Synthesis of Substituted Stilbene Probes Towards the Investigation of Antagonistic Effects Observed with 3,5-Substituted Paraben Derivatives

In practice, antagonistic xenoestrogen compounds have been used as drugs to treat cancer. Traditional strategies, include preparation of estrogen receptor antagonists exhibiting high affinity for the receptor while preventing rearrangement of the AF-2 binding domain. In a potentially new strategy, substituted parabens have proven to act as antagonists but do not bear the large sidechain associated with this common antagonist strategy. Weak phenolic interactions make determining such paraben binding confirmations and mode of action difficult. To investigate these activities associated with hindered phenolic compounds, substituted bisphenol probes have been synthesized via Wittig protocols to produce a series of stilbene derivatives. Herein we present the synthesis of such substituted stilbenes. A model system was used to test the synthesis of many different molecules, with success towards one of the probes. Further work will need to be completed to complete the synthesis of all the probes to allow for testing using TR-FRET and ELISA assays. Antagonism is expected to arise from similar disruption in the role of H12 in the AF-2 ligand binding domain albeit due to alternative binding interactions

Mexican Middle Schoolers’ Questions on Sexuality and Dating Relationships: A Descriptive Qualitative Analysis

Research in Mexico has found a lack of comprehensive sexual health education in school settings, as well as a lack of youth perspectives on sexual health and dating. Little is known about the questions Mexican youth have about dating and sexuality, despite research finding that they desire this information and perceive few resources available to them. This collaborative study between a U.S. university and a multi-disciplinary team of middle-school psychologists in Central Mexico aimed to understand youth’s questions on sexual health and dating. This study was a follow-up to focus group conversations, where youth voiced that they wanted more information about these topics. Specifically, school psychologists solicited anonymous questions about sexual health and dating relationships using a ‘question box’ (n = 60 written questions). This method offered a forum by which students could ask about sensitive topics individually. We analyzed questions using descriptive thematic analysis. A majority of the questions pertained to healthy relationships, followed by questions on violence and trauma in relationships, sexual education, and attraction and sexual orientation. The results of this study reflect a need to provide youth and their families accurate and developmentally appropriate information on sexual health and dating during early adolescence. Here, we discuss the process of forming a binational partnership, primary themes with regard to the questions asked, and the impact of findings from the perspectives of our Mexican collaborators

Photophysics in conventional and supercritical fluids: excited state dynamics and sensing applications

Chapter 1. This Chapter gives a brief introduction to photophysics and the study of excited states. The technique of time-resolved infrared spectroscopy (TRIR), which is used throughout this Thesis to ascertain the nature of excited states, is also introduced. The utility of the techniques to examine the nature and kinetics of excited states is detailed. Subsequently, the effect of solvent medium in which the measurements take place is also discussed. Chapter 2. The photophysical properties of rhenium dipyrido[3,2-a:2’,3’-c]phenazine complexes appended with diphenylamine (NPh2) groups have been investigated through the use of a range of techniques, including time-resolved infrared spectroscopy, cyclic voltammetry and DFT calculations. The effect of the diphenylamine donor group has been assessed with comparisons drawn between [Re(dppz-NPh2)(CO)3Cl] and [Re(dppz)(CO)3Cl]. The addition of the donor group results in the observation of three ligand centred excited states in the TRIR spectra, unlike the MLCT states observed for [Re(dppz)(CO)3Cl]. These states exhibit a complex interplay, whereby States I and III are initially formed, and the former decays to State II on the picosecond timescale. States II and III are then observed to decay to the ground state on the microsecond and nanosecond timescales respectively. A detailed assignment of these states is given, with States I and II assigned to 1ILππ* and 3ILππ* states respectively. State III was assigned to a NPh2(π)phz(π*) charge transfer state. Good evidence of the presence of three distinct states has been obtained through TRIR measurements conducted in the fingerprint region, where a marker band for State II has been observed. The molecular orbital calculations performed on the complexes indicate charge transfer character, where the highest occupied molecular orbital is observed to be based on the NPh2 ligand, unlike for [Re(dppz)(CO)3Cl] complexes where the highest energy occupied molecular orbitals are normally metal based. The lifetime of the charge transfer state is shown to be relatively independent of the number of NPh2 donors appended, where a similar lifetime is observed for [Re(dppz-PhNPh2)(CO)3Cl] and [Re(dppz-(PhNPh2)2)(CO)3Cl]. The effect of the bridge type between the NPh2 donor and phz acceptor has also been investigated. This work details the effects on all three excited states, with the charge transfer state of most interest. The effect of the bridge length has been assessed through study of phenyl-moiety bridges which possess varying lengths. It was observed that as the bridge length increased, the lifetime of the charge transfer state decreased, and this has been attributed to an increased level of insulator character. The nature of the bridge has been investigated, where phenyl, thiophene and triazole bridge moieties have been compared to an analogous complex without a bridge. The results indicated that insulator character of the bridges increases as follows, thiophene < phenyl < triazole, and this chantes the lifetimes of the charge transfer states of the resulting complexes by a factor of 100. Chapter 3. The photophysical properties of rhenium dipyrido[3,2-a:2’,3’-c]phenazine complexes modified on the phenazine like portions of the ligands have been investigated through the use of time resolved infrared spectroscopy and DFT calculations. Firstly, substitution with a nitrogen heteroatom at the ortho (2) and meta (3) positions (the phenazine like part of the ligand), resulting in [Re(dppp2)(CO)3Cl], [Re(dppp3)(CO)3Cl] and [Re(dppp2Br)(CO)3Cl] respectively, has been investigated. The additional nitrogen atom is observed to lower the energy of the molecular orbital based on the phenazine portion of the ligand and resulting in the population of an MCLT(phz) state. A marker band for the MLCT(phz) state has been assigned in the fingerprint region, a spectral region which has proven important to ascertain the nature of these excited states. The position of the nitrogen atom was also found to be significant, where substitution at the meta-position, [Re(dppp3)(CO)3Cl], is observed to lower the phz energy to a greater extent than in the ortho-position, [Re(dppp2)(CO)3Cl]. The effect of the solvent on the rate of the MLCT(phen)/MLCT(phz) states interconversion was found to be negligible, which is unlike observations made for [Re(dppz)(CO)3Cl]. However the nature of the most stable excited state was observed to change significantly. For the most polar solvent (DMSO, εr = 46.7), the most stable excited states is best described as an equilibrium of MLCT(phz)/ILππ* states, and for the lowest polarity solvent (toluene, εr = 2.3) the lowest excited state is MLCT(phen). Additionally, the excited state lifetime is observed to increase with decreasing solvent polarity. This has been attributed to a greater MLCT(phen) contribution observed in lower polarity media. The bromine substitution also has an effect on the excited state, where [Re(dppp2Br)(CO)3Cl] exhibits a lower energy phz state than for [Re(dppp2)(CO)3Cl]. This is further investigated with the previously unreported complex [Re(dppz-I)(CO)3Cl] and compared to other [Re(dppz-X)(CO)3Cl] complexes. Finally, the effect of amine substituents has been investigated by studying the complex [Re(dpppn-(NH2)2)(CO)3Cl] (amine substitution is at the 2nd and 4th positions of the phenazine like ligand) in a range of solvents, with dielectric constants ranging from 2.3 to 46.7 and again this was supplemented by DFT calculations. Comparisons have been made to the complexes detailed in Chapter 2, and to the [Re(dppp2)(CO)3Cl] and [Re(dppp3)(CO)3Cl] complexes. The TRIR spectral profile of the complex in the highest dielectric solvent is observed to be similar to the complexes in Chapter 2 and is assigned as a 1ILππ* state decaying to a 3ILππ* state. A marker band for the 3ILππ* state is observed in the fingerprint region and is comparable to the State II 3ILππ* marker band from Chapter 2 for the [Re(dppz-NPh2)(CO)3Cl] complexes. The nature of the excited states are observed to change with the solvent medium and these results are discussed. Chapter 4. The photophysical properties of the nitro-appended rhenium dipyrido[3,2-a:2’,3’-c]phenazine complexes [Re(dppz-12-NO2)(CO)3Cl] and [Re(dppz-13-NO2)(CO)3Cl], have been comprehensively investigated through time resolved infrared, cyclic voltammetry and DFT calculations. The electron withdrawing nitro-group is observed to lower the energy of the MLCT(phz) state compared to the unsubstituted complex. Furthermore, significant NO2 contribution in the excited state is observed, where the first reduction potential is considerably more positive than that observed for [Re(dppz)(CO)3Cl]. Therefore the radical anion is located on the phz like portion of the molecule with a significant contribution from the NO2 group. This is consistent with the molecular orbital calculations and the one electron reduced species absorption spectra in this Chapter. Furthermore, the 12-substituted nitro-group is shown to have a stronger electron withdrawing effect than the corresponding 13-substituted nitro-group. This has been attributed to an increase in resonance effects associated with the 12-position and is correlated to the dihedral angle between the NO2 group and the phz moiety. Chapter 5. The photophysical properties of rhenium diimine dyes in apolar media have been investigated in Chapter 5. As a result of poor solubility, photophysical studies of [Re(dppz)(CO)3L]+ and [Re(bpy)(CO)3L]+ complexes have been limited to higher polarity media. The ability to investigate organometallic dyes in apolar media opens up a range of avenues, including CO2 reduction without the need for a co-solvent. This Chapter explores these well reported complexes in the previously unstudied apolar media. The use of the large fluorinated anion of tetrakis[3,5-bis(perfluorohexyl)phenyl]borate has been implemented to yield the complexes [Re(dppz)(CO)3(DMAP)][BArf6] and [Re(bpy)(CO)3(DMAP)][BArf6]. Their photophysical properties have been investigated in perfluoromethylcyclohexane (εr 1.8) through TRIR, absorption and emission spectroscopies, and DFT calculations. [Re(dppz)(CO)3(DMAP)][BArf6] was shown to exhibit a long lived ILππ* state in perfluoromethyl cyclohexane. This state differs significantly from the ILππ*/MLCT(phen) states observed for [Re(dppz)(CO)3(DMAP)]+ complexes in more conventional polar media. Chapter 6. The drive for smaller technology is a foremost requirement in the fabrication of electrical devices which possess greater processing power. This Chapter discusses supercritical fluid electrodeposition as a fabrication method, along with its desirable properties which are also detailed. In order to guide the SCFED process, further understanding of fluid behaviour within the nanoporous templates employed is vital. The work within this Chapter focusses on the development and implementation of a method for high pressure luminescence spectroscopy to probe confined fluid behaviour. Luminescence spectroscopy of high pressure fluids confined within nanoporous templates has not previously been investigated. Therefore, the first section of this Chapter focusses on the development of a methodology in order to conduct luminescence measurements of supercritical fluids confined within nanopores. This includes an investigation into an appropriate dye, and the design of the high pressure apparatus required for luminescence measurements within porous materials. Anthracene and 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin have been identified as suitable luminescence probes for the measurements required. Following this, the density of CO2 under bulk conditions has been probed with both dyes. The former is observed to exhibit a solvatochromic shift in the emission, and the latter a change in the peak intensity with CO2 density. This has allowed for the calibration of the probe dye behaviour with CO2 density. The density of CO2 confined within nanoporous templates, possessing mean pore widths of 8.3, 4.5 and 3.2 nm are investigated. The results show that the density of CO2 is considerably higher in the confined environment than in the bulk. The results are consistent between the two dyes indicating that luminescence spectroscopy is a valid method to probe fluid behaviour both in bulk and confined environments. Finally, the use of luminescence measurements to elucidate fluid polarisability has been explored. An investigation towards quantifying fluid polarisability of CO2 when confined within the porous templates have been discussed. This includes the implementation of an anthracene dye to probe the polarisability of bulk CO2 conditions. These results are then compared to the literature. Subsequently, the method was used to elucidate the fluids polarisability. The polarisability of CO2 within the confines of the porous materials was observed to increase with increasing bulk CO2 pressure. Chapter 7. This Chapter summarises the results obtained within this work and outlines the implications that these results may have. This is followed by a detailed future outlook, including suggested avenues of study that may arise from this Thesis. Chapter 8. The apparatus and methodology developed to carry out this work is detailed, including the methodology for the high pressure luminescence spectroscopic measurements. The spectroscopic techniques used throughout this Thesis are detailed including descriptions of the equipment, procedures and materials used

Disease management projects and the Chronic CareModel in action: Baseline qualitative research

Background: Disease management programs, especially those based on the Chronic Care Model (CCM),are increasingly common in the Netherlands. While disease management programs have beenwell-researched quantitatively and economically, less qualitative research has been done. Theoverall aim of the study is to explore how disease management programs are implementedwithin primary care settings in the Netherlands; this paper focuses on the early developmentand implementation stages of five disease management programs in the primary care setting,based on interviews with project leadership teams. Methods: At the five sites, eleven semi-structured interviews were conducted at the five selected siteswith sixteen professionals interviewed; all project leaders were interviewed. The interviewsfocused on each project's chosen chronic illness (diabetes, eating disorders, COPD, multimorbidity,CVRM) and project plan, barriers to development and implementation, the projectleaders' action and reactions, as well as their roles and responsibilities, and diseasemanagement strategies. Analysis was inductive and interpretive, based on the content of theinterviews. After analysis, the results of this research on disease management programs andthe Chronic Care Model are viewed from a traveling technology framework. Results: This analysis uncovered four themes that can be mapped to disease management and theChronic Care Model: (1) changing the health care system, (2) patient-centered care, (3)technological systems and barriers, and (4) integrating projects into the larger system. Projectleaders discussed the paths, both direct and indirect, for transforming the health care systemto one that addresses chronic illness. Patient-centered care was highlighted as needed and aparadigm shift for many. Challenges with technological systems were pervasive.

Associations Between Subjective Tinnitus and Cognitive Performance: Systematic Review and Meta-Analyses

Tinnitus is the perception of sound in the absence of a corresponding external sound source, and bothersome tinnitus has been linked to poorer cognitive performance. This review comprehensively quantifies the association between tinnitus and different domains of cognitive performance. The review protocol was preregistered and published in a peer-reviewed journal. The review and analyses were reported according to Preferred Reporting Items for Systematic Review and Meta-analysis guidelines. Peer-reviewed literature was searched using electronic databases to find studies featuring participants with tinnitus who had undertaken measures of cognitive performance. Studies were assessed for quality and categorized according to an established cognitive framework. Random-effects meta-analyses were performed on various cognitive domains with potential moderator variables assessed where possible. Thirty-eight records were included in the analysis from a total of 1,863 participants. Analyses showed that tinnitus is associated with poorer executive function, processing speed, general short-term memory, and general learning and retrieval. Narrow cognitive domains of Inhibition and Shifting (within executive function) and learning and retrieval (within general learning and retrieval) were also associated with tinnitus

Identifying and explaining the variability in development and implementation costs of disease management programs in the Netherlands

BACKGROUND: In the Netherlands, disease management programs (DMPs) are used to treat chronic diseases. Their aim is to improve care and to control the rising expenditures related to chronic diseases. A bundled payment was introduced to facilitate the implementation of DMPs. This payment is an all-inclusive price per patient per year for a pre-specified care package. However, it is unclear to which extent the costs of developing and implementing DMPs are included in this price. Consequently, the organizations providing DMPs bear financial risk because the development and implementation (D&I) costs may be substantial. The aim of this paper is to investigate the variability in and drivers of D&I costs among 22 DMPs and highlight characteristics th

The Content and Quality of Information About Hyperacusis Presented Online

© 2020 American Speech-Language-Hearing Association. Purpose: Hyperacusis is a disorder characterized by reduced sound tolerance leading to ear pain, emotional distress, and reduced quality of life. Many people with hyperacusis turn to the Internet for information and support from online communities to discuss their condition. The purpose of this study was to assess the content and quality of hyperacusis information presented online. Method: The three most used Internet search engines were used to identify relevant websites using the single search term hyperacusis. Fifteen websites were selected for analysis. Details of the purpose, audience, and content of each website were extracted using a bespoke data extraction form. The quality of the information on each website was rated using the validated DISCERN questionnaire. Results: There was a wide disparity in the quality and content of hyperacusis information across websites. The website Hyperacusis Focus achieved the highest overall DISCERN score. Hyperacusis Focus and U.K. National Health Service websites were the most comprehensive online resources for health care professionals and patients, respectively. Wikipedia was judged useful for both health care professionals and patients. In general, hyperacusis-related information was accurate. However, no single website provided a complete account of hyperacusis, and some were judged to be selective in the information they provided. Conclusions: The Internet provides an important source of information for those who have hyperacusis and those who care for them. Revisions to the websites reviewed here are needed for each to provide a complete account of hyperacusis

A Delphi survey to determine a definition and description of hyperacusis by clinician consensus

ObjectiveThere is currently no singularly accepted definition of hyperacusis. The aim of this study was to determine a definition and description of hyperacusis by clinician consensus.DesignA three-round Delphi survey involving hearing healthcare professionals built towards clinical consensus on a definition of hyperacusis. Round 1 involved three open-ended questions about hyperacusis. Seventy-nine statements were generated on descriptions, impact, sounds, and potential features of hyperacusis. Agreement on the relevance of each statement to defining or describing hyperacusis was then measured in Rounds 2 and 3. General consensus was defined a priori as ≥70% agreement, or ≥90 for clinical decision making.Study sampleForty-five hearing healthcare professionals were recruited to take part in this study. Forty-one completed Round 1, 36 completed Round 2, and 33 completed Round 3.ResultsConsensus was reached on 42/79 statements. From these a consensus definition includes “A reduced tolerance to sound(s) that are perceived as normal to the majority of the population or were perceived as normal to the person before their onset of hyperacusis”. A consensus description of hyperacusis was also determined.ConclusionsThis consensus definition of hyperacusis will help to determine the scope of clinical practice guidelines and influence needed research on hyperacusis

Evaluatie van disease management programma's in Nederland

In het ZonMw programma ‘Disease Management Chronische Ziekten’ (DMCZ) zijn 22 praktijkprojecten ontwikkeld, gevolgd en geëvalueerd. Deze ZonMw-praktijkprojecten hadden een looptijd van ongeveer drie jaar. Gedurende deze periode zijn de projecten systematisch gevolgd op een aantal proces- en effectmaten en kosten-effectiviteit. De verwachting is dat disease management programma's gebaseerd op Ed Wagner's chronische zorgmodel bijdragen aan betere kwaliteit van chronische zorgverlening. Inzicht in de korte en lange termijn effecten van implementatie van dit type programma's voor verschillende chronische aandoeningen is echter nog schaars. [...

The management of cardiovascular disease in the Netherlands: analysis of different programmes

Background: Disease management programmes are increasingly used to improve the efficacy and effectiveness of chronic care delivery. But, disease management programme development and implementation is a complex undertaking that requires effective decision-making. Choices made in the earliest phases of programme development are crucial, as they ultimately impact costs, outcomes and sustainability. Methods: To increase our understanding of the choices that primary healthcare practices face when implementing such programmes and to stimulate successful implementation and sustainability, we compared the early implementation of eight cardiovascular disease management programmes initiated and managed by healthcare practices in various regions of the Netherlands. Using a mixed-methods design, we identified differences in and challenges to programme implementation in terms of context, patient characteristics, disease management level, healthcare utilisation costs, development costs and health-related quality of life. Results: Shifting to a multidisciplinary, patient-centred care pathway approach to disease management is demanding for organisations, professionals and patients, and is especially vulnerable when sustainable change is the goal. Funding is an important barrier to sustainable implementation of cardiovascular disease management programmes, although development costs of the individual programmes varied considerably in relation to the length of the development period. The large number of professionals involved in combination with duration of programme development was the largest cost drivers. While Information and Communication Technology systems to support the new care pathways did not directly contribute to higher costs, delays in implementation indirectly did. Conclusions: Developing and implementing cardiovascular disease management programmes is time-consuming and challenging. Multidisciplinary, patient-centred care demands multifaceted changes in routine care. As care pathways become more complex, they also become more expensive. Better preparedness and training can prevent unnecessary delays during the implementation period and are crucial to reducing costs