Optimization of Oxygen Dynamics, UV-A Delivery, and Drug Formulation for Accelerated Epi-On Corneal Crosslinking.

Purpose: Corneal collagen crosslinking (CXL) through an intact epithelium (epi-on) at high irradiance could potentially improve patient comfort, visual recovery, and clinical workflow compared to conventional epi-off CXL. However, intact epithelium limits stromal delivery of the oxygen, photosensitizer, and ultraviolet-A (UV-A) radiation needed to drive CXL. This ex vivo study evaluated three different epi-on CXL protocols compared to positive and negative controls, specifically focusing on the impact of supplemental oxygen. Endpoints included stromal oxygen levels, stiffness of crosslinked tissue, and acute flattening of whole eyes.Materials & Methods: Ex vivo porcine eyes were held in a custom environmental chamber. Intrastromal oxygen levels were continuously measured before, during, and after UV illumination by a fiberoptic probe inserted into a laser-cut flap. Accelerated, high irradiance, epi-on CXL protocols using riboflavin formulated with benzalkonium chloride (BAC) were studied, with and without supplemental oxygen. These were compared to an alternate, low irradiance, epi-on protocol using riboflavin formulated with sodium iodide. Both negative (no CXL) and positive (epi-off modified Dresden protocol) controls were performed. Post-CXL elastic modulus was measured using extensiometry and anterior tangential curvature was measured using a Scheimpflug tomographer.Results: Protocols including supplemental oxygen resulted in an approximately 5-fold increase in stromal oxygen levels prior to CXL. During epi-on, high-irradiance UV-A delivery under hyperoxic conditions, an aerobic state was maintained. Conversely, under normoxic conditions, stromal oxygen rapidly depleted to 0-5% for all other protocols. The combination of supplemental oxygen, BAC formulation, and high-irradiance UV-A resulted in the largest biomechanical changes and most pronounced flattening effects of the three epi-on protocols.Conclusions: Ex vivo analysis of stromal oxygen levels, corneal stiffness, and acute anterior curvature change indicates that simultaneous optimization of the oxygen environment, riboflavin formulation, and UV-A protocol can significantly increase the effects of corneal collagen crosslinking.

A Somatostatin Receptor Subtype-3 (SST3) Peptide Agonist Shows Antitumor Effects in Experimental Models of Nonfunctioning Pituitary Tumors.

PURPOSE: Somatostatin analogues (SSA) are efficacious and safe treatments for a variety of neuroendocrine tumors, especially pituitary neuroendocrine tumors (PitNET). Their therapeutic effects are mainly mediated by somatostatin receptors SST2 and SST5. Most SSAs, such as octreotide/lanreotide/pasireotide, are either nonselective or activate mainly SST2. However, nonfunctioning pituitary tumors (NFPTs), the most common PitNET type, mainly express SST3 and finding peptides that activate this particular somatostatin receptor has been very challenging. Therefore, the main objective of this study was to identify SST3-agonists and characterize their effects on experimental NFPT models. EXPERIMENTAL DESIGN: Binding to SSTs and cAMP level determinations were used to screen a peptide library and identify SST3-agonists. Key functional parameters (cell viability/caspase activity/chromogranin-A secretion/mRNA expression/intracellular signaling pathways) were assessed on NFPT primary cell cultures in response to SST3-agonists. Tumor growth was assessed in a preclinical PitNET mouse model treated with a SST3-agonist. RESULTS: We successfully identified the first SST3-agonist peptides. SST3-agonists lowered cell viability and chromogranin-A secretion, increased apoptosis in vitro, and reduced tumor growth in a preclinical PitNET model. As expected, inhibition of cell viability in response to SST3-agonists defined two NFPT populations: responsive and unresponsive, wherein responsive NFPTs expressed more SST3 than unresponsive NFPTs and exhibited a profound reduction of MAPK, PI3K-AKT/mTOR, and JAK/STAT signaling pathways upon SST3-agonist treatments. Concurrently, SSTR3 silencing increased cell viability in a subset of NFPTs. CONCLUSIONS: This study demonstrates that SST3-agonists activate signaling mechanisms that reduce NFPT cell viability and inhibit pituitary tumor growth in experimental models that expresses SST3, suggesting that targeting this receptor could be an efficacious treatment for NFPTs.

Life cycle environmental impacts of wastewater-based algal biofuels.

Recent research has proposed integrating wastewater treatment with algae cultivation as a way of producing algal biofuels at a commercial scale more sustainably. This study evaluates the environmental performance of wastewater-based algal biofuels with a well-to-wheel life cycle assessment (LCA). Production pathways examined include different nutrient sources (municipal wastewater influent to the activated sludge process, centrate from the sludge drying process, swine manure, and freshwater with synthetic fertilizers) combined with emerging biomass conversion technologies (microwave pyrolysis, combustion, wet lipid extraction, and hydrothermal liquefaction). Results show that the environmental performance of wastewater-based algal biofuels is generally better than freshwater-based algal biofuels, but depends on the characteristics of the wastewater and the conversion technologies. Of 16 pathways compared, only the centrate cultivation with wet lipid extraction pathway and the centrate cultivation with combustion pathway have lower impacts than petroleum diesel in all environmental categories examined (fossil fuel use, greenhouse gas emissions, eutrophication potential, and consumptive water use). The potential for large-scale implementation of centrate-based algal biofuel, however, is limited by availability of centrate. Thus, it is unlikely that algal biofuels can provide a large-scale and environmentally preferable alternative to petroleum transportation fuels without considerable improvement in current production technologies. Additionally, the cobenefit of wastewater-based algal biofuel production as an alternate means of treating various wastewaters should be further explored.

Family physicians' opinions on the primary care documentation, coding, and billing system: a qualitative study from the residency research network of Texas.

BACKGROUND AND OBJECTIVES: The study's aim was to deepen our understanding of family physicians' perceptions of the strengths and weaknesses of the widely used US documentation, coding, and billing rules for primary care evaluation and management (E/M) services. METHODS: This study used in-depth, qualitative interviews of 32 family physicians in urban and rural, academic, and private practices. Interviews were initiated with a series of grand tour questions asking participants to give examples and personal narratives demonstrating cost efficiencies and cost inefficiencies relating to the E/M rules in their own practices. Investigators independently used an immersion-crystallization approach to analyze transcripts to search for unifying themes and subthemes until consensus among investigators was achieved. RESULTS: The majority of participants reported that the documentation rules, coding rules, and common fees for procedures and preventive services were reasonable. The E/M documentation rules for all other visit types, however, were perceived by the participants as unnecessarily complicated and unclear. The existing codes did not describe the actual work for common clinic visits, which led to documenting and coding by heuristics and patterns. Participants reported inadequate payment for complex patients, multiple patient concerns in a single office visit, services requiring extra time beyond a standard office visit, non-face-to-face time, and others. The E/M rules created unintended negative consequences such as family physicians not accepting Medicare or Medicaid patients, inaccurate documentation, poor-quality care, and system inefficiencies such as unnecessary tests and referrals. CONCLUSIONS: Family physicians expressed many problems and frustrations with the existing E/M documentation, coding, and billing rules and felt the system undervalued and unappreciated them for the complex and comprehensive care they provide. Findings of this study could inform improved guidelines for primary care documentation, coding, and billing.

Environmental, economic, and energetic costs and benefits of biodiesel and ethanol biofuels.

Negative environmental consequences of fossil fuels and concerns about petroleum supplies have spurred the search for renewable transportation biofuels. To be a viable alternative, a biofuel should provide a net energy gain, have environmental benefits, be economically competitive, and be producible in large quantities without reducing food supplies. We use these criteria to evaluate, through life-cycle accounting, ethanol from corn grain and biodiesel from soybeans. Ethanol yields 25% more energy than the energy invested in its production, whereas biodiesel yields 93% more. Compared with ethanol, biodiesel releases just 1.0%, 8.3%, and 13% of the agricultural nitrogen, phosphorus, and pesticide pollutants, respectively, per net energy gain. Relative to the fossil fuels they displace, greenhouse gas emissions are reduced 12% by the production and combustion of ethanol and 41% by biodiesel. Biodiesel also releases less air pollutants per net energy gain than ethanol. These advantages of biodiesel over ethanol come from lower agricultural inputs and more efficient conversion of feedstocks to fuel. Neither biofuel can replace much petroleum without impacting food supplies. Even dedicating all U.S. corn and soybean production to biofuels would meet only 12% of gasoline demand and 6% of diesel demand. Until recent increases in petroleum prices, high production costs made biofuels unprofitable without subsidies. Biodiesel provides sufficient environmental advantages to merit subsidy. Transportation biofuels such as synfuel hydrocarbons or cellulosic ethanol, if produced from low-input biomass grown on agriculturally marginal land or from waste biomass, could provide much greater supplies and environmental benefits than food-based biofuels.