A toolset of functionalized porphyrins with different linker strategies for application in bioconjugation

The reaction of amines with pentafluorophenyl-substituted A3B-porphyrins has been used to obtain different useful reactive groups for further functionalization and/or conjugation of these porphyrins to other substrates or materials. Porphyrins with alkenyl, alkynyl, amino, azido, epoxide, hydroxyl, and maleimido groups have thus been synthesized. For the first time such functionalized porphyrins have been conjugated to hyperbranched polyglycerol (hPG) as a biocompatible carrier system for photodynamic therapy (PDT) using the copper(I)-catalyzed 1,3-dipolar cycloaddition (CuAAC). The photocytotoxicity of selected porphyrins as well as of the porphyrin-hPG- conjugates has been assessed in cellular assays with human epidermoid carcinoma A-253 and squamous carcinoma CAL-27 cells. For several biomedical applications a release of the active drug and/or fluorescent dye is desired. Therefore, additionally, the synthesis of A3B-porphyrins with cleavable linker moieties is presented, namely disulfide, cleavable in a reductive environment, and acetal linkers whose cleavage is pH triggered

Parental Perspectives on Decision-making about Hypospadias Surgery

Introduction Many parents who choose hypospadias repair for their son experience decisional conflict and regret. The utilization of a shared decision-making process may address the issue of decisional conflict and regret in hypospadias repair by engaging both parents and physicians in decision-making. Objective The objective of this study was to develop a theoretical framework of the parental decision-making process about hypospadias surgery to inform the development of a decision aid. Study Design We conducted semi-structured interviews with parents of children with hypospadias to explore their role as proxy-decision-makers, inquiring about their emotions/concerns, informational needs and external/internal influences. We conducted interviews until no new themes were identified, analyzing them iteratively using open, axial and selective coding. The iterative approach entails a cyclical process of conducting interviews and analyzing transcripts while the data collection process is ongoing. This allows the researcher to make adjustments to the interview guide as necessary based on preliminary data analysis in order to explore themes that emerge from early interviews with parents. We used grounded theory methods to develop an explanation of the surgical decision-making process. Results We interviewed 16 mothers and 1 father of 7 preoperative and 9 postoperative patients (n=16) with distal (8) and proximal (8) meatal locations. We identified four stages of the surgical decision-making process: 1) processing the diagnosis, 2) synthesizing information, 3) processing emotions and concerns and 4) finalizing the decision (Extended Summary Figure). We identified core concepts in each stage of the decision-making process. Primary concerns included anxiety/fear about the child not waking up from anesthesia and their inability to be present in the operating room. Parents incorporated information from the Internet, medical providers and their social network as they sought to relieve confusion and anxiety while building trust/confidence in their child’s surgeon. Discussion The findings of this study contribute to our understanding of decision-making about hypospadias surgery as a complex and multi-faceted process. The overall small sample size is typical and expected for qualitative research studies. The primary limitation of the study, however, is the underrepresentation of fathers, minorities and same-sex couples. Conclusions This study provides an initial framework of the parental decision-making process for hypospadias surgery that will inform the development of a decision aid. In future stages of decision aid development, we will focus on recruitment of fathers, minorities and same-sex couples in order to enrich the perspectives of our work

The Purdue Extension and Indiana CTSI's Community Health Partnerships collaboration: An innovative, generalizable, state-wide model to help communities build a culture of health

The Indiana Clinical and Translational Sciences Institute's Community Engagement Partners-Purdue Extension collaborative model demonstrates tremendous potential for creating state-wide programmatic efforts and improvements in both the health culture and status of Indiana residents across the state. It can serve as a prototype not only for others interested in pursuing wide geographic health improvements through Clinical and Translational Sciences Award-Cooperative Extension partnerships but also for broader collaborations among United States Department of Agriculture, National Institutes of Health, Centers for Disease Control and Prevention, state and local health departments, and health foundation efforts to improve population health

Community Engagement of Adolescents in the Development of a Patient-Centered Outcomes Tool for Adolescents with a History of Hypospadias Repair

Introduction Hypospadias may lead to long-term issues with urination, sexual function and psychosocial well-being. Limited evidence exists regarding the healthcare communication preferences of male adolescents regarding sensitive topics. Objective The purpose of this qualitative study was to explore the healthcare communication preferences of male adolescents regarding sensitive topics (e.g. urinary and sexual issues) and engage them in in the initial stages of development a patient-centered outcomes tool for adolescents with a history of hypospadias repair. Study Design A multi-disciplinary team with communication design expertise, pediatric urology experts, and health services researchers developed a self-reported toolkit for adolescent patients who had hypospadias repair as children. The toolkit featured short writing/diagramming exercises and scales to facilitate participant reflections about genital appearance, urination, sexual function and psychosocial well-being. We recruited students from two local high schools for two focus groups to obtain feedback about the usability/acceptability of the toolkit’s appearance/content. We inquired about language preferences and preferred format and/or setting for sharing sensitive information with researchers. The focus groups were audio recorded, professionally transcribed, checked for accuracy and analyzed by two coders using qualitative content analysis. Major themes and subthemes were identified and representative quotes were selected. Results We conducted two focus groups in January 2018 with 33 participants, ages 14-18. Participants preferred language that would make patients feel comfortable as well as serious, clinical language rather than slang terms/sexual humor (Extended Summary Table). They recommended avoidance of statements implying that something is wrong with a patient or statements that would pressure the patient into providing answers. They suggested fill-in-the-blank and open-ended responses to encourage freedom of expression and colorful graphics to de-emphasize the test-like appearance of the toolkit. Most participants preferred a toolkit format to a one-on-one interview to discuss sensitive topics such as urinary or sexual issues. Participants would prefer either a male interviewer or would like to have a choice of interviewer gender for individual qualitative interviews, and they recommended a focus group leader with a history of hypospadias repair. Discussion This study provides a rich description of a group of male high school students’ experiences with healthcare providers and researchers. Its qualitative design limits generalizability and our findings may not be similar to adolescents with a history of hypospadias repair. Conclusion We used focus group feedback on the toolkit prototype to refine the tool for use in a future study of adolescents with history of hypospadias repair

Statistics of selectively neutral genetic variation

Random models of evolution are instrumental in extracting rates of microscopic evolutionary mechanisms from empirical observations on genetic variation in genome sequences. In this context it is necessary to know the statistical properties of empirical observables (such as the local homozygosity for instance). Previous work relies on numerical results or assumes Gaussian approximations for the corresponding distributions. In this paper we give an analytical derivation of the statistical properties of the local homozygosity and other empirical observables assuming selective neutrality. We find that such distributions can be very non-Gaussian.Comment: 4 pages, 4 figure

Error threshold in finite populations

A simple analytical framework to study the molecular quasispecies evolution of finite populations is proposed, in which the population is assumed to be a random combination of the constiyuent molecules in each generation,i.e., linkage disequilibrium at the population level is neglected. In particular, for the single-sharp-peak replication landscape we investigate the dependence of the error threshold on the population size and find that the replication accuracy at threshold increases linearly with the reciprocal of the population size for sufficiently large populations. Furthermore, in the deterministic limit our formulation yields the exact steady-state of the quasispecies model, indicating then the population composition is a random combination of the molecules.Comment: 14 pages and 4 figure

Nonlinear deterministic equations in biological evolution

We review models of biological evolution in which the population frequency changes deterministically with time. If the population is self-replicating, although the equations for simple prototypes can be linearised, nonlinear equations arise in many complex situations. For sexual populations, even in the simplest setting, the equations are necessarily nonlinear due to the mixing of the parental genetic material. The solutions of such nonlinear equations display interesting features such as multiple equilibria and phase transitions. We mainly discuss those models for which an analytical understanding of such nonlinear equations is available.Comment: Invited review for J. Nonlin. Math. Phy

Should Failure to Protect Laws Include Physical and Emotional Sibling Violence?

Physical and emotional sibling violence is a problematic occurrence for many children, adults, and families, yet this form of violence rarely falls within the purview of state laws and policies. Failure to protect laws offer one avenue through which sibling violence can be addressed by holding parents and caregivers accountable for harm that occurs to a child in their custody. This article provides background information on physical and emotional sibling violence as well as a general overview of failure to protect laws in the context of intimate partner violence with particular consideration of these laws in addressing sibling violence. In addition, the role social work practitioners can play in intervening and addressing sibling violence through psychoeducation leading to policy (i.e., failure to act laws) is presented

User-centered development of a hypospadias decision aid prototype

Introduction: Many parents who choose hypospadias repair for their sons experience decisional conflict (DC) and decisional regret (DR). We previously found that parental decision-making about hypospadias surgery is a complex process characterized by cyclic information-seeking to alleviate anxiety and confusion. Objective: The objective of this study was to engage parents of hypospadias patients and pediatric providers in the co-design of a decision aid (DA) prototype to facilitate shared decision-making about hypospadias surgery and address DC and DR. Methods: From August 2018 to January 2019, we conducted three co-design workshops with parents of hypospadias patients, pediatric urology and general pediatric providers to discuss their recommendations for a DA prototype. Activities were audio recorded and professionally transcribed. Transcripts and worksheets were analyzed by six coders using qualitative analysis to identify key aspects of a hypospadias DA desired by stakeholders. We conducted a collaborative design and prototyping session to establish key features and requirements, created a content map visualizing this work, and then developed a DA prototype. Results: Parent participants included 6 mothers and 4 fathers: 8 Caucasian, 2 African-American; median age 31 years. Providers included pediatric urology (n = 7) and general pediatric providers (n = 10): median age 47.5 years, 83.3% Caucasian, 58.3% male, 58.3% MD's and 41.7% nurse practitioners. Participants created user-friendly, interactive DA prototypes with "24/7" availability that had three key functions: 1) provide accurate, customizable, educational content, 2) connect parents with each other, and 3) engage them in a decision-making activity. The prototype consisted of five modules (Extended Summary Figure). "Hypospadias Basics" includes epidemiology and a hypospadias severity scale. "Surgery Basics" includes goals, illustrated steps, and pros/cons of surgery. "Testimonials" includes videos of parents and adolescents discussing their experiences. "Help me Decide" includes a decisional conflict scale and a decision-making activity (i.e. values clarification method). "Frequently Asked Questions" covers general hypospadias information, perioperative expectations and a review of postoperative care. Discussion: To our knowledge, this is the first DA prototype developed for a pediatric urology condition using a human-centered design approach to engage many key stakeholders in the development process. One limitation of this study is the small population sampled, which limits generalizability and means that our findings may not reflect the views of all parents or pediatric providers involved in hypospadias decision-making. Conclusions: We created a parent-centered hypospadias DA prototype that provides decision support in an online, interactive format. Future directions include further testing with usability experts, providers and parents

Lipid-DNAs as Solubilizers of mTHPC

Hydrophobic drug candidates require innovative formulation agents. We designed and synthesized lipidDNA polymers containing varying numbers of hydrophobic alkyl chains. The hydrophobicity of these amphiphiles is easily tunable by introducing a defined number of alkyl chain-modified nucleotides during standard solid-phase synthesis of DNA using an automated DNA synthesizer. We observed that the resulting self-assembled micelles solubilize the poorly water-soluble drug, meta-tetra-hydroxyphenyl-chlorin (mTHPC) used in photodynamic therapy (PDT) with high loading concentrations and loading capacities. A cell viability study showed that mTHPCloaded micelles exhibit good biocompatibility without irradiation, and high PDT efficacy upon irradiation. LipidDNAs provide a novel class of drug-delivery vehicle, and hybridization of DNA offers a potentially facile route for further functionalization of the drug-delivery system with, for instance, targeting or imaging moieties