Nonlinear Optical Corneal Crosslinking, Mechanical Stiffening, and Corneal Flattening Using Amplified Femtosecond Pulses.

Purpose:We have shown that nonlinear optical corneal crosslinking (NLO CXL) and stiffening can be achieved in ex vivo rabbit corneas using an 80-MHz, 760-nm femtosecond (FS) laser, however the required power was beyond the American National Standard Institute limit. The purpose of this study was to test the efficacy of amplified FS pulses to perform CXL to reduce power by increasing pulse energy. Methods:A variable numerical aperture laser scanning delivery system was coupled to a 1030-nm laser with a noncollinear optical parametric amplifier to generate 760 nm, 50 to 150 kHz amplified FS pulses with 79.5-μm axial and 2.9-μm lateral two-photon focal volume. Ex vivo rabbit corneas received NLO CXL, and effectiveness was assessed by measuring collagen autofluorescence (CAF) and mechanical stiffening. NLO CXL was also performed in 14 live rabbits, and changes in corneal topography were measured using an Orbscan. Results:Amplified pulses (0.3 μJ) generated significant CAF that increased logarithmically with decreasing scan speed; achieving equivalent CAF to UVA CXL at 15.5 mm/s. Indentation testing detected a 62% increase in stiffness compared to control, and corneal topography measurements revealed a significant decrease of 1.0 ± 0.8 diopter by 1 month (P < 0.05). Conclusions:These results show that NLO CXL using amplified pulses can produce corneal collagen CXL comparable to UVA CXL. Translational Relevance:NLO CXL using amplified pulses can produce corneal CXL comparable to UVA CXL, suggesting a potential clinical application in which NLO CXL can be used to perform personalized crosslinking for treatment of refractive errors and keratoconus

Archeological Of The Proposed FM 1626 Pass-Through Toll Project From Ranch-To-Market 967 To Farm-To-Market 2770 In Hays County, Texas

Hicks & Company archeologists conducted an intensive, 100-percent linear archeological survey of approximately 3.3 miles of proposed expansions to Farm-to-Market (FM) 1626 west of the city of Buda, Hays County, Texas. The survey was conducted between July 2008 and October 2016 for compliance with the Antiquities Code of Texas and Section 106 of the National Historic Preservation Act on behalf of Hays County, the project engineer Klotz Associates, and the Texas Department of Transportation (TxDOT). The Area of Potential Effects (APE) for the proposed project is composed of 54.3 acres of existing right of way and 8.08 acres of proposed expanded right of way (measuring 62.38 acres of existing plus proposed expanded right of way), and approximately 1.07 acres of temporary construction easements located outside of the existing or proposed right of way. While the proposed expanded right of way corridor has been determined, the project engineer requested that a 200-foot-wide corridor be investigated (extending 100 feet in either direction from the existing centerline) to allow for flexibility in road design, potential utility relocation, and other possible areas of concern, resulting in a total of approximately 81 acres of land surveyed. Investigations were coordinated with the Texas Historical Commission through TxDOT under Texas Antiquities Committee Permit Number 4981. On three occasions between July 28, 2008, and August 10, 2009 Hicks & Company archeologists conducted an intensive linear archeological survey of the proposed FM 1626 improvements project west of the city of Buda, Texas, on behalf of Hays County and TxDOT, returning to the field on January 21, 2016 to survey for proposed temporary construction easements located outside of the existing right of way or proposed new right of way, and again on October 26, 2016 to survey proposed new right of way in previously inaccessible parcels, completing the survey. The survey consisted of pedestrian inspection supplemented by shovel testing (N=102) and mechanical backhoe trench excavations (N=7) in the area north of Onion Creek. One backhoe trench excavated on the north bank of Onion Creek was positive for two pieces of lithic debitage, along with 32 shovel tests throughout the APE that were positive for cultural materials. One previously unrecorded site (Site 41HY449) was documented during the survey. This prehistoric surficial scatter does not meet the significance criteria for listing on the National Register of Historic Places (NRHP) or as a State Antiquities Landmark (SAL). In addition to this newly recorded site, archeologists visited elements of seven previously recorded sites (Sites 41HY199-202, 41HY209-210, and 41HY219) within the APE. Elements of one of these, Site 41HY200, could not be found within the archeological APE. Of these, only elements of Site 41HY201 are considered to have potential to deem the site eligible for inclusion on the NRHP or for designation as an SAL. The project engineer has altered plans in the vicinity of the site to avoid impacts to those resources. All other sites were found to be heavily disturbed, no longer extant, or within shallow surficial contexts atop bedrock with limited research value. Archeologists also visited the expansion areas adjacent to historic Barton Cemetery. Although the cemetery lies in close proximity to the APE, the County proposes no expansions in the immediate vicinity of the cemetery beyond a proposed retaining wall with riprap slope within the existing right of way outside the cemetery. This retaining wall is to be constructed approximately ten feet within current existing right of way. By design, retaining walls planned for this project will be fixed in place to concrete leveling pads set in place on top of the current grade and supported by earth reinforcement buildup of imported fill material. During survey, an overgrown road or trail that follows the current cemetery fenceline reinforces the assumption that the existing cemetery boundary served as the historic boundary as well, significantly reducing the potential for unmarked burials to be located within the current archeological APE. Construction within the APE is recommended to proceed with no further cultural resources investigation. The current investigations followed a no-collection policy. All projectrelated records, forms, and photographs will be permanently housed at the Texas Archeological Research Laboratory in Austin, Texas

The Interaction of Calcium and Metabolic Oscillations in Pancreatic β-cells

Diabetes is a disease characterized by an excessive level of glucose in the bloodstream, which may be a result of improper insulin secretion. Insulin is secreted in a bursting behavior of pancreatic $\beta$-cells in islets, which is affected by oscillations of cytosolic calcium concentration. We used the Dual Oscillator Model to explore the role of calcium in calcium oscillation independent and calcium oscillation dependent modes and the synchronization of metabolic oscillations in electrically coupled $\beta$-cells. We implemented a synchronization index in order to better measure the synchronization of the $\beta$-cells within an islet and we studied heterogeneous modes of coupled $\beta$-cells. We saw that increasing calcium coupling or voltage coupling in heterogeneous cases increases synchronization; however, in certain cases increasing both voltage and calcium coupling causes desynchronization. To better represent an islet, we altered previous code to allow for a greater number of cells to be simulated

Protocol for the Promoting Resilience in Stress Management (PRISM) Intervention: A Multi-Site Randomized Controlled Trial for Adolescents and Young Adults with Advanced Cancer

Background Adolescents and young adults (AYAs) with cancer are at high risk of poor psychosocial outcomes, and evidence-based interventions designed to meet their psychosocial and communication needs are lacking. The main objective of this project is to test the efficacy of a new adaptation of the Promoting Resilience in Stress Management intervention for AYAs with Advanced Cancer (PRISM-AC). Methods/design The PRISM-AC trial is a 2-arm, parallel, non-blinded, multisite, randomized controlled trial. 144 participants with advanced cancer will be enrolled and randomized to either usual, non-directive, supportive care without PRISM-AC (“control” arm) or with PRISM-AC (“experimental” arm). PRISM is a manualized, skills-based training program comprised of four 30–60 min, one-on-one sessions targeting AYA-endorsed resilience resources (stress-management, goal-setting, cognitive-reframing, and meaning-making). It also includes a facilitated family meeting and a fully equipped smartphone app. The current adaptation includes an embedded advance care planning module. English- or Spanish-speaking individuals 12–24 years old with advanced cancer (defined as progressive, recurrent, or refractory disease, or any diagnosis associated with \u3c 50% survival) receiving care at 4 academic medical centers are eligible. Patients’ caregivers are also eligible to participate in this study if they are able to speak and read English or Spanish, and are cognitively and physically able to participate. Participants in all groups complete surveys querying patient-reported outcomes at the time of enrollment and 3-, 6-, 9-, and 12-months post-enrollment. The primary outcome of interest is patient-reported health-related quality of life (HRQOL) and secondary outcomes of interest include patient anxiety, depression, resilience, hope and symptom burden, parent/caregiver anxiety, depression and health-related quality of life, and family palliative care activation. We will conduct intention-to-treat analysis to compare the group means of primary and secondary outcomes between PRISM-AC arm and control arm with regression models. Discussion This study will provide methodologically rigorous data and evidence regarding a novel intervention to promote resilience and reduce distress among AYAs with advanced cancer. This research has the potential to offer a practical, skills-based curriculum designed to improve outcomes for this high-risk group. Trial registration ClinicalTrials.gov Identifier NCT03668223, September 12, 2018

safety and efficacy of fidaxomicin and vancomycin in children and adolescents with clostridioides clostridium difficile infection a phase 3 multicenter randomized single blind clinical trial sunshine

Abstract Background Fidaxomicin, a narrow-spectrum antibiotic approved for Clostridioides (Clostridium) difficile infection (CDI) in adults, is associated with lower rates of recurrence than vancomycin; however, pediatric data are limited. This multicenter, investigator-blind, phase 3, parallel-group trial assessed the safety and efficacy of fidaxomicin in children. Methods Patients aged <18 years with confirmed CDI were randomized 2:1 to 10 days of treatment with fidaxomicin (suspension or tablets, twice daily) or vancomycin (suspension or tablets, 4 times daily). Safety assessments included treatment-emergent adverse events. The primary efficacy end point was confirmed clinical response (CCR), 2 days after the end of treatment (EOT). Secondary end points included global cure (GC; CCR without CDI recurrence) 30 days after EOT (end of study; EOS). Plasma and stool concentrations of fidaxomicin and its active metabolite OP-1118 were measured. Results Of 148 patients randomized, 142 were treated (30 <2 years old). The proportion of participants with treatment-emergent adverse events was similar with fidaxomicin (73.5%) and vancomycin (75.0%). Of 3 deaths in the fidaxomicin arm during the study, none were CDI or treatment related. The rate of CCR at 2 days after EOT was 77.6% (76 of 98 patients) with fidaxomicin and 70.5% (31 of 44) with vancomycin, whereas the rate of GC at EOS was significantly higher in participants receiving fidaxomicin (68.4% vs 50.0%; adjusted treatment difference, 18.8%; 95% confidence interval, 1.5%–35.3%). Systemic absorption of fidaxomicin and OP-1118 was minimal, and stool concentrations were high. Conclusions Compared with vancomycin, fidaxomicin was well tolerated and demonstrated significantly higher rates of GC in children and adolescents with CDI. ClinicalTrials.gov identifier NCT0221837

Effects of 17-α-ethynylestradiol on Hybrid Striped Bass Sperm

Gemstone Team FISHOne of the most potent EDCs in the environment is 17-ethynylestradiol (EE2), the hormone in most birth control pills. EE2 is released into the ecosystem through human wastewater, affecting the environment and its inhabitants. Fish both live and reproduce in these affected ecosystems, which may make them particularly susceptible to the effects of EE2. This study investigates the impacts on reproductive efficacy of acute, direct exposure of male hybrid striped bass sperm cells to EE2. In the study, reproductive efficacy is measured by two endpoints: genetic integrity of sperm DNA and sperm cell viability. Genetic integrity and cell viability were assessed by the comet assay and SYBR-14/Propidium Iodide stains, respectively. The results concerning genetic integrity were not statistically significant, but the results of the sperm viability assay suggest that acute direct exposure to EE2 does not cause significant death within a population of sperm

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN