview or our understanding of how immune dysregulation is driven. Understanding these susceptibility factors is critical for the development of new vaccines and therapeutics to combat the next pandemic influenza

New patient-oriented tools for assessing atrophic acne scarring

Scarring on visible areas such as the face is associated with negative psychological impact. Many patients with acne have clinically relevant scarring for which they seek treatment, implying that there is an impact on their lives. Currently there are no validated tools to assess the burden of atrophic acne scarring from the patient’s perspective or to assess treatment benefit. Methods Two patient-reported outcome measures, the self-assessment of clinical acne-related scars (SCARS) and the facial acne scar quality of life (FASQoL) tools, both specific to facial atrophic acne scarring, were developed according to Food and Drug Administration guidance methodology. Patient interviews were conducted first to elicit patient-important concepts about scarring, then to validate patients’ understanding of wording in the tools. These tools focus on symptoms (SCARS) and psychological and social well-being (FASQoL) and were designed to be suitable for self-completion and to be rapidly completed (2–5 min) within a clinical research setting. Results Concept elicitation interviews were conducted with 30 subjects and cognitive interviews with 20 subjects. With acne scarring, important concepts for patients included size, surface area affected, counts, and depth. The SCARS and FASQoL tools were shown to address relevant concepts that were easily understood by patients. Conclusion Two patient-reported measures, SCARS and FASQoL, have been developed to help clinicians assess the severity and impact of acne scars. Responsivity of these instruments to treatment will require further evaluation

Fecal Contamination of Shallow Tubewells in Bangladesh Inversely Related to Arsenic

The health risks of As exposure due to the installation of millions of shallow tubewells in the Bengal Basin are known, but fecal contamination of shallow aquifers has not systematically been examined. This could be a source of concern in densely populated areas with poor sanitation because the hydraulic travel time from surface water bodies to shallow wells that are low in As was previously shown to be considerably shorter than for shallow wells that are high in As. In this study, 125 tubewells 6−36 m deep were sampled in duplicate for 18 months to quantify the presence of the fecal indicator Escherichia coli. On any given month, E. coli was detected at levels exceeding 1 most probable number per 100 mL in 19−64% of all shallow tubewells, with a higher proportion typically following periods of heavy rainfall. The frequency of E. coli detection averaged over a year was found to increase with population surrounding a well and decrease with the As content of a well, most likely because of downward transport of E. coli associated with local recharge. The health implications of higher fecal contamination of shallow tubewells, to which millions of households in Bangladesh have switched in order to reduce their exposure to As, need to be evaluated

Zebrafish SPI-1 marks a site of myeloid development independent of primitive erythropoiesis: implications for axial patterning.

The mammalian transcription factor SPI-1 (synonyms: SPI1, PU.1, or Sfpi1) plays a critical role in myeloid development. To examine early myeloid commitment in the zebrafish embryo, we isolated a gene from zebrafish that is a SPI-1 orthologue on the basis of homology and phylogenetic considerations. The zebrafish spi1 (pu1) gene was first expressed at 12 h postfertilization in rostral lateral plate mesoderm (LPM), anatomically isolated from erythroid development in caudal lateral plate mesoderm. Fate-mapping traced rostral LPM cells from the region of initial spi1 expression to a myeloid fate. spi1 expression was lost in the bloodless mutant cloche, but rostral spi1 expression and myeloid development were preserved in the mutant spadetail, despite its complete erythropoietic failure. This dissociation of myeloid and erythroid development was further explored in studies of embryos overexpressing BMP-4, or chordin, in bmp-deficient swirl and snailhouse mutants, and chordin-deficient chordino mutants. These studies demonstrate that, in zebrafish, spi1 marks a rostral population of LPM cells committed to a myeloid fate anatomically separated from and developmentally independent of erythroid commitment in the caudal LPM. Such complete anatomical and developmental dissociation of two hematopoietic lineages adds an interesting complexity to the understanding of vertebrate hematopoietic development and presents significant implications for the mechanisms regulating axial patterning

Genome-wide meta-analysis implicates mediators of hair follicle development and morphogenesis in risk for severe acne

Acne vulgaris is a highly heritable common, chronic inflammatory disease of the skin for which five genetic risk loci have so far been identified. Here, we perform a genome-wide association study of 3823 cases and 16,144 controls followed by meta-analysis with summary statistics from a previous study, with a total sample size of 26,722. We identify 20 independent association signals at 15 risk loci, 12 of which have not been previously implicated in the disease. Likely causal variants disrupt the coding region of WNT10A and a P63 transcription factor binding site in SEMA4B. Risk alleles at the 1q25 locus are associated with increased expression of LAMC2, in which biallelic loss-of-function mutations cause the blistering skin disease epidermolysis bullosa. These findings indicate that variation affecting the structure and maintenance of the skin, in particular the pilosebaceous unit, is a critical aspect of the genetic predisposition to severe acne